MEDDEV - Total (2016.06) PDF

EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
Unit 4 - Pressure Equipment, Medical Devices, Metrology
MEDICAL DEVICES : Guidance document
MEDDEV 2. 1/1
April 1994
GUIDELINES RELATING TO THE APPLICATION OF :
THE COUNCIL DIRECTIVE 90/385/EEC ON ACTIVE IMPLANTABLE MEDICAL DEVICES
THE COUNCIL DIRECTIVE 93/42/EEC ON MEDICAL DEVICES
Definition of "medical devices"

Definition of "accessory"
Definition of "manufacturer"
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LIST OF CONTENTS
I. FIELD OF APPLICATION - DEFINITIONS
1. Directive 93/42/EE on medical devices

2. Directive 90/385/EEC on active implantable medical devices1
3. Interface with other directives
- medical devices/medicinal products
- medical devices/electromagnetic compatibility2
- medical devices/personal protective equipment2
II. CLASSIFICATION OF MEDICAL DEVICES COVERED BY DIRECTIVE

93/42/EEC 3
III. CONFORMITY ASSESSMENT PROCEDURES(*):
1. CE-marking
2. Application
- Annex 5
- Annex 2
. Quality systems
. Examination of the design dossier
- Annex 3
3. Conduct of audits4
4. Format of decisions, design examination certificate
5. Technical Dossier
IV. CUSTOM MADE DEVICES(*):
V. DEVICES INTENDED FOR CLINICAL INVESTIGATIONS(*):
VI. MEDICAL DEVICE VIGILANCE(*):
VII. USE OF LANGUAGES(*):
VIII. TRANSITIONAL PERIOD(*):
1
see MEDDEV. 5/93 rev. 2
2
see MEDDEV 13/93
3
see MEDDEV.10/93 rev. 1
4
see MEDDEV. 1/94
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1. Directive 93/42/EEC on medical devices
1.1 Definition of "medical devices"
a) devices - accessory
The definition of the term "medical device" together with the

definition of "accessory" is determinant for the delimitation of the field
of application of Directive 93/42/EEC. A slight difference exists
between the definition in article 1(2) (a) of Directive 93/42/EEC and in
article 1(2) of Directive 90/385/EEC.
Following the latter directive, accessories are by definition medical

devices, whilst following Directive 93/42/EEC, a distinction is made
between "devices" and "accessories". Therefore within the meaning of
Directive 93/42/EEC, accessories are products in their own right and,
although being treated as devices (article 1(1)) do not follow, as a
general rule, the classification of related devices in conjunction with
which they are used.
Accessories are therefore following Directive 93/42/EEC to be

classified in their own right.
b) medical purpose
Medical devices are defined as articles which are intended to be used

for a medical purpose. The medical purpose is assigned to a product
by the manufacturer. The manufacturer determines through the label,
the instruction for use and the promotional material related to a given
device its specific medical purpose. As the directive aims essentially at
the protection of patients and users, the medical purpose relates in
general to finished products regardless of whether they are intended
to be used alone or in combination. This means that the protection
ensured by the directive becomes valid for products having a stage of
manufacture, where they are supplied to the final user.
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Following this concept, raw materials, components or intermediate

products are as such normally not medical devices. Such raw
materials may need to present properties or characteristics which are
determinant for the safety and quality of finished devices. It is
therefore the responsibility of the manufacturer of finished devices to
select and control by adequate means his raw materials or
intermediate products (see Annex I, section 7.1; Annex II, section 3.2;
Annex V, section 3.2 of Directive 93/42/EEC)
Spare parts supplied for replacement of existing components of a

device, the conformity of which has already been established, are not
medical devices. If spare parts, however, change significantly the
characteristics or performances of a device with regard to its already
established conformity, such spare parts are to be considered as
devices in their own right.
c) customizing
The concept of "finished device" does not imply that a device when
reaching the final user is already in a state ready for use. Prior to use
further preparatory processing, preparation, configuration,
installation, assembling, adaptation or fitting to the needs of the user
or patient may be required. Examples :
- sterilisation of medical devices supplied non-sterile

- assembling of systems
- configuration of electronic equipment
- preparation of a dental filling
- fitting of contact lenses
- adaptation of prosthesis to the needs of the patient.
The aforementioned activities are normally not manufacturers

activities if they are carried out by the final user as part of the use or
preparation for use. In this context a distinction needs to be made
between a typical professional activity performed by a healthcare
professional and processing and assembling activities done by a
specialist for such processing. In the latter case relevant activities may
become proper manufacturing or assembling activities relevant within
the meaning of articles 11 and 12.
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A particular consideration in this context needs to be given for the

manufacture of custom-made devices. Custom-made devices (such as
dental appliances, prosthesis, hearing-aid inserts) are in most cases
one-off devices and the Directive subjects their manufacture to the
procedure of article 11(6) in conjunction with Annex VIII. In these
cases intermediate products specifically intended for this kind of
custom-made devices may be considered also as medical devices.
This applies essentially to dental alloys, dental ceramics, modular
components for prosthesis, if the intended purpose of such products is
specifically related to medical devices.
d) medical - toiletry purpose
The definition of "medical device" should be understood to include

products intended to be used principally for a medical use. Therefore
products intended to have a toiletry or cosmetic purpose are not
medical devices even though they may be used for prevention of a
disease. Examples for products for which a medical purpose can
normally not be established :
- tooth brushes, dental sticks, dental floss;

- baby diapers, hygiene tampons;
- contact lenses without corrective function intended to
provide another colour to the eyes,
- bleaching products for teeth [needs to be further
discussed with regard to products intended
specifically for application by dentists]
- instruments for tattooing.
Examples for products, where depending on the circumstances, a

medical purpose can be established :
- incontinence products.
e) aids for handicapped persons
In the case of equipment intended for alleviation of or compensation

for a handicap, there must be a direct link between the corrective
function and the person concerned. Therefore the following
equipment are not medical devices :
- acoustic signals at traffic lights,

- special water taps, toilet equipment for handicapped
f) software
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The following distinction can be made : software influencing the

proper functioning of a device and software used in combination with
non-medical equipment.
Software related to the functioning of a medical device may be part of

a device or a device in its own right if it is placed on the market
separately from the related device.
In the case of software intended for use with multipurpose informatic

equipment a distinction has to be made between software providing
for a proper diagnostic or therapeutic tool and software for handling
general patient-related data. Only in the first case may a medical
purpose be determined. Examples for medical devices :
- calculation of anatomical sites of the body,

- image enhancing software intended for diagnostic
purpose.
- software for programming a medical device
There is no medical purpose in the case of software used for

administration of general patient data
g) multipurpose products
Products with a multiple purpose which may be used occasionally in a

medical environment are normally not medical devices, unless a
specific medical intended purpose is assigned to them. Examples :
- multipurpose PC, printer, scanner, ...

_ magnetoscope, screen.
1.2 Definition of "accessory"
The question whether a product is a "device" or a "accessory" has not

practical consequence. Following article 1(1) of Directive 93/42/EEC,
"accessories shall be treated as medical devices in their own right". Therefore
the main question is whether a product with a rather remote link to a
medical use can still be considered as "accessory" (article 1(2)b) and as a
matter of consequence is covered by the directive.
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The definition of "accessory" requires that the accessory is specifically

intended by the manufacturer of the accessory to be used together with a
device. The intended use of the accessory must be such as to enable a device
to be used in accordance with its intended use. Therefore a product can only
become an accessory to a medical device if the manufacturer of such a
product establishes an intended use in conjunction with one or several
medical devices.
Examples for accessories depending on defined circumstances of device-

related use :
- sterilizers for use in a medical environment,

- pouches for packaging re-sterilised medical devices,
- specific battery chargers for battery driven electromedical
devices,
- contact lens care products, disinfectants specifically
intended for invasive medical devices
- special water treatment device for use in conjunction with
dialyzing machines,
- gas cylinders/pressure release devices for use in
conjunction with anaesthesia machines.
1.3 Definition of "manufacturer"
Users in-house manufacturing
The Directive defines a manufacturer as the natural or legal person

responsible for defined manufacturing activities related to a device with a
view to its being placed on the market under the manufacturers own name.
The reason for this link with the placing on the market is that the directives
aims to subject to its protection requirements the transaction of a device from
the sphere of a manufacturer towards the public. The directive does not
provide any specific provisions for the case where a device is manufactured
by the user (for example, a hospital) without being transferred to another
person. The decision to which extent such in-house manufacturing activities
by hospitals are subjected to legal requirements, belongs therefore to the
national legislator. This relates however exclusively to such in-house
manufacturing activities where a device remains within the users, but not to
cases where, for example, a hospital produces orthopaedic devices for use
with patients.
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 1/2 rev 2
26 April 1994

FIELD OF APPLICATION OF DIRECTIVE 90/385/EEC
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1
INTRODUCTION
These guidelines should be read in conjunction with the Directive 90/385/EEC relating to active implantable medical
devices and the Directive 93/42/EEC relating to medical devices. They provide a practical support for the uniform
application of these Directives. The guidelines deal with specific issues in the context of the aforementioned
Directives. They are therefore of complementary nature to the general vade-mecum relating to the application of
New Approach Directives.
LIST OF CONTENTS

1. Directive 93/42/EE on medical devices(*)
2. Directive 90/385/EEC on active implantable medical devices
3. Interface with other directives (*):
- medical devices/medicinal products
- medical devices/electromagnetic compatibility
- medical devices/personal protective equipment
II. CLASSIFICATION OF MEDICAL DEVICES COVERED BY DIRECTIVE 93/42/EEC(*):

1. CE-marking
2. Application
- Annex 5
- Annex 2
. Quality systems
- Annex 3
3. Conduct of audits

(*)
These parts of the guidelines will be circulated as separate working documents
2
I. FIELD OF APPLICATION
I. 2. DIRECTIVE 90/385/EEC ON ACTIVE IMPLANTABLE MEDICAL DEVICES
The Directive 90/385/EEC covers the placing on the market and putting into service of "active implantable medical
devices".
2.1. Active implantable medical device

A product falls within the field of application of the Directive if it complies with the definition given in this
Directive. That means, it must be a "medical device" as defined which is, at the same time, both "active"
and "implantable".
2.1.1 The "device" definition within the meaning of Directive 90/385/EEC relates to a product
intended by the manufacturer for a medical purpose "whether used alone or in combination,
together with any accessories or software for its proper functioning". The medical purpose
may be achieved either by a "stand alone device" or as a result of several devices acting
each in combination with the other as part of a system. Where the medical purpose is
achieved by a system, each element of the system may be regarded as a medical device.
The device definition may consequently apply to the system as such or to interchangeable
parts intended to form a system together with other devices, therefore for the purposes of
the Directive on Active Implantable Medical Devices each part belonging to such system is
covered by the Directive regardless of whether such part on its own is "active", "active
implantable" or not.
Examples of AIMDs :
a) - implantable pulse generator for pacing including the electrode

- implantable pulse generator without electrode
- electrode
b) - implantable drug administration device with or without catheter

- catheter for implantable drug administration device
2.1.2. For the purpose of the Directive 90/385/EEC a medical device is active if it "relies for its
functioning on a source of electrical energy or any source of power other than that directly
generated by the human body or gravity. This includes, for instance, devices activated by
means of pressure unless this effect is achieved by energy resulting from the body of the
patient. The definition implies that the function of the device involves using the source of
power to perform useful work. The mere transmission of heat, light, pressure or vibration
does not mean that a device is active.
Examples :
- a hydrocephalus pressure relief allowing release of cerebro-spinal fluid when a spring
is overcome is not "active". Even where the setting of the spring can be adjusted by
electro-magnetic means, it remains non-active as the medical function of the device is
to relieve pressure, not to be adjusted,
3
- a drug delivery device in which the drug is driven from a reservoir by means of a stored
energy source (spring, fluid, gas, etc...) is "active"
- an intravascular cathether containing a fibre-optic bundle connected to an external light
source may be used to measure pressure or other characteristics of blood if some
quality of the light can be changed by the blood characteristic and detected. Although
the system as a whole depends on a power source to achieve its medical function (the
measurement of a blood characteristic) the invasive element is not "active" as it does
no more than transmit light
- a cochlear implant activated by an external power transmitter is regarded as "active"
as the implanted component clearly depends on a power source for its function and its
purpose is to convert the power it receives into electrical signals which trigger
appropriate sensory channels in the brain, i.e. it performs useful work.
2.1.3. An active medical device is defined as "implantable" if it is "totally or partly introduced,

surgically or medically, into the human body or by medical intervention into a natural orifice,
and which is intended to remain after the procedure".
The Directive has been conceived for active devices for which a potential high risk may be
inherent due to the fact that they are totally or partly implanted into the body. Such devices
may present hazards in particular with regard to impossibility of maintenance, calibration or
control and problems relating to the ageing of materials, as mentioned in several essential
requirements of Annex 1 to the Directive. The attribute "implantable" has therefore to be
interpreted bearing in mind those hazards typical for implantable devices.
For the aforementioned reasons, an external drug infusion pump, although for long-term or
permanent use, which is connected to a catheter "partially introduced" into the body is not
considered as an active implantable device.
One of the essential characteristics of an implantable device is its relatively long-term use.
Distinction is to be made between an intended use of a device which is permanent or long-
term in the order of several months compared to a temporary use during a given medical
intervention. An external pacemaker, including its electrode, used for an interim process is
thus not considered as "remaining after the procedure". The same applies to the use of an
intra-aortic balloon pump. For the purpose of the Directive 90/385/EEC, the term "procedure"
is to be interpreted as a process of diagnosis, monitoring or treatment which may last for
some days, generally in hospital, and not necessarily exclusively relating to an operation
carried out in the theatre in the course of which the device is placed in the body.
2.2. "Accessories" to an active implantable medical device are by definition "active implantable medical
devices" and therefore covered by the Directive 90/385/EEC. This does not presuppose that the
attributes "active" and "implantable" must be necessarily met by a product called "accessory". It is
sufficient that a product in its intended purpose is ancillary to the purpose of an active implantable
medical device in such a way that it enables the device to be used in accordance with the intended
device purpose or that it enhances the purpose of a device as intended by the device manufacturer.
Following this a programmer or an external transmitter intended for activating or controlling the
implantable part of the device is covered by the definition of "active implantable medical device".
2.3. exemplative list of active implantable medical devices. The subsequent list contains examples of types
of devices which are normally covered by Directive 90/385/EEC :
1. implantable cardiac pacemakers
2. implantable defibrillators
3. leads, electrodes, adaptors for 1. and 2.
4. implantable nerve stimulators
5. bladder stimulators
6. sphincter stimulators
7. diaphragm stimulators
8. cochlear implants
9. implantable active drug administration device
4
10. catheters, sensors for 9.
11. implantable active monitoring devices
12. programmers, software, transmitters.
5
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G

MEDDEV 2. 1/ 2.1
February 1998
TREATMENT OF COMPUTERS USED TO PROGRAM
IMPLANTABLE PULSE GENERATORS
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2
Purpose of the document
Identify the cases where commercially available computers should not be considered as
medical devices.
Background
- Implantable pulse generators (IPG) and Defibrillators (ICD) fall into the scope of the
AIMD Directive 90/385/EEC.
- Equipment specifically designed to program these implanted AIMD's are accessories

of AIMD's. Therefore, they fall also into the scope of the above mentioned directive.
Commercially available computers are being used more and more as programmer for
IPG's.
The Guidelines on medical classification specify that "multi-application equipment

which may be used in combination with medical devices are not a medical device unless
its manufacturer places it on the market with specific intended purpose of a medical
device".
The definition of a medical device in the AIMD Directive is as follows:
"Medical device means any instrument, apparatus, appliance, material or other article,
whether used alone or in combinations, together with any accessories or software for its
proper functioning, intended by the manufacturer to be used for human being in the ..."
Definition of "intended use" (EC Directive 93/42/EEC):
"The intended use means the use for which the device is intended according to the data
supplied by the manufacturer on the labelling, in the instructions and/or promotional
materials".
Definition of the system
The system allowing communication with the implantable parts of the AIMD is usually
constituted as follows:
- a commercially available computer
- a wand (part of the system in contact with the patient from one side and connected to
the computer on the other side. This part of the system may also include an interface
module which, among other functions, provides electrical isolation between computer
and wand).
- Software used to program the implantable parts of the AIMD.
2
3
Handling of the system
Manufacturers have the freedom
- either to consider the system as a whole and to affix the CE marking on the whole
system
- or to consider each part of the system and to affix the CE marking on each part of the
system.
Regulatory Status of the computer
A. The computer is a medical device in the following cases:
- the computer bears the trade name of the IPG manufacturer

- the original information provided with the computer has been replaced or modified
- modifications have been made to the software or hardware of the computer. These
modifications have not been made according to the instructions provided by the
manufacturer of the computer.
Note: For the purpose of this document it is understood that the insertion of a circuit
board to an available PMCIA slot is not considered as a modification of the
software as long as the insertion is performed in accordance with the
computers manufacturer's instructions for use.
B. The computer is not a medical device in the following cases:
- The wand is connected to an existing port located usually on the back of the
computer.
- The wand is connected to a dedicated circuit board to be inserted into an available

PCMCIA slot accessible from the outside of the computer or located inside the
computer.
The board is inserted into the computer according to the instructions given by the
computer manufacturer and/or the board manufacturer.
Conformity assessment procedures when each part is considered separately.
- Wand, equipment which makes the link between the patient and the computer,
dedicated programming software (program module, memory card or diskette) are
AIMD's.
Therefore they must satisfy all applicable essential requirements of the AIMD
directive and bear the CE marking.
- The computer if not considered as a medical device should comply with applicable
national regulations and as of January 1st, 1996 must bear the CE marking of
conformity with the EMC directive.
3
4
The applicable standards are IEC 950 as well as the relevant EMC harmonized standards
adopted by CENELEC and published in the Official Journal of the European
Communities.
In this case the manual of the software of the wand dedicated for use with the computer
must indicate either the characteristics of the computer required or some types of
equipment (trade name and model) available on the market with which it can be used.
The computer in this case shall not bear the CE marking of conformity with the AIMD.
- The computer if considered as a medical device, falls into the scope of the AIMD
directive and therefore shall meet all the applicable essential requirements and be
subject to the appropriate conformity assessment procedure. The computer shall bear
the CE marking of conformity with the AIMD directive.
- Irrespective of the fact the computer is considered as a medical device or not, the
manufacturer shall demonstrate that the system (wand + computer) is safe for the
patient and the user.
- In order to avoid possible confusion between the AIMD and the EMC directive, the
manual of the computer shall indicate the directive applied.
Conclusion
Unless the IPG/ICD manufacturer modifies its original intended purpose or affixes its
trade name, commercially a available computers shall not be considered as medical
device. Therefore the computer shall not be subject to the requirements of the AIMD
directive.
4
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 1/3 rev 2

July 2001

DEMARCATION BETWEEN : - DIRECTIVE 90/385/EEC ON ACTIVE IMPLANTABLE MEDICAL DEVICES

- DIRECTIVE 93/42/EEC ON MEDICAL DEVICES
AND - DIRECTIVE 65/65/EEC RELATING TO MEDICINAL PRODUCTS
AND -- RELATED DIRECTIVES

Foreword
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-Directives on medical devices. They are legally not binding. The
Guidelines have been carefully drafted through a process of intensive consultation of the various interested parties (Competent Authorities, Commission services,
industries and other interested parties in both the medical devices and the medicinal products sectors) during which intermediate drafts were circulated and comments
were taken up in the document. Therefore this document reflects positions taken in particular by the aforementioned interested parties.
Due to the participation of the aforementioned interested parties and of experts from Competent Authorities, it is anticipated that these guidelines will be followed within
the Member States and, therefore, ensure uniform application of relevant Directive provisions.
Note: This document is a revision of an earlier document published in July 1995 as MEDDEV 14/93 Rev. 4
Contents Pages
SECTION A. DEMARCATION BETWEEN MEDICAL DEVICES DIRECTIVES AND MEDICINAL PRODUCTS
DIRECTIVES
A.1. Introduction ....................................................................................... 3
A.2 General principles ............................................................................. 3
A.3 Examples of medical devices............................................................ 5
A.4 Examples of medicinal products........................................................ 7
A.5 Medical devices incorporating a medicinal substance with ancillary action 8
A.6 Drug delivery system......................................................................... 10
SECTION B. THE CONSULTATION PROCESS FOR DEVICES INCORPORATING A MEDICINAL SUBSTANCE
HAVING AN ANCILLARY ACTION
B.1 Purpose of the consultation procedure.............................................. 11
B.2 Notified Body action to initiate consultation process ......................... 12
B.3 Documentation to be provided by the Notified Body to the competent authority for medicinal products 12
B.4 The consultation process .................................................................. 15
SECTION C. CONSULTATION BY COMPETENT AUTHORITIES FOR MEDICINAL PRODUCTS WITH REGARD 16
TO MEDICINAL PRODUCTS WITH DEVICE-RELATED FEATURES
SECTION D. PROCEDURES FOR THE REPORTING OF ADVERSE INCIDENTS 16
Annex : Competent Authorities for the evaluation of medicinal products ....... 17
1
A. DEMARCATION BETWEEN MEDICAL DEVICES DIRECTIVES AND MEDICINAL PRODUCTS DIRECTIVES
A.1 Introduction
The determination of the borderline between the Medical Devices Directive 93/42/EEC (MDD) (OJ No.L 169, 12/7/93), the Active Implantable Medical Device Directive
90/385/EEC (AIMD) (OJ No. L189, 20/7/90) and the Medicinal Products Directive 65/65/EEC (MPD) including related directives, was one of the issues discussed at some
length during the legislative procedure on the MDD. Therefore, in the MDD several provisions to establish the demarcation between both legal regimes have been laid down.
It was recognised that the subject needs to be further explained and illustrated by practical guidance and examples. The present document has no legal force. It has
nevertheless been elaborated by an expert group including experts from Member States' competent authorities for both medical devices and medicinal products, the
European Commission, as well as industry trade associations. It is therefore intended that the document will provide useful guidance which should assist common positions to
be taken throughout the European Union.
For the relevant definitions and legal requirements reference is made to:
Directive 93/42/EEC Directive 65/65/EEC Medicinal Products

MDD MPD Extension Directives
Article 1 (2a): "medical device" Article 1(3) : medicinal product Directive 89/343/EEC relating to radiopharmaceuticals
Article 1 (3): "drug delivery devices" Directive 89/342/EEC relating to immunological products
Article 1 (4): "devices incorporating medicinal substances with Directive 89/381/EEC relating to blood products
ancillary action"
A.2 General principles
As a general rule a relevant product is regulated either by the MDD or by the MPD. The authorization or conformity assessment procedure to be followed prior to placing a
given product on the market will therefore be governed either by the MDD/AIMD or by the MPD. Normally the procedures of both directives do not apply cumulatively. For
defined features, however, some cross-references are made within one regime to specific provisions of the other regime (see Article 1(4) in conjunction with Annex I, section
7.4 MDD; Article 1(3) MDD).
The definitions of medical device and medicinal product are reproduced here for reference.
Medical device (93/42/EEC)

"Any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by
the manufacturer to be used on human beings for the purpose of:
- diagnosis, prevention, monitoring, treatment or alleviation of disease,
- diagnosis, monitoring, treatment, alleviation or compensation for an injury or handicap,
- investigation, replacement or modification of the anatomy or of a physiological process,
- control of conception,
2
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its
function by such means;"
Medicinal product (65/65/EEC)

"Any substance or combination of substances presented for treating or preventing disease in human beings or animals.
Any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or
modifying physiological functions in human beings or in animals is likewise considered a medicinal product."
In order to decide which regime applies, the following criteria should be examined:
Step 1 The intended purpose of the product taking into account the way the product is presented (this is likely to establish if either the MDD or the MPD apply, rather than
distinguish between the two regimes),
Step 2 The method by which the principal intended action is achieved.
The latter criterion, based on the "principal intended action" is crucial in the definition of a medical device. Typically the medical device function is fulfilled by physical means
(including mechanical action, physical barrier, replacement of or support to organs or body functions, ...). The action of a medicinal product is generally achieved by
pharmacological, immunological means or by metabolism.
The principal intended action of a product may be deduced from:
- the manufacturer's labelling and claims,

- scientific data regarding mechanism of action.
Although the manufacturer's claims are important, it is not possible to place the product in one or other category in contradiction with current scientific data. Manufacturers
may be required to justify scientifically their rationale for classification of borderline products.
Pharmacological means, in the context of the MDD and AIMD, is understood as an interaction between the molecules of the substance in question and a cellular
constituent, usually referred to as a receptor, which either results in a direct response, or which blocks the response to another agent. Although not a completely reliable
criterion, the presence of a dose-response correlation is indicative of a pharmacological effect.
Immunological means, in the context of the MDD and AIMD, is understood as an action in or on the body by stimulation and/or mobilisation of cells and/or products
involved in a specific immune reaction.
Metabolic means, in the context of the MDD and AIMD, is understood as an action which involves an alteration, including stopping, starting or changing the speed of the
normal chemical processes participating in, and available for, normal body function.
The fact that a product is itself metabolised does not imply that it achieves its principal intended action by metabolic means.
3
Medical devices may be assisted in their function by pharmacological, immunological or metabolic means, but as soon as these means are not any more ancillary with respect
to the principal purpose of a product, the product becomes a medicinal product. The claims made for a product, in accordance with its method of action may, in this context,
represent an important factor for its classification as medical device or medicinal product.
These principles are illustrated by bone cements and related products which appear in several of the following sections. Plain bone cement without antibiotics is a medical
device since it achieves its primary intended purpose (the fixation of a prosthesis) by mechanical means. Bone cements containing antibiotics, where the principal intended
purpose remains fixation of a prosthesis, are also medical devices. In this case the action of the antibiotic, which is to reduce the possibility of infection being introduced
during surgery, is clearly ancillary. If however the principal intended purpose is to deliver the antibiotic, the product would be a medicinal product.
These principles are subject to certain exemptions as a consequence of which a number of products fall within the definition of "medicinal product", even if they fulfil their
function by physical or chemical means, and not by pharmacological, immunological or metabolic means in the sense as described above. This applies, in particular, to
antacids, in-vivo diagnostics, and to the products listed in A.4.2 which are "administered to human beings with a view to making a medical diagnosis" or to fulfil another
purpose as indicated in the medicinal product definition. Unlike products which, in the absence of Community medical device legislation, had been assimilated to national
medicinal product law and which are now regulated by MDD/AIMD (reclassification will take place in those Member States during the transitional period), the grouping as
referred to in A.4.2 has been regarded throughout the EU as medicinal products within the meaning of Directive 65/65/EEC. The status of these products as medicinal
products is retained as specified under A.4.2
A.3 Examples of medical devices
3.1 The following examples should, in view of their mode of action, generally be considered as medical devices subject to relevant criteria being met; the function of some of the
devices indicated in these examples, e.g. bone cement, may be assisted by the presence of medicinal substances where such substances have an ancillary action to that of
the device (see also A.5).
- bone cement (see A.5 and A.6),

- dental filling materials (see A.5 and A.6),
- materials for sealing, approximation, or adhesion of tissues (e.g. cyanocrylates, fibrin-based adhesives not of human origin),
- resorbable materials used in osteo-synthesis (e.g. pins or bone screws manufactured using polylactic acid),
- sutures, absorbable sutures,
- soft and hard tissue scaffolds and fillers (e.g. collagen, calcium phosphate, bioglass),
- bone void fillers intended for the repair of bone defects where the primary action of the device is a physical means or matrix, which provides a volume and a scaffold
for osteoconduction (see A5 and A6),
- intrauterine devices (see A.5 and A.6),
- blood bags (see A.5),
- systems intended to preserve and treat blood (see A5),
Note : systems intended for the collection, storage and preservation of blood or blood components and as an ancillary function, the treatment of blood or blood components
where this effect is achieved outside the human body, are classified as devices provided that any residual material is not intended to achieve its intended effect when
the blood or cells are reintroduced into the body, e.g. systems incorporating chemicals activated by light to reduce the viral load where the quantity of chemical
remaining has no intended effect when transfused.
4
This note does not cover substances introduced into an extracorporal circuit.
- viscoelastic materials with intended use for mechanical/physical purposes such as protection of tissues during and after surgery and separation of tissues. Such
materials are also used as synovial fluid replacements where visco-supplementation provides support and lubrication.
Note : Additional pharmacological benefits claimed which are ancillary to the mechanical action do not alter the medical device status. However, certain of these materials
such as some hyaluranon based products, where the predominant claims are of a pharmacological nature and not primarily related to any viscoelastic characteristics,
are classed as medicinal products,
- gases and liquids for ocular endotamponades,

- cell separators, including those incorporating antibodies for cell marking,
- wound dressings, which may be in the form of liquids, gels and pastes, etc (e.g. hydrocolloid, hydrogel), (see A.4 and A.5),
- haemostatic products, for example patches, plugs and powders where the haemostatic effect results from the product's physical characteristics, or is due to the
surface properties of the material. This includes products such as those containing collagen, or calcium alginate or oxidised cellulose where adhesion of platelets to
the surface triggers platelet adhesion and aggregation (see A.4 and A.5).
- concentrates for haemodialysis,
- pressure reducing valves and regulators,
- irrigation solutions (including those used in the eye) intended for mechanical rinsing (see A5)
Note: If the solution contains a medicinal substance such as chlorhexidine where the principal intended purpose is to provide a local antimicrobial effect, it will be a
medicinal product. Solutions incorporating substances for other purposes, e.g. antimicrobial agent for the preservation of the solution remain a medical device.
- devices such as catheters, guidewires and stents containing or incorporating radio isotopes where the radioactive isotope as such is not released into the body, used
for example in cardiology for the prevention of restenosis.
3.2 The following products are covered by the MDD because they fall under the definition of "accessory". This is the case if they are intended specifically to be used together with
a device to enable the device to be used in accordance with its intended purpose or to enhance the performance of the device.
- contact lens care products (disinfecting, cleaning, rinsing and hydrating solutions including those which aid the insertion and/or wearing of contact lenses without a
therapeutic claim),
- disinfectants specifically intended for use with medical devices (e.g. endoscopes),
Note: Multipurpose disinfectants or sterilisation agents are not covered by MDD; they will be covered by the directive on biocides.
- lubricants specifically intended for use together with medical devices (e.g. for gloves, endoscopes, condoms),
- skin barrier powders and pastes or other skin care products specifically intended for use together with ostomy bags,
- challenge tests specifically intended to assess the tolerance to a given medical device, or its constituents (e.g. injectable collagen).
- gases used to drive cryoprobes and surgical tools (see A4)
5
A.4 Examples of medicinal products
The following examples should generally be considered as medicinal products subject to relevant criteria being met :
4.1. Products which fulfil their primary intended purpose by pharmacological, immunological or metabolic means,
- spermicidal preparations,
- gases intended to be used in anaesthesia and inhalation therapy, (e.g. Oxygen, medical air supplied in containers) including their primary containers,
Note: These gases are also used in minimal access surgery. However a product intended exclusively for minimal access surgery would be a medical device.
- topical disinfectants (antiseptics) for use on patients,

- haemostatic agents where primary mode of action is not mechanical such as certain collagens which have a molecular structure capable of a surface-independent
demonstrated interaction with platelet receptors, and which achieves platelet adhesion through a pharmacological process.
- zinc paste for dermatological use
4.2. The following products are assimilated to medicinal products and therefore dealt with in accordance with 65/65/EC as medicinal products:
- water for injections, IV fluids and plasma volume expanders,

- haemofiltration substitution solutions,
- in vivo diagnostic agents, e.g. x-ray contrast media, NMR enhancing agents, fluorescent ophthalmic strips for diagnostic purposes, carrier solutions to stabilize micro-
bubbles for ultrasound imaging,
- gases for in-vivo diagnostic purposes, including lung function, tests, e.g. carbon dioxide for vascular diagnostic purposes,
- solutions for peritoneal dialysis,
- antacids,
- artificial tears,
- fluoride dental preparations,
Note: Dental preparations with a typical device mode of action, such as cements or varnishes incorporating fluoride, are medical devices, where the fluorine is of ancillary
action to that of the device. Certain products where the claims are primarily cosmetic in nature and where the fluorine level is less than 0.15% are cosmetic products
(see 76/768/EEC and amending Directives).
- solutions administered in-vivo to the local circulation for the cooling of organs during surgery;
It should be noted that the Directive 89/343/EEC relating to radiopharmaceuticals applies also to generators, that means any system incorporating a fixed parent radionuclide
the daughter radionuclide of which is to be removed by elusion or by any other method and used in a radiopharmaceutical (see article 1(2) of Directive 89/343/EEC).
4.3. Agents for transport, nutrition and storage of organs intended for transplantation,
6
Note: These products are not currently regulated in all Member States as medicinal products. However there was general consensus of public authorities that the medicinal
products category is the most appropriate. Some of these products may have a metabolic effect, others however have no such effects.
A.5 Medical devices incorporating a medicinal substance with ancillary action
It follows from the definition of a medical device that devices may incorporate substances as an integral part which, if used separately, may be considered to be a medicinal
product. This is specifically addressed in article 1(4) MDD which makes it clear that such products are devices, provided that the action of the medicinal substance is ancillary
to that of the device, as reflected in the product claim and as supported by the scientific data provided by the manufacturer of the devices.
Examples of such devices are:
- catheters coated with heparin or an antibiotic agent,

- bone cements containing antibiotic (see A.3 and A.6),
- root canal fillers which incorporate medicinal substances with secondary action (see A.3 and A.6),
- blood bags containing anticoagulant or preservation agents (see A.3),
Note : rule18 of Annex IX of the MDD applies to these products.
- soft tissue fillers incorporating local anaesthetics,
- bone void filler intended for the repair of bone defects where the primary action of the device is a physical means or matrix, which provides a volume and a scaffold
for osteoconduction and where an additional medicinal substance is incorporated to assist and complement the action of the matrix by enhancing the growth of bone
cells. In such cases, the ancillary nature would be determined by the performance of the matrix on its own and the extent of the enhancement of growth due to the
presence of the substance. With reference to the overall purpose of the product, where the medicinal substance has such an effect that its ancillary nature cannot be
clearly established, then the product should be considered in accordance with the concept of a drug delivery system (see section A6.2),
- haemostatic devices enhanced by the incorporation of collagen, where the primary action of the device is mechanical even though there may be ancillary action due
to the presence of collagen having demonstrable action with platelet receptors resulting in platelet adhesion through a pharmacological process (see also A.3 and
A.4),
- condoms coated with spermicides,
- electrodes with steroid-coated tip,
- wound dressings, surgical or barrier drapes (including tulle dressings) with antimicrobial agent (see A.6),
- intrauterine contraceptives containing copper or silver,
- ophthalmic irrigation solutions principally intended for irrigation which contain components which support the metabolism of the endothelial cells of the cornea (see
A3).
7
It should be noted that the mere coating of a product with a chemical does not imply that the chemical is a medicinal substance. For example, hydroxyapatite, frequently used
as coating for orthopaedic and dental implants, is not considered a medicinal substance. Other coatings which are in use and which are not medicinal substances are
hydromers and phosphorylcholines.
Note : For the time being, products incorporating medicinal substances of human origin are excluded from the MDD.
A.6 Drug delivery system
6.1. The status of devices for drug delivery is addressed by article 1(3) MDD. A device which is intended to deliver a medicinal product is itself regulated as a medical
device. The medicinal product which the device is intended to administer must, of course, be approved according to the normal procedures for medicinal products.
Examples :
- drug delivery pump,

- implantable infusion pump,
- iontophoresis device,
- nebulizer,
- syringe, jet injector.
Note: in a kit comprising an insulin pen and insulin cartridges, the pen is subjected to the MDD whereas the insulin cartridge is a medicinal product.
- spacer devices for use with metered dose inhalers,

- port systems.
6.2. However, if the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not
reusable, that single product is regulated as a medicinal product (article 1(3), second subparagraph MDD). Examples of such products are :
- prefilled syringes,
- aerosols containing a medicinal product,
- nebulizers precharged with a specific medicinal product, and not for universal application,
- patches for transdermal drug delivery,
- implants containing medicinal products in a polymer matrix whose primary purpose is to release the medicinal product, for example plastic beads containing antibiotic
for treating bone infections, or a matrix to release osteoinductive proteins into the surrounding bone (see also A5)
- intrauterine contraceptives whose primary purpose is to release progestogens,
- single-use disposable iontophoresis devices incorporating a medicinal product,
- wound treatment products comprising a matrix whose primary purpose is the administration of medicinal products, (see A.3 and A.5), for example wound dressings
containing an antimicrobial agent where the primary action of the dressing is to administer the agent to the wound for the purpose of controlling infection,
- temporary root canal fillers incorporating medicinal products, whose primary purpose is to deliver the medicinal product (see A.3 and A.5).
8
In such cases the essential requirements of the MDD apply as far as the device related features of the product are concerned (for example as regards the mechanical safety
features of a prefilled syringe). The labelling, however, should comply with the requirements of Directive 92/27/EEC applicable to medicinal products.
B. THE CONSULTATION PROCESS FOR DEVICES INCORPORATING A MEDICINAL SUBSTANCE HAVING ANCILLARY ACTION
B.1 Purpose of the consultation procedure
When referring to the appropriate essential requirement in the MDD - Annex 1, section 7.4 -, a Notified Body so concerned has a responsibility to address this requirement by
"consulting one of the competent bodies established by the Member States in accordance with Directive 65/65/EEC before taking a decision (MDD: Annex II section 4.3 and
Annex III section 5).
The term "Competent Authority" is used in this document to represent such a competent body within the meaning of Directive 65/65/EEC, and indicates the authority
responsible for the evaluation of application for medicinal products being placed on the market (see Annex for list of appropriate Competent Authorities).
In Essential Requirement 7.4 the expression "substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive
65/65/EEC..." is used. This reflects the fact that in such cases, neither the device incorporating a medicinal substance nor the substance in itself is a medicinal product as
defined in Directive 65/65/EEC. This requirement relates to substances which, otherwise, in the context of medicinal products may be an active constituent of a medicinal
product and therefore be liable to act upon the body.
It is for this reason that the verification by the Competent Authority of the safety, quality and usefulness of the "medicinal substance" is to be carried out by analogy with the
appropriate methods specified in Directive 75/318/EEC as amended by Directive 91/507/EEC.
The assessment of "usefulness" and "safety" has a particular implication when applied to a medicinal substance which is of ancillary purpose within a device/medicinal
substance combination.
The aspect of "usefulness" relates to the rationale for using the medicinal substance in relation to the specific intended purpose of the device. It refers to the suitability of the
medicinal substance to achieve its intended action, and whether the potential inherent risks (aspects of "safety") due to the medicinal substance are justified in relation to the
benefit to be obtained within the intended purpose of the device.
By means of the consultation process the competent authority may make available relevant information concerning risks related to the use of the substance (e.g. resulting
from pharmacovigilance).
The ultimate responsibility for the decision, as to whether the pertinent legal requirements are met, belongs to the Notified Body.
The consultation process is only applicable for devices incorporating a medicinal substance as specified in Annex 1, section 7.4 and only where the substance is liable to act
upon the body with action ancillary to that of the device. Therefore, a contact lens solution containing an antiseptic agent where the purpose of the antiseptic is to preserve
the solution does not fall under this procedure.
9
In line with Article 22(3) of the MDD, for a device which has already been granted a marketing authorisation as a medicinal product in at least one Member State the
consultation procedure will be limited to a simple exchange of letters between the Notified Body and Competent Authority, provided the product is unchanged in all respects,
including the information provided with the device.
B.2 Notified Body actions to initiate consultation process
a) The Notified Body should ensure that data supplied by the manufacturer in relation to the device and its intended use includes a specific segment regarding the
medicinal substance being incorporated with ancillary purpose. Presentation of the data according to the format of the Notice to Applicants may facilitate the review
by the Competent Authority Ref:(The Rules governing medicinal products, volume 2B)
b) This segment should include data concerning the safety, usefulness and quality of the medicinal substance, also appropriate details regarding information to be
supplied with the device when placed on the market to permit the evaluation of the aforementioned features.
c) Before consulting a relevant Competent Authority the Notified Body should have come to a preliminary opinion regarding the suitability of the device with ancillary
medicinal substance.
d) It is at the discretion of the Notified Body to choose the Competent Authority with whom he consults from the listed Competent Authorities as indicated in the annex.
The European Medicines Evaluation Agency (EMEA) may be consulted, where the substance involved has been included in a medicinal product which has been
evaluated by the EMEA.
e) The Notified Body may consider it of benefit to utilise, for the consultation, the appropriate Competent Authority previously responsible for a marketing authorisation
for a medicinal product which incorporates the medicinal substance involved in the consultation process.
B.3 Documentation to be provided by the Notified Body to the competent authority for medicinal products
Because of the wide range of medical devices which incorporate medicinal substances, a flexible approach to the data requirements is necessary. Nevertheless the
information should be based in principle, to the extent relevant, on the annex to Directive 91/507/EEC, which modifies Directive 75/318/EEC, as outlined in (a) to (q) below. It
is envisaged that, where well-known medicinal substances for established purposes are involved, all aspects of safety and usefulness may not be required and many of the
headings will be addressed by reference to the literature, including standard textbooks, experience and other information generally available. Nonetheless all headings should
be addressed.
For new active substances and for known medicinal substances in a non-established purpose, comprehensive data is required to address items (a) to (q) below. The
evaluation of such active substances would be performed in accordance with the principles of evaluation of new active substances. The principal headings of Directive
91/507/EEC are given below, together with comments on their applicability to medical devices. This represents a comprehensive checklist covering headings which may be
appropriate depending on the circumstances relating to the case in question.
a) General information
10
A general description of the medical device including the manufacturer's claim regarding the purpose of the inclusion of the substance, together with a critical
appraisal of the results of the risk analysis.
b) Qualitative and quantitative particulars of the constituents

A description of the substance and the amount (giving a range where appropriate) of the medicinal substance incorporated into each medical device. If the
substance is modified during its incorporation into the device, relevant information shall be provided.
c) Description of method of manufacture

An overall description will already form part of the application to the Notified Body; the section dealing with incorporation of the medicinal substance in the device
should be provided.
d) Controls of starting materials

The specification for the medicinal substance shall be provided. Where applicable, reference shall be to the European Pharmacopoeia or in the absence of an EP
monograph to a national pharmacopoeia of one of the Member States. If no monograph is available from the Member States reference may be to other national
monographs or to the manufacturer's specification and methods of analysis.
For new active substances and certain known substances additional information will be required which may be provided in the form of a Drug Master File. The
guideline "Requirements in relation to active substances"1 may be of assistance in providing circumstances where reference to a Pharmacopoeia monograph may
need to be supplemented by further information.
e) Control tests carried out at intermediate stages of the manufacturing process of the medical device
This information is only necessary if it is directly relevant to the quality of the substance as incorporated in the medical device.
f) Control tests on finished product

Qualitative and quantitative tests carried out to control the medicinal substance in the device.
g) Stability
Information defined to show the medicinal substance maintains its desired function throughout the defined shelf-life of the device, taking account of the
manufacturer's recommended storage conditions.
h) Toxicity
Reference to the known toxicological profile of the medicinal substance may be provided. In the case of new active substances, the results of toxicity tests, should
be supplied. This may include information on toxicity and biocompatibility of the medical device which may be available from evaluation in accordance with the EN
30993 series of standards.
i) Reproductive function
Similar considerations to h) apply.
Sincerely yours, 1 In "The Rules Governing Medicinal Products in the European Community, Volume III Addendum II.
11
j) Embryo/foetal and perinatal toxicity
Similar considerations to (h) apply.
k) Mutagenic potential
Similar considerations to h) apply.
l) Carcinogenic potential
Similar considerations to h) apply. The need for data on carcinogenicity should be addressed taking account of available information on the medicinal substance, the
results of genotoxicity testing, the chemical structure of the medicinal substance, and the duration of potential exposure to the substance.
m) Pharmacodynamics
This section should address the intended action of the medicinal substance in the context of its incorporation into a medical device.
n) Pharmacokinetics
It is anticipated that pharmacokinetic studies will not be required in the majority of cases. Some or all of the following areas may need to be addressed as
appropriate:
- description of the pattern of local and systemic exposure to the medicinal substance,
- where the level of exposure fluctuates, the maximum level and duration of exposure should be considered,
- where it is considered possible that potential levels of systemic exposure may present a safety concern, maximum peak plasma concentration should be
established, taking due consideration of individual variability,
- new active substances will require information on the release from the device, and, if relevant, its subsequent distribution and elimination.
o) Local tolerance
This is of particular relevance since the route of exposure to the medicinal substance may be different from its conventional application. The relevant results of
device testing according to EN 30993 should be provided or, where appropriate, information from the scientific literature
p) Clinical documentation
Since the devices will normally be class III, clinical data will form part of the information provided to the Notified Body under annex II or III. This data will address the
safety of the device in its entirety. The usefulness of the medicinal substance in the medical device should be addressed by clinical data or in other sections of the
dossier.
An appropriate methodology for clinical investigations on medical devices is described in EN 540.
q) Labelling
Details supplied by the manufacturer of labelling or information to be provided with the device with regard to the medicinal substance, is to be supplied to the
Competent Authority to assist in the understanding of the safety and usefulness of the substance together with the device.
B.4 The consultation process
12
a) The Notified Body, having requested a Competent Authority to provide an opinion concerning the medicinal substance and its application, should, together with the
Competent Authority, agree such matters as: time-schedules, modalities to obtain further information, including clock stops, fees and practical arrangements for
submission of data.
b) The Notified Body should make available to the Competent Authority relevant data as specified in B.3.
c) The Competent Authority should verify the data provided by the Notified Body. It should consider the use of the medicinal substance by analogy with existing
information regarding the known applications and appropriate features of safety, quality and usefulness as they may be relevant to the specific intended purpose of
the device incorporating the medicinal substance.
d) The Competent Authority should inform the Notified Body of its conclusions and advice as to the suitability of the medicinal substance in its proposed use.
e) The Notified Body should take into account the opinion of the Competent Authority and use its judgement to either approve the drug/device combination, after
consideration of all aspects of risk/benefit in the intended or expected use of the product, or alternatively to reject the product. It may be that certain suggestions
from the Competent Authority may be adopted by the manufacturer to render the product acceptable.
f) The Notified Body should inform the Competent Authority which was consulted of the decision reached by the Notified Body, and where this decision deviates from
the opinion provided by the Competent Authority this will be shown. Where a Notified Body receives a negative opinion from the Medicinal Product Competent
Authority, they should consult with the device Competent Authority before issuing a certificate.
g) During the consultation process the Notified Body concerned may withdraw the request and ask for the opinion of an alternative relevant Competent Authority. In this
case, the previously consulted Competent Authority should be informed of the name of the new Competent Authority.
13
C. CONSULTATION BY COMPETENT AUTHORITIES FOR MEDICINAL PRODUCTS WITH REGARD TO MEDICINAL PRODUCTS WITH DEVICE RELATED FEATURES.
In accordance with Article 1(3) second subparagraph MDD, products placed on the market in such a way that a device and a medicinal product form a single integral product
which is intended exclusively for use in the given combination and which is not reusable, that single product shall be governed by Directive 65/65/EEC. In such cases the
relevant essential requirements of Annex I MDD shall apply with regard to safety and performance related device features. Examples of such products are listed in A.6.2).
In such cases Competent Authorities responsible for the evaluation of the medicinal products in question would consult, if necessary, one of the Competent Authorities or
Notified Bodies for medical devices. This consultation would cover the essential requirements of Annex I MDD for the relevant device features.
D. PROCEDURES FOR THE REPORTING OF ADVERSE INCIDENTS
The classification of the product, medicinal product or medical device, will determine which procedure should be followed for the reporting of an adverse incident; medicinal
products to meet the requirements for pharmacovigilance and medical devices (including those referenced under section A5) to meet the requirements for medical device
vigilance.
Note : guidelines are available on a medical device vigilance system (ref. MEDDEV. 2.12/1). Guidelines are available on a pharmacovigilance system.
A report should be made to a relevant authority and the authorities will liase as necessary.
LIST OF ADDRESSES OF COMPETENT AUTHORITIES FOR MEDICINAL PRODUCTS
14
COUNTRIES ASSOCIATIONS ADRESSES PHONE FAX
EUROPEAN UNION European Medicines Evaluation Agency 7 West Ferry Circus, Canary Wharf; UK- 44/171/418.84.00 44/171/418.84.16
London EO14 4HB
AUSTRIA Bundesministerium fr Arbeit, Gesundheit und Soziales, Gruppe Stubenring, 1 ; A-1010 Wien 43/1/71172-4673 43/1/714.92.22
VIII/C (4674)
BELGIUM Farmaceutische Inspectie Rijksadministratief Centrum, Vesaliusgebouw; 32/2/210.48.96 32/2/210.49.22
B-1010 Brussel
DENMARK Danish Medicines Agency Frederikssundsvej, 378; DK-2700 Brnshj 45/44/889.111 45/44/917.373
GERMANY * Bundesinstitut fr Arzneimittel und Medizinprodukte Seestrasse 10-11, Postfach 33 00 13; 49/30/4548-30 49/30/4548-3207
* For blood products : Paul-Ehrlich-Institut, Bundesanstalt fr D-14191 Berlin
Sera und Impfstoffe Postfach 1740; D-63207 Langen 49/6103/770 49/6103/770123
oder 124
SPAIN Direccion General Farmacia y Productos Sanitarios; Ministerio Paseo del Prado 18-20; E-28071 Madrid 34/1/596.40.15-16 34/1/596.40.69
de Sanidad y Consumo (596.15.47)
(596.15.48)
FINLAND National Agency for Medicines, Pharmacological Department Mannerheimintie 166; PO Box 55; 358/9/396.750 358/9/714.469
FIN-00301 Helsinki
FRANCE Agence du Mdicament; Direction de l'Evaluation 143/145 Bd Anatole France; F-93200 Saint 33/1/48.13.21.57 33/1/48.13.24.75
Denis (48.13.20.98)
GREECE E.O.F. (National Drug Organisation) Mesogion 284; GR-155 62 Holargos 30/1/652.62.16 30/1/654.55.35
IRELAND Irish Medicines Board The Earlsfort Centre, Earlsfort Terrace 353/1/676.49.71(7) 353/1/676.84.90
IRL-Dublin 2
ITALY Direzione Generale del Servizio Farmaceutico - Ministero della Viale della Civilt Romana, 7 39/6/592.58.63 39/6/599.441.17
Sanit I-00144 Roma EUR
LUXEMBOURG Direction de la Sant; Division de la Pharmacie et des 10, rue C.M. Spoo 352/478.55.93 352/224.458
Mdicaments L-2546 Luxembourg
NETHERLANDS College ter beoordeling van geneesmiddelen, Ministerie van Postbus 5811 31/70/340.72.10 31/70/340.51.55
Welzijn, Volksgezondheid en Cultuur NL-2280 HV Rijswijk (ZH)
PORTUGAL INFARMED - Instituto Nacional da Farmacia e do Medicamento Parque de Sade de Lisboa; Av. do Brasil, 53 351/1/790.85.00 351/1/795.91.16
P- 1700 Lisboa (795.78.36)
SWEDEN Medical Products Agency Husarg, 8; S-75103 Uppsala 46/18/174.691 46/1/548.566
UNITED KINGDOM Medicines Control Agency; Department of Health 1 Nine Elms Lane; UK-London SW8 5NQ 44/171/273.02.00 44/171/273.04.93
15
EUROPEAN COMMISSION
DG ENTERPRISE and INDUSTRY
Directorate F, Unit F3 Cosmetics and medical devices
MEDICAL DEVICES: Guidance document

-
Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal
substance or an ancillary human blood derivative
MEDDEV 2. 1/3 rev 3

GUIDELINES RELATING TO THE APPLICATION OF:
Foreword
The present Guideline is part of a set of Guidelines relating to questions of application of EC Directives on medical devices. This guideline is not legally binding, since only the
European Court of Justice can give an authoritative interpretation of Community law. It has been elaborated by an expert group including experts from Member States' Competent
Authorities, the Commission services, as well as industry trade associations. It is therefore intended that the document will provide useful guidance which should assist common
positions to be taken throughout the European Union. Due to the participation of the aforementioned interested parties and of experts from Competent Authorities, it is anticipated that
these guidelines will be followed within the Member States and, therefore, ensure uniform application of relevant Directive provisions.
The present guideline provides non-exhaustive lists of examples of medical devices, accessories to medical devices and medicinal products. Further examples may be found in the
manual on borderline and classification in the Community Regulatory framework for medical devices, published on the European Commission website.1 Particular attention should be
paid to borderline cases between medical devices and herbal medicinal products. This issue may be further developed in this guidance in the near future.
Note: This document is a revision of an earlier document published in July 2001 as MEDDEV 2.1/3 rev 2. Some of the examples given in the MEDDEV 2.1/3 rev 2 have not been
included in the present Guideline. These examples will be further elaborated in the above mentioned manual on borderline and classification in the Community Regulatory framework
for medical devices.
This guidance incorporates the changes introduced by the Directive 2007/47/EC. 2 These changes have to be applied as of 21 March 2010.
1 http://ec.europa.eu/enterprise/medical_devices/borderline_classification_en.htm
2 OJ L 247 , 21.09.2007
1
CONTENTS Pages
SECTION A. BORDERLINE MEDICAL DEVICES /MEDICINAL PRODUCTS
A.1. Introduction 4
A.2 General Principles 4
A.2.1 Medical devices 5

A.2.1.1 Definition of medical devices 5
A.2.1.2 Examples of medical devices 6
A.2.1.3 Definition of an accessory of a medical device 8
A.2.1.4 Examples of accessories of medical devices 8
A.2.2 Medicinal products 8

A.2.2.1 Definition of medicinal products 8
A.2.2.2 Examples of medicinal products 9
SECTION B. DRUG-DELIVERY PRODUCTS AND MEDICAL DEVICES INCORPORATING AS AN INTEGRAL PART, AN ANCILLARY 11
MEDICINAL SUBSTANCE OR AN ANCILLARY HUMAN BLOOD DERIVATIVE
B.1 Introduction 11
B.2 Drug-delivery products regulated as medicinal products 11
B.2.1 Examples of drug-delivery products regulated as medicinal products 11
B3 Drug-delivery products regulated as medical devices 12
B.3.1 Examples of drug-delivery products regulated as medical devices 12
B.4 Medical devices incorporating, as an integral part, an ancillary medicinal substance 13
B.4.1 Examples of medical devices incorporating, as an integral part, an ancillary medicinal substance 13
2
B.5 Medical devices incorporating, as an integral part, an ancillary human blood derivative 14
SECTION C. CONSULTATION PROCEDURE ON MEDICAL DEVICES INCORPORATING, AS AN INTEGRAL PART, AN ANCILLARY 14

MEDICINAL SUBSTANCES OR AN ANCILLARY HUMAN BLOOD DERIVATIVE
C.1 Purpose of the consultation procedure on medical devices incorporating, as an integral part, an ancillary medicinal substance or an 14
ancillary human blood derivative
C.2 Notified Body actions to initiate consultation process on medical devices incorporating, as an integral part, an ancillary medicinal 15
substance or an ancillary human blood derivative
C.3 Documentation to be provided by the Notified Body to the Competent Authority for medicinal products 16
C.4 Consultation process on medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human 19
blood derivative
SECTION D. PROCEDURES FOR THE REPORTING OF ADVERSE INCIDENTS 21
3
A. BORDERLINE PRODUCTS: MEDICAL DEVICES / MEDICINAL PRODUCTS
A.1 Introduction
The demarcation between the Medical Devices Directive 93/42/EEC (MDD)3 and the Active Implantable Medical Device Directive 90/385/EEC (AIMDD)4 on the one hand
and the Medicinal Products Directive 2001/83/EC5 (MPD) on the other hand is crucial for the proper implementation of these Directives and the correct interpretation and
enforcement of national laws.
Therefore, several provisions to establish the demarcation between both legal regimes have been laid down in the MDD, AIMDD and MPD.
However, it was recognised that the subject needs to be further explained and illustrated by practical guidance.
A.2 General Principles
Borderline cases are considered to be those cases where it is not clear from the outset whether a given product falls under the MDD, the AIMDD or the MPD.6
In order to fall under the MDD a product must fulfil the definition of a medical device7 and must also not be excluded from the scope of the MDD.8 It is therefore necessary to
examine both prerequisites.
3 OJ L 169, 12.07.1993, as last amended
6 A separate guidance document is available for IVD medical device borderlines
(http://ec.europa.eu/enterprise/medical_devices/meddev/2_14_ivd_borderline_issues_jan2004.pdf)
7 Article 1(2) a of the MDD
8 Article 1(3)5 of the MDD
4
As a general rule, a relevant product is regulated either by the MDD or the AIMDD or by the MPD. The conformity assessment procedure or the marketing authorization
procedure to be followed prior to placing a given product on the market will therefore be governed either by the MDD/AIMDD or by the MPD. The procedures of both
Directives do not apply cumulatively.
For defined features, however, some cross-references are made within one regime to specific provisions of the other regime.
The definitions of medical device and medicinal product are reproduced here for reference:
A.2.1 Medical device
A.2.1.1 Definition of medical device
Article 1(2) (a) MDD defines a medical device as:
"Any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be
used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the
purpose of:
- diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
- investigation, replacement or modification of the anatomy or of a physiological process,
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its
function by such means;"9
In deciding whether a product falls under the MDD, particular account shall be taken of the principal mode of action of the product. 10
Typically, the medical device function is achieved by physical means (including mechanical action, physical barrier, replacement of or support to organs or body functions ...).
The principal intended action of a medical device may be deduced from the scientific data regarding mechanism of action and the manufacturer's labelling and claims.
9 There is a small difference with the definition of medical devices in the AIMDD (Article 1(2)a) any instrument, apparatus, appliance, software, material or other article,
whether used alone or in combination, together with any accessories, including the software intended by its manufacturer to be used specifically for diagnostic and/or
therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: ()
10 Article 1(5) c of the MDD and article 1 (6) a of the AIMDD
5
Although the manufacturer's claims are important, it is not possible to place the product in one or other category in contradiction with current scientific data. Manufacturers
may be required to justify scientifically their rationale for the qualification of their product.
The following definitions for pharmacological, immunological or metabolic means are intended only to provide guidance as to the meaning of these terms.
Pharmacological means is understood as an interaction between the molecules of the substance in question and a cellular constituent, usually referred to as a receptor,
which either results in a direct response, or which blocks the response to another agent. Although not a completely reliable criterion, the presence of a dose-response
correlation is indicative of a pharmacological effect.
Immunological means is understood as an action in or on the body by stimulation and/or mobilisation of cells and/or products involved in a specific immune reaction.
Metabolic means is understood as an action which involves an alteration, including stopping, starting or changing the speed of the normal chemical processes
participating in, and available for, normal body function.
Note: The fact that a product is, or is not, itself metabolised does not imply that it achieves, or does not achieve, its principal intended action by metabolic means.
Medical devices may be assisted in their function by pharmacological, immunological or metabolic means, but as soon as these means are not ancillary with respect to the
principal intended action of a product, the product no longer fulfils the definition of a medical device. The claims made for a product, in accordance with its method of action
may, in this context, represent an important factor for its qualification as a medical device.
These principles can be, for example, illustrated by bone cements. Plain bone cement without antibiotics is a medical device since it achieves its principal intended action
(the fixation of prosthesis) by physical means. Bone cements containing antibiotics, where the principal intended action remains fixation of prosthesis, are also medical
devices. In this case the action of the antibiotic, which is to reduce the possibility of infection being introduced during surgery, is clearly ancillary. If however the principal
intended action is to deliver the antibiotic, the product no longer fulfils the definition of a medical device.
A.2.1.2 Examples of medical devices
The following examples should, in view of their principal intended action, generally be considered as medical devices subject to relevant criteria being met; the function of
some of the devices indicated in these examples may be assisted by the presence of medicinal substances where such substances have an ancillary action to that of the
device.
- Bone cements,
- Dental filling materials,
- Materials for sealing, approximation, or adhesion of tissues (e.g. cyanoacrylates, fibrin-based adhesives not of human origin)
6
- Resorbable materials used in osteo-synthesis (e.g. pins or bone screws manufactured using polylactic acid),
- Sutures, absorbable sutures,
- Soft and hard tissue scaffolds and fillers (e.g. calcium phosphate, bioglass),
- Bone void fillers intended for the repair of bone defects where the primary action of the device is a physical means or matrix, which provides a volume and a scaffold for
osteoconduction,
- Intrauterine devices, except products such as intrauterine contraceptives whose primary purpose is to release progestogens,
- Blood bags,
- Systems intended to preserve and treat blood,
Note: Systems intended for the collection, storage and preservation of blood or blood components and as an ancillary function, the treatment of blood or blood components
where this effect is achieved outside the human body, are classified as devices provided that any residual material is not intended to achieve its effect when the blood or cells
are reintroduced into the body, e.g. systems incorporating chemicals activated by light to reduce the viral load where the quantity of chemical remaining has no intended
effect when transfused.
This note does not cover substances introduced into an extracorporeal circuit.
- Gases and liquids for ocular endotamponades,
- Cell separators, including those incorporating fixed antibodies for cell binding,
- Wound dressings, which may be in the form of liquids, gels and pastes, etc (e.g. hydrocolloid, hydrogel),
- Haemostatic products, for example patches, plugs and powders where the haemostatic effect results from the product's physical characteristics, or is due to the surface
properties of the material. This includes products such as calcium alginate or oxidised cellulose where adhesion of platelets to the surface triggers platelet adhesion and
aggregation
- Concentrates for haemodialysis,
- Pressure reducing valves and regulators,
- Irrigation solutions intended for mechanical rinsing (e.g. bladder irrigation solution, ocular irrigation solution),
Note: If the solution contains a medicinal substance such as chlorhexidine where the principal intended purpose is to provide a local antimicrobial effect, it will be a
medicinal product. Solutions incorporating substances for other purposes, e.g. antimicrobial agent for the preservation of the solution remain a medical device.
- Devices such as catheters, guidewires and stents containing or incorporating radio isotopes where the radioactive isotope as such is not released into the body, used for
example in cardiology for the prevention of restenosis.
7
A.2.1.3 Definition of an accessory of a medical device
Article 1(2) (b) MDD defines an accessory of a medical device as follows:
Accessory means an article which whilst not being a (medical) device is intended specifically by its manufacturer to be used together with a device to enable it to be used in
accordance with the use of the device intended by the manufacturer of the device. 11
A.2.1.4 Examples of accessories of medical devices
The following products fall under the definition of "accessory".
- Contact lens care products (disinfecting, cleaning, rinsing and hydrating solutions including those which aid the insertion and/or wearing of contact lenses without
therapeutic claim),
- Disinfectants specifically intended for use with medical devices (e.g. endoscopes),
Note: Multipurpose disinfectants or sterilisation agents are not covered by MDD; they are covered by the directive on biocides.
- Lubricants specifically intended for use together with medical devices (e.g. for gloves, endoscopes, condoms),
- Skin barrier powders and pastes or other skin care products specifically intended for use together with ostomy bags,
- Gases used to drive cryoprobes and surgical tools.
A.2.2. Medicinal product
A.2.2.1 Definition of medicinal product
Article 1(2) MPD defines a medicinal product as follows:
(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or
11 Article 1(2) b MDD
8
(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological
functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
This definition comprises two limbs, one relating to presentation and the other to function. A product constitutes a medicinal product if it is covered by one or other or both of
those limbs.12
Due to the definition of medicinal product, substances used in or administered to human beings to make a medical diagnosis, even if they fulfil their function by physical or
chemical means and not by pharmacological, immunological or metabolic means in the sense as described above are considered to be medicinal products.
The definition of medicinal product must be applied case by case and must be read in accordance with the case law of the European Court of Justice.
Article 2(2) of MPD provides that in cases of doubt, where, taking into account all its characteristics, a product may fall within the definition of a medicinal product and within
the definition of a product covered by other Community legislation the provisions of this Directive shall apply.
The wording of Article 2(2) of the MPD shows that it only applies if, after a case-by-case assessment, taking in consideration all the characteristics of a product 13, the
product in question may fall within the definition of both, medical device and medicinal product. In such a case, the provisions of the MPD apply. The MDD and the MPD
cannot be applied cumulatively.
In deciding whether a product falls under the MDD or the MPD particular account shall be taken of the principal mode of action of the product.14
A.2.2.2 Examples of medicinal products:
The following examples should generally be considered as medicinal products subject to relevant criteria being met:
12 Cf., for the former Directive 65/65/EEC: ECJ, C- 290/90 of 20.5.1992 Eye lotions, ECR 1992 I-3317, para. 9
13 Whereas (7) of Directive 2004/27/EC, amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, specifies that where a
product comes clearly under the definition of other product categories, in particular food, food supplements, medical devices, biocides or cosmetics, this Directive should
not apply
14 Article 1(5) c of the MDD and article 1(6) a of the AIMDD
9
- Spermicidal preparations,
- Gases intended to be used in anaesthesia and inhalation therapy, (e.g. oxygen, medical air supplied in containers) including their primary containers,
Note: These gases are also used in minimal access surgery. However a product intended exclusively for minimal access surgery would be a medical device.
- Topical disinfectants (antiseptics) for use on patients,
- Haemostatic and sealant products interacting with the coagulation cascade through a pharmacological process i.e. where the primary mode of action is not mechanical
(such as certain collagens which have a molecular structure capable of surface independent demonstrated interaction with platelet receptors and therefore achieve platelet
adhesion through a pharmacological process).
- Water for injections, IV fluids and other fluids for drug injection and plasma volume expanders,
- In vivo diagnostic agents, e.g. x-ray contrast media, NMR enhancing agents, fluorescent ophthalmic strips for diagnostic purposes, carrier solutions to stabilize micro-
bubbles for ultrasound imaging, radiopharmaceuticals for diagnostic use
- Gases for in-vivo diagnostic purposes, including lung function, tests, e.g. carbon dioxide for vascular diagnostic purposes,
- Antacids,
- Fluoride dental preparations,
Note: Dental preparations with a typical device mode of action, such as cements or varnishes incorporating fluoride, are medical devices, where the fluoride is of ancillary
action to that of the device.15
- Solutions administered in-vivo to the local circulation for the cooling of organs during surgery,
15 See also Directive 76/768/EEC on cosmetic products
10
B. DRUG-DELIVERY PRODUCTS AND MEDICAL DEVICES INCORPORATING AS AN INTEGRAL PART, AN ANCILLARY MEDICINAL SUBSTANCE OR AN ANCILLARY
HUMAN BLOOD DERIVATIVE
B.1 Introduction
The term "Competent Authority" is used in this document to represent a competent body responsible for the evaluation of applications for medicinal products for human use
being placed on the market (i.e. national competent authority designated by the Member States or the European Medicines Agency (EMEA)).
This guideline aims to provide interested parties with appropriate guidance on procedural aspects to facilitate the consultation procedure to a Competent Authority by notified
bodies on:
Medicinal products, within the meaning of Article 1 of Directive 2001/83/EC incorporated, as an integral part, in a medical device and which are liable to act upon the
body with action ancillary to that of the device.
Medicinal product constituents or medicinal products derived from human blood or human plasma, within the meaning of Article 1 of Directive 2001/83/EC,
incorporated, as an integral part, in a medical device and which are liable to act upon the human body with action ancillary to that of the device.
These substances are referred to hereinafter respectively as ancillary medicinal substances and as ancillary human blood derivatives.
B.2 Drug-delivery products regulated as medicinal products
This category involves a device that is intended to administer a medicinal product in the case where the device and the medicinal product form a single integral product,
which is intended exclusively for use in the given combination and which is not reusable.
According to the MDD, this single product is governed by the MPD but the relevant essential requirements of Annex I to the MDD shall apply as far as the safety and
performance-related device features are concerned.16
B.2.1 Examples of drug-delivery products regulated as medicinal products
- Prefilled syringes,
16 Article 1(3) second subparagraph MDD.
11
- Aerosols containing a medicinal product,
- Nebulizers precharged with a specific medicinal product,
- Patches for transdermal drug delivery,
- Implants containing medicinal products in a polymer matrix whose primary purpose is to release the medicinal product, for example plastic beads containing
antibiotic for treating bone infections, or a matrix to release osteoinductive proteins into the surrounding bone,
- Intrauterine contraceptives whose primary purpose is to release progestogens,
- Single-use disposable iontophoresis devices incorporating a medicinal product,
- Wound treatment products comprising a matrix whose primary purpose is the administration of medicinal products, for example wound dressings containing an
antimicrobial agent where the primary action of the dressing is to administer the agent to the wound for the purpose of controlling infection,
- Temporary root canal fillers incorporating medicinal products, whose primary purpose is to deliver the medicinal product.
B.3 Drug-delivery products regulated as medical devices
This category concerns a device that is intended to administer a medicinal product within the meaning of the MPD.
In this case, that device is governed by the MDD or by the AIMDD without prejudice to the provisions of Directive 2001/83/EC with regard to the medicinal product. 17
B.3.1 Examples of drug-delivery products regulated as medical devices
- Drug delivery pump,

- Implantable infusion pump,
- Iontophoresis device,
- Nebulizer,
- Syringe, jet injector,
- Spacer devices for use with metered dose inhalers,
- Port systems.
17 Article 1(3) first subparagraph MDD and Article 1(3) first subparagraph AIMDD.
12
B.4 Medical devices incorporating, as an integral part, an ancillary medicinal substance
The MDD and the AIMDD also specify the case of medical devices incorporating, as an integral part, a medicinal substance with ancillary action.18
This case relates to a device that incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of
Article 1 of MPD and which is liable to act upon the body with action that is ancillary to that of the device.
That device shall be assessed and authorised in accordance with the MDD or the AIMDD.
Note: The substance incorporated in the device must meet the three following conditions:
- The substance, if used separately, may be considered to be a medicinal product;

- The substance is liable to act upon the human body;
- The action of this substance is ancillary to that of the device.
A medical device incorporates a medicinal substance as an integral part, within the meaning of Article 1 (4) MDD and Article 1 (4) AIMDD, if and only if the device and the
substance are physically or chemically combined at the time of administration (i.e. use, implantation, application etc) to the patient.
B.4.1 Examples of medical devices incorporating, as an integral part, an ancillary medicinal substance
- Catheters coated with heparin or an antibiotic agent,

- Bone cements containing antibiotic,
- Root canal fillers which incorporate medicinal substances with ancillary action,
- Soft tissue fillers incorporating local anaesthetics,
- Bone void filler intended for the repair of bone defects where the primary action of the device is a physical means or matrix, which provides a volume and a scaffold
for osteoconduction and where an additional medicinal substance is incorporated to assist and complement the action of the matrix by enhancing the growth of bone
cells. In such cases, the ancillary nature would be determined by the performance of the matrix on its own and the extent of the enhancement of growth due to the
presence of the substance. With reference to the overall purpose of the product, where the medicinal substance has such an effect that its ancillary nature cannot be
clearly established, then the product should be considered in accordance with the concept of a drug delivery system,
- Condoms coated with spermicides,
18 Article 1 (4) MDD and Article 1 (4) AIMDD.
13
- Electrodes with steroid-coated tip,
- Wound dressings, surgical or barrier drapes (including tulle dressings) with antimicrobial agent,
- Intrauterine contraceptives containing copper or silver.
- Ophthalmic irrigation solutions principally intended for irrigation which contain components which support the metabolism of the endothelial cells of the cornea
- Drug eluting coronary stents
It should be noted that the mere coating of a product with a chemical does not imply that the chemical is a medicinal substance. For example, hydroxyapatite, frequently used
as coating for orthopaedic and dental implants, is not considered a medicinal substance. Other coatings which are in use and which are not medicinal substances are
hydromers and phosphorylcholines.
B.5 Medical devices incorporating, as an integral part, an ancillary human blood derivative
The same rule applies when a medical device or an active implantable medical device incorporates, as an integral part, a substance which, if used separately, may be
considered to be a medicinal product constituent or a medicinal product derived from human blood or human plasma within the meaning of Article 1 of the MPD and which is
liable to act upon the human body with ancillary action to that of the device.
Such a device shall be assessed and authorised in accordance with the MDD or the AIMDD.19
C. Consultation procedure on devices incorporating, as an integral part, an ancillary medicinal substances or an ancillary human blood derivative
C.1 Purpose of the consultation procedure on devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood
derivative
For devices incorporating, as an integral part, an ancillary medicinal substance, the notified body shall, having verified the usefulness of the substance as part of the medical
device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States or the
19 Article 1(4a) MDD and Article 1 (4a) AIMDD
14
EMEA acting particularly through its committee in accordance with Regulation (EC) No 726/200420 on the quality and safety of the substance including the clinical benefit/risk
profile of the incorporation of the substance into the device.21
For devices incorporating, as an integral part, an ancillary human blood derivative, the notified body shall, having verified the usefulness of the substance as part of the
medical device and taking into account the intended purpose of the device, seek a scientific opinion from the EMEA, acting particularly through its committee, on the quality
and safety of the substance including the clinical benefit/risk profile of the incorporation of the human blood derivative into the device.22
Note: The consultation process is only applicable for devices incorporating a substance which is liable to act upon the body with action ancillary to that of the device.
Therefore, for example, a contact lens solution containing an antiseptic agent which does not act upon the body with an action ancillary to that of the device but which aims
to preserve the solution does not fall under this procedure.
In accordance with Annex I section 7.4 MDD and Annex I, section 10 AIMDD, the quality, safety and usefulness of an ancillary medicinal substance incorporated in a medical
device must be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. This is further elaborated in section C.3.
The assessment of "usefulness" and "safety" has a particular implication when applied to a medicinal substance which has an ancillary action within a device/medicinal
product combination.
The aspect of "usefulness" relates to the rationale for using the medicinal substance in relation to the specific intended purpose of the device. It refers to the suitability of the
medicinal substance to achieve its intended action, and whether the potential inherent risks (aspects of "safety") due to the medicinal substance are justified in relation to the
benefit to be obtained within the intended purpose of the device.
By means of the consultation process, the Competent Authority may make available relevant information concerning risks related to the use of the substance (e.g. resulting
from pharmacovigilance).
C.2 Notified Body actions to initiate consultation process on medical devices incorporating, as an integral part, an ancillary medicinal substance or an
20 OJ L 136, 30.04.2004.
21 Annex I section 7.4 second subparagraph MDD and Annex I section 10 second subparagraph AIMDD
22 Annex I section 7.4 third subparagraph MDD and Annex I section 10 third subparagraph AIMDD
15
a) The Notified Body should ensure that data supplied by the manufacturer in relation to the device and its intended use includes a specific segment regarding the
ancillary medicinal substance or the ancillary human blood derivative incorporated in the medical device. Presentation of the data according to the format of the
Notice to Applicants may facilitate the review by the Competent Authority. (Ref: The Rules governing medicinal products in the European Union, volume 2B)
b) This segment should include data concerning the quality, safety and usefulness of the ancillary medicinal substance or of the ancillary human blood derivative, also
appropriate details regarding information to be supplied with the device when placed on the market to permit the evaluation of the aforementioned features.
c) Except for human blood derivatives and for medicinal products which fall within the scope of the Annex I to Regulation (EC) N 726/2004 where consultation with
EMEA is mandatory, it is at the discretion of the manufacturer to choose the Competent Authority in consultation with its Notified Body. The EMEA may also be
consulted, e.g. where the substance involved was included in a medicinal product which has been evaluated by the EMEA.
C.3 Documentation to be provided by the Notified Body to the Competent Authority
Because of the wide range of medical devices which incorporate, as an integral part, an ancillary medicinal substances or an ancillary human blood derivative, a flexible
approach to the data requirements is necessary. Nevertheless the information should be based in principle, to the extent relevant, on Annex I to Directive 2001/83/EC, as
amended by Commission Directive 2003/63/EC23. It is envisaged that, where well-known medicinal substances for established purposes are the subject of the consultation,
all aspects of safety and usefulness may not be required and many of the headings will be addressed by reference to literature, including standard textbooks, experience and
other information generally available. Nonetheless all headings should be addressed; either with relevant data or justification for absence of data. The latter may be based on
the manufacturers risk assessment.
For new active substances and for known substances in a non-established purpose, comprehensive data is required to address the requirements of Annex I to Directive
2001/83/EC. The evaluation of such active substances would be performed in accordance with the principles of evaluation of new active substances.
Particular attention should be given to, as relevant:
- The EMEA recommendation on the procedural aspects and dossier requirements for the consultation to the EMEA by a Notified body on an ancillary medicinal substance
or an ancillary human blood derivative incorporated in a medical device, EMEA/CHMP/401993/2005." 24 This recommendation is intended to provide the relevant parties with
information about procedural aspects of the consultation procedure to the EMEA by Notified Bodies on an ancillary medicinal substance or an ancillary human blood
derivative incorporated as an integral part in a medical device, as well as guidance on data requirements and format of such applications for consultation;
- Published guidance from national competent authorities on the documentation requirements for consultations.
23 OJ L 159, 27.06.2003
24 http://www.emea.europa.eu/pdfs/human/regaffair/40199305en.pdf
16
1) General information
A general description of the medical device including the manufacturer's claim regarding the purpose of the incorporation of the ancillary medicinal substance or the ancillary
human blood derivative, together with a critical appraisal of the results of the risk assessment.
2) Quality Documentation
a) For the ancillary medicinal substance or the ancillary human blood derivative itself:
Relevant parts of CTD-Module 3 in accordance with the format of the Notice to Applicants (Ref: The Rules governing medicinal products in the European Union,
volume 2B). Relevant parts should be provided, depending on whether the ancillary medicinal substance or the ancillary human blood derivative is an active
pharmaceutical ingredient or a formulated medicinal product.
Information on the active substance may be provided in the form of an Active Substance Master File (ASMF)25, structured according to Module 3.2.S of the CTD-format.
Particular attention should be made to current CHMP quality guidelines on ASMF. 26
Where applicable, reference shall also be made to the European Pharmacopoeia (PhEur) or in the absence of a PhEur monograph to a national pharmacopoeia of one
of the Member States. If no monograph is available from the Member States reference may be to other national monographs or to the manufacturer's specification and
methods of analysis.
CTD-Module 2.3 (Quality Overall Summary) in accordance with the format of the Notice to Applicants (Ref: The Rules governing medicinal products in the European
Union, volume 2B)
b) For the ancillary medicinal substance or the ancillary human blood derivative as incorporated in the medical device:
Qualitative and quantitative particulars of the constituents

A description of the ancillary medicinal substance or the ancillary human blood derivative, and the amount (giving a range where appropriate) of the ancillary medicinal
substance or the ancillary human blood derivative incorporated into each medical device. If the medicinal substance or the ancillary human blood derivative is modified
during its incorporation into the medical device, relevant information shall be provided.
Description of method of manufacture

An overall description will already form part of the application to the Notified Body; the section dealing with incorporation of the ancillary medicinal substance or the
ancillary human blood derivative in the medical device should be provided.
25 This option does not apply to biological substances
26 http://www.emea.europa.eu/htms/human/humanguidelines/quality.htm
17
Controls of starting materials
The specification for the ancillary medicinal substance or the ancillary human blood derivative shall be provided.
Control tests carried out at intermediate stages of the manufacturing process of the medical device
This information is only necessary if it is directly relevant to the quality of the ancillary medicinal substance or the ancillary human blood derivative as incorporated in the
medical device.
Final Control tests of the ancillary medicinal substance or the ancillary human blood derivative in the medical device
Qualitative and quantitative tests carried out to control the ancillary medicinal substance or the ancillary human blood derivative incorporated in the medical device.
Stability
Information defined to show the ancillary medicinal substance or the ancillary human blood derivative maintains its desired function throughout the defined shelf-life of
the medical device including, taking account of the manufacturer's recommended storage conditions, potential interaction with other materials, and potential degradation
of the ancillary medicinal substance or the ancillary human blood derivative.
3) Non-clinical Documentation
Non-clinical pharmacology
Pharmacodynamics
This section should address the intended action of the ancillary medicinal substance or the ancillary human blood derivative in the context of its incorporation
into a medical device.
Pharmacokinetics
It is anticipated that pharmacokinetic studies will not be required in the majority of cases. Some or all of the following areas may need to be addressed as
appropriate:
- Description of the pattern of local and systemic exposure to the ancillary medicinal substance or to the ancillary human blood derivative,
- Where the level of exposure fluctuates (AUC), the maximum level and duration of exposure should be considered,
- Where it is considered possible that potential levels of systemic exposure may present a safety concern, maximum peak plasma concentration should be
established, taking due consideration of individual variability,
- New active substances will require information on the release from the medical device, and, if relevant, its subsequent absorption, distribution, metabolism
and excretion (AUC and eventually metabolites, if relevant).
18
Toxicity (including single-dose toxicity, repeat-dose toxicity, geno-toxicity, carcino-genicity and reproductive and developmental toxicity, as applicable).
Reference to the known toxicological profile of the ancillary medicinal substance or the ancillary human blood derivative may be provided. In the case of new active
substances, the results of toxicity tests should be provided, taking into account relevant CHMP guidelines.27 This may include information on toxicity and
biocompatibility of the medical device which may be available from evaluation in accordance with the EN 10993 series of standards.
Local tolerance
This is of particular relevance since the route of exposure to the ancillary medicinal substance or the ancillary human blood derivative may be different from its
conventional application. The relevant results of medical device testing according to EN ISO 10993 should be provided or, where appropriate, information from the
scientific literature.
4) Clinical evaluation
Since these medical devices will be class III, clinical data will form part of the information provided to the Notified Body under annex II or III of the applicable Directive. This
data will address the requirements for clinical evaluation of the medical device incorporating an ancillary medicinal substance or an ancillary human blood derivative as
required by Annex X of Directive 93/42/EEC or annex VII of Directive 90/385/EEC, respectively. This data will address the safety of the medical device in its entirety. The
usefulness of the ancillary medicinal substance or the ancillary human blood derivative incorporated in the medical device should be addressed by clinical evaluation or by
cross-reference to other sections of the dossier, as applicable.
An appropriate methodology for clinical investigations on medical devices is described in EN ISO 14155-1:2003 - Clinical investigation of medical devices for human subjects
- Part 1: General requirements and EN ISO 14155-2:2003 - Clinical investigation of medical devices for human subjects - Part 2: Clinical investigation plans.
Particular attention shall be given to any specific guidelines (e.g. EMEA guideline on the clinical and non clinical evaluation during the consultation procedure on medicinal
substances contained in drug eluting (medicinal substance-eluting) coronary stents28, MEDDEV guidance 2.7.1 Appendix 1 clinical evaluation of coronary stents29).
5) Labelling
Details supplied by the manufacturer of labelling or information to be provided with the medical device with regard to the ancillary medicinal substance or the ancillary human
blood derivative, is to be supplied to the Competent Authority to assist in the understanding of the safety and usefulness of the ancillary medicinal substance or the ancillary
human blood derivative together with the medical device.
27 http://www.emea.europa.eu/htms/human/humanguidelines/nonclinical.htm
28 http://www.emea.europa.eu/pdfs/human/ewp/11054007enfin.pdf
29 http://ec.europa.eu/enterprise/medical_devices/meddev/cetf.pdf
19
C.4 Consultation process on medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative
a) The Notified Body, having requested a Competent Authority to provide an opinion concerning the ancillary medicinal substance or the ancillary human blood
derivative and its application, should, together with the Competent Authority, agree such matters as: time-schedules, modalities to obtain further information,
including clock stops, fees and practical arrangements for submission of data.
- Further details about the procedure to follow for a consultation to the EMEA are detailed in the EMEA recommendation on the procedural aspects and dossier
requirements for the consultation to the EMEA by a Notified body on an ancillary medicinal substance or an ancillary human blood derivative incorporated in a
medical device, EMEA/CHMP/401993/2005" .30
- National competent authorities may also have published guidance on the procedure to follow for consultations.
b) The Notified Body should make available to the Competent Authority relevant data as specified in C.3 together with its own verification of the usefulness of the
ancillary medicinal substance or the ancillary human blood derivative incorporated in the device.
c) The Competent Authority should review the data provided by the Notified Body. It should consider the use of the ancillary medicinal substance or of the ancillary
human blood derivative by analogy with existing information regarding the known applications and appropriate features of safety, quality and usefulness as they may
be relevant to the specific intended purpose of the device incorporating, as an integral part, the ancillary medicinal substance or the ancillary human blood
derivative.
d) During the consultation process the Notified Body concerned may withdraw the request and ask for the opinion of an alternative relevant Competent Authority. In this
case, the previously consulted Competent Authority should be informed of the name of the new Competent Authority.
e) The Competent Authority should inform the Notified Body of its opinion, taking into account the manufacturing process and the data related to the usefulness of
incorporation of the ancillary medicinal substance or of the ancillary human blood derivative into the device as determined by the Notified Body.31
f) The scientific opinion of the competent authority must be included in the documentation concerning the device. The opinion of the Competent Authority must be
drawn up within 210 days after receipt of a valid documentation.32This time period excludes clock stops.
g) For medical devices incorporating an ancillary medicinal substance, the notified body will give due consideration to the views expressed in this consultation when
making its decision. It will convey its final decision to the Competent Authority concerned.33
30 http://www.emea.europa.eu/pdfs/human/regaffair/40199305en.pdf
31 Annex I section 7.4 second and third subparagraphs MDD, Annex I section 10 second and third subparagraphs AIMDD
32 Annex II Section 4.3 second and third subparagraphs MDD and Annex II section 5 second and third subparagraphs AIMDD
33 Annex II section 4.3 second subparagraph MDD and Annex III section 5 second subparagraph AIMDD
20
The Notified Body should take into account the opinion of the Competent Authority and use its judgement to either approve the product, after consideration of all
aspects of risk/benefit in the intended or expected use of the product, or alternatively to reject the product. It may be that certain suggestions from the Competent
Authority may be adopted by the manufacturer to render the product acceptable.
The Notified Body should inform the Competent Authority which was consulted of the decision reached by the Notified Body, and where this decision deviates from
the opinion provided by the Competent Authority this will be shown. Where a Notified Body receives a negative opinion from the Medicinal Product Competent
Authority, they should consult with the device Competent Authority before issuing a certificate.
For medical devices incorporating an ancillary human blood derivative, the notified body will give due consideration to the opinion of the EMEA when making its
decision. The notified body may not deliver the certificate if the EMEA's scientific opinion is unfavourable. It will convey its final decision to the EMEA.34
h) Where changes are made to an ancillary substance incorporated in a device (in particular related to the source, the manufacturing process, the amount and the
method of incorporation), the notified body shall be informed of the changes and shall consult the relevant medicines competent authority (i.e. the one involved in
the initial consultation), in order to confirm that the quality and safety of the ancillary substance are maintained. The competent authority shall take into account the
data related to the usefulness of the incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no
negative impact on the established benefit/risk profile of the addition of the substance in the device.35
i) When the relevant medicines competent authority (i.e. the one involved in the initial consultation) has obtained information on the ancillary substance, which could
have an impact on the established benefit/risk profile of the addition of the substance in the medical device, it shall provide the notified body with advice, whether this
information has an impact on the established benefit/risk profile of the addition of the substance in the medical device or not. The notified body shall take the updated
scientific opinion into account in reconsidering its assessment of the conformity assessment procedure.36
D. PROCEDURES FOR THE REPORTING OF ADVERSE INCIDENTS
The regulation of a product as a medicinal product or medical device, will determine which procedure should be followed for the reporting of an adverse incident; medicinal
products to meet the requirements for pharmacovigilance and medical devices to meet the requirements for medical device vigilance.
Note: Guidelines are available on a medical device vigilance system (ref. MEDDEV. 2.12/1 rev 5). 37 Guidelines are available on pharmacovigilance requirements.38
34 Annex II section 4.3 third subparagraph MDD and Annex II section 5 third paragraph AIMDD
35 Annex I section 7.4 fourth subparagraph MDD and Annex I section 10 fourth subparagraph AIMDD
36 Annex I section 7.4 fifth subparagraph MDD and Annex I section 10 fifth subparagraph AIMDD
37 http://ec.europa.eu/enterprise/medical_devices/meddev/2_12_1-rev_5-2007-fin3.pdf
38 http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev9.htm
21
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 1/4
March 1994
Demarcation with other Directives :

- Directive 89/336/EEC relating to electromagnetic compatibility
- Directive 89/686/EEC relating to Personal Protective Equipment
--- (())---
INTRODUCTION
These guidelines should be read in conjunction with the Directive 90/385/EEC

relating to active implantable medical devices and the Directive 93/42/EEC relating to
medical devices. They provide a practical support for the uniform application of these
Directives. The guidelines deal with specific issues in the context of the
aforementioned Directives. Therefore they are of complementary nature to the general
vade-mecum relating to the application of New Approach Directives.
]]]]]]]]]
2
LIST OF CONTENTS
1. Directive 93/42/EE on medical devices(*)

2. Directive 90/385/EEC on active implantable medical devices1
3. Interface with other directives
- medical devices/medicinal products(*)
- medical devices/electromagnetic compatibility
- medical devices/personal protective equipment
II. CLASSIFICATION OF MEDICAL DEVICES COVERED BY DIRECTIVE 93/42/EEC 2
1. CE-marking
2. Application
- Annex 5
- Annex 2
. Quality systems
- Annex 3
3. Conduct of audits
(*)
These parts of the guidelines will be circulated as separate working documents
1
2
3
I.3 INTERFACE WITH OTHER DIRECTIVES
3.1 MEDICAL DEVICES/MEDICINAL PRODUCTS
3.2 MEDICAL DEVICES/DIRECTIVE 89/336/EEC RELATING TO ELECTROMAGNETIC COMPATIBILITY
3.2.1 The Directive 90/385/EEC on active implantable medical devices (AIMD) and the Directive
93/42/EEC on medical devices (MDD) are "specific directives" with regard to Directive
89/336/EEC relating to electromagnetic compatibility 1.- (see Article 1(5) AIMD, Article 1(7) MDD)
The aforementioned medical devices directives cover all aspects related to electromagnetic
compatibility (immunity and electromagnetic interference) of medical devices (see AIMD, Annex I,
section 8; MDD, Annex I, sections 9.2, 11 and 12.5). Thus, in all cases when the medical devices
directives are applied, whether during the transitional period for these directives or when the
directives become mandatory, there is no need to apply the Directive 89/336/EEC with regard to
EMC aspects.
3.2.2 There are rather complicated situations presented during the transitional period of the three
Directives mentioned, caused by the different introduction dates for each Directive, and the
different finishing dates of the appropriate transitional periods. This complication is caused by the
fact that the medical devices directives, as with most other New Approach Directives, are only of
optional application during their transitional periods.To clarify the choices open, during the
transitional period, to a manufacturer in dealing with aspects relating to electromagnetic
compatibility, the alternatives are illustrated as follows :
1.-
Official Journal no. L 139 of 23 May 1989 as amended by :
- Directive 91/263/EEC of 29 April 1991 (L 128 of 23 May 1991, p. 1)
- Directive 92/31/EEC of 28 April 1992 (L 126 of 12 May 1992, p. 11)
- Directive 93/68/EEC of 22 July 1993 (L 220 of 30 August 1993).
4
-5-
ACTIVE IMPLANTABLE MEDICAL DEVICES
National legislation covering active implantable medical devices National legislation covering E M C
1.1.1992-31.12.1992 Option A Option B Option C Option D
Not applicable Pre-existing national legislation Legislation transposing EMC Directive Preexisting national legislation
CE marking, Dir. 89/336/EEC
1.1.1993-31.12.1994 National legislation transposing Pre-existing national legislation National legislation transposing EMC Pre-existing national legislation
AIMD (including necessarily EMC directive CE marking, Directive
aspects) CE marking , directive 89/336/EEC
90/385/EEC
from 1.1.1995 Exclusively national legislation Not applicable Not applicable Not applicable
transposing AIMD (including
necessarily EMC aspects) CE
marking, directive 90/385/EEC
5
-6-
MEDICAL DEVICES OTHER THAN ACTIVE IMPLANTABLE MEDICAL DEVICES AND IN VITRO DIAGNOSTIC
National legislation concerning medical devices National legislation covering E M C
Option A Option B Option C Option D
1.1.1992-31.12.1994 Not applicable Pre-existing national legislation Legislation transposing EMC Directive Preexisting national legislation
CE marking, Dir. 89/336/EEC
1.1.1995-31.12.1995 National legislation transposing Pre-existing national legislation Legislation transposing EMC directive Preexisting national legislation
MDD (including necessarily EMC CE marking, Directive 89/336/EEC
aspects) CE marking , directive
93/42/EEC
1.1.1996-13.6.1998 National legislation transposing Pre-existing national legislation Legislation transposing EMC directive Not applicable
MDD (including necessarily EMC CE marking, Directive 89/336/EEC
aspects) CE marking , directive
93/42/EEC
from 14.6.1998 Exclusively national legislation Not applicable Not applicable Not applicable
transposing MDD (including
necessarily EMC aspects) CE
marking , directive 93/42/EEC
6
-7-
3.2.3. Labelling requirements
In order to establish clearly which directives have been effectively applied, attention shall by given to
Article 4(5b) of Directive 90/385/EEC3 and Article 4(5), second subparagraph of Directive 93/42/EEC
relating to medical devices (MDD). Following these provisions, the manufacturer shall indicate in the
instructions for use which directive(s) has (have) been applied. The particulars of the (or these)
directive(s) as published in the Official Journal in conjunction with the relevant Directive, which has
(have) been applied shall be given in the instructions for use accompanying the device. The relevant
indication should relate to "Directive 90/385/EEC" in the case of application of AIMD, to "Directive
93/42/EEC" in the case of MDD and to "Directive 89/336/EEC" in the case of the EMC directive.
3.3. MEDICAL DEVICES DIRECTIVE - DIRECTIVE 89/686/EEC RELATING TO PERSONAL PROTECTIVE

EQUIPMENT.
Following Article 1(6) of Directive 93/42/EEC, this Directive does not apply to personal protective equipment
covered by Directive 89/686/EEC relating to personal protective equipment 4. In deciding whether a product falls
under Directive 93/42/EEC or under Directive 89/686/EEC, particular account shall be taken of the principle
intended purpose of the product.
As a consequence of this clause a given product is either covered by Directive 89/686/EEC or by Directive
93/42/EEC. As a general rule, the principal intended purpose can be established as being the one of a medical
device if the product is intended to be used in a medical context with the aim to provide protection of health and
safety for the patient, regardless of whether the product aims simultaneously to protect also the user. Where a
product is mainly intended to protect the person using it, irrespectively whether in a medical environment or not,
it falls under Directive 89/686/EEC.
The labelling of the product is crucial for its classification under one or the other Directive.
Examples for medical devices

- surgical gloves, examination gloves
- face masks
- corrective glasses (including those intended at the same time for sun protection)
- surgeons gowns and hats
Examples for personal protective equipment

- protective gloves (for example, for use in a medical laboratory)
- clothing for protection against ionizing radiation
- sun glasses
- eye protection devices for professional use (for example, for welders, regardless of whether or not they contain
corrective glasses adapted to the need of the user)
- gum shields for boxers.
-------------------------------------
3
It should be noted that Article 4 (5b) AIMD as amended by Directive 93/68/EEC (OJ no.
L 220, 30.8.1993) becomes applicable 1 January 1995 (see article 14 of Directive 93/68/EEC).
4
OJ Nr. L 399, 30.12.1989, p. 18 as last amended by Directive 93/95/EEC, OJ No. C 276,
29.10.1993
7
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 1/5
June 1998
MEDICAL DEVICES WITH A MEASURING FUNCTION
--- (())---
Background
Annex VII, paragraph 5 of MDD requires for class I devices with a measuring function
that the manufacturer must also follow one of the procedures referred to in annex IV, V
or VI, for the aspects of manufacture concerned with the conformity of the products
with the metrological requirements .
It is therefore necessary to specify criteria for the existence of a measuring function

in a medical device.
Criteria for devices with a measuring function
The following criteria, if fulfilled together, indicate that a device has a measuring
function:
a) The device is intended by the manufacturer to measure:
- quantitatively a physiological or anatomical parameter, or
- a quantity or a qualifiable characteristic of energy or of substances

delivered to or removed from the human body.
b) The result of the measurement
- is displayed in legal units or other acceptable units within the meaning of

Directive 80/181/ECC1 or
- is compared to at least one point of reference indicated in legal units or

other acceptable units in compliance with the pre-mentioned directive.
c) The intended purpose implies accuracy, claimed explicitly or implicitly, where a

non-compliance with the implied accuracy could result in a significant adverse
effect on the patients health and safety.
Note 1: The expression claimed implicitly covers cases where the user, on the
basis of the designation of the device or of its accompanying documents,
or on the basis of the common use is entitled to expect accuracy where the
accuracy of the measurement has an impact on the diagnosis or therapy of
the patient.
Note 2: Measuring activities during the manufacturing process including those for
calibration purposes are not covered by this recommendation and do not
imply a measuring function of the manufactured device.
Examples for devices with a measuring function
- device for measuring body temperature,
1 OJ n L39/40, 15.2.1980 as amended by Directive 89/617/EEC, OJ n L357/28, 7.12.1989
2
- pacifier which includes a temperature display including those with only a change
of colour where criteria b is met,
- device for indicating that a body temperature is above or below a specified value,
- non-active non-invasive device for measuring blood pressure ,
- non-active device for measuring intra-ocular pressure,
- device for measuring volume or pressure or flow of liquid or gases delivered to or

removed from the human body (included any container with a graduation scale or
with a single point graduation where criteria c is met).
Examples for devices without a measuring function
- patch for indicating trends of body temperature (where criteria b is not met),
- device for the delivery of liquid to the human body (e.g. medicine spoons, cups,
droppers, without graduation or scale or display of measuring unit),
- device for displaying trends of physiological parameters (e.g. urine bags without
graduation or scale, callipers for obesity),
- eye-test chart.
3
EUROPEAN COMMISSION
DG HEALTH AND CONSUMER
Directorate B, Unit B2 Health Technology and Cosmetics
____________________________________________________________________________________________________________
-
Qualification and Classification of stand alone software
____________________________________________________________________________________________________________
MEDDEV 2.1/6
January 2012
GUIDELINES ON THE QUALIFICATION AND CLASSIFICATION OF STAND ALONE SOFTWARE USED IN HEALTHCARE WITHIN THE
REGULATORY FRAMEWORK OF MEDICAL DEVICES
Foreword
The present guidelines are part of a set of guidelines relating to questions of application of the EU legislation on medical devices. They
are legally not binding.
The guidelines have been carefully drafted through a process of consultation of the various interested parties (Competent Authorities,
Commission services, industry and Notified Bodies in the medical device sector) during which intermediate drafts were circulated and
comments were taken up in the document where appropriate.
Therefore this document reflects positions taken in particular by the aforementioned interested parties.
Due to the participation of the aforementioned interested parties, it is anticipated that these guidelines will be followed within the
Member States and, therefore, ensure uniform application of relevant Directive provisions.
Content
Introduction ........................................................................................................................................................................................ 3
1. Definitions and abbreviations ........................................................................................................................................................ 4
2. Qualification .................................................................................................................................................................................. 7
2.1 Introduction to criteria for qualification.............................................................................................................................. 7
2.1.1 Qualification criteria as medical device ............................................................................................................... 7
2.1.2 Qualification criteria as IVD medical device..................................................................................................... 12
3. Classification of stand alone software ......................................................................................................................................... 15
3.1 Software as active therapeutic medical devices ................................................................................................................ 15
3.1.1 Software intended for diagnosis or therapy ....................................................................................................... 16
3.2 IVDD and software in conjunction with in vitro diagnostic devices ................................................................................ 17
4. Modules ..................................................................................................................................................................................... 17
Annex 1: Illustrative examples of qualification and classification for software used in the healthcare environment .................... 19
a) Hospital Information Systems ..................................................................................................................................................... 19
b) Decision Support Software ......................................................................................................................................................... 19
c) Information Systems .................................................................................................................................................................... 20
c.1) Electronic Patient Records Systems ................................................................................................................................ 20
c.1.1) Clinical Information Systems CIS/Patient Data Management Systems PDMS ......................................... 21
c.1.2) Pre-hospital Electrocardiograph (ECG) System ............................................................................................... 21
c.1.3) Radiological Information System (RIS)............................................................................................................ 21
c1.4) Picture Archive Communication System (PACS) ............................................................................................. 22
d) Communication Systems ............................................................................................................................................................ 22
1
d.1) Telemedicine Systems .................................................................................................................................................... 22
d.1.1) Telesurgery ..................................................................................................................................................... 23
d.1.2) Video appointment software ............................................................................................................................ 23
d.1.3) Home care monitoring, wired or mobile .......................................................................................................... 23
e) Web systems for monitoring of data ............................................................................................................................................ 23
f) In vitro diagnostic (IVD) software: LIS & WAM ....................................................................................................................... 24
f.1) Laboratory Information Systems (LIS) and Work Area Managers (WAM) ...24
f.2) Expert system25
f.3) Interpretation of raw data..26
f.4) Home care monitoring, wired or mobile26
2
Introduction
The purpose of this document is to define the criteria for the qualification of stand alone software, when used in healthcare setting, as a
medical device and the application of the classification criteria to such software.
This document only deals with stand alone software and provides some illustrative examples.
Software incorporated in medical devices is outside the scope of this guideline.
Directive 2007/47/EC1 amended the definition of the term "medical device" used in Directives 90/385/EEC2 and 93/42/EEC3.
Recital 6 of Directive 2007/47/EC states that "it is necessary to clarify that software in its own right, when specifically intended by the
manufacturer to be used for one or more of the medical purposes set out in the definition of a medical device, is a medical device.
Stand alone software for general purposes when used in a healthcare setting is not a medical device."
Stand alone software shall be qualified as an in vitro diagnostic (IVD) medical device or as an accessory to an IVD provided that it
satisfies the definition of an IVD or of an accessory to an IVD as set out in Directive 98/79/EC4.
1
OJ L 247, 5.9.2007, p. 21
2
OJ L 189, 20.7.1990, p. 17
3
OJ L 169, 12.7.1993, p. 1
4
OJ L 331, 7.12.1998, p. 1
3
1. Definitions and abbreviations
o Intended purpose:
intended purpose means the use for which the device is intended according to the data supplied by the manufacturer on the
labelling, in the instructions and/or in promotional materials.5
o Accessory:
accessory means an article which whilst not being a device is intended specifically by its manufacturer to be used together
with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device6.
o Placing on the market:

placing on the market means the first making available in return for payment or free of charge of a device other than a device
intended for clinical investigation, with a view to distribution and/or use on the Community market, regardless of whether it is
new or fully refurbished7.
o Putting into service:

putting into service means the stage at which a device has been made available to the final user as being ready for use on the
Community market for the first time for its intended purpose8.
o Medical Device:
5
Article 1(2)g of Directive 93/42/EEC
6
Article 1(2)b of Directive 93/42/EEC
7
Article 1(2)h of Directive 93/42/EEC
8
Article 1(2)i of Directive 93/42/EEC
4
medical device means any instrument, apparatus, appliance, software, material or other article, whether used alone or in
combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic
purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
diagnosis, prevention, monitoring, treatment or alleviation of disease,
diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
investigation, replacement or modification of the anatomy or of a physiological process,
control of conception,
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or
metabolic means, but which may be assisted in its function by such means9;
o In Vitro diagnostic medical device:

in vitro diagnostic medical device means any medical device which is a reagent, reagent product, calibrator, control material,
kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be
used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or
principally for the purpose of providing information:
concerning a physiological or pathological state, or
concerning a congenital abnormality, or
to determine the safety and compatibility with potential recipients, or
to monitor therapeutic measures10.
o Active medical device:

any medical device operation of which depends on a source of electrical energy or any source of power other than that directly
generated by the human body or gravity and which acts by converting this energy. Medical devices intended to transmit energy,
substances or other elements between an active medical device and the patient without any significant change, are not
considered to be active medical devices. Stand alone software is considered to be an active medical device11.
o Active implantable medical device:
9
Article 1(2)a of Directive 93/42/EEC
10
Article 1(2)b of Directive 98/79/EC
5
active implantable medical device means any active medical device which is intended to be totally or partially introduced,
surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain
after the procedure12.
o Active therapeutical device:

Any active medical device, whether used alone or in combination with other medical devices, to support, modify, replace or
restore biological functions or structures with a view to treatment or alleviation of an illness, injury or handicap13.
o Active device for diagnosis:

Any active medical device, whether used alone or in combination with other medical devices, to supply information for
detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities14.
o Stand alone software:

For the purpose of this guideline stand alone software means software which is not incorporated in a medical device at the
time of its placing on the market or its making available.
o Expert function software:
For the purpose of this document, the expert function software means software which is able to analyse existing information
to generate new specific information according to the intended use of the software.
11
Annex IX, section 1.4, of Directive 93/42/EEC
12
Article 1(2)c of Directive 90/385/EEC
13
14
6
2. Qualification
2.1 Introduction to criteria for qualification
Stand alone software must have a medical purpose to be qualified as medical device. It should be noted that only the intended purpose
as described by the manufacturer of the product is relevant for the qualification and classification of any device and not by virtue of the
way it may be called.
Stand alone software that does not meet the definition of a medical device or of an IVD medical device but is intended by the
manufacturer to be an accessory to a medical device, or an IVD medical device, falls respectively under the scope of Directive
93/42/EEC or Directive 98/79/EC.
It is to be noted that to be qualified as an IVD medical device, stand alone software must first fulfil the definition of a medical device.
Where a given product does not fall under the definition of medical device, or is excluded by the scope of the Directives, other
Community and/or national legislation may be applicable.
2.1.1 Qualification criteria as medical device
Software can be used for a large variety of medical purposes15. In that respect the arguments do not differ from those used for other
medical devices.
Stand alone software can directly control an apparatus (e.g. radiotherapy treatment), can provide immediate decision triggering
information (e.g. blood glucose meters), or can provide support for healthcare professionals (e.g. ECG interpretation).
Not all stand alone software used within healthcare can be qualified as a medical device.
Stand alone software may run on different operating systems or in virtual environments.
These operating systems or virtual environments do not impact the qualification criteria.
Stand alone software might also be an accessory of a medical device.
The risk related to a malfunction of the stand alone software used within healthcare is in itself not a criterion for its qualification or not
as a medical device.
15
MEDDEV 2.1/1: Definitions of "medical devices", "accessory" and "manufacturer"
7
It is, therefore, necessary to clarify some criteria for the qualification of stand alone software as medical devices.
The decision diagram (Figure 1) gives some guidance regarding the necessary steps to qualify stand alone software as medical device.
8
of software as medical device. START
ification of software as medical device.
, - - - - - - - - - - - - - -No-- - - - - - - - - - - - - - - - - - - - - - - - - c ~
The software does not

contain instructions or
subroutines in a
particular
programming
language
Yes
No Yes
E .g. software for
statistical
evaluation of
N
clinical studies or
epidemiological
studies or registers
Yes
Not a medical
device
E.g. The software

performs an action on
data for financial,
reimbursement, staff Part of a medical
scheduling, resource device
management or other
non-medical purposes
Such as software Yes

driving, monitoring
performance of. or
influencing
performance or the
use of a medical
device
Not covered by the medical device Covered by the medical device

directives directives
Figure 1: A decision diagram to assist qualification of software as medical device.
9
Decision step 1: if the stand alone software is a computer program16, then it may be a medical device. If the software is not a computer
program, then it is a digital document and therefore not a medical device.
Examples of computer programs are software applications, macros, scripts, dynamically linked libraries, batch files, style sheets and
any document containing active formatting or filtering instructions. Examples of digital documents are image files, DICOM files,
digital ECG recordings, numerical results from tests and electronic health records (EHR).
Note: While the EHR is usually not a computer program, the EHR system, i.e. the software writing, retrieving, representing, etc.
the information in the EHR, is a computer program. This is similar as for DICOM files vs. a PACS.
Decision step 2: if the software is incorporated into a medical device rather than stand alone software, it must be considered as part of
that medical device in the regulatory process of that device. If it is stand alone software17, proceed to decision step 3.
Decision step 3: if the software does not perform an action on data, or performs an action limited to storage, archival,
communication18, simple search or lossless compression (i.e. using a compression procedure that allows the exact reconstruction of
the original data) it is not a medical device.
Altering the representation of data for embellishment purposes does not make the software a medical device. In other cases, including
where the software alters the representation of data for a medical purpose, it could be a medical device.
Simple search refers to the retrieval of records by matching record metadata against record search criteria, e.g. library functions.
Simple search does not include software which provides interpretative search results, e.g. to identify medical findings in health records
or on medical images.
16
A computer program is defined as syntactic unit that conforms to the rules of a particular programming language and that is composed of declarations and
statements or instructions needed to solve a certain function, task, or problem. Source: ISO/IEC 2382-1:1993 (01.05.01) Information technology -- Vocabulary --
Part 1: Fundamental terms.
17
See chapter 2 - Definitions and Abbreviations for a definition of stand alone software.
18
Communication: The flow of information from one point, known as the source, to another, the receiver; Source: IEEE 610.10-1994.
10
Software which is intended to create or modify medical information might be qualified as a medical device. If such alterations are
made to facilitate the perceptual and/or interpretative tasks performed by the healthcare professionals when reviewing medical
information, (e.g. when searching the image for findings that support a clinical hypothesis as to the diagnosis or evolution of therapy)
the software could be a medical device.
Note: the display of images usually involves alterations to the representation because techniques are used such as contrast
stretching, edge enhancement, gray scale manipulation, smoothing, sharpening, zooming and re-sizing. Alterations may include
reconstruction, lossy compression, filtering, pattern recognition, modelling, interpolation, transformation, classification (e.g.
scoring of tumors against specific criteria), segmentation, registration (e.g. mapping a data set to a model or atlas or to another data
set, e.g. registering an MRI image on a CT image), calculations, quantification, qualification (e.g. comparison of data against
references), rendering, visualisation, interpretation, etc..
Decision step 4: an example of software for the benefit of individual patients is software intended to be used for the evaluation of
patient data to support or influence the medical care provided to that patient. Examples of software which are not considered as being
for the benefit of individual patients are those which aggregate population data, provide generic diagnostic or treatment pathways,
scientific literature, medical atlases, models and templates as well as software for epidemiologic studies or registers.
Decision step 5: if the manufacturer specifically intends the software to be used for any of the purposes listed in Article 1(2)a of
Directive 93/42/EEC, then the software shall be qualified as a medical device.
However, if only a non-medical purpose is intended by the manufacturer, such as invoicing or staff planning, it is not a medical device.
Note: A task such as e-mailing, web or voice messaging, data parsing, word processing, and back-up is by itself not considered as
being a medical purpose, according to Directive 93/42/EEC.
Decision step 6: if the software is an accessory to a medical device, it is not a medical device, but it falls under Directive 93/42/EEC.
The legal definition of 'putting into service' requires that a device is made available to the final user/operator as being ready for use on
the Community market. Software made available to the user over the internet (directly or via download) or via in vitro diagnostic
commercial services, which is qualified as a medical device, is subject to the medical devices directives.
11
2.1.2 Qualification criteria as IVD medical device
Stand alone software fulfilling the definition of medical device and intended to be used for the purpose of providing information
derived from in vitro examination of a specimen derived from the human body falls under Directive 98/79/EC.
Provided that stand alone software is intended specifically by its manufacturer to be used together with an IVD medical device to
enable that device to be used in accordance with its intended purpose, this stand alone falls under the scope of the IVD Directive and
shall be treated as an IVD device in its own right.
Example: analysis and interpretation of the optical density delivered by an ELISA reader, line or spot pattern of a blot.
12
Figure 2: Decision diagram to assist qualification of stand alone software as IVD device.
13
Decision step 1: please, start by making reference to figure 1.
Decision step 2: Stand alone software with expert function:

This stand alone software might provide information on e.g. differential diagnosis, prediction of the risks of developing a disease,
prediction of the percentage of efficiency or failure (e.g. of a treatment), identifying species of bacteria.
It may qualify differently based on the fact that the existing information is obtained from either IVD medical devices, other medical
devices or both.
Decision step 3:
if the information provided by the software is based on data obtained from IVD medical devices only, the software is an IVD medical
device or an accessory of an IVD medical device.
If data are obtained from both IVD medical devices and from medical devices are analysed together for the purpose of providing
information according to the definition of an IVD medical device, this software is an IVD medical device (e.g. evaluation of the risk of
Trisomy 21).
As described in Annex I B 3.1, for stand alone software that is intended for use in combination with other devices or equipment, the
whole combination must be safe and must not impair the specified performances of the devices. As a concretization of these general
requirements of the IVDD; the clinical evidence of this combined intended use of medical devices shall be performed for each of the
medical devices from which the data is obtained.
Decision step 4: if the information provided by the software is based on data obtained from medical devices only, the software would
be a medical device.
Note 1: Stand alone software that only collects results obtained from one or several IVD devices (directly and/or manually), and
transmits without modification this information to a centralised database (e.g. Laboratory Information Management System, LIMS)
or to healthcare providers is not an IVD medical device.
14
Note 2: Stand alone software (e.g. LIMS) managing the feed-back to an IVD (e.g. retesting of samples) based on collected IVD
results is not an IVD medical device as per decision step 5 of figure 1.
Note 3: Software intended to modify the representation of available IVD results is not considered as an IVD medical device as per
decision step 5 of Figure 1, e.g. basic operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function
of time, and/or a comparison of the result to the limits of acceptance set by the user.
Note 4: Stand alone software intended for archiving patient results or for transferring results from the home environment to the
healthcare provider is not an IVD device.
3. Classification of stand alone software
Stand alone software that meets the definition of a medical device shall be considered as an active medical device.19 This means that
rules 9, 10, 11 and 12 of Annex IX to Directive 93/42/EEC may apply.
Clause 2.3 of the implementing rules in Annex IX states that software 'which drives a medical device or influences the use of a device,
falls automatically into the same class20, as the device it drives.
3.1 Software as active therapeutic medical devices

According to rule 9 of Annex IX to Directive 93/42/EEC, all active therapeutic devices intended to administer or exchange energy are
in Class IIa unless their characteristics are such that they may administer or exchange energy to or from the human body in a
potentially hazardous way, taking account of the nature, the density and site of application of the energy, in which case they are in
Class IIb.
19
20
15
All active devices intended to control or monitor the performance of active therapeutic devices in Class IIb, or intended directly to
influence the performance of such devices are in Class IIb according to implementing rule 2.3.
Example: radiotherapy planning system used to calculate the dose of ionizing radiation to be administered to the patient, insulin
dosage planning stand alone software.
3.1.1 Software intended for diagnosis or therapy
According to rule 10 of Annex IX to Directive 93/42/EEC, active devices intended for diagnosis are in Class IIa:
- if they are intended to image in vivo distribution of radiopharmaceuticals.
Example: Clinical application of registration of PET datasets on CT datasets for follow-up tumour treatment.
- if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for
monitoring of vital physiological parameters, where the nature of variations is such that it could result in immediate danger to the
patient, for instance variations in cardiac performance, respiration, activity of CNS in which case they are in Class IIb.
Examples: - Software for the presentation of the heart rate or other physiological parameters during routine checkups (Class IIa);
- Software for the presentation of the heart rate or other physiological parameters for intensive care monitoring (Class IIb).
Active devices intended to emit ionizing radiation and intended for diagnostic and therapeutic interventional radiology including
devices which control or monitor such devices, or which directly influence their performance, are in Class IIb.
Rule 11 of Annex IX to Directive 93/42/EEC states that all active devices intended to administer and/or remove medicines, body
liquids or other substances to or from the body are in Class IIa, unless this is done in a manner:
16
- that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the
mode of application in which case they are in Class IIb.
Stand alone software which drives such medical device or influences the use of such device falls automatically into the same class as
the device it drives (implementing rule 2.3).
Rule 12 of Annex IX to Directive 93/42/EEC states that all other active devices are in Class I. Class I stand alone software can also
come with a measuring function.
Example: orthopaedic planning software to measure interpedicular distance or sagittal diameter of the spinal canal.
3.2 IVDD and software in conjunction with in-vitro diagnostic devices
Stand alone software qualified as in vitro diagnostic medical devices should be regulated according to Directive 98/79/EC.
When intended for evaluating the risk of trisomy 21, such software are specifically mentioned in Annex II List B of Directive
98/79/EC and shall therefore follow the conformity assessment procedure described in Article 9 of this Directive.
4. Modules
Some stand alone software may break down into a significant number of applications for the user where each of these applications is
correlated with a module. Some of these modules have a medical purpose, some not.
Such software may be intended to cover many needs, e.g.:
- Collect and maintain administrative patient details;
- Keep on file the medical history of the patient;
17
- Invoicing and other accounting functions;
- Provide a link to the social security system for reimbursement;
- Provide a link to drug prescription systems (with possible link to drug dispensing outlets);
- Provide expert system assistance for medical decision making (e.g. radiotherapy dose planner).
This raises the issue as to whether the whole product can be CE marked when not all applications have a medical purpose.
Computer programmes used in healthcare mostly have applications which consist of both medical device and non-medical device
modules.
The modules which are subject to the medical device Directives (Figures 1 and 2) must comply with the requirements of the medical
device Directives and must carry the CE marking. The non-medical device modules are not subject to the requirements for medical
devices.
It is the obligation of the manufacturer to identify the boundaries and the interfaces of the different modules.
The boundaries of the modules which are subject to the medical device Directives should be clearly identified by the manufacturer and
based on the intended use.
If the modules which are subject to the medical device Directives are intended for use in combination with other modules of the whole
software structure, other devices or equipment, the whole combination, including the connection system, must be safe and must not
impair the specified performances of the modules which are subject to the medical device Directives21.
21
i.e. essential requirements 3.1 of Directive 98/79/EC and essential requirements 9.1 of Directive 93/42/EEC
18
Annex 1: Illustrative examples of qualification for software used in the healthcare
environment
The sector of software pursuing a medical purpose is rapidly evolving.
The list of examples provided below is not exhaustive.
The examples have been drafted in the light of today's state of the art, in order to give the reader a better understanding of the
application of the principles set out in the guideline.
In the light of the technological progress, further examples will be regularly added into the Manual on borderline and classification in
the Community regulatory framework for medical devices22.
a) Hospital Information Systems
Hospital Information Systems mean, in this context, systems that support the process of patient management. Typically they are
intended for patient admission, for scheduling patient appointments, for insurance and billing purposes.
These Hospital Information Systems are not qualified as medical devices. However they may be used with additional modules, as
described hereafter.
These modules might be qualified in their own right as medical devices.
b) Decision Support Software
22
http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf
19
In general, they are computer based tools which combine medical knowledge databases and algorithms with patient specific data. They
are intended to provide healthcare professionals and/or users with recommendations for diagnosis, prognosis, monitoring and treatment
of individual patients.
Based on steps 3, 4, and 5 of Figure 1, they are qualified as medical devices.
- Radiotherapy treatment planning systems23 are intended to calculate the dosage of ionizing irradiation to be applied to a specific
patient. They are considered to control, monitor or directly influence the source of ionizing radiation and are qualified as medical
devices.
- Drug (e.g.: Chemotherapy) planning systems are intended to calculate the drug dosage to be administered to a specific patient and
therefore are qualified as medical devices.
- Computer Aided Detection systems are intended to provide information that may suggest or exclude medical conditions and,
therefore, qualified as medical devices. For example, such systems would be able to automatically read x-ray images or interpret
ECGs.
c) Information Systems
Information systems that are intended only to store, archive and transfer data are not qualified as medical devices in themselves.
However they may be used with additional modules. These modules might be qualified in their own right as medical devices.
c.1) Electronic Patient Record Systems
Electronic patient record systems are intended to store and transfer electronic patient records. They archive all kinds of documents and
data related to a specific patient. The electronic patient records themselves are not computer programs, therefore, they should not be
23
See EN 62083 Requirements for the safety of radiotherapy treatment planning systems
20
qualified as a medical device i.e. an electronic patient record that simply replaces a patients paper file does not meet the definition of a
medical device. The modules used with electronic patient record system modules that might be qualified in their own right as medical
devices are for example:
- an image viewer with functionality for diagnosis based on digital images;
- a medication module.
c.1.1) Clinical Information Systems CIS / Patient Data Management Systems - PDMS
A CIS/PDMS is a software based system primarily intended for e.g. intensive care units to store and transfer patient information
generated in association with the patients intensive care treatment.
Usually the system contains information such as patient identification, vital intensive care parameters and other documented clinical
observations.
These CIS/PDMS are not qualified as medical devices.
Modules that are intended to provide additional information that contributes to diagnosis, therapy and follow-up (e.g. generate alarms)
are qualified as medical devices.
c.1.2) Pre-hospital Electrocardiograph (ECG) System
A system for managing pre-hospital ECG is a software based system intended for ambulance services to store and transfer information
from patients, which are connected to an ECG monitor, to a doctor at remote location. Usually the system contains information about
patient identification, vital parameters and other documented clinical observations. These Pre-hospital Electrocardiograph (ECG)
Systems are not qualified as medical devices.
Modules that provide patient's treatment information to the paramedics in the ambulance to start the patients treatment while the
patient is being transported are qualified as Medical Devices.
c.1.3) Radiological Information System (RIS)
21
A RIS is a software based database used in radiology departments to store and transfer radiological images and patient information.
The system normally includes functions for patient identification, scheduling, examination results and imaging identification details.
These Radiological Information Systems are not qualified as medical devices.
However, if such a system includes additional modules they might qualify as medical devices according to step 3 of of Figure 1.
c.1.4) Picture Archive Communication System (PACS)
The Manual on Borderline and Classification in the Community Regulatory Framework for Medical Devices24, already addresses the
issue.
d) Communication Systems
The healthcare sector uses communication systems (e.g. email systems, mobile telecommunication systems, video communication
systems, paging etc.) to transfer electronic information. Different types of messages are being sent such as prescriptions, referrals,
images, patient records, etc.
Most of the communication systems handle other types of messages other than medical information. This communication system is
intended for general purposes, and is used for transferring both medical and non-medical information.
Communication systems are normally based on software for general purposes, and do not fall within the definition of a medical device.
Communication system modules might be used with other modules that might be qualified in their own right as medical devices.
Example: software generating alarms based on the monitoring and analysis of patient specific physiological parameters.
d.1) Telemedicine Systems
24
22
Telemedicine Systems are intended to allow monitoring and/or delivery of healthcare to patients at locations remote from where the
healthcare professional is located.
d.1.1) Telesurgery
Telesurgery is intended to conduct a surgical procedure from a remote location. Virtual reality technology may be used to support a
remote surgeon to control a surgical robot performing the surgical procedure.
Telesurgery systems should be qualified as medical devices according to steps 3, 4, and 5 of Figure 1.
Remote control software used in combination with telesurgery robots is qualified as a medical device. Communication modules
themselves are not medical devices.
Other modules that are intended to influence the surgery procedure are qualified as medical devices.
d.1.2) Video appointment software
Video appointment software is intended to perform remote consultations between clinics and patients. It does not fall under the
Medical Devices Directives.
d.1.3) Home care monitoring, wired or mobile
The telecommunication system (mobile, wireless, wire, etc) is not as such a medical device.
e) Web systems for monitoring of data

A web system for the monitoring of clinical data typically interacts with a medical device (e.g. implanted devices or homecare
devices), and uses a transmitter to send the information over the internet, a landline telephone or a mobile network.
The information is collected and stored on a web server usually run by an external party who is generally the manufacturer of the
system. The information can be reached by authorized health professionals or the patient through an internet connection.
23
- Monitoring of performance of medical devices:
Modules that are intended to monitor the medical performance of medical devices fall under the Medical Devices Directives.
This includes the clinical performance and failures that could affect medical performance of the device. One example of such product
is a web system for monitoring of active implants such as pacemakers or Intra cardiac defibrillators (ICDs).
- Monitoring of non medical performance of medical devices:
Modules that are intended to monitor non medical performance of medical devices do not fall under the scope of Medical Devices
Directives.
Example: software for the monitoring of medical devices in hospital systems for the purpose of maintenance and repair.
Software modules on server(s) might be qualified in their own right as medical devices depending on their intended purpose.
f) In vitro diagnostic (IVD) software: LIS & WAM
f.1) Laboratory Information Systems (LIS) and Work Area Managers (WAM)
Laboratory Information Systems (LIS) and Work Area Managers (WAM) mean, in this context, systems that support the process from
patient sample to patient result. Typically they have pre-analytical functions for ordering, sorting and distribution of test samples.
The main task is the management and validation of incoming information obtained from IVD analysers connected to the system, such
as calibration, quality control, product expiry and feedback (e.g. retesting of samples needed) through interconnections with various
analytical instruments (technical and clinical validation).
Finally the post analytical process takes care of communication of laboratory results, statistics and optional reporting to external
databases.
The software normally supports the following functions:
Ordering of laboratory tests, samples with labels and sorting;
Technical and clinical validation, connection to analytic instruments;
24
Laboratory results and reports on paper, fax or electronic records that can be directly returned to e.g. the ordering clinic's
patient record;
Analytical instruments can be interfaced with Hospital Information Systems (HIS), Electronic Patient Record Systems, Infectious
control databases etc.
Note: Software intended to modify the representation of available IVD results is not considered an IVD medical device, e.g. basic
operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function of time, and/or a comparison of the
result to the limits of acceptance set by the user.
The results are available, readable and understandable without the intervention of the software.
Laboratory Information Systems (LIS) and Work Area Managers (WAM) are not qualified as medical devices in themselves.
f.2) Expert system
Where software is intended to capture and analyze together several results obtained for one patient by one or more IVD devices by
means of in vitro examination of body samples (possibly combined with information from medical devices) to provide information
falling within the definition of an IVD medical device, e.g. differential diagnosis, this software is considered as an IVD in itself.
Examples: - software that integrates genotype of multiple genes to predict risk of developing a disease or medical condition;
- software that uses an algorithm to characterize viral resistances to various drugs, based on a nucleotide sequence
generated by genotyping assays. This software serves to generate new information (virus resistance profile) from
available information on the genotype of the virus;
- software intended to be used in microbiology for the identification of clinical isolates and/or the detection
antimicrobial resistances.
The information provided by the software is based on data obtained with IVD medical devices only or possibly combined with
25
information from medical devices.
The software is an IVD medical device or an accessory of an IVD medical device.
f.3) Interpretation of raw data
In the case where software is necessary to render raw data, obtained from an IVD by means of in vitro examination of body samples,
readable for the user, this software is to be considered as an accessory to an IVD when it is specifically intended to be used together
with this IVD to enable it to be used in accordance with its intended purpose.
Example: software intended for the analysis and interpretation of ELISA reader optical density results, line patterns or spot patterns
of a blot.
f.4) Home care monitoring, wired or mobile
Stand alone software intended for archiving patient results or for transferring results from the home environment to the healthcare
provider is not an IVD device. The results are available, readable and understandable by the user without the intervention of the
software.
26
Ref. Ares(2016)3473012 - 15/07/2016
EUROPEAN COMMISSION
DG Internal Market, Industry, Entrepreneurship and SMEs
Directorate Consumer, Environmental and Health Technologies
Unit Health technology and Cosmetics
____________________________________________________________________________________________________________
-
Qualification and Classification of stand alone software
____________________________________________________________________________________________________________
MEDDEV 2.1/6
July 2016
GUIDELINES ON THE QUALIFICATION AND CLASSIFICATION OF STAND ALONE SOFTWARE USED IN HEALTHCARE WITHIN THE
REGULATORY FRAMEWORK OF MEDICAL DEVICES
Foreword
The present guidelines are part of a set of guidelines relating to questions of application of the EU legislation on medical devices. They
are legally not binding.
The guidelines have been carefully drafted through a process of consultation of the various interested parties (Competent Authorities,
Commission services, industry and Notified Bodies in the medical device sector) during which intermediate drafts were circulated and
comments were taken up in the document where appropriate.
Therefore this document reflects positions taken in particular by the aforementioned interested parties.
Due to the participation of the aforementioned interested parties, it is anticipated that these guidelines will be followed within the
Member States and, therefore, ensure uniform application of relevant Directive provisions.
Content
Introduction ........................................................................................................................................................................................ 3
1. Definitions and abbreviations ........................................................................................................................................................ 4
2. Qualification .................................................................................................................................................................................. 7
2.1 Introduction to criteria for qualification.............................................................................................................................. 7
2.1.1 Qualification criteria as medical device ............................................................................................................... 7
2.1.2 Qualification criteria as IVD medical device..................................................................................................... 12
3. Classification of stand alone software ......................................................................................................................................... 15
3.1 Software as active therapeutic medical devices ................................................................................................................ 15
3.1.1 Software intended for diagnosis or therapy ....................................................................................................... 16
3.2 IVDD and software in conjunction with in vitro diagnostic devices ................................................................................ 17
4. Modules ..................................................................................................................................................................................... 17
Annex 1: Illustrative examples of qualification and classification for software used in the healthcare environment .................... 19
a) Hospital Information Systems ..................................................................................................................................................... 19
b) Decision Support Software ......................................................................................................................................................... 19
c) Information Systems .................................................................................................................................................................... 20
c.1) Electronic Patient Records Systems ................................................................................................................................ 20
c.1.1) Clinical Information Systems CIS/Patient Data Management Systems PDMS ......................................... 21
c.1.2) Pre-hospital Electrocardiograph (ECG) System ............................................................................................... 21
c.1.3) Radiological Information System (RIS)............................................................................................................ 21
c1.4) Picture Archive Communication System (PACS) ............................................................................................. 22
d) Communication Systems ............................................................................................................................................................ 22
1
d.1) Telemedicine Systems .................................................................................................................................................... 22
d.1.1) Telesurgery ..................................................................................................................................................... 23
d.1.2) Video appointment software ............................................................................................................................ 23
d.1.3) Home care monitoring, wired or mobile .......................................................................................................... 23
e) Web systems for monitoring of data ............................................................................................................................................ 23
f) In vitro diagnostic (IVD) software: LIS & WAM ....................................................................................................................... 24
f.1) Laboratory Information Systems (LIS) and Work Area Managers (WAM) ...24
f.2) Expert system25
f.3) Interpretation of raw data..26
f.4) Home care monitoring, wired or mobile26
2
Introduction
The purpose of this document is to define the criteria for the qualification of stand alone software, when used in healthcare setting, as a
medical device and the application of the classification criteria to such software.
This document only deals with stand alone software and provides some illustrative examples.
Software incorporated in medical devices is outside the scope of this guideline.
The criteria specified in this document apply also to mobile applications.
Directive 2007/47/EC1 amended the definition of the term "medical device" used in Directives 90/385/EEC2 and 93/42/EEC3.
Recital 6 of Directive 2007/47/EC states that "it is necessary to clarify that software in its own right, when specifically intended by the
manufacturer to be used for one or more of the medical purposes set out in the definition of a medical device, is a medical device.
Stand alone software for general purposes when used in a healthcare setting is not a medical device."
Stand alone software shall be qualified as an in vitro diagnostic (IVD) medical device or as an accessory to an IVD provided that it
satisfies the definition of an IVD or of an accessory to an IVD as set out in Directive 98/79/EC4.
1
OJ L 247, 5.9.2007, p. 21
2
OJ L 189, 20.7.1990, p. 17
3
OJ L 169, 12.7.1993, p. 1
3
1. Definitions and abbreviations
o Intended purpose:
intended purpose means the use for which the device is intended according to the data supplied by the manufacturer on the
labelling, in the instructions and/or in promotional materials.5
o Accessory:
accessory means an article which whilst not being a device is intended specifically by its manufacturer to be used together
with a device to enable it to be used in accordance with the use of the device intended by the manufacturer of the device6.
o Placing on the market:

placing on the market means the first making available in return for payment or free of charge of a device other than a device
intended for clinical investigation, with a view to distribution and/or use on the Community market, regardless of whether it is
new or fully refurbished7.
o Putting into service:

putting into service means the stage at which a device has been made available to the final user as being ready for use on the
Community market for the first time for its intended purpose8.
o Medical Device:
4
OJ L 331, 7.12.1998, p. 1
5
Article 1(2)g of Directive 93/42/EEC
6
Article 1(2)b of Directive 93/42/EEC
7
Article 1(2)h of Directive 93/42/EEC
8
Article 1(2)i of Directive 93/42/EEC
4
medical device means any instrument, apparatus, appliance, software, material or other article, whether used alone or in
combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic
purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
diagnosis, prevention, monitoring, treatment or alleviation of disease,
diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
investigation, replacement or modification of the anatomy or of a physiological process,
control of conception,
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or
metabolic means, but which may be assisted in its function by such means9;
o In Vitro diagnostic medical device:

in vitro diagnostic medical device means any medical device which is a reagent, reagent product, calibrator, control material,
kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be
used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or
principally for the purpose of providing information:
to determine the safety and compatibility with potential recipients, or
to monitor therapeutic measures10.
o Active medical device:

any medical device operation of which depends on a source of electrical energy or any source of power other than that directly
generated by the human body or gravity and which acts by converting this energy. Medical devices intended to transmit energy,
substances or other elements between an active medical device and the patient without any significant change, are not
considered to be active medical devices. Stand alone software is considered to be an active medical device11.
o Active implantable medical device:
9
Article 1(2)a of Directive 93/42/EEC
10
Article 1(2)b of Directive 98/79/EC
5
active implantable medical device means any active medical device which is intended to be totally or partially introduced,
surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain
after the procedure12.
o Active therapeutical device:

Any active medical device, whether used alone or in combination with other medical devices, to support, modify, replace or
restore biological functions or structures with a view to treatment or alleviation of an illness, injury or handicap13.
o Active device for diagnosis:

Any active medical device, whether used alone or in combination with other medical devices, to supply information for
detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities14.
o Input data:
Any data provided to software in order to obtain output data after computation of this data can be considered as an input data.
Input data examples (non-exhaustive):
Data given through the use of a human data-input device such as a keyboard, mouse, stylus, or touch screen;
Data given through speech recognition;
Digital document: formatted for general purpose such as Word file or pdf file or jpeg image, formatted for medical
purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document. Note that digital
documents have to be differentiated from software able to read such documents;
Data received from / transmitted by devices.
11
12
Article 1(2)c of Directive 90/385/EEC
13
14
6
o Output data:
Any data produced by a software can be considered as an output data.
Output data examples (non-exhaustive):
Screen display data (such as layout with number, characters, picture, graphics etc.);
Print data (such as layout with number, characters, picture, graphics etc.);
Audio data;
Digital document (formatted for a general purpose such as Word file or pdf file or jpeg image, or formatted for medical
purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document).
Haptic buzzing as an alternative to audio sound
o Software:
For the purpose of this guideline, software is defined as a set of instructions that processes input data and creates output data.
o Stand alone software:

For the purpose of this guideline stand alone software means software which is not incorporated in a medical device at the
time of its placing on the market or its making available.
o Expert function software:
For the purpose of this document, the expert function software means software which is able to analyse existing information
to generate new specific information according to the intended use of the software.
o Software as a medical device:
The term Software as a Medical Device (SaMD) is defined as software intended to be used for one or more medical purposes
that perform these purposes without being part of a hardware medical device.
Definition of the IMDRF/SaMD WG/N10FINAL:2013 : Software as a Medical Device (SaMD): Key Definitions.
7
2. Qualification
2.1 Introduction to criteria for qualification
The purpose of this part of the guidance is to clarify the distinction between different types of medical software, namely medical
software that is:
- part of MD or IVD
- accessories
- standalone Software
- not a Medical Device
Stand alone software must have a medical purpose to be qualified as medical device. It should be noted that only the intended purpose
as described by the manufacturer of the product is relevant for the qualification and classification of any device and not by virtue of the
way it may be called.
Stand alone software that does not meet the definition of a medical device or of an IVD medical device but is intended by the
manufacturer to be an accessory to a medical device, or an IVD medical device, falls respectively under the scope of Directive
93/42/EEC or Directive 98/79/EC.
It is to be noted that to be qualified as an IVD medical device, stand alone software must first fulfil the definition of a medical device.
Where a given product does not fall under the definition of medical device, or is excluded by the scope of the Directives, other
Community and/or national legislation may be applicable.
2.1.1 Qualification criteria as medical device
Software can be used for a large variety of medical purposes15. In that respect the arguments do not differ from those used for other
medical devices.
Stand alone software can directly control an apparatus (e.g. radiotherapy treatment), can provide immediate decision triggering
information (e.g. blood glucose meters), or can provide support for healthcare professionals (e.g. ECG interpretation).
Not all stand alone software used within healthcare can be qualified as a medical device.
15
MEDDEV 2.1/1: Definitions of "medical devices", "accessory" and "manufacturer"
8
Stand alone software may run on different operating systems or in virtual environments.
These operating systems or virtual environments do not impact the qualification criteria.
Stand alone software might also be an accessory of a medical device.
The risk related to a malfunction of the stand alone software used within healthcare is in itself not a criterion for its qualification or not
as a medical device.
It is, therefore, necessary to clarify some criteria for the qualification of stand alone software as medical devices.
The decision diagram (Figure 1) gives some guidance regarding the necessary steps to qualify stand alone software as medical device.
9
Figure 1: A decision diagram to assist qualification of software as medical device.
9
Legend of the flowchart:
MD: Medical Device
*Medical Device Directives means the 3 following directives:
o DIRECTIVE 93/42/EEC of 14 June 1993 concerning medical devices

o DIRECTIVE 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices
o DIRECTIVE 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active
implantable medical devices
10
Decision step 1: If the product is a software according to the definition of this document, then it may be a medical device; if the
product is not a software according to the definition of this document, then it is not covered by the medical device directives..
Decision step 2: if the software is incorporated into a medical device rather than stand alone software, it must be considered as part of
that medical device in the regulatory process of that device. If it is stand alone software16, proceed to decision step 3.
Decision step 3: if the software does not perform an action on data, or performs an action limited to storage, archival,
communication17, simple search or lossless compression (i.e. using a compression procedure that allows the exact reconstruction of
the original data) it is not a medical device.
Altering the representation of data for embellishment purposes does not make the software a medical device. In other cases, including
where the software alters the representation of data for a medical purpose, it could be a medical device.
Simple search refers to the retrieval of records by matching record metadata against record search criteria, e.g. library functions.
Simple search does not include software which provides interpretative search results, e.g. to identify medical findings in health records
or on medical images.
Software which is intended to create or modify medical information might be qualified as a medical device. If such alterations are
made to facilitate the perceptual and/or interpretative tasks performed by the healthcare professionals when reviewing medical
information, (e.g. when searching the image for findings that support a clinical hypothesis as to the diagnosis or evolution of therapy)
the software could be a medical device.
Note: the display of images usually involves alterations to the representation because techniques are used such as contrast
stretching, edge enhancement, gray scale manipulation, smoothing, sharpening, zooming and re-sizing. Alterations may include
reconstruction, lossy compression, filtering, pattern recognition, modelling, interpolation, transformation, classification (e.g.
scoring of tumors against specific criteria), segmentation, registration (e.g. mapping a data set to a model or atlas or to another data
16
See chapter 2 - Definitions and Abbreviations for a definition of stand alone software.
17
Communication: The flow of information from one point, known as the source, to another, the receiver; Source: IEEE 610.10-1994.
11
set, e.g. registering an MRI image on a CT image), calculations, quantification, qualification (e.g. comparison of data against
references), rendering, visualisation, interpretation, etc..
Decision step 4: an example of software for the benefit of individual patients is software intended to be used for the evaluation of
patient data to support or influence the medical care provided to that patient. Examples of software which are not considered as being
for the benefit of individual patients are those which aggregate population data, provide generic diagnostic or treatment pathways,
scientific literature, medical atlases, models and templates as well as software for epidemiologic studies or registers.
Decision step 5: if the manufacturer specifically intends the software to be used for any of the purposes listed in Article 1(2)a of
Directive 93/42/EEC, then the software shall be qualified as a medical device.
However, if only a non-medical purpose is intended by the manufacturer, such as invoicing or staff planning, it is not a medical device.
Note: A task such as e-mailing, web or voice messaging, data parsing, word processing, and back-up is by itself not considered as
being a medical purpose, according to Directive 93/42/EEC.
Decision step 6: if the software is an accessory to a medical device, it is not a medical device, but it falls under Directive 93/42/EEC.
The legal definition of 'putting into service' requires that a device is made available to the final user/operator as being ready for use on
the Community market. Software made available to the user over the internet (directly or via download) or via in vitro diagnostic
commercial services, which is qualified as a medical device, is subject to the medical devices directives.
2.1.2 Qualification criteria as IVD medical device
Stand alone software fulfilling the definition of medical device and intended to be used for the purpose of providing information
derived from in vitro examination of a specimen derived from the human body falls under Directive 98/79/EC.
Provided that stand alone software is intended specifically by its manufacturer to be used together with an IVD medical device to
enable that device to be used in accordance with its intended purpose, this stand alone falls under the scope of the IVD Directive and
shall be treated as an IVD device in its own right.
12
Example: analysis and interpretation of the optical density delivered by an ELISA reader, line or spot pattern of a blot.
13
Figure 2: Decision diagram to assist qualification of stand alone software as IVD device.
13
Decision step 1: please, start by making reference to figure 1.
Decision step 2: Stand alone software with expert function:

This stand alone software might provide information on e.g. differential diagnosis, prediction of the risks of developing a disease,
prediction of the percentage of efficiency or failure (e.g. of a treatment), identifying species of bacteria.
It may qualify differently based on the fact that the existing information is obtained from either IVD medical devices, other medical
devices or both.
Decision step 3:
if the information provided by the software is based on data obtained from IVD medical devices only, the software is an IVD medical
device or an accessory of an IVD medical device.
If data are obtained from both IVD medical devices and from medical devices are analysed together for the purpose of providing
information according to the definition of an IVD medical device, this software is an IVD medical device (e.g. evaluation of the risk of
Trisomy 21).
As described in Annex I B 3.1, for stand alone software that is intended for use in combination with other devices or equipment, the
whole combination must be safe and must not impair the specified performances of the devices. As a concretization of these general
requirements of the IVDD; the clinical evidence of this combined intended use of medical devices shall be performed for each of the
medical devices from which the data is obtained.
Decision step 4: if the information provided by the software is based on data obtained from medical devices only, the software would
be a medical device.
Note 1: Stand alone software that only collects results obtained from one or several IVD devices (directly and/or manually), and
transmits without modification this information to a centralised database (e.g. Laboratory Information Management System, LIMS)
or to healthcare providers is not an IVD medical device.
14
Note 2: Stand alone software (e.g. LIMS) managing the feed-back to an IVD (e.g. retesting of samples) based on collected IVD
results is not an IVD medical device as per decision step 5 of figure 1.
Note 3: Software intended to modify the representation of available IVD results is not considered as an IVD medical device as per
decision step 5 of Figure 1, e.g. basic operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function
of time, and/or a comparison of the result to the limits of acceptance set by the user.
Note 4: Stand alone software intended for archiving patient results or for transferring results from the home environment to the
healthcare provider is not an IVD device.
3. Classification of stand alone software
Stand alone software that meets the definition of a medical device shall be considered as an active medical device.18 This means that
rules 9, 10, 11 and 12 of Annex IX to Directive 93/42/EEC may apply.
Clause 2.3 of the implementing rules in Annex IX states that software 'which drives a medical device or influences the use of a device,
falls automatically into the same class19, as the device it drives.
3.1 Software as active therapeutic medical devices

According to rule 9 of Annex IX to Directive 93/42/EEC, all active therapeutic devices intended to administer or exchange energy are
in Class IIa unless their characteristics are such that they may administer or exchange energy to or from the human body in a
potentially hazardous way, taking account of the nature, the density and site of application of the energy, in which case they are in
Class IIb.
18
19
15
All active devices intended to control or monitor the performance of active therapeutic devices in Class IIb, or intended directly to
influence the performance of such devices are in Class IIb according to implementing rule 2.3.
Example: radiotherapy planning system used to calculate the dose of ionizing radiation to be administered to the patient, insulin
dosage planning stand alone software.
3.1.1 Software intended for diagnosis or therapy
According to rule 10 of Annex IX to Directive 93/42/EEC, active devices intended for diagnosis are in Class IIa:
- if they are intended to image in vivo distribution of radiopharmaceuticals.
Example: Clinical application of registration of PET datasets on CT datasets for follow-up tumour treatment.
- if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for
monitoring of vital physiological parameters, where the nature of variations is such that it could result in immediate danger to the
patient, for instance variations in cardiac performance, respiration, activity of CNS in which case they are in Class IIb.
Examples: - Software for the presentation of the heart rate or other physiological parameters during routine checkups (Class IIa);
- Software for the presentation of the heart rate or other physiological parameters for intensive care monitoring (Class IIb).
Active devices intended to emit ionizing radiation and intended for diagnostic and therapeutic interventional radiology including
devices which control or monitor such devices, or which directly influence their performance, are in Class IIb.
Rule 11 of Annex IX to Directive 93/42/EEC states that all active devices intended to administer and/or remove medicines, body
liquids or other substances to or from the body are in Class IIa, unless this is done in a manner:
16
- that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the
mode of application in which case they are in Class IIb.
Stand alone software which drives such medical device or influences the use of such device falls automatically into the same class as
the device it drives (implementing rule 2.3).
Rule 12 of Annex IX to Directive 93/42/EEC states that all other active devices are in Class I. Class I stand alone software can also
come with a measuring function.
Example: orthopaedic planning software to measure interpedicular distance or sagittal diameter of the spinal canal.
3.2 IVDD and software in conjunction with in-vitro diagnostic devices
Stand alone software qualified as in vitro diagnostic medical devices should be regulated according to Directive 98/79/EC.
When intended for evaluating the risk of trisomy 21, such software are specifically mentioned in Annex II List B of Directive
98/79/EC and shall therefore follow the conformity assessment procedure described in Article 9 of this Directive.
4. Modules
Some stand alone software may break down into a significant number of applications for the user where each of these applications is
correlated with a module. Some of these modules have a medical purpose, some not.
Such software may be intended to cover many needs, e.g.:
- Collect and maintain administrative patient details;
- Keep on file the medical history of the patient;
17
- Invoicing and other accounting functions;
- Provide a link to the social security system for reimbursement;
- Provide a link to drug prescription systems (with possible link to drug dispensing outlets);
- Provide expert system assistance for medical decision making (e.g. radiotherapy dose planner).
This raises the issue as to whether the whole product can be CE marked when not all applications have a medical purpose.
Computer programmes used in healthcare mostly have applications which consist of both medical device and non-medical device
modules.
The modules which are subject to the medical device Directives (Figures 1 and 2) must comply with the requirements of the medical
device Directives and must carry the CE marking. The non-medical device modules are not subject to the requirements for medical
devices.
It is the obligation of the manufacturer to identify the boundaries and the interfaces of the different modules.
The boundaries of the modules which are subject to the medical device Directives should be clearly identified by the manufacturer and
based on the intended use.
If the modules which are subject to the medical device Directives are intended for use in combination with other modules of the whole
software structure, other devices or equipment, the whole combination, including the connection system, must be safe and must not
impair the specified performances of the modules which are subject to the medical device Directives20.
20
i.e. essential requirements 3.1 of Directive 98/79/EC and essential requirements 9.1 of Directive 93/42/EEC
18
Annex 1: Illustrative examples of qualification for software used in the healthcare
environment
The sector of software pursuing a medical purpose is rapidly evolving.
The list of examples provided below is not exhaustive.
The examples have been drafted in the light of today's state of the art, in order to give the reader a better understanding of the
application of the principles set out in the guideline.
In the light of the technological progress, further examples will be regularly added into the Manual on borderline and classification in
the Community regulatory framework for medical devices21.
a) Hospital Information Systems
Hospital Information Systems mean, in this context, systems that support the process of patient management. Typically they are
intended for patient admission, for scheduling patient appointments, for insurance and billing purposes.
These Hospital Information Systems are not qualified as medical devices. However they may be used with additional modules, as
described hereafter.
These modules might be qualified in their own right as medical devices.
b) Decision Support Software
21
19
In general, they are computer based tools which combine medical knowledge databases and algorithms with patient specific data. They
are intended to provide healthcare professionals and/or users with recommendations for diagnosis, prognosis, monitoring and treatment
of individual patients.
Based on steps 3, 4, and 5 of Figure 1, they are qualified as medical devices.
- Radiotherapy treatment planning systems22 are intended to calculate the dosage of ionizing irradiation to be applied to a specific
patient. They are considered to control, monitor or directly influence the source of ionizing radiation and are qualified as medical
devices.
- Drug (e.g.: Chemotherapy) planning systems are intended to calculate the drug dosage to be administered to a specific patient and
therefore are qualified as medical devices.
- Computer Aided Detection systems are intended to provide information that may suggest or exclude medical conditions and,
therefore, qualified as medical devices. For example, such systems would be able to automatically read x-ray images or interpret
ECGs.
c) Information Systems
Information systems that are intended only to store, archive and transfer data are not qualified as medical devices in themselves.
c.1) Electronic Patient Record Systems
Electronic patient record systems are intended to store and transfer electronic patient records. They archive all kinds of documents and
data related to a specific patient. The electronic patient records themselves are not computer programs, therefore, they should not be
22
See EN 62083 Requirements for the safety of radiotherapy treatment planning systems
20
qualified as a medical device i.e. an electronic patient record that simply replaces a patients paper file does not meet the definition of a
medical device. The modules used with electronic patient record system modules that might be qualified in their own right as medical
devices are for example:
- an image viewer with functionality for diagnosis based on digital images;
- a medication module.
c.1.1) Clinical Information Systems CIS / Patient Data Management Systems - PDMS
A CIS/PDMS is a software based system primarily intended for e.g. intensive care units to store and transfer patient information
generated in association with the patients intensive care treatment.
Usually the system contains information such as patient identification, vital intensive care parameters and other documented clinical
observations.
These CIS/PDMS are not qualified as medical devices.
Modules that are intended to provide additional information that contributes to diagnosis, therapy and follow-up (e.g. generate alarms)
are qualified as medical devices.
c.1.2) Pre-hospital Electrocardiograph (ECG) System
A system for managing pre-hospital ECG is a software based system intended for ambulance services to store and transfer information
from patients, which are connected to an ECG monitor, to a doctor at remote location. Usually the system contains information about
patient identification, vital parameters and other documented clinical observations. These Pre-hospital Electrocardiograph (ECG)
Systems are not qualified as medical devices.
Modules that provide patient's treatment information to the paramedics in the ambulance to start the patients treatment while the
patient is being transported are qualified as Medical Devices.
c.1.3) Radiological Information System (RIS)
21
A RIS is a software based database used in radiology departments to store and transfer radiological images and patient information.
The system normally includes functions for patient identification, scheduling, examination results and imaging identification details.
These Radiological Information Systems are not qualified as medical devices.
However, if such a system includes additional modules they might qualify as medical devices according to step 3 of of Figure 1.
c.1.4) Picture Archive Communication System (PACS)
The Manual on Borderline and Classification in the Community Regulatory Framework for Medical Devices23, already addresses the
issue.
d) Communication Systems
The healthcare sector uses communication systems (e.g. email systems, mobile telecommunication systems, video communication
systems, paging etc.) to transfer electronic information. Different types of messages are being sent such as prescriptions, referrals,
images, patient records, etc.
Most of the communication systems handle other types of messages other than medical information. This communication system is
intended for general purposes, and is used for transferring both medical and non-medical information.
Communication systems are normally based on software for general purposes, and do not fall within the definition of a medical device.
Communication system modules might be used with other modules that might be qualified in their own right as medical devices.
Example: software generating alarms based on the monitoring and analysis of patient specific physiological parameters.
d.1) Telemedicine Systems
23
22
Telemedicine Systems are intended to allow monitoring and/or delivery of healthcare to patients at locations remote from where the
healthcare professional is located.
d.1.1) Telesurgery
Telesurgery is intended to conduct a surgical procedure from a remote location. Virtual reality technology may be used to support a
remote surgeon to control a surgical robot performing the surgical procedure.
Telesurgery systems should be qualified as medical devices according to steps 3, 4, and 5 of Figure 1.
Remote control software used in combination with telesurgery robots is qualified as a medical device. Communication modules
themselves are not medical devices.
Other modules that are intended to influence the surgery procedure are qualified as medical devices.
d.1.2) Video appointment software
Video appointment software is intended to perform remote consultations between clinics and patients. It does not fall under the
Medical Devices Directives.
d.1.3) Home care monitoring, wired or mobile
The telecommunication system (mobile, wireless, wire, etc) is not as such a medical device.
e) Web systems for monitoring of data

A web system for the monitoring of clinical data typically interacts with a medical device (e.g. implanted devices or homecare
devices), and uses a transmitter to send the information over the internet, a landline telephone or a mobile network.
The information is collected and stored on a web server usually run by an external party who is generally the manufacturer of the
system. The information can be reached by authorized health professionals or the patient through an internet connection.
23
- Monitoring of performance of medical devices:
Modules that are intended to monitor the medical performance of medical devices fall under the Medical Devices Directives.
This includes the clinical performance and failures that could affect medical performance of the device. One example of such product
is a web system for monitoring of active implants such as pacemakers or Intra cardiac defibrillators (ICDs).
- Monitoring of non medical performance of medical devices:
Modules that are intended to monitor non medical performance of medical devices do not fall under the scope of Medical Devices
Directives.
Example: software for the monitoring of medical devices in hospital systems for the purpose of maintenance and repair.
Software modules on server(s) might be qualified in their own right as medical devices depending on their intended purpose.
f) In vitro diagnostic (IVD) software: LIS & WAM
f.1) Laboratory Information Systems (LIS) and Work Area Managers (WAM)
Laboratory Information Systems (LIS) and Work Area Managers (WAM) mean, in this context, systems that support the process from
patient sample to patient result. Typically they have pre-analytical functions for ordering, sorting and distribution of test samples.
The main task is the management and validation of incoming information obtained from IVD analysers connected to the system, such
as calibration, quality control, product expiry and feedback (e.g. retesting of samples needed) through interconnections with various
analytical instruments (technical and clinical validation).
Finally the post analytical process takes care of communication of laboratory results, statistics and optional reporting to external
databases.
The software normally supports the following functions:
Ordering of laboratory tests, samples with labels and sorting;
Technical and clinical validation, connection to analytic instruments;
24
Laboratory results and reports on paper, fax or electronic records that can be directly returned to e.g. the ordering clinic's
patient record;
Analytical instruments can be interfaced with Hospital Information Systems (HIS), Electronic Patient Record Systems, Infectious
control databases etc.
Note: Software intended to modify the representation of available IVD results is not considered an IVD medical device, e.g. basic
operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function of time, and/or a comparison of the
result to the limits of acceptance set by the user.
The results are available, readable and understandable without the intervention of the software.
Laboratory Information Systems (LIS) and Work Area Managers (WAM) are not qualified as medical devices in themselves.
f.2) Expert system
Where software is intended to capture and analyze together several results obtained for one patient by one or more IVD devices by
means of in vitro examination of body samples (possibly combined with information from medical devices) to provide information
falling within the definition of an IVD medical device, e.g. differential diagnosis, this software is considered as an IVD in itself.
Examples: - software that integrates genotype of multiple genes to predict risk of developing a disease or medical condition;
- software that uses an algorithm to characterize viral resistances to various drugs, based on a nucleotide sequence
generated by genotyping assays. This software serves to generate new information (virus resistance profile) from
available information on the genotype of the virus;
- software intended to be used in microbiology for the identification of clinical isolates and/or the detection
antimicrobial resistances.
The information provided by the software is based on data obtained with IVD medical devices only or possibly combined with
25
information from medical devices.
The software is an IVD medical device or an accessory of an IVD medical device.
f.3) Interpretation of raw data
In the case where software is necessary to render raw data, obtained from an IVD by means of in vitro examination of body samples,
readable for the user, this software is to be considered as an accessory to an IVD when it is specifically intended to be used together
with this IVD to enable it to be used in accordance with its intended purpose.
Example: software intended for the analysis and interpretation of ELISA reader optical density results, line patterns or spot patterns
of a blot.
f.4) Home care monitoring, wired or mobile
Stand alone software intended for archiving patient results or for transferring results from the home environment to the healthcare
provider is not an IVD device. The results are available, readable and understandable by the user without the intervention of the
software.
26
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 2/1 Rev1
February 1998
" EMC REQUIREMENTS "
---(())---
Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel - Belgium - Office:
Telephone: direct line (+32-2)29.........., switchboard 299.11.11. Fax: 29...........
Telex: COMEU B 21877. Telegraphic address: COMEUR Brussels.
1. Background
The notified body group recognised the fact that different NB's chose different ways how
to check for EMC essential requirements and identified the need for harmonisation of the
ongoing practice. It therefore established a task force group which should collect data
and work out a proposal for a commonly agreed practice. This group should not perform
additional standardising work as it is already done by CENELEC committees but should
try to find a solution which is based on the already existing standards.
In its meeting of April, 29-30, 1996 the notified body group agreed on this position
paper.
2. Data Collection
With the aid of a questionnaire NB's were asked whether they already apply EN
60601-1-2 as a basis for testing against the essential requirements and how they handle
those points of the standard that are not sufficiently specified yet. Until the NB meeting
in April 1995, 12 NBs replied and until the beginning of July 1995 the task force group
succeeded to get back in total 22 filled out questionnaires and decided to base its
recommendations on that quorum. The first draft was discussed at the NB group meeting
in September 1995; the comments received until February, 29th were considered in this
2nd revision of the position paper.
The results of the inquiry can be summarised as follows:
1. Almost every NB accepts EN 60601-1-2 as a basis for testing according to the

essential requirements.
2. Due to some missing test procedures and limit values several specific clauses are
handled quite differently by different NBs. Some of the requirements of the EN
60601-1-2 that are only mentioned by headings are seen quite differently.
3. There is a need for detailed classification rules of devices and for setting limits for
various requirements.
3 Recommendations
Although EMC can become an important issue for electromagnetic devices, the
discussion at the NB Group meetings so far showed that there is some tendency of
overtesting this aspect. On the one hand, in fact, EMC testing cost already amount to
20 - 50 % of the overall testing cost of a medical electrical device. Already
IEC 801-1/1984 concludes that asking for highest immunity levels irrespective the
intended use and expected electromagnetic environment would lead to unjustifiable
loads.
Having assessed and analysed the present practice the EMC task force group would like
to make the following suggestions:
2
As a basic standard EN 60601-1-2 should be applied as harmonised standard for EMC
aspects of the essential requirements. It is recognised that there is still some missing
information which will hopefully be specified in the forthcoming 1st amendment to this
standard. In the meanwhile to allow a common approach based on the already existing
standards, the following recommendations are made:
3
I. Emission
Having in mind the increased use of medical electrical equipment the EMC task force
group is aware of the need for electromagnetic emission tests in the high frequency
range.
1. However, by now it does not support emission tests in the low frequency range due
to the following reasons:
a) In general extra low frequency field emitters do not cause safety problems.
Requirements for some specific devices should be defined in product standards.
b) There are no applicable standards available in this field yet.
c) The majority of the NBA does not agree on the necessity of such tests.
2. Problems with voltage variations of the general power supply in hospitals increase
with the increasing use of medical electrical device and might lead to safety-relevant
impairment of the device performance. The EMC task force group identified that
there is a need for testing the potential to disturb the local power supply within a
hospital, however, mandatory tests, e.g. according to EN 60555-2, 3 should not be
made before a harmonised requirement will be included into EN 60601-1-2. The EMC
task force group does not agree with the rational of clause 36.201.2.1 because
especially in a local power supply system disturbances caused by power consuming
devices can occur more frequently compared with a public system and might affect
the performance of live saving equipment.
II. Immunity
In general, the MDD's essential requirements address terms of safety and freedom of
unacceptable risks. In particular, clause 9.2 and 12.5 refer to risks due to magnetic fields,
external electric influences and electrostatic discharges rather than to any degradation of
performance.
The EMC task force group feels it necessary to clarify the terms "function" and "safe
fail" that are addressed in EN 60601-1-2, clause 36.202 where equipment under test is
required either "to fail without creating a safety hazard" or "to perform its intended
function as specified by the manufacturer".
In respect to the general requirements of the MDD which address safety-relevant aspects
only to minimise risk to an acceptable level the following clarifications are proposed:
"Function" refers to safety-relevant aspects rather than to any kind of device

performance. For example, this means that a slight distortion of a display could be
accepted whereas changing of any kind of energy release could not be tolerated.
"Fail safe" means any kind of change in performance that makes it obvious to the user
that the intended function is degraded if this does not pose hazard to the patient. This
4
may be either an interruption of operation or an audible and/or visible indication of
interference.
As a general rule, the risk assessment should include EMC risks and the influence of
the expected electromagnetic environment. However, it should be kept in mind that even
within hospitals the electromagnetic environment can be quite different. Based on this
analysis and the intended use, the manufacturer should
a) classify the equipment into class A or B according to EN 55011

b) design the interference properties of the equipment as
- immune to the applied test fields or

- irrelevant changes of device performance or
- fail safe in the sense as defined above
Although it is recommended that manufacturers should design their products in a way as

to increase immunity as high as it is reasonably achievable the necessity for mandatory
immunity tests should be made dependent on the risk potential of the medical products
as it results from the risk analysis of the product.
As a general rule the EMC task force group recommends to consider immunity tests not
being mandatory for class I devices which by definition do not pose inherent hazard to
the patient. The manufacturer should be allowed to demonstrate compliance with the
essential requirements by other means like drawing conclusions from the operation
principle and the chosen design of his equipment.
In special cases risk analysis, however, may make it necessary even for some class I
products to provide increased immunity performance as for instance electric wheelchairs
that need to be operated safely under high tension lines with fields exceeding the limit
values of the immunity requirements of EN 60601-1-2.
III. Application of EN 60601-1-2
Based on the results of the inquiry the EMC task force group recommends to apply the
clauses of EN 60601-1-2 related to EMC testing as follows:
36.201.1 Radio frequency emissions

Classification according to EN 55011 into class A or B is made by the
manufacturer, based on the intended use of the equipment and the fact, that even
within hospitals there are areas of quite different electromagnetic environment. In
general, equipment will be class A, equipment intended for home use, class B.
36.201.1.6 High frequency surgical equipment

Testing according to EN 55011, class A, group 2, operation condition of the
device according to EN 60601-2-2.
36.201.2 Low frequency emission

No tests required (64 % of the NBs do not agree on the necessity of this test).
36.202.1 Electrostatic discharge

5
Testing as specified according to EN 61000-4-2 with 3 kV and 8 kV respectively.
(The task force group is aware of that the standardising committee discusses an
increase of the test voltage for contact discharges but has to await the decision.)
36.202.2 Radiated radio frequency fields

Testing according to EN 61000-4-3, level 2 (3 V/m)
36.202.3.1 Bursts
Testing as specified according to EN 61000-4-4. (There may be a change in test
voltage level for plug-connected devices to 2 kV in the future.)
36.202.3.2 Surges
Testing as specified according to EN 61000-4-5
36.202.4 Voltage dips, short interruptions and voltage variations on power supply
input lines
Testing according to EN 61000-4-11
36.202.5 Conducted disturbances, induced by radio frequency fields

Testing according to IEC 1000-4-6
(86 % of the NBs agree on the necessity of this test)
36.202.6 Magnetic fields

Testing according to EN 61000-4-8
(77 % of the NBs agree on the necessity of this test)
Although EN 60601-1-2 does indicate tests according to 36.202.4, 36.202.5 and 36.202.6
being still under consideration, the EMC task force group recommends to perform this
tests due to the following reasons:
a) the overwhelming majority of NBs agreed on the necessity of the tests to demonstrate
compliance with the essential requirements
b) there are already standards of the EN 61000 or IEC 1000 series available.
6
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 2/3 rev.3
June 1998
USE-BY DATE
--- (())---
1. Requirements
The medical devices directives (MDD, AIMD, [draft IVD]) each require a statement
given on the label and/or the information provided with the device on any time limitation
on the safe use of the device. Although the wording differs, each addresses the need to
provide this information:
MDD, annex I, 13.3: AIMD, annex 1, 14: [IVD (draft 13 May 1997),
annex 1, 13.4]:
"The label must bear the fol- "Every device must bear ... : "The label must bear the fol-
lowing particulars: ... - an indication of the time lowing particulars ... :
... (e) where appropriate, an limit for implanting a device ... (e) if necessary, an indication
indication of the date by which safely." of the date by which the device
the device should be used, in or part of it should be used, in
safety, expressed as the year and safety, expressed as the year, the
month; ..." month and, where relevant, the
day, in that order; ..."
2. Purpose of this recommendation
In the case of devices covered by the AIMD, a time limit must always be given.
In the case of devices covered by the MDD [and the draft IVD], a time limit is only
required where "appropriate" [or "necessary"]. The purpose of this recommendation is to
a) assist the manufacturer in deciding whether a use-by date is required for his
particular device and
b) indicate what information is required to support his decision.
Note: The use-by time limit relates to the period before the first use of the device.
It does not relate to the number or period of subsequent uses (the lifetime
of the device).
If the device is reusable, the MDD separately requires (annex I, 13.6 (h)) ...
information on ... any restrictions on the number of reuses.
If the device is for single use, but over a prolonged period, any limitations on
what would be the expected pattern of use would be required as ... special
operating instructions or ... warnings and/or precautions to take (MDD,
annex I, 13.3 (j) and (k) respectively).
Note: There is nothing in the medical devices directives which prohibits a manu-
facturer voluntarily recommending a use-by date, even though the per-
formances and characteristics are not in fact affected by the passage of time.
3. How to decide if a use-by date is required

2
A use-by date is required where a safety-related characteristic or claimed perform-
ance is likely to deteriorate over time.
In deciding whether there is such a "safety-related" deterioration, the manufacturer must

have regard to the results of the risk analysis and measures taken to manage risk.
a) The risk analysis will identify those performances and characteristics necessary
for the safe use of the particular device.
- For example, the risk analysis may indicate that sterility is necessary for safe
use. Equally, the risk analysis would not cover the colour of the device if this is
purely aesthetic, but it might cover the colour of the device if that colour has a
purpose related to safe use of the device (e. g. the colour signifies the size of the
device).
b) The risk analysis and measures taken to manage risk will also identify the level or
extent of performance or characteristic but only in so far as they are relevant to safe
use of the device.
- For example, the level of resistance to gas flow or rate of leakage from a
breathing system, or the probability of non-sterility.
c) The risk analysis and measures taken to manage risk will also identify the period
over which the relevant performance or characteristic would be expected to be
maintained for safe use, including the shelflife and intended period of use.
- For example, the period over which a pacemaker battery maintains sufficient
energy to function after implantation as long as intended by the manufacturer.
4. Information that is required to support the decision
4.1 Information necessary if a use-by date is given
The manufacturer must demonstrate that the relevant performances and characteristics of
the device are maintained over the claimed shelf life which the use-by date reflects.
This may be achieved by
a) prospective studies using accelerated ageing, validated with real time degradation
correlation; or
b) retrospective studies using real time experience, involving e.g. testing of stored
samples, review of the complaints history or published literature etc.; or
c) a combination of a) and b).
4.2 Information necessary if a use-by date is not given

3
As the absence of a use-by date constitutes an implicit claim of an infinite shelf life,
the manufacturer must demonstrate either
a) that there are no safety-related performances or characteristics which are likely to

deteriorate over time (3a above), or
b) that the extent of any likely deterioration (3b above) does not represent an un-
acceptable risk, or
c) that the period over which unacceptable deterioriation occurs is far beyond the
likely time of the first use of the device (3c above), e.g. 30 years.
In doing so, the manufacturer must consider, amongst other
- materials of the device itself and those used in manufacture, including adhesives,
coatings, packaging etc.
- methods of manufacturing, (e.g. attachment of components, package sealing process);
- methods of protecting the device or parts thereof from deterioration (e.g. packaging,
storage instructions);
- if relevant, state in which the device is maintained prior to first use (e.g. without
battery fitted)
- the potential for inherent time dependent material degradation (e.g. due to long term
effects of sterilisation on materials such as that of free radicals from gamma
irradiation leading to polymer degradation).
If the manufacturer cannot meet the requirements of either 4.2a or 4.2b or 4.2c above, a
use-by date must be given.
5. Examples
5.1 Cardiac catheter with latex balloon
[Only aspect considered in this example: time-related deterioration of the balloon]
A cardiac catheter incorporates a latex balloon to locate the cather tip within, and
temporarily occlude, a blood vessel. The ability of the balloon to withstand certain
pressure is necessary for safe use. The latex of the balloon, however, deteroriates over
time. The packaging and the storage instructions to protect the device from light reduce
the rate of deteroriation, but do not prevent it. It is therefore necessary to give a use-
by date.
The manufacturer must demonstrate that
4
- the latex balloon remains able to withstand the relevant pressure over the claimed
shelf life, when the device is stored in accordance with the manufacturer's instruc-
tions.
5.2 Orthopaedic hip joint implant (supplied sterile)
[Only aspect considered in this example: time-related deterioration of the sterile

packaging]
A metal and ceramic orthopaedic implant is supplied sterile in a composite plastic/paper

unit container. The ability of the packaging to maintain sterility is necessary for safe use.
Whilst the maintenance of sterility is in part event-related (i.e. a function of the actual
storage and handling conditions), it is also a function of time, due to e.g. the reduction in
flexibility and seal strength of the package material over a period rendering it more
susceptible to the events which may compromise sterility.
Moreover, as such implants are available in a variety of sizes to suit different clinical
applications, a particular device may remain in the store over a long time until needed
for implantation.
It is therefore necessary to give a use-by date. In the case of maintenance of sterility,

the use-by date will reflect a combination of
a) the time-related deterioration in the performance of the pack, e.g. seal strength,
seal integrity and resistance to penetration of particles carrying micro-organisms,
b) the probability of events occurring during transport and storage which compro-
mise sterility, but are not evident and therefore where the warning not to use the
device when the package is opened or damaged will not assist.
The manufacturer must demonstrate that
- the packaging material is able to maintain device sterility over the claimed shelf life,
when stored in accordance with the manufacturer's instructions.
5.3 Implantable cardiac pacemaker
[Only aspect considered in this example: battery lifetime]
An implantable cardiac pacemaker is supplied with a battery fitted and sealed into the
device. Due to self-discharge, all batteries have a limited life even if not used. The period
for which the battery maintains sufficient energy for the device to function as intended by
the manufacturer following implantation is important to avoid the need for a surgical
operation to explant and replace the device unnecessarily soon. It is therefore necessary
to give a use-by date.
The manufacturer must demonstrate that the battery retains sufficient energy to function
for the manufacturer's claimed operating time even if implanted at the end of the claimed
shelf life.
5
EUROPEAN COMMISSION
DG HEALTH & CONSUMERS
Directorate B - Consumer Affairs
Unit B2 Health Technology and Cosmetics
MEDDEV 2.2/4
January 2012
Guidelines for conformity assessment of

In Vitro Fertilisation (IVF) and
Assisted Reproduction Technologies (ART) products
The present guidelines are part of a set of guidelines relating to questions of application of
EU-Directives on medical devices. They are legally not binding. The guidelines have been
carefully drafted through a process of intensive consultation of the various interested parties
(competent authorities, Commission services, industries, other interested parties) during
which intermediate drafts were circulated and comments were taken up in the document.
Therefore, this document reflects positions taken by representatives of interested parties in
the medical devices sector.
1
I. Objective and purpose
This guideline concerns media, substances or mixture of substances used during IVF and
ART procedures which fall under Directive 93/42/EEC (hereafter: "MDD") with the exception
of objects such as receptacles, petri dishes, pipettes or syringes.
The medical devices described above are called IVF/ART products in this guideline.
This guideline is intended to promote the safety and a high level of performance of IVF/ART
products. It aims at promoting a common approach of manufacturers of IVF/ART products
and of Notified Bodies involved in the conformity assessment procedures according to the
relevant annexes of the MDD. It also aims at assisting Member States authorities when
verifying, during post market surveillance, that the device meets the essential requirements
laid down in Annex I of the MDD.
This guideline describes the main requirements for affixing the CE mark on IVF/ART
products, taking account of the current state of the art. It does not attempt to exhaustively
cover the design of IVF/ART products. This guideline will be subject to the further evolution
of the state of the art.
II. Background and legal basis
II.1. Background
Since the first reported live birth conceived by in vitro fertilization, the birth of Louise Brown in
1978, the IVF/ART products and techniques have become common practice for medical
treatment for infertility all over the world. Many devices and products are necessary to apply
these techniques. The heterogeneity of IVF and ART procedures should also be noted. The
fluctuations of the pregnancy rates observed during the last decades could be partly due to
these procedures or products.
II.2. Legal basis
As they make pregnancies more frequent, the IVF/ART products may be qualified and
regulated as medical devices or medicinal products, depending on their principal mode of
action. The qualification must be made on a case by case basis, taking the two modes of
action and the intended purpose of the products into account.
When the IVF/ART products meet the definition of medical device, they should be classified
according to the rules set out in Annex IX to Directive 93/42/EEC. With regard to
classification, the present guideline should be read in conjunction with the Manual of
borderline and classification in the Community regulatory framework for medical devices.
The verification of the conformity with the performance and safety requirements to be fulfilled
under the normal conditions of use and the evaluation of side-effects and of the acceptability
of the risk/benefit ratio must be based on a preclinical evaluation and an evaluation of clinical
data. The objective of a clinical evaluation must be to verify that there is an overall positive
risk/benefit ratio of the device under normal conditions of use (see MEDDEV 2.7-1). Effects
on the gametes, on the embryo and on the mother-to-be shall be taken into account to this
end.
Some IVF/ART products fall under class III according to rule 13 since they incorporate one or
several medicinal product(s). For these products, a consultation procedure shall be
conducted according to point 7.4 of the Annex I to Directive 93/42/EEC.
2
III. Relevant documents
Council Directive 93/42/EEC concerning medical devices, last amended by

Directive 2007/47/EC of the European Parliament and of the Council
Regulation EC/1272/2008 of the European Parliament and of the Council of 16
December 2008 on classification, labelling and packaging of substances and
mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and
amending Regulation (EC) No 1907/2006
Commission Directive 2006/86/EC of 24 October 2006 implementing Directive
2004/23/EC of the European Parliament and of the Council as regards traceability
requirements, notification of serious adverse reactions and events and certain
technical requirements for the coding, processing, preservation, storage and
distribution of human tissues and cells
EN ISO 10993: Biological evaluation of medical devices
EN ISO 10993-3:2004: Biological evaluation of medical devices Part 3: tests for
genotoxicity, carcinogenicity and reproductive toxicity
EN ISO 10993-5: Biological evaluation of medical devices - Part 5: tests for in vitro
cytotoxicity
EN ISO 10993-10: Biological evaluation of medical devices Part 10: tests for
irritation and skin sensitization
EN ISO 10993-16: Toxicokinetic study design for degradation products and
leachables
EN ISO 14971:2007: Medical devices Application of risk management to medical
devices
EN ISO 13824:2004: Sterilization of medical devices aseptic processing of liquid
medical devices
EN ISO 14644: Cleanrooms and associated controlled environments
MEDDEV 2.1/3: Interface with other directive Medical devices/medicinal products
MEDDEV 2.7.1 (2003): Evaluation of clinical data: A guide for manufacturers and
notified bodies
MEDDEV 2.12-1 (2009): Guidelines on a medical devices vigilance system
MEDDEV 2.12-2 (2004): Guidelines on post market clinical follow-up
Manual on borderline and classification in the community framework for medical
devices: point 4.3 In-Vitro Fertilisation (IVF) and Assisted Reproductive
Technologies (ART) products
IV. Hazards/Risks associated with the design and manufacture of the

IVF/ART device
Medical devices must meet the essential requirements set out in Annex I to Directive
93/42/EEC which apply to them, taking into account the intended purpose of the devices
concerned.
When a medical device is in conformity with the relevant national standards adopted
pursuant to the harmonized standards the reference of which have been published in the
Official Journal of the European Communities or the monographs of the European
Pharmacopoeia, the device is presumed to conform to the essential requirements mentioned
in the Annex Z of the standard. If the standard is not applied or if it is only partly applied, the
manufacturer has to describe, in the technical documentation of the medical device, the
solutions adopted to meet the essential requirements of the Directive.
3
The technical documentation must contain the grounds for incorporating each component in
the final medical device. Taking account the utility of each component, each risk related to
each component should be considered and should constitute an acceptable risk when
weighed against the benefit to the gamete, to the embryo or to the mother-to-be. In addition,
all risks combined must be acceptable when weighed against the benefit to the gamete, to
the embryo or to the mother-to-be.
Among the essential requirements mentioned in Annex I to Directive 93/42/EEC, some risks
have been particularly identified and listed below.
Examples of risks associated with the aspect of quality:
- In Annex I point 1 and in Annex I point 3: risks raised by the packaging of the final
product
Some products are provided in a large container for multiple IVF/ART procedures. In case of
container for multiple procedures, special attention should be paid to contaminants dropped
off unintentionally during a procedure. Considering this risk, the manufacturer should justify,
in the technical documentation, that the selected packaging is ergonomic for the user and
suitable for the function(s) assigned by the manufacturer.
The instruction for use must include information on characteristics and technical factors
known to the manufacturer that could pose a risk when the container is for multiple IVF/ART
procedures. It must also include the restriction of the number of procedures.
- In Annex I point 2: solutions adopted by the manufacturer for the design and
construction of the devices must conform to safety principles and users must be informed
about the residual risks
The selection of each component on IVF/ART products must be based on its safety. The
information about residual risks, for example on allergic reaction against antibiotics, must be
provided in the instructions for use.
- In Annex I point 4: risks caused by the stability of the final product

The IVF/ART product may not be adversely affected to such a degree that the clinical
conditions and safety of the gamete, of the embryo, or of the mother-to-be are compromised
during the lifetime of the device and under the normal conditions for use.
The following information shall be included in the technical documentation and in the
instructions for use:
- Information on how to follow the evolution of the most unstable and the most crucial
components (such as glutamine, pyruvic acid, vitamins );
- Information on the storage conditions recommended by the manufacturer;
- Information on how to maintain, throughout the shelf-life of the device, the desired
functionality of the devices.
Special attention should be paid to the description of the devices composition that contribute
to the control of the stability of the final IVF/ART product and to the information which
accompanied the device.
- In Annex I point 7.1: risks raised by the choice of components used (development of the
formulation)
Special attention should be paid to the impurity profile of each component included in the
formulation/product, considering that impurities could have an impact on the toxicity and on
the performance of the final IVF/ART product.
Besides, special attention should be paid to the degradation profile of each component
included in the formulation, considering that the degradation product(s) could also have an
impact on the toxicity and on the performance of the final IVF/ART product. For example,
glutamine, an amino acid, is degraded in ammonium ions.
4
In order to evaluate the overall risk due to the IVF/ART products, pre-clinical testing is
necessary. If appropriate, the manufacturer should include the following biocompatibility
testing:
a. When selecting tests among EN ISO 10993 series of standards, particular
attention should be paid to local effects of the device, to the uterine tissue and
also to the acute toxicity of the device
b. EN ISO 10993-3:2004 Biological evaluation of medical devices Part 3: tests
for genotoxicity, carcinogenicity and reproductive toxicity
c. EN ISO 10993-5: Biological evaluation of medical devices - Part 5 : tests for in
vitro cytotoxicity
d. EN ISO 10993-10: Biological evaluation of medical devices Part 10 : tests
for irritation and skin sensitization
e. EN ISO 10993-16: Toxicokinetic study design for degradation products and
leachables
- In Annex I point 7.2: risks caused by contaminants and residues that could drop from
the material constituents during to the manufacturing of the devices or during the transport,
storage and use of the devices, whether they constitute risks for the gamete, for the embryo,
for the patient or for other persons
Thus, the level of endotoxins should be considered as acceptable to be used with gametes
and embryos.
- In Annex I point 7.4: risks caused by the incorporation of ancillary medicinal

substance(s) or ancillary human blood derivative, as an integral part, in the medical device
Irrespective of the concentration of the medicinal substance(s) and the direct contact with the
mother-to-be, the conformity assessment procedure for the IVF/ART products which
incorporate, as an integral part, a medicinal substance(s) must include the verification of the
quality, the safety and of the usefulness of the substance(s).
First, the Notified Body has to assess the usefulness of any ancillary medicinal substance(s)
with technical documentation provided by the manufacturer. To establish this statement on
the usefulness, the Notified Body has to pay special attention to the contact of the ancillary
medicinal substance with the gametes, with the embryo and with the mother-to-be. This
statement has to be transmitted with the initial demand to a competent authority for medicinal
products of the Member States or, as appropriate, to the European Medicines Agency
(EMA). This competent authority or the EMA will evaluate the quality and the safety of the
substance(s), including the clinical risk/benefit ratio for the addition of the substance(s) into
the device. When issuing its opinion, the competent authority or the EMA shall take into
account the manufacturing process and the data related to the usefulness of incorporation of
the substance into the device as determined by the notified body.
Examples of ancillary medicinal substances are: antibiotics, human serum albumin
- In Annex I point 7.5: risks linked to substances which are carcinogenic, mutagenic or
toxic to reproduction
If the IVF/ART solution incorporates substances which are known to be carcinogenic,
mutagenic or toxic to reproduction, in accordance with Annex I to Council Regulation
EC/1272/20081, the manufacturer must have duly justified their use in the formulation with
regard to compliance with the essential requirements, in particular if these substances could
be replaced by suitable alternatives. If a part of the device contains phthalates, the same
applies. In addition, the labelling on the device or the sales packaging must mention this
component and the instruction for use must also contain the information on residual risks
and, if applicable, on appropriate precautionary measures.
1
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF
5
- In Annex I point 7.6: risks caused by the unintentional ingress of substances into the
device during the manufacturing process
The EN ISO 14644 series of standards can be used, where appropriate. In the technical
documentation, the manufacturer must include elements on the manufacturing process and,
more specifically, on the level of cleanliness of rooms where the manufacture takes place.
- In Annex I point 8.1: risks caused by infection and microbial contamination (bacteria,
bacterial spores, mycobacteria, fungi including sporing forms, yeasts, parasites and viruses)
The standards EN 556-1 and EN 556-2 define the requirements for medical devices to be
designated STERILE.
For medical devices which could not be terminally-sterilized, EN 13824 can be used. The
sterilisation process must have been validated adequately and must have been documented
in the technical file.
Considering the invaluable character of the gamete or of the embryo and the risk of their
infection, these types of products are usually provided sterile. Where the device is
exceptionally not sterile, the level of contamination by micro-organisms still deemed
acceptable must be justified in the technical documentation.
The choice of the environment where the manufacture takes place (clean rooms, if
appropriate) must be duly justified in the technical documentation and must correspond to
the acceptable level of contamination defined for the device.
Where the device is manufactured utilizing animal tissues or derivatives rendered

non-viable, the processing, preservation, testing and handling of tissues, cells and
substances of animal origin must be carried out so as to provide optimal safety. This
essential requirement is also applicable where materials of animal origin are used in
manufacturing processes without being in the final device. In order to eliminate or reduce as
far as possible the risk of transmitting transmissible spongiform encephalopathies due to
tissues of animal from bovine ovine and of caprine species, as well as of deer, elk, mink and
of cats, the conformity assessment procedure shall include the evaluation of their compliance
with Directive 2003/32/EC.
Examples are: bovine serum albumin used during the process of production of synthetic
hyaluronic acid, hyaluronic acid extracted from the cock's comb.
- In Annex I point 9.1 and Annex I point 13.6.c: risks caused by the use in combination
with others devices
During an IVF/ART procedure, different kind of devices have to be used on gametes and
then on the embryo. The whole combination must be safe and may not impair the specified
performance of the devices.
In application of point 13.6.c of Annex I to Directive 93/42/EEC, the manufacturer must
describe the characteristics of its product in its instruction for use in order to identify the
devices which must be used in combination to obtain a safe combination. In order to reduce
the risk of combination error, the manufacturer must precisely indicate the references of the
medical devices concerned in the instruction for use. Furthermore, the user shall be informed
on known incompatibilities related to a combination with medical device(s) of other
manufacturers in the instruction for use.
- In Annex I point 13: risks caused by the information supplied by the manufacturer
Considering that each device must be accompanied by the information needed to use it
safely and properly and that the IVF/ART medical devices are usually composed of multiple
components, their instruction for use should contain the whole qualitative composition of the
device.
6
V. Classification
The Manual of borderline and classification in the community regulatory framework for
medical devices gives some examples of classification for IVF/ART products: "IVF/ART
products may be qualified and regulated as medical devices provided that they meet the
definition of a medical device as laid out in Directive 93/42/EEC, taking into consideration the
principal intended action and intended purpose of the product. The concept of used for
human beings is interpreted in the broadest sense. The whole IVF/ART procedure and
related products would be seen as (indirectly) () used for human beings for the purpose of
() replacement or modification of () a physiological process by promulgating pregnancy.
Therefore, the definition of medical devices can include IVF/ART products.
Examples of products which could be qualified as medical devices (classification is only

indicative and must be assessed on a case by case basis taking into account all product
characteristics):
- Devices that act in a physical or mechanical way intended to be used for IVF/ART (such as
pipettes or syringes) should be classified according to the rules set out in Annex IX of
Directive 93/42/EEC, depending mainly on their intended use;
- Devices, such as washing, separating, sperm immobilizing, cryoprotecting solutions, which
are liable to act with close contact on the inner or outer cells during the IVF/ART are likely to
be considered as Class IIb medical devices, in particular by analogy of Rule 32.
- Devices manufactured utilizing animal tissues or derivatives rendered non-viable are
considered as Class III medical devices according to rule 17;
- Devices incorporating, as an integral part,
(i) a human blood derivative or
(ii) a substance which, if used separately, can be considered to be a medicinal product, as
defined in Article 1 of Directive 2001/83/EC, and which is liable to act on the human body
with action ancillary to that of the devices,
are considered as Class III medical devices according to rule 13. The assessment of the
ancillary nature of the pharmacological, immunological or metabolic action of any medicinal
product contained in IVF/ART products should be done on a case by case basis, taking also
into account the purpose of the inclusion of this substance into the product. Although case by
case analysis should always be performed, media intended for use in the IVF process to
support the growth / storage of the embryo may generally be considered to be Class III
medical devices.
In case of doubt where taking into account all product characteristics, and provided that the
concerned product meets both definitions of a medicinal product and of a medical device,
Article 2(2) of Directive 2001/83/EC could apply."
VI. Traceability
Special attention should be paid to traceability since incidents might be disclosed several
months or years later, at the babys birth or even later during its life. The instruction for use
must inform the user on the need for traceability and, where appropriate, on the national
legal requirements in this field.
2
These products are considered to present the same level of risk as non-invasive devices intended for
modifying the biological or chemical composition of blood, other body liquids or other liquids intended
for infusion into the body.
7
VII. Vigilance
In case of assisted reproduction, special attention should be paid to the causes of the death
or deterioration of the gamete (spermatozoid, oocyte), of the embryo or of the mother-to-be.
If the product could be involved in this deterioration or death of the gamete, of the embryo or
of the mother-to-be, the manufacturer shall carry out an assessment and inform the
competent authority. In case of doubt, incidents shall be notified to the relevant national
competent authority.
Since Directive 2004/23/EC also applies to reproductive cells (eggs, sperm) and foetal
tissues, a notification of serious adverse reactions and events can be required according to
Directive 2006/86/EC.
VIII. Preclinical data and clinical data supporting CE marking including Post-
Market Clinical Follow-up (PMCF)
The demonstration of conformity with the essential requirements must include a pre-clinical
evaluation in accordance with Annexes II, III and VII to Directive 93/42/EEC and a clinical
evaluation in accordance with Annex X to Directive 93/42/EEC.
A PMCF programme must be planned and can take the form of clinical investigations and/or
registries. Postmarket surveillance should be carried out in all comers registries to better
provide the clinical safety and performance data on the IVF/ART solutions use in the clinical
practice.
IX. IVF/ART solutions modification
When the manufacturer does some subsequent modifications or when design iterations
occur to an already marketed IVF/ART products, it is essential to evaluate, based on a risk
analysis, preclinical data and clinical data, the impact of the modified characteristics. The
results of this evaluation will determine the need for any new or additional testing.
For medical device of class III falling under rule 13 of the Annex IX of the Directive
93/42/EEC, each modification influencing the specified drug characteristics requires a
consultation by the notified body of the Member State's Competent Authority for medicinal
products or of the European Medicine Agency (EMA).
8
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.4/1 Rev.8
July 2001
GUIDELINES FOR THE CLASSIFICATION
OF MEDICAL DEVICES
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-
Directives on medical devices. They are legally not binding. The Guidelines have been carefully
drafted through a process of intensive consultation of the various interested parties (competent
authorities, Commission services, industries, other interested parties) during which intermediate drafts
were circulated and comments were taken up in the document. Therefore, this document reflects
positions taken by representatives of interested parties in the medical devices sector.
Note : This document is a revision of an earlier document published in December 1999 as

MEDDEV. 2.4/1 rev. 6
-1-
Pages
1. PURPOSE AND PHILOSOPHY OF MEDICAL DEVICE

CLASSIFICATION ........................................................................ 3
2. PRACTICAL RELEVANCE OF CLASSIFICATION................
2.1. General requirements. ..............................................................
2.2. Conformity assessment .............................................................
2.3. Clinical data...............................................................................
2.4. Labelling ....................................................................................
2.5. Miscellaneous.............................................................................
3. HOW TO CARRY OUT CLASSIFICATION .................................
3.1. Basic definitions ........................................................................
3.2. Application rules........................................................................
3.3. How to use the rules and the decision tree ..............................
3.4. Practical example ......................................................................
3.5. Handling of interpretational problems.....................................
4. EXPLANATIONS OF INDIVIDUAL RULES ............................
4.1. Graphical summary - Guidance chart ......................................
4.2. General explanation of rules/Practical issues/Examples.........
APPENDICES:
1. Annex IX of the Medical Device Directive
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CLASSIFICATION
It is not feasible economically nor justifiable in practice to subject all

medical devices to the most rigorous conformity assessment procedures
available. A graduated system of control is more appropriate. In such a
system, the level of control corresponds to the level of potential hazard
inherent in the type of device concerned. A medical device classification
system is therefore needed, in order to channel medical devices into the
proper conformity assessment route.
In order to ensure that conformity assessment under the Medical Device

Directive functions effectively from January 1995, manufacturers should
be able to know as early as possible in which class their product is.
Identification of the class of each individual type of device by a committee
procedure would have taken too long to achieve this goal. It was therefore
decided to set up a system of classification rules within the directive, so
that each manufacturer could classify its own devices.
A simple set of classification rules based on technical features of medical

devices existing now and in the future is impossible, because of the vast
number and the changing nature of variables involved. The human body,
however, is a relatively unchanging element of the equation. The
European legislator established therefore a classification concept which is
essentially based on potential hazards related to the use and possible
failure of devices taking account of technology used and of health policy
considerations. This approach in turn allows the use of a small set of
criteria that can be combined in various ways: duration of contact with the
body, degree of invasiveness and local vs. systemic effect.
It is recognized that although the existing rules will adequately classify

the vast majority of existing devices, a small number of difficult cases may
arise. Such cases may in particular include the determination of the
borderline between two classes. In addition there may be devices that
cannot be classified by the existing rules because of their unusual nature
or situations where the classification would result in the wrong level of
conformity assessment in light of the hazard represented by the device.
-3-
2. PRACTICAL RELEVANCE OF CLASSIFICATION
2.1. General requirements
All devices must:

- meet the essential requirements irrespective of the class of the device
(see also Annex VIII of the Directive)
- be subject to the reporting requirements under the medical device
vigilance system;
- be CE marked (except custom-made devices and devices intended for
clinical investigation).
Note: If Annex VIII applies (custom made devices and devices intended
for clinical investigation) then all its requirements apply irrespective of
the class of the device. Class I custom made devices need not be
accompanied by the statement referred to in Annex VIII (Art. 4).
2.2. Conformity Assessment
CONFORMITY CLASSES
ASSESSMENT
PROCEDURES
ANNEXES I I I II A II B III
sterile meas.
II (+ Sect.4)
II (- Sect. 4)
III
IV
V
VI
VII
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2.3. Clinical data
2.3.1. Clinical evaluation
The Medical Devices Directive states that as a general rule,

confirmation of conformity with the requirements concerning the
characteristics and performances referred to in sections 1 and 3 of
Annex I of Directive 93/42/EEC under the normal conditions of use
of the device and the evaluation of the undesirable side-effects must
be based on clinical data. This rule applies in particular in the case
of implantable devices and devices in class III (Annex X, section 1.1)
2.3.2. Clinical investigation
Clinical investigation with Class III devices and implantable and

long-term invasive devices falling within Class II A or II B may
start 60 days after their notification to the Competent Authority
unless a negative decision from the Competent Authority has been
received within this timeframe. (Art. 15)
2.4. Instructions for use

Instructions for use are not required for Class I and II A devices if these
devices can be used safely without such instructions (Annex I Sect. 13.1.).
2.5. Miscellaneous
The manufacturer, or persons responsible for marketing of a Class I

product and designated by the manufacturer, must notify their address
and the devices concerned to the Competent Authority of the Member
State where they have their registered place of business (Art. 14).
3. HOW TO CARRY OUT CLASSIFICATION
The manufacturer should first decide if the product concerned is a medical

device as defined in the Directive 93/42 or an accessory to such a medical
device and if it therefore comes within the scope of this Directive.
Active implantable devices and devices for in vitro diagnosis are covered
by separate directives, which do not apply the classification rules reviewed
in these Guidelines.
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3.1. Basic definitions
The classification rules are based on terms related to duration of contact

with the patient, degree of invasiveness and the part of the body affected
by the use of the device. These terms are defined in Section I of Annex IX
of the Directive and reproduced below, together with some additional
guidance.
3.1.1. Time
3.1.1.1. Duration
Transient
Normally intended for continuous use for less than 60 minutes.
Short term
Normally intended for continuous use for not more than 30 days.
Long term
Normally intended for continuous use for more than 30 days.
3.1.1.2 Concept of continuous use
Concepts of duration such as transient, short term and long term

are defined in terms of continuous use. Continuous use must be
understood as an uninterrupted actual use for the intended
purpose. For instance, a scalpel may be used on the same patient
throughout an operation that may last for several hours. The
uninterrupted use for an intended purpose, i.e. cutting tissue, will
normally not last for more than a few seconds at a time. Therefore
a scalpel is a transient use device.
However where usage of a device is discontinued in order for the

device to be replaced immediately by the same or an identical device
(e.g. replacement of a ureteric catheter) this shall be considered an
extension of the continuous use of the device.
3.1.2. Invasiveness
Invasive devices
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A device which, in whole or in part, penetrates inside the body, either
through a body orifice or through the surface of the body.
Body orifice
Any natural opening in the body, as well as the external surface of

the eyeball, or any permanent artificial opening, such as a stoma.
Surgically invasive device
An invasive device which penetrates inside the body through the

surface of the body, with the aid or in the context of a surgical
operation.
For the purposes of this Directive devices other than those referred to
in the previous subparagraph and which produce penetration other
than through an established body orifice, shall be treated as
surgically invasive devices.
There are two exceptions to this:
A surgically created stoma used in colostomy and ileostomy or

permanent tracheostomy is considered to be a natural body
orifice. Therefore devices introduced into such a stoma are not
surgically invasive. A surgically created opening to allow access
to the circulatory system in contrast should not be considered to
be such a "natural body orifice". Devices introduced into such an
opening are surgically invasive.
A device that administers energy to the body should not be

considered as invasive if only energy penetrates the body and not
the device itself. Energy as such is not a device and therefore it
cannot be classified. Only the device generating the energy must
be classified. However, if a device administers a substance,
whether this substance is a medicine or a medical device, such a
substance must be assessed in its own right (e.g. substances
administered by a jet injector).
Any device which, in whole or in part, penetrates inside the body,

either through a natural body orifice or through the surface of the
body is an invasive device. A surgically invasive device always
implies that it enters through an artificially created opening. This
can be a large opening, such as a surgical incision, or it can be a
pinprick opening created by a needle. Therefore surgical gloves and
needles used with syringes are surgically invasive.
-7-
Implantable device
Any device which is intended:
- to be totally introduced into the human body or,

- to replace an epithelial surface or the surface of the eye,
by surgical intervention which is intended to remain in place after

the procedure.
Any device intended to be partially introduced into the human body
through surgical intervention and intended to remain in place after
the procedure for at least 30 days is also considered an implantable
device.
One of the key elements in defining what is an implantable device is the

concept of "procedure". Thus an implantable device must remain in the
patient after the procedure. A "procedure" must be understood in this
context to include the surgical procedure during which the implant is placed
into the body and the immediate post-operative care that is associated with
the procedure. The" procedure" does not extend to the conclusion of the
therapeutic treatment, e.g. the removal of an implant must be considered to
be another "procedure". Thus a plate used to reduce a fracture of the bone
is an implant even if it is taken out after the fracture has healed. In this
case the placing of the plate and its explantation are two different surgical
procedures.
Some partially implanted devices are deemed to be implants. For instance,

if an operation is carried out to specifically to place an infusion port into the
body, then such an infusion port would remain for at least 30 days after the
procedure and consequently be an implant.
However, a suture used for skin wound closure that is taken out prior to 30
days is not an implant.
3.1.3. Active devices
Definition of active medical device (Annex IX Sect. I clause 1.4):
Any medical device the operation of which depends on a source of electrical

energy or any source of power other than that directly generated by the
human body or gravity and which acts by converting this energy. Medical
devices intended to transmit energy, substances or other elements between an
active medical device and the patient, without any significant change, are
not considered to be active medical devices.
-8-
The concept act by converting energy includes conversion of energy in the
device and/or conversion at the interface between the device and the tissues
or in the tissues.
The concept of significant changes includes changes in the nature, level

and density of energy (see rule 9). This means that for instance an electrode
is not an active device under this classification system as long as the energy
input is intended to be the same as the energy output. For instance,
resistance in a wire that causes minor changes between input and output
cannot be considered to constitute "significant change". For example
electrodes used in electrosurgery for cutting tissues or cauterisation are
active devices because their operation depends on energy provided by a
generator and their action is achieved by conversion of energy at the
interface between the device and the tissue or in the tissue. Electrodes
intended for E.C.G. or E.E.G are normally not active devices because they
do not normally act by conversion of energy. However, it should be
understood that an electrode, which is an accessory of an active implant, is
covered under the relevant directive for active implants. Further
information on this issue can be found in "Guidelines relating to the
application of the Council Directive 90/385/EEC on active implantable
medical devices (Med.Dev. 2.1/2).
The application of energy from the human body does not make a device
"active" unless that energy is stored within the device for subsequent
release. For instance, energy generated by human muscle and applied to
the plunger of a syringe (thus causing a substance to be delivered to a
patient) does not make this syringe an "active device". However, if a drug
delivery system depends upon manual winding to preload a spring which is
subsequently released to deliver a substance, then the device incorporating
the spring is an "active device".
Medical devices using prestored gases and/or vacuum as a power source are
regarded as active devices, e.g. gas mixers with anesthesia machines and
gas powered suction pumps.
Heating/cooling pads intended only to release stored thermal energy are not
active devices because they do not act by conversion of energy. However,
heating/cooling pads which act by chemical action (e.g. endothermic or
exothermic reaction) are active devices as they are converting chemical
energy into heat energy and or vice versa.
Radioactive sources that are intended to deliver ionizing radiation are

regarded as active medical devices, unless they are radiopharmaceuticals as
defined in article 2 of Directive 89/343/EEC or radioactive implants as
defined in article 1 of Directive 90/385/EEC.
-9-
3.1.4 Devices with a measuring function
See MEDDEV 2.1/5
3.2. Application rules
In terms of further interpretation of the decision rules, the following should

be considered:
- It is the intended purpose that determines the class of the device and not
the particular technical characteristics of the device, unless these have a
direct bearing on the intended purpose.
- It is the intended and not the accidental use of the device that
determines the class of the device. For instance a suture organizer, that
is intended to keep order in the maze of the many threads of sutures
used in open heart surgery, should not be considered as an invasive
device if in the normal use it can be kept outside the patient. Similarly,
if a medical practitioner uses the device in a manner not intended by the
manufacturer, this does not change the class of the device for the purpose
of conformity assessment.
- It is the intended purpose assigned by the manufacturer to the device

that determines the class of the device and not the class assigned to other
similar products. For instance two sutures that have the same
composition may well have different intended purposes.
- As an alternative to classifying the system as a whole, the determination

of the class of a particular device may be made with respect to the
simplest configuration that can still be considered, in view of its proper
functional features, as a device in its own right. A device that is part of a
system, e.g. a tube in an extra corporeal circulation set, may be classed
as a device in its own right rather than classifying the system as a whole.
Similarly combination devices with parts that have different functional
purposes, may be analysed separately with respect to each of these parts.
For instance, a drainage device will have an invasive tube and a non-
invasive collection device. These components may be classified
separately.
- Accessories must be classified separately from their parent device.
- If a given device can be classified according to several rules, then the

highest possible class applies. For instance, a wound dressing
incorporating collagen is covered by rules 4 (Class I, Class IIa or Class
IIb depending on intended use) and 17 (Class III).
- 10 -
- If the device is not intended to be used solely or principally in a specific
part of the body, it must be considered and classified on the basis of the
most critical specified use. Classification of the device will have to be
determined on the basis of claims contained in the information provided
with the device. The manufacturer must be sufficiently specific in that
regard. If the manufacturer wants to avoid the particular higher
classification, then it must clearly define on the labelling the intended
purpose in such a way that the device falls into the lower class. The
manufacturer must provide as a minimum requirement either
appropriate positive or negative indications for use.
For a device to be "specifically intended" for the purpose referenced in a

particular classification rule, the manufacturer must clearly indicate that
the device is intended for such a specific purpose in the information
accompanying the device. Otherwise it is deemed to be intended to be
used principally for the purpose that is accepted in general medical
practice.
- Multi-application equipment such as laser printers and identification

cameras, which may be used in combination with medical devices, are
not medical devices unless their manufacturer places them on the
market with specific intended purpose as medical devices.
- Standalone software, e.g. software which is used for image enhancement

is regarded as driving or influencing the use of a device and so falls
automatically into the same class. Other standalone software, which is
not regarded as driving or influencing the use of a device, is classified in
its own right.
3.3. How to use the rules
The manufacturer must take into consideration all the rules in order to
establish the proper classification for his device. It is quite conceivable for
instance that one of the general rules that are not specific to active
devices, nevertheless applies to such a device. All the device
characteristics must be taken into consideration. The characteristic or
combination of characteristics in accordance with the intended purpose of
the device that rates the highest class determines the class for the device
as a whole.
3.4. Practical example
Example: a wound drainage device
- 11 -
A simple wound drainage device has three components that must be taken
into consideration: the cannula, the tubing and the collector unit. If the
device is sold without a cannula, then the classification of the cannula
does not need to be taken into account.
It is assumed here that the device is used for a short term duration, i.e.
that uninterrupted intended use is more than 60 minutes and less than 30
days. It is furthermore assumed that the collected liquids are not
intended to be re infused into the body nor reprocessed for eventual re
infusion and that the device is not intended to be connected to a powered
suction system.
Intended uses Rule Class
Surgically invasive cannula to reach a wound 7 II A

site in the pleural cavity to drain the cavity
Non-invasive tubing to evacuate body liquids 1 I
towards the collector.
Non-invasive collector to receive the body 1 I
liquids.
The clear conclusion here is that the manufacturer would have a choice of
applying Class II A to the whole device or carrying out separate
conformity assessment procedures for the cannula on one hand and the
tubing and collector on the other hand.
3.5. Handling of interpretational problems.
In case the manufacturer is unsure how its devices should be classified, it

should first consult a Notified Body. In case doubts remain or there is a
disagreement with the Notified Body, the relevant Competent Authority
should be approached in accordance with Art. 9 of the Directive. In
addition, the Directive provides Community wide mechanisms, including a
committee procedure, to address problems related to classification.
4. EXPLANATIONS OF INDIVIDUAL RULES
The explanations are given in the following manner. This section begins
with a graphical summary of the rules, as a preface to subsections on the
individual rules. Each subsection starts with a general explanation of the
rule followed by a tabular presentation of the rule and examples of devices
to which it applies. Any special terms used are explained and practical
issues related to the rule are clarified.
It must be emphasized that even if a particular device type is given as an

example, this does not mean that such devices are in all cases in the class
- 12 -
indicated by the example. It is always possible that some manufacturer
will assign to such a device an entirely different intended use than what
was used in the context of the example.
- 13 -
4.1 Graphical summary medical devices classification
guidance chart for initial identification of probable device
class
Note:
Always confirm definitive classification by reading all rules in
detail, and utilise additional assistance in this guidelines
document as provided in the form of general explanations of rules
and examples of devices (see section 4.2)
SUBJECTS
Non invasive devices Rules 1, 2, 3, 4
Invasive devices Rules 5, 6, 7, 8
Active devices Rules 9, 10, 11, 12
Special rules Rules 13, 14, 15, 16, 17, 18
Remember! The characteristics or combination of characteristics in accordance with

the intended purpose of the device that rates the highest class determinates the
class for the device as a whole.
NON INVASIVE DEVICES
Rule 1 Rule 3 Rule 4

Rule 2
Either do not touch Modify biological or chemical In contact with injured
Channelling or
patient or contact composition of blood, body liquids, skin (mechanical barrier -
storing for eventual
only intact skin other liguids intended for infusion absorb exudates)
administration
Class I Class IIb Class I

Class I
or or
or or
Only filtration, Intended for wounds which
For use with blood, May be connected to centrifugation or breach dermis and heal
other body fluids, an active medical exchange of gas or heat only by secondary intent
organs, tissues device
Class IIa Class IIb

Class IIa Class IIa
or
Intended to manage micro-
environment of wound +
others
Class IIa
- 14 -
INVASIVE DEVICES
R ul e 5 R ul e 6
Inv asi ve i n b od y Su rg ica ll y in vas ive
ori fice or sto ma - tran si en t u se
(n ot su rgi cal ly )
or or
C la ss IIa
Tra nsi en t u se Sh or t ter m L on g term C on ne cted to an

u se u se a ctive med ic al
d evi ce o f C la ss IIa
o r h ig h er D ia gn os e/co ntro l Su pp ly e ne rg y/
C la ss or
- de fec t o f h ea rt/ io n izi ng rad ia tio n
I C la ss C la ss
ce ntra l ci rcu la ti on syste m
IIa IIb
C la ss C la ss IIb
IIa C la ss III
or or R eu sa bl e su rgi ca l
in stru me nt or
If o nl y in ora l If o nl y in ora l
ca vity, e ar ca na l ca vity, e ar ca na l Bi ol og ica l e ffe ct
C la ss I
o r n a sal cav ity o r n a sal cav ity -m ai nl y ab sor be d
C la ss IIb
C la ss C la ss
I IIa
or
Sys te m to
a dmi ni ster m ed ic in es
- po ten tia ll y ha zar do us
C la ss IIb
INVASIVE DEVICES
Rule 8
Rule 7
Surgically invasive
Surgically invasive
Long-term use and
Short-term use
implantable devices
II b
or Class or or or
Specifically to II a Supply To be Biological effect
monitor/correct energy/ placed in or mainly
defect of heart ionizing teeth absorbed
or central radiation
or
circulatory II a III
system - by II b
direct contact
or
or
III
Undergo
or Biological effect Used in direct chemical change
mainly absorbed contact with heart in body - or
or central administer
III circulatory/ medicines (NOT
For use in direct
nervous system in teeth)
contact with central
nervous system or III III
III
Undergo chemical change
in body - or administer
medicines (NOT in teeth)
II b
- 15 -
ACTIVE DEVICES
Rule 9 Rule 10 Rule 11

Active therapeutic devices Active device for diagnosis. May
supply energy, for "imaging
Active devices to administer Rule 12
intended to administer or purpose" monitor vital
remove medicines & other All other active devices
exchange energy substances to or from the body
physiological processes
IIa IIa IIa

I
or or
or or
Administer or Intended to
When used to monitor If this is in a
exchange control &
Special rule vital processes where potentially
energy in monitor or
All devices emitting variations could result hazardous way
potentially influence
ionizing radiation and in immediate danger
hazardous way directly a class
related monitors in IIb
IIb active
medical procedure
therapeutic IIb
IIb
device
or
IIb IIb
SPECIAL RULE
All devices emitting
ionizing radiation
and related
monitors in medical
procedure
IIb
SPECIAL RULES
Rule 13 Rule 17
Devices incorporating Rule 15
Devices utilizing animal
integral medicinal Specific for disinfecting,
tissues or derivatives (not
product liable to act in cleaning, rinsing devices -
devices in contact only
ancillary way on human for contact lenses
with intact skin)
body
III IIb III
or
Rule 14 For
disinfecting Rule 16
Devices used for
other Non active devices Rule 18
contraception or
medical to record X-ray Blood Bags
prevention of sexually
devices diagnostic images
transmitted diseases
other than
by physical
IIb action IIa IIb
IIa
or
If implantable or
long-term invasive
III
- 16 -
End Part 1
......
Part 2 : ......See next document (starting with page 16 again).
...............................
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MEDDEV 2.4/1 rev. 8 PART 2: GUIDELINES FOR THE CLASSIFICATION OF MEDICAL DEVICES (July 2001)
.................
4.2 GENERAL EXPLANATION OF RULES/PRACTICAL ISSUES/EXAMPLES
Rule 1 - Devices that either do not touch the patient or contact intact skin only
General explanation of the rule
This is a fallback rule applying to all devices that are not covered by a more specific rule.
This is a rule that applies in general to devices that come into contact only with intact skin or that do not touch the patient.
RULE 1 EXAMPLES
All non-invasive devices are in Class I, unless one of the rules set out hereinafter - Body liquid collection devices intended to be used in such a way that a return flow is
applies. unlikely (e.g. to collect body wastes such as urine collection bottles, ostomy pouches,
incontinence pads or collectors used with wound drainage devices). They may be
connected to the patient by means of catheters and tubing.
- Devices used to immobilize body parts and/or to apply force or compression on them
(e.g. non-sterile dressings used to aid the healing of a sprain, plaster of Paris, cervical
collars, gravity traction devices, compression hosiery).
- Devices intended in general for external patient support (e.g. hospital beds, patient
hoists, walking aids, wheelchairs, stretchers, dental patient chairs).
- Corrective glasses, frames, stethoscopes for diagnosis, eye occlusion plasters, incision
drapes, conductive gels, non-invasive electrodes (electrodes for EEG or ECG), image
intensifying screens.
- Permanent magnets for removal of ocular debris
Practical issues of classification
Some non-invasive devices are indirectly in contact with the body and can influence internal physiological processes by storing,
channeling or treating blood, other body liquids or liquids which are returned or infused into the body or by generating energy that is
delivered to the body. These must be excluded from the application of this rule and be handled by another rule because of the
hazards inherent in such indirect influence on the body.
16
Rule 2 - Channeling or storing for eventual administration
These types of devices must be considered separately from the non-contact devices of rule 1 because they may be indirectly
invasive. They channel or store substances that will be eventually delivered into the body. Typically these devices are used in
transfusion, infusion, extracorporeal circulation, delivery of anaesthetic gases and oxygen.
In some cases devices covered under this rule are very simple gravity activated delivery devices.
RULE 2 EXAMPLES
All non-invasive devices intended for channeling or storing blood, body - Devices intended to be used as channels in active drug delivery systems, e.g.
liquids or tissues, liquids or gases for the purpose of eventual infusion, tubing intended for use with an infusion pump.
administration or introduction into the body are in Class IIa: - Devices used for channeling, e.g. antistatic tubing for anesthesia, anesthesia
breathing circuits and pressure indicator, pressure limiting devices.
- if they may be connected1 to an active medical device in Class IIa or a - Syringes for infusion pumps.
higher class,
- if they are intended for use for storing or channelling blood or other body - Devices intended to channel blood (e.g. in transfusion, extracorporeal
liquids or for storing organs, parts of organs or body tissues (are in Class circulation).
II a) - Devices intended for temporary storage and transport of organs for
transplantation.
- Devices intended for long term storage of biological substances and tissues such
as corneas, sperm, human embryos, etc.
in all other cases they are in Class I. - Devices that provide a simple channeling function, with gravity providing the
force to transport the liquid, e.g. administration sets for infusion.
- Devices intended to be used for a temporary containment or storage function
such as cups and spoons specifically intended for administering medicines2.
- Syringes without needles
17
Blood bags are covered as an exception under a separate rule (see rule 18).
If a device, e.g. tubing, can be used for a purpose that would cause it to be connected to an active device such a device will
be automatically in Class II A, unless the manufacturer clearly state that it should not be connected to an active device of
Class II A or higher.
Explanation of special concepts
Note 1: "May be connected to an active device". Such connection is deemed to exist between a non-active device and an
active device where a non-active device forms a link in the transfer of the substance between the patient and the active
device and the safety and performance of one of the devices is influenced by the other device. For instance, this applies to
tubing in an extracorporeal circulation system which is downstream from a blood pump and in the same blood flow circuit, but
not directly in contact with the pump.
Note 2: Solutions intended for preservation of organs during storage and transport are not medical devices.
18
Rule 3 - Devices that modify biological or chemical composition of blood, body liquids or other liquids
These types of devices must be considered separately from the non-contact devices of rule 1 because they are indirectly
invasive. They treat or modify substances that will be eventually delivered into the body. This rule covers mostly the more
sophisticated elements of extracorporeal circulation sets, dialysis systems and autotransfusion systems as well as devices for
extracorporeal treatment of body fluids which may or may not be reintroduced immediately into the body, including, where the
patient is not in a closed loop with the device..
RULE 3 EXAMPLES
All non-invasive devices intended for modifying the biological or - Devices intended to remove undesirable substances out of the blood by exchange of
chemical composition of blood, other body liquids or other liquids solutes such as hemodyalizers.
intended for infusion into the body are in Class IIb, - Devices intended to separate cells by physical means, e.g. gradient medium for
sperm separation.
- Haemodialysis concentrates.
unless the treatment consists of filtration, centrifugation or - Particulate filtration of blood in an extracorporeal circulation system. These are used
exchange of gas or heat, in which case they are in Class IIa. to remove particles and emboli from the blood.
- Centrifugation of blood to prepare it for transfusion or autotransfusion.
- Removal of carbon dioxide from the blood and/or adding oxygen.
- Warming or cooling the blood in an extracorporeal circulation system.
These devices are normally used in conjunction with an active medical device covered under rule 9 or rule 11.
Filtration and centrifugation should be understood in the context of this rule as exclusively mechanical methods.
19
Rule 4 - Devices in contact with injured skin
This rule is intended to cover primarily wound dressings independently of the depth of the wound. The traditional types of products
(e.g. used as a mechanical barrier) are well understood and do not result in any great hazard. There have also been rapid
technological developments in this area, with the emergence of new types of wound dressings for which non-traditional claims are
made, e.g. management of the micro-environment of a wound to enhance its natural healing mechanism. More ambitious claims
relate to the mechanism of healing by secondary intent, such as influencing the underlying mechanisms of granulation or epithelial
formation or preventing contraction of the wound. Some devices used on breached dermis may even have a life-sustaining or life-
saving purpose, e.g. when there is full thickness destruction of the skin over a large area and/or systemic effect. Dressings
containing medicinal products acting as ancillary to the dressing fall within Class III under Rule 13.
RULE 4 EXAMPLES
All non-invasive devices which come into contact with injured skin: - Wound dressings, such as absorbent pads, island dressings, cotton wool, wound
- are in Class I if they are intended to be used as a mechanical barrier, for strips and gauze dressings to act as a barrier or to maintain the wound positionally or
compression or for absorption of exudates, to absorb exudates from the wound.
- are in Class IIb if they are intended to be used principally with wounds which - Are principally intended to be used with severe wounds that have substantially and
have breached the dermis and can only heal by secondary intent extensively breached the dermis, and where the healing process can only be by
secondary intent such as:
- dressings for chronic extensive ulcerated wounds
- dressings for severe burns having breached the dermis and covering an extensive
area
- dressings for severe decubitis wounds
- dressings incorporating means of augmenting tissue and providing a temporary
skin substitute
- are in Class IIa in all other cases, including devices principally intended to - Have specific properties intended to assist the healing process by controlling the
manage the micro-environment of a wound. level of moisture at the wound during the healing process and to generally regulate the
environment in terms of humidity and temperature, levels of oxygen and other gases
and ph values or by influencing the process by other physical means .
- These devices may specify particular additional healing properties whilst not being
intended for extensive wounds requiring healing by secondary intent.
- Adhesives for topical use.
- Polymer film dressings, hydrogel dressings and non-medicated impregnated gauze
dressings.
20
Products covered under this rule are extremely claim sensitive, e.g. a polymeric film dressing would be in Class II A if the
intended use is to manage the micro-environment of the wound and in Class I if its intended use is limited to retaining an
invasive cannula at the wound site. Consequently it is impossible to say a priori that a particular type of dressing is in a given
class without knowing its intended use as defined by the manufacturer. However, a claim that the device is interactive or
active with respect to the wound healing process usually implies that the device is in Class II B.
Most dressings that are intended for a use that is in Class II A or II B, also perform functions that are in Class I, e.g. that of a
mechanical barrier. Such devices are nevertheless classed according to the intended use in the higher class.
For such devices incorporating medicines see rule 13 or animal tissues see rule 17.
- Breached dermis: the wound exposes at least partly the subcutaneous tissue.
- Secondary intent: the wound heals by first being filled with granulation tissue, subsequently the epithelium grows back over
the granulation tissue and the wound contracts. In contrast primary intent implies that the edges of the wound are close
enough or pulled together, e.g. by suturing, to allow the wound to heal.
21
Rule 5 Devices invasive in body orifices
Invasiveness with respect to the body orifices (ear, mouth, nose, eye, anus, urethra and vagina) must be considered
separately from invasiveness that penetrates through a cut in the body surfaces ( surgical invasiveness). For short term use,
a further distinction must be made between invasiveness with respect to the less vulnerable anterior parts of the ear, mouth
and nose and the other anatomical sites that can be accessed through natural body orifices.
The surgically created stoma, which for example allows the evacuation of urine or faeces, should also be considered as a
body orifice.
Devices covered by this rule tend to be diagnostic and therapeutic instruments used in particular specialities (ENT,
ophthalmology, dentistry, proctology, urology and gynecology).
RULE 5 EXAMPLES
All invasive devices with respect to body orifices, other than

surgically invasive devices and which are not intended for
connection to an active medical device:
- are in Class I if they are intended for transient use, - Handheld mirrors used in dentistry to aid in dental diagnosis and surgery, dental
impression materials, tubes used for pumping the stomach, impression tray, enema
devices, examination gloves and prostatic balloon dilation catheters.
- are in Class IIa if they are intended for short term use, - Contact lenses, urinary catheters, tracheal tubes, stents, vaginal pessaries and
perineal reeducation devices.
except if they are used in the oral cavity as far as the pharynx, in - Dressings for nose bleeds, dentures intended to be removed by the patient.
an ear canal up to the ear drum or in a nasal cavity , in which case
they are in Class I,
- Urethral stents.
- are in Class IIb if they are intended for long term use,
22
except if they are used in the oral cavity as far as the pharynx, in - Orthodontic wire, fixed dental prostheses, fissures sealants.
an ear canal up to the ear drum or in a nasal cavity and are not
liable to be absorbed by the mucous membrane, in which case they
are in Class IIa.
All invasive devices with respect to body orifices, other than - Tracheostomy or tracheal tubes connected to a ventilator, blood oxygen analysers
surgically invasive devices, intended for connection to an active placed under the eye-lid, powered nasal irrigators, nasopharyngeal airways, some
medical device in Class IIa or a higher class, are in Class IIa. enteral feeding tubes, fibreoptics in endoscopes connected to surgical lasers, suction
catheters or tubes for stomach drainage, dental aspirator tips.
23
Rule 6 - Surgically invasive devices for transient use
This rule covers principally three major groups of devices: devices that are used to create a conduit through the skin (needles,
cannulae, etc.), surgical instruments (scalpels, saws, etc.) and various types of catheters, suckers, etc.
RULE 6 EXAMPLES
All surgically invasive1 devices intended for transient use are in - Needles used for suturing, needles of syringes, lancets, suckers, single use scalpels,
Class IIa unless they are: single use scalpel blades, support devices in ophthalmic surgery, staplers, surgical
swabs, drill bits connected to active devices, surgical gloves, etchants, tester of
artificial heart valves, heart valve occluder, heart valve sizers and holders, trial hip
prosthesis heads or stems, swabs to sample exudates, single use aortic punches (see
note 2)
- intended specifically to diagnose, monitor or correct a defect 2 of - Cardiovascular catheters (e.g. angioplasty balloon catheters), including related
the heart or of the central circulatory system1 through direct contact guidewires and dedicated4 disposable cardiovascular surgical instruments e.g.
with these parts of the body, in which case they are in Class III 3 electrophysiological catheters, electrodes for electrophysiological diagnosis and
ablation.
- Catheters containing or incorporating sealed radioisotopes, where the radioactive
isotope as such is not intended to be released into the body, if used in the central
circulatory system
- reusable surgical instruments1, in which case they are in Class I3, - Scalpels, scalpel handles, drill bits, saws, that are not intended for connection to an
active device, and retractors forceps, excavators and chisels.
- intended to supply energy in the form of ionizing radiation in - Catheters containing or incorporating sealed radioisotopes, where the radioactive
which case they are in Class IIb, isotope as such is not intended to be released into the body, if used in the circulatory
system, excluding the central circulatory system
- intended to have a biological5 effect or to be wholly or mainly

absorbed4 in which case they are in Class IIb,
24
- intended to administer medicines by means of a delivery system, if - Devices for repeated self-application where dosage levels and the nature of the
this is done in a manner that is potentially hazardous6 taking into medicinal product are critical, e.g. insulin pens.
account of the mode of application, in which case they are Class
IIb.
Explanations of special concepts
Note 1: Terms such as "surgically invasive device", "central circulatory system" and "reusable surgical instruments" are
defined in Section I of Annex IX of the Directive. In particular surgical instruments connected to an active device are not
considered to be reusable surgical instruments.
Note 2: The expression "correct a defect" does not cover devices that are used accessorily in heart surgery, e.g. clamps. The
first indent of this rule does not apply to aortic punches and similar cutting instruments which perform a similar function to a
scalpel.
Note 3: Surgical instruments which are not specifically intended for purposes described in the first indent, and irrespective of
the site of application, are in class IIA, if they are intended for single use and in class I if they are reusable.
Note 4: Dedicated means that the intended purpose of the device is to diagnose, monitor or correct a defect of the heart or of
the central circulatory system.
Note 5:
Biological effect: All materials and devices have the potential to affect tissues following use in a surgically invasive procedure.
A material is considered to have a biological effect if it actively and intentionally induces, alters or prevents a response from
the tissues that is mediated by specific reactions at a molecular level. Such a device may be described as bioactive.
Wholly or mainly absorbed: The term absorption refers to the degradation of a material within the body and the metabolic
elimination of the resulting degradation products from the body.
Note 6: The concept of "potentially hazardous manner" is related to the characteristics of the device and not the competence
of the user.
25
Rule 7 - Surgically invasive devices for short-term use
These are mostly devices used in the context of surgery or post-operative care (e.g. clamps, drains), infusion devices
(cannulae, needles) and catheters of various types.
RULE 7 EXAMPLES
All surgically invasive devices intended for short term use are in - Clamps, infusion cannulae, skin closure devices, temporary filling materials.
Class IIa unless they are intended: - Tissue stabilisers2 used in cardiac surgery
- either specifically to diagnose, monitor or correct a defect2 of the - Cardiovascular catheters, cardiac output probes and temporary pacemaker leads.
heart or of the central circulatory system through direct contact - Thoracic catheters intended to drain the heart, including the pericardium
with these parts of the body, in which case they are in Class III, - Carotid artery shunts
- or specifically for use in direct contact with the central nervous - Neurological catheters, cortical electrodes and connonoid paddles.
system, in which case they are in Class III,
- or to supply energy in the form of ionizing radiation in which - Brachytherapy devices.

case they are in Class IIb,
- intended to have a biological effect or to be wholly or mainly - Absorbable sutures and biological adhesives.
absorbed in which case they are in Class III,
- or to undergo chemical change in the body, except if the devices - Adhesives
are placed in the teeth, or to administer medicines1, in which case
they are Class IIb.
26
Note 1: Administration of medicines is more than just channeling, it implies also storage and/or influencing the volume and
rate of the medicine delivered. Implanted capsules for the slow release of medicines are medicines and not medical devices.
Note 2: The expression correct a defect does not cover devices that are used accessorily in heart surgery, e.g. tissue
stabilisers.
27
Rule 8 - Surgically invasive devices for long-term use and implantable devices
These are mostly implants in the orthopaedic, dental, ophthalmic and cardiovascular fields as well as soft tissue implants such
as implants used in plastic surgery.
RULE 8 EXAMPLES
All implantable devices and long-term surgically invasive devices - Prosthetic joint replacements, ligaments, shunts, stents, nails, plates, intra-ocular
are in Class IIb unless they are intended: lenses, internal closure devices, tissue augmentation implants, infusion ports,
peripheral vascular grafts, penile implants, non-absorbable sutures, bone cements and
maxillo-facial implants, visco-elastic surgical devices intended specifically for
ophthalmic anterior segment surgery 1.
- to be placed in the teeth2, in which case they are in Class IIa, - Bridges, crowns, dental filling materials and pins, dental alloys, ceramics and
polymers.
- to be used in direct contact with the heart, the central circulatory - Prosthetic heart valves, aneurysm clips, vascular prostheses, spinal stents, vascular
system or the central nervous system, in which case they are Class stents, CNS electrodes and cardiovascular sutures.
III, - Permanent vena cava filters
- to have a biological effect or to be wholly or mainly absorbed, in - Absorbable sutures,adhesives and implantable devices claimed to be bioactive
which case they are in Class III, through the attachment of surface coatings such as phosphorylcholine.
- or to undergo chemical change3 in the body, except if the devices - Rechargeable non-active drug delivery systems.
are placed in the teeth, or to administer medicines, in which case
they are in Class III.
Note 1 :these products are implants because in normal conditions a significant amount of the substance remains at the
surgical site after the procedure. If these devices contain animal tissues or derivatives of animal tissues, they are covered by
rule 17.
28
Note 2: Implants without bioactive coatings intended to secure teeth or prostheses to the maxillary or mandibular bones are in
Class II B following the general rule. Hydroxy-apatite is considered as having biological effect only if so claimed and
demonstrated by the manufacturer.
Note 3: The clause about chemical change under this rule does not apply to products such as bone cements where the
chemical change takes place during the placement and does not continue in long term.
29
Rule 9 - Active therapeutic devices intended to administer or exchange energy
Devices classified by this rule are mostly electrical equipment used in surgery such as lasers and surgical generators. In addition
there are devices for specialised treatment such as radiation treatment. Another category consists of stimulation devices, although
not all of them can be considered as delivering dangerous levels of energy considering the tissue involved.
RULE 9 EXAMPLES
All active therapeutic devices intended to administer or exchange energy are in Electrical and/or magnetic and electromagnetic energy
Class IIa - Muscle stimulators and external bone growth stimulators, TENS devices and eye
electromagnets, electrical acupuncture
Thermal energy
- Cryosurgery equipment, heat exchangers, except the types described below
Mechanical energy
- Powered dermatomes, powered drills and dental hand pieces.
Light
- Phototherapy for skin treatment and for neonatal care
Sound
- Hearing aids
Ultrasound
- Equipment for physiotherapy
30
unless their characteristics are such that they may administer or exchange Kinetic energy
energy to and from the human body in a potentially hazardous way1, taking - Lung ventilators
account of the nature, the density and the site of application of the energy, in
which case they are in Class IIb. Thermal energy
- Incubators for babies, warming blankets, blood warmers, electrically powered heat
exchangers, for instance those used with patients incapable of reacting,
communicating and/or who are without a sense of feeling
Electrical energy
- High-frequency electrosurgical generators, and
electrocautery equipment, including their electrodes, external pacemakers, external
defibrillators, electroconvulsive therapy equipment
Coherent light
- Surgical lasers
Ultrasound
- Lithotriptors, surgical ultrasound devices
Ionizing radiation
- Radioactive sources for afterloading therapy, therapeutic cyclotrons, linear
accelerators, therapeutic X-ray sources.
All active devices intended to control and monitor the performance of active - External feedback systems for active therapeutic devices, afterloading control
therapeutical devices in Class IIb or intended to influence directly the devices.
performance of such devices are in Class IIb.
Note 1: The decision as to whether a medical device administers or exchanges energy to and from the human body in a
potentially hazardous way should take into account the following factors. The concept of "potentially hazardous" is dependent
on the type of technology involved and the intended application of the device to the patient and not on the measures adopted
by the manufacturer in view of good design management (e.g. use of technical standards, risk analysis). For instance all
devices intended to emit ionizing radiation, all lung ventilators and lithotriptors should be in Class IIB. However, the
manufacturer's obligation to comply with design requirements and solutions adopted, such as use of standards, exist
independently from the classification system.
31
Rule 10 - Active devices for diagnosis.
This covers principally a whole range of widely used equipment in the fields ultrasound diagnosis and capture of physiological
signals as well as therapeutic and diagnostic radiology.
RULE 10 EXAMPLES
Active devices intended for diagnosis are in Class IIa:
- if they are intended to supply energy which will be absorbed by - Magnetic resonance equipment, pulp testers, evoked response stimulators,
the human body, except for devices used to illuminate the diagnostic ultrasound.
patient's body, in the visible spectrum,
- if they are intended to image in vivo distribution of - Gamma cameras, positron emission tomography and single photon emission
radiopharmaceuticals, computer tomography.
- if they are intended to allow direct diagnosis or monitoring of - Electrocardiographs, electroencephalographs, cardioscopes with or without pacing
vital physiological processes1, pulse indicators2
- Electronic thermometers
- Electronic stethoscopes
- Electronic blood pressure measuring equipment
unless they are specifically intended for monitoring of vital - Intensive care monitoring and alarm devices (for e.g. blood pressure, temperature,
physiological parameters, where the nature of variations is such oxygen saturation), biological sensors, blood gas analysers used in open heart
that it could result in immediate danger to the patient, for surgery, cardioscopes and apnea monitors, including apnea monitors in home care
instance variations in cardiac performance, respiration, activity
of CNS in which case they are in Class IIb.
Active devices intended to emit ionizing radiation and intended - Diagnostic X-ray sources.
for diagnostic and therapeutic interventional radiology3
including devices which control or monitor4 such devices, or
which directly influence their performance, are in Class II B.
Examples of special concepts:
Note 1: Vital physiological processes and parameters, include for example respiration, heart rate, cerebral functions, blood
32
gases, blood pressure and body temperature. Medical devices intended to be used for continuous surveillance of vital
physiological processes in anesthesia, intensive care or emergency care are in Class IIB, whilst medical devices intended to
be used to obtain readings of vital physiological signals in routine check ups and in self-monitoring are in Class IIA. A
thermal imaging device intended to monitor blood flow is not considered to be a temperature measuring device.
Note 2: Devices specifically intended to monitor AIMDs fall under the AIMD Directive.
Note 3: Therapeutic interventional radiology refers to diagnosis being carried out during surgical procedures
Note 4: This refers to active devices for the control, monitoring or influencing of the emission of ionizing and not to the
subsequent processing, recording or viewing of the resulting image.
33
Rule 11 - Active devices to administer, remove medicines and other substances to or from the body
This rule is intended to cover primarily drug delivery systems and anesthesia equipment.
RULE 11 EXAMPLES
All active devices intended to administer and/or remove - Suction equipment, feeding pumps.
medicines, body liquids or other substances to or from the body - Jet injectors for vaccination
are in Class IIa, - Nebulisers to be used on conscious and spontaneously breathing patients
where failure to deliver the appropriate dosage characteristics is not potentially
hazardous
unless this is done in a manner: - Infusion pumps, ventilators, anesthesia machines, anesthetic vaporisers,
- that is potentially hazardous, taking account of the nature of the dialysis equipment, blood pumps for heart-lung machines, hyperbaric chambers,
substances involved, of the part of the body concerned and of pressure regulators for medical gases, medical gas mixers, moisture exchangers
the mode of application, in which case they are in Class IIb. in breathing circuits if used on unconscious or non-spontaneously breathing
patients
- Nebulisers where the failure to deliver the appropriate dosage characteristics
could be hazardous.
34
Rule 12 All other active devices
This is a fallback rule to cover all active devices not covered by the previous rules.
RULE 12 EXAMPLES
All other active devices are in Class I. - Active diagnostic devices intended to illuminate the patient's body in the
visible spectrum such as examination lights or to optically view the body such
as surgical microscopes.
- Devices intended in general for external patient support (e.g. hospital beds,
patient hoists, walking aids, wheelchairs, stretchers, dental patient chairs).
- Active diagnostic devices intended for thermography.
- Active devices intended for recording, processing or viewing of diagnostic
images.
- Dental curing lights.
35
4. Special rules
Rule 13 - Devices incorporating a medicinal substance (See MEDDEV. 2.1/3 rev. 1)
This rule is intended to cover combination devices that contain a medicinal substance incorporated into the device for the
purpose of assisting the functioning of that device. However this rule does not cover those devices incorporating substances
which under other circumstances may be considered as medicinal substances, but which are incorporated into the device
exclusively for the purpose at maintaining certain characteristics of the device and which are not liable to act on the body. For
instance agents for the preservation of solutions for contact lenses (see MEDDEV 2.1/3 rev. 5.1 Sections A.3, 3.1 3rd note and
b.1 9th paragraph). The primary function of the device does not rely on the pharmacological effect of the medicine. If the latter
is the case, the product is a medicine rather than a device and not covered by this Directive.
RULE 13 EXAMPLES
All devices incorporating, as an integral part1, a substance which, if used - Antibiotic bone cements, condoms with spermicide, heparin coated catheters,
separately, can be considered to be a medicinal product as defined in endodontic materials with antibiotics.
Article 1 of the Directive 65/65/EEC, and which is liable to act on the - Ophthalmic irrigation solutions principally intended for irrigation, which contain
human body with action ancillary to that of the devices, are in Class III. components which support the metabolism of the endothelial cells of the cornea
- Dressings incorporating an antimicrobial agent where the purpose of such an agent
is to provide ancillary action on the wound
Note 1: "Integral part" means that the device and the medicinal substance form one physical unit.
36
Rule 14 - Devices used for contraception or prevention of sexually transmitted diseases
These intended uses relate to special cases of human vulnerability that cannot be covered by the normal criteria of time,
invasiveness and organic function.
Although this rule covers two very different device applications, some devices may perform both functions, e.g. condoms.
Devices intended to prevent the sexual transmission of the HIV are also covered by this rule.
RULE 14 EXAMPLES
All devices used for contraception or the prevention of the - Condoms, contraceptive diaphragms.
transmission of sexually transmitted diseases are in Class IIb,
unless they are implantable or long term invasive devices, in - Contraceptive intrauterine devices (IUDs)1 .
which case they are in Class III.
Note 1: Intrauterine contraceptives whose primary purpose is to release progestogens are not medical devices.
37
Rule 15 - Specific disinfecting, cleaning and rinsing devices
This rule is principally intended to cover various contact lens fluids. It also covers substances used principally in a medical
environment to disinfect medical devices.
RULE 15 EXAMPLES
All devices intended specifically to be used for disinfecting, - Contact lens solutions, comfort solutions.
cleaning, rinsing or, when appropriate hydrating contact lenses are
in Class IIb.
All devices intended specifically to be used for disinfecting - Disinfectants specifically intended for instance for endoscopes or haemodialysis
medical devices are in Class IIa. equipment, sterilizers specifically intended to sterilize medical devices in a medical
environment and washer disinfectors.
- Cleaners which disinfect prosthetic dentures.
This rule does not apply to products that are intended to clean
medical devices other than contact lenses by means of physical
action1.
Note 1: This rule does not apply to mechanical means of cleaning of devices, such as brushes and ultrasound. Such
products will only fall under this directive if they are specifically intended for use with medical devices.
38
Rule 16 - Non-active devices to record X-ray diagnostic images
RULE 16 EXAMPLES
Non-active devices specifically intended for recording of X-ray X-ray films, photostimulable phosphor plates
diagnostic images are in Class II a.
Note: This refers to primary recording media such as X-ray films and not to media used for subsequent reproduction.
39
Rule 17 - Devices utilizing animal tissues or derivatives
Explanation of the rule
This rule covers devices that contain or are made of animal tissues that have been rendered non-viable or derivatives from
such tissues also being non-viable, i.e. where there is no longer any capacity for cellular metabolic activity. Devices
containing non-inactivated animal tissues and/or any human tissues or derivatives are excluded from the scope of this
Directive.
The manufacture of some devices may use industrial raw materials which contain small amounts of tallow or tallow derivatives
(e.g. stearates in polymers). Such substances are not considered as derivatives of animal tissues for the purpose of this rule
and therefore this rule does not apply.
RULE 17 EXAMPLES
All devices manufactured utilizing animal tissues or derivatives1 - Biological heart valves, porcine xenograft dressings, catgut sutures, implants and
rendered non-viable are Class III except where such devices are dressings made from collagen.
intended to come into contact with intact skin2 only.
Practical classification issues
- Devices made of non-viable animal tissue that come into contact with intact skin only (e.g. leather components of orthopedic
appliances) are in Class I in accordance to rule 1.
Note 1: Derivatives are products that are processed from animal tissues and exclude substances such as milk, silk, beeswax,
hair, lanolin
Note 2: Intact skin includes the skin around an established stoma unless the skin is breached.
40
Rule 18 - Blood bags
This is a special rule that covers only blood bags.
RULE 18 EXAMPLES
By derogation from other rules, blood bags are in Class IIb. - Blood bags (including those containing or coated with an anticoagulant).
Where blood bags have a function greater than for storing purposes and include
systems for preservation other than anti-coagulants then other rules (e.g. rule
13) may apply
Note: Blood bags are described in the European Pharmacopoeia in the monograph on "Containers for Blood and Blood
Components".
41
EUROPEAN COMMISSION
Directorate B, Unit B2 Cosmetics and medical devices

-
Classification of medical devices
MEDDEV 2. 4/1 Rev. 9

June 2010
GUIDELINES RELATING TO THE APPLICATION OF
Foreword
The present MEDDEV is part of a set of guidelines relating to questions of application of EU Directives on medical devices. They are not legally binding. Only the
European Court of Justice can give an authoritative interpretation of Community Law.
This MEDDEV contains guidance for the application of the classification rules for medical devices as set out in Annex IX of Directive 93/42/EEC 1 , as amended. It
is for the national Competent Authorities and national Courts to take legally binding decisions on a case-by-case basis.
Directive 93/42/EEC, as amended, allows for derogation from the classification rules outlined in its Annex IX in light of technical progress or on information
gathered from post-market experience with the device.
1
OJ L 169, 12.7.1993, p. 1
1
This MEDDEV has been revised after consultation with various interested parties (e.g. Competent Authorities, Commission services, industry and other
stakeholders) and therefore this document reflects a consensus view on the classification of medical devices.
Active implantable medical devices and in vitro diagnostic medical devices are covered by separate Directives, which do not apply the classification rules reviewed
in this MEDDEV.
Note: This document is a revision of an earlier document published in July 2001 as MEDDEV 2.4/1 rev 8. It includes information pertaining to the changes in
classification resulting from the amending and implementing Directives issued since the last revision of this document in 2001, including derogation of the
classification rules in the case of breast implants and hip, knee and shoulder joint replacements and requirements related to devices containing human blood
derivatives and medical devices manufactured utilising tissues of animal origin. In addition this guidance document takes account of the changes arising from
Directive 2007/47/EC 2 which further amends Directive 93/42/EEC and became applicable as from 21st March 2010.
2
OJ L 247, 21.9.2007, p. 21
2
CONTENTS Pages

CLASSIFICATION

2.2. Conformity assessment
2.3. Clinical evaluation and investigation
2.5. Miscellaneous

3.2. Application of the classification rules
3.5. Handling of interpretational problems
4.1. Graphical summary - Guidance chart

4.2 General explanation of rules/practical issues/examples
3
1. PURPOSE AND PHILOSOPHY OF MEDICAL DEVICE CLASSIFICATION
It is not feasible economically nor justifiable in practice to subject all medical devices to the most rigorous conformity assessment procedures available. A
graduated system of control is more appropriate. In such a system, the level of control corresponds to the level of potential hazard inherent in the type of device
concerned. A medical device classification system is therefore needed, in order to apply to medical devices an appropriate conformity assessment procedure.
In order to ensure that conformity assessment under the Medical Device Directive functions effectively, manufacturers should be able to determine the
classification of their product as early as possible in device development. It was therefore decided to set up a system of classification rules within the Directive, so
that each manufacturer could classify its own devices.
The classification of medical devices is a risk based system based on the vulnerability of the human body taking account of the potential risks associated with the
devices. This approach allows the use of a set of criteria that can be combined in various ways in order to determine classification, e.g. duration of contact with the
body, degree of invasiveness and local vs. systemic effect. These criteria can then be applied to a vast range of different medical devices and technologies.
These are referred to as the classification rules and are set out in Annex IX of Directive 93/42/EEC. They correspond, to a large extent, to the classification rules
established by the Global Harmonization Task Force (GHTF) in the guidance document GHTF/SG1/N15:2006 3 .
It is recognized that although the existing rules will adequately classify the vast majority of existing devices, a small number of products may be more difficult to
classify. Such cases may in particular include devices which are borderline cases between two different classes of medical devices. In addition there may be
devices that cannot be classified by the existing rules because of their unusual nature or situations where the classification would result in the wrong level of
conformity assessment in light of the hazard represented by the device (see also section 3.5).
Irrespective of the class of the device, all devices must:
- meet the essential requirements, including the requirements regarding the information to be supplied by the manufacturer (Annex I of the Directive 93/42/EEC);
- be subject to the reporting requirements under the medical device vigilance system;
3
http://www.ghtf.org/documents/sg1/SG1-N15-2006-Classification-FINAL.pdf
4
- be CE marked (except custom-made devices and devices intended for clinical investigation, in which case they should comply with the provisions of Annex VIII
of Directive 93/42/EEC regarding the statement on devices for special purposes.
2.2. Conformity Assessment
Conformity assessment is the method by which a manufacturer demonstrates that their devices comply with the requirements of Directive 93/42/EEC. The
classification of the medical device will have an impact on the conformity assessment route that the manufacturer should follow in order to affix the CE marking on
the medical device.
CONFORMITY CLASSES
ASSESSMENT
PROCEDURES
ANNEXES I I I IIa IIb III

Sterile measure
II (+ section 4)
II (- section 4)
III
IV
V
VI
VII
Technical documentation relating to products in class IIa and class IIb must be reviewed by a notified body of the basis of a programme of representative sampling
in the context of Annexes II, V and VI of Directive 93/42/EEC.
2.3. Clinical evaluation and investigation
As part of the Essential Requirements, a clinical evaluation in accordance with Annex X must be conducted for all medical devices. (Annex I part I, 6a of
Directive 93/42/EEC).
5
The Medical Devices Directive states in Annex X that as a general rule confirmation of conformity with the requirements concerning the characteristics and
performances referred to in sections 1 and 3 of Annex I of Directive 93/42/EEC under the normal conditions of use of the device and the evaluation of the
undesirable side-effects must be based on clinical data.
In addition, according to Annex X Section 1.1a of Directive 93/42/EEC in the case of implantable devices and devices in class III clinical investigations shall be
performed unless it is duly justified to rely on existing clinical data.
For further guidance on clinical evaluation see MEDDEV 2.7.1 Rev.3 4 .
Pursuant to article 15.1, in case of devices intended for clinical investigations, the manufacturer shall notify the Competent Authorities of the Member States in
which the investigations are to be conducted in accordance with section 2.2 of Annex VIII.
Clinical investigations with Class III devices and implantable and long-term invasive devices falling within Class IIa or IIb may start 60 days after the
manufacturer's notification to the Competent Authority unless the Competent Authority has notified a decision to the contrary based on considerations of public
health or public policy within this timeframe (article 15.2). For further details see article15 of Directive 93/42/EEC.
Instructions for use are not required for Class I and IIa devices if these devices can be used safely without any such instructions (Annex I Section 13.1. of Directive
93/42/EEC).
2.5. Miscellaneous
The manufacturer of a Class I medical device, or his relevant authorised representative in the European Union designated by him, must notify their address and a
description of the devices concerned to the Competent Authority of the Member State where they have their registered place of business (Article 14, paragraphs 1
and 2 of Directive 93/42/EEC).
For medical devices of classes IIa, IIb and III, Member States may request to be informed of all data allowing for identification of such devices together with the
label and the instructions for use when such devices are put into service within their territory (second sub-paragraph of Article 14, paragraph 1, of Directive
93/42/EEC).

4
http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_7_1rev_3_en.pdf
6
The manufacturer should first decide if the product concerned is a medical device as defined in Directive 93/42/EEC or an accessory to such a medical device, if it
is not excluded from the scope of this Directive and if it therefore comes within the scope of this Directive.
The classification rules are based on different criteria such as the duration of contact with the patient, the degree of invasiveness and the part of the body affected
by the use of the device. Intended purpose is defined in Article 1 paragraph 2(g) of Directive 93/42/EEC. The other terms are defined in chapter I section 1 of
Annex IX of Directive 93/42/EEC.
These definitions are reproduced below, together with some additional guidance.
3.1.1. Intended purpose
Intended purpose means the use for which the device is intended according to the data supplied by the manufacturer on the labelling, in the instructions and/or in
promotional materials.
3.1.2. Time
3.1.2.1. Duration
Transient
Normally intended for continuous use for less than 60 minutes.
Short term
Normally intended for continuous use for not more than 30 days.
Long term
Normally intended for continuous use for more than 30 days.
7
In certain instances the duration of effect for a product needs to be considered as the duration of use. For instance, application of a topical cream to the skin may
only take seconds to apply but the cream may remain in situ for many hours. The duration of use should therefore not be considered as the time taken to apply the
product but rather the duration for which the product achieves its intended purpose.
3.1.2.2 Concept of continuous use
In calculating the duration referred to in Section 1.1 of Chapter I of Annex IX to Directive 93/42/EEC, continuous use means an uninterrupted actual use of the
device for the intended purpose. However where usage of a device is discontinued in order for the device to be replaced immediately by the same or an identical
device this shall be considered as an extension of the continuous use of the device (Section 2.6 of Chapter II of Annex IX to Directive 93/42/EEC).
For example, a scalpel may be used on the same patient throughout an operation that may last for several hours. The uninterrupted use for an intended purpose,
i.e. cutting tissue, will normally not last for more than a few seconds at a time. Therefore a scalpel is a transient use device. However where usage of a device is
discontinued in order for the device to be replaced immediately by the same or an identical device (e.g. replacement of a ureteric catheter) this shall be considered
an extension of the continuous use of the device.
If it cannot be demonstrated that components of the device is totally eliminated in the interval between uses, this is also considered as an immediate replacement.
3.1.3. Invasiveness
Invasive devices
A device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body.
Body orifice
Any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma.
Surgically invasive device

An invasive device which penetrates inside the body through the surface of the body, with the aid of or in the context of a surgical operation.
For the purposes of this Directive devices other than those referred to in the previous subparagraph and which produce penetration other than through an
established body orifice, shall be treated as surgically invasive devices.
The term surgical operation used in this definition includes all clinical interventional procedures in which a device is placed into the body through the surface in the
context of a surgical operation or other clinical procedure
8
In this context it should be noted the following:
- A surgically created stoma used in urostomy, colostomy and ileostomy or permanent tracheostomy is considered to be a body orifice. Therefore devices
introduced into such a stoma are not surgically invasive. A surgically created opening to allow access to the circulatory system in contrast should not be
considered to be such a "body orifice". Devices introduced into such an opening are surgically invasive.
- A device that administers energy to the body should not be considered as invasive if only energy penetrates the body and not the device itself. Energy as
such is not a device and therefore it cannot be classified. Only the device generating the energy must be classified. However, if a device administers a
substance, whether this substance is a medicine or a medical device, such a substance must be assessed in its own right (e.g. substances administered
by a jet injector).
Any device which, in whole or in part, penetrates inside the body, either through a natural body orifice or through the surface of the body is an invasive device. A
surgically invasive device always implies that it enters through an artificially created opening. This can be a large opening, such as a surgical incision, or it can be
a pinprick opening created by a needle. Therefore surgical gloves and needles used with syringes are surgically invasive.
The concept of surgically invasive should be understood as covering also liquids that are in invasive contact with organs, tissue or other parts of the body if the
access for such liquids is through a surgically created opening.
Reusable surgical instrument
Instrument intended for surgical use by cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without connection to any
active medical device and which can be reused after appropriate procedures have been carried out (Section 1.3 of Annex IX of Directive 93/42/EEC).
Implantable device
Any device which is intended:

- to be totally introduced into the human body or,
- to replace an epithelial surface or the surface of the eye,
by surgical intervention which is intended to remain in place after the procedure.
Any device intended to be partially introduced into the human body through surgical intervention and intended to remain in place after the procedure for at least 30
days is also considered an implantable device.
9
One of the key elements in defining an implantable device is the concept of "procedure". Thus an implantable device must remain in the patient after the
procedure. A "procedure" must be understood in this context to include the surgical procedure during which the implant is placed into the body and the immediate
post-operative care that is associated with the procedure. The "procedure" does not extend to the conclusion of the therapeutic treatment, e.g. the removal of an
implant must be considered to be another "procedure". Thus a plate used to reduce a fracture of the bone is an implant even if it is taken out after the fracture has
healed. In this case the placing of the plate and its explantation are two different surgical procedures.
Some partially implanted devices are deemed to be implants. For instance, if an operation is carried out specifically to place an infusion port into the body, then
such an infusion port would remain for at least 30 days after the procedure and consequently be an implant. However, a non-tunnelled central venous catheter
which is intended for use for temporary vascular access and intended to be removed after 7 10 days is not a long-term implantable device. Nor would a suture
used for skin wound closure that is taken out prior to 30 days be considered an implant.
Critical anatomical locations
For the purposes of the Directive 93/42/EEC, central circulatory system means the following vessels:
arteriae pulmonales, aorta ascendens, arcus aorta, aorta descendens to the bifurcatio aortae, arteriae coronariae, arteria carotis communis, arteria carotis
externa, arteria carotis interna, arteriae cerebrales, truncus brachiocephalicus,
venae cordis, venae pulmonales, vena cava superior, vena cava inferior.
For the purposes of the Directive 93/42/EEC the central nervous system means brain, meninges and spinal cord.
3.1.4. Active medical devices
Any medical device operation of which depends on a source of electrical energy or any source of power other than that directly generated by the human body or
gravity and which acts by converting this energy. Medical devices intended to transmit energy, substances or other elements between an active medical device
and the patient, without any significant change, are not considered to be active medical devices. Stand alone software is considered to be an active medical
device.
The concept act by converting energy includes conversion of energy in the device and/or conversion at the interface between the device and the tissues or in the
tissues.
10
The concept of significant changes includes changes in the nature, level and density of energy (see Rule 9). This means that for instance an electrode is not an
active device under this classification system as long as the energy input is intended to be the same as the energy output. For instance, resistance in a wire that
causes minor changes between input and output cannot be considered to constitute "significant change". However, electrodes used in electrosurgery for cutting
tissues or cauterisation are active devices because their operation depends on energy provided by a generator and their action is achieved by conversion of
energy at the interface between the device and the tissue or in the tissue. Electrodes intended for E.C.G. or E.E.G are normally not active devices because they
do not normally act by conversion of energy.
However, it should be understood that an electrode, which is an accessory of an active implant, is covered under the relevant Directive for active implants. Further
information on this issue can be found in "Guidelines relating to the application of the Council Directive 90/385/EEC on active implantable medical devices 5 .
The application of energy from the human body does not make a device "active" unless that energy is stored within the device for subsequent release. For
instance, energy generated by human muscle and applied to the plunger of a syringe (thus causing a substance to be delivered to a patient) does not make this
syringe an "active device". However, if a drug delivery system depends upon manual winding to preload a spring which is subsequently released to deliver a
substance, then the device incorporating the spring is an "active device".
Medical devices using prestored gases and/or vacuum as a power source are regarded as active devices, e.g. gas mixers with anaesthesia machines and gas
powered suction pumps.
Heating/cooling pads intended only to release stored thermal energy are not active devices because they do not act by conversion of energy. However,
heating/cooling pads which act by chemical action (e.g. endothermic or exothermic reaction) are active devices as they are converting chemical energy into heat
energy and or vice versa.
Radioactive sources that are intended to deliver ionising radiation are regarded as active medical devices, unless they are radiopharmaceuticals as defined in
article 1 of Directive 2001/83/EC or radioactive implants as defined in article 1 of Directive 90/385/EEC.
3.1.5 Devices with a measuring function
Information on devices with a measuring function can be found in MEDDEV 2.1/5 6
3.1.6 Procedure packs
5
http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_1-2___04-1994_en.pdf
6
http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_1_5____06-1998_en.pdf
11
Procedure packs per Article 12 of Directive 93/42/EEC normally do not require classification as each device in the procedure pack keeps its own CE marking and
classification.
However, in cases where the procedure pack incorporates devices which do not bear a CE marking, or where the chosen combination of devices is not compatible
in view of their original intended use, the system or procedure pack shall be treated as a device in its own right and as such be subjected to the relevant procedure
pursuant to Article 11 of Directive 93/42/EEC.
For a procedure pack that is a device in its own right, the classification is normally determined by the intended use. In those cases where the intended use of the
procedure pack is not specific enough to determine the classification, the classification of the pack is at the level of the highest classified device included in the
pack, where applicable taking into account the new intended use of the device.
3.2. Application of the classification rules
In terms of further interpretation of the classification rules, the following should be considered:
- It is the intended purpose that determines the class of the device and not the particular technical characteristics of the device, unless these have a direct
bearing on the intended purpose. e.g. incorporation of an ancillary substance, tissue of animal origin etc.
- It is the intended and not the accidental use of the device that determines the class of the device. For instance a suture organizer, that is intended to
keep order of suture threads used in open heart surgery, should not be considered as an invasive device if in the normal use it can be kept outside the
patient. Similarly, if a medical practitioner uses the device in a manner not intended by the manufacturer, this does not change the class of the device for
the purpose of conformity assessment. However, if the normal clinical use of the device changes in time with evolving clinical practice such that the
intended purpose and classification of the device changes this should be addressed by the manufacturer and the conformity of the device assessed for
the new intended purpose.
- It is the intended purpose assigned by the manufacturer to the device that determines the class of the device and not the class assigned to other similar
products. For instance two sutures that have the same composition may well have different intended purposes.
- As an alternative to classifying the system as a whole, the determination of the class of a particular device may be made with respect to the simplest
configuration that can still be considered, in view of its proper functional features, as a device in its own right. A device that is part of a system, e.g. a
tube in an extra corporeal circulation set, may be classed as a device in its own right rather than classifying the system as a whole. The device, however,
must be CE marked in its own right as a separate device in such instances.
12
- Similarly combination devices with parts that have different functional purposes may be analysed separately with respect to each of these parts. For
instance, a drainage device will have an invasive tube and a non-invasive collection device. These components may be classified separately, provided
that they are also CE marked separately.
- Accessories are classified in their own right separately from the device with which they are used (Annex IX Section 2.2 of Directive 93/42/EEC).
- If a given device can be classified according to several rules, then the highest possible class applies. For instance, a wound dressing incorporating
collagen is covered by rules 4 (Class I, Class IIa or Class IIb depending on intended use) and 17 (Class III). All rules must be considered, for instance if
an active device is also surgically invasive, the relevant rules for surgically invasive devices must also be considered.
- If the device is not intended to be used solely or principally in a specific part of the body, it must be considered and classified on the basis of the most
critical specified use. Classification of the device will have to be determined on the basis of claims contained in the information provided with the device.
The manufacturer must be sufficiently specific in that regard. If the manufacturer wants to avoid the particular higher classification, then it must clearly
define on the labelling the intended purpose in such a way that the device falls into the lower class. The manufacturer must provide as a minimum
requirement either appropriate positive or negative indications for use.
- For a device to be "specifically intended" for the purpose referenced in a particular classification rule, the manufacturer must clearly indicate that the
device is intended for such a specific purpose in the information accompanying the device. Otherwise it is deemed to have the intended use which is
principally used and accepted in general medical practice.
- Multi-application equipment such as laser printers and identification cameras, which may be used in combination with medical devices, are not medical
devices unless their manufacturer places them on the market with specific intended purpose as medical devices.
- Due to its complexity, classification of standalone software will be covered in a specific guidance document.
The manufacturer must take into consideration all the rules in order to establish the proper classification for its device. It is quite conceivable for instance that one
of the general rules that are not specific to active devices, nevertheless applies to such a device. All the device characteristics must be taken into consideration.
The characteristic or combination of characteristics in accordance with the intended purpose of the device that rates the highest class determines the class for the
device as a whole.
By derogation to the classification rules set out in Annex IX of Directive 93/42/EEC, the manufacturers must also take account of additional Directives which may
affect the classification of their device or the conformity route to be followed, e.g.
13
- Directive 2003/12/EC 7 on the reclassification of breast implants in the framework of Directive 93/42/EEC concerning medical devices.
- Directive 2005/50/EC 8 on the reclassification of hip, knee and shoulder joint replacements in the framework of Council Directive 93/42/EEC concerning medical
devices.
- Directive 2003/32/EC 9 introducing detailed specifications as regards the requirements laid down in Council Directive 93/ 42/EEC with respect to medical devices
manufactured utilising tissues of animal origin.
A simple wound drainage device has three components that must be taken into consideration: the cannula, the tubing and the collector unit. If the device is sold
without a cannula, then the classification of the cannula does not need to be taken into account. It is assumed here that the device is used for short term duration,
i.e. that uninterrupted intended use is more than 60 minutes and less than 30 days. It is furthermore assumed that the collected liquids are not intended to be re
infused into the body nor reprocessed for eventual re infusion and that the device is not intended to be connected to a powered suction system.
Intended uses Rule Class

Surgically invasive cannula to reach a wound site in the pleural cavity to drain the cavity 7 IIa
Non-invasive tubing to evacuate body liquids towards the collector. 1 I
Non-invasive collector to receive the body liquids. 1 I
The clear conclusion here is that the manufacturer would have a choice of applying Class II A to the whole device or carrying out separate conformity assessment
procedures for the cannula on one hand and the tubing and collector on the other hand.
3.5. Handling of interpretational problems.
7
OJ L 28, 4.2.2003, p. 43
8
OJ L 210, 12.8.2005, p. 41
9
OJ L 105, 26.4.2003, p. 18
14
In case the manufacturer is unsure how its devices should be classified, it should first consult a Notified Body.
In case doubts remain or there is a disagreement with the Notified Body, the relevant Competent Authority (i.e. the Competent Authority to which the notified body
is subject) should be approached in accordance with Article 9 of Directive 93/42/EEC.
In addition, Directive 93/42/EEC provides Community wide mechanisms, including a committee procedure, to address problems related to classification.
Complex classification issues may be referred to the Borderline and Classification Medical Devices Expert Group for resolution. Consensus positions on
classification reached by this Expert Group are published for reference in the Manual on Borderline and Classification 10 .
In addition, MEDDEV 2.1/3 rev 3 11 provides with useful information relating to devices incorporating, as an integral part, a substance which, if used separately,
can be considered to be a medicinal product or a human blood derivative, and which is liable to act on the human body with action ancillary to that of the devices.
10
http://ec.europa.eu/consumers/sectors/medical-devices/documents/borderline/index_en.htm
11
http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_1_3_rev_3-12_2009_en.pdf
15
The explanations are given in the following manner. This section begins with a graphical summary of the rules, as a preface to subsections on the individual rules.
Each subsection starts with a general explanation of the rule followed by a tabular presentation of the rule and examples of devices to which it applies. Any special
terms used are explained and practical issues related to the rule are clarified. It must be emphasised that even if a particular device type is given as an example,
this does not mean that such devices are in all cases in the class indicated by the example. It is always possible that some manufacturer will assign to such a
device an entirely different intended use than what was used in the context of the example.
4.1 Graphical summary medical devices classification guidance chart for initial identification of probable device class
Note: Always confirm definitive classification by reading all rules in detail, and utilise additional assistance in this guidelines document as provided in the form of
general explanations of rules and examples of devices (see section 4.2)
SUBJECTS
Non invasive devices Rules 1, 2, 3, 4
Invasive devices Rules 5, 6, 7, 8
Active devices Rules 9, 10, 11, 12
Special rules Rules 13, 14, 15, 16, 17, 18
16
17
18
19
20
21
22
4.2 GENERAL EXPLANATION OF RULES/PRACTICAL ISSUES/EXAMPLES
Rule 1 - Devices that either do not touch the patient or contact intact skin only
This is a fallback rule applying to all devices that are not covered by a more specific rule.
This is a rule that applies in general to devices that come into contact only with intact skin or that do not touch the patient.
RULE 1 EXAMPLES
All non-invasive devices are in Class I, unless one of the rules set out - Body liquid collection devices intended to be used in such a way that a return
hereinafter applies. flow is unlikely (e.g. to collect body wastes such as urine collection bottles,
ostomy pouches, incontinence pads or collectors used with wound drainage
devices). They may be connected to the patient by means of catheters and
tubing
- Devices used to immobilise body parts and/or to apply force or compression
on them (e.g. non-sterile dressings used to aid the healing of a sprain, plaster
of Paris, cervical collars, gravity traction devices, compression hosiery)
patient hoists, walking aids, wheelchairs, stretchers, dental patient chairs)
- Corrective glasses and frames
- Stethoscopes for diagnosis.
- Eye occlusion plasters
- Incision drapes
- Conductive gels
- Non-invasive electrodes (electrodes for EEG or ECG)
- Image intensifying screens
- Permanent magnets for removal of ocular debris
23
Some non-invasive devices are indirectly in contact with the body and can influence internal physiological processes by storing, channelling or treating blood, other body
liquids or liquids which are returned or infused into the body or by generating energy that is delivered to the body. These must be excluded from the application of this Rule
and be handled by another rule because of the hazards inherent in such indirect influence on the body.
24
Rule 2 - Channelling or storing for eventual administration
These types of devices must be considered separately from the non-contact devices of rule 1 because they may be indirectly invasive. They channel or store substances that
will eventually be administered to the body. Typically these devices are used in transfusion, infusion, extracorporeal circulation and delivery of anaesthetic gases and oxygen.
In some cases devices covered under this rule are very simple gravity activated delivery devices.
RULE 2 EXAMPLES
All non-invasive devices intended for channelling or storing blood, body liquids - Devices intended to be used as channels in active drug delivery systems, e.g. tubing
or tissues, liquids or gases for the purpose of eventual infusion, administration intended for use with an infusion pump
or introduction into the body are in Class IIa: - Devices used for channelling, e.g. antistatic tubing for anaesthesia, anaesthesia breathing
- if they may be connected1 to an active medical device in Class IIa or a higher circuits, pressure indicator, pressure limiting devices
class, - Syringes for infusion pumps
- if they are intended for use for storing or channelling blood or other body - Devices intended to channel blood (e.g. in transfusion, extracorporeal circulation)
liquids or for storing organs, parts of organs or body tissues - Devices intended for temporary storage and transport of organs for transplantation (i.e.
containers, bags and similar products)
- Devices intended for long term storage of biological substances and tissues such as
corneas, sperm, human embryos, etc. (i.e. containers, bags and similar products)
- Fridges specifically intended for storing blood , tissues etc
- in all other cases they are in Class I. - Devices that provide a simple channelling function, with gravity providing the force to
transport the liquid, e.g. administration sets for infusion
- Devices intended to be used for a temporary containment or storage function, e.g. cups
and spoons specifically intended for administering medicines
- Syringes without needles
Blood bags are covered as an exception under a separate rule (see Rule 18).
25
If a device, e.g. tubing, can be used for a purpose that would cause it to be connected to an active device such a device will be automatically in Class IIa, unless the
manufacturer clearly state that it should not be connected to an active device of Class IIa or higher.
Note 1: "May be connected to an active device". Such a connection is deemed to exist between a non-active device and an active device where the non-active device forms a
link in the transfer of the substance between the patient and the active device and the safety and performance of one of the devices is influenced by the other device. For
instance, this applies to tubing in an extracorporeal circulation system which is downstream from a blood pump and in the same blood flow circuit, but not directly in contact
with the pump.
26
Rule 3 Non-invasive devices that modify biological or chemical composition of blood, body liquids or other liquids intended for infusion into the
body
These types of devices must be considered separately from the non-contact devices of Rule 1 because they are indirectly invasive. They modify substances that will eventually
be infused into the body. This rule covers mostly the more sophisticated elements of extracorporeal circulation sets, dialysis systems and autotransfusion systems as well as
devices for extracorporeal treatment of body fluids which may or may not be immediately reintroduced into the body, including, where the patient is not in a closed loop with
the device.
RULE 3 EXAMPLES
All non-invasive devices intended for modifying the biological or chemical - Devices intended to remove undesirable substances out of the blood by exchange of
composition of blood, other body liquids or other liquids intended for infusion solutes such as hemodialysers
into the body are in Class IIb, - Devices intended to separate cells by physical means, e.g. gradient medium for sperm
separation
- Haemodialysis concentrates
unless the treatment consists of filtration, centrifugation or exchange of gas or - Particulate filtration of blood in an extracorporeal circulation system. These are used to
heat, in which case they are in Class IIa. remove particles and emboli from the blood
- Centrifugation of blood to prepare it for transfusion or autotransfusion
- Removal of carbon dioxide from the blood and/or adding oxygen
- Warming or cooling the blood in an extracorporeal circulation system
These devices are normally used in conjunction with an active medical device covered under Rule 9 or Rule 11.
Filtration and centrifugation should be understood in the context of this rule as exclusively mechanical methods.
27
Rule 4 - Non-invasive devices which come into contact with injured skin
This rule is intended to primarily cover wound dressings independently of the depth of the wound. The traditional types of products, such as those used as a mechanical
barrier, are well understood and do not result in any great hazard. There have also been rapid technological developments in this area, with the emergence of new types of
wound dressings for which non-traditional claims are made, e.g. management of the micro-environment of a wound to enhance its natural healing mechanism.
More ambitious claims relate to the mechanism of healing by secondary intent, such as influencing the underlying mechanisms of granulation or epithelial formation or
preventing contraction of the wound. Some devices used on breached dermis may even have a life-sustaining or lifesaving purpose, e.g. when there is full thickness
destruction of the skin over a large area and/or systemic effect.
Dressings containing medicinal products which act ancillary to the dressing fall within Class III under Rule 13.
RULE 4 EXAMPLES
All non-invasive devices which come into contact with injured skin:
- are in Class I if they are intended to be used as a mechanical barrier, for - Wound dressings, such as: absorbent pads, island dressings, cotton wool, wound strips,
compression or for absorption of exudates, adhesive bandages (sticking plasters, band-aid) and gauze dressings which act as a
barrier, maintain wound position or absorb exudates from the wound
- are in Class IIb if they are intended to be used principally with wounds which - Are principally intended to be used with severe wounds that have substantially and
have breached the dermis and can only heal by secondary intent extensively breached the dermis, and where the healing process can only be by secondary
intent such as:
- dressings for chronic extensive ulcerated wounds
- dressings for severe burns having breached the dermis and covering an extensive area
- dressings for severe decubitis wounds
- dressings incorporating means of augmenting tissue and providing a temporary skin
substitute
- are in Class IIa in all other cases, including devices principally intended to - Have specific properties intended to assist the healing process by controlling the level of
manage the micro-environment of a wound. moisture at the wound during the healing process and to generally regulate the environment
in terms of humidity and temperature, levels of oxygen and other gases and pH values or by
influencing the process by other physical means
- These devices may specify particular additional healing properties whilst not being
intended for extensive wounds requiring healing by secondary intent.
- Adhesives for topical use
28
- Polymer film dressings
- Hydrogel dressings
- Non-medicated impregnated gauze dressings
Products covered under this rule are extremely claim sensitive, e.g. a polymeric film dressing would be in Class IIa if the intended use is to manage the micro-environment of
the wound or in Class I if its intended use is limited to retaining an invasive cannula at the wound site. Consequently it is impossible to say a priori that a particular type of
dressing is in a given class without knowing its intended use as defined by the manufacturer. However, a claim that the device is interactive or active with respect to the wound
healing process usually implies that the device is in Class IIb.
Most dressings that are intended for a use that is in Class IIa or IIb, also perform functions that are in Class I, e.g. that of a mechanical barrier. Such devices are nevertheless
classed according to the intended use in the higher class.
For such devices incorporating a medicinal product or a human blood derivative see Rule 13 or animal tissues or derivatives rendered non-viable see Rule 17.
- Breached dermis: the wound exposes at least partly the subcutaneous tissue.
- Secondary intent: the wound heals by first being filled with granulation tissue, subsequently the epithelium grows back over the granulation tissue and the wound contracts. In
contrast primary intent implies that the edges of the wound are close enough or pulled together, e.g. by suturing, to allow the wound to heal.
- A skin might be considered as "injured" either because of pathological (e.g. diabetic ulcers) or external factors (e.g. burns)
29
Rule 5 - Devices invasive with respect to body orifices
Invasiveness with respect to the body orifices (ear, mouth, nose, eye, anus, urethra and vagina) must be considered separately from invasiveness that penetrates through a
cut in the body surfaces (surgical invasiveness). For short term use, a further distinction must be made between invasiveness with respect to the less vulnerable anterior parts
of the ear, mouth and nose and the other anatomical sites that can be accessed through natural body orifices.
Surgically created stoma, which for example allows the evacuation of urine or faeces, should also be considered as a body orifice.
Devices covered by this rule tend to be diagnostic and therapeutic instruments used in particular specialities (ENT, ophthalmology, dentistry, proctology, urology and
gynaecology).
RULE 5 EXAMPLES
All invasive devices with respect to body orifices, other than
surgically invasive devices and which are not intended for
connection to an active medical device or which are intended for connection to
an active medical device in Class I:
- are in Class I if they are intended for transient use, - Handheld mirrors used in dentistry to aid in dental diagnosis and surgery
- Dental impression materials
- Tubes used for pumping the stomach
- Impression trays
- Enema devices
- Examination gloves
- Urinary catheters intended for transient use
- Prostatic balloon dilation catheters
- are in Class IIa if they are intended for short term use - Short term corrective contact lenses
- Tracheal tubes
- Stents
- Vaginal pessaries
- Indwelling urinary catheters intended for short term use
except if they are used in the oral cavity as far as the pharynx, in an ear canal - Dressings for nose bleeds
up to the ear drum or in a nasal cavity , in which case they are in Class I, - Materials for manufacturing dentures
30
- are in Class IIb if they are intended for long term use, - Urethral stents
- Long term corrective contact lenses
- Tracheal cannulae
- Urinary catheters intended for long term use
except if they are used in the oral cavity as far as the pharynx, in an ear canal - Orthodontic wires
up to the ear drum or in a nasal cavity and are not liable to be absorbed by the - Fixed dental prostheses
mucous membrane, in which case they are in Class IIa. - Fissures sealants
All invasive devices with respect to body orifices, other than surgically invasive - Tracheostomy or tracheal tubes connected to a ventilator
devices, intended for connection to an active medical device in Class IIa or a - Blood oxygen analysers placed under the eye-lid
higher class, are in Class IIa. - Powered nasal irrigators
- Nasopharyngeal airways
- Some enteral feeding tubes
- Fibre optics in endoscopes connected to surgical lasers
- Suction catheters or tubes for stomach drainage
- Dental aspirator tips
31
Rule 6 - Surgically invasive devices intended for transient use (< 60 minutes)
This rule primarily covers three major groups of devices: devices that are used to create a conduit through the skin (needles, cannulae, etc.), surgical instruments (scalpels,
saws, etc.) and various types of catheters, suckers, etc.
RULE 6 EXAMPLES
All surgically invasive1 devices intended for transient use are in Class IIa unless - Needles used for suturing
they are: - Needles of syringes
- Lancets
- Suckers
- Single use scalpels and single use scalpel blades
- Support devices in ophthalmic surgery
- Staplers
- Surgical swabs
- Drill bits connected to active devices
- Surgical gloves
- Etchants
- Tester of artificial heart valves
- Heart valve occluders, sizers and holders
- Swabs to sample exudates
- Single use aortic punches (see note 2)
- intended specifically to control, diagnose, monitor or correct a defect 2 of the - Cardiovascular catheters (e.g. angioplasty balloon catheters, stent delivery
heart or of the central circulatory system1 through direct contact with these parts catheters/systems), including related guidewires, related introducers and dedicated4
of the body, in which case they are in Class III 3 disposable cardiovascular surgical instruments e.g. electrophysiological catheters,
electrodes for electrophysiological diagnosis and ablation
- Catheters containing or incorporating sealed radioisotopes, where the radioactive isotope
is not intended to be released into the body, if used in the central circulatory system
- Distal protection devices
- reusable surgical instruments1, in which case they are in Class I3 - Scalpels and scalpel handles
32
- Reamers
- Drill bits
- Saws, that are not intended for connection to an active device
- Retractors forceps, excavators and chisels
- Sternum retractors for transient use
- intended specifically for use in direct contact with the central nervous system, - Neuro-endoscopes
in which case they are in Class III - Brain spatulas
- Direct stimulation canulae
- Spinal cord retractors
- spinal needles
- intended to supply energy in the form of ionizing radiation in which case they - Catheters containing or incorporating sealed radioisotopes, where the radioactive isotope
are in Class IIb, as such is not intended to be released into the body, if used in the circulatory system,
excluding the central circulatory system
- intended to have a biological5 effect or to be wholly or mainly absorbed6 in

which case they are in Class IIb,
- intended to administer medicines by means of a delivery system, if this is - Devices for repeated self-application where dosage levels and the nature of the medicinal
done in a manner that is potentially hazardous7 taking account of the mode of product are critical, e.g. insulin pens
application, in which case they are Class IIb.
Explanations of special concepts
Note 1: Terms such as "surgically invasive device", "central circulatory system", central nervous system and "reusable surgical instruments" are defined in Section I of Annex
IX of Directive 93/42/EEC. In particular surgical instruments connected to an active device are not considered to be reusable surgical instruments.
Note 2: The expression "correct a defect" does not cover devices that are used accessorily in heart surgery procedures, e.g. clamps, aortic punch instruments. The first indent
of this rule does not apply to aortic punches and similar cutting instruments which perform a similar function to a scalpel.
Note 3: Surgical instruments which are not specifically intended for purposes described in the first indent, and irrespective of the site of application, are in class IIa, if they are
intended for single use and in class I if they are reusable.
33
Note 4: Dedicated means that the intended purpose of the device or accessory is to specifically control, diagnose, monitor or correct a defect of the heart or of the central
circulatory system.
Note 5: Biological effect: All materials and devices have the potential to affect tissues following use in a surgically invasive procedure. A material is considered to have a
biological effect if it actively and intentionally induces, alters or prevents a response from the tissues that is mediated by specific reactions at a molecular level. Such a device
may be described as bioactive.
Note 6: Wholly or mainly absorbed: The term absorption refers to the degradation of a material within the body and the metabolic elimination of the resulting degradation
products from the body.
Note 7: The concept of "potentially hazardous manner" is related to the characteristics of the device and not the competence of the user.
34
Rule 7 - Surgically invasive devices intended for short-term use (>60 minutes, <30 days)
These are mostly devices used in the context of surgery or post-operative care (e.g. clamps, drains), infusion devices (cannulae, needles) and catheters of various types.
RULE 7 EXAMPLES
All surgically invasive devices intended for short term use are in Class IIa - Clamps
unless they are intended: - Infusion cannulae
- Skin closure devices
- Temporary filling materials
- Tissue stabilisers2 used in cardiac surgery
- either specifically to control, diagnose, monitor or correct a defect2 of the heart - Cardiovascular catheters
or of the central circulatory system through direct contact with these parts of the - Cardiac output probes
body, in which case they are in Class III, - Temporary pacemaker leads
- Thoracic catheters intended to drain the heart, including the pericardium
- Carotid artery shunts
- Ablation catheter
- or specifically for use in direct contact with the central nervous system, in - Neurological catheters
which case they are in Class III, - Cortical electrodes
- or to supply energy in the form of ionising radiation in which case they are in - Brachytherapy devices
Class IIb,
- intended to have a biological effect or to be wholly or mainly absorbed in - Absorbable sutures

which case they are in Class III, - Biological adhesives
- or to undergo chemical change in the body, except if the devices are placed in - Adhesives
the teeth, or to administer medicines1, in which case they are Class IIb.
35
Note 1: Administration of medicines is more than just channelling, it implies also storage and/or influencing the volume and rate of the medicine delivered. Implanted capsules
for the slow release of medicines are medicines and not medical devices.
Note 2: The expression correct a defect does not cover devices that are used accessorily in heart surgery, e.g. tissue stabilisers.
36
Rule 8 - Implantable devices and long-term surgically invasive devices (> 30 days)

These are mostly implants in the orthopaedic, dental, ophthalmic and cardiovascular fields as well as soft tissue implants such as implants used in plastic surgery.
RULE 8 EXAMPLES
All implantable devices and long-term surgically invasive devices are in Class - Prosthetic joint replacements not covered by Directive 2005/50/EC
IIb unless they are intended: - Ligaments
- Shunts
- Stents and valves (e.g. pulmonary)
- Nails and plates
- Intra-ocular lenses
- Internal closure devices.(including vascular closure devices2)
- Tissue augmentation implants
- Peripheral vascular catheters
- Peripheral vascular grafts and stents
- Penile implants
- Non-absorbable sutures, bone cements and maxillo-facial implants, visco-elastic surgical
devices intended specifically for ophthalmic anterior segment surgery 1
- to be placed in the teeth3, in which case they are in Class IIa, - Bridges and crowns
- Dental filling materials and pins
- Dental alloys, ceramics and polymers
- to be used in direct contact with the heart, the central circulatory system or the - Prosthetic heart valves
central nervous system, in which case they are Class III, - Aneurysm clips
- Vascular prosthesis and stents
- Central vascular catheters
- Spinal stents
- CNS electrodes
- Cardiovascular sutures
- Permanent and retrievable vena cava filters
- Septal occlusion devices
- Intra-aortic balloon pumps
37
- External left ventricular assisting devices
- to have a biological effect or to be wholly or mainly absorbed, in which case - Absorbable sutures
they are in Class III, - Adhesives and implantable devices claimed to be bioactive through the attachment of
surface coatings such as phosphorylcholine
- or to undergo chemical change4 in the body, except if the devices are placed - Rechargeable non-active drug delivery systems
in the teeth, or to administer medicines, in which case they are in Class III.
- Directive 2003/12/EC introduced a derogation from this rule, reclassifying - Breast implants
breast implants in Class III
Directive 2005/50/EC introduced a derogation from this rule, reclassifying hip, - Total hip, knee and shoulder joint replacements systems and components of systems 12
knee and shoulder joint replacements in Class III
Note 1: These products are implants because in normal conditions a significant amount of the substance remains at the surgical site after the procedure. If these devices
contain animal tissues or derivatives of animal tissues, they are covered by Rule 17.
Note 2: For closure of arteriotomies in the peripheral vascular system. (please refer to definition of central circulatory system)
Note 3: Implants without bioactive coatings intended to secure teeth or prostheses to the maxillary or mandibular bones are in Class IIb following the general rule. Hydroxy-
apatite is considered as having biological effect only if so claimed and demonstrated by the manufacturer.
Note 4: The clause about chemical change under this rule does not apply to products such as bone cements where the chemical change takes place during the placement and
does not continue in long term.
12
http://ec.europa.eu/consumers/sectors/medical-devices/files/guide-stds-directives/final_reclass_note_12jan2007_en.pdf
38
Rule 9 - Active therapeutic devices intended to administer or exchange energy
Devices classified by this rule are mostly electrical equipment used in surgery such as lasers and surgical generators. In addition there are devices for specialised treatment
such as radiation treatment. Another category consists of stimulation devices, although not all of them can be considered as delivering dangerous levels of energy considering
the tissue involved.
RULE 9 EXAMPLES
All active therapeutic devices intended to administer or exchange energy are in Electrical and/or magnetic and electromagnetic energy
Class IIa - Muscle stimulators
- External bone growth stimulators
- TENS devices
- Eye electromagnets
- Electrical acupuncture
Thermal energy
- Cryosurgery equipment.
- Heat exchangers, except the types described below
Mechanical energy
- Powered dermatomes
- Powered drills
- Dental hand pieces.
Light
- Phototherapy for skin treatment and for neonatal care
Sound
- Hearing aids
Ultrasound
- Equipment for physiotherapy
unless their characteristics are such that they may administer or exchange Kinetic energy
39
energy to and from the human body in a potentially hazardous way1, taking - Lung ventilators
account of the nature, the density and the site of application of the energy, in
which case they are in Class IIb. Thermal energy
- Incubators for babies
- Warming blankets
- Blood warmers
- Electrically powered heat exchangers (for example, those used with patients incapable of
reacting, communicating and/or who are without a sense of feeling)
Electrical energy
- High-frequency electrosurgical generators, and electrocautery equipment, including their
electrodes
- External pacemakers and defibrillators
- Electroconvulsive therapy equipment.
Coherent light
- Surgical lasers
Ultrasound
- Lithotriptors, surgical ultrasound devices
Ionizing radiation
- Radioactive sources for afterloading therapy
- Therapeutic cyclotrons and linear accelerators
- Therapeutic X-ray sources
All active devices intended to control or monitor the performance of active - External feedback systems for active therapeutic devices
therapeutic devices in Class IIb or intended to influence directly the - Afterloading control devices
performance of such devices are in Class IIb.
40
Note 1: The decision as to whether a medical device administers or exchanges energy to and from the human body in a potentially hazardous way should take into account
the following factors. The concept of "potentially hazardous" is dependent on the type of technology involved and the intended application of the device to the patient and not
on the measures adopted by the manufacturer in view of good design management (e.g. use of technical standards, risk analysis). For instance all devices intended to emit
ionizing radiation, all lung ventilators and lithotriptors should be in Class IIb. However, the manufacturer's obligation to comply with design requirements and solutions adopted,
such as use of standards, exist independently from the classification system.
41
Rule 10 - Active devices for diagnosis
This primarily covers a whole range of widely used equipment in various fields, e.g. ultrasound diagnosis, capture of physiological signals and therapeutic and diagnostic
radiology.
RULE 10 EXAMPLES
Active devices intended for diagnosis are in Class IIa: - Magnetic resonance equipment.
- if they are intended to supply energy which will be absorbed by the human - Pulp testers.
body, except for devices used to illuminate the patient's body, in the visible - Evoked response stimulators
spectrum, - Diagnostic ultrasound
- if they are intended to image in vivo distribution of radiopharmaceuticals, - Gamma cameras

- Positron emission tomography and single photon emission computer tomography
- if they are intended to allow direct diagnosis or monitoring of vital physiological - Electrocardiographs
processes1, - Electroencephalographs
- Cardioscopes with or without pacing pulse indicators2
- Electronic thermometers
- Electronic stethoscopes
- Electronic blood pressure measuring equipment.
unless they are specifically intended for monitoring of vital physiological - Intensive care monitoring and alarm devices (e.g. blood pressure, temperature, oxygen
parameters, where the nature of variations is such that it could result in saturation)
immediate danger to the patient, for instance variations in cardiac performance, - Biological sensors
respiration, activity of CNS in which case they are in Class IIb. - Blood gas analysers used in open heart surgery
- Cardioscopes
- Apnoea monitors, including apnoea monitors in home care
Active devices intended to emit ionizing radiation and intended for diagnostic - Diagnostic X-ray sources
and therapeutic interventional radiology3 including devices which control or
monitor4 such devices, or which directly influence their performance, are in
Class IIb.
42
Examples of special concepts:
Note 1: Vital physiological processes and parameters include, for example respiration, heart rate, cerebral functions, blood gases, blood pressure and body temperature.
Medical devices intended to be used for continuous surveillance of vital physiological processes in anaesthesia, intensive care or emergency care are in Class IIb, whilst
medical devices intended to be used to obtain readings of vital physiological signals in routine check ups and in self-monitoring are in Class IIa. A thermal imaging device
intended to monitor blood flow is not considered to be a temperature measuring device.
Note 2: Devices specifically intended to monitor AIMDs fall under the AIMD Directive.
Note 3: Therapeutic interventional radiology refers to diagnosis being carried out during surgical procedures.
Note 4: This refers to active devices for the control, monitoring or influencing of the emission of ionizing and not to the subsequent processing, recording or viewing of the
resulting image.
43
Rule 11 - Active devices intended to administer and/or remove medicines, body liquids or other substances to or from the body
This rule is intended to primarily cover drug delivery systems and anaesthesia equipment.
RULE 11 EXAMPLES
All active devices intended to administer and/or remove medicines, body liquids - Suction equipment
or other substances to or from the body are in Class IIa, - Feeding pumps
- Jet injectors for vaccination
- Nebulisers to be used on conscious and spontaneously breathing patients where failure to
deliver the appropriate dosage characteristics is not potentially hazardous
unless this is done in a manner: - Infusion pumps

- that is potentially hazardous, taking account of the nature of the substances - Ventilators
involved, of the part of the body concerned and of the mode of application, in - Anaesthesia machines
which case they are in Class IIb. - Anaesthetic vaporisers
- Dialysis equipment
- Blood pumps for heart-lung machines
- Hyperbaric chambers
- Pressure regulators for medical gases
- Medical gas mixers
- Moisture exchangers in breathing circuits if used on unconscious or non-spontaneously
breathing patients
- Nebulisers where the failure to deliver the appropriate dosage characteristics could be
hazardous
44
Rule 12 - All other active devices
This is a fallback rule to cover all active devices not covered by the previous rules.
RULE 12 EXAMPLES
All other active devices are in Class I - Active diagnostic devices intended to illuminate the patient's body in the
visible spectrum such as examination lights or to optically view the body such
as surgical microscopes
patient hoists, wheelchairs, dental patient chairs)
- Active diagnostic devices intended for thermography
- Dental curing lights
45
4. Special rules
Rule 13 - Devices incorporating, as an integral part, a medicinal product or a human blood derivative (See MEDDEV. 2.1/3 for further guidance)
This rule is intended to cover combination devices that contain a medicinal substance incorporated into the device for the purpose of assisting the functioning of that device.
However this rule does not cover those devices incorporating substances which under other circumstances may be considered as medicinal substances, but which are
incorporated into the device exclusively for the purpose at maintaining certain characteristics of the device and which are not liable to act on the body. The primary function of
the device does not rely on the pharmacological, metabolic or immunological effect of the medicine. If the latter is the case, the product is a medicinal product rather than a
device and not covered by this Directive.
RULE 13 EXAMPLES
All devices incorporating, as an integral part1, a substance which, if used - Antibiotic bone cements
separately, can be considered to be a medicinal product as defined in Article 1 - Condoms with spermicide
of the Directive 2001/83/EC, and which is liable to act on the human body with - Heparin coated catheters
action ancillary to that of the devices, are in Class III. - Endodontic materials with antibiotics
- Ophthalmic irrigation solutions principally intended for irrigation, which contain
components which support the metabolism of the endothelial cells of the cornea
- Dressings incorporating an antimicrobial agent where the purpose of such an agent is to
provide ancillary action on the wound
- Contraceptive intrauterine devices (IUDs) containing copper or silver
- Drug eluting stents, e.g. coronary, pulmonary
All devices incorporating as an integral part, a human blood derivative are in - Surgical sealants containing human serum albumin
Class III
Note 1: "Integral part" means that the device and the medicinal substance are physically or chemically combined at the time of administration (i.e. use, implantation,
application etc) to the patient.
46
Rule 14 - Devices used for contraception or prevention of sexually transmitted diseases
These intended uses relate to special cases of human vulnerability that cannot be covered by the normal criteria of time, invasiveness and organic function.
Although this rule covers two very different device applications, some devices may perform both functions, e.g. condoms.
Devices intended to prevent the sexual transmission of the HIV are also covered by this rule.
RULE 14 EXAMPLES
All devices used for contraception or the prevention of the transmission of - Condoms
sexually transmitted diseases are in Class IIb, - Contraceptive diaphragms
unless they are implantable or long term invasive devices, in which case they - Contraceptive intrauterine devices (IUDs)1
are in Class III.
Note 1: Intrauterine contraceptives whose primary purpose is to release progestogens are not medical devices (see Article 1.3 2nd paragraph of this Directive).
.
47
Rule 15 - Specific disinfecting, cleaning and rinsing devices
This rule is principally intended to cover various contact lens fluids. It also covers substances and other equipment used principally in a medical environment to disinfect
medical devices.
RULE 15 EXAMPLES
All devices intended specifically to be used for disinfecting, cleaning, rinsing or, - Contact lens solutions
when appropriate hydrating contact lenses are in Class IIb. - Comfort solutions
All devices intended specifically to be used for disinfecting medical devices are - Disinfectants specifically intended for non-invasive medical devices and
in Class IIa equipment such as sterilizers specifically intended to sterilize medical devices
in a medical environment and washer disinfectors
- Washers-disinfectors intended specifically for disinfecting non-invasive
medical devices
unless they are specifically to be used for disinfecting invasive devices in which - Denture disinfecting products
case they are in Class IIb. - Washers-disinfectors for endoscopes
- Disinfectants for the fluid pathways of haemodialysis equipment
- Disinfectants for ocular prosthesis, intraosseous transcutaneous amputation
prosthesis, surgical equipment and invasive dental equipment
This rule does not apply to products that are intended to clean medical devices
other than contact lenses by means of physical action1.
Note 1: This rule does not apply to mechanical means of cleaning of devices, such as brushes and ultrasound. Such products will only fall under this Directive if they are
specifically intended for use with medical devices.
48
Rule 16 - Devices to record X-ray diagnostic images
RULE 16 EXAMPLES
Devices specifically intended for recording of X-ray diagnostic images are in - X-ray films
Class IIa. - Photostimulable phosphor plates
Note: This refers to primary recording media such as X-ray films and not to media used for subsequent reproduction.
49
Rule 17 - Devices utilising animal tissues or derivatives
Explanation of the rule
This rule covers devices that contain or are made of animal tissues that have been rendered non-viable or derivatives from such tissues also being non-viable, i.e. where there
is no longer any capacity for cellular metabolic activity. Devices containing viable animal tissues and/or any human tissues or derivatives are excluded from the scope of this
Directive.
Further information on this issue can be found in MEDDEV 2.11/1 rev.2 13 .
The manufacture of some devices may use industrial raw materials which contain small amounts of tallow or tallow derivatives (e.g. stearates in polymers). Such substances
are not considered as derivatives of animal tissues for the purpose of this rule which therefore does not apply.
RULE 17 EXAMPLES
All devices manufactured utilizing animal tissues or derivatives1 rendered non- - Biological heart valves
viable are Class III except where such devices are intended to come into - Porcine xenograft dressings
contact with intact skin2 only. - Implants and dressings made from collagen
- Devices utilising hyaluronic acid of animal origin
Practical classification issues
- Devices made of non-viable animal tissue that comes into contact with intact skin only (e.g. leather components of orthopaedic appliances) are in Class I in accordance to
Rule 1.
Note 1: Derivatives are products that are processed from animal tissues and exclude substances such as milk, silk, beeswax, hair, lanolin
Note 2: Intact skin includes the skin around an established stoma unless the skin is breached.
13
http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_11_1_rev2_bsetse_january2008_en.pdf
50
Rule 18 - Blood bags
This is a special rule that covers only blood bags.
RULE 18 EXAMPLES
By derogation from other rules, blood bags are in Class IIb. - Blood bags (including those containing or coated with an anticoagulant).
Where blood bags have a function greater than for storing purposes and
include systems for preservation other than anti-coagulants then other rules
(e.g. rule 13) may apply
Note: Blood bags are described in the European Pharmacopoeia in the monograph on "Containers for Blood and Blood Components".
51
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representatives from national medical device regulatory authorities and the
MoU regulated industry. Since its inception, the GHTF has been comprised of
representatives from five founding members grouped into three geographical areas:
Study Group 1 Europe, Asia-Pacific and North America, each of which actively regulates medical
Study Group 2 devices using their own unique regulatory framework.
Study Group 3 The purpose of the GHTF is to encourage convergence in regulatory practices
Study Group 4 related to ensuring the safety, effectiveness / performance and quality of medical
devices, promoting technological innovation and facilitating international trade, and
Study Group 5 the primary way in which this is accomplished is via the publication and
dissemination of harmonized guidance documents on basic regulatory practices.
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Last Updated November 19, 2007
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GHTF Roles and Responsibilities
GHTF Steering Committ ee Final Document GH TF GHTF/SC/N2R9:2005
GHTF/SC/N2R9:2005
FINAL DOCUMENT
Global Harmonization Task Force
Title: GHTF Roles and Responsibilities
Authoring Group: GHTF Steering Committee
Endorsed by: The Global Harmonization Task Force
Date: May 20, 2005
Abraao Carvalho, GHTF Chair
This document was produced by the Global Harmonization Task Force, a voluntary international group of
representatives from medical device regulatory authorities and trade associations from Europe, the United
States of America (USA), Canada, Japan and Australia.
There are no restrictions on the reproduction, distribution or use of this document; however, incorporation
of this document, in part or in whole, into any other document, or its translation into languages other than
English, does not convey or represent an endorsement of any kind by the Global Harmonization Task
Force.
Copyright 2000 by the Global Harmonization Task Force
May 20, 2005

GHTF Steering Committee Final Document GHTF GHTF/AHPG/N2R9:2005
Table of Contents
Preface
1.0 Introduction ................................ ................................ .............................................................. 4
2.0 Membership ................................ ................................ .............................................................. 4
2.1 Founding Members ................................................................................................ .............. 4
2.2 Participating Members ................................ ................................ ................................ ......... 5
2.3 Liaison Bodies................................ ................................ ................................ ...................... 5
3.0 Observers ................................ ................................ ................................ ..................................6
4.0 GHTF Operational Structure ................................ ................................ ...................................6
4.1 GHTF Steering Committee ................................ ................................ ................................ .6
4.1.1 Steering Committee Composition ................................................................ .............. 6
4.1.2 Functions ................................ ................................ ................................ ...................... 7
4.1.3 Meetings ................................ ................................................................ ....................... 8
4.2 GHTF Chair................................ ................................ ................................ .......................... 8
4.2.1 Selection and Succession ................................ ............................................................ 8
4.2.2 Functions ................................ ................................ ................................ ...................... 9
4.2.3 GHTF Secretariat ................................ ................................ ................................ ......... 9
4.3 GHTF Vice Chair ................................................................................................ ............... 10
4.3.1 Appointment ................................................................ ................................ ..............10
4.3.2 Functions ................................ ................................ ................................ .................... 10
4.4 GHTF Study Groups ................................ ................................ ................................ ..........10
4.4.1 Creation/Termination/Renewal ................................ ................................ .................10
4.4.2 Membership ................................................................................................ ............... 10
4.5 GHTF Study Group Chairs ................................ ................................ ............................... 11
4.5.1 Appointment ................................................................ ................................ ..............11
4.5.2 Functions ................................ ................................ ................................ .................... 12
4.6 Study Group Meetings ................................ ................................ ................................ .......13
4.7 Joint Study Group Meetings ................................ ................................ .............................. 13
5.0 Conferences ................................ ................................ ............................................................ 13
5.1 GHTF Global Conference ................................ ................................ .................................13
5.1.1 Plenary Sessions ................................................................ ................................ ........14
5.1.2 Special Topic Sessions ................................ ................................ .............................. 15
5.1.3 Registration Fee ................................................................ ................................ .........15
5.2 Regional Conferences ................................................................ ................................ ........15
May 20, 2005 Page 2 of 16

Preface
representatives from medical device regulatory authorities and trade associations from the European
Union (EU) and EFTA (European Free Trade Association), the United States of America (USA), Canada,
Japan and Australia.
The original version of this document was endorsed by GHTF in September 2000 and it was foreseen at
that time that the text would unde rgo periodic revisions. A review of this document was undertaken in
2005. This text is the result of that review.
There are no restrictions on the reproduction, distribution, translation or use of this document however,
incorporation of this document, in part or in whole, into any other document does not convey or represent
an endorsement of any kind by the Global Harmonization Task Force .
May 20, 2005 Page 3 of 16

1.0 Introduction
This document is intended to facilitate the management of GHTF activities by adequately describing t he
roles and responsibilities of all those involved in GHTF work.
This document establishes the different membership categories and the governing procedures for the
components of GHTF.
The roles and responsibilities outlined in this document, in conju nction with the GHTF Guiding
Principles and GHTF Operating Procedures and the GHTF Strategic Directions , are designed to be
flexible, so that should the need arise, the GHTF can respond to challenges with respect to its objectives
in a timely manner.
2.0 Membership
GHTF was established as a voluntary international group of medical device regulatory authorities, and
medical device trade associations from Europe, the United States of America (USA), Canada, Japan and
Australia, grouped into three geographi cal areas, namely Europe, North America and Asia -Pacific. For
this purpose Europe means the European Union, including its candidate and associated countries, and
countries of the European Free Trade Association (EFTA).
Participation in GHTFs work takes place under different categories of membership Founding
Members, Participating Members, and Liaison Bodies.
2.1 Founding Members
Founding Members are regulatory authorities or industry representatives from Europe, the United States
of America (USA), Canad a, Japan and Australia. These Founding Members created GHTF and have well
established regulatory systems, allowing for technological innovation whilst promoting a high level of
safety and effectiveness/performance.
Founding Members will take appropriate steps to implement GHTF guidance and policies within the
boundaries of their legal and institutional constraints . Regulatory authorities agree to promote the GHTF
documents within their own jurisdictions and, in the course of time, seek convergence of re gulatory
practices. Regulators hold the ultimate responsibility for this implementation.
Founding Members participate in the Steering Committee, can propose participants for GHTF Study
Groups or other expert working groups, and take part in all GHTF acti vities, such as plenary meetings,
special topic sessions, regional meetings and GHTF training.
May 20, 2005 Page 4 of 16

2.2 Participating Members
Participating Members are representatives of medical device regulatory authorities or medical device
trade associations of countries ot her than the Founding Members.
Participating Members will take appropriate steps to implement GHTF guidance and policies within the
boundaries of their legal and institutional restraints. Regulatory authorities agree to promote the GHTF
documents within their own jurisdictions and, in the course of time, seek convergence of regulatory
practices. Regulators hold the ultimate responsibility for this implementation.
Participating Members can propose participants for GHTF Study Groups or other expert work ing groups
the GHTF establishes, and take part in GHTF activities, such as plenary meetings, special topic sessions,
regional meetings and GHTF training.
In terms of procedure:
Any country wishing to participate in GHTF should address a request to the GH TF Chair.
The Chair will submit this request to the Steering Committee, which will decide whether or not to
grant the requesting country Participating Member status.
The request must contain sufficient information to allow the Steering Committee members to
evaluate the interest of the respective country in GHTF s work, and its willingness to implement
GHTF guidance documents.
2.3 Liaison Bodies
Liaison Bodies are public health organizations, international standard -setting bodies or other groups who
can contribute to or benefit from participation in GHTF.
Liaison Bodies are urged to co-operate in promoting GHTF guidance documents work to their members,
as appropriate, and to consider GHTF guidance in their own work.
Liaison Bodies may nominate observers for GHTF Study Groups, or other expert working groups which
the GHTF establishes, and take part in GHTF activities, such as plenary meeting, special topic sessions,
regional meetings and GHTF training, on a meeting by meeting basis .
In terms of procedure:
Any organization or entity wishing to become a Liaison Body of GHTF should address a request
to the GHTF Chair.
The Chair will submit this request to the Steering Committee, which will decide whether or not to
grant the requesting organiz ation or entity Liaison Body status.
The request must contain sufficient information to allow the Steering Committee members to
evaluate the interest in GHTF s work and their willingness to promote GHTF guidance.
May 20, 2005 Page 5 of 16

3.0 Observers
Founding Members may nominate observers to the Steering Committee as well as to Study Groups. Such
nominations must be made for specific meetings and must be addressed to the GHTF C hair for the
Steering Committee, and to the Study Group Chair for participation in Study Groups. Participation
depends on the agreement of the respective Chair.
Other members may nominate observers to Study Groups. Requests must be addressed to the Study
Group Chair. Participation depends on the agreement of the Chair.
4.0 GHTF Operational Structure

GHTF carries out its activities through the Steering Committee, the Study Groups and the GHTF Chair.
4.1 GHTF Steering Committee
The role of the Steering Committee is to provide policy and strategic direction in order to ensure that
GHTF work continues to fulfil its goals and objectives. Its role is to:
provide strategic planning,

assign and provide oversight of new work items,
adopt GHTF guidance documents, and monitor their implementation,
authorize and promote training events as required.
4.1.1 Steering Committee Composit ion
The GHTF Steering Committee comprises representatives from the Founding Members . The GHTF
Steering Committee is composed of up to four regulatory and up to four industry representatives from
each of the three geographic areas in which they are groupe d.
The geographic area holding the Chair may de cide that the Chair and/or Vice Chair are not included in
that number. In t his case, the Chair and/or Vice Chair may not act as spokespersons for their geographic
area.
Each geographic area is responsible f or the selection of its representatives. Industry association
representatives should broadly represent industry.
When a Study Group document comes before the Steering Committee, any Steering Committee member
who also serves on that Study Group will not pa rticipate in the discussion , unless invited by the Chair.
Study Group Chairs participate in GHTF Steering Committee meetings by invitation of the GHTF Chair.
May 20, 2005 Page 6 of 16

Representatives of Participating Members and Liaison Bodies can be invited by the GHTF Chair, in
agreement with the Steering Committee, to attend Steering Committee meetings on specific agenda
points.
At its discretion, the GHTF Steering Committee may consult Members or outside parties in order to
gather information and solicit external advice rel evant to business matters pending before the Committee.
(see 4.1.3.)
4.1.2 Functions
In order to fulfil its role, the Steering Committee is responsible for:
(A) supporting the development o f a GHTF regulatory model,
(B) monitoring and modifying as needed the inst itutional rules of GHTF and in particular the
composition of the Steering Committee,
(C) granting status of Participa ting Members and Liaison Bodies,
(D) encouraging the participation of countries other tha n those of the Founding Members,
(E) establishing and dis charging Study Groups, and discussing and authorizing work programme
plans and work priorities pre pared by the Study Group Chairs,
(F) appointing and renewing Study Group Chairs and Vice Chairs,
(G) endorsing proposed new work items and final GHTF guidance docu ments, and encouraging their
implementation,
(H) overseeing GHTF activities, in particular
- ensuring Study Group progress,

- preventing duplication of Study Group activities and those of other external organizations,
- identifying and resolving problems that might delay project completion,
(I) reviewing GHTF policies and procedures at regular intervals and ensuring that GHTF documents
are updated regularly,
(J) providing assistance in the planning of the GHTF Conference and other meetings and ap proving
GHTF Conference agendas,
(K) providing support and/or guidance to the GHTF Chair on the resolutio n of any complaints or
disputes,
(L) in conjunction with the Chair, determine the invitees to the open session ,
(M) taking any other initiatives that contribute to achieving GHTFs goals and objectives.
May 20, 2005 Page 7 of 16

4.1.3 Meetings
The GHTF Steering Committee will meet as often as necessary to conduct GHTF work effectively, but
generally not less than two (2) times every 18 months.
Meetings are at the call of the Chair and may be conduct ed by teleconference or video -conference if
necessary.
As a rule, the Steering Committee meetings will take place in closed session. However, open
sessions may be convened, in total or in part, on the initiative of the Chair, in agreement with the
Steering Committee. Open sessions may deal with, in particular:
reports from Study Groups Chairs,

input for conferences,
identification of releva nt topics for training seminars,
analysis and assessment of new strategic approaches.
Steering Committee memb ers will be notified of all Steering Committee meetings with a minimum of
eight weeks notice and confirmation of all attendees should be sent to the current Chair at least four
weeks before each meeting. In addition, Steering Committee meeting dates will be posted on the GHTF
website.
Conduct of Committee work can only occur when all Founding Members are represented. Representation
may be in person, by video -conferencing, by tele -conferencing or by a proxy.
The GHTF Steering Committee will be chaired by the GHTF Chair, or the GHTF Vice Chair if the Chair
cannot fulfil his/her duties.
Within four weeks after each meeting, the Chair will circulate a meeting summary for comment.
Following incorporation of necessary revisions, the document will be made publicly available on the
GHTF website and archived in the official records of the GHTF. Similarly, if no comments are received,
the meeting summary will be deemed accepted and posted to the GHTF website.
4.2 GHTF Chair
4.2.1 Selection and Succession
Chairmanship of the GHTF will rotate between the national regulatory authorities of the three geographic
areas. The term of office will last three years.
It will be up to each individual geographic area to decide if the Chairmanship should be carried out by
one individual for the entire period or divided between two individuals for half the time period each.
May 20, 2005 Page 8 of 16

To help ensure continuity in leadership of the GHTF, the incoming Chair should offer assistance in the
management of any outstanding Steering Committee act ivities.
In addition, a transition meeting should be organized between the outgoing and incoming Chairs and staff
carrying out secretariat functions on or about the date of the actual transfer of Chairmanship.
4.2.2 Functions
The GHTF Chair is responsibl e for providing general management oversight of all work of the GHTF and
the Steering Committee. This includes:
(A) Ensuring that the Steering Committee effectively meets to execute its tasks, proposing an agenda
for the Steering Committee meetings and c hairing the meetings,
(B) resolving all disputes regarding GHTF decisions or actions brought forward by GHTF members
or persons outside the GHTF such as invitees, with the assistance of t he Steering Committee as
needed,
(C) representing the GHTF in ad hoc consultations with external parties concerning GHTF activities,
(D) making arrangements for regular Conferences of the GHTF and proposing the agenda for and
presiding over the plenary session,
(E) the provision of secretariat services and planning support to the GHTF for the duration of his/ her
term as Chair, either via an outside contract or through assignment of one of his/ her staff. In
agreement between the Steering Committee and the Chair certain tasks of the Secretariat can be
delegated to one of the Founding Member or be outsourced.
4.2.3 GHTF Secretariat
The GHTF Secretariat will have the following responsibilities:
(A) providing direct staff support to the GH TF Chair and Steering Committee,
(B) preparing records of proceedings for all Steering Com mittee meetings and GHTF conferences,
and arranging for their dissemination to Stee ring Committee and GHTF members,
(C) maintaining a current inventory of all completed and in -process documents and acting as
custodian of all GHTF historical, policy and other documents that ha ve a bearing on GHTF
operations,
(D) serving as the primary focal point for receipt of all Study Group and other GHTF documents for
distribution to the Steering Committee or the GHTF Study Groups for review and/or final
endorsement,
May 20, 2005 Page 9 of 16

(E) making arrangements for the transition meeting at which the physical transfer of GHTF records to
the incoming GHTF Chair will be effected, and
(F) supervising the maintenance of the GHTF website, in addition to ensuring that all documents
recommended for posting to t he website conform with established formats and have received all
necessary clearances.
4.3 GHTF Vice Chair
4.3.1 Appointment
To support the GHTF Chair, a GHTF Vice Chair will be designated by the industry association(s)
representing the region that holds the Chair.
4.3.2 Functions
The principal duty of the Vice Chair is to support the current Chair in his/ her activities and to substitute
for the Chair, should he/she no t be able to fulfil his/her duties .
In the event that the GHTF Ch air is unable to carry out h is/her full term of duty, he/ she should promptly
notify the Steering Committee so that the Vice Chair can act for him/ her until an alternate from their
national authority can be designated to take over.
Additionally, the Vice Chair may share the responsib ility of the Chair for the provision of secretariat
services.
4.4 GHTF Study Groups
4.4.1 Creation/Termination/Renewal
Study Groups may be formed at any time by the Steering Committee.
The Steering Committee may also discharge a Study Group from further respon sibility, instruct a Study
Group to re-define its original terms of reference, charge the Study Group with a new task, appoint a new
chair, and/or renew an existing Chairs appointment.
4.4.2 Membership
The size and overall composition of each Study Group is de termined by the Study Group Chair. It is
recommended that each Study Group include one or more representatives from each geographic area with
May 20, 2005 Page 10 of 16

Founding Member status and with an appropriate balance between the number of industry and regulatory
technical experts representing different device types or regulatory classes.
Participation in Study Group meetings by Participating Members, Liaison Bodies and Observer requires
prior written permission of the Study Group Chair.
In case of dispute over Study Group membership, the Study Group Chair and/or the applicant should ask
the Steering Committee to arbitrate.
Study Group Chairs are encouraged to look for the following qualities when assessing nominations for
Study Group membership:
(A) expert in the subject matter of the Study Group,
(B) ability to participate in most meetings related to Study Group activity,
(C) ability to represent effectively the interests of the geographic area and its regulators or industry,
(D) ability to report effectively on Study Group meetings, and
(E) ability to call for and consolidate comments and positions of the respective geographic area on
Study Group documents.
Nominations for Study Group members are made by the respective regulatory authority or industry
association. They should be accomp anied by a Curriculum Vitae allowing the Study Group Chair to
evaluate whether the nominee possesses the qualities listed above . The decision will be taken by the
Study Group Chair.
In exceptional cases, the Study Group Chair may authorize an individual, with appropriate knowledge and
expertise, to participate in a Study Group meeting as a substitute of a Study Group Member .
4.5 GHTF Study Group Chairs
4.5.1 Appointment
Study Group Chairs, normally a regulator, are appointed to a three -year term, but may have their
appointment renewed by the Steering Committee based on the needs of the Study Group.
Chairs may be supported by a Vice Chair, normally an industry representativ e, desirably from another
geographic area. Study Groups should be supported by a Secreta riat.
Appointment of a Study Group Chair should be based on the following considerations:
(A) possession of grou p and project management skills,
May 20, 2005 Page 11 of 16

(B) possession of technical expertise and/or regulatory experience (of the country or integrational
organization of states that he/ she represents) relevant to the task assigne d to the particular Study
Group,
(C) the ability of the individual to devote adequate time and attention to the assigned task,
(D) diversity in relation to the geographical areas represented by other Study Group Chairs, and
(E) other considerations, e.g., the capacity of the persons employer, or other sponsor, to support such
an outside activity that requires continuity.
Should a Study Group Chair be unable to fulfill his/her term, he/ she should prompt ly notify the GHTF
Chair who in turn will inform the Steering Committee. The GHTF Chair or his/her designee will then
consult within the Steering Committee (using teleconference or e -mail as needed) and appoint a
replacement, either on an interim or perma nent basis.
4.5.2 Functions
Each Study Group Chair is responsible for the following activities:
(A) supporting the development of a GHTF re gulatory model,
(B) ensuring an appropriate balance and breadth of membership in accordance with Section 4.4.2,
(C) preparing and maintaining a work plan for his/her Study Group and reporting to the Steering
Committee on the activities of his/her Group on a regular basis, or a t the request of the GHTF
Chair,
(D) organizing meetings, discussing assigned tasks, and developing documents a s required,
(E) proposing potential new work items including revisions of Final Documents to the GHTF
Steering Committee ,
(F) preparing summary reports regarding the work of their Study Group for dissemination on the
GHTF website,
(G) following each Study Group mee ting, circulating to his/her members, all relevant
documents and an agreed-to actions list,
(H) promoting open discussion during Study Group meetings and dissuading meeting
attendees from circulating their own personal notes, and
(I) consulting with other Study Group Chairs, to avoid duplication of effort and ensure consistency
between all GHTF outputs, irrespective of originating Study Group.
May 20, 2005 Page 12 of 16

4.6 Study Group Meetings
Study Groups meet as often as necessary to carry out the tasks assigned to them by the GHTF Steer ing
Committee.
Meetings are at the call of the individual Study Group Chairs and should be convened in different
locations on a rotational basis in order to accommodate as many Study Group members as possible.
When practical, meetings may also be condu cted by means of teleconferencing or videoconferencing.
Meeting agendas should be circulated to a ll Study Group members at least six weeks in advance. At each
meeting, time should be reserved for a discussion of issues arising after circulation of the age nda.
Study Group Chairs may, at their discretion , permit individuals who are not members of their Study
Group or of the GHTF to participate in their meetings as technical experts with observer status.
Participation of representatives of GHTF Founding Mem ber should be generally accepted.
Requests for non-member participation should be submitted in writing to the Study Group Chair at least
four weeks in advance of the meeting. The request should include information on the individuals
affiliation and an e xplanation of the individuals interest in the Study Group activities. The non -member
requesting permission to participate in the meeting will be notified in writing by the Study Group Chair.
A meeting summary including action items emerging from each St udy Group meeting is to be prepared
and forwarded to the GHTF Chair within six weeks of each meeting who will then forward it to the
members of the GHTF Steering Committee. The summary will also be posted on the GHTF website.
4.7 Joint Study Group Meetings
The Steering Committee will encourage joint meetings of all Study Groups as appropriate.
5.0 Conferences
5.1 GHTF Global Conference
To promote the progress that is made on GHTF activities, the GHTF will meet in a Conference, in
principle, once every eighteen months. Responsibility for planning and organizing GHTF Conferences
resides chiefly with the GHTF Chair and Steering Committee, who may solicit the assistance and support,
if necessary, from other members of the GHTF. The Chair may be assisted by an organizing committee.
In proposing the GHTF Global Conference programme to the GHTF Steering Committee for review and
approval, the Chair will take into account that the programme should foresee the possibility for :
(A) meeting of the Steering Committee,
(B) meetings of individual Study Groups, as well as a joint Study Group meeting, as appropriate ,
May 20, 2005 Page 13 of 16

(C) a Plenary Session,
(D) Special Topic Sessions, as described below, and
(E) Area Meetings, at which members from specific geographic areas may meet to discuss issues
pertinent to them.
All GHTF members are to be notified of the date(s) of the next GHTF Conference by the Chair, in
principle no later than twelve months prior to the event.
5.1.1 Plenary Sessions
The purpose of the Plenary Session at a GHTF Confer ence is to provide information on ongoing GHTF
activities and initiatives . In addition, the Plenary Session may serve as a forum for members to discuss
pertinent issues or present material that may be of interest to regulators or industry representatives, and
also to non-member countries or representatives of international organizations.
The Plenary Session is open to all registered participants.
The Plenary Session agenda must be reviewed and approved by the GHTF Steering Committee, and will
include the following:
(A) a report, prepared by the current GHTF Chair on behalf of the Steering Committee, outlining
accomplishments since the previous Conference including new strategic initiatives and proposed
or effected changes to existing GHTF procedures, a summary of work as signments, and other
actions taken by the Steering Committee,
(B) reports, prepared by each Study Group Chair, outlining the status of the Groups work, its current
standing and future direction(s),
(C) presentations fro m Area Meetings, as appropriate,
(D) special presentations, by any participant, on a topic relevant to the Conf erence agenda (see
Section 5.1.2),
(E) reports highlighting significant new regulatory initiatives from each Founding Member, including
the implementation of GHTF guidance documents ,
(F) an open session during which any participant may n ominate a topic for discussion.
A summary of the proceedings of each GHTF Conference will be prepared by the Chair and circulated to
the GHTF Steering Committee for comment in a timely manner.
Following incorpor ation of necessary revisions, if any, the document will be made publicly available on
the GHTF website and archived in the official records of the GHTF.
May 20, 2005 Page 14 of 16

5.1.2 Special Topic Sessions
Special workshops, symposia, technical and single topic sessions may be co nvened during a GHTF
Conference. Requests to have such meetings as part of the Conference programme should be directed to
the GHTF Chair, who will then forward them to members of the GHTF Steering Committee for
discussion and approval.
Prior to each Conf erence, the GHTF Chair will invite members to suggest topics for inclusion in the
Conference programme.
5.1.3 Registration Fee
In order to defray the administrative and ancillary costs associated with planning and hosting GHTF
Conferences, and at the discreti on of the host, a reasonable registration fee may be charged to all
Conference attendees. Differential registration fees may be applied.
5.2 Regional Conferences
Without prejudice to the GHTF Global Conferences GHTF may organize Regional Conferences in ord er
to promote its activities and guidance in specific geographic areas.
Such conferences may offer GHTF training and /or training on GHTF.
The organization of Regional Conferences takes place on proposal of the Chair and in agreement with the
Steering Committee.
Such Conferences may be organized in conjunction with other regional events, such as for example
APEC, AHWP, WHO or MERCOSUR or similar organizations and cooperation arrangement events.
May 20, 2005 Page 15 of 16

Appendices
ANNEX A:
Steering Steering Study Groups Other meetings,

Committee Committee such as Plenary
Closed Session Open Session Sessions,
Regional
Conferences,
Training etc.
Founding Yes Yes Yes Yes
Members
Participating No Yes, on Yes, can Yes
Members invitation of propose
Chair members
Liaison No Yes, on Can propose Yes
Bodies invitation of observers
Chair
Observers Yes, on Yes, on Yes, on
from meeting-by- meeting-by- meeting-by- Yes
Founding meeting basis meeting basis meeting basis
Members and agreement and agreement and agreement
by Chair by Chair by Study Group
Chair
Observers No No Yes, on -
from meeting-by-
Participating meeting basis
Members and agreement
and Liaison by Study Group
Bodies Chair
May 20, 2005 Page 16 of 16

GHTF Guiding Principles
GHTF Steering Committee Final Document GHTF/SC/N1R8:2005
GHTF/SC/N1R8:2005
FINAL DOCUMENT
Title: GHTF Guiding Principles
Date: May 20, 2005
States of America (USA), Canada, Japan and Aus tralia.
English, does not convey or re present an endorsement of any kind by the Global Harmonization Task
Force.
May 20, 2005 Page 1 of 7

Table of Contents
Preface
1.0 Introduction ................................ ................................ .............................................................. 4
2.0 Goals and Objectives ................................ ................................ ................................ ............... 4
2.1. Goals ................................................................................................ ................................ .......... 4
2.2. Objectives ................................ ................................ ................................ ..................................4
3.0 Governing Principles ................................ ................................ ................................ ............... 5
3.1 International Cooperation ................................ ................................ ................................ ....5
3.2 Consensus ................................ ................................ ................................ ............................. 5
3.3 Implementation ................................ ................................................................ .................... 5
3.4 Cooperation ................................ ................................ ................................ .......................... 5
3.5 Transparency ................................ ........................................................................................ 5
3.6 Continuous Review ................................................................................................ .............. 6
May 20, 2005 Page 2 of 7

Preface
representatives from medical device regu latory authorities and trade associations from the European
The original version of this document was endorsed by GHTF in September 20 00 and it was foreseen at
that time that the text would undergo periodic revisions. A review of this document was undertaken in
There are no restrictions on the reproduction, distribution, translation or use of this document however,
an endorsement of any kind by the Global Harmonization Task Force.
May 20, 2005 Page 3 of 7

1.0 Introduction
The guiding principles outlined in this do cument, in conjunction with the GHTF Roles and
Responsibilities and GHTF Operating Procedures and the GHTF Strategic Directions, are designed
to be flexible so that should the need arise, the GHTF can respond to challenges with respect to its
objectives in a timely manner.
2.0 Goals and Objectives
2.1. Goals
The goal of the Global Harmonization Task Force is to provide a collaborative forum for representatives
of member national regulatory authorities and industry representatives to promote internationa l
convergence in regulatory requirements and practices, in particular to:
promote the safety, effectiveness/ performance and quality of medical devices,

encourage technological innovation,
foster international trade,
serve as an information exchange fo rum through which countries with medical device regulatory
systems under development can benefit from the experience of those with established systems
and/or pattern their practices upon those of GHTF documents,
Notwithstanding the above, it is recognized that participating regulatory authorities retain the right to
regulate according to their applicable sovereign regulations .
2.2. Objectives
To achieve the above goals the objectives of GHTF are:
(A) to encourage the development of a harmonized regulatory environment, allowing for better
protection of public health, and thereby facilitating the availability of medical technologies
consistent with the state o f the art and current knowledge,
(B) the development of guidance documents and recommended pr ocedures in order to work towards
convergence of the medical device regulatory systems of its Members within the boundaries of
their legal and institutional constraints ,
(C) to define common elements of the regulatory systems of its Members and to work towards a
coherent implementation of these elements, to encourage the development of related common
data sets and their acceptance by regulatory authorities with the aim of avoiding duplication of
files,
(D) to facilitate the development of an internati onal post-market and vigilance system that will reduce
the likelihood of repeated adverse events and influence the development of new medical devices,
May 20, 2005 Page 4 of 7

(E) serve as platform for the exchange of information between Competent Authorities with
established regulatory systems,
(F) to foster international cooperation between countries with established and developing regulatory
systems.
3.0 Governing Principles
3.1 International Cooperation
The guiding spirit of GHTF is one of international cooperation betw een regulators and industry to achieve
its goals and objectives.
3.2 Consensus
GHTF takes all decisions and actions by consensus.
3.3 Implementation
GHTF members will take appropriate steps to implement GHTF guidance and policies within the
boundaries of their legal and institutional constraints .
Regulatory authorities agree to promote the GHTF documents within their own jurisdictions and , in the
course of time, seek convergence of regulatory practices.
While regulators hold the ultimate responsibility for im plementation, it is recognized that successful
implementation requires the concerted best efforts of regulators and industry.
3.4 Cooperation
GHTF is committed to collaboration with non -founding members, international standard -setting bodies
and/or public heal th organizations in ord er to share the experiences gained with its Members regulatory
systems. The intent is to promote the implementation of GHTF guidance and to avoid duplication of
work.
3.5 Transparency
GHTF is guided by the principle that its activ ities are transparent. This includes making documents in
development available for comment at appropriate stages and keeping the GHTF website as current and
accurate as possible.
May 20, 2005 Page 5 of 7

3.6 Continuous Review
In order to keep all GHTF guidance up to date GHTF w ill regularly review its documents and guidance
and revise them as required.
May 20, 2005 Page 6 of 7

May 20, 2005 Page 7 of 7

GHTF Operating Procedures
GHTF/SC/N3R9:2005
FINAL DOCUMENT
Title: GHTF Operating Procedures
Date: May 20, 2005
States of America (USA), Canada, Japan and Aus tralia.
English, does not convey or re present an endorsement of any kind by the Global Harmonization Task
Force.
Date: May 20, 2005 Page 1 of 17

Table of Contents
1.0 Introcuction................................ ................................ ............................................................... 4

2.0 Language ................................ ................................ ................................ ..................................4
3.0 GHTF Document Management ................................ ............................................................... 4
3.1 Stage Assignment of New Work ................................................................ .................... 4
3.2 Stage 2 Document Development ..................................................................................... 5
3.3 Stage 3 Consultation on Working Drafts ................................ ................................ ........ 5
3.4 Stage 4 Advancement from Working Draft to Proposed Document ............................. 5
3.5 Stage 5 Consultation of Proposed Documents ................................ ................................ 6
3.6 Stage 6 Advancement from Proposed Document to Final Document ........................... 6
3.7 Stage 7 Publication ................................................................ ................................ ........... 7
4.0 Document Status Desi gnation ................................ ................................ ................................ .7
4.1 Location of Designation Code ................................ ............................................................ 7
4.2 Working Drafts ................................ ................................................................ .................... 8
4.3 Proposed Documents ................................................................ ................................ ........... 8
4.4 Final Document ................................ ................................................................ .................... 8
5. Maintenance of GHTF Documents ................................ ................................ ................................ .9
6. Record-Keeping/ Information Archives ................................ ................................ .......................... 9
7. GHTF-Related Presentations and Training ..................................................................................... 9
8. GHTF Logo ................................................................ ................................ ....................................10
ANNEX A ................................ ................................................................ ................................ ...........12
ANNEX B ................................ ................................................................ ................................ ...........14
ANNEX C ................................ ................................................................ ................................ ...........15
ANNEX D ................................ ................................................................ ................................ ...........16
ANNEX E ................................ ................................................................ ................................ ...........17

Preface
This document was produced by the Global Harmonization Task Force, a voluntary international group o f
representatives from medical device regulatory authorities and trade associations from the European
The original version of this docu ment was endorsed by GHTF in September 2000 and it was foreseen at
that time that the text would undergo periodic revisions. A review of this document was undertaken in
There are no restrictions on the reprod uction, distribution, translation or use of this document, however,
an endorsement of any kind by the Global Harmonization Task Force.

1.0 Introcuction
This document is intended to describe the basic procedures that the Global Harmonization Task Force
(GHTF) follows in developing GHTF documents.
The Operating Procedures outlined in this document, in conjunction with the GHTF Roles and
Responsibilities and GHTF Guiding Principles and the GHTF Strategic Directions , are designed to
be flexible so that should the need arise, the GHTF can respond to challenges with respect to its
objectives in a timely manner.
2.0 Language
The GHTF working language, writte n and spoken, is English. Translation of GHTF work products into
other languages is the responsibility of each individual member wishing to do so. Translations of GHTF
work products are not reviewed for accuracy by GHTF.
3.0 GHTF Document Management

The procedures set forth in this section apply to all guidance documents which are intended to be
published on the website as Final Documents.
Annex A provides a schematic ove rview of these procedures. Annex B provides an overview of the
different types of GHTF documents.
To enhance transparency a procedural sheet follow ing the format included in Annex C will be drawn up
and kept with each GHTF document.
3.1 Stage Assignment of New Work
New work item proposals developed by Study Groups should be sent to the Chair and the Secretariat at
least six weeks prior to the next Steering Committee meeting to allow dissemination to all members prior
to the meeting. They should include rationale, purpose and scope.
The GHTF Steering Committee is responsible for approvi ng new work item proposals proposed by each
Study Group. The project must be approved by the GHTF Steering Committee before any work is
initiated.
Alternatively, the GHTF Steering Committee may direct a Study Group or an ad hoc group to undertake
the analysis of a new issue and/or establish a new Study Group to examine a new issue unrelated to
regulatory aspects being assessed by existing Study Groups. In both cases, the GHTF Steering
Committee will be responsible for proposing the rationale for the work assignment.

New Work Item Proposals should be drawn up following t he format attached in Annex D . The GHTF
Steering Committee and Study Group members should, in particular, consider the following issues:
scope, purpose and rationale including an outline of issues to be addressed and opportunit ies for
regulatory convergence,
relation to the goals set out in the GHTF strategic direction,
proposed sources of necessary expertise,
relevant existing documents at GHTF and national level.
The GHTF Steering Co mmittee may allocate priorities to Study Group work items.
3.2 Stage 2 Document Development
The Study Group will undertake the development of a Working Draft consistent with the scope, purpose
and rationale of the approved new work proposal.
3.3 Stage 3 Consultation on Working Drafts
Once a Study Group has decided that a Working Draft is suitable for circulation, the Chair should invite
members to disseminate the Working Draft to relevant experts amongst their countrys regulatory
authority and industry a ssociation(s) or to external experts.
Working Drafts should, however, not be posted on the GHTF Website and not be publicly available, as
they are subject to considerable changes.
Comments should be submitted to the Chair of the Study Group, either dire ctly, or via the countrys or
industrys representative to the group.
By the time consensus on the revised Working Draft document is reached, the Study Group Chair should
have sought the broadest consultation appropriate.
3.4 Stage 4 Advancement from Worki ng Draft to Proposed Document
Final Working Drafts should be forwarded, in the prescribed GHTF format (see GHTF Style Guide), in
electronic format to the GHTF Chair. The GHTF Chair will forward a copy of the document to the GHTF
Steering Committee , which will review the document against the following criteria, before proceeding
with the advancement process:
consistency with the proje ct scope, purpose and rationale as originally approved by the Steering
Committee in the New Work Item Proposal, and
coordination of the project with other Study Group work, where appropriate, and conformity to
GHTF procedures with respect to title, numbering and status designation.
The Steering Committee will have eight weeks to review the document.
Decisions regarding Stud y Group requests for advancement of a document to Proposed Document stage
will occur by consensus of the Steering Committee. In the absence of consensus, however, the document
in question will be referred back to the Study Group with the reasons for rejec tion and a specified time
period for additional review and direct action 1.
The Steering Committee may also determine that the document should not be advanced further.
3.5 Stage 5 Consultation of Proposed Documents
All Proposed Documents will be posted on the GHTF website by the Chair through t he Secretariat within
three weeks of approval as a Proposed Document. Generally, the comment period for Proposed
Documents will be six months, starting from the date the document was posted on the GHTF website.
This may be modified, however, by individual Study Group Chairs or by the Steering Committee Chair.
Study Group Chairs should also indicate an appropriate contact person to whom persons accessing the
document via the website can address their comments, using the appropriate format. Documents which
remain on the website shall be marked with a disclaimer once the comment period has closed. It shall
state that the document is under revision.
It is also recommended that each GHTF Steering Committee member establ ishes a process for soliciting
comments from interested persons and organizations within their area and that Study Group members
then use this process to solicit comments within their jurisdictions.
All documents should be available in electronic format.
The Study Group will evaluate the submissions and issue a revised document expeditiously, generally
within six months. The Study Group Chair will inform the Chair and the S teering Committee if more time
is needed.
3.6 Stage 6 Advancement from Propose d Document to Final Document
Once consensus is reached within a Study Group that its work on a document is complete, the Study
Group Chair will present the document proposed as final to the GHTF Steering Committees Secretariat.
The following mechanism will then be used to obtain GHTF endorsement as a Final Document:
The Steering Committee will then have eight weeks to review the document.
Generally, decisions regarding Study Group requests for endorsement of a Final Document will occur by
consensus of the Steering Commit tee; however, in the absence of consensus, the document in question
1
Typically the Steering Committee would provide direction and not redraft the do cument.
will be referred back to the Study Group with the reasons for rejection and a specified time for additional
review, modification and re -submission.
The Steering Committee may also determine that the document should not be advanced further.
Endorsement of the document will be formalized with the signature of the current GHTF Chair on a
standardized cover page (see Annex E ), authorizing publication as a GHTF document . The signature can
be given in electronic format.
Signature by the GHTF Chair signifies acceptance of the Final Document by all members on the
Committee and their commitment to promote it within their respective country or integrational
organization of states, and, in the course of time, to seek convergence of regulatory practices.
3.7 Stage 7 Publication
Once endorsement of a Final Document is obtained, the Chair will make the necessary arrangements to
have it available in electronic format on the GHT F website.
Posting on the GHTF website will include a contact name and e -mail address.
In addition, an electronic notification on the availability of the signed -off document on the GHTFs web
site will also be sent by the GHTF Chair to the Steering Co mmittee Members for the purposes of general
reference and potential adoption.
4.0 Document Status Designation

Documents will bear appropriate identification codes.
The document identification practices described below are intended to apply to all GHTF outpu ts created
by any person or group involved in GHTF activities.
4.1 Location of Designation Code
All GHTF documents are to have their official designation code noted in the upper right hand corner of
the cover sheet.
Each document is designated a document n umber, which remains the same throughout the development
of the document. The Secretariat will distribute the document number.

4.2 Working Drafts
All document identification codes are to include identification of the authoring group, ie. SG2 for Study
Group 2 or SC for Steering Committee, followed by an indication of WD for the document status,
followed by an oblique and then the document number (N) and revision number (R) . Document numbers
will be given according to the following system:
Examples: SG2 (WD)/N21R5
SG3 (WD)/N7R3
SC/N1R2
Other authoring group codes might include AHPG for Ad Hoc Procedures Group or WG for Working
Group.
4.3 Proposed Documents
Because documents at the Proposed Document Stage are being disseminated for public comm ent, the
document code described above is to be modified with the addition of the letters PD and version of the
document posted in parentheses (i.e., PD1, PD2 , after the authoring group identifier.
Example: SC(PD3)/N1R3
4.4 Final Document
Once endorsed by the Steering Committee and signed off by the GHTF Chair, all GHTF documents are to
be designated using the letters GHTF, followed by an oblique and the authoring group identifier. This
will then be followed by an oblique, the document number (N), th e revision number (R), a colon and the
current calendar year.
Examples: GHTF/SG2/N21:1999
GHTF/SG3/N7:1997
Final documents should normally be published in PDF documents, unless PDF is not appropriate. Any
forms and related documents intended for download ing and use of the public may be posted in another
format.

5. Maintenance of GHTF Documents

Due to the changing regulatory environment in which the GHTF operates, and the fact that GHTF
documents are in the public domain, all GHTF documents are to be rev iewed and revised every three
years or, on an as -needed basis. The contact person for the document should also be re -designated if
needed.
Documents undergoing revision must receive Steering Committee endorsement and therefore, Study
Group Chairs shou ld indicate what changes have been made, by highlighting additions and deletions,
when they submit a document for re -endorsement. For minor editorial changes, not involving su bstantive
changes, agreement of the GHTF Chair is sufficient.
When re-published (and therefore re-posted on the GHTF website), amended documents must be
designated as described above but with the inclusion of the text (Edition X) (where X represents the
number of the current revision).
Example: GHTF/SG4/N10R2:1999 (Edition 2)

GHTF/SC/N3R2:2000 (Edition 3)
It should be noted that the original year in which the document was originally endorsed will change in the
document identification code.
Example: GHTF/SC/N3R2:2000 (Edition 3)

GHTF/SC/N3R2:2001 (Edition 4)
6. Record-Keeping/ Information Archives

Each Study Group Chair or Secretariat will maintain a listed inventory and actual texts of their
documents. The inventory will show the stage of development of each document, e.g., WD or PD, along
with any relevant notes, e.g., the deadline for comment, etc. This inventory shall also be copied to the
current GHTF Chair and the Secretariat. The Secretariat will maintain a master list of all Study Group and
GHTF documents.
The GHTF Secretariat will make an updated master lis t available at each GHTF Conference. In addition,
the GHTF Secretariat has custodial responsibility for all hard -copy records passed on from previous and
current Chair.
A searchable repository of all GHTF Final Documents and in -process Proposed Document s will also be
maintained on the GHTF website
7. GHTF-Related Presentations and Training

It is recognized that as the work of the GHTF progresses, those involved in Study Group or Steering
Committee work may be called upon to do presentations or provide i nformation on a part or parts of the
GHTFs activities to their peers, trade association groups or regulatory authorities.

In all cases, the member being asked to do the presentation is asked to inform the GHTF Chair and/or
GHTF Secretariat of the request . In the future, copies of slides used in these presentations may be made
available to interested parties via the GHTF website.
When persons or groups organize a training event and claim to represent GHTF they shall seek prior
consent through the GHTF Ch air.
8. GHTF Logo
The GHTF has adopted the logo depicted on the front cover of this document. This logo should appear
on all formal GHTF correspondence, reports, the front cover of all GHTF documents, and should be
displayed within the GHTF website.
The GHTF logo is not registered or trademarked in any way so its use by persons outside the GHTF is not
impossible. Knowledge of such activity however, should therefore be reported to the GHTF Chair

Appendices

ANNEX A
ANNEX A
Assignment of New Work Stage 1 A New Work Item Proposal is submitted to the Steering
Committee. The Steering Committee approves the work proposal.
The GHTF Steering Committee may allocate a priority to each
task.
Stage 2 The Study Group develops Working Draft using input

SG develops Working Draft
from appropriate interested parties.
Stage 3 After reaching internal consensus on the Working Draft,

Consultation on Working Drafts the SG Chair invites its members to obtain comments from other
Study Groups, etc. with the aim of soliciting the
broadest consultation appropriate without making the document
publicly available. The Working Draft will not be posted on the
website.
Advancement from Working Stage 4 The SG Chair

Draft to Proposed Document forwards the Working Draft
to the GHTF Chair for
circulation to members of the Steering Committee. The Steering
Committee must receive the document at least eight weeks in
advance of the next meeting to review it and make
recommendations.
Consultation on Proposed Stage 5 Proposed Documents are posted on the we bsite with a
Documents comment period of six months. Study Groups have six months to
issue a revised document.
Advancement from Proposed

Document to Final Document Stage 6 The SG Chair forwards the
document to the GHTF
Chair who circulates it to
the Steering Committee for review. The Steering Committee

must receive the document at least two months in advance of its
next meeting in order to make recommendations. When
consensus is achieved, the do cument can be signed off (cover
sheet).
GHTF Document is published Stage 7 The GHTF Chair posts document on the GHTF
website for adoption and implementation.

ANNEX B
ANNEX B
Different types of GHTF documents*:
Guidance documents
Reference document s
Status document
Meeting minutes
Summary of meetings
Training documents
Work Plans of Study Groups
Etc.
* The above described procedures apply foremost to GHTF guidance documents, the Steering
Committee decides about the procedures applying to other ty pes of documents.
Document Status Designations:
NWI = New Work Item Proposal

WD = Working Draft
PD = Proposed Document
FD = Final Document
FD (edition) = Edition of Final Document

ANNEX C
ANNEX C
PROCEDURAL SHEET
FOR GUIDANCE DOCUMENT
Study Group N : Date of Last update:

Work item: Reference :
Stage Procedural steps Check
1. Assignment of new work item by the SC

Date of decision :
2. Working draft development
Date of completion :
3. Consultation on working draft
4. Working draft advances to proposed document
WD forwarded by SG chair to GHTF chair
GHTF chair circulates WD to SC members
Recommendation of SC to advance to PD
5. Public consultation on proposed document
PD posted on website by SG chair
Revised document issued by SG
6. Proposed document advances to final document
SG chair forwards revised PD to GHTF
GHTF chair forwards PD to SC members
SC issues a recommendation
SC recommends advanc ement to FD
SC issues another recommendation
SC chair signs the FD
7. Final Document publication
GHTF chair posts final document on website
Latest update of the procedural sheet ..

ANNEX D
ANNEX D
FORMAT FOR GHTF NEW WORK ITEM PROPOSALS (NWIP)
NWIP shall be submitted to the GHTF Secretariat at least six weeks prior to the
upcoming Steering Committee Meeting to allow the Secretariat to propose the NWIP to
the Steering Committee for approval
Proposed title of
the project
Initiator
Purpose and
rationale
(including a
reference to one or
more of the goals
the GHTF
Strategic
Direction)
Scope (including
outline of issues to
be addressed and
opportunities for
regulatory
convergence)
General Work Plan
and timelines
Proposed project
leader
Proposed sources
of necessary
expertise
Relevant existing
documents at
GHTF and national
level, as well as in
international
bodies.

ANNEX E
ANNEX E
Cover Page For Final GHTF Documents
FINAL DOCUMENT
Title:
Authoring Group:
Endorsed by:
Date:
[Signature], GHTF Chair
representatives from medical device regulatory authori ties and trade associations from Europe, the United
States of America (USA), Canada, Japan and Australia.
The document is intended to provide non-binding guidance to regulatory authorities for use in the
regulation of medical devices, and has been subject to consultation throughout its development.
of this document, in part or in whole, into any other document, or its translation into languages oth er than
English, does not convey or represent an endorsement of any kind by the Global Harmonization Task
Force.

GHTF/AHPG/ N1R3:2000
FINAL DOCUMENT
Title: Document Format & Style Guide
Authoring Group: Ad Hoc Procedures Group
Date: September 19, 2000
Beth Pieterson, GHTF Chair
The document herein was produced by the Global Harmonization Task Force, a voluntary group
of representatives from medical device regulatory agencies and the regulated industry. The
document is intended to provide non-binding guidance for use in the regulation of medical
devices, and has been subject to consultation throughout its development.
There are no restrictions on the reproduction, distribution or use of this document; however,
incorporation of this document, in part or in whole, into any other document, or its translation
into languages other than English, does not convey or represent an endorsement of any kind by
the Global Harmonization Task Force.

GHTF Document Format & Style Guide
Ad Hoc Procedures Group- Final Document
CONTENTS
1.0 Introduction ......................................................................................................................... 4

2.0 Scope ................................................................................................................................... 4
3.0 References ........................................................................................................................... 4
4.0 Definitions........................................................................................................................... 4
5.0 Document Format ............................................................................................................... 5
5.1 Word Processing Software...................................................................................... 5
5.2 Paper Size................................................................................................................ 5
5.3 Margins ................................................................................................................... 5
5.4 Font ......................................................................................................................... 5
5.5 Line Spacing ........................................................................................................... 6
5.6 Page Numbering...................................................................................................... 6
6.0 Document Elements ............................................................................................................ 6
6.1 Table of Contents .................................................................................................... 6
6.2 Preface..................................................................................................................... 7
6.3 Cover Page .............................................................................................................. 7
6.4 Introduction ............................................................................................................. 7
6.5 Scope ....................................................................................................................... 8
6.6 References ............................................................................................................... 8
6.7 Definitions............................................................................................................... 8
6.8 Document Body ...................................................................................................... 8
6.9 Examples ................................................................................................................. 9
6.10 Appendices.............................................................................................................. 9
7.0 Installing the GHTF Document Template .......................................................................... 9
8.0 Using the GHTF Document Template .............................................................................. 10
8.1 Opening the Document Template ......................................................................... 10
8.2 Filling in the Template .......................................................................................... 10
8.3 Using the Template Header .................................................................................. 11
8.4 Using the Template Footer.................................................................................... 11
8.5 Creating a Table of Contents ................................................................................ 12
September 19, 2000 Page 2 of 14

Preface
The document herein was produced by the Global Harmonization Task Force, a voluntary
group of representatives from medical device regulatory agencies and the regulated industry.
The document is intended to provide non-binding guidance for use in the regulation of medical

1.0 Introduction
The primary way in which the Global Harmonization Task Force (GHTF) achieves its
goals is through the production of harmonized guidance documents suitable for implementation
or adoption by member regulatory authorities or by nations with developing regulatory
programmes.
The purpose of this document is to act as guidance to all those involved in developing
and issuing GHTF documents and it is designed to be used with the accompanying Microsoft
Word GHTF Document Template. By using the GHTF Document Template, members involved
in developing new documents will be using a prescribed format, resulting in each new GHTF
document having a common and consistent appearance. This in turn, will contribute to their
important use in achieving harmonized regulatory practices for medical devices around the world.
Comments or questions about the use of the Document Template or this guidance
document should be directed to the GHTF Secretariat.
2.0 Scope
All persons involved in or responsible for the creation or issuance of GHTF documents
are encouraged to read this document and to use the accompanying GHTF Document Template.
The GHTF document template was created, and should be used, in the application
Microsoft Word.
3.0 References
Throughout this document, references are made to the GHTF document entitled Operating
Procedures.
4.0 Definitions
Template: the file ghtf document template.dot
Field: a pre-formatted area of the template where specific text can be entered.
Click: one mouse click, using the primary button on the mouse
Right-click: one mouse click, using the secondary button on the mouse
Double-click: two mouse clicks, using the primary button on the mouse

5.0 Document Format

The following document format requirements have been incorporated into the GHTF
Document Template.
5.1 Word Processing Software
Microsoft Word was chosen as the word-processing software for the GHTF Document
Template since it is the most commonly used software amongst GHTF members. Documents
not created using the template will be converted by the GHTF Secretariat prior to posting.
5.2 Paper Size
While it is preferable that a common paper size be used when creating GHTF documents,
it is recognized that different standard paper sizes are used around the world, i.e., A4 Letter size
in Europe and Letter size (81/2" x 11") in North America. Document authors should therefore be
advised that the arrangement of text from page to page in a document may be altered by the
GHTF Secretariat in preparation for posting on the GHTF website.
5.3 Margins
All margins of GHTF documents except the top margin, i.e., bottom, right and left,
should be 2.54 centimeters (cm) unless a smaller margin is warranted, i.e., a page containing a
schematic or flow chart that will not fit without the use of smaller margins. The top margin for
all GHTF documents will be 2.0 cm.
5.4 Font
All GHTF documents will be generated in Times New Roman font, pitch 12. Document
headings and subheadings will be numbered, i.e., 1.0, 1.1, 1.2, 2.0, etc. and headings will appear
in bold text, pitch 14. Sub-headings will appear in bold text, pitch 12. Each word of a heading
or sub-heading should be capitalized.
Examples: 2.0 Requirements
2.1 Role of the Auditor

5.5 Line Spacing
GHTF documents will be single-spaced with a double space appearing between text and
each heading or sub-heading and a double space appearing between each separate section and
sub-section. Paragraphs will be separated by a double space.
Example: 2.0 Method of Estimating Audit Duration

This document provides guidelines for auditing organizations responsible
for planning, carrying out and documenting quality system audits....
2.1 Factors Which May Increase the Initial Audit Duration
5.6 Page Numbering
All pages of a GHTF document, with the exception of the cover page, will be numbered
in the bottom right hand corner of each page, using the format Page 1 of X, with the page
number appearing within the footer on each page (see section 8.4).
6.0 Document Elements

GHTF members involved in GHTF document development should consider the inclusion
of each of the following sections. It is to be noted however, that in some cases, depending on
intent or scope, a GHTF document may not include a particular section because it does not apply.
For convenience, each of these sections with the exception of Section 6.1 Table of
Comments has been included in the GHTF Document Template.
6.1 Table of Contents
All GHTF documents over four (4) pages in length will have a Table of Contents specific
to heading and sub-heading level.
Example: 1.0 Introduction.....................................2
2.0 Types of Audits...............................2
2.1 Initial Audit.........................3

2.2 Surveillance Audit...............3
2.3 Special Audit.......................4

6.2 Preface
All GHTF documents, regardless of their authoring group or intent, will bear a preface
designed to summarize the composition of the GHTF and its goals as an organization. The
preface of any given document should not bear any document-specific information as this may
be found in the Introduction section (see Section 6.4).
For convenience, the GHTF Document Template has been formatted to include the
generic preface statement shown in Appendix A.
6.3 Cover Page
Documents at either the Working Draft or Proposed Document stage will bear a cover
page containing the following information:
(A) the title of the document;

(B) the authoring group, e.g., Study Group 1;
(C) the date of issue, i.e., the date that the document was created on or was last
worked on
Note that the acceptable date format is Month Day, Year, e.g., June 25, 2000
(D) the words Global Harmonization Task Force, and
(E) the document identification code, as described in Section 3.0 of the Operating
Procedures document.
For convenience, each of the pieces of information listed above has been included as
fields in the cover page of the GHTF Document Template.
Final Documents endorsed by the Steering Committee will use the formal cover page
attached as Appendix B to the Operating Procedures document, with the cover sheet being
signed by the Chair of the organization at the time of endorsement.
6.4 Introduction
This section of the document should lay out the background leading to the documents
development and should include identification of the authors or authoring group involved in its
creation, the documents current stage of development, a brief summary of the process used to
obtain comment on the document throughout its development (if applicable), a description of the
documents intended audience and a statement of the documents purpose.
The introduction may also include reference to a contact person, to whom comments or
questions about the document should be directed.

6.5 Scope
The scope of a GHTF document should outline its applicability to a particular aspect or
aspects of medical device regulation and/or the usefulness of the document to different sectors of
industry or government.
The scope of the document should also clearly state any exclusions that may apply.
6.6 References
This section should list any references that may have used in developing the document and/or
any international standards that are referred to in the document, i.e., ISO 9001:1992.
If no references were used, enter Not Applicable in the template.
6.7 Definitions
This section should contain a lexicon of all terms found within the document for which
there may be different interpretations, the purpose being to provide the interpretation used by the
document creators and therefore to facilitate implementation or use of the document by
eliminating any uncertainties about the meaning of a certain term or requirement.
Each term in the lexicon should appear in bold text followed by a colon and the definition
in an indented paragraph. See Section 4.0 for examples.
Enter Not Applicable in the template, if appropriate.
6.8 Document Body
Since each GHTF document will differ in subject matter, it is expected that the body of
each document will differ in the sections that it contains also. For example, a document on
auditing of quality systems may include sections on the audit team, types of audits and the audit
process while another document on essential principles of device design may include sections on
chemical properties and reduction of microbial contamination.
The organization of the text body of each document is therefore at the discretion of each
authoring group, provided it is broken into logical and numbered sections. For convenience, the
header and text for the first document section have been created as fields in the GHTF Document
Template. Additional sections should then be added as required.
The numbering of headings and sub-headings is controlled using Styles, which can be
accessed from the pull-down menu on the control bar. Using the styles included in the template
ensures that the table of contents can be generated correctly.

The default style setting is Normal and this style should be used for all text in a GHTF
document, with the exception of headings and sub-headings, etc.
Style 1.0 Heading 1 should be used for the titles of major sections within a document
because it will automatically apply top-level numbering, i.e. 1.0, 2.0 , to the text. There is no
limit to the number of sections you can create in a document.
Style 1.1 Heading 2 should be used for sub-headings within major sections of your
document because it will automatically apply second-level numbering, i.e. 1.1, 1.2 , to the text.
Style 1.1.1 Heading 3 should be used for sub-sub-headings if required because it will
automatically apply third-level numbering, i.e. 1.1.1, 1.1.2 , to the text.
6.9 Examples
The use of examples is encouraged as a way of promoting understanding of the document

text. Examples should be preceded by the word Example: followed by the actual example in
an indented paragraph (see the examples in this document).
6.10 Appendices
All diagrams, forms or flow charts, etc., not included in the body of the document should
be included as appendices at the end of the document.
The GHTF Document Template has been formatted to include a blank page with the
word Appendices on it and this should be used to separate the body of the document and its
appendices.
The template also comes formatted with one appendix (labeled Appendix A) and a field
in which the title of the first appendix can be entered. If necessary, additional appendices should
be added, following the same format. Alternatively, if there are no appendices, these sections of
the document template can be deleted.
7.0 Installing the GHTF Document Template

Before installing the document template, ensure that you close any Microsoft Word
windows that are currently open on your computer.
The GHTF document template is a Microsoft Word file, called ghtf document
template.dot. This file can be found on the GHTF web site (www.ghtf.org) on the General
Information page under the GHTF Documents heading.

This file should be saved to your computer, using the instructions on the web site. It
should then be copied to the Templates folder in your Microsoft Word or Microsoft Office
folder. If you are not sure where this is, contact your technical support provider. A typical
location would be C: \ Program Files \ Microsoft Office \ Templates.
8.0 Using the GHTF Document Template
8.1 Opening the Document Template
The following instructions will allow you to open the template and start to create a new
document:
(A) Start Microsoft Word;

(B) Select New from the File menu;
(C) In the New window that appears, select General;
(D) Double-click on the icon marked GHTF Document Template.dot (if the icon is not
there, go back and make sure that you followed the installation instructions in Section
7.0), and
(E) A new, untitled Word document, with the template fields in place, will appear.
At this point, it is recommended that the new document be saved with an appropriate
name. Completed work should also be saved regularly to avoid loss in case of system failure.
8.2 Filling in the Template
The template comes with a number of pre-defined fields allowing pertinent information
to be entered in the correct place. These fields are identified by square brackets enclosing
instructions about what information should be included.
Example: [Click here to enter document title].
Clicking on the field will highlight it,.
Example: [Click here to enter document title].
When the field is highlighted, text can be typed into it. Note that the appropriate
formatting for that section of the document will be automatically applied.

8.3 Using the Template Header
The GHTF Document Template has been formatted to include a document header which
appears on every page except the cover page. The header provides the following information:
(A) the document title and document identification code;

(B) the authoring group, and
(C) the document status, i.e., Final Document, Proposed Document, Draft#4, etc.
To edit the document header, follow these instructions:
(A) Go to any page other than the cover page, and

(B) Select Header and Footer from the View menu to display the header/footer
control bar:
and the header region in a hatched box at the top of the page:
Text can then be entered by clicking on the different fields.
8.4 Using the Template Footer
The GHTF Document Template also includes a document footer which appears on every
page except the cover page. The footer provides the following information:
(A) the date of issue, and

(B) the page number
After completing the document header fields, switch to the document footer by clicking
on the button on the header/footer control bar. The footer region will be displayed in a
hatched box at the bottom of the page:

Enter the date as entered on the cover page of the document but do not edit the page
count as this is updated automatically by Microsoft Word. If you see what appears to be an
incorrect page count, e.g., Page 9 of 7, save the document and then click on Print Preview from
the File menu. The correct page numbers should appear.
To close the header & footer view and return to normal document editing, press the Close
button on the header/footer control bar.
8.5 Creating a Table of Contents
Once all the information fields have been created and the sections numbered appropriately, a
Table of Contents should be added to the document:
(A) Delete the text The Table of Contents should be created on this page. See GHTF
Document Format and Style Guide for instructions from page 2 of the
document;
(B) Click on Index and Tables from the Insert menu on the control bar;
(C) Select the Table of Contents tab;
(D) Click on From Template in the Format window;
(E) Ensure that the Show page numbers and Right align page numbers check
boxes are selected and that the Show levels box is set to 3, and
(F) Click on the OK button.
The table of contents should be generated, using the numbered headings and sub-headings that
you have added to the document.
Note that the Table of Contents will require updating if changes (even small ones) are made to
the document. To update the Table of Contents, repeat steps (B) through (F). When the prompt
Do you want to replace the selected Table of Contents? appears, click OK.

APPENDICES

Appendix A: Generic Preface Statement for Use in All Documents
Preface
The document herein was produced by the Global Harmonization Task Force, a voluntary
group of representatives from medical device regulatory agencies and the regulated industry.
The document is intended to provide non-binding guidance for use in the regulation of medical
There are no restrictions on the reproduction, distribution or use of this document;

however, incorporation of this document, in part or in whole, into any other document, or its
translation into languages other than English, does not convey or represent an endorsement of
any kind by the Global Harmonization Task Force.

[Click here to enter Document Identification Code - see 'Operating Procedures' document]
[Type PROPOSED or WORKING DRAFT]

DOCUMENT
Title: [Click here to enter Document Title]
Authoring Group: [Click here to enter Authoring Group]
Date: [Click here to enter Date of Issue]

[Click here to enter document title and identification code - see 'Operating Procedures' document]
[Click here to enter authoring group and status]
Table of Contents
The table of contents should be created on this page. See GHTF Document Format & Style
Guide for instructions.
[Click here to enter date of issue] Page 2 of 6

Preface
The document herein was produced by the Global Harmonization Task Force, a voluntary group
of representatives from medical device regulatory agencies and the regulated industry. The
document is intended to provide non-binding guidance for use in the regulation of medical

Introduction
[Click here to enter Introduction. See GHTF Document Format & Style Guide for details.]
1.0 Scope
[Click here to enter Scope. See GHTF Document Format & Style Guide for details.]
2.0 References
[Click here to enter References. See GHTF Document Format & Style Guide for details.]
3.0 Definitions
[Click here to enter Definitions. See GHTF Document Format & Style Guide for details.]
4.0 [Click to enter the title of the first section of the document body]
[Click to enter the body of document. See GHTF Document Format & Style Guide for details.]

Appendices

Appendix A: [Click here to enter appendix title]
[Click here to enter Appendix text. Add other appendices as needed, following the same format]

FINAL
K. Brekelmans, M. Gropp; 2 July 2002
Page 1 of 1
Global Harmonization Task Force Steering Committee

Reference Guidance -- GHTF Training
1.0 Background and history: During the third meeting of the GHTF Steering Committee
(London, October 2001), members discussed policy considerations related to GHTF
training, the handling of any formal requests for training, and a proposal to establish a
GHTF Training Institute. The Committee agreed that a working group should prepare
for further consideration a framework document addressing the future conduct of GHTF
training. That proposed document was accepted in substance at the fourth meeting of
the Steering Committee (Singapore, May 2002).
2.0 Objectives: As part of its Strategic Direction, GHTF has adopted as a goal:
GHTF members will support and advocate the adoption of the global regulatory
model in their own systems and those of other countries/regions
3.0 Definitions: GHTF-related training may take two forms:
3.1 GHTF training: Training, offered under the auspices and with the authority of
GHTF, which is directly related to GHTF core activities. Training activities commit
GHTF and participants and are part of the GHTF work programme. As such, they
are approved by the Steering Committee.
3.2 Training on GHTF: Training that provides general information about, and raises
general audience awareness of, GHTF recommendations and activities, but
which is not offered under the auspices and under the authority of GHTF. These
activities will normally be part of national programmes, commercial events, or
industrial co-operation; they do not commit GHTF and are not subject to approval
by the GHTF Steering Committee.
GHTF-related training is in addition to other mechanisms for the dissemination of GHTF

work products, e.g., the GHTF website.
Events in which training on GHTF is provided will probably be held more frequently than
GHTF training.
4.0 GHTF training:
4.1 Examples:
4.1.1 Preparation for participation in a GHTF system or project, e.g., the
exchange of vigilance information
4.1.2 Training requested by affiliated regional parties, e.g., Asia Harmonization
Working Party
4.1.3 Training requested by cooperating entities, e.g., World Health
Organization
4.1.4 Specific training event associated with a GHTF conference
File name: GHTF Training Discussion Paper11.doc

FINAL
Page 2 of 1
4.2 Guidance:
4.2.1 The scope and content of such an event shall be predominantly, but not
limited to, GHTF recommendations, including how members use GHTF
documents
4.2.2 The training session event, agenda, and speakers must be endorsed by
the GHTF Steering Committee
4.2.2.1 Endorsement does not imply that GHTF will necessarily provide
funding for the event. Such events will be funded by the sponsor
and/or through existing GHTF cooperative funding mechanisms.
4.2.3 Publicity and press releases must be reviewed and approved by the
GHTF Chair or his/her delegate
4.2.4 The event shall be publicised on the GHTF website
4.2.5 Speakers shall use the standard GHTF slide template
4.2.6 Training events shall be reported on during GHTF Steering Committee
meetings and GHTF conferences.
5.0 Training on GHTF:
5.1 Examples:
5.1.1 Presentations on national regulatory systems which include the effects of
GHTF on national systems;
5.1.2 Training sessions as part of co-operation programmes between GHTF
regulatory members and third countries or other regions, e.g. on national
regulation, international regulatory convergence, trade facilitation.
5.1.3 Events organised by industry representatives of GHTF member countries
5.1.4 Commercially organized events on medical device regulation
5.1.5 Training events organized by countries not participating in GHTF
5.2 Guidance:
5.2.1 GHTF members are encouraged to participate in such events.
5.2.2 In addition to speaking about their home regulatory systems and how or
why they differ from GHTF recommendations, speakers may speak about
GHTF and its activities and effects on national systems.
6.0 General guidance:
To the extent that guidance can be given by GHTF on training events in which GHTF
activities are being presented, GHTF members are encouraged to observe the following
guidelines:
6.1 Where appropriate, the speaker should specify the position he/she is speaking
from (i.e., member of GHTF Study Group, GHTF Steering Committee, industry,
regulator, interested party, Founder Member/Task Force member).
6.2 Emphasis should be given to GHTF documents that have reached final stage
(as the others are still subject to change), but it is recognised that speakers may
also discuss work in progress.
6.3 Citations to GHTF documents should clearly specify the document status (i.e.,
working draft, proposed, final).
6.4 It is appropriate to outline the Study Group work programmes so that the
audience can see the general context and direction of GHTF work.

FINAL
Page 3 of 1
6.5 The speaker should make a clear distinction between positions as expressed in
GHTF documents and the personal/national/interest views of the speaker, in
particular where the speaker is involved in GHTF activities
6.6 Copies of presentations may be posted on the GHTF website.
7.0 Website:
7.1 GHTF should establish an information page on the GHTF website which lists
GHTF training events and their agendas. The site may also include reference to
training events on GHTF, where the GHTF secretariat has been informed of such
events. The site may also include copies of presentations given.

2007 - 2008 Calendar for GHTF Activities
Nov 07 Dec 07 Jan 08 Feb 08 Mar 08 Apr May 08 Jun July Aug Sep Oct
08 08 08 08 08 08
SC 3-5
Kuala
Lumpur
SG1 5-8 Days:
Bonn TBD
Buenos
Aires
SG2 27-29
Lisbon
SG3 5-8 Days:

Bonn TBD
Canberra
SG4 1-3
Paris
SG5 28 - 29 Days:
Brussels TBD
Tokyo
IVD 6-8
Subgroup San
Diego,
CA
SG1 meeting tentatively scheduled for May/June 2008 in Buenos Aires

SG3 meeting tentatively scheduled for May/June in Canberra
SG5 meeting tentatively scheduled for late May/early June 2008 in Tokyo
Secretariat
c/o US Food and Drug
Administration
Center for Devices and Radiological
Health (HFZ-84)
2098 Gaither Road, Room 171
Rockville, MD 20850 United States
Telephone: +1 240-276-0559
Facsimile: +1 240-276-1358
May 24, 2007
STATEMENT FROM THE CHAIRMAN

Today the GHTF releases a new strategic action plan. The plan aims to enhance
the capacity of GHTF to deal effectively with emerging medical technology issues
and broaden the impact of its regulatory harmonization activities around the world.
The four-pronged plan comes as the GHTF celebrates the 15th anniversary of its
founding.
Essentially, this plan is a call to action. Its core objectives are designed to energize
the process by which the harmonization work results of GHTF are put into actual
practice, make the GHTF more inclusive, and establish a forward-looking work
agenda that responds to todays challenges and those on the horizon.
The Action Plan for 2007-2010: Path Forward for the Global Harmonization
Task Force (available on this website) serves as a working road map. The plan
focuses on various GHTF operations: guidance implementation, organizational
logistics, expansion, and new topics for GHTF attention. It also calls for a study
of the organizations accomplishments as a way of beginning the identification
of new operational directions that may be needed to enable GHTF to fully carry
out its mission.
Larry G. Kessler, Sc.D.

GHTF Chairman
Discussion Draft for GHTF Steering Committee
ACTION PLAN FOR 2007-2010:

Path Forward for the
No Implied Agreement With Any of These

Provisions By Any Party Should Be Inferred or Implied
Offered by
United States and Canadian Delegations to the GHTF
With Endorsement by GHTF Steering Committee
April 2007
Introduction
Since 1992, with clarity of purpose and a firm commitment to international cooperation,
medical device government regulators and industry representatives from around the
world have closely collaborated through the Global Harmonization Task Force (GHTF)
in the pursuit of international consensus on product regulatory controls and practices.
In partnership, the European Union, United States, Canada, Japan and Australia, as
GHTF Founding Members, have in good faith put forth considerable time and energy
toward the convergence of national, sovereign regulatory systems.
The work of the GHTF has been guided by two overarching goals:
first and foremost, enhancing medical device safety -- thus improving public
health -- through information-sharing, general agreement on principles of pre-market,
post-market, inspectional/regulatory enforcement activities and national import-export
systems;
fostering medical technology innovation and facilitating global trade among major
medical device-producing nations of the world by reducing or eliminating redundant
or conflicting regulatory systems, without diminishing public health protections.
Since inception of the GHTF nearly 15 years ago, much has been accomplished. In that
time, the GHTF has been able to produce 27 voluntary guidance documents, fulfilling
its pledge to develop a global regulatory model for medical devices. While more work
remains, GHTF has developed and made publicly available the foundational building
blocks of a comprehensive, tiered approach to medical device regulation. Indeed, the
GHTF story is one worth telling because it well illustrates the public health value of
international dialogue and cooperation. It shows how parties with different interests
and sometimes polar differences of view can come together to do what is truly in the
interest of advancing global health.
As important as it is to acknowledge and celebrate cumulative achievement, however,

it is just as important to continue to be forward-looking, to continually plan -- strategically
-- for the future of this international enterprise. The United States and Canadian
Delegations would offer that it is now time for GHTF to move from a consensus-building
mode to an implementation mode: from focusing on organizational management to
organizational transformation.
GHTF should re-focus its attention to both the form and direction of the organization.
In that regard, this plan, which incorporates aspects of the New Approach working
Paper [1], is designed to position the GHTF for the 21st century in terms of organizational
growth and leadership potential.
___________________
[1] Time for a New Approach to the Work Processes of GHTF? - Proposal to GHTF Steering
Committee, 9-10 November 2006, London; Michael Gropp.
Action Plan for 2007-2010 1

Action Plan Elements
With the foregoing discussion as a backdrop, this section outlines four specific goals
that will serve as guideposts for the Task Forces next three years of operation (i.e.,
2007-2010), and perhaps beyond: Guidance Implementation, Organizational Logistics,
Expansion and New Topics for GHTF Attention.
GOAL I. GUIDANCE IMPLEMENTATION
Perhaps the single most important of the four goals is the need to implement consensus
documents in order to further demonstrate the will of Founding Members to carry out
the GHTF mandate and move the output of the organization forward. Understandably,
this step may pose the greatest challenge Task Force Members have had to face given the
varying laws, regulatory controls and policies, and operational resources and conditions
that exist within individual Member nations or nation clusters. This challenge is made
even greater by the fact that the GHTF is a voluntary organization whose work outputs
carry no mandatory force.
Yet, ultimately, the real success of the Task Force will be evidenced by the actions of
Founding Members and others to adopt and utilize, as national laws allow, consensus
guidance produced by the Task Force as part of their device regulatory systems. A
related measure of success can be seen when non-Founding Member countries incorporate
substantial elements of GHTF guidance into their own regulatory programs.
Only when this happens will the true benefit of the work of the GHTF be achieved and
the GHTF, as an organization, will be able to tangibly demonstrate a return on investment
by Founding Members over the past 15 years. To do this requires shared commitment on
the part of all Founding Members. As a first step, it is recommended that Members join
together to declare their intent (or commitment) to promulgate -- to the extent allowed
by their laws -- relevant existing and future GHTF guidance and to document their
implementation experience so other GHTF Members can benefit from these efforts.
Initially, this full-scale implementation experiment (or exercise) should focus on:
single audits used in multiple jurisdictions, in order to economize GHTF partner

operations and resources by minimizing duplicative inspections and sharing
inspectional findings by developing pilot projects;
and,
improvement in the operation of the National Competent Authority Report system,

in order to facilitate the exchange of vigilance reports, including confidential
information (consistent with existing national laws and regulations) to enable GHTF
partners to take preventive or regulatory actions to avert device safety problems.
Should these pilot efforts succeed, the Task Force should endeavor to address more
challenging guidances, such as mutual convergence and, possibly at some future point,
acceptance of others decisions to allow or withhold market clearance.

GOAL II. ORGANIZATIONAL LOGISTICS
Since its founding, the GHTF has continually strived to enhance the efficiency, process
order and continuity of its operations. To a large extent, this has been facilitated by
todays communications technology. Yet given the pace of technological change and
the ever-increasing world-wide interest in deliberations of the Task Force, we should
not be content with the status quo.
This ongoing search for improvements in organizational management is particularly

crucial in light of potential resource impacts on traditional means of conducting GHTF
business. It is therefore suggested that the GHTF concentrate on the following admini-
strative actions in an effort to streamline and otherwise improve current management
oversight practices.
A. Administrative enhancements.
Every enterprise, regardless of its longevity or success, can be improved. Greater

process efficiency, orderliness, transparency and self-renewal are essential to an
organizations long-term growth and impact. With this in mind, the following reforms
are suggested for further discussion.
narrowly focused and unambiguous objectives for work products (i.e., single
guidance documents or position papers addressing narrowly-defined topics or
issues, as assigned by the Steering Committee and where possible, in collaboration
with the Study Groups)
work products based on existing GHTF guidance (i.e., elaboration of specific

points or issues)
work performed by small, ad hoc working groups with designated experts drawn
from government and industry rather than exclusively from large Study Groups
limited timeframes for production of proposed guidance documents
adherence to established GHTF Operating Procedures for all guidance documents
avoidance of duplicative work by GHTF and related ongoing activities of international

standards bodies and the strengthening of ties between GHTF and standards
bodies to better leverage the ongoing efforts in those organizations
introduction of a process for nomination and approval [1] of work topics and
project accountability.
__________________________
Ibid. [1]

B. GHTF website utility and visibility.
Since coming on-line in the late 1990s, the GHTF website has undergone a series of
design changes aimed at giving it more screen appeal and making it more user friendly
and navigable. While periodic improvements are advised to attract and maintain user
interest, a concerted effort is needed to enhance the utility of the site and make it an
authoritative resource for governments, industry, academia, accrediting organizations
and the public. The website should provide definitive information on trends in major
medical device regulatory systems throughout the world in addition to a global regulatory
model on which developing systems in the future can be based.
Also, since more and more countries are following GHTF activities, it seems appropriate
for GHTF to foster and facilitate in-country translation of its work products by those
nations with an interest in learning from or using GHTF work products. Furthermore,
GHTF should explore the use of current-day electronic translation technology to help
ensure that translated GHTF documents stay current with Task Force deliberations.
Additionally, more hyperlinking with sites from which interested parties can obtain
supplemental or hot topic information may also be beneficial. Also, it would be helpful
to post recognized GHTF training materials on the website, including for example, the
global regulatory model.
GOAL III. EXPANSION
Medical device manufacturing is surging in a number of the worlds countries that are
not participants in the GHTF. These and other countries are developing new medical
device regulatory programs. Given the rising wave of interest in international colla-
boration and harmonization of certain aspects of its processes among nations with
advancing regulatory programs and those with programs in early stages of development,
the GHTF should reach out to non-member countries in a manner consistent with the
procedures set forth in GHTF/SC/N2R9:2005 GHTF Roles and Responsibilities. The
Task Force will commit itself to increasingly welcome nations and regions wishing to
be more active participants in the ongoing work of the organization.
However, in making inclusiveness a future hallmark of the GHTF, organizational

expansion must be gradual in order to avoid unwieldiness and overtaxing current GHTF
management capacities. Participation and membership criteria, thoughtfully defined
and transparently applied, should allow for incremental and beneficial growth of GHTF,
especially in cases when nations or regions are able to demonstrate a level of experience
in managing medical device market controls and surveillance programs.
As presently envisaged, this move to expand GHTFs membership would involve the
following steps.

A. Involve other organizations in a manner similar to the Asia Harmonization
Working Party (AHWP).
The AHWP has made great strides in bringing together government and industry from
Asian countries to participate in the GHTF and has recently been granted Liaison Member
status. The GHTF should similarly engage other nations, world regions and organizations
that show an interest in medical device regulatory harmonization and the ongoing
work of our organization, such as Central and South America and the World Health
Organization, and encourage their active participation. As a precursor to this action,
the GHTF should develop and adopt clear procedures that:
elucidate the criteria by which the Steering Committee will evaluate requests for
membership from applicant nations and organizations; and
set forth the specific rights and privileges, differentiated from those accorded the
general public, that are conferred upon applicants whose membership requests have
been accepted.
B. Increased public availability of procedures and documents.
As stated previously, interest in GHTF harmonization activities throughout the world

is burgeoning and thus a concomitant demand for information and materials exists.
Whether by electronic means only or hard copy of such material is deemed to be the
most efficient and cost-effective method for sharing information, the Task Force has
a unique opportunity to establish an international clearinghouse. At least for now,
the GHTF website should be used as the primary conduit for relaying regulatory
system guidance.
C. Development and implementation of a GHTF training plan.
Of the three expansion goals, this action may provide the greatest opportunity for the
GHTF to provide world leadership and, over the long haul, position the organization as
the preeminent resource on medical device regulation. The development of a training
plan that encompasses, for example, the global regulatory model and accompanying
handbook, would be a useful first step to more broadly connect the GHTF with the
world community.
With this as a springboard, and over the longer term, GHTF could explore the possibility
of establishing an international training institute (perhaps in partnership with other
organizations) that provides general and specialized training for nations interested in
establishing medical device regulatory systems or upgrading existing regulatory controls.
Such an entity could serve as a quality assurance point for training materials and
trainers. It could also, for example, produce a GHTF training manual containing a
compilation of GHTF guidance documents with accompanying explanations of how they
are interrelated and can be implemented to form a comprehensive or partial regulatory
system.
Such an institute could conceivably serve as a revenue generator, making GHTF less
dependent in the future on financial support from Founding Members. Exactly what if
any institutional framework reforms might be required to pursue such activity deserves

further consideration. Were this commercial activity possible, training proceeds could
be reinvested into GHTF operational activities, thereby enabling the organization to
broaden its consensus-building activities, patient safety and product hazard commu-
nications, audit and inspectional information sharing, etc. In turn, in the true spirit
of global harmonization, this could prevent (or at least curtail) the spread of disparate
regulatory systems and avoid the problem of nations having to revamp their regulatory
practices after the fact in order to conform to harmonized practices elsewhere in the
world.
It is recommended that the Steering Committee consider forming an ad hoc group

to examine the merits, legal feasibility and other relevant aspects of this proposal.
GOAL IV. NEW TOPICS FOR GHTF ATTENTION
New regulatory issues will assuredly develop as technology advances and as public
health threats emerge. To keep pace, the GHTF should vigorously embark upon new
guidance development initiatives that address these leading-edge issues in a way
that builds a global regulatory model based on future considerations, not just the
regulatory status quo in Founding Member jurisdictions.
In keeping with the May 2002 GHTF Strategic Direction: 2002-2007 document, GHTF
must position itself as a forum for concerted efforts to identify and address these
challenges in a more proactive fashion. In doing so, the Task Force should be
operationally flexible, i.e.: as new issues arise and either overtake current issues
or are outside the purview of standing Study or Ad Hoc Groups, such Groups should
be reorganized or disbanded, or new issues addressed in some alternative fashion.
Listed below are examples of possible new issues, arrayed by priority, that should
be discussed further by the GHTF to determine whether they involve real or potential
problems in need of international collaboration and/or harmonization solutions.
High Priority
defining the boundary between medical devices and medicinal substances or

other regulated products and the way of handling combination products (drug-
device, biologic-device)
regulatory considerations for medical device software (now underway by the

Ad Hoc Group on Medical Device Software)
documenting lessons learned from pilot exercises relating to single manufacturer

audits and the National Competent Authority Report system so others can benefit
from this trial experience and feedback
development of a global regulatory model handbook drawing together all

existing GHTF guidance documents and explaining their interaction and possible
implementation
development of training programs on GHTF guidance

Medium Priority
compilation of voluntary international standards recognized by GHTF Founding

Members for conformity assessment purposes (as endorsed by the Steering
Committee at the November 2005 meeting in London, UK)
finalization of a list of harmonized standards
device use in home and other non-clinical settings (e.g., regulatory purview)
application of nanotechnology in medical devices and combination products

involving medical devices
registration of manufacturers/authorized representatives and listing of devices

and unique device identification
Low Priority
compatibility of implantable medical devices and high magnetic field intensity

imaging devices
regulatory treatment of telehealth systems (e.g., definition, classification,

applicability of essential principles, conformity assessment, etc.)
study of counterfeit (grey market) devices and potential cooperation among

GHTF Members on prevention, detection, information-sharing
Taking Steps Now to Prepare for the Future
Articulating the above goals is but a first step in charting a new course for the future.
This draft proposal recommends a systematic process for ensuring broad engagement,
obtaining substantive input, and reaching agreement on which specific actions merit
pursuit and how best to insure a positive result. To do this, while at the same time
avoiding processes that are time-consuming and labor- and/or resource-intensive, it is
proposed that a number of small working groups be formed, one for each of the above
work initiatives, in addition to the retrospective assessment described below.
RETROSPECTIVE ASSESSMENT/PROSPECTIVE COMMUNICATIONS STRATEGY
In 2007, the GHTF will mark its 15th anniversary. On this occasion, it seems timely
and appropriate to conduct a review of its work, which could be helpful in attracting
more nations interested in medical device collaboration and harmonization as well as
setting the stage for the next evolutionary phase of the GHTF.
To this end, GHTF Founding Members have agreed that in the coming year an inde-
pendent project should be initiated that publicly communicates the vital work of the
GHTF and thereby helps to ensure the organizations future viability. This action alone
seems advisable given the unpredictability of resources and priorities that could affect
participation by Founding Members in the years ahead.

Current funding constraints and the purported lack of financial resources in the
foreseeable future among Founding Members preclude contracting a professional
strategic communications/public relations firm to conduct this assessment. Instead,
it is planned to assemble a small panel of former GHTF leaders to lead this effort.
This study will commence as soon as practicable.
Summary
This Action Plan is intended as a path forward for the GHTF, building on its success of
the past, with the goal for the GHTF to be seen as a world leader and have its work
serve as a model that nations with emerging medical device regulatory systems can
emulate, thus furthering the real aims of global harmonization.
# # #

GHTF Organizational Structure
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What's New GHTF Organizational Structure
General
Information The original concept behind the formation of the Global Harmonization Task Force
(GHTF) was to bring together experienced regulators and industry members on a
GHTF regular basis in order to discuss ways in which medical device regulatory practices
Documents within their jurisdictions could be harmonized. As such, the Study Groups charged
MoU with examining discrete aspects of medical device regulation were established without
the auspices of a "formal" organizing committee. In later years, it was decided that
Study Group 1 chairmanship of the organization would rotate between the five founding members
Study Group 2 and that meetings would be hosted in varying locations around the world, largely in an
attempt to ease the financial burden of any one group always having to travel long
Study Group 3 distances.
Study Group 4
The Chairs Advisory Group was the first attempt at establishing a body charged with
Study Group 5
providing strategic direction to those involved in GHTF activities. This committee,
Steering which was established in 1998 by Dr. Bruce Burlington of the United States Food and
Committee Drug Administration (FDA), during his term as Chair, met twice in 1999, and was
responsible for initiating the concept of ensuring transparency and promoting progress
Liaison Bodies in the organization's work. The Chairs Advisory Group was also responsible for
Conferences initiating work on a set of basic principles of operation and an organizational structure
for the Task Force.
Although the FDA-drafted document entitled Guiding Principles and Operating

Procedures was included as an agenda item at the Chair's Advisory Group Meeting of
the 7th GHTF Meeting (June, 1999 in Bethesda, Maryland), no consensus was
reached on its acceptability. In addition, following comments from industry members,
who had been at the table since 1992 but had not been involved in drafting the
Guiding Principles and Operating Procedures document because the Chairs Advisory
Group included only regulatory representatives; the GHTF Chair, Dr. Elizabeth
Jacobson, called for the establishment of a joint industry and regulator ad hoc working
group. This group, which would consist of one industry and one regulatory
representative from each founding member would be charged with evaluating all
relevant proposals, reconciling differences and developing a consensus document for
consideration by the GHTF at their next plenary meeting. The Ad Hoc Procedures
Working Group (as it came to be called) would also examine and make
recommendations regarding guidance document development and endorsement and
in certain cases, act as an advisory body to the GHTF Chair.
In early August, 2000, the Ad Hoc Procedures Group posted three draft procedural
documents on the GHTF website for comment. The documents, "Guiding Principles",
Roles and Responsibilities" and Operating Procedures" propose among other things,
the creation of a governing body for the organization, defined responsibilities for those
http://www.ghtf.org/information/structure.htm (1 / 2)2008.03.28 1:15:21

GHTF Organizational Structure
involved in GHTF activities and clear procedures for document development and
approval.
At the Plenary Session of the 8th GHTF Conference (21 September 2000), the three
procedural documents were presented by Members of the Ad Hoc Procedures Group
(AHPG) and accepted by all GHTF Members. The GHTF Chair (Ms Beth Pieterson
from Health Canada) subsequently proceeded with establishing the membership of
the new GHTF Steering Committee which replaced the AHPG.
Ms Rita Maclachlan of Australia's Therapeutic Goods Administration (the new GHTF

Chair as at 1 January 2001) hosted the inaugural meeting of the GHTF Steering
Committee in Sydney, Australia, from 28 February - 2 March 2001. As specified by the
procedural document, "GHTF Roles and Responsibilities", the Steering Committee is
now the governing body responsible for management oversight and policy setting for
the GHTF.
Last Updated June 22, 2004
http://www.ghtf.org/information/structure.htm (2 / 2)2008.03.28 1:15:21

GHTF Contacts
Home > General Information > GHTF Contacts

HOME
What's New GHTF Contacts
General
Dr. Larry Kessler from the Food and Drug Administration is the current Chair
Information
of the Global Harmonization Task Force (GHTF). Dr. Kessler can be
GHTF contacted at the following address:
Documents
MoU Dr. Larry Kessler, Sc.D. (Chair)
Director, Office of Science and Engineering Laboratories
Study Group 1 Center for Devices and Radiological Health
Study Group 2 Food and Drug Administration
10903 New Hampshire Ave.,
Study Group 3 Building 62, Room 3214
Study Group 4 Silver Spring
MD 20993-002
Study Group 5 UNITED STATES
Steering Tel: +1 301 796-2530
Committee Fax: +1 301 796-9959
e-mail: GHTFChair@fda.hhs.gov
Liaison Bodies
Conferences Ms. Janet Trunzo from United States Industry is the current Vice Chair of the
Global Harmonization Task Force (GHTF). Ms. Trunzo can be contacted at
the following address:
Ms. Janet E. Trunzo (Vice Chair)

Executive Vice President
Technology and Regulatory Affairs
Advanced Medical Technology Association (AdvaMed)
1200 G Street, NW - Suite 400
Washington DC 20005-3814
UNITED STATES
Tel: +1 202 434 7228
Fax: +1 202 783 8750
e-mail: jtrunzo@advamed.org
Ms. Jean Olson from the Food and Drug Administration is the current
Permanent Secretariat. Please contact the Permanent Secretariat for
questions relating directly to the website, document control and training
documents. Ms. Olson can be contact at the following address:
Jean Olson
Program Analyst
Center for Devices and Radiological Health
http://www.ghtf.org/information/contacts.htm (1 / 2)2008.03.28 1:15:42

GHTF Contacts
Food and Drug Administration

2098 Gaither Road (HFZ-84)
Rockville
MD 20850
UNITED STATES
Fax: +1 240-276-0559
Fax: +1-240-276-1358
e-mail: jean.olson@fda.hhs.gov
Last Updated May 24, 2007
http://www.ghtf.org/information/contacts.htm (2 / 2)2008.03.28 1:15:42

History of GHTF
Home > General Information > History of GHTF

HOME
What's New History of GHTF
General
Information Inception
1993 - 1994
GHTF
1994 - 1996
Documents
1998 - September 1999
MoU September 1999 - December 2000
Study Group 1 January 2001 - July 2002
July 2002 - December 2003
Study Group 2
January 2004 - Present
Study Group 3
Study Group 4 Inception
Study Group 5
The idea for an international partnership between medical device regulatory
Steering authorities and the regulated industry, one that would aim to achieve
Committee harmonisation in medical device regulatory practices, was conceived in 1992.
In September of that year, senior regulatory officials and industry
Liaison Bodies representatives from the European Union, the United States of America,
Conferences Canada and Japan met in Nice, France to explore the feasibility of forming
such a global consultative partnership aimed at harmonising medical device
regulatory practices.
These talks would develop into a working framework put forth by the
representatives of the European Commission two months later, and would
lead to the inaugural meeting of the organisation now known as the Global
Harmonization Task Force (hereinafter referred to as the GHTF), in January
1993.
Top of page
1993-1994
The first priority of the GHTF was to establish three "study groups" and
charge each one with the task of examining a discrete aspect of medical
device regulation.
Study Group 1 was asked to compare the operations of each member nation's
regulatory program. Study Group 2 was assigned the task of reviewing the
Good Manufacturing Practice (GMP) requirements and methodologies used
by national regulatory bodies, and Study Group 3 was directed to evaluate
existing quality design systems and develop a guidance document that
http://www.ghtf.org/information/history.htm (1 / 7)2008.03.28 1:15:58

History of GHTF
reflected the optimal features of each.
During the second meeting of the GHTF, held in Tokyo, Japan, in November
1993, representatives from Australia joined the organisation and Study
Group 4 was founded to develop guidance on harmonised regulatory auditing
practices. In addition, participants from the member states of the European
Free Trade Area (EFTA), the European Committee for Standardisation
(CEN), the European Committee for Electrotechnical Standardisation
(CENELEC), the International Organisation for Standardisation (ISO), and the
World Health Organisation (WHO) were present.
Top of page
1994-1996
In June 1994, the GHTF met for a third time in Montreal, Canada. At this
meeting, Study Group 1's activities were redefined as the identification of
regulatory aspects that would lend themselves to harmonisation, in particular,
those relating to the safety and efficacy/performance of medical devices.
At the next meeting, held in Vancouver, Canada, in June 1995, the GHTF
determined that it needed to broaden its focus to encompass a review of
current adverse incident reporting and post-marketing surveillance
requirements, with the intent being to examine the possibility of harmonising
data collection and adverse event reporting systems, thereby enhancing
worldwide public health.
To accommodate this new activity, the responsibilities of the existing Study

Group 2 were consolidated with those of Study Group 3 and a new Study
Group 2 was established. In addition, the GHTF assigned Study Group 1 with
the task of developing a standardised format for pre-market submissions and
to determine the similarities and differences between each country's product
labelling requirements.
At its October 1996 meeting in Lisbon, Portugal, the GHTF gave preliminary
consideration to the concept of forming a "steering committee" as a means of
developing and standardising procedures for managing Task Force activities.
Top of page
1998-September 1999
In February 1998, the GHTF held its sixth Conference in Sydney, Australia.
At that Conference, several preliminary Study Group documents were
presented as being ready for dissemination for comment and/or publication,
and these included documents addressing the following topics:

History of GHTF
a) essential principles of safety and performance of medical

devices on a global basis;
b) the role of standards in the assessment of medical devices;
c) comparison of device adverse reporting systems in the

European Union, United States, Japan, Canada and Australia;
d) the management of information related to medical device

vigilance reporting;
e) adverse event reporting rules for device manufacturers,

including minimum data sets for manufacturer reporting to
competent authorities;
f) design control guidance for medical devices; and
g) guidelines for regulatory auditing of quality systems of medical

device manufacturers.
However, because no procedures for consultation or document approval had

been established to date, it was decided that these documents could not be
distributed any further and that the development of such procedures would
be the next task of the organisation.
At that same meeting, it was also decided that chairmanship of the

organisation would be transferred from Europe to North America for three
years commencing in February 1998, after which rotation would continue
between Australia and Japan and then on to Europe.
Under the auspices of their role as Chair, representatives of the United

States then volunteered to draft a set of practices and procedures
encompassing document development and distribution.
The Task Force also agreed to pursue a formal liaison relationship with ISO/
TC 210, the ISO Technical Committee responsible for Quality Management
and Corresponding General Aspects for Medical Devices, and whose focus is
to ensure the harmonisation of quality system standards.
At the 7th GHTF Conference in Bethesda, Maryland, a set of draft principles

and procedures was presented to the general membership and although it
was extremely comprehensive, the document was also seen as too
prescriptive for an organisation in its developmental phase. It was proposed
and agreed to that during Canada's term as Chair, an ad hoc committee would
be established with the goal of developing guiding principles and operating
procedures for the organisation. The ad hoc committee was also authorised
to act as an advisory body to the GHTF Chair, for the purposes of ensuring
document progression until a governance model was in place.

History of GHTF
In September, 1999, chairmanship of the GHTF passed to Canada.
Top of page
September 1999 - December 2000
The Ad Hoc Procedures Group, as the ad hoc committee came to be called,

held its inaugural meeting in October 1999 in Ottawa, Canada. At that
meeting, members worked on three draft documents entitled "Guiding
Principles", "Roles and Responsibilities" and "Operating Procedures", each
designed to scope out an important aspect of GHTF activity.
Besides ensuring a way for GHTF Study Group outputs to be formalised and
distributed to those who could use them, work on these documents was also
important because it was recognised that in order for the organisation to
move forward, a governance model and clear responsibilities for all those
involved in GHTF deliberations needed to be established. It was also felt that
this in turn, would ensure that the similar but independent interests of the
regulatory and industry representatives involved would be preserved and
that the organisation's outputs would also be further legitimised.
At the second meeting of the Ad Hoc Procedures Group, held in February

2000 in Santa Clara, California, work on the three draft documents
progressed and it was agreed that the documents could be posted for all
members to see and provide comment on prior to the 8th GHTF Conference,
scheduled for 18-22 September 2000.
The 8th GHTF Conference was the largest GHTF gathering to date with over
200 representatives from over 30 countries in attendance. In addition to
endorsing three additional Study Group documents, the Conference also saw
the acceptance of the three draft procedural documents.
It was also agreed that as its first priority, the newly formed GHTF Steering
Committee, as would be established according to the "Roles and
Responsibilities" document, would undertake a strategic review of its
accomplishments and objectives.
On 1 January 2001, chairmanship of the GHTF passed to Australia.
Top of page
January 2001 - July 2002
In accordance with the "GHTF Roles and Responsibilities" document,

transition meetings involving officials from Health Canada's Medical Devices
Bureau and Australia's Therapeutic Goods Administration (TGA) took place

History of GHTF
in Canberra, Australia during March 2001.
Immediately prior to this, Australia hosted the inaugural meeting of the

GHTF Steering Committee in Sydney, Australia from 28 February - 2 March
2001. The Steering Committee is the GHTF's governing body responsible for
management oversight and policy setting for the organisation, and replaces
the Ad Hoc Procedures Group established under the US FDA's Chairmanship.
The Committee met on three further occasions through May of 2002 and
some of its major work initiatives have included -
the undertaking of the GHTF Strategic Review which identified six, key
strategic themes and lead to the development of the 'Strategic
Directions' document. A focus for the Committee going forward will be
to implement the GHTF Strategic Directions;
the Global Medical Devices Nomenclature (GMDN) and the GMDN
Maintenance Agency Policy Group;
considering implementation of the National Competent Authority Report
(NCAR) Exchange Program;
approval of several GHTF Study Group guidance documents as "Final
Documents";
Consideration given to the establishment of a permanent secretariat for
the GHTF; and
Planning of the 9th GHTF Conference.
The 9th GHTF Conference was originally scheduled to be held in Barcelona,

Spain during October 2001, but was subsequently postponed due to the 11
September 2001 terrorist attacks in the United States.
With the unanimous agreement of the Steering Committee, the TGA re-
scheduled the event and in conjunction with Singapore's Health Sciences
Authority (HSA), co-hosted a highly successful 9th GHTF Conference in
Singapore from 12 - 16 May 2002. The two agencies also co-hosted an
equally successful GHTF training event, the 2nd APEC Seminar on the
Harmonization of Medical Device Regulations, from 17 - 18 May 2002.
Both events were heavily attended and the Conference was the largest GHTF
gathering to date, with 220 delegates representing 29 countries. 180
delegates attended the APEC Seminar - primarily regulators and industry
representatives from countries with developing regulatory systems, including
41 regulators and 59 industry representatives from Latin American and
Asian Countries.
All Delegates to the Conference benefited from an exciting and interactive

program, the major highlight being the one and a half day GHTF Plenary
which included individual Sessions on the Global Regulatory Model, New and
Emerging Technologies and The Total Product Life Cycle: A Focus on
Postmarket Surveillance and Vigilance.

History of GHTF
Topics discussed during the APEC Seminar included an overview of the

GHTF, a presentation on the global medical device market and regulatory
harmonization, and presentations by Members of the four GHTF Study
Groups on Quality Systems and Auditing requirements, Postmarket
Surveillance requirements and the harmonized approaches to medical device
registration, classification and approval.
The dedicated efforts made by Members of the GHTF Steering Committee

and Study Groups, representing Australia, Japan, Europe, USA and Canada
were a significant contributing factor to the success of the events.
On 1 July 2002, chairmanship of the GHTF passed to Japan.
Top of page
July 2002 - December 2003

transition meetings to transfer the GHTF Chair and Secretariat from
Australia's Therapeutic Goods Administration (TGA) to Japan's Ministry for
Health, Labour and Welfare (MHLW) were held in Tokyo, Japan on 5 to 9
August 2002. These meetings involved officials from the TGA, the MHLW,
the Japan Federation of Medical Device Manufacturers (JFMDA) and
secretaries.
The GHTF Steering Committee held its 5th meeting in Tokyo, Japan on 28 to
30 October 2002 and its 6th meeting in San Francisco, USA on 5 to 7
November 2003. The major work initiatives included:
the finalization of the GHTF Strategic Directions which identified 6 goals

establishment of a fundamental framework of GHTF activities such as
clarification of its scope, roles and work procedures of the Steering
Committee, Study Groups, etc.
approval of 13 GHTF Study Group documents to be advanced to next
stage
consideration of common data
establishment of a permanent secretariat for the GHTF
The 10th GHTF Conference was originally scheduled to be held in Tokyo,

Japan during May 2003. However, it was cancelled due to the outbreak of
SARS. The sixth meeting of the GHTF Steering Committee meeting and
meetings of four Study Groups, scheduled in parallel with the Conference,
were postponed as well.
Despite the cancellation of these events, there were significant achievements

in GHTF activities owing to the dedicated efforts made by Members of the
GHTF Steering Committee and Study Groups.

History of GHTF
On 1 January 2004, chairmanship of the GHTF passed to the European

Commission.
Top of page
January 2004 - Present

transition meetings to transfer the GHTF Chair and Secretariat from Japan's
Ministry of Health, Labour and Welfare (MHLW) to the European
Commission (EC) were held in Brussels, Belgium from January 26 to 28,
2004. These meetings involved officials from the MHLW, the EC, the Japan
Federation of Medical Device Manufacturers (JFMDA), the European
Confederation of Medical Suppliers Association (EUCOMED) and secretaries.
The 7th Meeting of the GHTF Steering Committee will be held in Paris,
France in June 2004.
Last Updated November 17, 2004

News and Information Releases
Home > General Information > News and Information Releases

HOME
What's New News and Information Releases
General
Information 10 February 2004 SPECIAL NOTICE: Rotation of the GHTF Chair and
GHTF Secretariat from Japan to the European Commission
Documents 9 February 2004 GHTF Annual Report 2002-2003 [PDF format: 84kb]
MoU
17 November 2003 Global Harmonization Task Force (GHTF) Statement
Study Group 1 on ISO 13485:2003
Study Group 2
1 October 2002 Announcement regarding the appointment of Dr
Study Group 3 Taisuke Hojo as GHTF Chair [PDF format: 71kb]
Study Group 4 Announcement regarding the retirement of Mr Souichi
Study Group 5 Ikegaya as GHTF Chair [PDF format: 75kb]
Steering 17 September 2002 The last 18 months - written by Rita Maclachlan,
Committee published in The Regulatory Affairs Journal
Liaison Bodies (Devices). [PDF format: 147kb NOTE: This
document cannot be printed.] [Word format: 89kb
Conferences
NOTE: essentially the same content as the published
version, but different layout. This document can be
printed.]
28 August 2002 SPECIAL NOTICE: Rotation of the GHTF Chair and
Secretariat from Australia to Japan - Summary
Report of Transition Meetings
3 June 2002 Statement from the Fourth Steering Committee

Meeting - 12-13 May 2002
24 October 2001 Statement from the Third Steering Committee

Meeting - 24 October 2001
29 August 2001 In Memory of Mr Gordon Higson
12 July 2001 Article from Chair published in July 2001 edition of

Regulatory Affairs Focus
22 June 2001 Statement from the Second Steering Committee

Meeting - 22 June, 2001
8 March 2001 Notice About Transition Meetings
http://www.ghtf.org/information/releases.html (1 / 2)2008.03.28 1:16:15

News and Information Releases
5 March 2001 Statement from the Inaugural Steering Committee

Meeting
3 March 2000 Second meeting of the Ad Hoc Procedures Group
6 October 1999 First meeting of the Ad Hoc Procedures Group
14 September 1999 Information about Canada becoming Chair of GHTF
Last Updated June 22, 2004
http://www.ghtf.org/information/releases.html (2 / 2)2008.03.28 1:16:15

EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2. 5/3 Rev 2
June 1998

SUBCONTRACTING QUALITY SYSTEMS RELATED

According to MDD Annex II, item 3.3, Annex V, 3.3 and Annex VI, 3.3 an inspection on the
premises of the manufacturers subcontractor will take place in duly substantiated cases.
When contemplating the necessity of such an inspection, the inspection team shall take into
account the manufacturers obligation on the evaluation of subcontractors as laid down in
article 4.6.2 of EN ISO 9001.
The two main issues a Notified Body should address when reviewing subcontractors are:
a) Whether the subcontractor has a substantial involvement with the design and/or
production of the device.
b) Whether the subcontractor is undertaking the supply of a part, material or service,

which may affect the compliance of the device with the essential requirements.
If the answer to both a) and b) above is NO, no further action is required.
If the answer to a) or b) above is YES, then the Notified Body must evaluate whether there is
sufficient evidence provided of the competence of the subcontractor to undertake supply of
the part, material or service in relation to the medical device(s) in question. The evaluation
will consider various matters including the control exercised by the manufacturer over the
subcontractor and the certification held by the subcontractor.
The circumstances where the Notified Body should be expected not to consider an audit of the
subcontractor are where it can be demonstrated that another Notified Body competent in
relation to the evaluation of the part, material or service has undertaken an assessment of the
subcontractor in relation to the part, material or service and has attested to the competence of
the subcontractor in relation to the part, material or service. In all other circumstances, the
Notified Body must be allowed to review the relevance or criticality of the subcontractor to
the medical device and, if not satisfied by the evidence available from the manufacturer,
undertake an audit/assessment of the subcontractor or require the manufacturer to undertake a
re-evaluation of the subcontractor.
Note: For the purpose of this recommendation the term subcontractor is used to
designate both subcontractor and supplier as used in the directives.
--- (())---
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.5/5 Rev. 3
February 1998
" TRANSLATION PROCEDURE "
---(())---
Translation procedures
As part of the quality system or of the documents defining the manufacturing process, the
manufacturer should have procedures for ensuring accurate translation of e.g. labelling,
instructions for use and product claims in marketing material.
These are especially important for user instructions where the safety and claimed
performance of the device may be compromised through inadequate translation.
---(())---
2
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.5/6 Rev. 1

February 1998
HOMOGENEOUS BATCHES
Homogeneity of production batches
Certain statistical verification procedures are only meaningful when batches, (lots), are
homogeneous.
A batch is considered homogeneous when equivalent parts or materials are manufactured

and/or tested in the same manner, without interruption, typically on the same day or in the same
time period, and produced by the same person, or with the same machine/equipment set-up
and fulfil the same specifications.
For IVD's and certain other medical devices, such as dental material the following
complementary definition shall apply: Mixtures of substances such as reagents aliquoted from
the same bulk mixture are considered homogeneous if the mixing and aliquoted processes are
validated.
Note: In ISO 2859, lot is defined similar to homogeneous batch of this paper.
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.5-7 rev 1

(Entire document)
July 1998
GUIDELINES FOR CONFORMITY ASSESSMENT

OF BREAST IMPLANTS ACCORDING TO
DIRECTIVE 93/42/EEC RELATING TO MEDICAL DEVICES
These guidelines aim at promoting a common approach by the manufacturers of breast

implants, the Notified Bodies involved in the conformity assessment procedures
according to the relevant annexes of the MDD and by the Competent Authorities
charged with safeguarding Public Health.
They have been carefully drafted through a process of consultation with various
interested parties during which intermediate drafts were circulated and comments were
taken up in the document. Therefore, this document reflects positions taken in particular
by representatives of Competent Authorities and Commission Services, Notified Bodies,
industry and other interested parties in the medical devices sector.
These guidelines are not legally binding. It is recognised that under given circumstances,
for example, as a result of scientific developments, an alternative approach may be
possible or appropriate to comply with the legal requirements.
Due to the participation of the aforementioned interested parties and of experts from
Competent Authorities, it is anticipated that these guidelines will be followed within the
Member States and, therefore, ensure uniform application of relevant Directive
provisions.
Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel Belgium Office : SC15 3/133
Telephone : direct line (+32/2) 295.93.39, switchboard 299.11.11. Fax : 296.70.13
Telex : COMEU B 21877. Telegraphic address : COMEUR Brussels
-2
TABLE OF CONTENTS
PAGES
1. INTRODUCTION ............................................................................. 3
2. GUIDELINES
2.1 Table of hazards associated with the design and manufacture of the
device with the related guidelines.................................................... 3
2.2 Use of animal studies for estimating risks...................................... 5
2.3 Clinical evaluation........................................................................ 5
2.4 Post-marketing surveillance.......................................................... 6
2.5 Hazards associated with the surgery and inherent hazards
associated with the clinical use of breast implants..........................
6
3. REFERENCES
3.1 Standards ................................................................................... 7

3.2 Report ........................................................................................ 7
ANNE XES
Annex IA : informative annex relating to pre-clinical investigation............

8
Annex IB : informative annex relating to clinical evaluation......................
16
Annex IC : informative annex relating to evaluation and acceptability
criteria to be used for the clinical evaluation............................................
20
Annex II: EQUAM Informative annex relating to information to be
provided to patients patient questionnaire and declaration of consent ...
27
-3
1. INTRODUCTION
Breast implants are usually Class IIb products, in some cases they are class III
according to MDD, Annex IX, Rules 8, 13 or 17.
The product related hazards of breast implants can be divided into the following
categories:
- hazards associated with the design and manufacture of the device (see 2.1, 2.2,
2.3 and 2.4)
- hazards associated with the surgery and inherent hazards associated with the
clinical use of breast implants (see 2.5).
In the following table, the hazards and the related guidelines are listed.
The manufacturer must evaluate the risk associated with each hazard listed below. The
second column of the table gives the corresponding guidelines to be considered.
The information is not exhaustive.
This information can be considered as one of the basis for the risk analysis which must
be performed.
2. GUIDELINES
2.1 Table of hazards associated with the design and manufacture of the device with
the related Guidelines.
Hazards Guidelines
Mechanical failure Results of mechanical testing according to pr EN 12180, 7.1 and adequate quality control at the relevant
steps of manufacture must be available.
With regard to the test of abrasion, the manufacturer should address these related hazards even for
implants filled with silicone gel and estimate the corresponding risk. He should describe the test used and
justify it
Rupture after implantation To be addressed in the clinical evaluation
Capsular contraction To be addressed in the clinical evaluation
Other local complications To be addressed in the clinical evaluation
Lack of sterility of the product The product must be provided sterile. The EN 550 series of standards can be used where appropriate.
The sterilisation process must have been validated adequately and documented in the technical file.
The validation must demonstrate the fulfilment of EN 556.

-4
Lack of biocompatibility Biological evaluation can be performed according to prEN 14630 and prEN 12180, 6 and 7.1.7 in
combination with EN 30993-1, ISO/DIS 14538, and EN 1441, annex B.
Evaluation of biocompatibility should cover the shell, the filling material and the bleed materials as well as
all other materials which could be in contact with the tissues in case of rupture of the envelope, as identified
in the risk analysis.
All identified hazards should be addressed.
In particular, all the following hazards should be object of the appropriate in-vitro tests or animals studies,
unless a justification is given for not performing them. In vitro tests could also be used to assess propensity
to induce the release of pro-inflammatory cytokines.
- Envelope : cytotoxicity, haemocompatibility ( haemolysis, {activation of complement}),

genotoxicity, carcinogenicity .
- Filling material : cytotoxicity, systemic toxicity, intradermal irritation, sensitisation , genotoxicity,

carcinogenocity, haemocompatibility (hemolysis, activation of coagulation, platelet activation,
{activation of complement}),
- End product: cytotoxicity, systemic toxicity, intradermal irritation, sensitisation, genotoxicity,

carcinogenocity .
- Chronic toxicity is addressed in EN 30993-1
- Immunotoxicity: this hazard should be specifically addressed in the dossier taking account of the
results of the risk analysis
Bleeding The effects of bleeding on the biological tissues as well as on the mechanical characteristics of the
envelope are not known. For these reasons, it is suggested that, on the basis of the risk analysis, the
manufacturer should provide the justification for the tests performed; he should also provide the results of
the tests and the criteria used for accepting the estimated risk.
The in-vitro test described in annex 1 of the present guidelines is provided as an example .
Physical/ chemical Data about compatibility between shell and filler must be available
incompatibilities
Osmotic changes Data about the osmotic situation must be available, if applicable
Interference with medical Information about possible interference with subsequent diagnosis and treatment must be addressed in the
diagnosis and treatment labelling
Lack of traceability prEN 12180, 11.6 has to be applied
Limited lifetime Expected lifetime of implants (stability after implantation) must be addressed and documented using the
information available (including results of animal studies). Data shall be available to justify expected lifetime
of all components (durability and age related changes).
The manufacturer has to provide adequate information in the instructions for use in relation to limitation of
lifetime
Unknown shelf-life The use-by date based on stability data has to be given and is addressed in prEN 1041 and EN 980
2.2 Use of animal studies for estimating risks

-5
As a general principle, in vivo animal studies may be considered as part of pre-clinical
evaluation when the three following conditions are fulfilled:
- the risk analysis points out a lack of relevant data,
- no alternate appropriate ways for obtaining the missing data are available,
- such studies are likely to provide the missing data.
In particular, in vivo animal studies remain the only means to evaluate chronic toxicity
and immuno-toxicity as well as ageing. They also constitute the only means to evaluate
the biological effects of bleeding.
2.3 Clinical evaluation
The Notified Body shall, during the conformity assessment procedure, review the
clinical evaluation in the technical file in compliance with MDD, Annex I, Section 1 in
conjunction with annex X.
Clinical evidence covers all identified hazards, nevertheless, the main objective of the
pre-market clinical evaluation is the estimation of the risks associated with the hazards
due to local complications, including capsular contracture and rupture after implantation.
Clinical data to be provided by the manufacturer should originate :
- either from clinical investigations performed with the concerned prosthesis or

with a sufficiently similar prosthesis, taking account of the objectives of the
Study, and following a specific clinical investigation plan. Such clinical
investigations should be performed when the risk analysis points out a lack of
relevant clinical data.
- or from retrospective data obtained from previous use of the concerned

prosthesis or of a sufficiently similar prosthesis, taking into account the
objectives of the study
The acceptability criteria should be clearly documented and justified with a clear
identification of the expected benefits to the patients.
-6
2.4 Post-marketing surveillance
The manufacturer must institute and keep up to date a systematic active procedure
defined in accordance with the results of the risk analysis, in order to gain and review
experience from devices in the marketing phase including reviews of risk analysis and
plans for any necessary corrective action. This systematic procedure should specifically
include the review of data relating to long term effects, in particular those in relation to
chronic toxicity.
During each surveillance audit the Notified Body shall review the experience gained by
the manufacturer in the marketing phase and any subsequent action.
2.5 Hazards associated with the surgery and inherent hazards associated with the clinical
use of breast implants
Information about the risks associated with surgery shall be provided in the labelling
These shall include:
1. clear indications for the use of the implant,

2. clear contraindications,
3. known adverse reactions,
4. a statement that breast implants are single use devices and must not be
resterilized and/or reused.
Risks associated with lack of expertise of the surgeon and the need for follow-up of the
patient shall be addressed.
There are certain risks particularly inherent in the use of breast implants or postulated
from their use. These are addressed specifically during consultation between physician
and patient and subject to informed consent.
A patients card is an appropriate way to provide the involved parties with all the
information needed during the life-cycle of the breast implants
Note: The informative annexes IA, IB and IC attached to this document give
examples of some particular pre-clinical tests, as well as an example of
clinical investigation plan and of criteria of acceptability.
The informative annex II provides an example of information to be

provided to the patient prior to an implantation as well as an example of
a patient questionnaire and of a patient consent form. These documents
have been developed and issued by the European Committee on Quality
Assurance and Medical Devices in Plastic Surgery (EQUAM).
-7
3. REFERENCES
3.1 Standards
prEN 12180 Non active surgical implants Body contouring implants Specific requirements for mammary
implants
prEN 14630 Non active surgical implants General re quirements
EN 550: 1994 Sterilization of medical devices Validation and routine control of ethylene oxide sterilization
EN 552: 1994 Sterilization of medical devices - Validation and routine control of sterilization by irradiation
EN 554: 1994 Sterilization of medical devices Validation and routine control of sterilization by moist heat
EN 556: 1994 Sterilization of medical devices Requirements for devices to be labelled Sterile
EN 30993-1: 1993 Biological evaluation of medical devices - Part 1: Guidance on selection of tests
ISO/DIS 14538: 1996 Methods for the establishment of allowable limits for residues in medical devices using health
based risk assessment
EN 1441: 1997 Medical devices - Risk analysis
EN 1041: 1998 Terminology, symbols and information provided with medical devices; information provided by
the manufacturer with medical devices
EN 980: 1996 Graphical symbols for use in the labelling of medical devices (under review)
3.2 Reports
* Recommendations for evaluating breast implants prior to

Marketing approval (June 1997) :
Coordinators : Anne-Claude Koeger and Frdric Fleurette.
Panel of experts : Daniel Marzin, Marc Pallardy, Grard Ballon, Lise

Barreau-Pouhaer, Nathalie Bricout, Monique L, Jean-
Michel Nguyen, Claude Nicoletis, Jean-Marie Servant,
Anne Tardivon, Henri Tristant.
Consulted specialists : Rosy Eloy, Marie-Franoise Harmand, Jean-Luc Jannic,

Olivier Meyer.
* Silicone implants and connective tissue disease : evaluation of evidence for an

association between the implantation of silicones and connective tissue disease.
Data published from end 1991 till July 1994. D.M. Gott and J.B. Tinkler.
Published Medical Devices Agency, London 1994.
-8
ANNEX I A TO THE GUIDELINES FOR CONFORMITY ASSESSMENT OF

BREAST IMPLANTS (as mentioned in chapter 2)
Informative annex relating to preclinical evaluation
This annex is mainly constituted by large extracts taken from the report of the experts group
mentioned in chapter 3. It provides examples of some elements of preclinical studies which
could be performed in the context of conformity assessment.
1. Abrasion resistance and analysis of abraded surfaces. The silicone elastomers

of the shell are in fact relatively soft and susceptible to deterioration due to surface
abrasion. When placed in the thoracic wall of a woman, they are subjected to
permanent friction forces exerted by the soft parts above them.
2. Bleeding. An in vitro bleed test, identifying and characterising all the constituents
remaining in the shell and all those that have passed into the solvent at the end of the
test. In future, it would be desirable to carry out the test in two solvents, one consisting
of an electrolyte solution and one containing lipoproteins. In fact, leakage is a
secondary effect, currently unavoidable, for breast implants. The product of leakage
may be dispersed in the body in two ways : simple diffusion in the extra-cellular liquid,
or phagocytosis by peri-prosthetic macrophages. After a long period of leakage, which
is theoretically infinite, and in the event of rupture of the implant, the product contained
in the shell may present a different constitution from the initial filling material. It is
necessary to know the composition of these products.
This in vitro bleed test is complemented by an in vivo bleed test. The contents of the
explanted implant is analysed (composition of the silicones, cohesivity of the gel, etc.) a
quantitative and qualitative analysis of the bleed products in the peri-prosthetic tissue
and in the drainage ganglions is carried out.
3. Ageing. Comparison of the mechanical, physical and physical-chemical properties of

implants (shell, filling material and complete implant) before and after ageing, in order to
document any modifications of these same properties as a result of ageing is
performed.1
1 The original report provides a list of tests to be performed. These tests are described in parts of that report which
have not been reproduced in the present document. The tests performed for the comparison should be the same as
those indicated in section 2.1 of the main part of the present document.
-9
4. Evaluation of the biocompatibility of breast implants
4.1 Foreword
Generally, it should be noted, that there have been to date no tests carried out
in bleeding conditions, i.e. involving the passage of the contents through the wall
of the silicone shell.
All the following tests were carried out either on aqueous extracts or in a
solvent, or by direct contact (cf. table in annex 1).
In order to establish bleeding conditions, it is important to define the extraction

conditions, since it is on an extract that these tests are carried out, and the
extraction conditions must reproduce the bleeding conditions.
The following points relate to the product of the extract :
- surface/volume ratio of at least 6 cm/ml or 4 g/ml,

- extraction duration higher than that enabling the acquisition of a
significant extract,
- extraction temperature :37C,
- conditions of mechanical agitation whereby the implant is subjected to
stress may permit the extraction duration to be reduced.
Finally it is vital that analysis of the composition of the extracts is carried out
using sensitive and specific methods.
4.2 Evaluation of biological risks
4.2.1 Evaluation of cytotoxicity : in a standardised model, cytotoxicity is evaluated

by direct or indirect contact (via the agar) lasting 24 to 72 hours with the
material to be tested and/or on the extracts. The cells used are in general
fibroblastic cell lines. The culture rarely lasts beyond 72 hours. The
appreciation criteria relate to modifications to the metabolism, the cell cycle or
the cellular viability.
4.2.2 Systemic toxicity : this systemic toxicity test may be carried out either
intravenously or intraperitoneally. Bearing in mind the nature of the extracted
molecules, it is preferable to carry out toxicity testing intraperitoneally in mice
using 50 ml/kg of the extract or of a bleeding product injected peritoneally.
Survival and signs of toxicity are the analytical criteria.
It is also possible to endeavour to investigate activation signs, particularly of

peritoneal macrophages (tissue plasminogen activators, or interleukins
activation). This model should be validated for the silicones.
This model may be extended from 72 hours (time required for standards) to 15
days (by using repeated injections).
- 10
4.2.3 Intradermal irritation test : here again, this test investigates a local effect and
the standard test may be applied. The question may simply be raised whether it
is really relevant to carry out a test with one single intradermal injection of the
product, bearing in mind the exposure conditions to products of bleeding in the
human.
4.2.4 Sensitisation tests : these tests are treated in the immuno-toxicity studies
4.2.5 Hemocompatibility tests : these tests investigate the existence of an interaction

between the products of bleeding and the blood cells or the major blood
systems:
- coagulation activation,
- platelet system activation,
- fibrinolytic system activation or inhibition,
- complement system activation,
- haemolysis activation
These tests are in vitro tests carried out in static conditions using a control, in
the presence of human blood, seeking for each of the systems explored the
appearance or the appearance kinetics of a specific system marker :
- fibrinopeptide or coagulation time of the coagulation system,

- platelet activation markets: betathromboglobuline,
- complement activation: liberation of C3a, C5a or of the fraction of the
terminal complex,
- hemolysis: measurement of the rate of haemoglobin after a contact
period of 1 to 3 hours
4.3 Immunotoxicity tests
4.3.1 Introduction : certain pathological conditions associated with the implantation

of breast implants are of immunological origin. By virtue of this fact, it is
necessary to evaluate the impact of implantation of this type of material on the
immune system. Immuno-toxicity studies will be included in the chronic toxicity
testing and will be based essentially on a histology of the lymphoid organs.
These tests should bring to light any effect of implants on the immune system
and therefore indicate if it is necessary to proceed with supplementary testing.
However these tests are not able to cast light on the potential of the material
tested to induce auto-immune diseases. At the present time, there is no
satisfactory approach concerning these aspects. The sensitisation potential will
also be evaluated according to a conventional protocol using the
recommendations of OECD guideline 406.
- 11
4.3.2 Immunotoxicity study during toxicity tests by repeated administration
4.3.2.1 Method and protocol : the end-product is tested along with the filler
solution. The selected animal for the study if the miniature pig (only
the female of the species is used). The practical details of the test
protocol (doses, implantation sites, animal batches) are covered by
the protocol for studies of chronic toxicity and by the OECD
guideline 409.
At the end of the study and each time an animal is killed, samples will
be taken of the following lymphoid organs : thymus, spleen, bone
marrow, ganglions draining the implantation site, mesentery
ganglions. For the thymus, a cortical/medullary zone ratio is
calculated as well as the histopathological examination. For the
ganglions, in addition to the histopathological examination, weight
and cellularity data must also be supplied and the presence of
germination centres is of particular interest.
For the implanted animals, a histological analysis is carried out on the

fibrous shell surrounding the implant, involving investigation of the
infiltrating granulocytes, monocytes and lymphocytes.
4.3.2.2 Analysis of results : in the event of histological alteration of the

examined lymphoid tissues which shows a diminishing or
modification of the cellular populations, it is necessary to proceed
with further testing aimed at evaluating a possible immuno-
suppressive effect. The testing should take account of the latest
scientific advances at the time the testing takes place. If there is an
increase in the number of germination centres with relation to the
controls in the ganglions or the spleen, it is necessary to proceed
with supplementary testing designed to characterise this response.
The testing should take account of the latest scientific advances at
the time the testing takes place.
4.3.2.3. Sensitisation power study : this study is to be carried out according

to the OECD 406 directives concerning the Magnusson and
Kligman maximisation test. The materials tested will be the filling
material and the shell intradermally. Several non-irritant
concentrations will be tested in order to determine the minimal irritant
concentration before this test is begun.
- 12
4.4 Genotoxicity study
4.4.1 General : the genotoxicity studies must enable evaluation of the

genotoxicity of the filling material which may accidentally be released by
rupture or by leakage within the organism and the genotoxicity of the
end-product. In the event of the filling material representing too great a
toxicity for one of the reactive systems (e.g. bacteriostatic activity in the
case of bacterial tests), the test is replaced for this system by a test of
the end-product and the filling material separately. The genotoxicity
tests must be carried out before each clinical trial.
4.4.2 Products : where the products cannot themselves be studied, an

extract of these products should be studied instead. Before any
extraction or test, each material or device must be in its usage state,
including all sterilisation processes (i.e. in the state in which it would be
used clinically).
Two suitable extraction forms must be used, one with a physiological

medium (e.g. 0.9% NaCl isotonic solute or cellular culture medium, the
second with a solvent such as dimethylsulfoxide (DMSO) which is
compatible with the testing system.
DMSO is known to be cytotoxic on mammal cells in the selected

testing systems at concentrations higher than 5 g/l in an aqueous solvent.
The greatest quantity possible per volume of extractant (expressed in
cm3/ml or in g/ml) must be used.
The materials and devices hardened in situ must be tested in their state
before and after hardening.
Extraction must be carried out in closed receptacles with a minimum

overhead clearance.
4.4.3. Test methods : a sequence of at least 3 in vitro genotoxicity tests must

be carried out on each extract. This sequence must comprise at least :
- one gene mutation on bacteria (in accordance with OECD

guidelines 471-472),
- one on in vitro gene mutation test on mammal cells (in

accordance with OECD guideline 476),
- one on in vitro chromosome mutation test on mammal cells (in

accordance with OECD guideline 473),
In the event of conflicting test results or dubious results from one of the
tests of this sequence, supplementary tests designed to show up any
primary lesions of the DNA must be carried out in vitro (in accordance
with the OECD guideline 482). In vivo tests for chromosome
aberrations (in accordance with OECD guidelines 474 and/or 475) and
for primary lesions of the DNA may be required.
- 13
4.5 Carcinogenicity study
4.5.1 General : the carcinogenicity study must enable evaluation of the local
and systemic carcinogenic risk of the complete device but also of the
filling material which may be released in the event of accidental rupture
or as a result of leakage.
Carcinogenicity studies should be carried out before any clinical trial.
4.5.2 Preparing samples
Finished products : a properly shaped implant should be the basis of the

test material when considering the carcinogenic potential of the solid
state (Oppenheimer effect). The implant must be subjected to all the
processes that an implant undergoes in clinical use.
Filling materials : the filling materials shall be injected subcutaneously

into a site comparable to that used clinically once at the start of the test.
4.5.3 Test methods : carcinogenicity tests must be carried out using at least
one species of rodent in accordance with OECD guidelines 451 or
453, after appropriate modification, for the materials to be tested in the
conditions described above.
Implantation at the maximum implantable dose, which is the maximum

quantity (dose) of an implantable material that a test animal may tolerate
without harmful physical or mechanical effects, will be carried out once
at the start of the study. The animals from the negative control batch
will undergo the same operative treatment as the implanted animals (i.e.
anaesthesia, implantation operation, etc..). At least 4 batches of animals
will be used :
- batch 1 : negative control receiving the 0.9% NaCl isotonic

solute subcutaneously,
- batch 2 : receiving the filling material subcutaneously,
- batch 3 : implant containing 0.9% subcutaneously,
- batch 4 : implant containing material meant for human
implantation
In the case of a filling material, the carcinogenic potential of which has

already been evaluated subcutaneously in one species of rodent, in the
conditions described above, this type of study may be limited to the
implementation of batches 1 and 4.
In addition to the tissues examined macroscopically and histologically,

the surrounding tissues and the ganglions draining the implantation point
should also be included.
4.6. Chronic toxicity studies

- 14
4.6.1 General
The chronic toxicity studies must enable evaluation of the potential local
and systemic toxic effects of the complete device but also of the filling
material which may be released in the event of accidental rupture or as
a result of leakage.
Chronic toxicity studies should be carried out before any clinical trial.
Testing should be carried out on at least one non-rodent animal species,
where implantation of the product designed to be used on women is
possible.
This study is accompanied by the biodistribution study (paragraph 4 of

this chapter) and the immunotoxicity study (chapter on Immunotoxicity
Studies).
4.6.2 Products administered
Solid products : where possible, the device must be tested in its

condition for use. If this is no the case, an appropriately shaped implant
must be composed from the test material.
Filling materials : the filling materials are to be injected subcutaneously in

a site comparable to that used clinically once at the start of the test.
4.6.3 Tests methods
The chronic toxicity tests must be carried out in accordance with

OECD guidelines 408 and 409 after appropriate modifications to the
materials to be tested in the conditions described above.
The studies are limited to female animals.
The duration of the studies must be at least 1 year after administered

implantation. Implantation at the maximum implantable dose (which is
the maximum quantity {dose} of an implantable material that a test
animal may tolerate without harmful physical or mechanical effects : this
maximum implantable dose must, for larger animals, include several
implantation sites) will be carried out once at the start of the study. All
the animals will undergo the same operative treatment (i.e. anaesthesia,
implantation operation, )
At least 4 batches of animal will be used :
- batch 1 : negative control receiving the 0.9% NaCl isotonic

solute subcutaneously,
- batch 2 : receiving the filling material subcutaneously,
- batch 3 : implant containing 0.9% NaCl,
- batch 4 : implant containing material meant for human
implantation
- 15
In the case of an implant containing only the 0.9% NaCl isotonic solute,
only batches 1 and 3 are relevant.
In addition to the tissues examined macroscopically and histologically,

the surrounding tissues (involving investigation for infiltrating monocytes
and lymphocytes) and the ganglions draining the implantation point
should also be included. Part of the peri-prosthetic tissues and the
ganglions will be used for a qualitative and quantitative evaluation of the
migration of the filling material.
In the case of a filling material, the toxicity of which has already been
evaluated subcutaneously for at least one year in a non-rodent species,
in the conditions described above, this type of study may be limited to
the implementation of batches 1 and 4.
For a species in which it is possible to implant the product in the form

designed for human implantation, one animal per batch will be killed at
3 to 6 months in order to study local tolerance (examination of the peri-
prosthetic and ganglion tissue and evaluation of the migration of the
filling material, along with physical-chemical and mechanical study of the
explanted implants).
4.6.4 Kinetics of toxicity : the objective of this model is, during chronic
administration, to identify the organs targeted by the bleeding. Dosages
are carried out on animals that have received implants and been
injected with the filling material. The detection of the distribution of
these products is then carried out in the blood, liver, spleen, brain,
kidney and lung, using appropriate methods. The examination
sequences are carried out as soon as the animals are killed.
- 16
ANNEX I B TO THE GUIDELINES FOR CONFORMITY ASSESSMENT OF

BREAST IMPLANTS (as mentioned in chapter 2)
Informative annex relating to clinical evaluation
mentioned in chapter 3. It provides an example for a method of clinical evaluation using data
obtained from a prospective clinical trial.
I. OBJECTIVES
The purpose of the pre-market clinical evaluation is to estimate the frequency at which
complications occur as a result of the implantation of breast implant. Two types of
complication may occur : local and general.
General complications occur infrequently, if at all. They cannot therefore be evaluated

within the framework of a prospective clinical trial carried out prior to marketing
approval. A large number of patients would have to be recruited, monitored over
several years and compared with a reference group. But, any occurrence of this type of
complication will have to be declared, then analysed within the framework of the post-
marketing surveillance. This applies both for connective tissue diseases and other, as
yet unidentified, diseases.
Local complications occur on a much more frequent basis than general complications,
but, paradoxically, have been less evaluated than the latter. Local complications can be
either peri-prosthetic contractures of the implants or ruptures and sudden or
progressive collapse. Peri-prosthetic contractures would be the first and most frequent
local complications. These may lead to pain, aesthetic damages and, eventually, further
surgical intervention. Ruptures would occur less frequently than the contractures, but
would almost always require further surgical intervention. This also applies in the case
of collapse.
The risk of these complications occurring needs to be analysed, since this can
potentially negate the benefits for women receiving breast implants. This risk, as
opposed to the risk of general complications, can be analysed in the framework of trials
carried out prior to authorising the marketing of breast implants. Post-marketing
surveillance must also be carried out so that the long term evolution can be specified.
In addition to evaluating these risks, which is essential, other complications could be

studied, for example, local-regional post-operative rate of infection, hematoma, badly
positioned implant, folding, pain and local-regional inflammation during the monitoring
period.These complications are, however, more related to surgical conditions and to the
- 17
medical context, than to the actual material, except perhaps for inflammatory
phenomena and pain.
II. BREAST IMPLANTS CONCERNED
All types of internal breast implants, containing isotonic solution, silicone gel or other
types of filling material, are exposed to the risk of local complications.
As a consequence, manufacturers need to analyse these risks for each type of implant
they wish to produce commercially.
If modifications are made by the manufacturer following authorisation for marketing,

those concerning the nature of the shell, the filling material and any device incorporated
in the implant may require further evaluation.
With respect to the shell and any device incorporated in the implant, any major
modification must be followed by both toxicological evaluation and a new evaluation of
the risk of local complications.
If a new filling material is used, it is essential that a toxicological evaluation of the new
material and its interaction with the shell is carried out. However, an evaluation of local
complications must also be made.
III. METHODS OF OBTAINING CLINICAL DATA
An appropriate method of evaluating the risk of local complications caused by breast

implants is that of a prospective clinical trial carried out prior to their authorisation for
marketing. The recommendations for carrying out such trials are presented in this
document.
The European Directive presents the information extracted from the literature as a
possible alternative to carrying out prospective clinical trials. However, the information
published does not always enable the data and results to be controlled in the case of an
implant which a manufacturer wishes to commercialise. Thus, a clinical dossier must be
put together on the basis of trials that have already been performed. This dossier
should therefore be subject to retrospective analysis using the evaluation criteria
described in this document. Therefore, with respect to the methodology, this
retrospective approach is the only acceptable alternative to the prospective clinical trial.
IV. METHODS OF CARRYING OUT THE PROSPECTIVE CLINICAL TRIAL
Only breast implants having satisfied the pre-clinical evaluation presented in the part one
of this document could be used for clinical evaluation in patients.
- 18
1. Methodology
* The group of patients should consist, on the one hand of those whose
surgical indication was reconstruction following breast cancer, and on
the other hand of those surgical indication was implantation for aesthetic
purposes. A one third (reconstruction) two thirds (aesthetics)
distribution is desirable, except for implants which are to be used
exclusively for one of these operative indications.
* The minimum duration of the following-up will be 2 years for each

patient.
* The total number of implants evaluated should not be less than 150. If
two prostheses are implanted in the same patient, these could be
evaluated independently. Providing that all the patients have been
monitored for at least 2 years, a total of 150 implants will enable the
following to be estimated :
= a rate of rupture of 1% with a 95 % confidence interval of

between 0 and 4%,
= a rate of peri-prosthetic contracture of 5% with a 95%

confidence interval of between 2% and 10% (see graph below)
5% confidence intervals for a sample of 150 protheses
Upper limit
Proba
bility 20
of
event 15
%
10 Lower limit
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Number of ruptures or contractures at 2 years
In order to reduce the variation in estimating the rate of peri-prosthetic

contracture, it is preferable, where possible, not to include patients who have
had the following :
- a previous breast implant,

- a recurrence of breast cancer,
- a previous breast radiation treatment.
- 19
In order to reduce the number of missing patients, it is recommended not to
include the following :
- patients residing in a foreign country,

- patients who reside too far away from their monitoring centre.
* Choice of diagnostic methods :
The diagnosis of local complications is first made or suspected through

the clinical examination. If rupture of the prosthetic integrity is
diagnosed, this should be completed using an imaging technique. A
single digital mammogram (external costal profile) is sufficient. If any
doubt remains, a second mammogram with compression of the breast
(external oblique) may prove necessary. An additional mammary
ultrasound examination is required only in the case where, in spite of
two mammograms, doubt still remains.
* Choice of investigating surgeon(s) and radiologist(s)
The choice should be made by the promoter of the clinical trial. The
promoter will be responsible for ensuring that the investigators respect
the legislation in force, including the legislation transposing annex X of
MD directive and annex 7 of AIMD directive (see also EN 540)
= The surgeon(s) should have the necessary qualifications and

sufficient implantation experience (50 implants per year). They
should perform the operations themselves on the patients
included in the clinical trial (i.e. without delegating the task)
= The radiologist(s) should be experienced in the imaging of

women with breast implants. They should perform the
radiographic examination specified in the protocol themselves
(i.e. without delegating the task).
- 20
ANNEX I C TO THE GUIDELINES FOR CONFORMITY ASSESSMENT OF

BREAST IMPLANTS
Informative annex relating to evaluation and acceptability criteria to be

used for the clinical evaluation.
mentioned in chapter 3. It provides an example for evaluation criteria, evaluation procedure
and acceptability criteria.
I. EVALUATION CRITERIA
Accurate details cannot always be given on the evaluation criteria, since they depend on
current knowledge of the subject.
* Evaluation of the peri-prosthetic contracture
The Baker classification will be used as a reference for this evaluation. This
classification defines four stages :
= stage I : completely nature appearance of the breast, as if there was no

implant
= stage II : minor peri-prosthetic contracture ascertained by simple
palpation of the breast. The patient feels no discomfort
= stage III : moderate peri-prosthetic contracture ascertained by clearer
perception of the implant on palpation. The patient also perceives
some hardness
= stage IV : severe peri-prosthetic contracture ascertained visually.
Increased symptoms.
Only stages III and IV will be classed as peri-prosthetic contractures.
* Evaluation of ruptures and of sudden or progressive collapse
- There are certain clinical signs which may lead to suspicion of prosthetic
rupture, possibly requiring radiological exploration :
= collapse of the breast if the implant contains a re-absorbable or

biodegradable filling material,
= change in the volume, shape, consistency of the breast and its
cutaneous appearance,
= peri-prosthetic contracture occurring after an interval of one
year,
= appearance of local-regional inflammatory signs.
- 21
This list is non-exhaustive. Ruptures of silicone implants may arise occasionally
without any clinical signs.
- 22
- During the mammographic examination, the diagnostic signs are as
follows :
= for breast implants filled with silicone gel :
a) Near certainty of normality : visibility of superficial folds

in the shell
b) Doubts on the normality : poor visibility of superficial

folds in the shell
c) Near certainty of rupture confirmed by at least one of

the following signs: visible enlargement of the implant,
spontaneous visibility of the shell collapsed into the gel,
direct visibility of the breach, direct visibility of the
extra-capsulary intrusion of the silicone gel, and less
specifically : presence of watery liquids mixed with the
silicone.
= for other types of implants, the rupture may be confirmed by

direct visibility of the collapse :
The visibility of an intra-capsulary liquid effusion is an indirect

sign as it is less specific than a rupture diagnosis.
During the ultrasound examination, the rupture of a breast implant filled

with silicone gel may be suspected if one of the following signs is
apparent :
* heterogeneous echostructure of the silicone gel,

* presence of hyper-echogenic double lines (rails) in the gel,
* snowstorm appearance (extra-capsulary leakage). The
ultrasound examination also reveals certain intra-capsulary
effusion.
The protocol should specify action to be taken when faced with :
* near certainty of clinical rupture (radiographic investigation or

removal of the implant),
* near certainty of clinical and radiographic rupture (systematic
removal or not),
* any doubts on the integrity of the prosthetic cavity in spite of the
radiographic investigation (whether or not ablation of the
implant is required).
II. FREQUENCY AND NATURE OF THE FOLLOW-UP
* Clinical follow-up
- 23
Clinical monitoring will be guaranteed at least four points in time following
implantation of the internal mammary prosthesis : at 1 month, 6 months, 1 year
and 2 years.
During each of these examinations, the clinical information specified in the

Evaluation criteria paragraph should be collected.
Outside of this framework, any patient should be examined by his surgeon if

new clinical signs appear. Equally, any associated pathologies should be noted.
This information will also be reported in the observation record file.
* No biological evaluation is required
It should be noted that toxicological and immunological evaluation will have

been carried out previously. However, biological examinations could be
performed at the surgeons request. Obviously, these tests should be carried
out as soon as clinical signs of a general illness become apparent, in particular
those for a connective tissue disease.
* Radiological follow-up
- If there is no incident which causes prosthetic deflating or rupture to be

suspected during clinical follow-up or during spontaneous visits, a single
evaluation will be performed at the end of the clinical trial, i.e. at 2 years
for each patient and each implant. This evaluation could be performed
at an earlier date if the patient is due to move away from the area.
- If a rupture is suspected during clinical follow-up (compulsory or

spontaneous visit), a radiological evaluation will be performed. The
results must be recorded in the observation record file.
III. COLLECTION METHODS FOR THE CLINICAL AND PARACLINICAL DATA
This data are recorded in accordance with a reference model (see EN540)
Clinical information must obligatorily be collected by the investigative surgeon who

operated on the patient.
Radiographic information must obligatorily be collected by the radiologist who carried

out the examination.
This information should be sent to the person in charge of the clinical trial.
Besides the clinical and radiological data concerning the evaluation criteria, other
information must be collected. This involves in particular :
* the precise description of the implant and the identification number,

* the date of implantation,
* the surgical indication (reconstruction or cosmetic),
* the operative technique used,
- 24
* certain information about the patient :
= date of birth,
= medical/surgical history (in particular, cardio-vascular illnesses,

hemostatis diseases, diabetes, connective tissues),
= smoker/non-smoker,
= weight/height
In the event of ablation of the implant, whatever the cause, the collected information
must contain at least :
* the clinical and radiological factors and any other examination having led to the
ablation of the implant,
* in the event of a reported rupture, the (probable) date and the circumstances of
the incident,
* in the event of general complications, the examinations which enabled the
diagnosis(es) and the date that the first symptoms appeared.
Finally, the product of the ablation, comprising the implant and one or two peri-
prosthetic tissue fragments, must be analysed as follows.
In the event of bilateral explantation for unilateral rupture, the damaged and undamaged
implants are submitted to the following trials.
The mechanical and physical-chemical properties of the undamaged implants should be

documented.
For the damaged implants, and in the absence of a large rupture, only the physical-
chemical properties of the gel inside the implant are analysed :
. histological study of the peri-prosthetic tissue of damaged and undamaged implants,
. identification of the cellular sub-populations of the infiltrates.
. investigation in particular of granulomas.
For undamaged implants, quantitative and qualitative analysis of the silicones present in
the peri-prosthetic tissue.
If the excision of satellite ganglions is considered necessary, the ganglion samples are to
be studied, whether or not the implant is damaged, in addition to the standard histology,
weight, cellularity, particular existence of germination centres, and quantitative and
qualitative analysis of the silicones.
IV. ANALYSIS AND PRESENTATION OF THE RESULTS

- 25
It must include :
* an analysis per patient and per implant,

* a global analysis of the population per item,
* an analysis in sub-group in terms of the indications (for reconstruction or for
aesthetic purposes),
* an analysis of the clinical evaluation criteria by the Kaplan-Meier method,
carried out globally and for each instruction group,
* a presentation of the complication rates with their 95% confidence interval
according to the exact binomial method,
* missing data concerning the Baker classification or radiographic evaluation, lost
files or interrupted follow-up of a patient should lead to additional specific
investigations. In the absence of such investigations, these elements may be
considered as the worst result, i.e. : a Baker stage IV or a rupture.
V. LOGISTICS
The data must be recorded in observation record files(see EN 540);
In order to ensure an adequate match between the number of inclusions and the
number of actual implants (to avoid non-declaration in the case of a bad
operative result or monitoring), a counterfoil record will be required for delivery
of the implants;
The implants delivered by the promoter must include a unique identification

number (engraved on the implant) which will be the same as that on the
counterfoil record. A (carbon) copy of this record must be sent to the body
responsible for judging the dossiers;
The protocol must furthermore provide for quality assurance of the clinical trial
and of the procedures to be implemented in the event of a control of this trial.
VI. RETROSPECTIVE ANALYSIS METHOD FOR EXISTING DATA
The validation of this evaluation may be carried out on existing data, if the whole of this
pre-existing data can be found by the promoter, i.e. :
A study involving at least 150 implants taken from one or several series. Each of
these series must be consecutive;
Results concerning mammography evaluation after two years for each implant, or
even longer;
Results concerning the clinical evaluation of :

- 26
* peri-prosthetic contracture (Baker classification) at regular intervals at
least up to two years after implantation of the breast implant,
* prosthetic rupture at regular intervals for up to at least two years; the

same applying to collapse.
Furthermore analysis and presentation of data and results must conform with the criteria
defined in section IV of the present Annex.
VII STATISTICAL CRITERIA FOR JUDGING THE MAGNITUDE OF THE

IDENTIFIED RISK
One of the arguments in the decision to authorise or refuse marketing of an implant is

the value of the upper limit of the 95% confidence interval for the rates assessed in
clinical trial. This value in fact corresponds to the value which could be observed
potentially in the population if the breast implants were marketed.
The table below presents the upper limits of the unilateral 95% confidence interval
(according to the exact binomial method) in terms of the number of observed events
and the size of the clinical trial sample. These limits feature in italics in the table.
Number of implants studied

100 150 500 2000
Number of 0 2,95 1,97 0,59 0,29
events : rupture
orcontracture
1 4,65 3,12 0,94 0,47
2 6,16 4,13 1,25 0,62
3 7,57 5,08 1,54 0,77
4 8,91 5,99 1,82 0,91
5 10,22 6,88 2,09 1,04
6 11,49 7,74 2,37 1,18
7 12,74 8,58 2,61 1,31
8 13,97 9,41 2,86 1,43
9 15,17 10,23 3,12 1,56
10 16,37 11,04 3,36 1,69
Thus, for a trial involving 100 breast implants, even where no rupture has been
identified after two years of monitoring, it is possible for a rupture rate of 3% to be
observed if this implant is more widely distributed.
- 27
By the same token, for a trial involving 150 implants, if two ruptures have been
identified after two years of monitoring, it is possible for a rupture rate of 4% to be
observed if this implant is more widely distributed.
The same applies to peri-prosthetic contractures.
Surgeons consider that the maximum acceptable rate for ruptures after two years is 4%.
Consequently, a trial involving 150 implants should not give rise to more than one
rupture.
For the peri-prosthetic contractures, after aesthetic surgery, the experts consider that
the maximum acceptable rate after two years is 9%. Consequently, a trial involving 150
implants should not give rise to more than seven peri-prosthetic contractures. This
acceptability rate could be reconsidered for reconstructive surgery after breast cancer.
This is to inform you about the options you have as well as about the risks and possible side
effects. This brochure is designed to give you all the information you need to make your decision.
Please read this form carefully before discussing the details with your physician.
The following statements are based on current scientific knowledge, but there is still research
going on in this field.
There is always a reactive response to every foreign material implanted in a human body, which
should not be confused with auto-immune disease.
Multiple large scientific studies have not demonstrated a link between auto-immune diseases and
implantations of silicone implants.
Existing disease predisposition may be further strengthened in case of unspecific activation of the
immune system due to any implant.
Recent studies indicate clearly that silicone breast implants do not increase the incidence of breast
tumors in women.
Polyesterurethane coated breast implants pose an unquantifiable but extremely low carcinogenic
risk. However, the U.S. health authorities estimate this risk to be below 1 : 1 million.
Published data on damage to breast fed children of mothers with silicone gel filled implants are
lacking valid scientific evidence.
Which risks and side effects could be related to breast implants ?
The human body will always produce a fibrous capsule to surround a breast implant.
This capsule may shrink and/or calcify. Subsequently the breast can be painful and firm. The
aesthetic result may be unfavourable.
The risk to developing this complication is higher if you have had radiotherapy. The implant may
move and/or change shape as a result of contracture. Then a surgical correction might be
necessary. Please be aware of the fact that capsular contracture can also occur after a previous
correction.
- 28
To break the capsule by application of pressure only (so called closed capsulotomy) should not
be performed anymore, because of increased risk of rupture.
If the implant is positioned under the breast muscle, the position of the implant may be distorted
when you move your arm.
Sometimes rippling of the skin over the implant surface is visible, when the implant is located
underneath the skin (particularly in very slender individuals).
The life span of an implant is limited; therefore there may be a need for a replacement or
removal. The manufacturers of your implant will provide data about rupture rates.
Therefore you should have your implant examined regularly. In general the following time
intervals are considered to be appropriate : one month after surgery, six months after surgery,
twelve months after surgery and after then every twelve months.
Pain, decreased breast size, nodules or uneven appearance of the breast could occur along with
implant failure. If any of these symptoms occur, you should contact your physician immediately.
If the implant is suspected to have a defect it needs to be removed and, if you wish, to be
replaced.
Gel bleeding means that gel passes through the shell of an implant. This occurs in every gel filled
implant. The amount of gel bleeding depends on the design of the device. Normally the gel that
passes through the shell remains within the capsule , but absorption of silicone into other tissues or
organs can occur.
Silicone in these tissues can also originate from other sources, since silicone is used widely in
medicine and in many products used in daily life.
Mammographies in patients with silicone gel filled implants are more difficult to interpret.
Therefore you must inform your radiographer that you have silicone implants before
mammography. Computerized mammography by an experienced radiographer may be a method
for confirming a rupture. An echography of the breast is only indicated as a complement when a
doubt remains. If mammograms do not give enough information magnetic resonance imaging
(MRI) is strongly recommended.
MRI is also indicated if rupture, deflation or leakage suspected.
The most frequent malignant tumour in women is breast cancer. There is no increased
occurrence of breast cancer in patients with breast implants. Nevertheless detection of a tumour
by palpation or by mammography can be more difficult when implant surgery was performed.
Your physician will discuss your individual risk for breast cancer disease with you.
Which risks and side effects could be related to every operative procedure?
Major bleeding during or after the procedure may require another operation and/or blood
transfusion.
Local infection is rare but can occur. It could be a possible source of wound healing problems.
In stubborn cases the removal of the implant might be necessary.
The risk of developing thrombosis (blood clots) after surgical procedures cannot be eliminated
completely. This is one of the reasons why a hospital stay is highly recommended.
- 29
Preventive measures to minimise these risks will be discussed with you. Preparation for surgery
and pre-operative measures also carry some risks. For example it is possible that nerves or
vessels may be damaged by injection or infusion catheters (inflammation of veins, thrombosis).
There is also a small risk of infection with these measures (for example injection abcess).
It is extremely rare that blood transfusion or transfer of blood components become inevitable. In
these cases a risk of infection with viral diseases (e.g. hepatitis, HIV) cannot be ruled out
completely.
However the rate of infection is extremely low.
What happens after the operation ?
Please take note of the following facts :
Discoloration of the skin, loss of sensitivity and some feeling of tenseness are normal for the early
postoperative period. These symptoms generally disappear within a few weeks.
Sensitivity of the nipple might be reduced temporarily or permanently.
The ability for breast feeding is maintained in most of the techniques (applies only to
augmentation). Nevertheless we suggest that in case of pregnancy you should see your physician
for a check-up and discuss your ability to breast feeding with him/her.
Please avoid activities in which you need to work with the muscles of your arm (carrying heavy
things, tennis, etc.) for at least six weeks.
Please postpone taking showers, a bath or swimming until your physician allows you to do so.
After having received an implant, your doctor will inform you whether massaging of the implant is
indicated. He/she will also tell you how long you need a special bra or a breast compression
garment.
What can be achieved by a breast reconstruction procedure ?
We aim for the reconstruction of your breast, so that the shape has an aesthetic and natural
appearance. This can be achieved by an implant or by your own tissues. In some patients
reconstruction can be done immediately after the mastectomy procedure within one anaesthetic
procedure. If this is not possible, breast reconstruction can always be performed later on.
If additional therapies (like chemotherapy or radiation) are necessary, we will recommend a delay
of the reconstructive procedure until these therapies are completed.
Simultaneously or later on the size and shape of the opposite breast can be adjusted to the
reconstructed one. In most cases an aesthetically satisfactory result can be achieved.
Nevertheless no surgeon can guarantee, that the result will be completely symmetrical.
Please consider that nowhere in nature is complete symmetry found.
The ability for breast feeding and full sensitivity of the nipple can not be restored.
- 30
(schema to be inserted)
What can be achieved by an augmentation procedure ?
We aim for the augmentation of your breast so that the shape and size have an aesthetic and
natural appearance.
Particularly in patients with different breast sizes it can be difficult to achieve symmetry.
Please consider that nowhere in nature is complete symmetry found.
In order to enlarge the breast, usually a silicone device is implanted. In case that the enlargement
should be achieved by using your own tissue, we give you special information about this
procedure.
A small incision along the underside of your breast or along the areola of your nipple or in the
axilla will be used. A pocket for the implant will be formed above or behind the breast muscle.
If a small and loose breast is enlarged, it might be necessary to perform a mastopexy with
removal of excess skin and repositioning of the nipples to the original level. This procedure
creates additional scars.
Full sensitivity of the nipple and the ability for breast feeding might be reduced after an
augmentation.
(schema to be inserted)....................
The selection of procedures
Usually general anaesthesia is used for all the above mentioned procedures. In selected cases
local anaesthesia can be sufficient.
There are different types of implants which consist totally or partly of silicone. Your physician
will explain the advantages and disadvantages of the different types and he/she will suggest the
appropriate type of implant for you.
The procedures we suggest for you are marked :
Implantation of breast implant
a) with silicone
b) with textured surface silicone
c) polyesterurethane foam coated surface
d) by implantation of a silicone device, called a tissue expander, which will gradually be filled
postoperatively with increasing amounts of saline solution until there is enough expansion
of the skin. The filling phase normally takes between four and ten weeks. Two to five
- 31
months later the expander can be removed and a permanent implant will be inserted.
There are also expander implants available which do not need to be exchanged.
Filled with : a) silicone gel
b) saline
c) silicone gel and saline
d) other filler substances (.......................)
Implanted : a) under the pectoral muscle
b) above the pectoral muscle
Breast implants patient questionnaire
Dear patient,
The more we know about your history the better we can judge your risks. Please answer the
following questions. We would be happy to assist you in doing so.
1. Do you take medication ?
Pain medication (for example Aspirin) or any other medication that interferes with the
blood clotting system (for example Marcurriar, Heparin), sleeping pills, laxatives or
contraceptives and/or other medications
Type / dose ......................./........................
2. Do you smoke ?
If yes : how many cigarettes per day ? ..........................

No
3. Are you allergic or sensitive to food, medication, tapes, rubber or ...?
Yes, type .....................................................................

No
4. Did you ever develop red, raised or wide scars?
Yes
No
- 32
5. Do you have a tendency (you or relatives related by blood) to develop frequent
nasal bleeding or prolonged bleeding after injuries or for developing blue spots
without injury ?
Yes, type .................................................................... .

No
6. Do you or relatives related by blood suffer from haematological (blood related)

diseases and/or autoimmune disease (for example Lupus erythematodes,
sclerodermia, rheumatic arthritis, vasculitis) ?
Yes, type .....................................................................

No
7. Do you frequently suffer from swelling or pains in your joints ?
Yes, type, location.......................................................

No
8. When you are exposed to cold : do you suffer from severe pains of your hands
and/or do your hands turn white in the cold ?
Yes
No
9. Do you suffer from stiffness of your hands, feet or knees in the morning ?
Yes
No
10. Do you experience a strong feeling of tension of your skin, of your face, your
arms or your legs frequently?
Yes
No
11. Is it possible that you are pregnant?
Yes
No
12. Did you or do you suffer from any other disease (for example neurological or
psychiatric disorders, diabetes, imbalance of hormones, etc.)?
- 33
Yes, type .....................................................................
No
Breast implants patient declaration of consent
I have read the informative part of this form. I will follow the instructions carefully.
I have answered all questions to my best knowledge.
During the interview with Dr ........................................... we discussed the following :
Selection of procedure, advantages and disadvantages of the different techniques, individual
circumstances which might increase the risks, possible complications, additional surgical
procedures, probability of blood transfusion, possibility of the use of my own blood as well as :
...............................................................................................................................................
...............................................................................................................................................
I have been allowed to ask all questions which concern me as follows :
...............................................................................................................................................
...............................................................................................................................................
My questions were answered completely and in an understandable way.
Declaration of consent
After careful consideration I authorize Dr ................................... to perform the following
procedure :
...............................................................................................................................................
...............................................................................................................................................
I accept the need for changes or additional surgical procedures of the selected technique, if
necessary.
Yes No
I am aware of the fact that I have to go for regular check-ups.
In case I develop pain or any other signs which indicate that there might be a complication I shall
contact my physician immediately.
Date : .................
Signature : ..........................................................(patient)
Signature : ..........................................................(witness)
----------------(())-------------------
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.5-8 rev 2
February 1999
Guidelines on assessment of medical devices incorporating

materials of animal origin with respect to viruses
and transmissible agents
These guidelines have been carefully drafted through a process of consultation with
various interested parties during which intermediate drafts were circulated and
comments were taken up in the document. Therefore this document reflects positions
taken in particular by representatives of Competent Authorities and Commission
Services, Notified Bodies, Industry and other interested parties in the medical devices
sector.
These guidelines are legally not binding. It is recognised that under given
circumstances, for example, as a result of scientific developments, an alternative
approach may be possible or appropriate to comply with the legal requirements. This
guideline document utilizes the word shall; in order to claim compliance to this
guideline, these elements must be addressed.
- 2/15 -
TABLE OF CONTENTS
Pages
INTRODUCTION
SECTION NUMBER
1. MEETING THE ESSENTIAL REQUIREMENTS RELEVANT STANDARDS AND

OTHER DOCUMENTS. ............................................................................................................................. 3
1.1. ESSENTIAL REQUIREMENTS: ............................................................................................................. 3
1.2. RISK ANALYSIS AND MANAGEMENT: ............................................................................................... 4
1.3. HARMONISED STANDARDS: .............................................................................................................. 4
1.3.1 pr EN 12442-1: Animal tissues and their derivatives utilised in the manufacture of medical
devices - Part 1: Analysis and management of risk.............................................................................. 4
devices - Part 2: Controls on sourcing, collection and handling......................................................... 5
devices - Part 3: Validation of the elimination and/or inactivation of viruses and transmissible
agents ................................................................................................................................................ 6
1.4. ADDITIONAL RELEVANT DECISIONS AND OPINIONS:......................................................................... 6
2. DOCUMENTATION REQUIREMENTS ....................................................................................... 7
2.1 MANUFACTURERS' DOCUMENTATION ............................................................................................... 7
2.2 DOCUMENTATION PROVIDED TO THE NOTIFIED BODY BY MANUFACTURERS .................................... 7
2.3 SPECIFIC GUIDANCE FOR NOTIFIED BODIES ...................................................................................... 8
3. CONDUCT OF CONFORMITY ASSESSMENT........................................................................... 8
4. NOTIFIED BODY'S SPECIFIC PROCEDURES AND EXPERTISE ......................................... 8

4.1 NOTIFIED BODIES INTERNAL PROCEDURES ....................................................................................... 8
4.2 EXPERTISE ........................................................................................................................................ 8
5. BIBLIOGRAPHY............................................................................................................................... 9
APPENDIX 1.............................................................................................................................................. 11
ESSENTIAL REQUIREMENTS OF DIRECTIVE 93/42/EEC RELATING TO INFECTION AND

MICROBIAL CONTAMINATION ......................................................................................................... 11
APPENDIX 2.............................................................................................................................................. 12
DEFINITIONS AND REQUIREMENTS FOR SOURCING FROM PREN 12442-1 + PREN 12442-2
(EXTRACTS) ............................................................................................................................................. 12
APPENDIX 3.............................................................................................................................................. 13
REQUIREMENTS ON LITERATURE SEARCH FROM PR EN 12442-3
APPENDIX 4.............................................................................................................................................. 14
REQUIREMENTS AND GUIDANCE ON BSE/TSE RISKS IN PR EN 12442-2

- 3/15 -
INTRODUCTION
This document has been elaborated to provide guidance to Notified Bodies,

manufacturers and interested parties on the assessment of medical devices covered by
Active Implantable Medical Device directive and Medical Device directive incorporating
materials of animal origin. This principally relates to class III devices and associated
conformity assessment procedures shall apply. The use of this document shall also be
considered where materials of animal origin are used in manufacturing processes but
where the materials are not included in the final device.
NOTE:The manufacture of some devices may use industrial raw materials, which contain
small amounts of substances derived from animal tissues (e.g. tallow) through a
chemical/physical process, which is likely to destroy the structure of the original
molecules. Where such chemicals (e.g. stearates in plastics) are not intended to
have any direct effect in relation to the medical function of the device and to be
released into the body (see risk analysis), then the application of some of the
following guidance may not be relevant. This is justified by the fact that the
intensive industrial processing of the substance has removed the original
characteristics, which are specific to the animal tissue as well as the risk of
transmission of many pathogens.
1. MEETING THE ESSENTIAL REQUIREMENTS RELEVANT

STANDARDS AND OTHER DOCUMENTS.
1.1. Essential Requirements:

Essential requirements 1 - 6 of Directive 93/42/EEC of 14 June 1993 stipulate the
requirements for the safety of the device, more specific requirements regarding
'Infection and microbial contamination' are detailed in Essential Requirements 8.1
and 8.2 (see Appendix 1).
The primary principle is to eliminate or reduce risk as far as possible and

provide optimal security; these concepts are paramount during assessment. The
application of these primary principles shall also take into account the benefit of
the device as well as the generally acknowledged state of the art. It shall be
understood that the risk considered in the benefit/risk analysis includes the
current epidemiological risk. Furthermore it shall be considered to what extent
alternative materials to those of animal origin are available and can be used.
Bearing in mind the special risk of TSE (Transmissible Spongiform
Encephalopathies), a rationale shall be provided for the use of ruminant origin
material.
Where relevant and taking into account the risk analysis and risk management,
identified residual risks shall be mentioned (including, where appropriate, the
presence of a specific substance of animal origin) in the information provided
with the device as required in essential requirements 2 and 13 (see Appendix 1).
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1.2. Risk Analysis and Management:

In order to provide optimal security, minimisation of risks shall address all
relevant aspects including those in relation to:
- Animals (species see 2.2 and appendices 2 and 4).
- Sourcing (including geographical origin see 2.2, 2.3 and appendix 4).
- Nature of starting material used.
- Methods used to remove and/or inactivate viruses or transmissible agents.
- Quantities of animal starting material required to produce one unit of the
medical device.
- Quantities of material of animal origin coming into contact with the
patients and users
- Route of administration.
These aspects are interrelated and all of them shall be considered during risk
analysis. The risk management strategy will be a combination of measures related
to some or all of these aspects (see 1.3).
The chosen approach shall be justified in the documentation submitted to a
Notified Body and be explicitly addressed in the overall risk analysis and
management.
1.3. Harmonised Standards:

Drafts of harmonised standards addressing the use of animal materials (see
definition of animal in Appendix 2) in medical devices are available:
pr EN 12442 Animal tissues and their derivatives utilised in the manufacture of

medical devices -
Part 1: Analysis and management of risk
Part 2: Controls on sourcing, collection and handling
Part 3: Validation of the elimination and/or inactivation of viruses and
transmissible agents (see definition of transmissible agents in
appendix 2).
These documents shall be utilised when performing an assessment of medical

devices containing materials of animal origin. Notified Bodies shall apply the
principles described in these documents as the basis for their assessment
methodology. If a manufacturer chooses to follow a different approach, its
relevance and adequacy in achieving an adequate level of safety has to be
demonstrated.
Other guidance documents and standards are available from national, European
and international sources, which may provide useful background information.
Currently available documents are detailed in the bibliography.
The following standards address the essential requirements 8.1 and 8.2:
1.3.1 pr EN 12442-1: Animal tissues and their derivatives utilised in the

manufacture of medical devices - Part 1: Analysis and management of risk
(see appendix 2)
This standard provides requirements and guidance on:
- 5/15 -
Definitions: Transmissible agents has been defined in
prEN 12442-1. This term is equivalent to Transferable agents
used in section 8.2 of Annex 1 of Directive 93/42/EEC.
Several definitions including animal, tissue, cell,
derivative, transmissible agents are provided in prEN
12442-1. The definitions provided complement those in
Directive 93/42/EEC.
Risk analysis: by providing additional requirements and guidance
to EN 1441,
Risk management: Risk management shall be implemented by
taking into account separately the risks related to viruses and
transmissible agents. After having defined the characteristics of
the product, the medical device manufacturer shall comply with
the relevant requirements of Part 2 and Part 3 of prEN 12442
cumulatively. The manufacturer shall document his rationale and
justification for any requirements considered not to be relevant
(see 2.2).
NOTE 1: For medical devices which cannot withstand an inactivation

process, without undergoing unacceptable degradation, medical
device manufacturers may rely principally on Part 2 of prEN
12442 in order to meet the requirements of this Part.
NOTE 2: When the animal species is such that manufacturers cannot fully
meet the requirements of Part 2 of prEN 12442, they should
demonstrate a level of inactivation of viruses and transmissible
agents in a validated manufacturing process, as required in Part 3
of prEN 12442, in order to meet the requirements of this Part of
prEN 12442
This part of the standard also provides a specific guidance on risk

analysis and risk management for transmissible agents.

manufacture of medical devices - Part 2: Controls on sourcing, collection
and handling (see appendices 2 and 4)
Quality system for the collection (including traceability),
Requirements or guidance on the veterinarian surveillance of the
animals and the slaughter,
Requirements or guidance to avoid further cross-contamination
during dissection, storage and transport.
This part of the standard also provides a specific Annex for

additional requirements relating to bovine sourced materials.
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manufacture of medical devices - Part 3: Validation of the elimination and/or
inactivation of viruses and transmissible agents (see appendix 3).
Quality system for the inactivation/elimination studies,
Requirements or guidance to assess that inactivation/elimination
studies' parameters are equivalent to those of the manufacturing
process,
Requirements or guidance to design and perform
inactivation/elimination studies,
Requirements or guidance on the role of literature search.
1.4. Additional relevant Decisions and Opinions:

Particular attention is drawn to the Decisions taken at Community level in
relation to the restriction of use of defined material from animal origin for the
manufacture of medical devices.
The concept of level of infectivity in relation to the nature of tissues, and the
concept of incidence are currently in evolution. In bibliography, the latest
available versions of such concepts at the moment of issuance of the present
document are referenced.
The manufacturer of medical devices shall not involve the use of high
infectivity tissues1 taking also into account the origin of the animal and other
relevant parameters (see bibliography), unless the use of such tissues may under
exceptional circumstances be justified, taking into account the benefit for the
patient and the absence of adequate therapeutic alternative.
The Scientific Steering Committee2 has adopted an opinion on the safety of

gelatine dated 26-27 March 1998 (see bibliography).
The Scientific Steering Committee has also adopted an opinion on the safety of
tallow derived from ruminant tissues, dated 26-27 March 1998 (see
bibliography).
The Scientific Steering Committee has also adopted an opinion on BSE risk,
dated 26-27 March 1998 (see bibliography).
The Scientific Steering Committee has also adopted an opinion on the definition
of BSE risk for specified geographical areas, dated 23 January 1998 (see
bibliography).
The Scientific Committee on Medicinal Products and Medical Devices has also
adopted an opinion on the equivalency of alternative products to intestines of
1
The definition of such tissues is provided in World Health Organization report as Category I.
2
The web site of the Scientific Committees can be consulted: http://europa.eu.int/comm/dg24 (choose
icons Consumer health protection Scientific Committees).
- 7/15 -
animal origin for use as surgical sutures, dated 16 September 1998 (see
bibliography).
The manufacturer shall duly take into account the aforementioned opinions of the
Scientific Committee and follow further developments in this area.
2. DOCUMENTATION REQUIREMENTS
2.1 Manufacturers' documentation
Examples of documentation are laid down in prEN 12442-1, prEN 12442-2 and
prEN 12442-3.
2.2 Documentation provided to the Notified Body by manufacturers
Documentation provided to the Notified Body by manufacturers shall enable the

Notified Body to assess conformance with the requirements of the directives in
relation to the utilization of animal material.
The result of the risk analysis report3, including a rationale on the use of animal
origin material, shall be submitted to the Notified Body (e.g. see directive
93/42/EEC, annex II point 3.2.c and 4.2 or annex III point 3 as appropriate).
The following documentation shall also be provided, depending on the nature of

the material used:
Information from the risk analysis report on the origin of animal material used
(animal species, animal age, animal feeding, nature of tissue, quantity)
Statement on the presence of animal materials in the finished device and/or
utilised during manufacture.
Certificates or other documents establishing the origin of the animals,
Certificates or documents to demonstrate conformance with veterinary
inspection criteria and the nature of this inspection.
Documentation related to the slaughtering of animals, and contractual
arrangements with the abattoir.
Documentation and work instructions relating to the collection, transport and
storage of the material.
Documentation relating to controls performed on raw materials and/or final
product.
Detailed documentation describing the inactivation/elimination process and
validation of this inactivation/elimination process.
Manufacturers audit and review of sub-contractors.
Where it is not possible to provide a part of this documentation, a justification

shall be given with reference to the risk analysis.
3
The risk analysis report is described in prEN 12442-1, clause 4.9.
- 8/15 -
2.3 Specific guidance for Notified Bodies
All information contained in section 1 of the present document is relevant for

Notified Bodies activities.
Essential Requirements 8.2 requires Notified Bodies to retain information on the

geographical origin of the animals. The concept of geographical origin includes
place of birth, rearing and slaughtering. Special consideration shall be given to
the feeding practices for transmissible agent's susceptible species. The depth of
information required shall be commensurate with the risk of the material and the
reliance on sourcing as a means of risk management.
Notified Bodies are not required to hold all batch specific information, which
shall be available from the manufacturer on request. Nevertheless, the Notified
Body shall be aware of how this information is kept by the manufacturer.
The manufacturer shall inform the Notified Body of changes in the geographical
origin of animals, the incidence of BSE in a source country, sourcing, processing
and use of animal materials.
3. CONDUCT OF CONFORMITY ASSESSMENT
The Notified Body shall review the documentation (see 2.2) as part of the
assessment process (e.g. see directive 93/42/EEC).
The processes involved in sourcing control and handling and inactivation of

relevant animal materials are to be considered as special processes. Any
substantial change of the quality assurance system in relation to special processes
shall be notified to the Notified Body for the purpose of an additional approval
prior to its implementation.
Notified Bodies shall pay particular attention to verification of manufacturer's

control of raw materials, finished products and subcontractors. Notified Bodies
shall consider and document the need to audit matters relating to sourcing
including subcontractors.
4. NOTIFIED BODY'S SPECIFIC PROCEDURES AND EXPERTISE
4.1 Notified Bodies internal procedures
Notified Body shall establish and implement internal policy and procedures for
assessing medical devices manufactured from materials of animal origin.
4.2 Expertise
The Notified Body shall possess relevant knowledge in order to:

Identify the potential hazards and estimate the associated risks arising from
the use of animal materials for the manufacture of medical devices,
Evaluate the manufacturer's risk analysis and risk management strategy,
- 9/15 -
Evaluate information provided by the manufacturer including information
referred to in section 2.2,
Interpret the results of any elimination and/or inactivation study and/or
literature search.
This knowledge shall reside within the Notified Body, which may be
supplemented by external experts. Such external experts shall have a sufficient in
depth and up to date knowledge in the field concerned.
The Notified Body shall maintain awareness of legislation relevant to a particular

application and of the incidence of animal disease in sourced countries.
5. BIBLIOGRAPHY
- Council Directive 93/42/EEC of 14 June 1993 concerning medical devices

(Official Journal of European Communities No. L 169/L)
- Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws
of the Member States relating to active implantable medical devices (Official
Journal of European Communities No. L 189/17)
- pr EN 12442-1 : Animal tissues and their derivatives utilized in the manufacture
of medical devices - Part 1 : Analysis and management of risk.
of medical devices - Part 2 : Controls on sourcing, collection and handling.
of medical devices - Part 3 : Validating of the elimination and/or inactivation of
viruses and transmissible agents.
- European guideline CPMP/BWP/268/95, FINAL version 2 Note for guidance on
virus validation studies: the design, contribution and interpretation of studies
validating the inactivation and removal of viruses.
- Notification on the marketing authorization and registration of drugs, Measures to
avert risks associated with drugs, stage II, of March 28, 1996 of the
Bundesinstitut fr Arzneimittel, Germany (BfArM).
- Guidelines for minimizing the risk of transmission of agents causing spongiform
encephalopathies via medicinal products - III/3298/91 - EN FINAL.
- Note for Guidance for minimising the risk of transmitting animal Spongiform
Encephalopathy Agents via medicinal products - EMEA - CPMP/BWP/877/96 -
draft of October 1997
- Commission decision 98/256/EC, Official Journal no. L113, 15.4.1998, p. 32
- Opinion of the Scientific Steering Committee on the safety of meat and bone
meal from mammalian animals naturally or experimentally susceptible to
transmissible spongiform encephalopathies (March 1998).
- Listing of Specified Risk Materials: a scheme for assessing relative risks to man.
- Opinion on BSE risk adopted by the Scientific Steering Committee at its plenary
meeting of 26-27 March 1998, following a public consultation on the preliminary
opinion adopted on 19-20 February 1998.
- Opinion on the Safety of Gelatine adopted at the Scientific Steering Committee at
its plenary meeting of 26-27 March 1998 following a public consultation on the
preliminary opinion adopted on 19-20 February 1998 (Version updated on
3.04.1998) Background
- Opinion on the Safety of tallow derived from ruminant tissues Background
- 10/15 -
- Opinion & report on the equivalency of alternative products to intestines of
animal origin for use as surgical sutures adopted by the Scientific Committee on
Medicinal Products and Medical Devices on 16 September 1998.
- Opinion of the Scientific Steering Committee on defining the BSE risk for
specified geographical areas 23 January 1998
- 11/15 -
APPENDIX 1
Essential Requirements Of Directive 93/42/Eec Relating To Infection And Microbial

Contamination
=======================================
8.1. The devices and manufacturing processes must be designed in such a way as to
eliminate or reduce as far as possible the risk of infection to the patient, user and
third parties. The design must allow easy handling and, where necessary,
minimize contamination of the device by the patient or vice versa during use.
8.2. Tissues of animal origin must originate from animals that have been subjected to
veterinary controls and surveillance adapted to the intended use of the tissues.
Notified Bodies shall retain information on the geographical origin of the

animals.
Processing, preservation, testing and handling of tissues, cells and substances of

animal origin must be carried out so as to provide optimal security. In particular
safety with regard to viruses and other transferable agents must be addressed by
implementation of validated methods of elimination or viral inactivation in the
course of the manufacturing process.
Essential requirements of Directive 93/42/EEC relating to labelling:
2. - inform users of the residual risks due to any shortcomings of the protection
measures adopted.
13.3.k any warnings and/or precautions to take
13.6.e where appropriate, information to avoid certain risks in connection with

implantation of the device
- 12/15 -
APPENDIX 2
Definitions and requirements for sourcing from

Pren 12442-1 + pren 12442-2 (extracts)
==================
Definition of animal from pr EN 12442-1:

All vertebrates including fish, amphibians, reptiles, birds and mammals, excluding
humans (Homo sapiens).
Definition of Transmissible agents from pr EN 12442-1:

Unclassified pathogenic entities, prions and similar entities.
Note: e.g. BSE agent, scrapie agent.
Requirements on sourcing from pr EN 12442-2:
6 Sourcing of animal materials: Inspection, certification and traceability
6.1 Sourcing of animal material shall where technically practicable be subject to control and
individual inspection by a veterinarian. There will however be some source species where this
is not possible (e.g. fish). If individual animals cannot be inspected, the justification for this
shall be documented and a relevant sampling plan provided. To minimize the potential risk of
the causative agents of spongiform encephalopathies in medical devices the requirements of
normative Annex A shall be applied to relevant animal species.
6.2 Material of animal origin intended for utilization in medical devices shall have
originated from animals confirmed by a veterinarian as being fit for human consumption. For
species not usually consumed by humans a status equivalent to fit for human consumption is
required. Records to demonstrate conformance with veterinary inspection criteria at the
abattoir, certificate details and source shall be available.
NOTE: Animals should be subject to ante-mortem veterinary inspection. Prior to

certification, a post-mortem inspection should be performed immediately after slaughter
and should include:
a) visual inspection;
b) palpation of specified organs;
c) incision of organs and lymph nodes;
d) investigation of anomalies, for example inconsistency, colour, and smell;
e) if necessary laboratory tests.
6.4 Depending on the source species of the tissues used, the perceived risk from pathogens,
and the ability to obtain appropriate assurances, it may be necessary to specify the origin of the
animals (such as place of birth; country, region or farm of rearing; and place of slaughter) and to
obtain additional assurances on their state of health and system of management (see Part 1 of
EN 12442). (For bovine species, see Annex A).
NOTE: When official information systems are in place, animals should be individually
traceable, where the results of the risk analysis indicate that this is necessary.
- 13/15 -
APPENDIX 3
Requirements On Literature Search From Pr En 12442-3

==========================================
5 Literature search
5.1 Conduct of the literature search

A literature search shall be performed as specified in Annex A, to identify and analyse
data on the elimination and/or inactivation of viruses and transmissible agents (see C.2).
5.2 Application of literature search output

Technical information from the literature search shall be used in optimising the design of
an inactivation and/or elimination study.
Any extrapolation based on the inactivation of viruses and transmissible agents shall be
justified and documented.
Intrinsic variability of materials of animal origin utilised in medical devices and of

manufacturing processes can lead to misinterpretation of the validity of published data
and shall be taken into account.
5.3 Viruses
The manufacturer shall demonstrate whether the literature search provides an indication
of which inactivation and/or elimination steps are likely to be effective and is a
prerequisite to performing a viral inactivation study. In exceptional cases, if a
manufacturer chooses not to perform a study this shall be justified and documented.
5.4 Transmissible agents

The manufacturer shall demonstrate whether the literature search provides an indication
of which methods are likely to be effective in the elimination and/or inactivation of
transmissible agents. In particular it shall be demonstrated that the specific materials of
animal origin and the specific processes referred to in the literature are comparable to
those used for the medical devices concerned. Where the materials or processes are not
comparable, an inactivation study shall be performed.
If the available information does not support the elimination and/or inactivation of
transmissible agents, then an alternative risk management strategy shall be implemented
(see EN 12442-1).
- 14/15 -
APPENDIX 4
Requirements And Guidance On Bse/Tse Risks In Pr En 12442-2

==========================================
Annex A of prEN 12442-2 stipulates
Additional requirements relating to the application of Part 2 of EN 12442 for bovine sourced
materials
NOTE 1: Taking into account the current state of science and technology, similar
principles to those discussed in this annex should also be applicable to other
transmissible spongiform encephalopathies in animals.
NOTE 2: The agent that causes BSE presents a hazard to humans. Experimentally it has
been shown that sheep and goats are susceptible to the BSE agent via the oral route
The risk from the hazard of BSE will vary with the incidence of BSE in cattle, which
will depend on the measures taken by government competent authorities to prevent,
control or eradicate the disease. Determination of incidence of disease depends on the
extent and quality of surveillance measures. The best guarantees can be given when the
results of effective surveillance show that neither BSE nor scrapie exists in a country,
region, herd or flock.
A.1 General aspects
Assurance on BSE incidence shall be verified using the latest information from OIE (Office
International des Epizooties, Paris) and FAO (Food and Agricultural Organization, Rome),
taking into account the most recent information from relevant government competent
authorities. The manufacturer shall assess the incidence and trend using at least the last 3 years
data and preferably the last 5 years data.
NOTE: The aim is to source all tissues from countries which present little or no
risk. It is acknowledged that this may not always be achievable. The highest risk will
be represented by high risk tissues (e.g. brain, spinal cord and eye) derived from
countries of high incidence. Whether or not a risk is unacceptably high will depend on
the use to which the tissue is put. Risk analysis and risk management are addressed in
Part 1 of EN 12442.
The use of tissues of bovine origin shall take into account the following factors:
a) the BSE status of the country, the herd(s) or origin of the animals and the breeding
history (maternal line) (see also Annex A.2);
NOTE:Factors involved in the BSE status of a country include:

i) the incidence of disease in the country,
ii) whether or not there is compulsory notification of disease (official veterinary
surveillance),
iii) whether there is compulsory clinical and laboratory verification of suspected
cases.
- 15/15 -
b) the age of the donor animals; and the nature of tissues used (see Annex E of Part 1 of
EN 12442);
NOTE: As clinical BSE has not been diagnosed in young animals (less than 20
months), sourcing from animals particularly under 6 months of age gives an
additional level of safety.
c) whether or not the tissues will be pooled or derived from single animals, and
d) feeding history (A.3).
A higher level of risk shall be assumed if a collected tissue cannot comply with the above
criteria.
pr EN 12 442-2 is defining a low risk herd

Low risk herd (closed herd): a herd in which for at least the previous six years:
a) there has been documented veterinary monitoring;

b) there has been no case of BSE;
c) there has been no feeding of mammalian-derived protein;
d) there is a fully documented breeding history;
e) each animal is traceable, and
f) genetic material has been introduced only from herds with the same BSE-free
status.
NOTE: Attention is drawn to possible future regulatory definition of this term
---------((()))---------
EUROPEAN COMMISSION
ENTERPRISE DIRECTORATE-GENERAL
Single Market : regulatory environment, standardisation and New Approach

Pressure equipment, medical devices, metrology
MEDDEV. 2.5/9 rev.1

February 2004
GUIDELINES ON MEDICAL DEVICES
IMPLICATIONS OF THE MEDICAL DEVICES DIRECTIVES (93/42/EEC)

IN RELATION TO MEDICAL DEVICES CONTAINING NATURAL
RUBBER LATEX:
A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES
Note
The present Guidelines are part of a set of Guidelines relating to questions of

application of EC-Directives on medical devices. They are legally not binding.
The Guidelines have been carefully drafted through a process of intensive
consultation of the various interest parties (competent authorities,
Commission services, industries, other interested parties) during which
intermediate drafts were circulated and comments were taken up in the
document. Therefore, this document reflects positions taken by
representatives of interest parties in the medical devices sector.
1
Background and Scope
Due to the combination of its superior barrier qualities, strength, flexibility and
comfort, natural rubber latex (NRL) has been increasingly used in a variety of medical
devices. In particular, the properties of NRL make it a preferred material for medical
gloves. The clinical use of latex gloves has increased considerably during the last 20
years, due mainly to escalating risks associated with blood-borne infectious agents.
The main function of these gloves is to create a protective barrier between the patient
and health care worker and also to facilitate general hand hygiene.
In response to the growing apprehension surrounding medical devices containing

NRL, the Directorate General for Enterprise of the European Commission presented
questions to the Scientific Committee on Medicinal Products and Medical Devices
(SCMPMD). The committee prepared an opinion in June 2000 based on information
available from scientific literature and various public reports. The Commissions
Medical Devices Experts Group subsequently set up a Working Group on Natural
Rubber Latex, composed of representatives from the Member States, to consider and
discuss the SCMPMD opinion and explore the possibilities for minimising problems
relating to the use of NRL in medical devices. After hearing representations from
industry and users, the Working Group was satisfied that the Medical Devices
Directive contained adequate provisions to ensure the safety of healthcare workers
and patients exposed to NRL medical devices. However, the Working Group was
concerned that the interpretation of the Directive in terms of the risk control measures
applicable to NRL-containing products appeared to be in some doubt. A guidance
document was therefore considered necessary to clarify the implications of the
relevant Essential Requirements.
To meet this objective, the Working Group felt it necessary to identify, in this
document, the hazards and exposures associated with NRL, and discuss the effects of
the limitations in the current state of the art. The document is based on the principle
that the appropriate way to manage the risks arising from NRL is to reduce allergenic
protein levels to a level as low as reasonably practicable and provide warnings about
the residual risks.
This document therefore provides guidance for manufacturers, Notified Bodies and
Competent Authorities on the interpretation of the Essential Requirements of the
Medical Devices Directive, as they relate to the risk of allergy to natural rubber latex
(NRL). The risk control measures recommended in this document do not apply to
devices made from other materials. However, similar measures, commensurate with
the degree of risk, may be applicable to control risks arising from other materials
presenting hazards of a similar nature (for example dry natural rubber (DNR)).
2
The Medical Devices Directive
As with all products which meet the definition of a medical device (as detailed in
Article 1 of the Medical Devices Directive 93/42/EEC) NRL-containing medical
devices (i.e. examination and surgeons gloves, condoms, catheters, etc.) must meet
certain conditions as specified by the relevant Essential Requirements under Annex 1
of the Directive. This represents the minimum standard a manufacturer is expected to
demonstrate when claiming conformity of a product with the Directive.
Due to the nature of the concerns raised about NRL (i.e. the inherent biological
hazards), those Essential Requirements that relate to biological safety are of particular
relevance to this guidance document. The Essential Requirements that are most
relevant to this situation are 1, 2, 6, 7.1, 7.2, 7.5 and 13. Toxicological risks need to
be assessed through an expert scientific assessment that takes into account the extent,
relevance and quality of the available data (such as that provided by the SCMPMD in
relation to allergenic risks). The conclusions from the scientific assessment, and the
level of confidence in it, are used to determine appropriate control measures to ensure
the safety of those exposed to the toxic hazards identified. EN/ISO10993-17 provides
a method of determination of acceptable levels of exposure relevant to toxic
substances that can leach out of medical devices.
In determining whether a product meets these Essential Requirements, it is necessary

to balance the risks arising from the biological hazards known to be associated with
NRL against the benefits attributed to the use of NRL, particularly in respect of
effectiveness as a barrier to infection. EN/ISO 14971 specifies an appropriate process
for judging of the acceptability of risk.
Essential Requirement 2 indicates that the first priority is the elimination of risk. It is
recognised, however, that no medical procedure is without risk and it is inevitable that
some risk must be accepted in the interests of improving the health or prognosis of the
patient. In practice, the elimination, or minimisation of risk is taken to mean that the
risk can be considered to be so low that there is no need to bother about it. Such
risks are termed broadly acceptable (see Annex E of EN/ISO 14971)
If it is impossible to implement controls that ensure that a risk is broadly acceptable,

the Medical Devices Directive requires that the risk must be reduced as far as
possible. In such cases it is necessary to implement risk control measures to ensure
that the risk is reduced to a level as low as reasonably practicable (ALARP). That
is to say the risk is placed in the ALARP region of the chart in Annex E of EN/ISO
14971. The ALARP concept recognises that exposure to an appreciable degree of risk
is inherent in the use of many medical devices. The expectation is that the risk should
be reduced to the lowest practical level, bearing in mind the practicality of any further
risk reduction, the benefits arising from the use of the product and the state of the art.
Because the state of the art is a moving target and the Essential Requirements
preferred option of broadly acceptable risk is not yet achieved, risk control
measures need to be reviewed regularly. Changes in the state of the art could lower
the ALARP levels.
3
For risks in the ALARP region, assessments of risks, benefits and the feasibility of
risk control are indispensable components of the conformity assessment process. A
manufacturer has to determine what risk control measures can reasonably be adopted
to achieve the optimum balance of risks and benefits. Any risk remaining after all
applicable risk control measures have been taken is termed the residual risk. The
residual risk must be outweighed by benefits.
The manufacturer has a responsibility to communicate effectively with users to inform

them about residual risks to allow them to manage these risks effectively. Therefore it
is necessary to include appropriate warnings in the documents accompanying the
product. This may include the provision of specific advice to users and healthcare
managers on any measures that should be taken to mitigate the risk. Users may take
risk control measures in addition to those advised by the manufacturer, such as the
establishment of local policies on the purchase and use of NRL-containing products,
however this aspect of risk management lies outside the scope of the Medical Devices
Directive.
Hazard identification
Allergy to natural rubber latex
Various studies have verified that immediate (Type I) hypersensitivity to NRL

appears to be caused by certain naturally occurring soluble allergenic proteins found
in latex. Reported symptoms encountered range from mild wheal and flare reactions
to gloves, to fatal anaphylaxis from latex balloons used with barium enema
examinations. The identity of most of the clinically relevant allergenic proteins in
NRL (both major and minor allergens) now appears to have been established, and
there has been a progressive decline of glove allergen content. Although the
manufacturing process includes washing phases for the removal of excess proteins
and chemicals, residues of proteins and chemicals remain in the material. More
complete removal of latex proteins from NRL-containing products manufactured
using current technology may adversely effect their properties, such as elasticity,
tensile strength and barrier function.
The prevalence of NRL sensitisation varies between the different populations that
have been studied. Principal risk groups for NRL allergy include atopic individuals,
patients with hand dermatitis and atopic children, especially those with food allergy.
Among health care workers the reported prevalence rates range from 2.7% to 15% in
most studies, depending on the methods used for diagnosis and on the allergenicity of
the latex gloves used, although studies do not always distinguish between those who
are positive in skin prick testing and those with clinical allergy. NRL allergy has been
described in several other occupations in which protective gloves are used (e.g.
housekeeping personnel, hairdressers, greenhouse workers and workers in textile
factories). The frequency of Type I NRL allergy in the general population, based on
skin prick testing and stringent diagnostic criteria, is relatively low, clearly under 1%.
There is evidence suggesting that latex devices with low levels of leachable allergenic
protein do not induce sensitisation.
4
The use of powder in latex gloves
The use of modified cornstarch powder as a glove donning / manufacturing aid has
also been the subject of particular anxiety in recent years. Latex proteins bind to
cornstarch powder particles in gloves and the powder can thus act as a carrier of the
allergen. The dust aerosol that can be created when donning and removing powdered
gloves may increase the risk of allergic reactions because uptake, via the lungs, by
people in the vicinity represents an additional route of exposure. Case reports had
been published to indicate that this sort of exposure may provoke allergic symptoms
(asthma, rhinoconjunctivitis, urticaria, anaphylaxis) in latex sensitised individuals.
However, the SCMPMD1 reported that there has been no conclusive scientific study
to indicate that the use of powdered latex gloves increases the frequency or rate of
sensitisation when compared to powder-free gloves, so long as the powdered glove
has an equivalent total extractable allergenic protein concentration. Thus, the extent to
which powder can play a role in allergic reactions is limited to its activity as an
airborne carrier of allergens.
Concerns have been expressed regarding the use of powdered gloves in surgical
operations and the formation of adhesions or starch granuloma, however a causative
relationship has not been firmly established.
NRL additives
A wide range of hazardous processing chemicals is used during the manufacture of

NRL products. These include accelerators such as thiurams, carbamates and
mercaptobenzothiazoles, which are known contact sensitisers posing a risk for the
development of Type IV allergic contact dermatitis. Currently only one study is
available ranking the relative hazard potential of these chemicals.
Quantification of chemicals present in latex medical devices and determination of

their bioavailability are problematic. The composition of the final product is highly
dependent on the initial ingredients, which fluctuates more than with synthetic
polymers, and the chemical reactions and leaching that occurs during processing. The
uptake of chemical residues by the skin or tissues is dependent on the
physicochemical properties of the substances and the conditions of use of the devices.
For example, chemical uptake via mucosal membrane exposure such as for condoms,
is likely to exceed that of exposure of an equal concentration to intact skin. However,
regardless of these variables, a reduction in the amount of chemical residues in rubber
products has been shown to also result in a reduction in the bioavailable amounts of
chemicals and in the Type IV sensitising capacity of the material.
The risk of Type IV allergic contact dermatitis is not confined to NRL products; the
currently available synthetic alternatives may pose a similar risk, depending on the
chemicals used for their production.
1
European Commission Scientific Committee on Medicinal Products and Medical Devices
(SCMPMD); Opinion on Natural Rubber Latex Allergy; Adopted 27 June, 2000.
Doc.SANCO/SCMPMD/2000/0009 Final
5
Exposure Assessment
Exposure to NRL may come from dermal (cutaneous) or mucous membrane contact.
The latter includes inhalation, and genito-urinary tract exposure (e.g. from condoms,
wound drains, tracheostomy tubes, balloons used in barium enema examinations and
urinary catheters). Direct tissue or intra-vascular exposure also occurs via an open
surgical wound through the use of surgeons gloves and containers of injectable
materials.
Exposure to allergenic proteins
The risk of sensitisation or allergic reaction to NRL can be reduced by minimising the
amount of leachable allergenic protein to which a subject is exposed. A distinction
should be made, however, between the prevention of sensitisation and the prevention
of allergenic reactions in those individuals already sensitised to latex allergenic
proteins. Once a person is sensitised to NRL, any subsequent exposure to latex may
trigger an allergic reaction. It is not currently possible to establish a threshold level of
exposure for sensitisation, but it is generally understood that greater exposure is
required to sensitise an individual than to elicit a response in a sensitised individual.
Studies have shown that latex gloves with a low leachable protein content elicit a
lower percentage of positive responses in latex sensitised individuals than gloves with
higher protein residues. However, the correlation between protein content and
allergen content is not strong enough to justify selection of low allergen gloves on the
basis of leachable protein content. Nevertheless, it can be expected that lower levels
of leachable protein will also result in a lower prevalence of induction of sensitisation.
A precise indication of an individuals susceptibility to latex allergy is difficult to

achieve. One standardised extract for skin prick testing is available in Europe and
Canada, but not in the U.S. Extracts of latex materials (e.g. gloves) can be useful but
are far from standardised and can only provide information on allergenic proteins or
allergens present in a particular extract from a particular product.
Considerable progress has been made in the identification and characterisation of

latex allergens, indicated by the fact that 15 allergens had received WHO/IUIS
Allergen Nomenclature designation by August 20022. Exposure assessment is,
however, hampered by the lack of validated methods for their direct detection. While
direct allergen measurement would be the preferred option, specific assays currently
available are waiting for international validation. Since a relationship between
leachable protein levels and the risk of allergic reaction or sensitisation has been
demonstrated in several studies, leachable protein levels are currently used as a
surrogate for allergen exposure. Two methods, the modified Lowry and an amino
acid analysis, both measuring total extractable protein, have been described and
standardized for some types of products, making the comparison between alternative
brands of products possible. However, neither of these methods distinguishes between
sensitising and non-sensitising proteins.
Although some European laboratories may produce rather consistent results in their
modified Lowry tests, experience from many round-robin tests performed in high-
2
www.allergen.org
6
standard laboratories both in the US and in Europe has revealed serious problems in
the reproducibility of the results.
Immunoassays based on the use of human IgE antibodies recognising specific NRL
allergens have been developed and used in a limited scale to measure total allergen
contents of latex gloves and other NRL devices. The major drawback in such assays
is the limited availability of proper human sera and problems in standardisation.
Specific tests for measuring individual latex allergens in medical devices have
recently been developed and are currently under international evaluation. Interim
recommendations now are thus not well grounded.
Exposure to powder
A standardised technique for the determination of the powder content of medical

gloves is available. Relevant standards require that surgeons gloves carry labelling
advising users that powder must be removed by washing prior to use. Some studies
have questioned the effectiveness of such washing.
Exposure to chemical residues
Several techniques are available for the detection of the chemicals present in latex
products such as medical gloves. Although these methods allow the identification of
the chemicals present in NRL products, this does not mean that these chemicals are
also bioavailable for the induction of allergy or the elicitation of a response. Cross
reactivity can occur between various chemicals and mixtures of chemicals may also
be present. There seems to be no agreement on the best applicable method of analysis.
In vitro tests that measure clinically relevant, bioavailable residues of rubber

chemicals in the products are not yet available.
Risk Estimation and Evaluation

Extractable Protein
Studies that suggest a correlation between the presence of leachable protein in NRL
gloves and the risk of allergic reaction or sensitisation lead to the conclusion that
reducing the amount of available leachable protein can reduce the risk. Determination
of a leachable protein level that represents an acceptable risk is problematic, however,
because of the significant uncertainties that limit the extent to which this risk can be
analysed.
While the SCMPMD was able to reach clear conclusions on a number of important
issues relevant to the management of risks arising from medical devices manufactured
from NRL, the number of good quality scientific studies relevant to the current
situation across the EU is limited. Moreover, exposure assessments are inaccurate
because analytical methods available today do not differentiate between allergenic
7
and non-allergenic proteins, but detect the amount of total protein instead. As a result,
the risk of sensitisation or elicitation arising from contact with NRL-containing
products cannot be estimated with any confidence.
Even if a more meaningful risk estimate were possible, limits for elicitation and
sensitisation are likely to be close to or below the quantification limits of the protein
assays currently available, so the protein level cannot be used to define a level of
exposure that could be deemed safe with a realistic margin of safety.
In addition to the lack of a sufficiently sensitive analysis method, it is recognised that
there is currently no toxicological method available to identify a threshold for either
of these endpoints. One implication of this is that terms implying minimal allergenic
risk (e.g. hypoallergenic) are inappropriate.
Because the probability of harm occurring at low levels of exposure cannot be

estimated on the basis of scientific data, the risk to patients or users cannot be
estimated. For a significant hazard, such as sensitisation, no level of exposure can
therefore be determined that corresponds to a broadly acceptable risk. Elimination of
the risk (in line with the primary expectation of the first bullet point of Essential
Requirement 2) is thus not possible.
For the above reasons, the rationale behind various proposed limits is subject to strong
criticism: biologically significant amounts of relevant allergens may be overlooked
and, on the other hand, the amounts of irrelevant non-allergenic proteins may exceed
any selected upper limits. Under these circumstances it is inappropriate to set an
allowable limit for leachable protein content in medical devices containing NRL.
Failing the implementation of controls that ensure a broadly acceptable risk, it is

necessary to reduce the allergic risk arising from NRL to a level as low as is
reasonably practicable (ALARP) and consider the presence of protein residues to be a
residual risk.
For medical gloves containing NRL, both their effectiveness as a barrier to infection
and the cost of their production have public health implications that are relevant to the
risk:benefit assessment. Efforts to reduce the leachable protein content of NRL gloves
must therefore be balanced against any reduction in properties of the product that are
critical to their function and any financial implications that have an impact upon the
preservation, promotion or improvement of human health.
Starch Powder
While powder-free products exist for which acceptable performance is claimed, it

does not necessarily follow that these are appropriate for all uses. It is important to
recognise that both risks and benefits can vary appreciably with the intended use of a
product. This is particularly so in the case of powdered medical gloves, where risks
and benefits need to be considered in relation their use in surgical intervention and
non-invasive procedures.
The use of powder does not increase the allergenicity of the gloves, but allows
airborne exposure to the allergen. Thus, there is an additional risk of reactions to
8
respiratory exposure in sensitised individuals. However the population at risk is the
same as that at risk of allergic reaction to NRL alone. If the content of latex allergens
in the gloves is low, the use of powdered gloves has not increased sensitisation rates,
implying that controlling the powder content of gloves provides no additional
protection to non-sensitised individuals.
The risk of adhesions or granuloma formation is relevant only to patients undergoing

surgical procedures. The SCMPMD was not asked to advise on this risk and, in the
absence of clear evidence that powder causes these complications, it is not appropriate
to introduce regulatory measures to prevent the use of powdered surgeons gloves.
However, in view of the scientific uncertainty, the presence of powder remains a
residual risk.
The presence of glove powder does not significantly affect the barrier properties of
gloves so a lack of glove powder does not itself introduce a risk to patients or users.
The benefits of glove powder lie in ease and comfort of use, which have an indirect
effect on effectiveness. User preference is therefore a significant factor in determining
the acceptability of powdered gloves. Cost and the additional environmental impact
of processes involved in producing powder-free gloves can also be important
considerations for the purchaser, which will vary with the circumstances of use. Users
need to be in a position to weigh these factors and take effective action to manage the
residual risks relating to the use of powdered gloves.
Chemical residues
Exposure to residues of chemicals added to NRL formulations or resulting from

reactions during processing should be kept below a level that could result in harm to
users or patients. For most chemicals, a level of exposure can be determined which is
considered to be without risk of appreciable harm to health. This level, termed the
tolerable intake, is determined on the basis of available toxicological and clinical
data. It incorporates a safety margin that accounts for the uncertainties inherent in
estimating potential effects in humans from the scientific data available (see EN/ISO
10993-17). The risk arising from exposure to chemicals at levels up to the tolerable
intake can be classified as broadly acceptable.
Exposure below the tolerable intake cannot be guaranteed where it is not feasible to
manufacture products with sufficiently low residue levels. Moreover, for some
chemicals (particularly sensitisers), it may not be possible to determine a tolerable
intake. In these circumstances, exposure must be reduced to a level as low as
reasonably practicable, the risk must be outweighed by benefits arising from the use
or presence of the chemical and the presence of the residue must be treated as a
residual risk.
Substituting the most potent sensitisers with less sensitising chemicals can
theoretically reduce the risk but, so far, only one dose-response study capable of
ranking sensitisers is available. The acceptability of any such risk control measure
must be judged as part of the overall risk evaluation.
9
Clinical aspects
Persons who know or suspect that they may have Type I latex allergy must avoid
contact with latex products. If they are treated in healthcare they should inform the
personnel about their allergy. Alternatives to NRL gloves are available, but these
alternatives may pose risks depending on the chemicals used during the production
process. Data on the risk associated with substitute non-latex materials is very limited.
Risk Control
Extractable Protein
Any risk control measures adopted must reflect the nature of the hazard, and should
therefore be directed towards both the risk of induction of sensitisation and the risk of
elicitation of an allergic reaction. Because of the variabilities and uncertainties
inherent in the risk estimate, it is inappropriate to stipulate risk control measures
specific to particular exposure groups. Furthermore, the nature of the risk means that
no single risk control measure can protect all of them.
As long as NRL-containing products are used, the possibility of exposure to allergenic

proteins cannot be eliminated, since the presence of these proteins is currently
essential to some of the critical properties of latex products. Nor is it possible to
determine a level of exposure that would not be expected to lead to sensitisation in
either atopic or non-atopic individuals. It is therefore not possible to reduce residues
of leachable protein in NRL products to a level that can be guaranteed either to induce
sensitisation or to elicit a reaction in sensitised individuals. Controlling leachable
protein levels is thus not a quantifiable option for the control of risks to these groups
and the only viable risk minimisation measure is avoidance of exposure wherever
possible.
Non-latex alternatives are available for some products such as medical gloves and
condoms. However, where exposure avoidance is not possible, lowering leachable
protein levels to as low as reasonably practicable (ALARP) is indicated because the
lower the bio-available allergenic protein level, the lower the risk for inducing
sensitisation and eliciting reactions. To decide what protein level is acceptable in any
particular case, it is necessary to take account of the generally accepted state of the art
and balance protein content against technological and financial factors relevant to the
supply of products that meet users needs. The state of the art in this respect has
shifted considerably in recent years, resulting in a gradual reduction in leachable
protein levels. Future technological developments may allow further reductions in
protein levels without adversely affecting product quality or increasing production
costs, in which case further reductions would be prudent. Until then, pressure for
further reduction in residue levels can only come from evidence indicating that levels
of protein currently found in medical products present a problem. Such evidence is
limited at present.
A number of risk control measures are considered necessary, including measures to

ensure that exposure to allergenic protein is maintained below an acceptable level.
10
For any medical device containing NRL, the technical documentation needs to
contain:
a technical justification, including reference to supporting data, for the use
of NRL;
an indication of the allergen content, determined and reported in line with
the state of the art3. (Such information to be made available to users on
request).
a technical justification for the measured level of allergen, indicating how
this conforms to the ALARP (as low as reasonably practicable)
principle.
Since the risk to non-sensitised, sensitised or atopic individuals cannot be eliminated

from the product, this must be treated as a residual risk. Product labelling should
thus include a warning about the presence of NRL.
For any medical device containing NRL, the product labelling needs to include:
a prominent indication, on the products primary packaging, that the
device contains natural rubber latex;
a warning that the product may elicit allergic responses in individuals who
are sensitised to latex;
Warnings on product labelling need to convey an accurate estimate of the risk. For
the vast majority of NRL products, it is not possible to establish relative allergenicity,
so any labelling claims suggesting a lower than usual level of risk cannot be justified.
Similarly, it is important that only those devices with an appreciable NRL content are
labelled as such. Labelling a device with a statement such as may contain natural
rubber latex simply because the possibility of contamination with small amounts of
NRL cannot be excluded, would lead to devices being withheld unnecessarily from
sensitised patients or users. Such warnings should not be applied unless they are
justified.
For any medical device, the product labelling may not include:
any term suggesting relative safety, such as low allergenicity,
hypoallergenic or low protein;
any unjustified indication of the presence of allergens
Unfortunately, there is no standardised definition by which NRL-free products can be

distinguished from those containing NRL. The European Standards Committee is
3
The state of the art for the measurement of allergens will be reflected in the appropriate harmonised
European Standard when it becomes available. Meanwhile the current harmonised standard specifies a
method for measuring a broad approximation for the allergen content, i.e. total leachable protein. There
is no direct correlation between total leachable protein and allergen content. A commercially available
quantitative method to measure allergenic NRL proteins is in the process of validation. Until the
validation results are available, allergen levels should be estimated by currently available state of the
art methods.
11
therefore requested to clarify the distinction between products containing NRL and
those that can be designated NRL-free, and to define symbols for NRL-containing and
NRL-free devices.
Glove Powder
A control limit has been established by ISO for the designation of powder-free gloves
(2 g/glove). The implementation of labelling requirements in conjunction with this
definition is an appropriate risk control measure. There is no case for introducing
further controls on the powder content of gloves, since users can mitigate the residual
risk effectively, providing they have access to appropriate information on the risks
and benefits of powdered gloves.
For any medical glove, the technical documentation needs to contain:

data verifying that any glove labelled powder-free conforms to an
appropriate standard.
For any medical glove, the product labelling needs to include:

a prominent indication of whether the glove is powdered or powder-free.
For sterile powdered gloves, the product labelling needs to include:

a warning about the need to minimise tissue exposure to powder residues.
Chemical residues
Control measures are needed to verify that, as far as possible, exposure of users and
patients to chemicals is maintained below levels that could result in harm to health.
Where this cannot be guaranteed, the ALARP principle applies.
Wherever possible, for each hazardous chemical used or generated during NRL
processing, the technical documentation needs to include:
identification of a tolerable intake, determined on the basis of a
toxicological risk analysis;
an estimate of anticipated exposure to patients and users, to the extent
necessary to verify that the tolerable intake will not be exceeded.
identification of process control limits or quality control measures,
sufficient to verify that exposure will not exceed the tolerable intake.
Where the above is not possible, the technical documentation needs to include:
a technical justification for not being able to apply the risk control
measures described above;
data providing confirmation that the total residues level is as low as
reasonably practicable;
12
an evidence-based assessment indicating the level of risk from the residues
is broadly acceptable (for example via finished product testing);
a technical justification for the method chosen to demonstrate acceptable
risk;
identification of process control limits, determined on the basis of the risk
assessment, and corresponding quality control measures;
Clinical aspects
In order to manage the residual risks associated with NRL products effectively, users
need to be adequately informed about the nature of the risks and applicable risk
control options. To facilitate effective control of residual risks by healthcare
providers, it is desirable that healthcare establishments implement appropriate
management policies relevant to purchasing and the provision of treatment to
sensitised patients or by sensitised users. Member states are therefore invited to
consider measures for the provision of information on the risks and benefits of NRL-
containing medical devices (including those related to allergenic protein, residual
chemicals and glove powder) to healthcare providers to assist their management of
residual risks.
13
Annex 1 : Necessary Risk Control Measures
For any medical device containing NRL, the technical documentation needs to
contain:
a technical justification, including reference to supporting data, for the use of
NRL;
an indication of the allergen content, determined and reported in line with the
state of the art4. (Such information to be made available to users on request).
a technical justification for the measured level of allergen, indicating how this
conforms to the ALARP (as low as reasonably practicable) principle.
For any medical device containing NRL, the product labelling needs to include:
a prominent indication, on the products primary packaging, that the device
contains natural rubber latex;
a warning that the product may elicit anaphylactic responses in individuals
who are allergic to latex;
For any medical device, the product labelling may not include:
any term suggesting relative safety, such as low allergenicity, hypoallergenic
or low protein;
any unjustified indication of the presence of allergens
For any medical glove, the technical documentation needs to contain:

data verifying that any glove labelled powder-free conforms to an appropriate
standard;
For any medical glove, the product labelling needs to include:

a prominent indication of whether the glove is powdered or powder-free.
For sterile powdered gloves, the product labelling needs to include:

a warning about the need to minimise tissue exposure to powder residues.
Wherever possible, for each hazardous chemical used or generated during NRL
processing, the technical documentation needs to include:
identification of a tolerable intake, determined on the basis of a toxicological
risk analysis;
4
The state of the art for the measurement of allergens will be reflected in the appropriate harmonised
European Standard when it becomes available. Meanwhile the current harmonised standard specifies a
method for measuring a broad approximation for the allergen content, i.e. total leachable protein. There
is no direct correlation between total leachable protein and allergen content. A commercially available
quantitative method to measure allergenic NRL proteins is in the process of validation. Until the
validation results are available, allergen levels should be estimated by currently available state of the
art methods.
14
an estimate of anticipated exposure to patients and users, to the extent
necessary to verify that the tolerable intake will not be exceeded.
identification of process control limits or quality control measures, sufficient

to verify that exposure will not exceed the tolerable intake.
Where the above is not possible, the technical documentation needs to include:
a technical justification for not being able to apply the risk control measures
described above;
data providing confirmation that the total residue level is as low as reasonably
practicable;
an evidence-based assessment indicating that the level of risk from the
residues is broadly acceptable (for example via finished product testing);
a technical justification for the method chosen to demonstrate the acceptable
risk;
identification of process control limits, determined on the basis of the risk
assessment, and corresponding quality control measures;
The European Standards Committee is requested to clarify the distinction between

products containing NRL and those that can be designated NRL-free and to define
symbols for NRL-containing and NRL-free devices.
Member states are invited to consider measures for the provision of information on
the risks and benefits of NRL-containing medical devices (including those related to
allergenic protein, residual chemicals and glove powder) to healthcare providers to
assist their management of residual risks.
15
EUROPEAN COMMISSION
DG HEALTH & CONSUMERS
Directorate B -Consumer Affairs
Unit B2 Health technology and Cosmetics
MEDDEV 2.5/10
January 2012
GUIDELINE FOR AUTHORISED REPRESENTATIVES
EC-Directives on MEDICAL DEVICEs. They are legally not binding. The guidelines have
been carefully drafted through a process of intensive consultation of the various interested
parties (competent authorities, Commission services, industries, other interested parties)
during which intermediate drafts were circulated and comments were taken up in the
document. Therefore, this document reflects positions taken by representatives of interested
parties in the MEDICAL DEVICEs sector.
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Foreword
This guidance document is informative and advisory and has no legal authority.
Individual national enforcement authorities are bound by their own legislation and can
only apply this guidance within their confines.
Only the text of the Directives is authentic in law. The text of the Directives is
applicable where there are differences between the provisions of the Directives and
the contents of this guide. The interpretation of Community law is ultimately the
responsibility and the privilege of the European court of Justice (ECJ). Any legal
analysis set out in this guide does not in any way preclude a different interpretation
by the ECJ in a particular case, and does not in any way commit the European
Commission.
Introduction
Concern has been expressed for a number of years about the lack of clarity on the
role of an authorised representative in the three Medical Devices Directives. There
has been particular confusion because manufacturers have delegated certain
responsibilities to their authorised representatives. There has also been confusion
about what information authorised representatives could/should be able to provide.
Decision 768/2008/EC of the European Parliament and of the Council of 9 July 2008
on a common framework for the marketing of products1 and Regulation 765/2008/EC
of the European Parliament and of the Council of 9 July 2008 setting out the
requirements for accreditation and market surveillance relating to the marketing of
products2 lay down common principles across sector legislation and will eventually be
considered at the next revision of the Medical Devices Directives.
The purpose of this guideline is (a) to set out what the Directives currently say on the
role and the responsibilities of authorised representatives and (b) to set out the
Member States' expectations as to the role of the authorised representatives in terms
of market surveillance.
References made to the Medical Device Directives include the Council Directive
93/42/EEC concerning medical devices3 (MDD), the Council Directive 90/385/EEC of
20 June 1990 on the approximation of the laws of the Member States relating to
active implantable medical devices4 (AIMDD), and the Directive 98/79/EC of the
European Parliament and of the Council of 27 October 1998 on in vitro diagnostic
medical devices5 (IVDD). If appropriate, selective reference to either of these
Directives will be made.
1
Official Journal L218/82 of 13.8.2008, http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:218:0082:0128:en:PDF
2
Official Journal L218/30 of 13.8.2008, http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:218:0030:0047:en:PDF
3
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:20071011:EN:PDF
4
5
2/17
When reference is made to the EU, this is meant to include the EEA, Switzerland and
Turkey.
A. Summary of current provisions of the medical device Directives
The definition of a manufacturer in the Medical Devices Directives is:

manufacturer means the natural or legal person with responsibility for the design,
manufacture, packaging and labelling of a device before it is placed on the market
under his own name, regardless of whether these operations are carried out by that
person himself or on his behalf by a third party.
The manufacturer is responsible for his obligations under the Medical Device
Directives, not the authorised representative.
Where a manufacturer who places a device on the market under his own name does
not have a registered place of business in EU, he shall designate an authorised
representative (AIMDD Art 10a(2); MDD Art 14(2); IVDD Art 10.3). Recital 14 of
Directive 2007/47/EC clarifies: to introduce the obligation for such manufacturers to
designate an authorised representative for a device. This designation should be
effective at least for all devices of the same model. It is not the intention that this
provision restricts a manufacturer to a single authorised representative for the whole
range of his products. The manufacturer may have more than one authorised
representative as long as each device (type/model) is linked to only one authorised
representative.
For MD and IVD, the label or outer packaging or instructions for use shall contain the
name and the address of the authorised representative where the manufacturer does
not have a registered place of business in the Community (MDD Annex I Section
13.3(a); IVDD Annex I Section 8.4 (a)). For AIMD this information shall be affixed on
the sales packaging (AIMDD Annex 1 Section 14.2).
The purpose of this compulsory designation is, as expressed in Recital 16 (MDD),

Recital 14 (Directive 2007/47/EC), and Recital 29 (IVDD), that the authorities must be
able to contact a person responsible for placing the device on the market and
established in the Community, particularly in cases of emergency.
The definition of an authorised representative in the Medical Devices Directives, is:

authorised representative means any natural or legal person established in the
Community who, explicitly designated by the manufacturer, acts and may be
addressed by authorities and bodies in the Community instead of the manufacturer
with regard to the latters obligations under this directive;
The definition of an authorised representative in Regulation 765/2008/EC is as

follows:
authorised representative shall mean any natural or legal person established within
the Community who has received a written mandate from a manufacturer to act on
his behalf in relation to specified tasks with regard to the latter's obligations under the
relevant Community legislation;
The authorised representative has certain obligations as defined by the relevant

Directives, such as:
3/17
- informing the competent authorities of his registered place of business (MDD: class
I, procedure packs and custom made devices; AIMDD: custom made devices; IVDD),
and of the devices and certificates (IVDD);
- keeping certain information at the disposal of the national authorities, such as
declarations of conformity and technical documentation (AIMDD Annex II 6.1; MDD
Annex II 6.1, Annex III Section 7.3, Annex IV Section 7, Annex V Section 5.1, Annex
VI Section 5.1, Annex VII Section 2; IVDD Arts 9(7) and 10(3)).
The manufacturers may instruct his authorised representative to initiate certain

procedures provided for in the conformity assessment annexes (IVDD Art 9(6), MDD
Art 11(9), AIMD Art 9(3)).
A.1. Role of the authorised representative
A.1.1. General
As the directives do not include a detailed description of the role and obligations of
an authorised representative it will be of vital importance to both the manufacturer
and the authorised representative to set up a contract specifying the task and
authority the manufacturer will delegate to the authorised representatives, also where
the authorised representative is a daughter company of the manufacturer established
outside the EU.
The appointment of an authorised representative does not change the responsibilities

of the manufacturer. The authorised representative must be duly selected and
supervised by the manufacturer.
However, in some Member States the authorised representative will have

responsibilities directly under national law. For instance he might have the
responsibility to ensure that the appropriate conformity assessment procedure has
been carried out, that the device is properly CE marked and that information is
provided in a specified national language. Another example may be that the
authorised representative must have a vigilance system in place which is compatible
with that of the manufacturer. An authorised representative must therefore be fully
informed about the legal obligations included in the national legislation of the Member
State in which he has his residence / where devices are placed on the market.
Those national obligations should be reflected in the above mentioned contract with
the manufacturer.
Given the Authorised Representative's limited role with regard to the placing on the
market of a medical device, he cannot be held responsible for actions by the
manufacturer over which it has no control, unless national legislation specifies
otherwise.
A.1.2. Designation of an authorised representative
A manufacturer who places a medical device on the market must designate a single
authorised representative in the European Union if he does not have a registered
place of business in EU (AIMDD Art 10a(2), MDD Art 14(2)). The same request is
made by IVDD Art 10(3), though without the inclusion of the specification single.
4/17
As clarified in Recital 14 of Directive 2007/47/EC, an authorised representative must
be the single authorized representative within EU for at least all devices of the same
type. A manufacturer may have different authorized representatives for different
devices (types).
The requirement to have an authorised representative is applicable to all medical

devices placed on the Community market, where the manufacturer is based outside
of the EU.
The requirement to have an authorised representative is also applicable to devices

intended for clinical investigation (MDD, AIMDD) or performance evaluation (IVDD)
within the Community market, where the manufacturer is based outside of the EU.
A.1.3. Registration
In addition to the requirements described hereunder, there may be specific national

notification requirements, which are incumbent to the manufacturer, but which can be
delegated to the authorised representative.
MDD and AIMDD

Registration of the authorised representatives, manufacturers and devices
An authorised representatives designated for a device covered by the obligation to
notify the Competent Authorities (MDD class I, procedure packs and custom made
devices and AIMDD custom made devices) is obliged to register with the competent
authority of the member state in which he is located and to inform the Competent
Authorities of the address of the registered place of business of the manufacturer and
the description of the devices concerned (AIMDD Art 10a, MDD Art 14).
Registration of Clinical Investigations

The manufacturer or the authorised representative must notify of the intention to
carry out a clinical investigation to the Competent Authorities of the Member States in
which the investigations are to be conducted. They shall also notify when it ends and
shall make available the written report of the clinical investigation (AIMDD Art 10,
MDD Art 15). The manufacturer may delegate these tasks entirely or in part to the
authorised representative (MDD Annex VIII Section 2.2; AIMDD Annex VI Section
2.2).
IVDD
Registration of the authorised representatives, manufacturers, devices and
certificates
An authorised representative designated for a device covered by the IVDD is
required to register with the competent authority of the Member State in which he is
located and to inform the Competent Authorities of the address of the registered
place of business of the manufacturer, and to provide information related to the
devices, and to the certificates (Art 10).
Registration of performance evaluations

A manufacturer who does not have a registered place of business in a Member State
of the EU, and who wants to undertake a performance evaluation of a diagnostic
5/17
device, within these territories, must appoint an authorised representative. The
authorised representative will communicate the information on the manufacturer and
on the device to the Competent Authorities of the Member State in which he has his
registered place of business. The declaration required for devices for performance
evaluation (IVDD Annex VIII) is drawn up by the manufacturer or the authorised
representative
A.1.4. Conformity Assessment
The Directive enables a manufacturer to delegate the performance of certain

requirements of the Directive to his designated authorized representative. This
should be specifically taken on board in the contract between the manufacturer and
the authorized representative.
MDD
Art 11(8): The manufacturer may instruct his authorized representative to initiate the
procedures provided for in Annexes III, IV, VII and VIII.
- Lodge a conformity assessment application for EC type-examination (Annex III),
- Establish the declaration of conformity to the type described in the EC type-
examination certificate (EC Verification: Annex IV),
- Establish the Annex VII EC declaration of conformity, including Annex VII Section
5 in case of products placed on the market in sterile condition and Class I devices
with a measuring function,
- Establish the statement for custom-made devices (Annex VIII Section 2.1).
AIMDD
Art 9.3.: Where appropriate, the procedures provided for in Annexes 3, 4 and 6 may
be discharged by the manufacturer's authorized representative established in the
Community.
- Lodge a conformity assessment application for EC type-examination (Annex III),
examination certificate (EC Verification: Annex IV),
- Establish the statement for custom-made devices (Annex VI Section 2.1).
IVDD
Art 9.6.: The manufacturer may instruct his authorised representative to initiate the
procedures provided for in Annexes III, V, VI and VIII.
- Establish the Annex III EC declaration of conformity,
- Lodge a conformity assessment application for EC type-examination (Annex V),
examination certificate (EC Verification: Annex VI).
A.1.5. An authorised representative will be addressed by authorities and other

bodies in the Community instead of the manufacturer with regard to the latters
obligations under this directive
a) Information requested from the manufacturer
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The authorised representative is obliged to keep certain information at the disposal of
the national authorities, such as declarations of conformity and technical
documentation (AIMDD Annex 2 Section 6.1; MDD Annex II Section 6.1, Annex III
Section 7.3, Annex IV Section7, Annex V Section 5.1, Annex VI Section 5.1, Annex
VII Section 2; IVDD Arts 9(7) and 10(3)).
An authorised representative must be able to provide all documentation and

information that a market surveillance authority may require for the purpose of market
surveillance (Art 19 of Regulation 765/2008/EC).
Any request for information by an authority would be made under the national
legislation that transposes the Directives or under Regulation 765/2008/EC. Any
question as to the legitimacy or not of such a request or Order is therefore a matter
for national courts to decide.
The information may be stored with the authorised representatives who shall be
authorized to distribute the information directly to the authority. In this case the
contract should include an obligation from the manufacturer to keep the information
updated at all times.
If the manufacturer chooses not to store information with the authorised

representatives, he shall provide the authorised representatives with all
documentation and information that a market surveillance authority may require for
the purpose of market surveillance upon the reception of the request forwarded by
the authorised representatives to the manufacturer. The authorised representatives
should have access to all documentation and information.
In this case the contract must secure that the manufacturer will provide the requested
information to the authorised representatives in a timely manner, and should include
an obligation from the manufacturer to keep the authorised representatives informed
of any changes at all times.
The authorised representatives shall rescind his contract with the manufacturer if the
latter does not provide him with the access to the necessary information.
The requested information may include

i) Declaration of conformity,
ii) Copy of the label, packaging and instructions for use (in all languages
requested by the countries where the device is marketed),
iii) Notified Body certification (where relevant),
iv) Post market surveillance process and data, vigilance reports and
complaints, processes and data,
v) Technical documentation relevant to market surveillance investigation
being undertaken by the Member State,
vi) Relevant clinical data / notification,
vii) Details of any distributors / suppliers putting the CE marked devices on
the market,
viii) Incident reports and corrective actions taken.
A manufacturer must keep his authorised representative informed in all matters that
may be connected to the devices placed on the market in the EU. At the minimum,
the exchange of information concerning paragraphs c) to e) hereunder shall be
covered. This should be included in the contract between the two parties.
7/17
b) Information requested from the authorised representative
An authorised representative must keep the manufacturer informed in all matters that
may be connected to the devices placed on the market in the EU. At the minimum,
the exchange of information concerning paragraphs c) to e) hereunder shall be
covered. This should be included in the contract between the two parties.
c) Safeguard Clause
Where a Member State ascertains that a medical devices, when correctly installed,
maintained and used for their intended purpose may compromise the health and/or
safety of patients, users or, where applicable, other persons, or the safety of
property, it shall take all appropriate interim measures to withdraw such devices from
the market or prohibit or restrict their being placed on the market or put into service.
If the relevant Competent Authority contacts the authorised representative, he should
immediately communicate such measures to the manufacturer and advise the
manufacturer as to the implications of this decision.
When the Commission finds that national measures taken under the Safeguard
Clause are unjustified, it shall immediately so inform the Member State which took
the measures and the manufacturer or his authorised representative.
immediately communicate such information to the manufacturer and advise the
d) Vigilance
The Guideline on a Medical Device Vigilance System (MEDDEV 2.121 rev 6)1
describes the requirements of the Medical Device Vigilance System as it applies to or
involves manufacturers, including their authorised representatives.
In the event of an incident with a medical device, the Competent Authority must carry
out an assessment if possible together with the manufacturer or his authorised
representative.
After carrying out an assessment, Member States shall immediately inform the
Commission and the other Member States of the incidents for which appropriate
measures, have been taken or are contemplated.
immediately communicate such information to the manufacturer and advise the
The manufacturer should ensure that the involved authorised representative is kept
informed of incident reports and Field Safety Corrective Actions.
e) Serious adverse events during clinical investigation, i.e. in the pre-

market phase
According to Annex 7 to Directive AIMDD and according to Annex X to Directive
MDD all serious adverse events must be fully recorded and immediately notified to
1
http://ec.europa.eu/health/medical-devices/files/meddev/2_12_1-rev_6-12-2009_en.pdf
8/17
all Competent Authorities of the Member States in which the clinical investigation is
being performed; see MEDDEV 2.7/3 (Dec 2010) Clinical investigations: Serious
Adverse Event reporting under Directives AIMDD and MDD1.
Reportable events have to be reported by the sponsor of the clinical investigation,
which could be the manufacturer (MFR), the authorized representative (AR) or
another person or entity.
f) Enforcement
Where a Member State establishes that the CE marking has been affixed unduly or
is missing in violation of the Directives, the manufacturer or his authorised
representatives shall be obliged to end the infringement under conditions imposed by
the Member States (AIMDD Art 13; MDD Art 18; IVDD Art 17).
The authorised representatives shall inform the manufacturer of such an infringement
and the action required to end it.
g) Decisions in respect of refusal or restriction

Any decision taken pursuant to this Directive (a) to refuse or restrict the placing on
the market or putting into service of a device, or (b) to withdraw devices from the
market, shall state the exact grounds on which it is based. Such decisions shall be
notified without delay to the manufacturer or his authorised representatives
(common content of: MDD Art 19(1), AIMDD 14, IVDD Art 18(1)).
The measures envisaged by the CA relating to the actions of the authorised

representatives should be proportionate and reasonable.
, the manufacturer or his authorised representatives shall have an opportunity to

put forward his point of view in advance, unless such consultation is not possible
because of the urgency of the measure to be taken as justified in particular by public
health requirements (MDD Art 19(2), AIMDD 14, IVDD Art 18(2)).
1
http://ec.europa.eu/health/medical-devices/files/meddev/2_7_3_en.pdf
9/17
B. Member States' Expectations
Manufacturers shall delegate tasks explicitly to the authorised representatives, and

this preferably in a written contract. They shall define the authorised representatives
tasks and the limits of his powers (Guide to the implementation of directives based on
the New Approach and the Global Approach1).
To ensure that the roles of the authorised representative and the manufacturer are
clear, it is recommended, therefore that the responsibilities be specified in a written
contract between the manufacturer and his authorised representative.
The contract between the manufacturer and the authorised representative shall
stipulate that the authorised representative is obliged to inform the manufacturer of
decisions of a Member State in respect of refusal or restriction of the placing on the
market or any making available or putting into service of a device pursuant to this
Directive.
stipulate that the authorised representative is obliged to inform the manufacturer of
incidents brought to his knowledge.
stipulate that the manufacturer is obliged to inform the authorised representative of all
matters that may be connected to the devices placed on the EU market.
The Notified Bodies should verify that a manufacturer who does not have a place of
business in the EU, has designated an authorised representative and that the
appropriate contract demonstrating delegation of appropriate responsibilities is
available.
Hereunder are listed the expectations of Member States Competent Authorities.

These should be ideally covered in a contract between the manufacturer and the
authorised representative.
- The authorised representative should be able to assess whether the manufacturer

has the ability to fulfil his regulatory obligations. In order to carry out the assessment
the authorised representative should have access to the technical documentation.
- The authorised representatives should be in a position to verify that the required

information / documentation exists with their manufacturer and that the necessary
processes (e.g. for post market surveillance) are established.
- The authorised representative must possess appropriate knowledge, expertise and

resources to assess and verify the above.
- A Member State must be able to assume, when it addresses an authorised

representative, that it will receive all the information that it requests (see A.1.5.)
- A Member State can expect an authorised representative to provide on request the

following information:
i) Declaration of conformity,
1
http://ec.europa.eu/enterprise/policies/single-market-goods/documents/blue-guide/index_en.htm
10/17
ii) Copy of the label, packaging and instructions for use (in all languages
requested by the countries where the device is marketed),
iii) Notified Body certificates (where relevant),
iv) Post market surveillance process and data, vigilance reports and
complaints, processes and data,
v) Technical documentation relevant to market surveillance investigation
being undertaken by the Member State,
vi) Relevant clinical data / notification,
vii) Details of any distributors / suppliers putting the CE marked devices on
the market,
viii) Incident reports and reports on corrective actions taken.
- In the event of a disagreement, where the authorised representative considers that

the manufacturer is not complying with the requirements of the Directives, it has a
duty to communicate this to the manufacturer. If the disagreement continues, the
matter should be submitted to the authorised representatives Competent Authority
for decision. The authorised representative may opt to rescind the contract.
- In the event of a clear non-compliance by the manufacturer that could engage the
responsibility of the authorised representative and which the manufacturer refuses
to correct, the authorised representative has the right to rescind his contract with the
manufacturer. The authorised representative has even the obligation to rescind the
contract if the non-fulfilment of the manufacturers obligations causes him to infringe
national law. It should then notify his Competent Authority and the manufacturers
Notified Body of this.
11/17
ANNEX I
The table lists the articles and the sections of the Annexes of the three Medical
Devices Directives which contain requirements relating to authorised representatives.
MDD IVD AIMD

Medical Devices Directive InVitro Diagnostic Medical Active Implantable Medical
93/42/EEC (as amended by Devices Directive 98/79/EC Devices Directive
Directive 2007/47/EC) 90/385/EEC (as amended
by Directive 2007/47/EC)
DESIGNATION
Article 14(2) 1st sentence Article 10(3) 1st sentence Article 10a(2) 1st sentence
Where a manufacturer who places a Where a manufacturer who places Where a manufacturer who places a
device on the market under his own devices on the market under his own device on the market under his own
name does not have a registered name does not have a registered name does not have a registered
place of business in a Member State, place of business in a Member place of business in a Member State,
he shall designate a single State, he shall designate an he shall designate a single
authorised representative in the authorised representative. authorised representative in the
European Union. European Union.
REGISTRATION
Article 14(2) 2nd sentence Article 10(3) 2nd sentence Article 10a(2) 2nd sentence
For devices referred to in the first The authorised representative shall For devices referred to in the first
subparagraph of paragraph 1, the notify the competent authorities of subparagraph of paragraph 1 the
authorised representative shall the Member State in which he has authorised representative shall
inform the competent authority of the his registered place of business of all inform the competent authority of the
Member State in which he has his particulars as referred to in Member State in which he has his
registered place of business of the paragraph 1. registered place of business of all
details referred to in paragraph 1. details as referred to in paragraph 1.
Article 14(1) Article 10(1) Article 10a(1) 1st

Any manufacturer who, under his Any manufacturer who places
own name, places devices on the devices on the market under his own subparagraph
market in accordance with the name shall notify the competent Any manufacturer who, under his
procedures referred to in Article 11 authorities of the Member State in own name, places devices on the
(5) and (6) and any other natural or which he has his registered place of market in accordance with the
legal person engaged in the activities business: procedure referred to in Article 9(2)
referred to in Article 12 shall inform of the address of the registered shall inform the competent
the competent authorities of the place of business, authorities of the Member State in
Member State in which he has his of information relating to the which he has his registered place of
registered place of business of the reagents, reagent products and business of the address of the
address of the registered place of calibration and control materials in registered place of business and the
business and the description of the terms of common technological description of the devices concerned.
devices concerned. characteristics and/or analytes and
of any significant change thereto
For all medical devices of classes including discontinuation of placing
IIa, IIb and III, Member States may on the market; for other devices, the
request to be informed of all data appropriate indications,
allowing for identification of such in the case of devices covered by
devices together with the label and Annex II and of devices for
the instructions for use when such selftesting,
devices are put into service within of all data allowing for identification
their territory. of such devices, the analytical and,
where appropriate, diagnostic
parameters as referred to in Annex I,
part A, section 3, the outcome of
performance evaluation pursuant to
Annex VIII, certificates and any
significant change thereto, including
discontinuation of placing on the
market.
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MDD IVD AIMD
CONFORMITY ASSESSMENT PROCEDURE
Article 11(8) Article 9(6) Article 9(3)
The manufacturer may instruct his The manufacturer may instruct his Where appropriate, the procedures
authorized representative to initiate authorised representative to initiate provided for in Annexes 3, 4 and 6
the procedures provided for in the procedures provided for in may be discharged by the
Annexes III, IV, VII and VIII. Annexes III, V, VI and VIII. manufacturer's authorized
representative established in the
Community.
See also See also
Annex III section 2 Annex III section 1
See also
Annex IV section 1 Annex V section 2
Annex 2 section 2
Annex VII section 1 Annex VI section 1
Annex 3 section 2
Annex VIII section 1 Annex VIII section 1
Annex 4, sections 1 and 2
Annex 5 section 2
Annex 6 section 1
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MDD IVD AIMD
CONFORMITY ASSESSMENT DOCUMENTATION
Annex III section 7 Article 9(7) Annex 2 section 6.1
7.2. Other notified bodies may obtain The manufacturer must keep the For at least 15 years from the last
a copy of the EC type-examination declaration of conformity, the date of manufacture of the product,
certificates and/or the supplements technical documentation referred to the manufacturer or his authorised
thereto. The Annexes to the in Annexes III to VIII, as well as the representative shall keep available
certificates must be made available decisions, reports and certificates, for the national authorities:
to other notified bodies on reasoned established by notified bodies, and the declaration of conformity,
application, after the manufacturer make it available to the national the documentation referred to in
has been informed. authorities for inspection purposes the second indent of Section 3.1, and
for a period ending five years after in particular the documentation, data
7.3. The manufacturer or his the last product has been and records referred to in the second
authorised representative must keep manufactured. Where the paragraph of Section 3.2,
with the technical documentation manufacturer is not established in the amendments referred to in
copies of EC type-examination the Community, the obligation to Section 3.4,
certificates and their additions for a make the aforementioned the documentation referred to in
period ending at least five years after documentation available on request Section 4.2,
the last device has been applies to his authorised the decisions and reports of the
manufactured. In the case of representative. notified body referred to in Sections
implantable devices, the period shall 3.4, 4.3, 5.3 and 5.4.
be at least 15 years after the last
product has been manufactured.
Annex 3 section 7.3
The manufacturer or his authorized
Annex IV section 7 representative shall keep with the
The manufacturer or his authorised technical documentation a copy of
representative must, for a period the EC type-examination certificates
ending at least five years, and in the and the supplements to them for a
case of implantable devices at least period of at least 15 years from the
15 years, after the last product has manufacture of the last product.
been manufactured, make available
to the national authorities:
the declaration of conformity, Annex 4 section 6.5
the documentation referred to in The manufacturer or his authorized
Section 2, representative shall ensure that he is
the certificates referred to in able to supply the notified body's
Sections 5.2 and 6.4, certificates of conformity on request.
where appropriate, the type-
examination certificate referred to in Annex 6 section 3
Annex III. The manufacturer shall undertake to
keep available for the competent
Annex V section 5.1 national authorities:
5.1. The manufacturer or his
authorised representative must, for a 3.1. For custom-made devices,
period ending at least five years, and documentation, indicating
in the case of implantable devices at manufacturing
least 15 years, after the last product site(s) and enabling the design,
has been manufactured, make manufacture and performances of
available to the national authorities: the product, including the expected
the declaration of conformity, performances, to be understood, so
the documentation referred to in as to allow conformity with the
the fourth indent of Section 3.1, requirements of this Directive to be
the changes referred to in Section assessed.
3.4, The manufacturer shall take all
the documentation referred to in necessary measures to see that the
the seventh indent of Section 3.1, manufacturing process ensures that
the decisions and reports from the products manufactured conform
the notified body as referred to in to the documentation referred to in
Sections 4.3 and 4.4, the first paragraph.
where appropriate, the type-
examination certificate referred to in 3.2. For devices intended for clinical
Annex III. investigations, the documentation
shall also contain:
a general description of the
Annex VI section 5.1 product and its intended use,
Administrative provisions design drawings, manufacturing
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MDD IVD AIMD
5.1. The manufacturer or his methods, in particular as regards
authorised representative must, for a sterilization, and diagrams of parts,
period ending at least five years, and sub-assemblies, circuits, etc.,
in the case of implantable devices at the descriptions and explanations
least 15 years, after the last product necessary for the understanding of
has been manufactured, make the said drawings and diagrams and
available to the national authorities: of the operation of the product,
the declaration of conformity, the results of the risk analysis and
the documentation referred to in a list of the standards laid down in
the seventh indent of Section 3.1, Article 5, applied in full or in part,
the changes referred to in Section and a description of the solutions
3.4, adopted to satisfy the essential
the decisions and reports from requirements of the
the notified body as referred to in the Directive where the standards in
final indent of Section 3.4 and in Article 5 have not been applied,
Sections 4.3 and 4.4, if the device incorporates, as an
where appropriate, the certificate integral part, a substance or human
of conformity referred to in Annex III. blood derivative referred to in
Section 10 of Annex 1, the data on
the tests conducted in this
Annex VII section 2 connection which are required to
The manufacturer must prepare the assess the safety, quality and
technical documentation described in usefulness of that substance, or
Section 3. The manufacturer or his human blood derivative, taking
authorised representative must make account of the intended purpose of
this documentation, including the the device,
declaration of conformity, available to the results of the design
the national authorities for inspection calculations, checks and technical
purposes for a period ending at least tests carried out, etc.
five years after the last product has The manufacturer shall take all
been manufactured. In the case of necessary measures to see that the
implantable devices the period shall manufacturing process ensures that
be at least 15 years after the last the products manufactured conform
product has been manufactured. to the documentation referred to in
3.1 and in the first paragraph of this
Annex VIII section 4 section. The manufacturer may
The information contained in the authorize the evaluation, by audit
declarations concerned by this where necessary, of the
Annex shall be kept for a period of effectiveness of these measures.
time of at least five years. In the case
of implantable devices the period
shall be at least 15 years.
LABELLING
Annex I Section 13.3(a) Annex I section 8.4 (a) Annex I section 14.2
(The label must bear the following (The label must bear the following (Every device must bear, legibly and
particulars:) particulars which may take the form indelibly, the following particulars,
(a) the name or trade name and of symbols as appropriate:) where appropriate in the form of
address of the manufacturer. For (a) the name or trade name and generally recognized symbols:)
devices imported into the address of the manufacturer. For
Community, in view of their devices imported into the On the sales packaging:
distribution in the Community, the Community with a view to their the name and address of the
label, or the outer packaging, or distribution in the Community, the manufacturer and the name and
instructions for use, shall contain in label, the outer packaging, or the address of the authorised
addition the name and address of instructions for use shall contain in representative, where the
the authorised representative where addition the name and address of manufacturer does not have a
the manufacturer does not have a the authorised representative of the registered place of business in the
registered place of business in the manufacturer; Community,
Community; a description of the device,
the purpose of the device,
the relevant characteristics for its
use,
if the device is intended for
clinical investigations, the words:
exclusively
for clinical investigations,
15/17
MDD IVD AIMD
if the device is custom-made, the
words: custom-made device,
a declaration that the implantable
device is in a sterile condition,
the month and year of
manufacture,
an indication of the time limit for
implanting a device safely,
the conditions for transporting
and staring the device ,
in the case of a device within the
meaning of Article 1(4a), an
indication that the device contains a
human blood derivative.
CLINICAL INVESTIGATIONS (performance evaluation IVDD)

Article 15(1) Annex VIII section 1 Article 10(1)
In the case of devices intended for For devices for performance In the case of devices intended for
clinical investigations, the evaluation the manufacturer or his clinical investigations, the
manufacturer or the authorised authorised manufacturer or authorized
representative, established in the representative shall draw up the representative established in the
Community, shall follow the statement containing the information Community shall, at least 60 days
procedure referred to in Annex VIII stipulated in section 2 and ensure before the commencement of the
and notify the competent authorities that the relevant provisions of this investigations, submit the statement
of the Member States in which the Directive are met. referred to in Annex 6 to the
investigations are to be conducted by competent authorities of the Member
means of the statement mentioned in State in which the investigations are
Section 2.2 of Annex VIII. to be conducted.
ENFORCEMENT
Article 18 (a) Article 17(1) (a) Article 13(a)
(Without prejudice to Article 8:) (Without prejudice to Article 8:) (Without prejudice to Article 7:)
(a) where a Member State (a) where a Member State (a) where a Member State
establishes that the CE marking has establishes that the CE marking has establishes that the CE marking has
been affixed unduly or is missing in been wrongly affixed, the been affixed unduly or is missing in
violation of the Directive, the manufacturer or his authorised violation of this Directive, the
manufacturer or his authorised representative shall be obliged to manufacturer or his authorised
representative shall be obliged to end the infringement under representative established within the
end the infringement under conditions imposed by the Member Community shall be obliged to end
conditions imposed by the Member State; the infringement under conditions
State; imposed by the Member State;
DECISIONS IN RESPECT OF REFUSAL OR RESTRICTION
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MDD IVD AIMD
Article 19(2) Article 18(2) Article 14
In the event of a decision as referred In the event of a decision as referred Any decision taken pursuant to this
to in paragraph 1, the manufacturer, to in paragraph 1, the manufacturer Directive
or his authorized representative, or his authorised representative shall (a) to refuse or restrict the placing on
shall have an opportunity to put have an opportunity to put forward the market or the putting into service
forward his viewpoint in advance, his point of view in advance, unless of a device or the carrying out of
unless such consultation is not such consultation is not possible clinical investigations;
possible because of the urgency of because of the urgency of the or
the measure to be taken. measure to be taken as (b) to withdraw devices from the
justified in particular by public health market shall state the exact grounds
requirements. on which it is based. Such a decision
shall be notified without delay to the
party concerned, who shall at the
same time be informed of the
remedies available to him under the
laws in force in the Member State in
question and of the time limits to
which such remedies are subject.
In the event of a decision as referred

to in the previous paragraph the
manufacturer, or his authorized
representative, shall have an
opportunity to put forward his
viewpoint in advance, unless such
consultation is not possible because
of the urgency of the measures to be
taken.
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EUROPEAN COMMISSION

MEDDEV. 2.7.1
April 2003
EVALUATION OF CLINICAL DATA :
Note
Directives on medical devices. They are legally not binding. The Guidelines have been carefully
drafted through a process of intensive consultation of the various interest parties (competent
authorities, Commission services, industries, other interested parties) during which intermediate
drafts were circulated and comments were taken up in the document. Therefore, this document
reflects positions taken by representatives of interest parties in the medical devices sector.
Commission europenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel Belgium.

Telephone: (32-2)299.11.11. Fax: (32-2) 296 70 13. E-mail: entr-medical-devices@cec.eu.int
Version 2003-03-27
EVALUATION OF CLINICAL DATA:

A GUIDE FOR MANUFACTURERS AND NOTIFIED
BODIES
1. Introduction and purpose
It is the primary purpose of this document to provide guidance to Manufacturers on

reviewing and analysing clinical data and to Notified Bodies when reviewing the
manufacturers evaluation of clinical data as part of the conformity assessment
procedures required by 90/385/EEC (AIMD) [1] and 93/42/EEC (MDD) [2].
This document will also assist manufacturers, by providing guidance on what is ex-
pected.
2. Background
The manufacturer must demonstrate that his intended purpose(s) and claim(s) made
in relation to safety and performance are achieved, as referred to in the Directives.
As a general rule, such demonstration will require clinical data (Annex X, 1.1 of
MDD).
Evaluation of clinical data as described in Annex X of the MDD and Annex 7 of the
AIMD is particularly relevant to assessment of conformity with essential requirements
given in MDD Annex I: General Requirements, sections 1 and 3 and AIMD Annex 1:
General requirements, sections 1 and 2. Attention should also be paid to Annex I,
I.6 (MDD) and Annex 1, I.5 (AIMD).
3. Explanation of terms
For the purpose of this document:
3.1 Clinical data is data which is relevant to the various aspects of the clinical safety
and performance of the device. This must include data obtained from:
(i) published and/or unpublished data on market experience of the device

in question; or a similar device for which equivalence to the device in
question can be demonstrated; or
(ii) a prospective clinical investigation(s) of the device concerned; or
2
(iii) results from a clinical investigation(s) or other studies reported in the
scientific literature of a similar device for which equivalence to the
device in question can be demonstrated.
3.2. The Evaluation of clinical data is the process by which clinical data from all se-
lected sources (literature, results of clinical investigations and other) is as-
sessed, analysed and deemed appropriate and adequate to establish
conformity of the device with the pertinent essential requirements of the
Directive as they relate to safety and performance, and to demonstrate that the
device performs as intended by the manufacturer. The outcome of this process
is a report which includes a conclusion on the acceptability of risks and side
effects when weighed against the intended benefits of the device.
4. Clinical data to be provided by the manufacturer
The Active Implantable Medical Devices Directive and the Medical Devices Directive
state that as a general rule, and in particular in the case of implantable devices,
active implantable devices and devices in Class III, evidence of the clinical
performance and safety of a medical device is provided by means of clinical data,
which is supplied by the manufacturer in accordance with Annex X (MDD) or Annex 7
(AIMD). The decision as to whether clinical data is necessary however must be taken
for every device on the basis of the type of data required to demonstrate compliance
with the relevant Essential Requirements, the claims being made for the device in
question and the risk management assessment. All the conformity assessment
procedures leading to CE marking, address the issue of clinical evaluation by the
manufacturer. In the case of Annexes II and III, the Notified Body is involved.
Clinical evaluation is based on the assessment of the risks and the benefits, associ-
ated with use of the device, through either:
(i) a compilation of relevant scientific literature, that is currently available

as well as, where appropriate, a written report containing a critical evaluation of
this compilation (the "literature route"); or
(ii) the results of all the clinical investigations relevant to the device in
question (the "clinical investigation route"); or
(iii) a combination of (i) and (ii) above. Where the clinical evaluation is
based on such a combination, it should include an overall assessment. This
assessment should take account of market experience, if available. It is
important that the manufacturer relates the data to the specific device, having
regard to the hazards identified (see 4.2).
The manufacturer must demonstrate whether the available data is sufficient to

establish conformity with the Directive, having regard to:
(i) the demonstration of equivalence of the device to which the data

relates and the device(s) for which conformity is being assessed, and
3
so the applicability of the findings to the device being assessed (see
section 4.3.1 (i)d) ); and
(ii) the adequacy of the data in addressing the relevant aspects of

Directive conformity.
4.1. Manufacturers statement on the clinical data used to affix the CE

marking
The manufacturer should include in the technical documentation a simple statement

on the clinical data used to affix the CE marking. The statement should make clear
whether that clinical data was obtained from the published literature or the results of
clinical investigations or a combination of both. Where data relates to other devices,
the statement should indicate analogy with which device(s) and how equivalence
was established. The full clinical data used for CE marking should be included within
the technical documentation.
4.2. Identification of aspects of safety and performance to be addressed

through clinical data
The manufacturer is required by the Directive to perform a risk analysis. A risk

analysis is important in helping the manufacturer identify known or reasonably fore-
seeable hazards associated with use of the device, and decide how best to estimate
the risks associated with each hazard1. From the results of the risk analysis, the
manufacturer lays out how each risk is addressed and decides on the acceptability of
risks when weighed against the intended benefits.
The risk analysis includes technical and clinical aspects relating to the particular
device concerned. It should distinguish between aspects associated with:
(i) the medical procedure for which the device is intended;
eg the risks versus benefits associated with extracorporeal lithotripsy as

compared with conventional (surgical and non-surgical) methods of
kidney stone removal.
(ii) the technical solutions adopted;
eg the risks versus benefits associated with different technologies of

extracorporeal lithotripsy such as those involving generating shock
waves with electric sparks (electrohydraulic method), with an
electromagnetic generator or a piezoelectric system.
(iii) aspects specific to the design and use of the particular device
concerned;
1
The loss/absence of the performance of a given device as claimed by the manufacturer and which
could result in the loss of benefit of a treatment may be considered a hazard.
4
eg the risks versus benefits associated with the shock wave coupling
method, size of the focal zone, the stone localisation and targeting
system (X-ray, ultrasound) and the trigger method
This distinction should be used to identify the type and specificity of clinical data
needed. Where the available data is not sufficient to address the identified clinical
hazards relating to one or more of the above aspects, a clinical investigation(s) will
be needed (see also section 4.4.1). The objectives of the clinical investigation(s)
should focus on those aspects not sufficiently addressed by the available data. The
manufacturer should also set out the intended benefits of the device and relate those
to the accepted benefits associated with the generally acknowledged state of the
art
4.3. Literature route
Due regard needs to be paid to the extent to which the published data are relevant
and applicable to the relevant characteristics of the device under assessment and
the medical procedure for which the device is intended.
A literature review should be performed by person(s) suitably qualified in the relevant

field, knowledgeable in the state of the art and able to demonstrate objectivity.
4.3.1 Requirements
When the manufacturer's clinical evaluation to be submitted to the Notified Body

takes the form of a review of the relevant scientific literature, the following
requirements should be fulfilled:
(i) Methodology
a) General
A protocol for the identification, selection, collation and review of relevant

studies should be written and preferably be based on recognised practice for
systematic review for literature.
b) Objective
The objective of the literature review should be clearly defined. The types of
studies that are relevant to the objective of the literature review should be
specified, taking into account the already well established knowledge of the
device.
5
c) Identification of data
Data should be taken from recognised scientific publications. Unpublished

data should also be taken into account in order to avoid publication bias.
The literature review should state:
the sources of data and the extent of the searches of databases or

other sources of information;
the rationale for the selection/relevance of the published literature;
the reasons for believing that all relevant references, both favourable
and unfavourable, have been identified;
the criteria for exclusion of particular references together with a

justification for this exclusion.
Note: possible data sources for a systematic literature review are for example:
medical and paramedical databases

technical papers from relevant Standards Committees
foreign language literature
grey literature (theses, internal reports, non peer review journals, the
internet, industry files)
references listed in primary sources
other unpublished sources known to experts in the field (obtained by
personal communication)
raw data from published trials (obtained from personal communication)
d) Relevance of data
A literature review should clearly establish the extent to which the literature
relates to the specific characteristics and features of the device under
consideration.
If the published studies do not directly refer to the device in question, the
following must apply.
The manufacturer must demonstrate equivalence in all the following

essential characteristics with the device, which is the subject of the
published reports. Equivalence means:
Clinical:
-used for the same clinical condition or purpose;
-used at the same site in the body;
-used in similar population (including age, anatomy, physiology);
6
-have similar relevant critical performance according to expected
clinical effect for specific intended use.
Technical:
-used under similar conditions of use;
-have similar specifications and properties eg tensile strength,
viscosity, surface characteristics
-be of similar design;
-use similar deployment methods (if relevant);
-have similar principles of operation
Biological:
-use same materials in contact with the same human tissues or

body fluids;
To be equivalent, the devices should have similarity with regard to the clinical,
technical and biological parameters with special attention to the performance,
principles of operation and materials; or if there are differences identified, an
assessment and demonstration of the significance these might have on safety
and performance must be set out.
For example we can consider the case where the device under consideration
and the device referred to in the published studies do not have the same
principles of operation ie the new device has a new principle of operation.
Since a new mechanism of action does not necessarily result in a new clinical
benefit, demonstration of the clinical benefit of the new device has to be
generated by data resulting from a specifically designed clinical investigation
since the 2 devices cannot be considered equivalent.
The manufacturer must be able to demonstrate the adequacy of the data

in addressing the aspects of conformity set out in the objective
e) Assessment of clinical data
The literature review should make clear the significance that is attached to
particular references based on a number of factors. These include:
the relevance of the authors background and expertise in relation to the

particular device and/or medical procedure involved.
whether the authors conclusions are substantiated by the available data
whether the literature reflects the current medical practice and the
generally acknowledged state of the art technologies.
7
whether references are taken from recognised scientific publications and
whether or not they have been reported in peer reviewed journals
the extent to which the published literature is the outcome of a

study/studies which have followed scientific principles in relation to design,
for example, in having demonstrable and appropriate endpoints, inclusion
and exclusion criteria, an appropriate and validated number of patients
submitted, carried out for an appropriate duration, providing evidence and
analysis of all adverse incidents, deaths, exclusions, withdrawals and
subjects lost follow-up and identifying an appropriate statistical plan of
analysis.
Ideally, evidence should be generated from a clinical trial (controlled if appropriate),

properly designed cohort/case controlled study, well documented case histories or
sequential reports conducted by appropriate experienced experts, whether in relation
to the device itself or an equivalent device. If unpublished data is being included in
the assessment, the literature review will need to weigh the significance that is
attached to each report.
The evidence should not consist of:
isolated case reports;
random experience;
reports lacking sufficient detail to permit scientific evaluation (including lack of

accepted and validated statistical design if this is relevant to the design of the
intended study);
unsubstantiated opinions.
(ii) Critical evaluation of the literature
The literature review should contain a critical evaluation of the literature. This critical
evaluation should:
be written by a person suitably qualified in the relevant field, knowledgeable in

the state of the art and able to demonstrate objectivity;
contain a short description of the medical device, its intended functions,

description of the intended purpose and application of use;
contain an analysis of all the available data considered, both favourable and
unfavourable;
establish the extent to which the literature relates to the specific

characteristics and features of the device being assessed, taking due account
8
of the extend of similarity between the device(s) covered by the literature and
the device under assessment;
demonstrate that those aspects of the use of the device, including

performance, addressed in the clinical part of the risk analysis are met as
claimed by the manufacturer, and that the device fulfils its intended purpose
as a medical device;
analyse the identified hazards, the associated risks and the appropriate safety
measures of patients, medical staff and third parties involved in the
study/studies, for example by reference to the manufacturers risk analysis
(see also ISO14155-2);
contain a risk analysis relevant to the device design, materials and procedures
involved, taking into account any adverse events, results of post-market
surveillance studies, modifications and recalls (if known) (see also ISO14155-
2);
contain a description of the methods of weighting of different papers and the

statistical methods of analysis employed taking into account the assessment
methods, the type and duration of study and the heterogeneity of the
population included within the study. Particular attention should be given in
circumstances where there are repeated publications on the same group of
patients by the same authors in order to avoid overweighting the experience;
include an analysis of the market experience of the same or similar devices,

including the results of post-marketing studies, post-market surveillance and
short- and long-term adverse events;
contain a list of publications appropriately cross-referenced in the evaluation;
if the clinical data relates to an equivalent device, contain a statement that

equivalence with all the relevant characteristics has been demonstrated;
include a conclusion with a justification, including an assessment of any

probable benefit to health from the use of the device as intended by the
manufacturer, against probable risks of injury or illness from such use taking
account of the state of the art. If applicable, the findings should be compared
with other studies covering the same field of application. These studies may
involve other modalities, including alternative medical devices, medical
therapy, surgery or other accepted health care methods provided they employ
methods which are generally accepted as being common practice. The
conclusions should make clear how the objectives of the literature review have
been met and identify any gaps in the evidence necessary to cover all relevant
aspects of safety and performance.
Note 1: conclusions should be relevant in the field of use,

indications, contra-indications and instructions for use intended by the
manufacturer
Note 2: the critical evaluation should be signed and dated by the

author
9
4.3.2 Conclusions from Analysis of Literature Review
As a result of a literature review, the Notified Body needs to be able to answer the
following:
that the manufacturers conclusions are valid;
that the data, taken together with the available pre clinical data, is
sufficient to demonstrate compliance with the essential requirements
covering safety and performance of the device in question under normal
conditions of use; or
identify gaps in the demonstration of compliance with the relevant

essential requirements or in the demonstration of equivalence that need
addressing through the means of a specifically designed clinical
investigation(s); and
that the claims made in the device labelling are substantiated by the
clinical data taken together with the pre-clinical data.
The manufacturers report of the literature review should be written in a format that
enables the Notified Body to answer the questions above.
4.4 Clinical investigations route
4.4.1. Need for clinical investigation(s)
When reviewing the manufacturers evaluation of clinical data and whether or not a
clinical investigation(s) is needed as part of this, due regard should be paid to NB-
MED/2.7/R1 [5].
4.4.2. Conduct of clinical investigations
Where the results of clinical investigation(s) form part of the clinical data, the clinical
investigations should comply with the relevant sections of Annex X MDD or Annex 7
AIMD. Compliance with the EN 540 [3] carries the presumption that the design,
conduct and monitoring of the clinical investigation(s) conforms with the
requirements of these Annexes. Whilst not carrying such a presumption of
conformity, other equivalent standards may be used.2[4]
4.4.3 Requirements
2
Where justified, the Notified Body may require further information to assess the manufacturers
clinical investigation data.
10
When the manufacturers clinical evaluation to be submitted to the Notified Body
takes the form of presentation and analysis of results from a specifically designed
clinical investigation(s) involving the device in question, the following requirements
should be fulfilled.
(i) Identification of Relevant Documents
The following documents must be requested:
copy of the Protocol submitted to the Competent Authority for which no

grounds for objection were raised;
copy of the letter of no objection from Competent Authority/Authorities (if
available), together with comments made (was this a first submission to a
Competent Authority? If rejected, a copy of the original grounds for
objection should be requested);
copy of the Ethics Committee opinion(s) and comments (was this the first
submission to Ethics Committee? If previously rejected, a copy of the
letter of objection should be requested);
copy of the signed and dated final report.
(ii) Information to be checked
The following must be checked in all cases.
Letter of no objection from the Competent Authority(ies)
Clinical Investigation Plan (CIP): Is the CIP used for the clinical
investigation the same as that submitted to the Competent Authority?
Particular attention should be paid to:
- number of patients entered
- objectives of investigation(s) (in particular which Essential
Requirements are being addressed)
- duration of investigation(s) and patient follow up (short and long
term)
- end points in terms of diagnostic tools and patient assessment
- inclusion and exclusion criteria;
If parameters, especially those mentioned above, are not as set out in the
original CIP, the rationale for non adherence (particularly important to note
whether inclusion numbers and duration of study are cut short);
Identification of any changes to CIP and rationale for any such changes
(important to ensure Competent Authority was notified of changes, if this
is relevant);
Where the clinical investigation(s) was performed outside the EU, the
manufacturer must demonstrate that the use of the device (including
clinical practice and techniques) and patient population are equivalent to
those for which the device will be used within the EU (if relevant).
11
(iii) Final Report
The contents of the Final Report should always be checked and should contain the
following information
a) Summary
A structured abstract should be provided, presenting the essentials of the

study, including:
title of investigation(s);
identification of the medical device(s), including names, models

as relevant for complete identification;
name of sponsor;
statement indicating whether the investigation(s) was performed
in accordance with CEN/ISO Standards;
objectives;
subjects;
methodology;
investigation(s) initiation and completion dates, including date of
early termination, if applicable;
results;
conclusions;
authors of report;
date of report.
b) Introduction
A brief statement placing the study in the context of the development of the
medical device in question and an identification of guidelines followed in
the development of the Protocol.
c) Materials and methods
device description;
summary description of the device and its intended use, together
with any modifications performed during the investigation;
Clinical Investigation Plan summary.
d) Summary of the clinical investigation plan
This should be accompanied by any modification described. The summary

should include a brief description of:
12
the clinical investigation objectives;
the investigation design;
type of investigation;
investigation end points;
ethical considerations;
subject population;
inclusion/exclusion criteria;
sample size;
treatment and treatment allocation;
investigation variables;
concomitant medications/treatments;
duration of follow up;
statistical analysis including investigation hypothesis or pass/fail
criteria, sample size calculation, statistical analysis methods.
e) Results
This section should contain summary information with a description of the

analysis and results including:
the investigation initiation date;

investigation completion/suspension date;
the disposition of patients/devices;
the patient demographics;
clinical investigation plan compliance;
the analysis to include safety report, including a summary of all
adverse events and adverse device events seen in the investigation,
including a discussion of the severity, treatment required, resolution
and assessment by the investigator of relation to treatment;
performance or efficacy analysis; any sub group analysis for special
population; a description of how missing data, including patients lost
to follow up or withdrawn, were dealt with in the analysis.
f) Discussions and conclusions
These should contain:
the performance and safety results of the study;

the relationship of risks and benefits;
clinical relevance and importance of the results, particularly in the light of
other existing data and discussion of comparison with state of the art;
any specific benefits or special precautions required for individual subjects
or at risk groups;
any implications for the conduct of future studies.
g) Signature
13
The final report should be signed off by the sponsor, the co-ordinating clincal
investigator (if appointed) and principal investigator at each centre
h) Annex to the report
There should be an Annex to the report containing the following:
clinical investigation plan, including amendments.

list of investigators and their institutions;
list of other parties involved;
list of monitors;
list of statisticians, if applicable;
list of Ethics Committees and their approval letters.
4.4.4 Independent Analysis
An assessment and analysis carried out by an independent and unbiased expert in

the field should always be considered, particularly if in-house expertise is not
available.
4.4.5 Conclusions from Analysis of Clinical Investigation Data
As a result of a review and analysis of the data generated by a specifically designed

clinical investigation(s), the Notified Body needs to be able to answer the following:
that any identified pass/fail criteria of the investigation(s) have been met
e.g. 98% of patient implanted with a hip prosthesis have no device
related adverse events at 2 years ;
that the results and conclusions of the clinical investigation(s) have
demonstrated that compliance with the identified relevant essential
requirements;
that the claims made in the device labelling are substantiated by
clinical data when taken together with the relevant pre-clinical data;
and
that the risk analysis has demonstrated that the risks associated with
the use of the device as set out by the manufacturer is acceptable
when balanced against the benefits to the patient.
5.0 The Role of the Notified Body
With regard to the evaluation of clinical data the Notified Body has different roles
depending on the conformity assessment procedure followed.
As part of the design/type examination under Annexes II.4 or III, the Notified Body
assesses the clinical data assembled by the manufacturer and the manufacturers
evaluation and the validity of the conclusions drawn. (see 5.1)
14
As part of quality system approval under Annex II.3, the Notified Body assesses the
manufacturers procedure for clinical data evaluation. This may include a review of
examples of such evaluations. (see 5.2)
5.1. Examination of a design dossier (Annex II.4) or of a type examination

dossier (Annex III)
The Notified Body (NB) examines the documentation submitted according to the pre-
ceding sections. In order to do so, the NB should possess enough knowledge and
experience in clinical evaluation as stated in section 6 of this document.
5.1.1. Decision-making
In reviewing the evaluation of clinical data submitted by the manufacturer, the

Notified Body decides whether or not the manufacturer has adequately:
described and verified the intended characteristics and performances related

to clinical aspects;
performed a risk analysis and estimated the undesirable side effects;
concluded on the basis of documented justification that the risks are

acceptable when weighed against the intended benefits.
The assessment carried out by the Notified Body will typically cover the following
aspects of the manufacturers clinical data evaluation:
the listing and characterisation of the clinical performance of the device in-
tended by the manufacturer and the expected benefits for the patient;
the use of the list of identified hazards to be addressed through evaluation

of clinical data as described in paragraph 4.1. of this document;
the adequate estimation of the associated risks for each identified hazard
by:
a) characterising the severity of the hazard;

b) estimating and characterising the probability of occurrence of the
harm (or health impairment or loss of benefit of the treatment)
(document with rationale);
the decision on the acceptability of risks in relation to each identified hazard,

based on the combination of the above using the ALARP3 philosophy [6,7], and
characterisation of the corresponding risk/benefit ratio as:
- unacceptable; or
- broadly acceptable; or
3
ALARP means "As Low As Reasonably Practicable"
15
- acceptable under specified conditions4 (see ISO/IEC Guide 51
[9]).
5.1.2. The report of the Notified Body
The Notified Body writes a report on its assessment of the submitted clinical docu-
mentation. The report may be a separate report or part of the Notified Bodys overall
report. In the latter case the clinical part should be clearly identified.
The Notified Bodys report should include:
- identification of the manufacturer;

- identification of the medical device;
- basis of evaluation (which Directive and which Annex(es));
- submitted documents;
- description of the device;
- assessment of clinical safety and performance;
- conclusion. The NB should justify and document each step of the decision making
process referred in 5.1.1. One single unacceptable risk/benefit ratio leads to a
negative conclusion;5
- the names of all NB internal assessors and external experts involved in the as-
sessment of the manufacturers documentation, together with details of the as-
pects assessed by each;
- date and signature of the responsible assessor(s).
5.2. Evaluation as part of quality system related procedures (Annex II.3)
5.2.1. Review of the procedures
When the manufacturer selects this procedure, the Notified Body should, as part of
the review of the manufacturers quality system, assess the establishment, mainte-
nance and application of the manufacturers procedures for the documented evalua-
tion of clinical data. This should cover:
a) the responsibility for the evaluation of the clinical data by a suitably qualified
person;
b) the identification of clinical data, both unpublished (for example contained in the
manufacturers files e.g. the complaints history) and published.
c) the relevance of the clinical data identified as demonstrating compliance with

particular requirements of the Directive or cited in particular aspects of the risk
analysis6.
4
The assessment of a risk/benefit ratio as acceptable under specified conditions implies the
determination of those specified conditions under which it can be accepted. At the stage of
assessment, the expected benefit to the patient, as well as the risk, has to take account of the
generally acknowledged state of the art.
5
In some cases, the combination of the conditions specified in order to characterise different
Risk/benefit ratios as acceptable may be contradictory or impracticable, and so also leads to a
negative conclusion.
6
The record of this may take the form of relevant entries in the ER Checklist or the risk analysis
document within the manufacturers technical documentation (check with Explanation of terms)
16
d) assuring that clinical investigation(s) are performed in compliance with the
applicable regulations and the clinical investigation plan, with a suitable
justification for any deviations
e) identification and evaluation of undesirable side effects.
This latter point involves identification of known or reasonably foreseeable

hazards, qualification of their severity and of their probability of occurrence. It is
part of the manufacturers documented risk analysis based on both favourable
and unfavourable data identified as relevant in order to give a balanced view.
5.2.2. Review of samples
The Notified Body, when reviewing samples of the manufacturers clinical data
evaluation, should pay special attention to the following:
(a) whether or not the data is relevant to the device or medical procedure involved;
(b) where the manufacturer, in the selected sample, has chosen the literature
route (see 4.3.), whether the criteria defined in 4.3. have been applied;
(c) where the manufacturer, in the selected sample, has selected the clinical in-
vestigations route (see.4.4.), whether the criteria defined in 4.4. have been
applied.
When performing the assessment on samples of a manufacturers risk/benefit as-

sessment, the Notified Body will follow the steps indicated in 5.1.1.
6. Notified Body Specific Procedures and Expertise
Notified Bodies should establish and implement internal policies and procedures for
the assessment of clinical data in order to:
a) ensure that suitable resources, especially relevant knowledge and competence

necessary for such evaluation, are available within the Notified Body and/or by
contracting external experts.
Such expertise should be sufficient to identify and estimate the risks and
benefits associated with the use of the medical devices. The evaluation
team should be able to evaluate a risk analysis and the risk management
strategy performed by the manufacturer. The evaluation team should
understand the device technology as well as the medical procedure [8].
Such an evaluation may require input from a qualified medical

practitioner (for example physician, dentist, nurse), as appropriate for the
particular device, who has clinical experience in the pathology of the
condition being treated, the usual treatment, the therapeutic alternatives
etc.
17
When examining the results of clinical investigations, the evaluation team
should have knowledge in planning, conduct and interpretation of clinical
investigations. All evaluators should be trained and qualified.
Particular attention should be drawn to training of external experts with

regard to the conformity assessment procedure. The Notified Body
should be responsible for reviewing the opinion of these experts, taking
account of their level of knowledge of the provisions of the Directives;
b) review the evaluation of clinical data provided by the manufacturer;
c) document the opinion with rationale of all experts involved;
d) ensure that any external experts involved are impartial and independent from any
parties involved, having due regard to any conflict of interest which may compro-
mise impartiality (see also MedDev 2.10/2 [11]);
e) document the result of their assessment. This is achieved through a specific

report which may be part of, or may be referenced, in the overall design / type
examination report;
f) preserve confidentiality of the information and data received from the

manufacturer, especially within the terms for contracting external experts.
18
7. References
1. Council Directive 90/385/EEC of 20 June 1990 concerning active implantable

medical devices
2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
3. EN 540: Clinical investigation of medical devices for human subjects, 1993
4. ISO 14155 Clinical investigation of medical devices
5. Guidance on when a clinical investigation is needed for CE marking, NB-

MED/2.7/Rec1
6. Task force on CE marking of existing products, NBM/026/95 rev 2.
7. EN 60601-1-4: Medical electrical equipment Part 1: General requirements for

safety, 4. Collateral Standard: Programmable electrical medical systems
8. Committee draft ISO/CD 14971,Medical Devices - Risk Management Dated

1998-05-21.
9. MedDev 1/94 Rev 10: Guidelines for Regulatory Auditing of Quality Systems of
Medical Device Manufacturers.
10. ISO/IEC Guide 51 Guideline for the inclusion of safety aspects in Standards
11. MedDev 2.10/2 Rev 01.03.99: Designation and monitoring of Notified Bodies
within the framework of EC Directives on medical devices.
19
Fin- 26 09 08
EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL
Consumer goods
Cosmetics and Medical Devices
MEDDEV 2.7.2
December 2008
GUIDE FOR COMPETENT AUTHORITIES

IN MAKING AN ASSESSMENT OF CLINICAL INVESTIGATION
NOTIFICATION
Note
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully
drafted through a process of intensive consultation of the various interest parties (competent authorities,
Commission services, industries, other interested parties) during which intermediate drafts where
circulated and comments were taken up in the document. Therefore, this document reflects positions
taken by representatives of interest parties in the medical devices sector.
Fin- 26 09 08
MEDICAL DEVICES DIRECTIVES - CLINICAL INVESTIGATION-
GUIDELINES FOR COMPETENT AUTHORITIES IN MAKING AN

ASSESSMENT OF CLINICAL INVESTIGATION NOTIFICATION
INTRODUCTION
Roles of Competent Authorities may vary between Member States in relation to assessment
of clinical investigation notifications under the provisions of article 10 of Council Directive
90/385/EEC1 and of article 15 of Council Directive 93/42/EEC2, as amended.
It is important however that everybody responsible for raising no grounds for objection to a
clinical investigation progressing ensures that the information submitted in the notification
pursuant to annex 6 of Directive 90/385/EEC or annex VIII of Directive 93/42/EEC contains all
the following items listed below (if appropriate) and is adequate in detail. It is equally
important to note that any change to clinical investigation plan or other amendments and
updates to the original document, must be equally submitted in a timely manner to the
relevant Regulatory Bodies.
The information requested below is in line with the requirements of the harmonised standard
EN ISO 14155.
CHECKLIST
NOTE: The following is a list of items that must be covered although the information may be
provided in different documents or in different formats as required by individual Competent
Authorities. Competent Authorities may also require additional documentation for their
assessment needs.
1. General Information
1.1 Sponsors and/or manufacturers name and contact points for communication
(similarly for authorised representative in the EU if relevant).
1.2 Whether first submission or resubmission.
1.3 If resubmission with regard to same device, previous date(s) and reference
number(s) of earlier submission(s).
1.4 Other Member States and non European countries participating in clinical
investigation as part of a multicentre/multinational study at the time of filing.
1.5 A signed statement (by the managing director or regulatory affairs manager or
manager responsible for compliance with the essential requirements)to the effect that
the device in question complies with the essential requirements except with regard to
those aspects of the device which are to be investigated; and that, in respect of those
aspects, every precaution has been taken to protect the health and safety of the
subject.
1.6 Copy of the Ethics committee opinion as soon as available according to national
requirements.
1
Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable
medical devices, last amended by Directive 2007/47/EC of the European Parliament and of the Council.
2
Council Directive 93/42/EEC concerning medical devices, last amended by Directive 2007/47/EC of the European
Parliament and of the Council.
Fin- 26 09 08
2. INVESTIGATOR BROCHURE: Devices Identification
2.1 Details allowing device to be identified
2.2 Trade name of device.
2.3 Generic name of device.
2.4 Model name of device.
2.5 Model number(s) including revision number(s), if any (or reference from apparent
model number if appropriate).
3. INVESTIGATOR BROCHURE: Other Device Details
3.1 Classification.
3.2 Description of the intended clinical performance (ISO 14 155).
3.3 A description of device including a list of accessories, principles of operation and

block or flow diagrams of major components, together with a brief description of other
devices designed to be used in combination for purpose of the investigation, if
applicable.
3.4 Identification of any features of design that are different from a previously similar
marketed product (if relevant).
3.5 Details of any new or previously untested features of the device including, where
applicable, function and principles of operation.
3.6 Summary of experience with any similar devices made by same manufacturer
including length of time on market and a review of performance related problems,
complaints any actions taken to address. Clinical data on device in question or
similar device, if available. Reference should be made as to how experience with
previous device models has affected the current iterations of design, if applicable.
3.7 Benefit/Risk analysis to include identification of hazards and estimated risks

associated with the manufacture (including factors relating to device choice, choice of
materials, software) and the use of the device, together with the description of what
actions have been taken to minimise or eliminate the identified risks. (Note: may
also be included in the clinical investigation plan).
3.8 Summary and analysis of pre-clinical testing and experimental data including results
of design calculations, mechanical tests, electrical tests, tests for validation of
software, reliability checks and any performance and safety tests in animals.
3.9 Description of materials coming into contact with the body, rationale for choice of
materials and which Standards apply (if relevant).
3.10 Description of how biocompatibility and biological safety have been addressed
including identification of the risks and hazards associated with the use the device
and how these have been addressed.
Fin- 26 09 08
3.11 Identification of any pharmacological components of device with description of

intended purpose and previous experience with the use this substance (see attached
annex).
3.12 Design drawings, if necessary for the understanding of the functioning of the device.
3.13 Description of software, logic and constraints (if relevant).
3.14 Method of sterilisation and validation (method, justification, if ETO-residuals) (if

applicable) and methods of cleaning, disinfection and sterilisation for reusable
devices.
3.15 Identification of any tissues of animal origin incorporated within the device together
with information on the sourcing and collection of animal tissue(s) prior to
manufacturing operation; and details with regard to validation of manufacturing
procedures employed for the reduction or inactivation of unconventional agents. This
is also applicable in circumstances of genetically produced material.
3.16 Identification of any special manufacturing conditions required and if so, how such
requirements have been met.
3.17 List of relevant Standards applied in full or in part, or description of solutions adapted
to meet the essential requirements of the Directive if relevant standards have not
been fully applied.
3.18 Instructions for use/labelling including risks, contra indications and warnings (if
available).
3.19 What provisions, if any have been made by the manufacturer for the recovering of the
device (if applicable, i.e. implantable devices, multiple use devices) and subsequent
prevention of unauthorised use.
4. CLINICAL INVESTIGATION PLAN (CIP): General Information
4.1 Name(s), qualifications, professional positions, address(es) of clinical investigator(s),

of principle clinical investigator and co-ordinating investigator (if relevant) from
multicentre clinical investigation at the time of filing. NOTE: this can be provided
separately from the CIP.
4.2 Name(s), address(es) of the institution(s) in which the clinical investigation(s) will be
conducted; identification of the Sponsor and other institutions playing a critical role in
the trial, ie centralised laboratories. NOTE: this can be provided separately from the
CIP.
4.3 Name(s), address(es) of the Sponsor and Manufacturer.
4.4 Synopsis of the clinical investigation plan; reference to GCP standards followed, ie
Declaration of Helsinki and ISO 14155.
4.5 A summary of necessary training experience for use of device in question, if

applicable.
4.7 Copy of informed consent or the draft informed consent submitted in parallel to the
Ethics Committee. NOTE: this can be a separate document
4.8 Copy of draft Clinical Research Form (CRF) if required. NOTE: this can be a
separate document.
Fin- 26 09 08
4.9 Rationale and justification of the clinical investigation; Summary of background to

study with reference to important relevant scientific literature (if any) with analysis and
bibliography; pre-clinical testing and previous clinical experience overview in support
of justification for conducting the clinical investigation; device and investigation risk
analysis and risk assessment.
5 CLINICAL INVESTIGATION PLAN: Investigation Parameters and Design
5.1 Objectives of clinical investigation.
5.2 Investigation design, eg randomised, controlled, including clear statement of the

endpoints corresponding to the objectives of the clinical investigation, variables to be
used, methods and timing of the assessments.
5.3 Numbers of subjects (with justification).
5.4 Duration of study with estimated start and finish dates and proposed follow up period
(with justification).
5.5 Criteria for subject selection.
5.6 Criteria for withdrawal from study
5.7 Description and justification of hazards caused by invasive procedures that are not
medically required (if applicable).
5.8 Description of general methods of diagnosis or treatment of the medical condition for
which the investigation testing is being proposed.
5.9 Monitoring arrangements during the clinical investigation including request for direct
access to source documents including extent of source data verification.
6 CLINICAL INVESTIGATION PLAN: Data Collection/Analysis/Statistics
6.1 Description of endpoints to demonstrate safety and performance and the data
recorded to achieve the endpoints, method of subjects follow up, assessment and
monitoring arrangements during investigation.
6.2 Description and justification of statistical design, method and analytical procedures.
Statistical considerations including statistical design and methods describing how to
reach endpoints to demonstrate safety and performance. Level of significance and
the power of the clinical investigation, any criteria for termination of the clinical
investigation (if applicable) with statistical justifications.
6.3 Procedures for data collection, review, cleaning, and issuing and resolving queries, if
appropriate.
6.4 Recording and reporting procedures of clinical investigation plan deviations, if

appropriate
Fin- 26 09 08
7 CLINICAL INVESTIGATION PLAN : Safety Reporting
7.1 Definitions of adverse events and adverse device effects.
7.2 Definitions of serious adverse events and serious adverse device effects.
7.3 Details of procedures of those events to be reported to the relevant Ethics

Committees and Competent Authority, including timelines.
7.4 List of foreseeable adverse events and adverse device effects, likely incidence,
mitigation and/or treatment.
7.5 Emergency contact details for reporting serious adverse events and serious adverse
device effects to the Sponsor.
8 CLINICAL INVESTIGATION PLAN : Other
8.1 Reference to Insurance coverage in case of injury
8.2 Device accountability procedures.
8.3 Ethics and informed consent procedures
8.4 Procedure for early termination or suspension of the investigation giving criteria and
risk analysis.
8.5 Procedure for clinical investigation plan amendments
8.6 Final report and publication policy.

Fin- 26 09 08
ANNEX
GUIDANCE NOTES ON MEDICAL DEVICES INCORPORATING A MEDICINAL

SUBSTANCE HAVING ANCILLARY ACTION
Additional information required with regard to the medicinal substance.
Intended purpose within the context of the device and the risk analysis.
Source, product license (where applicable), quantity/dosage of the medicinal

component, and the method by which the substance is incorporated into the device.
Method of manufacture (solvents/reagents used in processing, residuals).
Control of the starting materials
- (medicinal substance specifications eg, summary of the European Drug

Master File, reference to European Pharmacopoeia or national monograph of
a European Member State).
- Manufacturers may wish to cross-reference a granted Clinical Trial
Exemption (CTE).
- Please refer to The rules governing medicinal products in the European
Community volume III, Addendum II.
Qualitative and quantitative tests carried out on the medicinal substances.
Stability data in relation to the expected shelf-life/lifetime of the device.
Toxicological profile (summary of results of toxicity testing/biological compatibility).
- This should include the effect on reproductivity, embryo/foetal and perinatal

toxicity and the mutagenic/carcinogenic potential of the medicinal substance.
Pharmacodynamics of the medicinal substance in relation to the device.
Pharmokinetic characteristics (local/systemic exposure patterns, duration and

maximum exposure and the maximum plasma concentration peak taking into account
individual variability).
- New active substances should address the release of the substance from the
device, its subsequent distribution and elimination.
Local tolerance (particularly where the route of exposure is different to the

conventional application) eg, the results of EN/ISO 10993 testing, or a review o
NOTE: Referral to MEDDEV 2.1.3, Section B3, which describes the documentation to be
provided by the Notified Body to the Medicinal Product Competent Authority for medicinal
products as part of the consultation procedure may be helpful.
EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE GENERAL
Consumer Goods
MEDDEV. 2.7.1 Rev.3
December 2009
CLINICAL EVALUATION:
BODIES
The present guidelines are part of a set of guidelines relating to questions of application of EU-Directives
on MEDICAL DEVICEs. They are legally not binding. The guidelines have been carefully drafted through
a process of intensive consultation of the various interested parties (competent authorities, Commission
services, industries, other interested parties) during which intermediate drafts were circulated and
comments were taken up in the document. Therefore, this document reflects positions taken by
representatives of interested parties in the MEDICAL DEVICEs sector.
These guidelines incorporate changes introduced by Directive 2007/47/EC amending Council Directive
90/385/EEC and Council Directive 93/42/EEC and will be applicable as of 21st March 2010. The
transitional period allowing a gradual implementation of the guidelines will therefore end on 20 March
2010.
Note:
This document is a revision of an earlier document published in April 2003 as MEDDEV 2.7.1
This document has been drafted on the basis of GHTF Guideline SG5/N2R8:2007 Clinical Evaluation of 29
June 2007 published at www.ghtf.org
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Contents
Preface............................................................................................................................ 4
1.0 Introduction...................................................................................................................... 5
2.0 Scope................................................................................................................................ 6
3.0 References........................................................................................................................ 7
4.0 Definitions........................................................................................................................ 7
5.0 General principles of clinical evaluation ......................................................................... 9
6.0 Sources of data/documentation used in a clinical evaluation (Stage 1).......................... 12
6.1 Data generated through literature search 12
6.2 Data generated through clinical experience 13
6.3 Data from clinical investigations 14
7.0 Appraisal of clinical data (Stage 2)................................................................................. 16
8.0 Analysis of the clinical data (Stage 3) ............................................................................ 17
9.0 The Clinical Evaluation Report....................................................................................... 18
10 The role of the notified body in the assessment of clinical evaluation data 19
10.1 Examination of design dossier 20
10.2 Evaluation as part of the quality system procedure 23
10.3 Notified body specific procedure and expertise 24
Appendices.................................................................................................................... 27
A: A possible format for the literature search report 28
B: A possible methodology for documenting the screening and selection of literature 29
within a literature search report
C: Some examples to assist with the formulation of criteria 30
D: A possible method of appraisal 32
E: A possible format for a clinical evaluation report 34
F: Clinical evaluation checklist for Notified Bodies 37
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Preface
These guidelines on Clinical Evaluation are part of a set of Medical Device Guidelines that
promote a common approach by Manufacturers and Notified Bodies involved in clinical
evaluation procedures according to the relevant annexes of the Medical Devices Directives
and by the National Competent Authorities charged with safeguarding public health.
They have been carefully drafted through a process of consultation with various interested
parties during which comments were taken up in the documents. Therefore, it reflects
positions taken in particular by representatives of National Competent Authorities and
Commission Services, Notified Bodies, industry and other interested parties in the MEDICAL
DEVICEs sector.
The guidelines are regularly updated accordingly with regulatory developments. The latest
version of the guidelines should always be used. This revision of these guidelines has:
amended the document according to the most recent amendment to the Medical
Device Directives (Directive 2007/47/EC) and in the light of experience
and has carefully considered and transposed into the European context the Global
Harmonisation Task Force (GHTF) international regulatory guidance document on
clinical evaluation (SG5/N2R8:2007).
These guidelines are not legally binding. It is recognised that under given circumstances, for
example, as a result of scientific developments, an alternative approach may be possible or
appropriate to comply with the legal requirements.
Nevertheless, due to the participation of the aforementioned interested parties and of experts
from National Competent Authorities, it is anticipated that the guidelines will be followed
within the Member States and, therefore, work towards uniform application of relevant EU
Directive provisions and common practices within Member States.
However, only the text of the Directives is authentic in law. On certain issues not addressed in
the Directives, national legislation may be different from these guidelines.
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1. Introduction
What is clinical evaluation?
Clinical evaluation is the assessment and analysis of clinical data pertaining to a medical
device in order to verify the clinical safety and performance of the device.
When is clinical evaluation undertaken?
Clinical evaluation is an ongoing process conducted throughout the life cycle of a medical
device. It is first performed during the conformity assessment process leading to the
marketing of a medical device and then repeated periodically as new clinical safety and
performance information about the device is obtained during its use. This information is fed
into the ongoing risk analysis and may result in changes to the Instructions for Use.
Why is clinical evaluation important?
When placing a medical device on the market the manufacturer must have demonstrated
through the use of appropriate conformity assessment procedures that the device complies
with the relevant Essential Requirements covering safety and performance. Generally, from a
clinical perspective, it is expected that the manufacturer has demonstrated the device achieves
its intended performance during normal conditions of use and that the known and foreseeable
risks, and any adverse events, are minimised and acceptable when weighed against the
benefits of the intended performance, and that any claims made about the devices
performance and safety (e.g. product labelling and instructions for use) are supported by
suitable evidence.
With regard to post market activities, manufacturers are expected to implement and maintain
surveillance programs that routinely monitor the clinical performance and safety of the device
as part of their Quality Management System. The scope and nature of such post market
surveillance should be appropriate to the device and its intended use. Using data generated
from such programs (e.g. safety reports, including adverse event reports; results from
published literature, any further clinical investigations and formal post market surveillance
studies; etc), a manufacturer should periodically review performance, safety and the benefit-
risk assessment for the device through a clinical evaluation, and update the clinical evidence
accordingly. This ongoing clinical evaluation process should allow manufacturers to
communicate with conformity assessment bodies and Regulatory Authorities in accordance
with local reporting requirements, any information that has an important bearing on the
benefit-risk assessment of the device or that would indicate a need for labelling changes
regarding contraindications, warnings, precautions or instructions for use etc.
What is the process?
To conduct a clinical evaluation, a manufacturer needs to:

identify the Essential Requirements that require support from relevant clinical data;
identify available clinical data relevant to the device and its intended use;
evaluate data in terms of its suitability for establishing the safety and performance of
the device;
generate any clinical data needed to address outstanding issues;
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bring all the clinical data together to reach conclusions about the clinical safety and
performance of the device.
The results of this process are documented in a clinical evaluation report. The clinical
evaluation report and the clinical data on which it is based serve as the clinical evidence that
supports the marketing of the device.
The clinical evidence, along with other design verification and validation documentation,
device description, labelling, risk analysis and manufacturing information, is needed to allow
a manufacturer to demonstrate conformity with the Essential Requirements and is part of the
technical documentation of a medical device.
How detailed should the clinical evaluation be?
A clinical evaluation should be thorough and objective (i.e. it should consider both favourable
and unfavourable data), with the intention of demonstrating valid clinical evidence of the
safety and performance of the device. However, it is important to recognise that there is
considerable diversity in the types and history of technologies used in medical devices and the
risks posed by them. Many devices are developed or modified by incremental innovation, so
they are not completely novel. Thus, it is often possible to draw on the clinical experience and
literature reports of the safety and performance of equivalent devices to establish the clinical
evidence, thereby reducing the need for clinical data generated through clinical investigation
of the device in question. Similarly, it may be possible to use compliance with recognised
standards to satisfy the clinical evidence requirements for devices based on technologies with
well established safety and performance characteristics.
The depth and extent of clinical evaluations should be flexible, not unduly burdensome, and
appropriate to the nature, classification, intended use, manufacturers claims and risks of the
device in question. Therefore, this guidance is not intended to impose specific requirements.
2. Scope
The primary purpose of this document is to provide manufacturers and notified bodies with
guidance on how to conduct and document the clinical evaluation of a medical device as part
of the conformity assessment procedure prior to placing a medical device on the market as
well as to support its ongoing marketing. It is also intended to provide guidance to regulators
and other stakeholders when assessing clinical evidence provided by manufacturers.
This document provides the following guidance:

general principles of clinical evaluation;
how to identify relevant clinical data to be used in a clinical evaluation;
how to appraise and integrate clinical data into a summary; and
how to document a clinical evaluation in a clinical evaluation report.
The guidance contained within this document is intended to apply to medical devices
generally and the device component of combination products. It is not intended to cover in
vitro diagnostics.
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3. References
European Legislation
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical

devices
Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
GHTF final documents
SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to

the Essential Principles of Safety and Performance of Medical Devices
(STED)
SG1-N44:2008 Role of Standards in the Assessment of Medical Devices
SG1/N029:2005 Information Document Concerning the Definition of the Term
Medical Device
SG1/N040:2006 Principles of Conformity Assessment for Medical Devices
SG1-N41R9:2005 Essential Principles of Safety and Performance of Medical Devices
SG5/N1R8:2007 Clinical Evidence Key definitions and Concepts
SG5/N2R8:2007 Clinical Evaluation
International standards
ISO 14155-1: 2003 Clinical investigation of medical devices for human subjects Part 1
General requirements
ISO 14155-2: 2003 Clinical investigation of medical devices for human subjects Part 2
Clinical investigation plan
ISO14971: 2007 Medical devices application of risk management to medical devices.
European guidance documents
MEDDEV 2.10/2 Designation and monitoring of Notified Bodies within the framework of EC
Directives on medical devices
MEDDEV 2.12/2 Guidelines on post-market clinical follow up
NBOG BPG 2009-1 Guidance on design dossier examination and report content
http://www.nbog.eu/resources/NBOG_BPG_2009_1.pdf
NBOG BPG 2009-4 Guidance on NBs Tasks of Technical Documentation Assessment on a
Representative Basis
http://www.nbog.eu/resources/NBOG_BPG_2009_4_EN.pdf
4. Definitions
Adverse Event: Any untoward medical occurrence in a subject.

Note: For the purposes of this document, this is intended to include any
adverse event whether device related or not
Clinical Data: Safety and/or performance information that are generated from the use of a
medical device. (This term is further explained in GHTF document
SG5/N1R8:2007)
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Clinical Evaluation: The assessment and analysis of clinical data pertaining to a medical
device to verify the clinical safety and performance of the device when used
as intended by the manufacturer. (This term is further explained in GHTF
document SG5/N1R8:2007)
Clinical Evidence: The clinical data and the clinical evaluation report pertaining to a medical
device. (This term is further explained in GHTF document SG5/N1R8:2007)
Clinical Investigation: Any systematic investigation or study in or on one or more human

subjects, undertaken to assess the safety and/or performance of a medical
device. (This term is further explained in GHTF document SG5/N1R8:2007)
Clinical Investigation Plan: Document that states the rationale, objectives, design and
proposed analysis, methodology, monitoring, conduct and record-keeping of
the clinical investigation.
Clinical Investigator: The individual responsible for the conduct of a clinical investigation
who takes the clinical responsibility for the well-being of the subjects
involved.
Clinical Performance: The ability of a medical device to achieve its intended purpose as
claimed by the manufacturer.
Clinical Safety: The absence of unacceptable clinical risks, when using the device according
to the manufacturers Instructions for Use.
Conformity Assessment: The systematic examination of evidence generated and procedures

undertaken by the manufacturer, under requirements established by the
Regulatory Authority, to determine that a medical device is safe and
performs
as intended by the manufacturer and, therefore, conforms to the Essential
Requirements.
Serious Adverse Event: An adverse event that

1 led to a death;
2 led to a serious deterioration in health of a patient, user, or others that:
(a) results in a life threatening illness or injury;
(b) results in a permanent impairment of a body structure or body
function;
(c) requires in patient hospitalisation or prolongation of existing
hospitalisation
(d) results in medical or surgical intervention to prevent permanent
impairment to body structure or a body function;
(e) led to foetal distress, foetal death or a congenital abnormality/
birth defect.
Harmonised Standards: Standards deemed to offer the presumption of conformity to the

Essential Requirements of the Directives.
Technical Documentation: The documented evidence, normally an output of the quality

management system that demonstrates compliance of a device to the
Essential Requirements.
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5. General principles of clinical evaluation
5.1 What is the scope of a clinical evaluation?
The clinical evaluation is based on a comprehensive analysis of available pre- and post market
clinical data relevant to the intended use of the device in question, including clinical
performance data and safety data. This includes data specific to the device in question as well
as any data relating to devices claimed as equivalent by the manufacturer.
The evaluation must also address any clinical claims made about the device, the adequacy of
product labelling and product information (particularly claims, contraindications,
precautions/warnings), and the suitability of instructions for use.
Before a clinical evaluation is undertaken the manufacturer should define its scope, based on
the Essential Requirements that need to be addressed from a clinical perspective.
Considerations should include:
(a) whether there are any design features of the device or target treatment populations that
require specific attention.
The clinical evaluation should cover any design features that pose special performance or
safety concerns (e.g. presence of medicinal, human or animal components), the intended
purpose and application of the device (e.g. target treatment group and disease, proposed
warnings, contraindications and method of application) and the specific claims made by the
manufacturer about the clinical performance and safety of the device. The scope of the
clinical evaluation will need to be informed by and cross referenced to the manufacturers risk
management documents. The risk management documents are expected to identify the risks
associated with the device and how such risks have been addressed. The clinical evaluation is
expected to address the significance of any risks that remain after design risk mitigation
strategies have been employed by the manufacturer;
(b) whether data from equivalent devices can be used to support the safety and/or
performance of the device in question.
The devices should have the same intended use and will need to be compared with
respect to their technical and biological characteristics. These characteristics should be
similar to such an extent that there would be no clinically significant difference in the
performance and safety of the device. The intended use relates to the clinical condition
being treated, the severity and stage of disease, the site of application to/in the body and
the patient population; the technical characteristics relate to the design, specifications,
physiochemical properties including energy intensity, deployment methods, critical
performance requirements, principles of operation and conditions of use; and biological
characteristics relate to biocompatibility of materials in contact with the same body
fluids/tissues. In such cases the manufacturer is expected to include the supporting non
clinical information within the technical documentation for the device and cite its
location within the clinical evaluation report. (Note: the clinical evaluation is not
intended to assess the technical and biological characteristics per se); and
(c) the data source(s) and type(s) of data to be used in the clinical evaluation.
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Manufacturers are able to draw on any one or combination of data sources set out in
Section 6.0. Factors that should be considered when choosing the type of data to be used
in the clinical evaluation include the design, intended use and risks of the device; the
developmental context of the technology on which the device is based (new vs.
established technology); and, for established technology, the proposed clinical
application of that technology. Clinical evaluation of medical devices that are based on
existing, well established technologies and intended for an established use of the
technology is most likely to rely on compliance with recognised standards and/or
literature review and/or clinical experience of equivalent devices.
High risk devices, those based on technologies where there is little or no experience, and
those that extend the intended purpose of an existing technology (i.e. a new clinical use)
are most likely to require clinical investigation data. Therefore for implantable or class
III devices, clinical investigations are required unless it can be duly justified to rely on
existing clinical data alone, as stated in the annex X of Directives 93/42/EEC and annex
7 of 90/385/EEC as amended. The manufacturer will need to give consideration to the
advantages and limitations of each data type.
5.2 How is a clinical evaluation performed?
Once the scope has been defined, there are three distinct stages in performing a clinical
evaluation (Figure 1):
identification of pertinent standards and clinical data;
appraisal of each individual data set, in terms of its relevance, applicability, quality and
clinical significance; and
analysis of the individual data sets, whereby conclusions are reached about the
performance, safety and presentational aspects (labelling, patient information and
instructions for use) of the device.
Each of these stages is covered in separate sections later in this document.
At the end of the clinical evaluation a report is prepared and combined with the relevant
clinical data to form the clinical evidence for the device. If the manufacturer concludes there
is insufficient clinical evidence to be able to declare conformity with the Essential
Requirements, the manufacturer will need to generate additional data (e.g. conduct a clinical
investigation, broaden the scope of literature searching) to address the deficiency. In this
respect clinical evaluation can be an iterative process.
5.3 Who should perform the clinical evaluation?
The clinical evaluation should be conducted by a suitably qualified individual or individuals.

A manufacturer must be able to justify the choice of the evaluator(s) through reference to
qualifications and documented experience.
As a general principle, evaluators should possess knowledge of the following:

the device technology and its application;
research methodology (clinical investigation design and biostatistics); and
diagnosis and management of the conditions intended to be treated or diagnosed by
the device.
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Figure 1: Stages of clinical evaluation
Stage 1* Stage 2
Identify clinical data from Appraisal of individual data sets

Literature searching &/or Suitability
Clinical experience &/or Contribution of results to
Clinical investigation demonstration of performance
and safety
Generate new or additional clinical

data
N
O
Stage 3
Is clinical evidence
sufficient to be Analysis of relevant data
able to declare Strength of overall evidence
conformity with Conclusions about performance
relevant ERs? and safety
Y
E
S
Produce clinical evaluation report
*Conformity to harmonized performance standards may be sufficient to demonstrate

compliance to relevant Essential Requirements (ERs)
6. Sources of data/documentation used in a clinical evaluation (Stage 1)

Data relevant to the clinical evaluation may be held by the manufacturer (e.g. manufacturer
sponsored pre and post market investigation reports and adverse event reports for the device
in question) or in the scientific literature (e.g. published articles of clinical investigations and
adverse event reports for the device in question or for equivalent devices).
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The manufacturer is responsible for identifying data relevant to the device and determining
the types and amount of data needed for the clinical evaluation.
Where data are used from a combination of sources, the principles applicable to each source
apply to that data component within the clinical evaluation.
6.1 Data generated through literature search
Literature searching can be used to identify published clinical data that is not in the
possession of the manufacturer that may assist the manufacturer to establish acceptable
performance and safety of a medical device. The data generated through literature searching
may relate directly to the device in question (e.g. reports of clinical investigations of the
device in question that have been performed by third parties, adverse event reports) or to
equivalent devices.
For some devices, clinical data generated through literature searching will represent the
greater part (if not all) of the clinical evidence. Thus, when conducting a literature review
reasonable efforts should be made to conduct a comprehensive search.
Published data will need to be assessed with respect to its possible contribution and weighting
in establishing both the performance of the device in question and its safety. Papers
considered unsuitable for demonstration of performance because of poor study design or
inadequate analysis may still contain data suitable for assessing the safety of the device.
The key elements of literature search
The search strategy should be based on carefully constructed review questions. A protocol
should be developed to identify, select and collate relevant publications to address these
questions. This should be developed and executed by persons with expertise in information
retrieval, having due regard to the scope of the clinical evaluation set out by the manufacturer.
The involvement of information retrieval experts will help to maximise data retrieval.
The literature search protocol should include:

the sources of data that will be used and a justification for their choice;
the extent of any searches of scientific literature databases (the database search
strategy);
the selection/criteria to be applied to published literature and justification for their
choice; and
strategies for addressing the potential for duplication of data across multiple
publications;
Once the literature search has been executed, a report should be compiled to present the
results of the search. A copy of the protocol should be included and any deviations noted. A
possible format for the literature search report is located at Appendix A.
It is important that the literature search is documented to such a degree that the methods can
be appraised critically, the results can be verified, and the search reproduced if necessary. A
possible methodology is presented in Appendix B.
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Which data/documentation from the literature search should be included in the clinical
evaluation?
The following documentation should be used in the clinical evaluation by the clinical
evaluator:
the literature search protocol;
the literature search report; and
published articles and other references identified as being relevant to the device in
question and suitable for evaluation.
The literature search protocol, the literature search report and copies of relevant references
become part of the clinical evidence and, in turn, the technical documentation for the medical
device. With respect to the clinical evaluation, it is important that the clinical evaluator be
able to assess the degree to which the selected papers reflect the intended application/use of
the device, etc.
Copies of the actual papers and references are necessary to allow the evaluator to review the
methodology employed (potential sources of bias in the data), the reporting of results and the
validity of conclusions drawn from the investigation or report. Abstracts may lack sufficient
detail to allow these issues to be assessed thoroughly and independently.
6.2 Data generated through clinical experience
These types of clinical data are generated through clinical use that is outside the conduct of
clinical investigations and may relate to either the device in question or equivalent devices.
Such types of data may include:
manufacturer-generated post market surveillance reports, registries or cohort studies

(which may contain unpublished long term safety and performance data);
adverse events databases (held by either the manufacturer or Regulatory Authorities);
data for the device in question generated from individual patients under compassionate
usage programs prior to marketing of the device;
details of clinically relevant field corrective actions (e.g. recalls, notifications, hazard
alerts)
The value of clinical experience data is that it provides real world experience obtained in
larger, heterogeneous and more complex populations, with a broader (and potentially less
experienced) range of end-users than is usually the case with clinical investigations1.
The data are most useful for identifying less common but serious device-related adverse
events; providing long term information about safety and performance, including durability
data and information about failure modes and elucidating the end-user learning curve. It is
also a particularly useful source of clinical data for low risk devices that are based on long
1
In contrast, clinical investigations involve the use of specific inclusion criteria to create a homogenous
population to reduce sources of variation and, therefore, increase confidence that the outcomes observed in the
investigation are due to intervention with the device in question. Also, investigators participating in the
investigation are chosen on the basis of their expertise and competence and often undergo training over and
above that available to other end-users of the device.
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standing, well-characterised technology and, therefore, unlikely to be the subject of either
reporting in the scientific literature or clinical investigation.
How may clinical experience data/documentation be used in the clinical evaluation?
If a manufacturer chooses to use clinical experience data it is important that any reports or
collations of data contain sufficient information to be able to undertake a rational and
objective assessment of the information and make a conclusion about its significance with
respect to the performance and safety of the device in question. Reports of clinical experience
that are not adequately supported by data, such as anecdotal reports or opinion, should not be
used.
Post market surveillance reports are compiled by the manufacturer and often include details of
the devices regulatory status (countries in which the device is marketed and date of
commencement of supply), regulatory actions undertaken during the reporting period (e.g.
recalls, notifications), a tabulation of adverse events (particularly serious events and deaths,
stratified into whether the manufacturer considers them to be device-related or not) and
estimates of the incidence of adverse events. Post-marketing data about adverse events are
generally more meaningful when related to usage but caution is needed because the extent of
reporting may vary considerably between countries. The analyses of data within these reports
may, for some devices, provide reasonable assurance of both clinical safety and performance.
It may be helpful to provide a table summarising device-related adverse events, paying

particular attention to serious adverse events, with comments on whether observed device-
related adverse events are predictable on the basis of the mode of action of the device.
Manufacturers should comment specifically on any clinical data that identifies hazards not
previously considered in the risk management documentation, outlining any additional
mitigation required (e.g. design modification, amendment of product literature such as
inclusion of contraindications etc).
6.3 Data from clinical investigations
The guidance included within this section applies to clinical investigations carried out by or
on behalf of a manufacturer specifically for the purposes of conformity assessment in
accordance with applicable regulations. Such clinical investigations are generally expected to
be designed, conducted and reported in accordance with EN ISO 14155, Parts 1 and 2,
Clinical Investigations of Medical Devices for Human Subjects, or to a comparable standard,
and in compliance with local regulations.
It is recognised that where manufacturers source clinical investigation data reported in the
scientific literature (i.e. investigations of either the device in question or equivalent devices
that are undertaken by a third party), the documentation readily available to the manufacturer
for inclusion in the clinical evaluation is likely to be no more than the published paper itself.
What clinical investigation documentation/data should be used in the clinical

evaluation?
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is

expected that documentation relating to the design, ethical and regulatory approvals, conduct,
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results and conclusions of the investigation needed for the clinical evaluation will be available
for consideration, as appropriate. These may include:
the clinical investigation plan;
clinical investigation plan amendments and the rationale for these changes;
the relevant Ethics Committee(s) documentation, opinion(s) and comments for each;
investigation site, including a copy of the approved informed consent form(s) and
patient information documents;
case report forms, monitoring and audit records;
Regulatory Authority approvals and associated correspondence as required by
applicable regulations; and
the signed and dated final report.
The clinical investigation plan sets out how the study was intended to be conducted. It
contains important information about the study design such as the selection and assignment of
participants to treatment, masking (blinding of participants and investigators) and
measurement of responses to treatment, which may be important sources of bias that can be
assessed and discounted when trying to determine the actual performance of the device. In
addition the clinical investigation plan sets out the intended participant follow-up, approaches
to statistical analyses and methods for recording outcomes, which may impact on the quality,
completeness and significance of results obtained for performance and safety outcomes.
Also, by having the clinical investigation plan, its amendments and the final report available,
the evaluator will be able to assess the extent to which the investigation was conducted as
planned and, where deviations of from the original plan have occurred, the impact those
deviations had on the veracity of the data generated and the inferences that can be drawn
about the performance and safety of the device from the investigation.
The final report should be signed by its author and appropriate reviewers to provide assurance
that the final report is an accurate reflection of the conduct and results of the clinical
investigation.
Another important consideration of the evaluation will be to assess whether the conduct of the
investigation was in accordance with the current applicable ethical standards that have their
origin in the Declaration of Helsinki and in accordance with applicable regulations. Clinical
investigations not in compliance with applicable ethical standards or regulations should be
rejected. The reasons for rejection of the investigation should be noted in the report.
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7. Appraisal of clinical data (Stage 2)
The purpose of undertaking appraisal of the data is to understand the merits and limitations of
the clinical data. Each piece of data is appraised to determine its suitability to address
questions about the device, and its contribution to demonstrating the safety and performance
of the device (including any specific claims about safety or performance).
What should be covered by the appraisal?
The data needs to be suitable for appraisal. It should be assessed for its quality and for its
relevance to the device in question (i.e. the data must be either generated for the device in
question or for an equivalent device) and its intended use. In addition, any reports or
collations of data should contain sufficient information for the evaluator to be able to
undertake a rational and objective assessment of the information and make a conclusion about
its significance with respect to the performance and/or safety of the device in question.
Further appraisal needs to be undertaken to determine the contribution of each data subset to
establishing the safety and performance of the device. The evaluator should examine the
methods used to generate/collect the data and assess the extent to which the observed effect
(performance or safety outcome(s)) can be considered to be due to intervention with the
device or due to confounding influences (e.g. natural course of the underlying medical
condition, concomitant treatment(s)) or bias.2
There is no single, well established method for appraising clinical data. Therefore, the
evaluator should identify, in advance, the appropriate criteria to be applied for a specific
circumstance
These criteria should be applied consistently. Some examples to assist with the formulation of
criteria are given in Appendix C.
For many lower risk devices and devices based on long standing technology, the available
data may be qualitative rather than quantitative in nature, so the evaluation criteria should be
adjusted accordingly. The criteria adopted for the appraisal should be justified by the
evaluator.
Although there will be some overlap of safety and performance data, the data should be
categorised to allow for separate analysis. Additional categories may also be needed,
depending on the nature and intended use of the device to address additional claims. The data
should also be weighted according to its relative contribution. An example of a method of
data appraisal is shown in Appendix D.
2
Bias is a systematic deviation of an outcome measure from its true value, leading to either an overestimation or
underestimation of a treatments effect. It can originate from, for example, the way patients are allocated to
treatment, the way treatment outcomes are measured and interpreted, and the recording and reporting of data.
page 15 of 46
8. Analysis of the clinical data (Stage 3)
The goal of the analysis stage is to determine if the appraised data sets available for a medical
device collectively demonstrate the clinical performance and safety of the device in relation to
its intended use.
The methods available for analysis of clinical data generally are either quantitative or
qualitative. Given the context within which most medical devices are developed (i.e. limited
need for clinical investigations because of incremental changes in device design and therefore
high use of literature and experience data), often qualitative (i.e. descriptive) methods will
need to be used primarily to address such incremental changes, if justified.
Any evaluation criteria developed and assigned during the appraisal stage can be used to
identify those sets of data which may be considered to be pivotal to the demonstration of
the performance and safety of the device, respectively. It may be useful to explore the results
of the pivotal datasets, looking for consistency of results across particular device performance
characteristics and identified risks. If the different datasets report similar outcomes, certainty
about the performance increases. If different results are observed across the datasets, it will be
helpful to determine the reason for such differences. Regardless, all data sets should be
included.
As a final step the evaluator should consider the basis on which it can be demonstrated that
the combined data show:
the device performs as intended by the manufacturer;
the device does not pose any undue safety concerns to either the recipient or end-user;
and
any risks associated with the use of the device are acceptable when weighed against
the benefits to the patient.
Such considerations should take into account the number of patients exposed to the device,
the type and adequacy of patient monitoring, the number and severity of adverse events, the
adequacy of the estimation of associated risk for each identified hazard, the severity and
natural history of the condition being diagnosed or treated. The availability of alternative
diagnostic modalities or treatments and current standard of care should also be taken into
consideration.
The product literature and instructions for use should be reviewed to ensure they are
consistent with the data and that all the hazards and other clinically relevant information have
been identified appropriately.
page 16 of 46
9. The Clinical Evaluation Report
At the completion of the clinical evaluation process a report should be compiled that outlines
the scope and context of the evaluation; the inputs (clinical data); the appraisal and analysis
stages; and conclusions about the safety and performance of the device in question.
The clinical evaluation report should contain sufficient information to be read as a stand alone
document by an independent party (e.g. Regulatory Authority or Notified Body). It is
important that the report outline:
the technology on which the medical device is based, the intended use of the device
and any claims made about the devices clinical performance or safety;
the nature and extent of the clinical data that has been evaluated; and
how the referenced information (recognised standards and/or clinical data)
demonstrate the clinical performance and safety of the device in question.
The clinical evaluation report should be signed and dated by the evaluator(s) and
accompanied by the manufacturers justification of the choice of evaluator.
A suggested format for the clinical evaluation report is located at Appendix E. Again, it
should be noted that the level of detail in the report content can vary according to the scope of
the clinical evaluation. For example, where a manufacturer relies on clinical data for an
equivalent device which has been the subject of an earlier clinical evaluation (for which the
manufacturer holds the evaluation report), it may be possible to cross-reference the data
summary and analysis sections to the earlier clinical evaluation report, which also becomes
part of the clinical evidence for the device in question.
page 17 of 46
10. The role of the Notified Body in the assessment of clinical evaluation
data
The Notified Body plays a key role in the assessment and verification of clinical evaluations
provided by medical device manufacturers to support demonstration of conformity of a device
with the essential requirements of the relevant Directive.
This section of the document is intended to act as guidance to a Notified Body on the
assessment of clinical evaluations provided by medical device manufacturers as part of
technical documentation/design dossiers and as a part of their procedures for medical devices.
It might also be useful as best practice guidance for national Competent Authorities in their
market surveillance activities.
Pursuant to section 6a of Annex I to Directive 93/42/EEC and to section 5a of Annex 1 to

Directive 90/385/EEC), the demonstration of conformity with Essential Requirements must
include a clinical evaluation conducted in accordance with Annex X to Directive 93/42/EEC
or with Annex 7 to Directive 90/385/EEC. This is applicable for all classes of medical
devices.
Demonstration of conformity without clinical data in accordance with section 1.5 of Annex 7
to Directive 90/385/EEC and section 1.1d of Annex X to Directive 93/42/EEC must be
adequately justified and based on the output of the risk management process. The device-body
interaction, the intended use and the claims of the manufacturer have to be specifically
considered. Adequacy of demonstration of conformity based on performance evaluation,
bench testing and pre-clinical evaluation in the absence of clinical evaluation must be duly
substantiated. The Notified Body must review the manufacturers justification, the adequacy
of data presented and whether or not conformity is demonstrated.
Notified Body Assessment of Clinical Evaluation by Conformity Assessment Route
With regard to the review of clinical evaluations the Notified Body has different roles
depending on the classification of the device and the conformity assessment procedure
followed.
This includes for medical devices in accordance with Directive 93/42/EEC:

An audit as part of a quality system approval procedure (Annex II, section 3):
- The notified body assesses the manufacturers procedure for clinical evaluation.
- As part of the representative sampling of devices for review of their technical
documentation the notified body verifies the clinical evaluation data presented for
class IIa and IIb devices in accordance with the criteria outlined in this section.
A design dossier (Annex II, section 4) or type examination dossier (Annex III)
assessment:
- the notified body assesses the data presented in the clinical evaluation, verifies the
manufacturers assessment of that data and assesses the validity of the conclusions
drawn by the manufacturer.
For active implantable medical devices in accordance with Directive 90/385/EEC:

A design dossier (Annex 2, section 4) or type examination dossier (Annex 3) assessment:
page 18 of 46
manufacturers assessment of that data and assesses the validity of the clinical
evaluation report and the conclusions drawn by the manufacturer.
The Notified Body should also have documented procedures to cover review of updates to
clinical evaluation data during their scheduled surveillance activities and at the time of
changes to or extensions of EC design-examination/EC type-examination certificates. This
arises from the obligation placed on the manufacturer to actively update the clinical
evaluation with data obtained from post-market surveillance e.g. post-market clinical follow-
up and ongoing literature reviews/surveys.
10.1. EXAMINATION OF A DESIGN DOSSIER (ANNEX II.4; ANNEX 2.4) OR OF A TYPE

EXAMINATION DOSSIER (ANNEX III; ANNEX 3)
The Notified Body examines the clinical evaluation documentation submitted (relevant
documentation referenced in sections 5 to 9 of this MEDDEV), verifies the manufacturers
identification, appraisal, analysis and assessment of that data and validates the conclusions
drawn by the manufacturer. In order to do so, the Notified Body should possess enough
knowledge and experience in clinical evaluation as stated in section 10.3 of this document.
In Appendix F of this document a checklist is provided for use by a Notified Body during the
assessment of clinical evaluation data. This checklist should be used as a supplementary tool
but should not replace the Notified Body Report outlined below.
10.1.1 Decision-making by the Notified Body
In reviewing the evaluation of clinical data submitted by the manufacturer, the Notified Body
verifies and decides whether or not the manufacturer has adequately:
- supplied clinical evaluation documentation (as referenced in sections 5 to 9);

- followed relevant procedures (as addressed by sections 5 to 9);
- described and verified the intended characteristics and performances related to clinical
aspects;
- performed an appropriate risk analysis and estimated the undesirable side effects;
- involved appropriate clinical expertise in the compilation of the risk analysis to ensure
risks and benefits associated with real clinical use are adequately defined;
- justified the chosen route(s) of clinical data retrieval (according to sections 5 and 6);
- identified, appraised, analysed and assessed the clinical data (according to sections 5
to 9) and demonstrated the relevance and any limitations of the clinical data identified
in demonstrating compliance with particular requirements of the Directive or cited in
particular aspects of the risk analysis;
- provided sufficient clinical data relating to the safety, performance, design
characteristics and intended purpose of the device in order to demonstrate conformity
with each of the relevant essential requirements;
- if a critical evaluation of relevant scientific literature is provided, the notified body
verifies that this data relates to the safety, performance, design characteristics and
intended purpose of the device;
- if a critical evaluation of relevant scientific literature is provided the notified body
verifies that the device under assessment is demonstrated as equivalent to the device to
which the data relates in all necessary areas (i.e. clinical, design, biological etc.);
page 19 of 46
- if a critical evaluation of relevant scientific literature is provided the notified body
verifies that the data presented for equivalent devices adequately addresses each of the
relevant essential requirements;
- provided specific justification if a specific clinical investigation was not performed for
class III or implantable devices.
Note: A clinical evaluation is required for all classes of medical devices, the relevance
of the data or the need for clinical investigation data should always be assessed and
documented by the notified body;
- provided evidence that clinical investigations presented are in compliance with
applicable regulatory and ethical requirements e.g. ethics committee approval,
competent authority approval;
- justified the appropriateness of the planned post-market clinical follow up;
- justified and documented if post-market clinical follow-up is not planned as part of the
post-market surveillance plan for the device;
- concluded on the basis of documented justification that the risks are acceptable when
weighed against the intended benefits and the relevant Essential Requirements are
met.
The assessment carried out by the Notified Body will typically cover the following aspects of
the manufacturers clinical evaluation:
- appraisal to determine suitability and any limitations of the data presented to address
the essential requirements in particular relating to the safety and performance of the
device as outlined in section 7;
- complete and adequate documentation (according to sections 5 to 9);
- adequate procedures (according to sections 5 to 9)
- the validity of any justification given;
- the listing, characterisation and proof of the clinical performance of the device
intended by the manufacturer and the expected benefits for the defined patient
group(s);
- the use of harmonised standards
- the use of the list of identified hazards to be addressed through evaluation of clinical
data as described in section 8;
- the adequate estimation of the associated risks for each identified hazard by:
b) estimating and characterising the probability of occurrence of harm, health
impairment or loss of benefit of the treatment (document with rationale).
The decision on the acceptability of risks3 in relation to each identified hazard, and
- unacceptable; or
- acceptable under specified conditions.
For drug-device combination products where a scientific opinion from a medicinal competent
authority or from the EMEA has been sought, the notified body should consider any
comments or considerations raised in the medicinal clinical assessment when making its final
decision on the device. In the case of devices with a human blood derivative the notified body
3
Valid decision making criteria from applicable guidance and standards may be employed e.g. ISO 14971.
page 20 of 46
may not deliver a positive decision to issue a certificate if the EMEA's scientific opinion is
unfavourable.
10.1.2 The report of the Notified Body
The Notified Body writes a report on its assessment of the submitted clinical evaluation
documentation.
If a design dossier report is applicable the clinical report should be incorporated into this
report. The report should clearly identify the Notified Bodys assessment, verification on each
of the critical elements and overall conclusions.
NBOG BPG 2009-1 defines the minimum content for a design dossier review report in the
following sections:
- Manufacturer details
- Details relating to the application and NB review (including staff and experts involved
in the review and the aspects assessed by each, signatures of responsible reviewers
etc.)
- Device description and product specification
- Classification
- Requirements regarding manufacturing
- Requirements regarding design and construction
- Pre-clinical evaluation
- Clinical evaluation/performance evaluation
- Other applicable Directives
- Risk analysis and risk management
- Review of declaration of conformity
- Post-market surveillance
- Summary of review
The Notified Body should justify and document each step of the decision making process
referred in 10.1.1.above. One single unacceptable risk/benefit ratio leads to a negative
conclusion4;
The clinical evaluation assessment report should:

- Record whether the clinical evaluation documentation was complete and adequate
- Record the Notified Bodies verification of each step of the clinical evaluation process,
from scoping, choice of route(s), identification, appraisal, analysis and overall
assessment of the clinical data, to concluding and reporting
- Record the completeness of the clinical evaluation conducted and its accordance with
this document
- Record the Notified Bodys assessment of the clinical investigation data and/or
literature review assembled, relevant procedures and compliance to relevant standards
- Verify that the device has met the claimed performance/intended use and side-effects
and risks have been properly evaluated
4
In some cases, the combination of the conditions specified in order to characterise different individual
risk/benefit ratios as acceptable may be contradictory or impracticable, and so also leads to an overall negative
conclusion. Positive benefit/risk ratios for specific aspects do not compel an overall positive benefit/risk ratio for
the device.
page 21 of 46
- Record the Notified Bodys assessment of the clinical safety, performance and
benefit/risk ratio
- Record the Notified Bodys assessment of the conclusions drawn by the manufacturer
from the clinical data presented
- Record the Notified Bodys assessment of the validity of the clinical evaluation and its
steps
- Record the Notified Bodys conclusions on the clinical evaluation, documenting each
step in the decision making process as per section 10.1.1.
10.2. EVALUATION AS PART OF QUALITY SYSTEM RELATED PROCEDURES (Annex II.3 of

Directive 1993/42/EEC)
10.2.1. Review of the manufacturers procedures
The Notified Body shall, as part of the review of the manufacturers quality system, assess the
establishment, maintenance and application of the manufacturers documented procedures for
the evaluation of clinical data. This should cover:
(a) the proper assignment of responsibilities to suitably qualified persons involved in the
clinical evaluation [e.g. clinical evaluator(s), information retrieval expert(s), clinical
investigator(s)];
(b) the integration of clinical evaluation into the quality system as a continuous process, to
be specifically inter-related to, and informed by, preclinical evaluation and risk
management;
(c) standard operating procedures to assure proper planning, conduct, evaluation, control
and documentation of scoping, identification of clinical data (section 5), literature
searching (section 6.1), collection of clinical experience (section 6.2), clinical
investigation (section 6.3 and EN ISO 14155), appraisal of clinical data (section 7),
analysis of clinical data (section 8), concluding, reporting (section 9) and update of
clinical evaluation, including PMCF (MEDDEV 2.12/2);
(d) Document control as part of overall documentation of procedures, reporting,
qualifications and technical documentation/design dossier(s);
(e) identification and evaluation of undesirable side effects and of clinical performance(s).
This involves identification of known or reasonably foreseeable hazards and
verification of unfavourable and favourable outcome(s), qualification of their
severity/magnitude and of their probability of occurrence. (It is part of the
manufacturers documented risk analysis based on both favourable and unfavourable
data identified as relevant in order to give a balanced view).
10.2.2. Review of the technical documentation of representative samples
The Notified Body is required to assess the technical documentation for class IIa and class IIb
devices on a representative basis. Clinical evaluation data should be assessed by the Notified
Body for at least one representative sample for each device subcategory for class IIa devices
and at least one representative sample for each generic device group for class IIb devices.
Further representative samples have to be assessed as part of the annual surveillance
assessment cycle.
Regarding the choice of representative sample(s) the notified body will consider the novelty
of the technology, similarities in design, technology, manufacturing and sterilisation methods,
page 22 of 46
the intended use and the results of previous relevant assessments. Assessment of
representative samples includes assessment of clinical evaluation data according to the criteria
outlined in this document rather than solely confirming that the manufacturer has a clinical
evaluation procedure in place.
The criteria for the technical documentation assessment on a representative basis outlined in
NBOG BPG 2009-4 should be applied.
When performing the assessment on samples of a manufacturers clinical evaluation, the

Notified Body will follow the steps indicated in section 10.1 of this document.
The Notified Body, when reviewing samples of the manufacturers clinical data evaluation,
should pay special attention to the following:
(a) whether or not the data is relevant to the device, its intended use(s) or medical
procedure(s) involved and adequately cover the related clinical performance, safety
and benefit/risk relation
(b) where the manufacturer, in the selected sample, has chosen the literature route,
whether the criteria defined in section 6.1 have been applied;
(c) where the manufacturer, in the selected sample, has selected the clinical
investigations route, whether the criteria defined in section 6.3 have been applied.
10.3. NOTIFIED BODY SPECIFIC PROCEDURES AND EXPERTISE
A Notified Body should have formal procedures in place controlled by their quality system
relating to the assessment of clinical evaluations provided by medical device manufacturers.
These procedures should also cover the review of updates to clinical evaluation data during
their scheduled surveillance activities and at the time of changes to or extensions of EC
design-examination/EC type-examination certificates.
Notified Bodies should establish and implement internal policies and procedures for the
assessment of clinical evaluations in order to:
(a) ensure that suitable resources, especially relevant regulatory knowledge and clinical
competence necessary for such evaluation, are available within5 the Notified Body and
by contracting external clinical experts if required.
Such expertise should be sufficient to identify and estimate the risks and benefits
associated with the use of the medical devices. The evaluation team should be able to
evaluate a risk analysis and the risk management strategy performed by the
manufacturer.
The evaluation team should understand the device technology as well as the medical
procedure.
Such an evaluation may require input from a qualified medical practitioner (for
example physician, dentist, nurse etc.), as appropriate for the particular device, who
5
Annex XI.3 of Directive 93/42/EEC. This presupposes the availability of sufficient scientific staff within the organisation
who possess experience and knowledge sufficient to assess the medical functionality and performance of devices for which it has
been notified, having regard to the requirements of this Directive and, in particular, those set out in Annex I.
page 23 of 46
has clinical experience in the pathology of the condition being treated, the usual
treatment, the therapeutic alternatives etc.
When examining the results of clinical investigations, the evaluation team shall have
knowledge in planning, conduct and interpretation of clinical investigations. All
evaluators should be appropriately trained and qualified.
Particular attention should be drawn to training of external experts on the conformity

assessment procedure(s), relevant guidance, standards and the context of the
assessment they are providing. The Notified Body should be responsible for reviewing
the opinion of these experts, taking account of their level of knowledge of the
provisions of the Directives.
The opinion of an external clinical expert may form part of the assessment conducted
by the notified body. The opinion and conclusions of the notified body, in part based
on this external opinion, should be clearly documented.
The impartiality and the potential for conflict of interest of an external expert reviewer
should be assessed and documented by the notified body.
(b) review the evaluation of clinical data provided by the manufacturer;
(c) document the opinion with rationale of all experts involved;
(d) ensure that any external experts involved are impartial and independent from any
parties involved, having due regard to any conflict of interest which may compromise
impartiality (see also MEDDEV 2.10/1);
(e) document the result of their assessment. This is achieved through a specific report
which may be part of, or may be referenced, in the overall audit report, design / type
examination report (as per 10.1.2 of this document) or the report on the assessment of
representative samples documentation;
(f) preserve confidentiality of the information and data received from the manufacturer,
especially within the terms for contracting external experts.
page 24 of 46
APPENDICES
B: A possible methodology for documenting the screening and selection of

literature within a literature search report 29
page 25 of 46
APPENDIX A
A POSSIBLE FORMAT FOR THE LITERATURE SEARCH REPORT
1. Device name/model
2. Scope of the literature search [should be consistent with scope of clinical evaluation]
3. Methods
(i) Date of search
(ii) Name of person(s) undertaking the literature search
(iii) Period covered by search
(iv) Literature sources used to identify data:
- scientific databases bibliographic (e.g. MEDLINE, EMBASE),
specialised databases (e.g. MEDION)
- systematic review databases (e.g. Cochrane Collaboration)
- clinical trial registers (e.g. CENTRAL),
- adverse event report databases (e.g. MAUDE, IRIS)
- reference texts
Include justification for choice of sources and describe any supplemental

strategies (e.g. checking bibliography of articles retrieved, hand searching of
literature) used to enhance the sensitivity of the search.
(v) Database search details:

- search terms (key words, indexing headings) and their relationships
(Boolean logic)
- medium used (e.g. online, CD-ROM (including publication date and edition))
Attach copy of downloaded, unedited search strategy.
(vi) Selection criteria used to choose articles
4. Outputs
(i) Attach copy of literature citations retrieved from each database search
(ii) Data selection process
Attach flow chart and associated tables showing how all citations were assessed
for suitability for inclusion in the clinical evaluation (see Appendix B).
Notes:
EMBASE Excerpta Medica published by Elsevier
CENTRAL The Cochrane Central Register of Controlled Trials
IRIS The TGAs medical device Incident Report Investigation Scheme
MAUDE US FDAs Manufacturer And User Facility Device Experience database
MEDION Database that indexes literature on diagnostic tests
MEDLINE Published by US National Library of Medicine
page 26 of 46
APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
6
LITERATURE WITHIN A LITERATURE SEARCH REPORT
Potentially relevant literature identified

through the search
(copy of all citations)
Literature excluded, with reasons
Literature retrieved for more detailed

assessment
Literature excluded from clinical

evaluation, with reasons
Literature with relevant useable data

included in the clinical evaluation, by
outcome:
Device performance*
Device safety*
Device comparability
(if applicable)
*some literature will address issue of both performance and safety
6
Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF . Improving the quality of
reports and meta-analyses of randomised controlled trials: the QUORUM statement. Quality of Reporting of
Meta-analyses. Lancet 1999; 354:1896-1900
page 27 of 46
APPENDIX C:
SOME EXAMPLES TO ASSIST WITH THE FORMULATION OF CRITERIA7
_______________________________________________________________________________________________________________________________________________________________________________________________________________________________
-
_________
The following are examples of questions to ask to assist with the formulation of criteria for
data appraisal for different type of data sets. These examples are not meant to be
comprehensive with regards to study types or all potential questions.
Randomised controlled trial

Clinical investigation where subjects are randomised to receive either a test or reference
device or intervention and outcomes and event rates are compared for the treatment groups.
Were the inclusion and exclusion criteria specified?
Was the assignment to the treatment groups really random?
Was the treatment allocation concealed from those responsible for recruiting subjects?
Was there sufficient description about the distribution of prognostic factors for the
treatment groups?
Were the groups comparable at baseline for these factors?
Were outcome assessors blinded to the treatment allocation?
Were the care providers blinded?
Were the subjects blinded?
Were all randomised participants included in the analysis?
Was a point estimate and measure of variability reported for the primary outcome?
Cohort study
Data are obtained from groups who have and have not been exposed to the device (e.g.
historical control) and outcomes compared.
Were subjects selected prospectively or retrospectively?
Was an explicit description of the intervention provided?
Was there sufficient description about how the subjects were selected for the new
intervention and comparison groups?
new intervention and comparison groups?
Were the groups comparable for these factors?
Did the study adequately control for potential confounding factors in the design or
analysis?
Was the measurement of outcomes unbiased (i.e. blinded to treatment group and
comparable across groups)?
Was follow-up long enough for outcomes to occur?
What proportion of the cohort was followed up and were there exclusions from the
analysis?
Were drop-out rates and reasons for drop-out similar across intervention and
unexposed groups?
7
Adapted from: Guidelines for the assessment of diagnostic technologies. Medical Services Advisory
Committee; Commonwealth of Australia 2005.
page 28 of 46
Casecontrol study
Patients with a defined outcome and controls without the outcome are selected and
information is obtained about whether the subjects were exposed to the device.
Was there sufficient description about how subjects were defined and selected for the
case and control groups?
Was the disease state of the cases reliably assessed and validated?
Were the controls randomly selected from the source of population of the cases?
case and control groups?
analysis?
Was the new intervention and other exposures assessed in the same way for cases and
controls and kept blinded to case/control status?
How was the response rate defined?
Were the non-response rates and reasons for non-response the same in both groups?
Was an appropriate statistical analysis used?
If matching was used, is it possible that cases and controls were matched on factors
related to the intervention that would compromise the analysis due to over-matching?
Case series
The device has been used in a series of patients and the results reported, with no control group
for comparison.
Was the series based on a representative sample selected from a relevant population?
Were the criteria for inclusion and exclusion explicit?
Did all subjects enter the survey at a similar point in their disease progression?
Was follow-up long enough for important events to occur?
Were the techniques used adequately described?
Were outcomes assessed using objective criteria or was blinding used?
If comparisons of sub-series were made, was there sufficient description of the series
and the distribution of prognostic factors?
page 29 of 46
APPENDIX D:
A POSSIBLE METHOD OF APPRAISAL
___________________________________________________________________________
___
There are many methods that can be used to appraise and weight clinical data. An example of
possible appraisal criteria is given in Tables D1 and D2. The criteria may be worked through
in sequence and a weighting assigned for each dataset. The data suitability criteria can be
considered generic to all medical devices (Table D1), however the actual method used will
vary according to the device considered.
To assess the data contribution criteria of the suitable data, the evaluator should sort the data
sets according to source type and then systematically consider those aspects that are most
likely to impact on the interpretation of the results (Table D2). There is scope for the
evaluator to determine what types of issues are most important in relation to the nature,
history and intended clinical application of the device. The criteria used in the example below
are based around the sorts of issues that could be considered for devices of higher risk, such
as characteristics of the sample, methods of assessing the outcomes, the completeness and
duration of follow-up, as well as the statistical and clinical significance of any results.
In this example, the weightings would be used to assess the strength of the datasets
contribution to demonstrating overall performance and safety of the device (Stage 3, see
section 8). As a general guide in using this example, the more level 1 grades, the greater the
weight of evidence provided by that particular dataset in comparison to other datasets,
however, it is not intended that the relative weightings from each category be added into a
total score.
Table D1 Sample Appraisal Criteria for Suitability
Sutability Criteria Description Grading System

Appropriate device Were the data generated from the D1 Actual device
device in question? D2 Equivalent device
D3 Other device
Appropriate device Was the device used for the same A1 Same use
application intended use (e.g., methods of A2 Minor deviation
deployment, application, etc.)? A3 Major deviation
Appropriate patient Where the data generated from a P1 Applicable
group patient group that is representative of P2 Limited
the intended treatment population P3 Different population
e.g., age, sex, etc.) and clinical
condition (i.e., disease, including
state and severity)?
Acceptable report/data Do the reports or collations of data R1 High quality
collation contain sufficient information to be R2 Minor deficiencies
able to undertake a rational and R3 Insufficient information
objective assessment?
page 30 of 46
Table D2 Sample Appraisal Criteria for Data Contribution
Data Contribution Criteria Description Grading System

Data source type Was the design of the study T1 Yes
appropriate? T2 No
Outcome measures Do the outcome measures O1 Yes

reported reflect the intended O2 No
performance of the device?
Follow up Is the duration of follow-up long F1 Yes
enough to assess whether F2 No
duration of treatment effects and
identify complications?
Statistical significance Has a statistical analysis of the S1 Yes
data been provided and is it S2 No
appropriate?
Clinical significance Was the magnitude of the C1 Yes
treatment effect observed C2 No
clinically significant?
page 31 of 46
APPENDIX E:
A POSSIBLE FORMAT FOR A CLINICAL EVALUATION REPORT
___________________________________________________________________________
1. General details
State the proprietary name of the device and any code names assigned during device
development.
Identify the manufacturer(s) of the device.
2. Description of the device and its intended application
Provide a concise physical description of the device, cross referencing to relevant sections of
the manufacturers technical information as appropriate. The description should cover
information such as:
materials, including whether it incorporates a medicinal substance (already on the market
or new), tissues, or blood products;
the device components, including software and accessories;
mechanical characteristics; and
others, such as sterile vs. non-sterile, radioactivity etc.
State the intended application of the device single use/reusable; invasive/non invasive;
implantable; duration of use or contact with the body; organs, tissues or body fluids contacted
by the device.
Describe how the device achieves its intended purpose.
3. Intended therapeutic and/or diagnostic indications and claims
State the medical conditions to be treated, including target treatment group and diseases.
Outline any specific safety or performance claims made for the device
4. Context of the evaluation and choice of clinical data types
Outline the developmental context for the device. The information should include whether the
device is based on a new technology, a new clinical application of an existing technology, or
the result of incremental change of an existing technology. The amount of information will
differ according to the history of the technology. Where a completely new technology has
been developed, this section would need to give an overview of the developmental process
and the points in the development cycle at which clinical data have been generated. For long
standing technology, a shorter description of the history of the technology (with appropriate
references) could be used. Clearly state if the clinical data used in the evaluation are for an
equivalent device. Identify the equivalent device(s) and provide a justification of the
equivalency, cross-referenced to the relevant non-clinical documentation that supports the
claim.
State the Essential Requirements relevant to the device in question, in particular, any special
design features that pose special performance or safety concerns (e.g. presence of medicinal,
page 32 of 46
human or animal components) that were identified in the device risk management
documentation and that required assessment from a clinical perspective.
Outline how these considerations were used to choose the types of clinical data used for the
evaluation. Where published scientific literature has been used, provide a brief outline of the
searching/retrieval process, cross-referenced to the literature search protocol and reports.
5. Summary of the clinical data and appraisal
Provide a tabulation of the clinical data used in the evaluation, categorised according to
whether the data address the performance or the safety of the device in question. (Note: many
individual data sets will address both safety and performance.) Within each category, order
the data according to the importance of their contribution to establishing the safety and
performance of the device and in relation to any specific claims about performance or safety.
Additionally, provide a brief outline of the data appraisal methods used in the evaluation,
including any weighting criteria, and a summary of the key results.
Include full citations for literature-based data and the titles and investigation codes (if
relevant) of any clinical investigation reports.
Cross-reference the entry for each piece of data to its location in the manufacturers technical
documentation.
6. Data analysis
6.1 Performance
Provide a description of the analysis used to assess performance.
Identify the datasets that are considered to be the most important in contributing to the
demonstration of the overall performance of the device and, where useful, particular
performance characteristics. Outline why they are considered to be pivotal and how they
demonstrate the performance of the device collectively (e.g. consistency of results, statistical
significance, clinically significance of effects).
6.2 Safety
Describe the total experience with the device, including numbers and characteristics of
patients exposed to the device; and duration of follow-up of device recipients.
Provide a summary of device-related adverse events, paying particular attention to serious

adverse events.
Provide specific comment on whether the safety characteristics and intended purpose of the
device requires training of the end-user.
6.3 Product Literature and Instructions for Use
State whether the manufacturers proposed product literature and Instructions for Use are
consistent with the clinical data and cover all the hazards and other clinically relevant
information that may impact on the use of the device.
page 33 of 46
7. Conclusions
Outline clearly the conclusions reached about the safety and performance of the device from
the evaluation, with respect to the intended use of the device. State whether the risks
identified in the risk management documentation have been addressed by the clinical data.
For each proposed clinical indication state whether:

the clinical evidence demonstrates conformity with relevant Essential Requirements;
the performance and safety of the device as claimed have been established; and
the risks associated with the use of the device are acceptable when weighed against the
benefits to the patient
page 34 of 46
APPENDIX F
Clinical evaluation checklist for Notified Bodies

Ref Requirement Fulfilled Comment
0 Conformity without Clinical Data
0.1 Any demonstration of conformity without clinical data Yes
(Annex 7.1.5 of 90/385/EEC and Annex X.1.1d of No
93/42/EEC) must be adequately justified and based on N/A.
the output of the risk management process
viewed in the context of the device-body interaction
the intended clinical performance
the claims of the manufacturer.
Adequacy of demonstration of conformity based on

performance evaluation, bench testing and pre-clinical
evaluation in the absence of clinical evaluation must be
duly substantiated.
The notified body must review the manufacturers

justification, the adequacy of data presented and whether
or not conformity is demonstrated.
Is the manufacturers justification adequate?
Is the performance evaluation, bench testing and pre-
clinical evaluation adequate to demonstrate
conformity to the Essential Requirements?
1 Clinical Evaluation, General
1.1 The manufacturer should include in the technical Yes Clinical literature
documentation a statement on the route(s) applied to No Published
retrieve the clinical data used to affix the CE N/A.
marking. Unpublished
Equivalence demonstrated
The statement should make clear whether that
Clinical investigation
clinical data was obtained from the published
literature or the results of clinical investigations or a Combination of literature and investigation data
page 35 of 46
combination of both and shall include an adequate Comment
justification of the route(s) selected and a
demonstration of equivalency (technical, biological,
clinical) and adequacy if clinical data from similar
devices have been used
1.2 The Clinical Evaluation Report and the full clinical Yes
data used for CE marking should be included within No
the technical documentation N/A.
1.3 The manufacturer has clearly documented the Yes
objectives and the scope of the clinical evaluation No
and specified the clinical ERs [e.g. clinical N/A.
performance(s), safety, risks and favourable
benefit/risk ratio related to intended use, target
group(s) and indication(s)] to be met
1.4 The manufacturer has clearly outlined the performed Yes
steps and procedures of clinical evaluation according No
to this MEDDEV (specifically sections 5 to 9), N/A.
adequate justification given for deviations
2 Clinical investigation route
2.1 Need for clinical investigation
2.1.1 Classification of device Yes
Is the device an implantable or class III medical No
device or an active implantable medical device? N/A.
2.1.2 If a clinical investigation is not presented for an Yes
implantable or class III MD or an AIMD, has this No
been adequately justified by the manufacturer in his N/A.
risk analysis and clinical evaluation?
2.1.3 If clinical literature is presented for equivalent Yes
devices, is this clinical data when taken together with No
the available pre clinical data sufficient to N/A.
demonstrate conformity with the essential
requirements covering safety and performance of the
device in question under normal conditions of use?
page 36 of 46
devices, are there gaps in either the demonstration of No
compliance with each relevant essential requirement N/A.
or in the demonstration of equivalence that needs
addressing through the means of a specifically
designed clinical investigation(s)?
devices, is the data sufficient to address the clinical No
hazards identified in the risk analysis? N/A.
If no, a clinical investigation(s) will be needed.
The objectives of the clinical investigation(s) should
focus on those aspects not sufficiently addressed by
the available data.
2.2 Conduct of clinical investigation
2.2.1 Were the relevant annexes of the medical devices Yes
Directives (Annex 7 AIMD, Annex X MDD) and the No
relevant standards (EN ISO 14155-1, -2) taken into N/A.
account?
2.2.2 Requirements for clinical investigations
2.2.3 Identification of relevant documentation, the
following documentation should be requested and
reviewed by the notified body:
2.2.4 Copy of the Protocol submitted to the Competent Yes
Authority or other regulatory agency for which no No
grounds for objection were raised N/A.
2.2.5 Copy of the letter of no objection/approval from Yes
Competent Authority/Authorities (if available) or No
other approval from the relevant regulatory N/A.
agency(ies), together with any comments made
arising from regulatory review
2.2.6 Copy of the Ethics Committee opinion(s) and Yes
comments arising from their review or a summary of No
all Ethics Committee opinions and any N/A.
comments/conditions arising from their reviews
page 37 of 46
2.2.7 Copy of the signed and dated final report Yes
No
N/A.
2.3 Information to be checked the following
information should be checked by the notified
body
2.3.1 Letter of no objection from the Competent Yes
Authority(ies) No
N/A.
2.3.2 Clinical Investigation Plan (CIP): Is the CIP, used for the Yes
clinical investigation, the same as that submitted to the No
Competent Authority? 8 N/A.
2.3.3 If parameters are not as set out in the original CIP, the Yes
rationale for non-adherence No
N/A.
2.3.4 Identification of any changes to CIP and rationale for any Yes
such changes No
N/A.
2.3.5 Where the clinical investigation(s) was performed outside Yes
the EU, the manufacturer must demonstrate that the use of No
the device (including clinical practice and techniques) and N/A.
patient population are equivalent to those for which the
device will be used within the EU (if relevant).
2.3.6 For drug-device combinations, have any issues or Yes
concerns raised as part of the clinical assessment of the No
medicinal substance by the medicinal competent authority N/A.
or EMEA been considered and/or resolved?
2.4 Final report of investigation
The report should be reviewed and should include the
2.4.1 Summary a structured abstract should be provided, Yes
8 Particular attention should be paid to: number of patients entered; objectives of investigation(s) (in particular which Essential Requirements are being addressed); duration of investigation(s) and patient follow up (short and long-term); end points in terms of
diagnostic tools and patient assessment; inclusion and exclusion criteria
.
page 38 of 46
presenting the essentials of the study9 No
N/A.
2.4.2 Introduction a brief statement placing the study in the Yes
context of the development of the medical device in No
question and an identification of guidelines followed in N/A.
the development of the Protocol
2.4.3 Materials and methods10 Yes
No
N/A.
2.4.4 Summary of the clinical investigation plan 11 Yes
No
N/A.
2.4.5 Results this section should contain summary Yes
information with a description of the analysis and results12 No
N/A.
2.4.6 Discussions and conclusions 13 Yes
No
N/A.
2.4.7 Signature the final report should be signed off by the Yes
9
Including title of investigation(s); identification of the medical device(s), including names, models as relevant for complete identification; name of sponsor; statement
indicating whether the investigation(s) was performed in accordance with CEN/ISO Standards; objectives; subjects; methodology; investigation(s) initiation and completion
dates, including date of early termination, if applicable; results; conclusions; authors of report; date of report.
10
Including device description; summary description of the device and its intended use, together with any modifications performed during the investigation.
11
Including the clinical investigation objectives; the investigation design; type of investigation; investigation end points; ethical considerations; subject population;
inclusion/exclusion criteria; sample size; treatment and treatment allocation; investigation variables; concomitant medications/treatments; duration of follow up; statistical
analysis including investigation hypothesis or pass/fail criteria, sample size calculation, statistical analysis methods.
12
Including the investigation initiation date; investigation completion/suspension date; the disposition of patients/devices; the patient demographics; clinical investigation
plan compliance; the analysis to include safety report, including a summary of all adverse events and adverse device events seen in the investigation, including a discussion of
the severity, treatment required, resolution and assessment by the investigator of relation to treatment; performance or efficacy analysis; any sub group analysis for special
population; a description of how missing data, including patients lost to follow up or withdrawn, were dealt with in the analysis.
13
Including the performance and safety results of the study; the relationship of risks and benefits; clinical relevance and importance of the results, particularly in the light of
other existing data and discussion of comparison with state of the art; any specific benefits or special precautions required for individual subjects or at risk groups; any
implications for the conduct of future studies.
page 39 of 46
sponsor, the co-ordinating clinical investigator (if No
appointed) and principal investigator at each centre N/A.
2.4.8 Annex to the report, containing clinical investigation plan, Yes
including amendments, list of investigators and their No
institutions, list of other parties involved, list of monitors, N/A.
list of statisticians (if applicable), list of Ethics
Committees and their approval letters.
2.5 NB assessment of the clinical investigation(s) data
presented
2.5.1 Have any identified pass/fail criteria of the Yes
investigation(s) been met? No
N/A.
2.5.2 Have the results and conclusions of the clinical Yes
investigation(s) demonstrated compliance with the No
identified relevant essential requirements? N/A.
2.5.3 Are the claims made in the device labelling substantiated Yes
by clinical data when taken together with the relevant No
pre-clinical data? N/A.
2.5.4 Has the risk analysis demonstrated that the risks Yes
associated with the use of the device, as set out by the No
manufacturer, are acceptable when balanced against the N/A.
benefits to the patient?
2.5.5 Was the assessment performed in a critical and objective Yes
manner? No
N/A.
3 Clinical literature data
A critical evaluation of relevant scientific literature that is currently available relating to safety, performance, design characteristics
and intended purpose in the form of a written report
3.1 Methodology
3.1.1 A critical evaluation of relevant scientific literature has Yes
been presented No
N/A.
3.1.2 A search protocol for the identification, selection, Yes
collation and review of relevant publications should be No
page 40 of 46
written. N/A.
3.1.3 The objective of the literature review should be clearly Yes
defined No
N/A.
3.1.4 The types of studies that are relevant to the objective of Yes
the literature review should be specified No
N/A.
3.1.5 Data should be taken from recognised scientific Yes
publications. Unpublished data should also be taken into No
account in order to avoid publication bias. N/A.
3.1.6 The literature review should state:
3.1.6.1 sources of data, extent of the searches of databases or Yes
other sources of information No
N/A.
3.1.6.2 rationale for the selection/ relevance of the published Yes
literature No
N/A.
3.1.6.3 reasons for believing that all relevant references, both Yes
favourable and unfavourable, have been identified No
N/A.
3.1.6.4 criteria for exclusion of particular references together Yes
with a justification for this exclusion. No
N/A.
3.1.6.5 detailed description of the different stages of Yes
literature search (including identification, appraisal, No
analysis and conclusion of hits) N/A.
3.2 Relevance of data presented
3.2.1 A literature review should clearly establish the extent Yes
to which the literature relates to the specific No
characteristics and features of the device under N/A.
consideration.
3.2.2 If the published studies do not directly refer to the Yes
device in question, the manufacturer must No
page 41 of 46
demonstrate equivalence with the device, which is N/A.
the subject of the published reports.
3.2.3 To be equivalent, the devices should have similarity Yes
with regard to the clinical, technical and biological No
parameters with special attention to the performance, N/A.
principles of operation and materials; or if there are
differences identified, an assessment and
demonstration of the significance these might have
on safety and performance must be set out14.
3.2.4 The manufacturer must be able to demonstrate the Yes
adequacy of the data in addressing the aspects of No
conformity set out in the objective N/A.
3.3 NB Assessment of clinical data
The literature review should make clear the
significance that is attached to particular references
based on a number of factors. These include:
3.3.1 relevance of the authors background and expertise in Yes
relation to the particular device and/or medical procedure No
involved N/A.
3.3.2 whether the authors conclusions are substantiated by the Yes
available data No
N/A.
3.3.3 whether the literature reflects the current medical practice Yes
and the generally acknowledged state of the art No
technologies N/A.
3.3.4 whether references are taken from recognised scientific Yes
publications and whether or not they have been reported No
14
Equivalence means:
Clinical: used for the same clinical condition or purpose, at the same site in the body, in similar population (including age, anatomy, physiology); have similar relevant
critical performance according to expected clinical effect for specific intended use.
Technical: used under similar conditions of use; have similar specifications and properties e.g. tensile strength, viscosity, surface characteristics; be of similar design; use
similar deployment methods (if relevant); have similar principles of operation.
Biological: use same materials in contact with the same human tissues or body fluids.
page 42 of 46
in peer reviewed journals N/A.
3.3.5 the extent to which the published literature is the outcome Yes
of a study/studies which have followed scientific No
principles in relation to design15 N/A.
3.4 Critical evaluation of the literature
The literature review should contain a critical evaluation of the literature. This critical evaluation should:
3.4.1 be written by a person suitably qualified in the relevant Yes
field, and reviewed and approved by an expert No
knowledgeable in the state of the art and able to N/A.
demonstrate objectivity
3.4.2 contain a short description of the medical device, its Yes
intended functions, description of the intended purpose No
and application of use N/A.
3.4.3 contain an analysis of all the available data considered, Yes
both favourable and unfavourable No
N/A.
3.4.4 establish the extent to which the literature relates to the Yes
specific characteristics and features of the device being No
assessed, taking due account of the extend of similarity N/A.
between the device(s) covered by the literature and the
device under assessment
3.4.5 demonstrate that those aspects of the use of the device, Yes
including performance, addressed in the clinical part of No
the risk analysis are met as claimed by the manufacturer, N/A.
and that the device fulfils its intended purpose as a
medical device
3.4.6 analyse the identified hazards, the associated risks and the Yes
appropriate safety measures of patients, medical staff and No
15
For example in having demonstrable and appropriate endpoints, inclusion and exclusion criteria, an appropriate and validated number of patients submitted, carried out for
an appropriate duration, providing evidence and analysis of all adverse incidents, deaths, exclusions, withdrawals and subjects lost follow-up and identifying an appropriate
statistical plan of analysis. Ideally, evidence should be generated from a clinical trial (controlled if appropriate), properly designed cohort/case controlled study, well
documented case histories or sequential reports conducted by appropriate experienced experts, whether in relation to the device itself or an equivalent device. If unpublished
data is being included in the assessment, the literature review will need to weigh the significance that is attached to each report.
page 43 of 46
third parties involved in the study/studies N/A.
3.4.7 contain a risk analysis relevant to the device design, Yes
materials and procedures involved, taking into account No
any adverse events, results of post-market surveillance N/A.
studies, modifications and recalls (if known)
3.4.8 contain a description of the methods of weighting of Yes
different papers and the statistical methods of analysis No
employed taking into account the assessment methods, the N/A.
type and duration of study and the heterogeneity of the
population included within the study
3.4.9 include an analysis of the market experience of the same Yes
or similar devices, including the results of post-marketing No
studies, post-market surveillance and short- and long-term N/A.
adverse events
3.4.10 contain a list of publications appropriately cross- Yes
referenced in the evaluation No
N/A.
3.4.11 if the clinical data relates to an equivalent device, contain Yes
a statement that equivalence with all the relevant No
characteristics has been demonstrated N/A.
3.4.12 include a conclusion16 with a justification, including an Yes
assessment of any probable benefit to health from the use No
of the device as intended by the manufacturer, against N/A.
probable risks of injury or illness from such use taking
account of the state of the art. The conclusions should
make clear how the objectives of the literature review
have been met and identify any gaps in the evidence
necessary to cover all relevant aspects of safety and
performance
3.4.13 The critical evaluation should be signed and dated by the Yes
author No
16
Conclusions should consider the claimed use - indications, contra-indications and instructions for use proposed by the manufacturer.
page 44 of 46
N/A.
3.5 NB Assessment of the critical evaluation of literature
presented by the manufacturer
3.5.1 Are the manufacturers conclusions valid? Yes
No
N/A.
3.5.2 Is the data, taken together with the available pre clinical Yes
data, sufficient to demonstrate compliance with the No
essential requirements covering safety and performance of N/A.
the device in question under normal conditions of use? 17
by the clinical data taken together with the pre-clinical No
data? N/A.
manner? No
N/A.
4 Post-market clinical follow up the notified body
should check and review the manufacturers post
market clinical follow up plan:
4.1 Has the manufacturer presented an appropriate plan for Yes
post-market clinical follow up in line with appropriate No
guidance? N/A.
4.2 If no post-market clinical follow up plan is presented, has Yes
this been adequately justified by the manufacturer? No
N/A.
4.3 Has the manufacturer an adequate post-market Yes
surveillance system in place? No
N/A.
4.4 Has the manufacturer committed to inform the NB of Yes
significant updates to their clinical evaluation arising from No
17
If not, identify gaps in the demonstration of compliance with the relevant essential requirements or in the demonstration of equivalence that need addressing through the
means of a specifically designed clinical investigation(s).
page 45 of 46
PMS/PMCF? N/A.
5 Notified Body Decision Making
5.1 In reviewing the evaluation of clinical data submitted by the manufacturer the NB must decide whether the manufacturer
has adequately
5.1.1 described and verified the intended characteristics and Yes
performances related to clinical aspects No
N/A.
5.1.2 performed a risk analysis and estimated the undesirable Yes
side effects No
N/A.
5.1.3 concluded on the basis of documented justification that Yes
the risks are acceptable when weighed against the No
intended benefits N/A.
5.2 NB assessment of benefit/risk presented in the clinical
evaluation data
5.2.1 the listing and characterisation of the clinical performance Yes
of the device intended by the manufacturer and the No
expected benefits for the patient N/A.
5.2.2 the use of the list of identified hazards to be addressed Yes
through evaluation of clinical data No
N/A.
5.2.3 the adequate estimation of the associated risks for each Yes
identified hazard by: No
a) characterising the severity of the hazard; N/A.
b) estimating and characterising the probability of
occurrence of the harm (or health impairment or loss of
benefit of the treatment) (document with rationale)
5.2.4 the decision on the acceptability of risks in relation to Yes
each identified hazard No
N/A.
page 46 of 46
EUROPEAN COMMISSION
ENTERPRISE AND INDUSTRY DIRECTORATE GENERAL
Consumer Goods
MEDDEV. 2.7/1 Rev. 4

(draft version of 1.5.2013 prepared by
the CAMD Clinical TF)
XXX 2013

BODIES
The present guidelines are part of a set of guidelines relating to questions of application of EU-
Directives on MEDICAL DEVICEs. They are legally not binding. The guidelines have been carefully
drafted through a process of intensive consultation of the various interested parties (competent
authorities, Commission services, industries, notified bodies, other interested parties) during which
intermediate drafts were circulated and comments were taken up in the document. Therefore, this
document reflects positions taken by representatives of interested parties in the MEDICAL DEVICEs
sector.
These guidelines incorporate changes introduced by Directive 2007/47/EC amending Council

Directive 90/385/EEC and Council Directive 93/42/EEC.
Note:
This document is a revision of an earlier document published in December 2009 as MEDDEV 2.7.1
This document has been drafted taking into consideration the GHTF Guideline SG5/N2R8:2007
Clinical Evaluation of 29 June 2007 published at www.imdrf.org. [vs1]: www.ghtf.org is no longer
present.
page 1 of 60
Contents
[[Write new table when the contents have been updated]]
Preface............................................................................................................................ 4
1.0 Introduction...................................................................................................................... 5
2.0 Scope................................................................................................................................ 6
3.0 References........................................................................................................................ 7
4.0 Definitions........................................................................................................................ 7
5.0 General principles of clinical evaluation ......................................................................... 9
6.0 Sources of data/documentation used in a clinical evaluation (Stage 1).......................... 12
6.1 Data generated through literature search 12
6.2 Data generated through clinical experience 13
6.3 Data from clinical investigations 14
7.0 Appraisal of clinical data (Stage 2)................................................................................. 16
8.0 Analysis of the clinical data (Stage 3) ............................................................................ 17
9.0 The Clinical Evaluation Report....................................................................................... 18
10 The role of the notified body in the assessment of clinical evaluation data 19
10.1 Examination of design dossier 20
10.2 Evaluation as part of the quality system procedure 23
10.3 Notified body specific procedure and expertise 24
Appendices.................................................................................................................... 27
B: A possible methodology for documenting the screening and selection of literature 29
within a literature search report
page 2 of 60
Preface
These guidelines on Clinical Evaluation are part of a set of Medical Device Guidelines that
promote a common approach by Manufacturers and Notified Bodies involved in clinical
evaluation procedures according to the relevant annexes of the Medical Devices Directives
and by the National Competent Authorities charged with safeguarding public health.
They have been carefully drafted through a process of consultation with various interested [sci2]:
Improved document structure:
parties during which comments were taken up in the documents. Therefore, it reflects Paragraph deleted because of redundancy.
positions taken in particular by representatives of National Competent Authorities and This text is also on the front page of this
MEDDEV document (newer version there)
Commission Services, Notified Bodies, industry and other interested parties in the MEDICAL (CAMD Clinical TF members)
DEVICEs sector.
streamlined the interpretation of the definitions of clinical data, clinical evidence and
clinical evaluation to promote a homogenous interpretation and further understanding
of the requirements of Directive 93/42/EEC concerning medical devices and Directive
90/385/EEC relating to active implantable medical devices.
rephrased some paragraphs to reflect the above listed changes.
described key aspects of clinical evaluation known to be previously used in a variable
way.
within the Member States and, therefore, work towards uniform application of relevant EU
Directive provisions and common practices within Member States.
However, only the text of the Directives is authentic in law. On certain issues not addressed in
the Directives, national legislation may be different from these guidelines.
page 3 of 60
1. Introduction
Pursuant to section 6a of Annex I to Directive 93/42/EEC and to section 5a of Annex 1 to [sci3]:
CAMD Clinical TF member input:
Directive 90/385/EEC), the demonstration of conformity with Essential Requirements must - Improvement of structure of the document
include a clinical evaluation conducted in accordance with Annex X to Directive 93/42/EEC by moving most contents to later sections,
and resolving the previous duplication of
or with Annex 7 to Directive 90/385/EEC. This is applicable for all classes of medical devices. contents in sections 1 an 10
- This paragraph was formerly in section 10
and has been moved to this location
2. Scope
The primary purpose of this document is to provide manufacturers and notified bodies with
guidance on how to conduct and document the clinical evaluation of a medical device as part
of the conformity assessment procedure prior to placing a medical device on the market as
well as to support its ongoing marketing. It is also intended to provide guidance to regulators
and other stakeholders when assessing clinical evaluation reports provided by manufacturers.
This document provides the following guidance:

general principles of clinical evaluation;
how to identify relevant clinical data to be used in a clinical evaluation;
how to appraise and integrate clinical data into a summary; and
how to document a clinical evaluation in a clinical evaluation report.
vitro diagnostics.
3. References
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical

devices
SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to

the Essential Principles of Safety and Performance of Medical Devices
(STED)
SG1-N44:2008 Role of Standards in the Assessment of Medical Devices
SG1/N029:2005 Information Document Concerning the Definition of the Term
Medical Device
SG1/N040:2006 Principles of Conformity Assessment for Medical Devices
SG1-N41R9:2005 Essential Principles of Safety and Performance of Medical Devices
SG5/N2R8:2007 Clinical Evaluation
International standards [sci4]:

- Standards information in this chapter
updated in January 2013
page 4 of 60
ISO 14155:2011 Clinical investigation of medical devices for human subjects Good
clinical practice
ISO14971:2012 Medical devices application of risk management to medical devices.
MEDDEV 2.7/2 Guide for Competent Authorities in making an assessment of clinical

investigation notification
MEDDEV 2.7/4 Guidelines on Clinical investigations: a guide for manufacturers and
notified bodies
MEDDEV 2.10/2 Designation and monitoring of Notified Bodies within the framework of EC
Directives on medical devices
MEDDEV 2.12/2 Guidelines on post-market clinical follow up studies
NBOG BPG 2009-1 Guidance on design dossier examination and report content
http://www.nbog.eu/resources/NBOG_BPG_2009_1.pdf
NBOG BPG 2009-4 Guidance on NBs Tasks of Technical Documentation Assessment on a
Representative Basis
http://www.nbog.eu/resources/NBOG_BPG_2009_4_EN.pdf
NBOG CL2010-1 Checklist for audit of notified bodies review of clinical data/clinical
evaluation
REMARK. Check if NBOG checklist CL2010 and the Checklist in Appendix F of this [sci5]:
(Discussed by CA participants during
MEDDEV should be merged and/or better aligned 13.2.2013 meeting, and during 22.4.2013
CAMD Clinical TF teleconference)
4. Definitions
Adverse Event: Any untoward medical occurrence in a subject. Note: For the purposes of
this document, this is intended to include any adverse event whether device
related or not.
Bias: Bias is a systematic deviation of an outcome measure from its true value, [sci6]:
Improvement of document structure:
leading to either an overestimation or underestimation of a treatments Definition unchanged, but moved from
effect. It can originate from, for example, the way patients are allocated to former section 7 to this location since the
term is used in different parts of this
treatment, the use of outcome measures and/or subgroup analysis different MEDDEV.
from the protocol, the way treatment outcomes are measured and
interpreted, and the recording and reporting of data.
Clinical Data: Safety and/or performance information that are generated from the use of a
medical device in humans. (This term is further explained in GHTF
document SG5/N1R8:2007)
Clinical Evaluation: A methodologically sound procedure to collect and analyse clinical data [sci7]:
Improved structure of the document: shorter
pertaining to a medical device and to assess whether there is sufficient description, since details are given in the
clinical evidence to confirm compliance with relevant essential requirements body text of this MEDDEV document.
(As suggested by CAMD Clinical TF
for safety and performance. members)
[J8]: Side effects are an aspect of
Clinical Evidence: Clinical data of an amount and quality as to prove the validity and safety
accuracy 1 of a claim or a statement. [sci9]:
- New definition provided by Sweden
based on existing definitions and standards
(Definition reviewed and confirmed by CA
1 participants during 13.2.2013 meeting)
Work on Footnote to further explain accuracy (data such as ranges,.),
page 5 of 60
Clinical Evaluation Report: The documentation of the clinical evaluation
Clinical Investigation: Any systematic investigation or study in or on one or more human

subjects, undertaken to assess the safety and/or performance of a medical
device. (This term is further explained in GHTF document SG5/N1R8:2007) [sci10]:
Now MEDDEV 2.7/4 cited above
(as suggested by CAMD Clinical TF
Clinical Investigation Plan: Document that states the rationale, objectives, design and members)
proposed analysis, methodology, monitoring, conduct and record-keeping of
Clinical Investigator: The individual responsible for the conduct of a clinical investigation
who takes the clinical responsibility for the well-being of the subjects
involved. [J11]: This differs from ISO 14155,
which defines both investigator and
Principal Investigator. It would be better to
Clinical Performance: The ability of a medical device to achieve its intended purpose as use ISO definitions
Clinical Safety: Freedom from unacceptable risk, when using the device according to the [J12]: To align with the definition of
safety in ISO 14971.
manufacturers Instructions for Use.
Conformity Assessment: The systematic examination of evidence generated and procedures

undertaken by the manufacturer, under requirements established by the
Regulatory Authority, to determine that a medical device is safe and
performs as intended by the manufacturer and, therefore, conforms to the
Feasibility study: A clinical investigation that is commonly used to capture preliminary

information on a medical device (at an early or late stage of product design)
to adequately plan further steps of device development, including needs for
design modifications or parameters for a pivotal study.
Pivotal study: A clinical investigation adequately designed and powered to collect

definitive evidence of benefits to the patients, clinical risks, clinical
performance, and/or clinical aspects of the usability of a device for a
specified intended use. [sci13]:
- Definition of feasibility and pivotal
studies added
Device Deficiency: Inadequacy of a medical device with respect to its identity, quality, durability, (Change reviewed and confirmed by CA
reliability, safety or performance. NOTE Device deficiencies include malfunctions, participants during 13.2.2013 meeting,
transferred to definitions section and
use errors, and inadequate labelling. adapted following suggestion of Italian CA,
text presented for 22.4.2013 CAMD
Clinical TF teleconference, modiefied
Serious Adverse Event: An adverse event that according to input of CAMD Clinical
1 led to a death; taskforce member)
2 led to a serious deterioration in health of a patient, user, or others that:
[sci14]:
(a) results in a life threatening illness or injury; Is the term Device deficiency used in this
(b) results in a permanent impairment of a body structure or body MEDDEV document? If not, delete the
definition.
function; (Input of CAMD Clinical taskforce
(c) requires in-patient hospitalisation or prolongation of existing members)
hospitalisation [J15]: Additional definition needed
(d) results in medical or surgical intervention to prevent life- to ensure consistency with ISO 14155 and
MEDDEV 2.7/3
threatening illness or injury or permanent impairment to body
structure or a body function;
page 6 of 60
(e) led to foetal distress, foetal death or a congenital abnormality/
birth defect.
Harmonised Standards: Standards published by the European Commission deemed to offer

the presumption of conformity to the Essential Requirements of the
Directives.
Technical Documentation: The documented evidence, normally an output of the quality

management system that demonstrates compliance of a device to the
page 7 of 60
5. General principles of clinical evaluation [sci16]:
- Need for in depth review of the section
and the structure of the MEDDEV
identified by CA at 13.2.2013 meeting,
What is clinical evaluation? revision carried out by chair, revised texts
presented for 22.4.2013 CAMD Clinical TF
teleconference, contributions by members
Clinical evaluation is the analysis of clinical data pertaining to a medical device in order to of CAMD Clinical TF before and after the
assess whether there is clinical evidence to verify compliance with Essential Requirements of teleconference of 22.4.2013.
- Structure of the document improved by
the medical devices directives, in particular with the following requirements that relate to moving large parts of section 1 into this
clinical properties of devices: section.
- Better aligned with essential requirements.
- Annex 1 (sections 1, 2, 5) of Directive 90/385/EEC relating to active implantable medical [J17]: While the Essential
devices, Requirements listed are the most relevant, it
is restrictive to suggest that only these ERs
- Annex I (sections 1, 3, 6) of Directive 93/42/EEC concerning medical devices. can be addressed by a Clinical Evaluation.
[J18]: Including ERs 5a and 6a of
Generally, from a clinical perspective, it is expected the respective Directives here does not
make sense A Clinical Evaluation meets
a) that the clinical evaluation demonstrates that any risks which may be associated with the the requrement to have a Clinical
intended use are minimised and acceptable when weighed against the benefits to the Evaluation. Better to mention these ERs in
the introductory sentence.
patient and are compatible with a high level of protection of health and safety;
b) that the device achieves its intended performance during normal conditions of use, and are
supported by suitable evidence (clinical performance includes all claims about clinical
properties of the device that the manufacturer intends to make use of);
c) that any undesirable side-effect constitutes an acceptable risk when weighed against the
performances intended;
d) that the instructions for use correctly describe the intended use of the device as supported
by clinical evidence; and
e) that the instructions for use contain correct information about usability aspects, residual
risks and their management as supported by clinical evidence (e.g. handling instructions,
type and frequency of risks, warnings, precautions, contraindications).
When is clinical evaluation undertaken?
Clinical evaluation is an ongoing process conducted throughout the life cycle of a medical [sci19]:
- Update according to revision of chapter 5
device. Usually, it is first performed during the development of a medical device in order to of MEDDEV 2.7/4 of December 2010
identify data that needs to be generated for market access. The evaluation is updated for the - alignment with Section 1 of the Essential
Requirements in Annex I of the medical
needs of the conformity assessment procedure leading to the marketing of a medical device. It devices directive 93/42/EEC and risk
is then updated periodically and as new information appear (information on clinical properties management standard EN ISO 14971:2012
(Changes to this chapter reviewed and
of the device obtained during its use, information regarding the state of the art in the confirmed by CA participants during
corresponding medical field, including general changes to the performance of devices in the 13.2.2013 meeting)
market and the level of protection of health and safety of users and patients). This information
is also fed into the ongoing risk analysis and may result in changes to the Instructions for Use
or other activities.
Why is clinical evaluation important? [sci20]:

- Chapter updated for closer alignment with
essential requirements
Clinical evaluation is important to assert that the clinical properties of the device (benefits to - Changes first presented, reviewed and
confirmed by CA participants during
the patient, risks, clinical performances described by the manufacturer) and their acceptability 13.2.2013 meeting
are based on clinical evidence throughout the life time of the medical device on the market. - Presented for 22.4.2013 CAMD Clinical
TF teleconference
- original statement covering safety and
When placing a medical device on the market the manufacturer must have demonstrated performance described with closer
alignment to the essential requirements in a
through the use of appropriate conformity assessment procedures that the device complies new paragraph at the beginning of the
with the relevant Essential Requirements. chapter and deleted below.
What is the process?

page 8 of 60
To conduct a clinical evaluation, a manufacturer needs to:
- Specify the intended use (including the medical conditions and target groups in which the [sci21]:
List completed for better alignment with the
manufacturer foresees the device to be used) and any claims about clinical properties of rest of the document
the device the manufacturer intends to make use of; (Suggestions of CAMD Clinical TF
members)
- identify the Essential Requirements with performance characteristics and safety criteria
[J22]: The ERs that are likely to be
that require support from relevant clinical data; relevant are mentioned above. It would be
- generate the scoping report; sensible to be a bit more specific here to
focus on the results of the gap analysis that
- identify available clinical data relevant to the device and its intended use; is necessary.
- evaluate data in terms of their suitability for establishing the safety and clinical
[sci23]:
performance of the device; List completed for better alignment with
- generate any clinical data needed to address outstanding issues; changes introduced in the rest of the
document
- bring all the clinical data regarding the device together to reach conclusions about clinical (Suggestions of CAMD Clinical TF
properties and their acceptability. members)
The results of this process are documented in a clinical evaluation report and its updates.
The clinical evaluation report, along with other design verification and validation
documentation, device description, labelling, risk analysis and manufacturing information, is
needed to allow a manufacturer to demonstrate conformity with the Essential Requirements
and is part of the technical documentation of a medical device.
How detailed should the clinical evaluation be?
A clinical evaluation should be thorough and objective (i.e. it should consider both favourable
and unfavourable data), with the intention of demonstrating valid clinical evidence of the
safety and performance of the device. However, it is important to recognise that there is
considerable diversity in the types and history of technologies used in medical devices and the
risks posed by them. Most devices are developed or modified by incremental innovation, and [J24]: The role of equivalency has
previously been presented in a simplistic
none are completely novel. Thus, it is usually possible to draw on the clinical experience and way. We should provide a more
literature reports of the safety and clinical performance of existing devices and therapies to informative explanation of the use of
existing data.
establish the clinical evidence, thereby defining the scope of the clinical evaluation more
precisely and reducing the need for clinical data generated through clinical investigation of
the device in question. Similarly, it may be possible to use compliance with recognised
standards to satisfy the clinical evidence requirements for devices based on technologies with
well established safety and performance characteristics.
The depth and extent of clinical evaluations should be flexible, not unduly burdensome, and
appropriate to the nature, classification, intended use, manufacturers claims and risks of the
device in question. Therefore, this guidance is not intended to impose specific requirements.
What is a clinical evaluation based on [sci25]:

- corrected title, since the scope of a clinical
evaluation is described in a previous
The clinical evaluation is based on a comprehensive analysis of available pre- and post market chapter
- better aligned with Essential
clinical data relevant to the intended use of the device in question, including data on benefits Requirements and the rest of the document
to the patients, risks, and the clinical performance defined by the manufacturer. This includes - clearer and more specific
- takes into consideration recurrent issues
- clinical data specific to the device in question, about insufficient or irrelevant sources
- clinical data relating to devices considered to be equivalent by the manufacturer, being used and cited in clinical evaluations
(Part of in depth review identified by CA at
- pre-clinical data demonstrating equivalence, 13.2.2013 meeting, presented for 22.4.2013
- clinical data regarding the state of the art in the corresponding medical field, such as CAMD Clinical TF teleconference).
benefits, risks, and the clinical performance of available interventions.
page 9 of 60
The evaluators will take into consideration and summarise relevant data, analyse why data can
be considered to constitute relevant evidence supporting conformity to the essential
requirements, and identify any gaps and needs for further investigations. In doing so, they will
take into consideration
- the scientific quality of available data;
- what parameters can be used to describe benefits, clinical performance and safety, and if
they are relevant for the different medical conditions and target populations covered by
the intended use of the device;
- the acceptability of the benefit-to-risk ratio for all medical conditions and target
populations covered by the intended use;
- clinical evidence supporting claims about clinical properties of the device the
manufacturer intends to make use of;
- the adequacy of product labelling and the contents of the instructions for use, including
handling instructions, type and frequency of risks, warnings, precautions,
contraindications.
6. Specific aspects of clinical evaluation
6.1. Equivalence [sci26]:
- Structure of the document improved: Text

Directives 90/385/EEC and 93/42/EEC foresee that a clinical evaluation can be based on data regarding equivalence unchanged but
moved to chapter 5.2.
of a similar device for which equivalence to the device in question can be demonstrated. - Aim of this chapter is to merge the two
Clinical, technical and biological characteristics should usually be taken into consideration for texts previously describing equivalence in
MEDDEV 2.7.1 (the first one was in
the demonstration of equivalence: Chapter 5.1 letter b, the second was in
Annex F footnote 14). The previous two
- Clinical: Used for the same clinical condition or purpose (including similar severity and texts differed and therefore caused recurrent
stage of disease), at the same site in the body, in a similar population (including age, questions regarding the interpretation of the
term "equivalence". There should be only
anatomy, physiology); have similar relevant critical performance according to the one section describing equivalence in this
expected clinical effect for a specific intended use. MEDDEV document.
- Technical: be of similar design; used under similar conditions of use; have similar
specifications and properties (e.g. physicochemical properties such as intensity of energy,
tensile strength, viscosity, surface characteristics, wavelength); use similar deployment
methods (if relevant); have similar principles of operation and critical performance
requirements.
- Biological: Use same materials or substances in contact with the same human tissues or
body fluids.
These characteristics should be similar to such an extent that there would be no clinically
significant difference in the performance and safety of the device.
[[Need for more specific guidance and examples regarding equivalence identified by notified
body representative at 14.2.2013 meeting, waiting for suggestions]]
6.2. Assessment of the clinical benefits of devices [sci27]:

- New chapters (6.2 to 6.9) with new
contents
Examples of clinical benefits include but are not limited to the devices impact on the clinical - Specific examples provided
(Need for in depth review identified by CA
management of patients, patient health and patient satisfaction, such as allowing a correct at 13.2.2013 meeting; importance of
diagnosis to be made, significantly improving quality of life (including by simplifying care), providing specific examples in MEDDEV
documents commented by NB representant
reducing the probability of adverse outcomes, improving patient function, providing relief at 14.2.2013 CIE meeting; texts prepared by
from symptoms. Ideally, these parameters should be directly clinically relevant. In certain CAMD Clinical TF members and presented
for 22.4.2013 TF teleconference, further
cases benefits can be assumed when validated surrogate endpoints are met (such as obtaining refined by CAMD Clinical TF members).
page 10 of 60
certain results with laboratory tests or measurements of anatomical or physiological
properties). Defining specified endpoints is indispensible for setting up clinical investigations
and properly perform the literature review. Based on the current state of medical knowledge,
the evaluators shall justify and document the clinical relevance of endpoints used for a clinical
evaluation of a device, including the validity of all surrogate endpoints used. For diagnostic
medical devices 2, a benefit may be assessed according to the public health impact of a
particular device, due to its ability to identify a specific disease and therefore prevent its
spread, to identify phases, stages, location, severity or variants of disease, predict future
disease onset, provide earlier diagnosis of diseases or specifics of diseases, or identify patients
more likely to respond to a given therapy.
The magnitude of the benefit(s) benefit(s) are often assessed along a scale or according to
specific endpoints or criteria (types of benefits), or by evaluating whether a pre-identified
health threshold was achieved. The change in subjects condition or clinical management as
measured on that scale, or as determined by an improvement or worsening of the endpoint, is
what allows to determine the magnitude of the benefit(s) in subjects, the clinical relevance of
which must be discussed and justified. Variation in the magnitude of the benefit across a
population may also be considered.
The probability of the patient experiencing one or more benefit(s) is another important
aspect of assessing benefits and the clinical performance of a device. Based on the clinical
data provided, a reasonable prediction (based on a sound statistical approach) of the
proportion of "responders" out of the target group or subgroups can be expected. The data
may show that a benefit may be experienced only by a small portion of patients in the target
population, or, on the other hand, that a benefit may occur frequently in patients throughout
the target population. It is also possible that the data will show that different patient subgroups
are likely to experience different benefits or different levels of the same benefit. If the
subgroups can be identified, the device may be indicated for those subgroups. In some cases,
however, the subgroups may not be identifiable. Magnitude and probability of clinical
benefits will have to be put together when weighing benefits against risks. That is, a large
benefit experienced by a small proportion of subjects may raise different considerations than
does a small benefit experienced by a large proportion of subjects. For example, a large
benefit, even if experienced by a small population, may be significant enough to outweigh
risks, whereas a small benefit may not, unless experienced by a large population of subjects.
The duration of effect(s) (i.e., how long the benefit can be expected to last for the patient)
should be predictable (maybe as a statistical distribution) on the basis of sound clinical data
and appropriate statistical approaches. Post Market Clinical Follow-up will be decisive to
refine and corroborate reasonable predictions over time. The mode of action may play an
important role: Some treatments are curative, whereas, some may need to be repeated
frequently over the patients lifetime. To the extent that it is known, the duration of a
treatments effect may directly influence how its benefit is defined. Treatments that must be
repeated over time may introduce greater risk, or the benefit experienced may diminish each
time the treatment is repeated.
6.3. Assessment of the clinical risks of devices
To demonstrate the extent of the probable risk(s)/harm(s) the following factors - individually
and in the aggregate - will have to be addressed:
2
IVDs are not covered by this MEDDEV
page 11 of 60
- Severity, types, number and rates 3 of harmful events associated with the use of the
device:
- Device-related serious adverse events: Those events that may have been or were
attributed to the use of the device and produce an injury or illness that is life-
threatening, results in permanent impairment or damage to the body, or requires
medical or surgical intervention to prevent permanent harm to the body.
- Device-related non-serious adverse events: Those events that may have been or were
attributed to the use of the device and that do not meet the criteria for classification as
a device-related serious adverse event.
- Procedure-related complications: Harms to the patient that would not be included
under serious or non-serious adverse events, and that do not directly result from use of
the device. For example, anesthetic-related complications associated with the
implantation of a device.
- Probability of a harmful event:

The proportion of the intended population that would be expected to experience a harmful
event. FDA would factor whether an event occurs once or repeatedly into the measurement
of probability.
- Duration of harmful events (i.e., how long the adverse consequences last): Some devices
can cause temporary, minor harm; some devices can cause repeated but reversible harm;
and other devices can cause permanent, debilitating injury. The severity of the harm should
be considered along with its duration.
- Risk from false-positive or false-negative results for diagnostic medical devices 4: If a

diagnostic device gives a false-positive result, the patient might, for example, receive an
unnecessary treatment and incur all the risks that accompany that treatment, or might be
incorrectly diagnosed with a serious disease. If a diagnostic device gives a false-negative
result, the patient might not receive an effective treatment (thereby missing out on the
benefits that treatment would confer), or might not be diagnosed with the correct disease or
condition. The risks associated with false-positives and false-negatives can be multifold,
but have to be considered in light of probable risks.
It is also important to look at the totality of the harmful events associated with the device.
The number of different types of harmful events that can potentially result from using the
device and the severity of their aggregate effect has to be considered. When multiple
harmful events occur at once, they have a greater aggregate effect.
6.4. Assessment of specified intended target populations:
The intended use of devices will have to specify the intended target populations, characterized
by demographic aspects (e.g. age, gender, race, weight, out- or inpatients ) and by disease
aspects (e.g. diagnosis/medical condition, type, kind, severity, stage, phase, location,
extension, duration of disease, medical history and treatment history, etc.) and important
accompanying factors (e.g. co-morbidities, concomitant treatments, genetic or other
susceptibilities, allergies, etc). Subgroup analyses will have to be properly considered and
planned and implemented in a valid statistical approach.
3
For purposes of this guidance, rates means the number of harmful events per patient or number of
harmful events per unit of time.
4
this MEDDEV does not cover IVDs
page 12 of 60
6.5. Assessment of acceptability of the benefit-to-risk ratio
The evaluators will assess if the clinical data on benefits and risks are acceptable for all
medical conditions and target populations covered by the intended use when compared with
the current state of the art in the corresponding medical field. The current state of the
therefore needs to be identified, possibly also relevant comparators. Evidence based data
suitable for that purpose can be found in scientific medical literature, medical guidelines, and
in the assessments, systematic reviews, meta-analyses of HTA- and EBM-Institutes and
networks. 5
Even if a device cannot cope with an agreed first line treatment or the best in class, it may add
to the portfolio of acceptable treatments, as also a first line treatment will have
contraindications or non-responders. Devices, while not being best-in-class, might provide
clinical evidence for an acceptable benefit/risk-ratio for specific, defined subgroups or even
superior clinical performance under specific conditions (e.g. emergency outdoor conditions).
The position within the treatment portfolio has however to be specified properly in the IFU,
clinical evaluation report, summary of safety and clinical performance and other relevant
documentation.
6.6. Scientific validity of clinical investigations and publications
Data that are not methodologically sound should not be used as a basis for evaluating clinical
properties of medical devices. If an evaluation is based on data such as the following, this shall be
described and justified in the clinical evaluation report:
- Omission of a control arm in situations with probable bias due to regression to the mean or
similar influences 6: This includes use of non-controlled clinical trials for obtaining evidence of
efficacy in pathologies with a self-limiting natural course, fluctuating symptoms, subjective
symptoms, with patients likely to have used effective concomitant therapies, in seasonal
pathologies.
- Use of improper pass/fail criteria 7: When outcomes are multifactorial and do not solely
depend on the device, favourable results obtained by comparing historical data from
unfavourable settings with those in optimised investigational settings can be misleading. Even
harmful interventions may seem beneficial when inadequate pass/fail criteria are used.
5
Special reference is made to the forthcoming voluntary European HTA Network under Art. 15 of
Directive 2011/24/EU on the application of patients rights in cross-border healthcare and the
assessments produced there, or the Cochrane library.
6
Example: Non-controlled observational study of an active medical device in acute back pain which
demonstrates patients feel significantly better days to weeks after the device was used. The condition
being self limiting, the results are in line with the natural course of an episode of acute back pain and
allow no conclusions regarding the efficacy of the device. In this population, bias is also probable in
this indication due to concomitant use of effective and readily available drugs.
7
Example: Data from all-comers implant registries used to define pass/fail criteria for a clinical
investigation carried out in very different conditions (selected patients, selected hospitals, selected
surgeons using high-end methods of surgery-planning, anaesthesia, intervention, hospital care,
medication).
page 13 of 60
- Lack of proper randomisation of patients in controlled studies: If patients are attributed to
the different study arms in a non random manner (e.g. by the investigator or his study
personnel, by patient preferences), selection bias is likely to influence results.
- Improper statistical methods: This includes reports and publications that do not disclose the
results the original clinical study protocol was intended to obtain, present results the original
study protocol was not designed to address and do not describe how the situation was dealt
with statistically, assume significance by omitting corrections for multiple comparisons, or do
not describe statistical methods.
- Improper collection of mortality and serious adverse events data: Demonstration of
benefits and safety can be based on mortality or other events that will limit the ability of
subjects to live in their homes and be contacted. In clinical investigations having such
endpoints, after a missed contact with a study subject, attempts should be made to contact the
subject. When these attempts fail, other persons or institutions should be contacted in order to
investigate the subjects outcome. Adequate 8 procedures should be described, numbers of
subjects lost to follow-up should be fully disclosed in reports and publications. When subjects
cannot be contacted and their outcomes cannot be identified, the subjects should be considered
to meet the adverse endpoint.
6.7. Assessment of the description of the intended use of the device
The evaluators should assess if the description foreseen by the manufacturer correctly
identifies in which medical conditions and target groups conformity with the relevant
essential requirements has been demonstrated through clinical evidence. When reading the
instruction for use, there should be no uncertainties for users as to the question if use in a
given medical condition or target population is covered by the CE marking or entirely falls
under his own responsibility (off label use).
6.8. Devices allowing a therapeutic breakthrough
High potential benefits to patients may be present when there are no acceptable alternatives
on the market for a serious medical condition, and current interventions are inadequate or
highly burdensome or carry significant risks. The potential benefits may legitimate high level
of uncertainties, an early access to the market, and a clinical evaluation based on little clinical
data, and/or little long term data. The evaluator shall fully address the uncertainties and all
consequences, including
- The limitation of the intended use to the niche indication the product was developed for
and were risks and uncertainties where considered acceptable;
8
Examples of inadequate procedures, reports and publications: (1) The clinical investigation protocol
foresees only direct contacts with the patients themselves (phone calls and letters sent to potentially
dead patients), and excludes patients from further analysis when no answers are obtained. (2) The
clinical investigation protocol does not foresee to collect the subjects written consent which will
allow to obtain outcome data from other persons or institutions. (3) Reports and publications that do
not disclose procedures used when patients could no longer be contacted, or do not disclose numbers
of patients lost to follow-up.
page 14 of 60
- inclusion in the instruction for use of correct descriptions of the limited intended use, the
current low level of experience, the large level of uncertainties, uncertainties about residual
risks 9;
- the need for a stringent PMCF plan that will allow to rapidly gather more complete data in
the post-market phase, and for frequent updates of the clinical evaluation report, risk
management file and instructions for use.
6.9. Devices entering the market subsequent to a therapeutic breakthrough
In case of a therapeutic breakthrough, clinical evidence is likely to rapidly grow in the post
market phase. When medical knowledge evolves, large uncertainties will no longer be
acceptable. Late devices will have to meet the new state of the art in the corresponding
medical field. Manufacturers shall not assume devices can continue to enter the market with
the minimal dataset that was formerly acceptable for earlier products.
6.10. Post market surveillance [sci28]:

Structure of the document improved by
moving existing texts to this new chapter
Systematic collection of information from post-market surveillance and post-market clinical [sci29]:
follow-up of the device should always be planned and properly considered. (Change reviewed and confirmed by CA
participants during 13.2.2013 meeting)
With regard to post market activities, manufacturers are expected to implement and maintain [sci30]:
Paragraph moved from section 1 to this
surveillance programmes that routinely monitor the clinical performance and safety of the location.
device as part of their Quality Management System. The scope and nature of such post market (Suggested by CAMD Clinical TF members)
surveillance should be appropriate to the device and its intended use. Using data generated
from such programmes (e.g. safety reports, including adverse event reports; results from
published literature, any further clinical investigations and formal post market clinical follow-
up studies; registry evaluation data, etc.), a manufacturer should periodically/regularly review
performance, safety and the benefit-risk assessment for the device through a clinical
evaluation, and update the clinical evaluation report accordingly. This ongoing clinical
evaluation process should allow manufacturers to communicate with conformity assessment
bodies and Regulatory Authorities in accordance with local reporting requirements, any
information that has an important bearing on the benefit-risk assessment of the device or that
would indicate a need for labelling changes regarding contraindications, warnings,
precautions, appropriate training and/or qualification criteria for users or instructions for use
etc.
6.11. How is a clinical evaluation performed?
There are distinct stages in performing a clinical evaluation (Figure 1), seamlessly followed [sci31]:
Adapted to updated figure below and better
by PMS and PMCF: aligned with the rest of the document
- Scoping of clinical evaluation; (Suggested by CAMD Clinical TF members)
- identification of pertinent standards, Common Technical Specifications and clinical data
through suitable, justified routes;
- appraisal of each individual data set, in terms of its relevance, applicability, quality and
clinical significance;
9
Example of inadequate descriptions of uncertainties in the instructions for use: No serious long-
term adverse effects have been reported to date.
page 15 of 60
- analysis of relevant data, whereby conclusions are reached about the clinical performance,
safety and presentational aspects (labelling, patient information and instructions for use)
of the device; and
- production of the clinical evaluation report, introduction into risk management as well as
PMS and PMCF planning.
Each of these stages is covered in separate sections in this document.
The clinical evaluation report is prepared, summarising the relevant clinical evidence for the [sci32]:
(Change reviewed and confirmed by CA
device. If the manufacturer concludes there is insufficient clinical evidence to be able to participants during 13.2.2013 meeting,
declare conformity with the Essential Requirements, the manufacturer will need to generate further adapted by CAMD Clinical TF
members)
additional data (e.g. conduct a clinical investigation or broaden the scope of the literature
review) to address the deficiency. In this respect clinical evaluation is an iterative continuous
process, which is prolonged by Post Market Clinical Follow-Up (PMCF) as part of Post
Market Surveillance (PMS).
If a manufacturer, when evaluating new clinical data pertinent to a medical device already on [sci33]:
- New texts
the market, concludes in the clinical evaluation report that there is insufficient clinical (Reviewed and confirmed by CA
evidence to be able to verify conformity with the Essential Requirements, the manufacturer participants during 13.2.2013 meeting)
should take appropriate actions. [[should also be included in Checklist for NB]]
The manufacturer should have a plan on when to formally update the clinical evaluation
report. Changes to the report should be documented. Corresponding core data should be made
available to notified bodies regularly and to competent authorities on demand. Unless
omission of PMCF can be properly justified, , the manufacturer will set up a proper PMCF-
plan with general and specific measures (e.g. PMCF-studies, register evaluations), implement
and evaluate it, draw necessary conclusions and regularly update the PMCF report and the
clinical evaluation report [[should also be included in Checklist for NB]].
6.12. Who should perform the clinical evaluation?
The clinical evaluation should be conducted by a suitably qualified individual or individuals). [J34]: There is a diffference
between obtaining suitable expert opinion
A manufacturer must be able to justify the choice of the evaluator(s) through reference to and conducting an evaluation (which is
qualifications and documented experience. Evidence of contribution or review by individuals something that should never be done by a
committee!)
with appropriate clinical expertise should be provided (e.g. the opinions of a suitable
medical/scientific Board).
As a general principle, evaluators should possess knowledge of the following:

- the device technology and its application;
- research methodology (clinical investigation design, scientific literature retrieval and
review, and biostatistics); and
- diagnosis and management of the conditions intended to be treated or diagnosed by the
device.
(Proposals welcome to include thoughts about independence of authors of a clinical

evaluation from the manufacturer (can the owner of the company or shareholders or main
shareholder write the report)? Or about need to be objective and to include also negative data?
Or add to the report a section with declarations of interests for each author?)
page 16 of 60
Figure 1: Stages of clinical evaluation
Working group:
Check in the whole document and update in this flowchart : Interaction into risk management
process, does the flowchart also cover the period after CE-marking adequately?
Boxes in this Flowchart:
- Would a box Stage 0-Scoping be necessary (setting specific intended use/ specific claims)?
- Would an additional last box be necessary for integration into risk management?
- Where is the route when the manufacturer does not need a clinical evaluation report and
chooses to document why?
page 17 of 60
Figure 1: Stages of clinical evaluation [J35]: I dont think this diagram is
helpful.
If it is retained, it needs to show that, at

Stage 1, the context and scope of the
evaluation must be determined and the state
of the art defined in terms of complication
rates and expected performance. At
Stages2 and 3, the ability of the data to
meet the objectives defined by stage 1 is
determined.
Usually, when you generate new data, you

do not need to repeat Stage 1.
[sci36]:
Figure entirely updated by CAMD Clinical
TF Memvbers: including Stage 0, Stage 2
and Stage PMS
page 18 of 60
Stage 0
Scoping: Specify medical indications, target
population(s), claims, aspects of benefits and
risks and of acceptability of the benefit/risk-ratio,
added value issues, whether conformity can be
assessed without clinical data
Need to
assess
clinical data?
Y
N E
O S
Stage 1 Stage 2
Identify clinical data from Appraisal of individual data sets
Literature searching and/or Suitability, scientific validity
Clinical experience and/or Contribution of results to
Clinical investigation and/or demonstration of clinical
Standards* performance and safety
Generate new or additional clinical

data
N
O
Stage 3
Analysis of relevant data
Is clinical evidence Strength of overall evidence
sufficient to be Conclusions about clinical
able to declare performance and safety
conformity with
relevant ERs?
Y
E
S
Produce clinical evaluation report,

integration into risk management
Stage PMS/PMCF: PMCF-plan, general PMCF measures, specific PMCF

measures, PMCF implementation, PMCF reports, vigilance/PMS reports
page 19 of 60
*Conformity to harmonized standards may be sufficient to demonstrate compliance to
relevant Essential Requirements (ERs)
7. Scoping (Stage 0) [sci37]:

Contribution of CAMD Clinical TF
members: New chapter with new text.
The manufacturer shall issue and periodically update a scoping report to document aspects of
scoping mentioned in previous sections of this MEDDEV. The scoping report is included in
the clinical evaluation report.
If clinical data are not required for demonstration of conformity, a written justification is
included in the clinical evaluation report in accordance with section 1.5 of Annex 7 to
Directive 90/385/EEC and section 1.1d of Annex X to Directive 93/42/EEC.
8. Sources of data/documentation used in a clinical evaluation (Stage 1)

Data relevant to the clinical evaluation may be held by the manufacturer (e.g. manufacturer
sponsored pre and post market investigation reports and adverse event reports for the device
in question) or in the scientific literature (e.g. published articles of clinical investigations and
adverse event reports for the device in question or for equivalent devices, literature describing
the state of the art in the corresponding medical field).
The manufacturer is responsible for identifying data relevant to the device and the state of the
art and determining the types and amount of data needed for the clinical evaluation.
Where data are used from a combination of sources, the principles applicable to each source
apply to that data component within the clinical evaluation.
8.1. Data generated through literature search
Literature searching will be used to identify published clinical data that is not in the
possession of the manufacturer that may assist the manufacturer to establish acceptable
performance and safety of a medical device. The data generated through literature searching
may relate directly to the device in question (e.g. reports of clinical investigations of the
device in question that have been performed by third parties, adverse event reports), to
equivalent devices or to devices or therapies that define the state of the art in the
corresponding medical field.
greater part (if not all) of the clinical evidence. Thus, when conducting a literature review
evidence should be provided that a comprehensive search has been conducted and
equivalence to the device in question has been established. [sci38]:
CA contribution during 13.2.2013 meeting
Published data will need to be assessed with respect to its possible contribution and weighting
page 20 of 60
in establishing both the performance and safety of the device in question. Papers considered
unsuitable for demonstration of performance because of poor study design or inadequate
analysis may still contain data suitable for assessing the safety of the device or the state of the
art.
(Working group: Check where to integrate that authors of the report shall also elaborate on
need for PMCF)
The key elements of literature search
The search strategy should be based on carefully constructed review questions. A protocol
should be developed to identify, select and collate relevant publications to address these
questions. This should be developed and executed by persons with expertise in information
retrieval, having due regard to the scope of the clinical evaluation set out by the manufacturer.
The involvement of information retrieval experts will help to maximise data retrieval.
The literature search protocol should include:

- the sources of data that will be used and a justification for their choice;
- the extent of any searches of scientific literature databases (the database search strategy);
- the selection/criteria to be applied to published literature and justification for their choice;
and
- strategies for addressing the potential for duplication of data across multiple publications;
Once the literature search has been executed, a report should be compiled to present the
results of the search. A copy of the protocol should be included and any deviations noted. A
possible format for the literature search report is located at Appendix A.
It is important that the literature search is documented to such a degree that the methods can
be appraised critically, the results can be verified, and the search reproduced if necessary. A
possible methodology is presented in Appendix B.
Which data/documentation from the literature search should be included in the clinical
evaluation?
The following documentation should be used in the clinical evaluation by the clinical
evaluator:
- the literature search protocol;
- the literature search report; and
- published articles and other references identified as being relevant to the device in
question and suitable for evaluation.
The literature search protocol, the literature search report and copies of relevant references
become part of the technical documentation for the medical device. With respect to the
clinical evaluation, it is important that the clinical evaluator be able to assess the degree to
which the selected papers reflect the intended application/use of the device, etc. The selection
of literature should be objective and justified, i.e. include both favourable and unfavourable
data.
Copies of the actual papers and references are necessary to allow the evaluator to review the
methodology employed (potential sources of bias in the data), the reporting of results and the
validity of conclusions drawn from the investigation or report. Abstracts may lack sufficient
detail to allow these issues to be assessed thoroughly and independently.
page 21 of 60
8.2. Data generated through clinical experience
These types of clinical data are generated through clinical use that is outside the conduct of
clinical investigations and may relate to either the device in question or equivalent devices.
Such types of data may include:
- manufacturer-generated post market surveillance reports, registries or cohort studies

(which may contain unpublished long term safety and performance data);
- adverse events databases (held by either the manufacturer or Regulatory Authorities);
- data for the device in question generated from individual patients under compassionate
usage programs prior to marketing of the device; and
- details of clinically relevant field corrective actions (e.g. recalls, notifications, hazard
alerts).
The value of clinical experience data is that it provides real world experience obtained in
larger, heterogeneous and more complex populations, with a broader (and potentially less
experienced) range of end-users than is usually the case with clinical investigations 10.
The data are most useful for identifying less common but serious device-related adverse
events; providing long term information about safety and performance, including durability
data and information about failure modes and elucidating the end-user learning curve. It is
also a particularly useful source of clinical data for low risk devices that are based on long
standing, well-characterised technology and, therefore, unlikely to be the subject of either
reporting in the scientific literature or clinical investigation. However, there is also a
possibility that data are distorted by under-reporting.
How may clinical experience data/documentation be used in the clinical evaluation?
If a manufacturer chooses to use clinical experience data it is important that any reports or
collations of data contain sufficient information to be able to undertake a rational and
objective assessment of the information and make a conclusion about its representativity and
significance with respect to the performance and safety of the device in question. Reports of
clinical experience that are not adequately supported by data, such as anecdotal reports or
opinion, should not be used.
Post market surveillance reports are compiled by the manufacturer and often include details of
the devices regulatory status (countries in which the device is marketed and date of
commencement of supply), regulatory actions undertaken during the reporting period (e.g.
recalls, notifications), a tabulation of adverse events (particularly serious events and deaths,
stratified into whether the manufacturer considers them to be device-related or not) and
estimates of the incidence of adverse events. Post-marketing data about adverse events are
generally more meaningful when related to usage but caution is needed because the extent of
10
In contrast, clinical investigations involve the use of specific inclusion criteria to create a homogenous
population to reduce sources of variation and, therefore, increase confidence that the outcomes observed in the
investigation are due to intervention with the device in question. Also, investigators participating in the
investigation are chosen on the basis of their expertise and competence and often undergo training over and
above that available to other end-users of the device.
page 22 of 60
reporting may vary considerably between countries. The analyses of data within these reports
may, for some devices, provide reasonable assurance of both clinical safety and performance.
It may be helpful to provide a table summarising device-related adverse events, paying

particular attention to serious adverse events, with comments on whether observed device-
related adverse events are predictable on the basis of the mode of action of the device.
Manufacturers should comment specifically on any clinical data that identifies hazards not
previously considered in the risk management documentation, outlining any additional
mitigation required (e.g. design modification, amendment of product literature such as
inclusion of contraindications etc).
8.3. Data from clinical investigations
The guidance included within this section applies to clinical investigations carried out by or
on behalf of a manufacturer specifically for the purposes of conformity assessment in
accordance with the applicable European medical device directive. Such clinical
investigations are generally expected to be designed, conducted and reported in accordance
with EN ISO 14155 Clinical investigation of medical devices for human subjects Good
clinical practice, or to a comparable standard, and in compliance with local regulations.
It is recognised that, where manufacturers source clinical investigation data reported in the
scientific literature (i.e. investigations of either the device in question or equivalent devices
that are undertaken by a third party), the documentation readily available to the manufacturer
for inclusion in the clinical evaluation is likely to be no more than the published paper itself.
High risk devices, those based on technologies where there is little or no experience, and [sci39]:
Improved structure of the document,
those that extend the intended purpose of an existing technology (i.e. a new clinical use) are paragraph moved to this location from
most likely to require clinical investigation data. Therefore, clinical investigations are previous section 5.1.
(Suggestion of CAMD Clinical TF
required unless it can be duly justified to rely on existing clinical data alone, as stated in the members)
annex X of Directives 93/42/EEC and annex 7 of 90/385/EEC as amended. The manufacturer
will need to give consideration to the advantages and limitations of each data type and justify
their use properly. [sci40]:
What are the types of clinical investigations?
[sci41]:
-Untimely CE marking based on
The type of clinical investigations used for clinical evaluations should be primarily pivotal unreliable data has been identified as a
major and recurrent problem.
studies that adequately address regulatory questions. Feasibility studies are not intended to -Retain clear and well understandable
deliver answers to regulatory questions. Therefore, while observations made in feasibility statements.
-Clearly state that a clinical evaluation
studies can complement such data, feasibility studies alone are not normally considered to be should not be based on a feasibility trial
a valid basis for demonstration of compliance to the medical devices directives. If feasibility - Early access to the market of
breakthrough devices addressed with a
studies are used for this purpose, reasons shall be explained in the clinical evaluation report. new chapter in a previous section.
- Pivotal and feasibility studies defined
in the definitions section.
What clinical investigation documentation/data should be used in the clinical evaluation? -Term piolot study changed to feasibility
study
(First changes reviewed and confirmed
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is by CA participants during 13.2.2013
expected that documentation relating to the design, ethical and regulatory approvals, conduct, meeting, then adapted following
suggestion of Italian CA, with
results and conclusions of the investigation needed for the clinical evaluation will be available definitions of feasibility and pivotal
for consideration by the clinical reviewer and the Notified Body, as appropriate. These may studies moved to the definitions section,
text presented for 22.4.2013 CAMD
include: Clinical TF teleconference, then reviewd
- the original clinical investigation plan; by Task force members)
page 23 of 60
- clinical investigation plan amendments and the rationale for these changes;
- the relevant Ethics Committee(s) documentation, opinion(s) and comments for each;
- investigation site, including a copy of the approved informed consent form(s) and patient
information documents;
- case report forms, monitoring and audit records;
- Regulatory Authority approvals and associated correspondence as required by applicable
regulations; and
- the original signed and dated final report.
The clinical investigation plan sets out how the study was intended to be conducted. It
contains important information about the study design such as the selection and assignment of
participants to treatment, masking (blinding of participants and investigators) and
measurement of responses to treatment, which may be important sources of bias that can be
assessed and discounted when trying to determine the actual performance of the device. In
addition the clinical investigation plan sets out the primary and secondary endpoints, the
intended participant follow-up, approaches to statistical analyses (including planned subgroup
analyses and whether per protocol (PP) or intent to treat (ITT)-analysis is planned with a
justification) and methods for recording outcomes, which may impact on the quality,
completeness and significance of results obtained for performance and safety outcomes.
Also, by having the clinical investigation plan, its amendments and the final report available,
the evaluator will be able to assess the extent to which the investigation was conducted as
planned and, where deviations of from the original plan have occurred, the impact those
deviations had on the veracity of the data generated and the inferences that can be drawn
about the performance and safety of the device from the investigation.
The final clinical investigation report should be signed by its author(s) and appropriate
reviewers to provide assurance that the final report is an accurate reflection of the conduct and
results of the clinical investigation.
Another important consideration for the evaluation will be to assess whether the conduct of
the investigation was in accordance with the current applicable ethical standards that have
their origin in the Declaration of Helsinki and in accordance with applicable regulations.
Clinical investigations not in compliance with applicable ethical standards or regulations
should be rejected. The reasons for rejection of the investigation should be noted in the report.
Compliance with ISO 14155 ensures that the above expectations have been met.
page 24 of 60
9. Appraisal of clinical data (Stage 2)
The purpose of undertaking appraisal of the data is to understand the merits and limitations of
the clinical data. Each piece of data is appraised to determine its suitability to address
questions about the device, and its contribution to demonstrating the safety and performance
of the device (including any specific claims about clinical properties of the device the
manufacturer intends to make use of).
What should be covered by the appraisal?
The data needs to be suitable for appraisal. It should be assessed for its quality and for its
relevance to the device in question (i.e. the data demonstrating the safety and performance of
the device must be either generated for the device in question or for an equivalent device) and [J42]: As opposed to defining the
state of the art
its intended use. In addition, any reports or collations of data should contain sufficient
information for the evaluator to be able to undertake a rational and objective assessment of
the information and make a conclusion about its significance with respect to the performance
and/or safety of the device in question, in line with essential requirements.
Further appraisal needs to be undertaken to determine the contribution of each data subset to
establishing the safety and performance of the device. The evaluator should examine the
methods used to generate/collect the data and assess the extent to which the observed effect
(performance or safety outcome(s)) can be considered to be due to intervention with the
device or due to confounding influences (e.g. natural course of the underlying medical
condition, concomitant treatment(s)) or bias.
There is no single, well established method for appraising clinical data. Therefore, the
evaluator should identify, in advance, the appropriate criteria to be applied for a specific
circumstance
These criteria should be applied consistently. Some examples to assist with the formulation of
criteria are given in Appendix C.
For many lower risk devices and devices based on long standing technology, the available
data may be qualitative rather than quantitative in nature, so the evaluation criteria should be
adjusted accordingly. The criteria adopted for the appraisal should be justified by the
evaluator.
Although there will be some overlap of safety and performance data, the data should be
categorised to allow for separate analysis. Additional categories may also be needed,
depending on the nature and intended use of the device to address additional claims. The data
should also be weighted according to its relative contribution. An example of a method of
data appraisal is shown in Appendix D.
[[CAMD Clinical TF: Aspect covered in the grading? Multiple publications of same
data/study population]]
page 25 of 60
The goal of the analysis stage is to determine if the appraised clinical data sets available for a
medical device collectively demonstrate compliance with essential requirements. The level of [sci43]:
New text
clinical evidence needed to demonstrate compliance with essential requirements should be (Text reviewed and confirmed by CA
justified. Usually a higher level of clinical evidence is justified for medical devices of higher participants during 13.2.2013 meeting)
risk and/or class.
The methods available for analysis of clinical data generally are either quantitative or
qualitative. Given the context within which most medical devices are developed (i.e. limited
need for clinical investigations because of incremental changes in device design and therefore
high use of literature and experience data), often qualitative (i.e. descriptive) methods will
need to be used primarily to address such incremental changes, if justified.
Any evaluation criteria developed and assigned during the appraisal stage can be used to
identify those sets of data which may be considered to be pivotal to the demonstration of
the performance and safety of the device, respectively. It may be useful to explore the results
of the pivotal datasets, looking for consistency of results across particular device performance
characteristics and identified risks. If the different datasets report similar outcomes, certainty
about the performance increases. If different results are observed across the datasets, it will be
helpful to determine the reason for such differences. Regardless, all data sets should be
included.
As a final step the evaluator should consider the basis on which it can be demonstrated that
the combined data show:
- any risks which may be associated with their intended use constitute acceptable risks [sci44]:
- Order changed so as to better align with
when weighed against the benefits to the patient and are compatible with a high level of order used in the Essential Requirements
protection of health and safety; (Text reviewed and confirmed by CA
- the device does not pose any undue safety concerns to either the recipient or end-user;
- the device performs as intended by the manufacturer; and
- any undesirable side-effect constitutes an acceptable risk when weighed against the
performances intended.
Such considerations should take into account the number of patients exposed to the device,
the type and adequacy of patient monitoring, the number and severity of adverse events, the
adequacy of the estimation of associated risk for each identified hazard, the severity and
natural history of the condition being diagnosed or treated. The availability of alternative
diagnostic modalities or treatments and the risks and benefits associated with the current
standard of care should also be taken into consideration.
The product literature and instructions for use should be reviewed to ensure they are
consistent with the data and that all the hazards and other clinically relevant information have
been identified appropriately.
11. The Clinical Evaluation Report

[[Check elements of the clinical evaluation report: Still OK? Adapt to revised previous
chapters]]
page 26 of 60
At the completion of the clinical evaluation process a report should be compiled that outlines [sci45]:
- Better aligned with Essential
the scope and context of the evaluation; the inputs (clinical data); the appraisal and analysis Requirements
stages; and conclusions about the safety, and performance, including side-effects and (Text reviewed and confirmed by CA
benefit/risk assessment, for the device in question.
The clinical evaluation report should contain sufficient information to be read as a stand alone
document by an independent party (e.g. Regulatory Authority or Notified Body). It is
important that the report outline:
- the technology on which the medical device is based, the intended use of the device and
claims about clinical properties of the device the manufacturer intends to make use of;
- the nature and extent of the clinical data that has been evaluated together with relevant
documentation of the literature search and the clinical investigations; and
- how the referenced information (together with recognised standards, Common Technical
Specifications and/or clinical data) demonstrate the conformity to relevant Essential
Requirements (General Safety and Performance Requirements) for the device in question.
The clinical evaluation report should be signed and dated by the evaluator(s) and evidence of
the suitability of evaluator. It should also be signed by the manufacturer.
A suggested format for the clinical evaluation report is located at Appendix E. It should be
noted that the level of detail in the report content can vary according to the scope of the
clinical evaluation. For example, where a manufacturer relies on clinical data for an
equivalent device which has been the subject of an earlier clinical evaluation (for which the
manufacturer holds the evaluation report), it may be possible to cross-reference the data
summary and analysis sections to the earlier clinical evaluation report, which also becomes
part of the clinical evidence for the device in question.
12. The role of the Notified Body in the assessment of clinical evaluations
The Notified Body plays a key role in the assessment and verification of clinical evaluations
provided by medical device manufacturers to support demonstration of conformity of a device
with the essential requirements of the relevant Directive.
This section of the document is intended to act as guidance to a Notified Body on the
assessment of clinical evaluations provided by medical device manufacturers as part of
technical documentation/design dossiers and as a part of their procedures for medical devices.
It might also be useful as best practice guidance for national Competent Authorities in their
market surveillance activities.
Demonstration of conformity without clinical data in accordance with section 1.5 of Annex 7
to Directive 90/385/EEC and section 1.1d of Annex X to Directive 93/42/EEC must be
adequately justified and based on the output of the risk management process. The device-body
interaction, the intended use and the claims of the manufacturer have to be specifically
considered. Adequacy of demonstration of conformity based on performance evaluation,
bench testing and pre-clinical evaluation in the absence of clinical data must be duly [J46]: As noted in ERs 5a or 6a, a
clinical evaluation in accordance with
substantiated. The Notified Body must review the manufacturers justification, the adequacy Annex X or7 is always required. The ERs
of data presented and whether or not conformity is demonstrated. mentioned in this paragraph talk about
demonstration of conformity without
clinical data.
Notified Body Assessment of Clinical Evaluation by Conformity Assessment Route

page 27 of 60
With regard to the review of clinical evaluations the Notified Body has different roles
depending on the classification of the device and the conformity assessment procedure
followed.

- The notified body assesses the manufacturers procedure for clinical evaluation.
- As part of the representative sampling of devices for review of their technical
documentation the notified body verifies the clinical evaluation data presented for
class IIa and IIb devices in accordance with the criteria outlined in this section.
A design dossier (Annex II, section 4) or type examination dossier (Annex III) assessment:
manufacturers assessment of that data and assesses the validity of the conclusions
drawn by the manufacturer.

manufacturers assessment of that data and assesses the validity of the clinical
evaluation report and the conclusions drawn by the manufacturer.
The Notified Body should also have documented procedures to cover review of updates to
clinical evaluation data during their scheduled surveillance activities and at the time of
changes to or extensions of EC design-examination/EC type-examination certificates. This
arises from the obligation placed on the manufacturer to actively update the clinical
evaluation with data obtained from post-market surveillance e.g. post-market clinical follow-
up and ongoing literature reviews/surveys.
12.1. E XAMINATION OF A DESIGN DOSSIER (ANNEX II.4; ANNEX 2.4) OR OF A TYPE

EXAMINATION DOSSIER (ANNEX III; ANNEX 3)
The Notified Body examines the clinical evaluation documentation submitted (relevant
documentation referenced in previous sections of this MEDDEV), verifies the manufacturers
identification, appraisal, analysis and assessment of that data and validates the conclusions
drawn by the manufacturer. In order to do so, the Notified Body should possess enough
knowledge and experience in clinical evaluation as stated in previous sections of this
document.
In Appendix F of this document a checklist is provided for use by a Notified Body during the
assessment of clinical evaluation data. This checklist should be used as a supplementary tool
but should not replace the Notified Body Report outlined below.
12.1.1. Decision-making by the Notified Body

[[Replace occurrences of the text previous sections by correct section numbers once the
contents and final structure of the document is available]]
In reviewing the evaluation of clinical data submitted by the manufacturer, the Notified Body
verifies and decides whether or not the manufacturer has adequately:
- supplied clinical evaluation documentation (as referenced in previous sections);

page 28 of 60
- followed relevant procedures (as addressed by previous sections);
aspects;
- performed an appropriate risk analysis and estimated the undesirable side effects;
- involved appropriate clinical expertise in the compilation of the risk analysis to ensure
risks and benefits associated with real clinical use are adequately defined;
- justified the chosen route(s) of clinical data retrieval (according to previous sections);
- identified, appraised, analysed and assessed the clinical data (according to previous
sections) and demonstrated the relevance and any limitations of the clinical data identified
- provided sufficient clinical data relating to the safety, including benefits to the patients, [sci47]:
30.4.2013 CETF Clinical TF member input.
the clinical performance intended by the manufacturer (including any claims on clinical Closer aligned with essential requirements
properties of the device the manufacturer intends to make use of), design characteristics
and intended purpose of the device in order to demonstrate conformity with each of the
relevant essential requirements;
- if a critical evaluation of relevant scientific literature is provided, the notified body
verifies that this data relates to the safety, benefits, performance, design characteristics
and intended purpose of the device;
- if a critical evaluation of relevant scientific literature is provided the notified body verifies
that the device under assessment is demonstrated as equivalent to the device to which the
data relates in all necessary areas (i.e. clinical, technical, biological etc.); [sci48]:
- if a critical evaluation of relevant scientific literature is provided the notified body verifies Aligned with chapter 5.2.1
that the data presented for equivalent devices adequately addresses each of the relevant
essential requirements;
- provided specific justification if a specific clinical investigation was not performed for
class III or implantable devices.
Note: A clinical evaluation is required for all classes of medical devices, the relevance of
the data or the need for clinical investigation data should always be assessed and
documented by the notified body;
- provided evidence that clinical investigations presented are in compliance with applicable
regulatory and ethical requirements e.g. scientific validity, ethics committee approval, [sci49]:
competent authority approval; Scientific quality required by Annex X
- justified the appropriateness of the planned post-market clinical follow up; 93/42/CEE and Annex 8 90/385/CEE
- justified and documented if post-market clinical follow-up is not planned as part of the
post-market surveillance plan for the device;
- concluded on the basis of documented evidence that the risks are acceptable when
weighed against the intended benefits and are compatible with a high level of protection [sci50]:
Better aligned with essential requirements
of health and safety, that the intended clinical performances described by the manufacturer and the rest of the document
are achieved by the device, that any undesirable side-effect constitutes an acceptable risk (As suggested by CAMD Clinical TF
members)
when weighed against the performances intended;
- concluded that the contents of the instructions for use are supported by clinical evidence
(description of the intended use, handling instructions, type and frequency of risks,
warnings, precautions, contraindications, etc.).
The assessment carried out by the Notified Body will typically cover the following aspects of
the manufacturers clinical evaluation:
- appraisal to determine suitability and any limitations of the data presented to address the
essential requirements in particular relating to the safety, and performance of the device as
outlined in previous sections;
- complete and adequate documentation (according to previous sections);
page 29 of 60
- adequate procedures (according to previous sections)
- the listing, characterisation and proof of the clinical performance of the device intended
by the manufacturer and the expected benefits for the defined patient group(s);
- the use of harmonised standards;
- the use of the list of identified hazards to be addressed through evaluation of clinical data
as described in section 8;
b) estimating and characterising the probability of occurrence of harm, health impairment
or loss of benefit of the treatment (documented and discussed based on scientifically
valid clinical data); [sci51]:
- the adequate description and estimation of the current state of the art in the corresponding No guesses based on unvalidated
medical field. assumptions Should be based on evidence.
[sci52]:
Better aligned with previous sections of this
The decision on the acceptability of risks 11 in relation to each identified hazard, and MEDDEV, and with section 1 of the
essential requirements.
- unacceptable; or
- acceptable under specified conditions.
For drug-device combination products where a scientific opinion from a medicinal competent
authority or from the EMEA has been sought, the notified body should consider any
comments or considerations raised in the medicinal clinical assessment when making its final
decision on the device. In the case of devices with a human blood derivative the notified body
may not deliver a positive decision to issue a certificate if the EMEA's scientific opinion is
unfavourable.
12.1.2. The report of the Notified Body
The Notified Body writes a report on its assessment of the submitted clinical evaluation
documentation.
If a design dossier report is applicable the clinical report should be incorporated into this
report. The report should clearly identify the Notified Bodys assessment, verification on each
of the critical elements and overall conclusions.
NBOG BPG 2009-1 defines the minimum content for a design dossier review report in the
following sections:
- Manufacturer details
- Details relating to the application and NB review (including staff and experts involved
in the review and the aspects assessed by each, signatures of responsible reviewers etc.)
- Device description and product specification
- Classification
- Requirements regarding manufacturing
- Requirements regarding design and construction
- Pre-clinical evaluation
11
Valid decision making criteria from applicable guidance and standards may be employed e.g. ISO 14971.
page 30 of 60
- Clinical evaluation/performance evaluation
- Other applicable Directives
- Risk analysis and risk management
- Review of declaration of conformity
- Post-market surveillance
- Summary of review
The Notified Body should justify and document each step of the decision making process
referred in 10.1.1.above. One single unacceptable risk/benefit ratio leads to a negative
conclusion 12;
The clinical evaluation assessment report should:

- Record whether the clinical evaluation documentation was complete and adequate
- Record the Notified Bodies verification of each step of the clinical evaluation process,
from scoping, choice of route(s), identification, appraisal, analysis and overall
assessment of the clinical data, to concluding and reporting
- Record the completeness of the clinical evaluation conducted and its accordance with
this document
- Record the Notified Bodys assessment of the clinical investigation data and/or
literature review assembled, relevant procedures and compliance to relevant standards
- Verify that the device has met the claimed performance/intended use and benefits, [sci53]:
side-effects and risks have been properly evaluated Better aligned with previous sections of this
- Record the Notified Bodys assessment of the clinical safety, performance and document and with section I of the essential
requirements.
benefit/risk ratio
- Record the Notified Bodys assessment of the conclusions drawn by the manufacturer
from the clinical data presented
- Record the Notified Bodys assessment of the validity of the clinical evaluation and its
steps
- Record the Notified Bodys conclusions on the clinical evaluation, documenting each
step in the decision making process as per section 10.1.1.
12.2. E VALUATION AS PART OF QUALITY SYSTEM RELATED PROCEDURES (Annex II.3 of

Directive 93/42/EEC)
12.2.1. Review of the manufacturers procedures (Working group: Rewording of the rest of
the title, difficult to understand, maybe not in the right chapter, notified body should verify if
the procedures work in practice)(validation and verification)
The Notified Body shall, as part of the review of the manufacturers quality system, assess the
establishment, maintenance and application of the manufacturers documented procedures for
the evaluation of clinical data. This should cover:
(a) the proper assignment of responsibilities to suitably qualified persons involved in the
clinical evaluation [e.g. clinical evaluator(s), information retrieval expert(s), clinical
investigator(s)];
12
In some cases, the combination of the conditions specified in order to characterise different individual
risk/benefit ratios as acceptable may be contradictory or impracticable, and so also leads to an overall negative
conclusion. Positive benefit/risk ratios for specific aspects do not compel an overall positive benefit/risk ratio for
the device.
page 31 of 60
(b) the integration of clinical evaluation into the quality system as a continuous process, to be
specifically inter-related to, and informed by, preclinical evaluation and risk management;
(c) standard operating procedures to assure proper planning, conduct, evaluation, control and
documentation of scoping, identification of clinical data (previous section), literature
searching (previous section), collection of clinical experience (previous section), clinical
investigation (previous section and EN ISO 14155), appraisal of clinical data (previous
section), analysis of clinical data (previous section), concluding, reporting (previous
section) and update of clinical evaluation, including PMCF (MEDDEV 2.12/2?);
(d) Document control as part of overall documentation of procedures, reporting, qualifications
and technical documentation/design dossier(s);
(e) identification and evaluation of undesirable side effects and of clinical performance(s).
This involves identification of known or reasonably foreseeable hazards and verification
of unfavourable and favourable outcome(s), qualification of their severity/magnitude and
of their probability of occurrence. (It is part of the manufacturers documented risk
analysis based on both favourable and unfavourable data identified as relevant in order to
give a balanced view).
12.2.2. Review of the technical documentation of representative samples
The Notified Body is required to assess the technical documentation for class IIa and class IIb
devices on a representative basis. Clinical evaluation data should be assessed by the Notified
Body for at least one representative sample for each device subcategory for class IIa devices
and at least one representative sample for each generic device group for class IIb devices.
Further representative samples have to be assessed as part of the annual surveillance
assessment cycle.
Regarding the choice of representative sample(s) the notified body will consider the novelty
of the technology, similarities in design, technology, manufacturing and sterilisation methods,
the intended use and the results of previous relevant assessments. Assessment of
representative samples includes assessment of the clinical evaluation report and available
clinical data according to the criteria outlined in this document rather than solely confirming [sci54]:
that the manufacturer has a clinical evaluation procedure in place. Align terminology with previous sections
When performing the assessment on samples of a manufacturers clinical evaluation, the

Notified Body will follow the steps indicated in previous section of this document.
The Notified Body, when reviewing samples of the manufacturers clinical evaluation and
clinical data, should pay special attention to the following: [sci55]:
(a) whether or not the data is relevant to the device, its intended use(s) or medical procedure(s) Use specific terminology and better aligned
involved and adequately cover the related clinical performance, safety and benefit/risk with previous sections
relation
(b) where the manufacturer, in the selected sample, has chosen the literature route, whether
the criteria defined in previous sections have been applied;
(c) where the manufacturer, in the selected sample, has selected the clinical investigations
route, whether the criteria defined in previous sections have been applied.
12.3. NOTIFIED BODY SPECIFIC P ROCEDURES AND E XPERTISE

page 32 of 60
A Notified Body should have formal procedures in place controlled by their quality system
relating to the assessment of clinical evaluations provided by medical device manufacturers.
These procedures should also cover the review of updates to clinical evaluation data during
their scheduled surveillance activities and at the time of changes to or extensions of EC
design-examination/EC type-examination certificates.
Notified Bodies should establish and implement internal policies and procedures for the
assessment of clinical evaluations in order to:
(a) ensure that suitable resources, especially relevant regulatory knowledge and clinical
competence necessary for such evaluation, are available within 13 the Notified Body and
by contracting external clinical experts if required.
Such expertise should be sufficient to identify and estimate the risks and benefits
associated with the use of the medical devices. The evaluation team should be able to
evaluate a risk analysis, the risk management strategy performed by the manufacturer, and
the scientific validity of clinical investigations and publications. [sci56]:
Better aligned with scientific requirements
The evaluation team should understand the device technology as well as the medical described in Annex X of 93/42/EEC and
Annex 8 of 90/385/CEE.
procedure.
Such an evaluation may require input from a qualified medical practitioner (for example
physician, dentist, nurse etc.), as appropriate for the particular device, who has clinical
experience in the pathology of the condition being treated, the usual treatment, the
therapeutic alternatives etc.
When examining the results of clinical investigations, the evaluation team shall have
knowledge in planning, conduct and interpretation of clinical investigations. All
evaluators should be appropriately trained and qualified.

assessment procedure(s), relevant guidance, standards and the context of the assessment
they are providing. The Notified Body should be responsible for reviewing the opinion of
these experts, taking account of their level of knowledge of the provisions of the
Directives.
The opinion of an external clinical expert may form part of the assessment conducted by
the notified body. The opinion and conclusions of the notified body, in part based on this
external opinion, should be clearly documented.
The impartiality and the potential for conflict of interest of an external expert reviewer
should be assessed and documented by the notified body.
(b) review the evaluation of clinical data provided by the manufacturer. The notified body [sci57]:
-Chapter reviewed by CA with the aim to
should verify the validity of key statements made in the clinical evaluation report, be clearer and more specific
especially for devices with significant risks or with unknown or uncertain mechanisms of - recurrent issue about insufficient or
irrelevant sources being used and cited in
action. The notified body should cross check clinical evaluations included
13
Annex XI.3 of Directive 93/42/EEC. This presupposes the availability of sufficient scientific staff within the organisation
who possess experience and knowledge sufficient to assess the medical functionality and performance of devices for which it has
been notified, having regard to the requirements of this Directive and, in particular, those set out in Annex I.
page 33 of 60
- statements based on published literature using the full text version of publications;
- statements regarding equivalence to other devices using the original full text version
of pre-market study reports assessing parameters of interest.
- statements regarding results of own clinical investigations of the manufacturer using
the original full text version of the clinical investigation plan and the clinical
investigation report.
(c) document the opinion with rationale of all experts involved;
(d) ensure that any external experts involved are impartial and independent from any parties
involved, having due regard to any conflict of interest which may compromise
impartiality (see also MEDDEV 2.10/1);
(e) document the result of their assessment. This is achieved through a specific report which
may be part of, or may be referenced, in the overall audit report, design / type examination
report (as per 10.1.2 of this document) or the report on the assessment of representative
samples documentation;
(f) preserve confidentiality of the information and data received from the manufacturer,
especially within the terms for contracting external experts.
page 34 of 60
APPENDICES
[[Correct titles and page numbers when contents have been updated]]
B: A possible methodology for documenting the screening and selection of

literature within a literature search report 29
page 35 of 60
APPENDIX A
A POSSIBLE FORMAT FOR THE LITERATURE SEARCH REPORT
A.1. Device name/model
A.2. Scope of the literature search [should be consistent with scope of clinical evaluation]
A.3. Methods
(i) Date of search
(ii) Name of person(s) undertaking the literature search
(iii) Period covered by search
(iv) Literature sources used to identify data:
- scientific databases bibliographic (e.g. MEDLINE, EMBASE),
specialised databases (e.g. MEDION)
- systematic review databases (e.g. Cochrane Collaboration)
- clinical trial registers (e.g. CENTRAL),
- adverse event report databases (e.g. MAUDE)
- reference texts
Include justification for choice of sources and describe any supplemental

strategies (e.g. checking bibliography of articles retrieved, hand searching of
literature) used to enhance the sensitivity of the search.
(v) Database search details:

- search terms (key words, indexing headings) and their relationships
(Boolean logic)
- medium used (e.g. online, CD-ROM (including publication date and edition))
Attach copy of downloaded, unedited search strategy.
(vi) Selection criteria used to choose articles
A.4. Outputs
(i) Attach copy of literature citations retrieved from each database search
(ii) Data selection process
Attach flow chart and associated tables showing how all citations were assessed
for suitability for inclusion in the clinical evaluation (see Appendix B).
Notes:
EMBASE Excerpta Medica published by Elsevier
CENTRAL The Cochrane Central Register of Controlled Trials
MAUDE US FDAs Manufacturer And User Facility Device Experience database
MEDION Database that indexes literature on diagnostic tests
MEDLINE Published by US National Library of Medicine
page 36 of 60
APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
14
LITERATURE WITHIN A LITERATURE SEARCH REPORT
Potentially relevant literature identified

through the search
(copy of all citations)
Literature excluded, with reasons
Literature retrieved for more detailed

assessment
Literature excluded from clinical

evaluation, with reasons
Literature with relevant useable data included

in the clinical evaluation, by outcome:
Device performance*
Device safety*
Device comparability (if applicable)
State of the art in the corresponding
medical field
*some literature will address issue of both performance and safety
14
Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF . Improving the quality of
reports and meta-analyses of randomised controlled trials: the QUORUM statement. Quality of Reporting of
Meta-analyses. Lancet 1999; 354:1896-1900
page 37 of 60
APPENDIX C:
SOME EXAMPLES TO ASSIST WITH THE FORMULATION OF CRITERIA 15
_________________________________________________________________________________________________________________________________________________________________________________________________________________________-_________
The following are examples of questions to ask to assist with the formulation of criteria for
data appraisal for different type of data sets. These examples are not meant to be
comprehensive with regards to study types or all potential questions.
Randomised controlled trial

Clinical investigation where subjects are randomised to receive either a test or reference
device or intervention and outcomes and event rates are compared for the treatment groups.
Were the inclusion and exclusion criteria specified?
Was the assignment to the treatment groups really random?
Was the treatment allocation concealed from those responsible for recruiting subjects?
treatment groups?
Were the groups comparable at baseline for these factors?
Were outcome assessors blinded to the treatment allocation?
Were the care providers blinded?
Were the subjects blinded?
Were all randomised participants included in the analysis?
Was a point estimate and measure of variability reported for the primary outcome?
Cohort study
Data are obtained from groups who have and have not been exposed to the device (e.g.
historical control) and outcomes compared.
Were subjects selected prospectively or retrospectively?
Was an explicit description of the intervention provided?
Was there sufficient description about how the subjects were selected for the new
Was there sufficient description about the distribution of prognostic factors for the new
analysis?
Was the measurement of outcomes unbiased (i.e. blinded to treatment group and
comparable across groups)?
Was follow-up long enough for outcomes to occur?
What proportion of the cohort was followed up and were there exclusions from the
analysis?
Were drop-out rates and reasons for drop-out similar across intervention and unexposed
groups?
15
Adapted from: Guidelines for the assessment of diagnostic technologies. Medical Services Advisory
Committee; Commonwealth of Australia 2005.
page 38 of 60
Casecontrol study
Patients with a defined outcome and controls without the outcome are selected and
information is obtained about whether the subjects were exposed to the device.
Was there sufficient description about how subjects were defined and selected for the case
and control groups?
Was the disease state of the cases reliably assessed and validated?
Were the controls randomly selected from the source of population of the cases?
Was there sufficient description about the distribution of prognostic factors for the case
and control groups?
analysis?
Was the new intervention and other exposures assessed in the same way for cases and
controls and kept blinded to case/control status?
How was the response rate defined?
Were the non-response rates and reasons for non-response the same in both groups?
Was an appropriate statistical analysis used?
If matching was used, is it possible that cases and controls were matched on factors
related to the intervention that would compromise the analysis due to over-matching?
Case series
The device has been used in a series of patients and the results reported, with no control group
for comparison.
Was the series based on a representative sample selected from a relevant population?
Were the criteria for inclusion and exclusion explicit?
Did all subjects enter the survey at a similar point in their disease progression?
Was follow-up long enough for important events to occur?
Were the techniques used adequately described?
Were outcomes assessed using objective criteria or was blinding used?
If comparisons of sub-series were made, was there sufficient description of the series and
the distribution of prognostic factors?
page 39 of 60
APPENDIX D: [J58]: This Appendix proposes
too rigid a classification system for
A POSSIBLE METHOD OF APPRAISAL literature reports. In practice, a
___
_________________________________________________________________________________________________________________________________________________________________________________________________________________________-_________
literature search would never produce
(Working group: Add concept of equivalence-biological, technical etc, to this annex) enough hits to get anything useful out
There are many methods that can be used to appraise and weight clinical data. An example of of such a scheme. It is more usual to
take the published evidence in sections
possible appraisal criteria is given in Tables D1 and D2. The criteria may be worked through with descending evidence quality
in sequence and a weighting assigned for each dataset. The data suitability criteria can be
considered generic to all medical devices (Table D1), however the actual method used will 1) randomised, controlled trials (these
always have adequate stats)
vary according to the device considered. 2) non-randomised trials (generally
case series with with historic controls)
3) uncontrolled case series - useful for
To assess the data contribution criteria of the suitable data, the evaluator should sort the data adverse event reports, but no evidence
sets according to source type and then systematically consider those aspects that are most of efficacy
likely to impact on the interpretation of the results (Table D2). There is scope for the The point is that only randomised
evaluator to determine what types of issues are most important in relation to the nature, controlled trials can provide strong
evidnece of efficacy, but that all reports
history and intended clinical application of the device. The criteria used in the example below are valuable for assessing safety, as
are based around the sorts of issues that could be considered for devices of higher risk, such long as they list side effects and
as characteristics of the sample, methods of assessing the outcomes, the completeness and adverse events.
duration of follow-up, as well as the statistical and clinical significance of any results.
In this example, the weightings would be used to assess the strength of the datasets
contribution to demonstrating overall performance and safety of the device (Stage 3, see
section 8). As a general guide in using this example, the more level 1 grades, the greater the
weight of evidence provided by that particular dataset in comparison to other datasets,
however, it is not intended that the relative weightings from each category be added into a
total score.
Table D1 Sample Appraisal Criteria for Suitability
Sutability Criteria Description Grading System

Appropriate device Were the data generated from the D1 Actual device
device in question? D2 Equivalent device
D3 Other device
Appropriate device Was the device used for the same A1 Same use
application intended use (e.g., methods of A2 Minor deviation
deployment, application, etc.)? A3 Major deviation
Appropriate patient Where the data generated from a P1 Applicable
group patient group that is representative of P2 Limited
the intended treatment population P3 Different population
e.g., age, sex, etc.) and clinical
condition (i.e., disease, including
state and severity)?
Acceptable report/data Do the reports or collations of data R1 High quality
collation contain sufficient information to be R2 Minor deficiencies
able to undertake a rational and R3 Insufficient information
objective assessment?
page 40 of 60
Table D2 Sample Appraisal Criteria for Data Contribution
Data Contribution Criteria Description Grading System

Data source type Was the design of the study T1 Yes
appropriate? T2 No
Outcome measures Do the outcome measures O1 Yes

reported reflect the intended O2 No
performance of the device?
Follow up Is the duration of follow-up long F1 Yes
enough to assess whether F2 No
duration of treatment effects and
identify complications?
Statistical significance Has a statistical analysis of the S1 Yes
data been provided and is it S2 No
appropriate?
Clinical significance Was the magnitude of the C1 Yes
treatment effect observed C2 No
clinically significant?
page 41 of 60
APPENDIX E:
A POSSIBLE FORMAT FOR A CLINICAL EVALUATION REPORT [J59]: This format simply does not
work. It is not follow a logical structure
___________________________________________________________________________ and has some significant omissions (such as
risk:benefit assessment)
Rather than suggest a format that does not
F.1. General details work, the Appendix should be deleted.
[sci60]:
30.4.2013 CETF Clinical TF member input:
State the proprietary name of the device, any code names assigned during device development, - Having a template is useful for small and
the version of the device. medium sized companies.
- It would therefore be useful to improve
Identify the manufacturer(s) of the device. this appendix (instead of deleting it)
- A format should be proposed that is more
in line with good current practice.
F.2. Description of the disease or condition and of the state of the art in the [sci61]:
corresponding medical field - New chapter with necessary information
- corresponds to current location of the
information in evaluation reports of a
Provide a description, and cite the references data is based on, including on the following majority of manufacturers
aspects:
disease or condition, and its consequences;
therapeutic and/or diagnostic possibilities currently in use (devices, medicinal products,
surgical interventions, watchful waiting or other strategies);
advantages and disadvantages of the therapeutic and/or diagnostic possibilities currently
in use;
current level of evidence regarding benefits and risks of therapeutic and/or diagnostic
possibilities currently in use;
parameters/endpoints used for a state of the art assessment of benefits to the patients, risks,
the clinical performance defined by the manufacturer. Advantages and limitations of these
parameters. Validity of surrogate endpoints (if used). State of the art values of these
parameters in given target populations;
sub-indications and patient sub-populations known to be associated with specific traits
that affect the choice of an intervention, the use of products, the risk-analysis / benefit-to-
risk ratio of interventions. Discussion of issues, effects and their magnitude.
F.3. Description of the device and its intended application
Provide a concise physical description of the device, cross referencing to relevant sections of
the manufacturers technical information as appropriate. The description should cover
information such as:
materials, including whether it incorporates a medicinal substance (already on the market
or new), tissues, or blood products;
the device components, including software and accessories;
mechanical characteristics; and
others, such as sterile vs. non-sterile, radioactivity etc.
State the intended application of the device single use/reusable; invasive/non invasive;
implantable; duration of use or contact with the body; organs, tissues or body fluids contacted
by the device.
[sci62]:
Describe how the device achieves its intended purpose. 30.4.2013 CETF Clinical TF member input.
- New paragraph
- corresponds to current location of the
How does the device compare to existing products? information in reports written by most
manufacturers (instead of separate chapter
Context of the evaluation.)
page 42 of 60
What elements, properties or technologies of the device are new and what advantages does the
manufacturer expect from these changes?
What elements of the device and technologies have already been used in other products, in
which products?
What elements remained unchanged compared to previously commercialised versions of the
device?
Intended therapeutic and/or diagnostic indications and claims
In line with the product information that is intended for the device,
- state the indications of the device, including diseases or medical conditions and target
populations (all patients not excluded in the instructions for use). [sci63]:
- outline any specific claims regarding clinical properties of the device the manufacturer Aligned with term used in the rest of the
intends to make use of (including benefits to the patient, safety or clinical performance documents
claims).
Do these indications and claims entirely correspond to those of similar or equivalent products [sci64]:
already the on market, which products? - New paragraph with necessary
information
Are there indications and claims that are new?
Context of the evaluation and choice of clinical data types
Outline the context for the clinical development of the device, the Scoping Report, including
the Clinical Development Plan.
State the Essential Requirements relevant to the device in question, in particular, any special
design features that pose special performance or safety concerns (e.g. presence of medicinal,
human or animal components) that were identified in the device risk management
documentation and that required assessment from a clinical perspective.
Outline how these considerations were used to choose the types of clinical data used for the
evaluation.
For all relevant Essential Requirements outline the choice of parameters/endpoints to assess
the different aspects of compliance, including reasons for choosing these
parameters/endpoints,
F.5. Summary of the clinical data and appraisal

For all relevant Essential Requirements state if the evaluation of a given aspect was based on
clinical data of equivalent devices. If so,
- identify the equivalent device(s), describe aspects taken into consideration for
assessing clinical, technical and biological characteristics of the device in question and
devices considered to be equivalent (see previous sections).
- provide a summary of preclinical tests carried out to demonstrate equivalence, results
obtained, and cross-references to the relevant reports in the technical file.
- provide a brief outline of the searching/retrieval process for scientific literature, and
cross-references to the literature search protocols and reports in the technical file. For
clinical data generated by the manufacturer, references to the clinical investigation
protocol(s), amendments (inf any) and clinical investigation report(s) are
indispensable.
page 43 of 60
Provide a tabulation of the clinical data used in the evaluation, categorised according to
whether the data address the safety, benefits to the patients, other clinical performance of the
device in question. (Note: many individual data sets will address both safety and
performance). Within each category, order the data according to the importance of their
contribution to establishing the safety, benefits to the patient and other clinical performance of
the device in relation to any specific claims about clinical properties of the device the
manufacturer intends to use. Additionally, provide a brief outline of the data appraisal
methods used in the evaluation, including criteria for scientific validity, any weighting criteria,
and a summary of the key results.
Include full citations for literature-based data and the titles and investigation codes (if relevant)
of any clinical investigation reports.
Cross-reference the entry for each piece of data to its location in the manufacturers technical
documentation.
F.6. Data analysis
6.1. Clinical performance
Provide a description of the analysis used to assess performance.
Identify the datasets that are considered to be the most important in contributing to the
demonstration of the overall performance of the device and, where useful, particular
performance characteristics. Outline why they are considered to be pivotal and how they
demonstrate the performance of the device collectively (e.g. consistency of results, statistical
significance, clinically significance of effects).
F.6.2. Safety
Describe the total experience with the device, including numbers and characteristics of
patients exposed to the device; and duration of follow-up of device recipients.
Provide a summary of benefits and device-related adverse events, paying particular attention
to serious adverse events.
Provide specific comment on whether the safety characteristics and intended purpose of the
device requires training of the end-user.
F.6.3. Product Literature and Instructions for Use
State whether the manufacturers proposed product literature and Instructions for Use are
consistent with the clinical data and cover all the hazards and other clinically relevant
information that may impact on the use of the device. Relevant aspects include the description
of the intended use, usability aspects, residual risks and their management as supported by
clinical evidence (e.g. handling instructions, type and frequency of risks, warnings,
precautions, contraindications).
page 44 of 60
F.7. Conclusions
Outline clearly the conclusions reached about the safety and clinical performance of the
device from the evaluation, with respect to the intended use of the device, and if the risks
identified in the risk management documentation have been addressed by the clinical data.
State whether
a) the clinical evaluation demonstrates that any risks which may be associated with the
intended use are minimised and acceptable when weighed against the benefits to the
patient and are compatible with a high level of protection of health and safety;
b) the device achieves its intended performance/claims during normal conditions of use, and
are supported by suitable evidence;
c) any undesirable side-effects constitute an acceptable risk when weighed against the
performances intended;
d) the instructions for use correctly describe the intended use of the device that is supported
by clinical evidence;
e) the instructions for use contain correct information about usability aspects, residual risks
and their management as supported by clinical evidence (e.g. handling instructions, type
and frequency of risks, warnings, precautions, contraindications).
If the device can be used in different medical condition and target populations: State whether
the clinical performance and safety of the device as claimed have been established for
these different situations;
the clinical evidence demonstrates conformity with relevant Essential Requirements
(General Safety and Performance Requirements) for all these situations;
and the risks associated with the use of the device are acceptable when weighed against
the benefits to the patient compared to the state of the art in the corresponding medical
field for all these situations.
State needs for further investigations, including for post market clinical follow-up studies
(PMCF).
page 45 of 60
page 46 of 60
APPENDIX F
Clinical evaluation checklist for Notified Bodies

Ref Requirement Fulfilled Comment
0 Conformity without Clinical Data
0.1 Any demonstration of conformity without clinical data Yes
(Annex 7.1.5 of 90/385/EEC and Annex X.1.1d of No
93/42/EEC) must be adequately justified and based on N/A.
the output of the risk management process
viewed in the context of the device-body interaction
the intended clinical performance
the claims of the manufacturer.
Adequacy of demonstration of conformity based on

performance evaluation, bench testing and pre-clinical
evaluation in the absence of clinical evaluation must be
duly substantiated.
The notified body must review the manufacturers

justification, the adequacy of data presented and whether
or not conformity is demonstrated.
Is the manufacturers justification adequate?
Is the performance evaluation, bench testing and pre-
clinical evaluation adequate to demonstrate
conformity to the Essential Requirements?
1 Clinical Evaluation, General
1.1 The manufacturer should include in the technical Yes Clinical literature
documentation a statement on the route(s) applied to No Published
retrieve the clinical data used to affix the CE N/A.
marking. Unpublished
Equivalence demonstrated
The statement should make clear whether that
Clinical investigation
clinical data was obtained from the published
literature or the results of clinical investigations or a Combination of literature and investigation data
page 47 of 60
combination of both and shall include an adequate Comment
justification of the route(s) selected and a
demonstration of equivalence (technical, biological, [sci65]: Term adapted (equivalence
is used in European medical devices
clinical) and adequacy if clinical data from similar directives, not equivalency)
devices have been used
1.2 The Clinical Evaluation Report and the full clinical Yes
data used for CE marking should be available in the No
technical documentation N/A.
[sci66]:
- For statements based on published literature: The -New contents (all bullet points)
full text version of the publication cited in the (Change presented for CAMD Clinical TF
teleconference of 22.4.2013)
clinical evaluation report is available (not
abstracts only).
- For statements regarding equivalence to other
products: The original full text version of pre-
market study reports assessing parameters of
interest (not abbreviated versions or versions
prepared for customers).
- For statements regarding results of own clinical
investigations: The original version of the clinical
investigation protocol as accepted by the ethics
committee and the competent authority, protocol
amendments, the original full text version of the
clinical investigation report (not abbreviated
versions or versions prepared for customers).
1.3 The manufacturer has clearly documented the Yes

objectives and the scope of the clinical evaluation No
and specified the clinical ERs [e.g. clinical N/A.
performance(s), safety, risks and favourable
benefit/risk ratio related to intended use, target
group(s) and indication(s)] to be met
1.4 The manufacturer has clearly outlined the performed Yes
steps and procedures of clinical evaluation according No
page 48 of 60
to this MEDDEV (specifically sections 5 to 9), N/A.
adequate justification given for deviations
2 Clinical investigation route
2.1 Need for clinical investigation
2.1.1 Classification of device Yes
Is the device an implantable or class III medical No
device or an active implantable medical device? N/A.
2.1.2 If a clinical investigation is not presented for an Yes
implantable or class III MD or an AIMD, has this No
been adequately justified by the manufacturer in his N/A.
risk analysis and clinical evaluation?
devices, is this clinical data when taken together with No
the available pre clinical data sufficient to N/A.
demonstrate conformity with the essential
requirements covering safety and performance of the
device in question under normal conditions of use?
devices, are there gaps in either the demonstration of No
compliance with each relevant essential requirement N/A.
or in the demonstration of equivalence that needs
addressing through the means of a specifically
designed clinical investigation(s)?
devices, is the data sufficient to address the clinical No
hazards identified in the risk analysis? N/A.
If no, a clinical investigation(s) will be needed.
The objectives of the clinical investigation(s) should
focus on those aspects not sufficiently addressed by
the available data.
2.2 Conduct of clinical investigation
2.2.1 Were the relevant annexes of the medical devices Yes
Directives (Annex 7 AIMD, Annex X MDD) and the No
page 49 of 60
relevant standards (EN ISO 14155-1, -2) taken into N/A.
account?
2.2.2 Requirements for clinical investigations
2.2.3 Identification of relevant documentation, the
following documentation should be requested and
reviewed by the notified body:
2.2.4 Copy of the Protocol submitted to the Competent Yes
Authority or other regulatory agency for which no No
grounds for objection were raised N/A.
2.2.5 Copy of the letter of no objection/approval from Yes
Competent Authority/Authorities (if available) or No
other approval from the relevant regulatory N/A.
agency(ies), together with any comments made
arising from regulatory review
2.2.6 Copy of the Ethics Committee opinion(s) and Yes
comments arising from their review or a summary of No
all Ethics Committee opinions and any N/A.
comments/conditions arising from their reviews
2.2.7 Copy of the signed and dated final report Yes
No
N/A.
2.3 Information to be checked the following
information should be checked by the notified
body
2.3.1 Letter of no objection from the Competent Yes
Authority(ies) No
N/A.
2.3.2 Clinical Investigation Plan (CIP): Is the CIP, used for the Yes
clinical investigation, the same as that submitted to the No
Competent Authority? 16 N/A.
16 Particular attention should be paid to: number of patients entered; objectives of investigation(s) (in particular which Essential Requirements are being addressed); duration of investigation(s) and patient follow up (short and long-term); end points in terms of
diagnostic tools and patient assessment; inclusion and exclusion criteria
.
page 50 of 60
2.3.3 If parameters are not as set out in the original CIP, the Yes
rationale for non-adherence No
N/A.
2.3.4 Identification of any changes to CIP and rationale for any Yes
such changes No
N/A.
2.3.5 Where the clinical investigation(s) was performed outside Yes
the EU, the manufacturer must demonstrate that the use of No
the device (including clinical practice and techniques) and N/A.
target population are equivalent to those for which the
device will be used within the EU (if relevant).
2.3.6 For drug-device combinations, have any issues or Yes
concerns raised as part of the clinical assessment of the No
medicinal substance by the medicinal competent authority N/A.
or EMEA been considered and/or resolved?
2.4 Final report of investigation
The report should be reviewed and should include the
2.4.1 Summary a structured abstract should be provided, Yes
presenting the essentials of the study 17 No
N/A.
2.4.2 Introduction a brief statement placing the study in the Yes
context of the development of the medical device in No
question and an identification of guidelines followed in N/A.
the development of the Protocol
2.4.3 Materials and methods 18 Yes
No
N/A.
2.4.4 Summary of the clinical investigation plan 19 Yes
17
Including title of investigation(s); identification of the medical device(s), including names, models as relevant for complete identification; name of sponsor; statement
indicating whether the investigation(s) was performed in accordance with CEN/ISO Standards; objectives; subjects; methodology; investigation(s) initiation and
completion dates, including date of early termination, if applicable; results; conclusions; authors of report; date of report.
18
Including device description; summary description of the device and its intended use, together with any modifications performed during the investigation.
page 51 of 60
No
N/A.
2.4.5 Results this section should contain summary Yes
information with a description of the analysis and results 20 No
N/A.
2.4.6 Discussions and conclusions 21 Yes
No
N/A.
2.4.7 Signature the final report should be signed off by the Yes
sponsor, the co-ordinating clinical investigator (if No
appointed) and principal investigator at each centre N/A.
2.4.8 Annex to the report, containing clinical investigation plan, Yes
including amendments, list of investigators and their No
institutions, list of other parties involved, list of N/A.
monitors, list of statisticians (if applicable), list of
Ethics Committees and their approval letters.
2.5 NB assessment of the clinical investigation(s) data
presented
2.5.1 Have any identified pass/fail criteria of the Yes
investigation(s) been met? No
N/A.
2.5.2 Have the results and conclusions of the clinical Yes
investigation(s) demonstrated compliance with the No
19
Including the clinical investigation objectives; the investigation design; type of investigation; investigation end points; ethical considerations; subject population;
inclusion/exclusion criteria; sample size; treatment and treatment allocation; investigation variables; concomitant medications/treatments; duration of follow up; statistical
analysis including investigation hypothesis or pass/fail criteria, sample size calculation, statistical analysis methods.
20
Including the investigation initiation date; investigation completion/suspension date; the disposition of patients/devices; the patient demographics; clinical
investigation plan compliance; the analysis to include safety report, including a summary of all adverse events and adverse device events seen in the investigation, including
a discussion of the severity, treatment required, resolution and assessment by the investigator of relation to treatment; performance or efficacy analysis; any sub group analysis
for special population; a description of how missing data, including patients lost to follow up or withdrawn, were dealt with in the analysis.
21
Including the performance and safety results of the study; the relationship of risks and benefits; clinical relevance and importance of the results, particularly in the light
of other existing data and discussion of comparison with state of the art; any specific benefits or special precautions required for individual subjects or at risk groups;
any implications for the conduct of future studies.
page 52 of 60
identified relevant essential requirements? N/A.
by clinical data when taken together with the relevant No
pre-clinical data? N/A.
2.5.4 Has the risk analysis demonstrated that the risks Yes
associated with the use of the device, as set out by the No
manufacturer, are acceptable when balanced against the N/A.
benefits to the patient?
manner? No
N/A.
2.5.6 Cross checking of one or several key statements contained Yes [sci67]:
in the clinical evaluation report: Are the statements in line No
- This item is new
(Contribution of CAMD Clinical TF
with the contents of the referenced documents? N/A. members, be more specific as to the
activities carried out by the notified bodies)
3 Clinical literature data
A critical evaluation of relevant scientific literature that is currently available relating to safety, performance, design characteristics
and intended purpose in the form of a written report
3.1 Methodology
3.1.1 A critical evaluation of relevant scientific literature has Yes
been presented No
N/A.
3.1.2 A search protocol for the identification, selection, Yes
collation and review of relevant publications should be No
written. N/A.
3.1.3 The objective of the literature review should be clearly Yes
defined No
N/A.
3.1.4 The types of studies that are relevant to the objective of Yes
the literature review should be specified No
N/A.
3.1.5 Data should be taken from recognised scientific Yes
publications. Unpublished data should also be taken into No
account in order to avoid publication bias. N/A.
page 53 of 60
3.1.6 The literature review should state:
3.1.6.1 sources of data, extent of the searches of databases or Yes
other sources of information No
N/A.
3.1.6.2 rationale for the selection/ relevance of the published Yes
literature No
N/A.
3.1.6.3 reasons for believing that all relevant references, both Yes
favourable and unfavourable, have been identified No
N/A.
3.1.6.4 criteria for exclusion of particular references together Yes
with a justification for this exclusion. No
N/A.
3.1.6.5 detailed description of the different stages of Yes
literature search (including identification, appraisal, No
analysis and conclusion of hits) N/A.
3.2 Relevance of data presented
3.2.1 A literature review should clearly establish the extent Yes
to which the literature relates to the specific No
characteristics and features of the device under N/A.
consideration.
3.2.2 If the published studies do not directly refer to the Yes
device in question, the manufacturer must No
demonstrate equivalence with the device, which is N/A.
the subject of the published reports.
3.2.3 To be equivalent, the devices should have similarity Yes
with regard to the clinical, technical and biological No
parameters with special attention to the performance, N/A.
principles of operation and materials; or if there are
differences identified, an assessment and
page 54 of 60
demonstration of the significance these might have
on safety and performance must be set out 22.
3.2.4 The manufacturer must be able to demonstrate the Yes
adequacy of the data in addressing the aspects of No
conformity set out in the objective N/A.
3.3 NB Assessment of clinical data
The literature review should make clear the
significance that is attached to particular references
based on a number of factors. These include:
3.3.1 relevance of the authors background and expertise in Yes
relation to the particular device and/or medical procedure No
involved N/A.
3.3.2 whether the authors conclusions are substantiated by the Yes
available data No
N/A.
3.3.3 whether the literature reflects the current medical practice Yes
and the generally acknowledged state of the No
art technologies N/A.
3.3.4 whether references are taken from recognised scientific Yes
publications and whether or not they have been reported No
in peer reviewed journals N/A.
3.3.5 the extent to which the published literature is the outcome Yes
of a study/studies which have followed scientific No
principles in relation to design 23 N/A.
3.4 Critical evaluation of the literature
The literature review should contain a critical evaluation of the literature. This critical evaluation should:
22
Meaning of the term equivalence: see chapter 5.2.1
23
For example in having demonstrable and appropriate endpoints, inclusion and exclusion criteria, an appropriate and validated number of patients submitted, carried out for
an appropriate duration, providing evidence and analysis of all adverse incidents, deaths, exclusions, withdrawals and subjects lost follow-up and identifying an appropriate
statistical plan of analysis. Ideally, evidence should be generated from a clinical trial (controlled if appropriate), properly designed cohort/case controlled study, well
documented case histories or sequential reports conducted by appropriate experienced experts, whether in relation to the device itself or an equivalent device. If unpublished
data is being included in the assessment, the literature review will need to weigh the significance that is attached to each report.
page 55 of 60
3.4.1 be written by a person suitably qualified in the relevant Yes
field, and reviewed and approved by an expert No
knowledgeable in the state of the art and able to N/A.
demonstrate objectivity
3.4.2 contain a short description of the medical device, its Yes
intended functions, description of the intended purpose No
and application of use N/A.
3.4.3 contain an analysis of all the available data considered, Yes
both favourable and unfavourable No
N/A.
3.4.4 establish the extent to which the literature relates to the Yes
specific characteristics and features of the device being No
assessed, taking due account of the extend of similarity N/A.
between the device(s) covered by the literature and the
device under assessment
3.4.5 demonstrate that those aspects of the use of the device, Yes
including performance, addressed in the clinical part of No
the risk analysis are met as claimed by the manufacturer, N/A.
and that the device fulfils its intended purpose as a
medical device
3.4.6 analyse the identified hazards, the associated risks and the Yes
appropriate safety measures of patients, medical staff and No
third parties involved in the study/studies N/A.
3.4.7 contain a risk analysis relevant to the device design, Yes
materials and procedures involved, taking into account No
any adverse events, results of post-market surveillance N/A.
studies, modifications and recalls (if known)
3.4.8 contain a description of the methods of weighting of Yes
different papers and the statistical methods of analysis No
employed taking into account the assessment methods, the N/A.
type and duration of study and the heterogeneity of the
population included within the study
3.4.9 include an analysis of the market experience of the same Yes
page 56 of 60
or similar devices, including the results of post-marketing No
studies, post-market surveillance and short- and long-term N/A.
adverse events
3.4.10 contain a list of publications appropriately cross- Yes
referenced in the evaluation No
N/A.
3.4.11 if the clinical data relates to an equivalent device, contain Yes
a statement that equivalence with all the relevant No
characteristics has been demonstrated N/A.
3.4.12 include a conclusion 24 with a justification, including an Yes
assessment of any probable benefit to health from the use No
of the device as intended by the manufacturer, against N/A.
probable risks of injury or illness from such use taking
account of the state of the art. The conclusions should
make clear how the objectives of the literature review
have been met and identify any gaps in the evidence
necessary to cover all relevant aspects of safety and
performance
3.4.13 The critical evaluation should be signed and dated by the Yes
author No
N/A.
3.5 NB Assessment of the critical evaluation of literature
presented by the manufacturer
3.5.1 Are the manufacturers conclusions valid? Yes
No
N/A.
3.5.2 Is the data, taken together with the available pre clinical Yes
data, sufficient to demonstrate compliance with the No
essential requirements covering safety and performance of N/A.
the device in question under normal conditions of use? 25
24
Conclusions should consider the claimed use - indications, contraindications and instructions for use proposed by the manufacturer.
25
If not, identify gaps in the demonstration of compliance with the relevant essential requirements or in the demonstration of equivalence that need addressing through the
means of a specifically designed clinical investigation(s).
page 57 of 60
by the clinical data taken together with the pre-clinical No
data? N/A.
manner? No
N/A.
4 Post-market clinical follow up the notified body
should check and review the manufacturers post
market clinical follow up plan:
4.1 Has the manufacturer presented an appropriate plan for Yes
post-market clinical follow up in line with appropriate No
guidance? N/A.
4.2 If no post-market clinical follow up plan is presented, has Yes
this been adequately justified by the manufacturer? No
N/A.
4.3 Has the manufacturer an adequate post-market Yes
surveillance system in place? No
N/A.
4.4 Has the manufacturer committed to inform the NB of Yes
significant updates to their clinical evaluation arising from No
PMS/PMCF? N/A.
5 Notified Body Decision Making
5.1 In reviewing the evaluation of clinical data submitted by the manufacturer the NB must decide whether the manufacturer
has adequately
5.1.1 described the current state of the art in the corresponding Yes
medical field, using valid parameters/endpoints for the No
quantification of benefits to the patients, risks, claims N/A.
about clinical properties of the device the manufacturer
intends to make use of
5.1.2 for the given medical device, described and verified Yes
benefits to the patients, risk, clinical claims the No
manufacturer intends to make use of N/A.
5.1.3 performed a risk analysis and estimated the undesirable Yes
page 58 of 60
side effects No
N/A.
5.1.4 concluded on the basis of documented justification that Yes
the risks are acceptable when weighed against the No
intended benefits N/A.
5.1.5 provided such conclusions and sufficient clinical evidence Yes [sci68]:
New text. (Change presented for CAMD
for all the medical conditions and target populations No Clinical TF teleconference of 22.4.2013)
covered by the IFU 26 N/A
5.2 NB assessment of benefit/risk presented in the clinical
evaluation data
5.2.1 the listing and characterisation of the clinical performance Yes
of the device intended by the manufacturer and the No
expected benefits for the patient N/A.
5.2.2 the use of the list of identified hazards to be addressed Yes
through evaluation of clinical data No
N/A.
5.2.3 the adequate estimation of the associated risks for each Yes
identified hazard by: No
a) characterising the severity of the hazard; N/A.
b) estimating and characterising the probability of
occurrence of the harm (or health impairment or loss of
benefit of the treatment) (document with rationale)
5.2.4 the decision on the acceptability of risks in relation to Yes
each identified hazard No
N/A.
5.3. Audits after CE-marking (surveillance audits, re- [sci69]:
All points under 5.3 are new (NB activities
certification audits) after CE marking previously missing in this
5.3.1 Have PMCF activities been carried out as planned? Yes checklist).
(Change presented for CAMD Clinical TF
teleconference of 22.4.2013)
26
Footnote: Special attention is needed when the intended use is ill defined and covers a wide range of medical conditions, types of patients, and severities of diseases.
Example: Cardiac implant, closure device for open foramen. What are the specific indications? Use in patients at risk of recurrent stroke or in patients with migraine is not
likely to share the same benefit-to-risk assessment. The intended use shall be clarified if necessary and indications with different benefit-to-risk parameters shall be addressed
separately.
page 59 of 60
No
N/A.
5.3.2 Has the clinical evaluation report been updated with Yes
clinical data obtained during the use of the device? No
- new data from PMCF, vigilance, complaint handling N/A.
- data published by third parties, information that affects
the benefit to risk ratio and its acceptability:
- information about equivalent devices used as a
basis for the clinical evaluation of the device
- information about similar devices that point to
possible class hazards
- information about similar devices, alternative
treatments and methods that affect the state of the
art in the corresponding medical field (extent of
benefits patients can expect, risk levels considered
to be acceptable)
- if no additional information became available during
the period, this is clearly stated.
page 60 of 60
EUROPEAN COMMISSION
Consumer, Environmental and Health Technologies
Health technology and Cosmetics
MEDDEV 2.7/1 revision 4
June 2016
UNDER DIRECTIVES 93/42/EEC and 90/385/EEC
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-Directives on medical
Devices. They are legally not binding. The Guidelines have been carefully drafted through a process of intensive
consultation of the various interested parties (competent authorities, Commission services, industries, other interested
parties) during which intermediate drafts where circulated and comments were taken up in the document. Therefore, this
document reflects positions taken by representatives of interest parties in the medical devices sector. These guidelines
incorporate changes introduced by Directive 2007/47/EC amending Council Directive 90/385/EEC and Council Directive
93/42/EEC.
MEDDEV 2.7/1 revision 4 page 1 of 65

MEDICAL DEVICES DIRECTIVES
CLINICAL INVESTIGATION
Index
1. Introduction......................................................................................................................... 4
2. Scope ................................................................................................................................. 4
3. References ......................................................................................................................... 4
4. Definitions........................................................................................................................... 5
5. Abbreviations...................................................................................................................... 8
6. General principles of clinical evaluation ............................................................................. 9

6.1. What is clinical evaluation? ................................................................................................ 9
6.2. When is clinical evaluation undertaken and why is it important?...................................... 10
6.2.1. Clinical evaluation undertaken for the development of a medical device ......................... 10
6.2.2. Clinical evaluation for initial CE-marking .......................................................................... 11
6.2.3. Updating the clinical evaluation ........................................................................................ 11
6.3. How is a clinical evaluation performed? ........................................................................... 13
6.4. Who should perform the clinical evaluation? .................................................................... 14
7. Definition of the scope of the clinical evaluation (Stage 0) ............................................... 15
8. Identification of pertinent data (Stage 1)........................................................................... 17

8.1. Data generated and held by the manufacturer ................................................................. 17
8.2. Data retrieved from literature............................................................................................ 18
9. Appraisal of pertinent data (Stage 2)................................................................................ 19

9.1. General considerations..................................................................................................... 19
9.2. The appraisal plan ............................................................................................................ 20
9.3. Conduct of the appraisal................................................................................................... 20
9.3.1. How to evaluate methodological quality and scientific validity ......................................... 20
9.3.2. How to determine the relevance of a data set for the clinical evaluation.......................... 24
9.3.3. How to weight the contribution of each data set............................................................... 26
10. Analysis of the clinical data (Stage 3)............................................................................... 27

10.1. General considerations..................................................................................................... 27
10.2. Specific considerations..................................................................................................... 27
10.3. Where demonstration of conformity based on clinical data is not deemed appropriate ... 29
11. The clinical evaluation report (CER, Stage 4) .................................................................. 29
12. The role of the notified body in the assessment of clinical evaluation reports.................. 31
Appendices...................................................................................................................................... 32

A1. Demonstration of equivalence .......................................................................................... 32
A2. When should additional clinical investigations be carried out?......................................... 34
A3. Device description - typical contents ................................................................................ 35
A4. Sources of literature ......................................................................................................... 36
A5. Literature search and literature review protocol, key elements ........................................ 37
A5.1. Background to the literature search and the literature review .......................................... 38
A5.2. Objective........................................................................................................................... 38
A5.3. Methods............................................................................................................................ 39
A6. Appraisal of clinical data - examples of studies that lack scientific validity for
demonstration of adequate clinical performance and/or clinical safety ............................ 39
A7. Analysis of the clinical data - compliance to specific Essential Requirements ................. 41
A7.1. Conformity assessment with requirement on safety (MDD ER1 / AIMDD ER1)............... 41
A7.2. Conformity assessment with requirement on acceptable benefit/risk profile
(MDD ER1 / AIMDD ER1) ................................................................................................ 42
A7.3. Conformity assessment with requirement on performance (MDD ER3 / AIMDD ER2) ... 46
A7.4. Conformity assessment with requirement on acceptability of undesirable side-effects
(MDD ER6 / AIMDD ER5) ................................................................................................ 47
A8. Devices for unmet medical needs - aspects to consider .................................................. 48
A9. Clinical evaluation report - proposed table of contents, examples of contents................. 49
A10. Proposed checklist for the release of the clinical evaluation report.................................. 54
A11. Information on declarations of interests............................................................................ 56
A12. Activities of notified bodies ............................................................................................... 56

A12.1. Notified body assessment of clinical evaluation by conformity assessment route ........... 56
A12.2. Examination of a design dossier (Annex II.4; Annex 2.4) or of a type examination dossier
(Annex III; Annex 3).......................................................................................................... 57
A12.3. Evaluation as part of quality system related procedures .................................................. 61
A12.4. Notified body specific procedures and expertise .............................................................. 62

1. Introduction
Pursuant to
- section 6a of Annex I to Directive 93/42/EEC (amended by Directive 2007/47/EC) and to
- section 5a of Annex 1 to Directive 90/385/EEC (amended by Directive 2007/47/EC),
the demonstration of conformity with Essential Requirements for a medical device must include a
clinical evaluation, which is conducted in accordance with Annex X to Directive 93/42/EEC or with
Annex 7 to Directive 90/385/EEC.
This document promotes a common approach to clinical evaluation for medical devices regulated
by directives 90/385/EEC and 93/42/EEC. It does not concern in vitro diagnostic devices.
The depth and extent of clinical evaluations should be flexible and appropriate to the nature,
intended purpose, and risks of the device in question. Therefore, this guidance is not intended to
impose device-specific requirements.
This document uses the terms "must", "shall", "have to" where these terms are used in the
Directives. "Should" is used in other instances.
2. Scope
This guide is not legally binding; only the text of the Directives is authentic in law. It is recognised
that under given circumstances, for example as a result of scientific developments, an alternative
approach may be possible or appropriate to comply with the legal requirements.
Nevertheless, due to the participation of interested parties and of experts from national Competent
Authorities, it is anticipated that this guide will be followed within the Member States, thereby
supporting uniform application of relevant provisions of EU Directives and common practices.
On certain issues not addressed in the Directives, national legislation may be different from this
guide.
This guide is regularly updated according to regulatory developments. The latest version of the
guide should always be used. This version is a complete revision of the previous texts.
The medical device legislation in Europe is currently being significantly revised. A new Regulation
of the European Parliament and of the Council on medical devices will be published, which may
result in changes to important concepts or definitions relating to clinical evaluation. Parts or all of
this document are likely to be revised. Some contents (such as contents about notified bodies) are
likely to be removed and integrated in other series of documents.
3. References
European Legislation:
- Council Directive 90/385/EEC of 20 June 1990 relating to active implantable medical devices
- Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
- Commission Regulation 722/2012 of 8 August 2012 concerning active implantable medical
devices and medical devices manufactured utilising tissues of animal origin

- Commission Implementing Regulation 920/2013 of 24 September 2013 on the designation and
the supervision of notified bodies under Council Directive 90/385/EEC on active implantable
medical devices and Council Directive 93/42/EEC on medical devices
Harmonised and International standards:

- EN ISO 14155:2011 Clinical investigation of medical devices for human subjects Good clinical
practice
- EN ISO 14971:2012 Medical devices application of risk management to medical devices
European guidance documents:

- MEDDEV 2.12/1 Guidelines on a medical devices vigilance system
- MEDDEV 2.12/2 Guidelines on post market clinical follow-up studies: a guide for manufacturer
and notified body
- MEDDEV 2.4/1 Classification of medical devices
- MEDDEV 2.7/2 Guidelines for competent authorities for making a validation/assessment of a
clinical investigation application under directives 90/385/EEC and 93/42/EC
- Manual on borderline and classification in the Community regulatory framework for medical devices
- NBOG BPG 2006-1 Change of notified body
- NBOG BPG 2009-1 Guidance on design-dossier examination and report content
- NBOG BPG 2009-4 Guidance on notified bodys tasks of technical documentation assessment
on a representative basis
- NBOG BPG 2010-2 Guidance on audit report content
- NBOG BPG 2014-1 Renewal of EC design-examination and type-examination certificates:
Conformity assessment procedures and general rules
- NBOG BPG 2014-2 Guidance on the information required for notified body medical device
personnel involved in conformity assessment activities
- NBOG BPG 2014-3 Guidance for manufacturers and notified bodies on reporting of design
changes and changes of the quality system
Other guidance documents:

- GHTF SG5 N1R7:2007: Clinical evidence - Key definitions and concepts
- GHTF SG5 N2R8:2007: Clinical evaluation
- GHTF SG5 N41R9:2005: Essential principles of safety and performance
This list contains documents available at the time this MEDDEV document was published. In
general, the most recent versions of standards and legal texts should be used.
4. Definitions
Adverse event: any untoward medical occurrence, unintended disease or injury, or any untoward
clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether
or not related to the investigational medical device.

NOTE 1: This includes events related to the investigational device or the comparator.
NOTE 2: This includes events related to the procedures involved.
NOTE 3: For users or other persons this is restricted to events related to the investigational
medical device.
[EN ISO 14155:2011]
Bias: bias is a systematic deviation of an outcome measure from its true value, leading to either an
overestimation or underestimation of a treatments effect. It can originate from, for example, the
way patients are allocated to treatment, the way treatment outcomes are measured and
interpreted, and the way data are recorded and reported. [Adapted from GHTF SG5/N2R8:2007]
Clinical data: the safety and/or performance information that is generated from the clinical use of
a device. Clinical data are sourced from:
- clinical investigation(s) of the device concerned; or
- clinical investigation(s) or other studies reported in the scientific literature, of a similar device for
which equivalence to the device in question can be demonstrated; or
- published and/or unpublished reports on other clinical experience of either the device in
question or a similar device for which equivalence to the device in question can be
demonstrated.
[derived from Article 1.2.k MDD and Art. 1.2.k AIMDD]
Clinical evaluation: a methodologically sound ongoing procedure to collect, appraise and analyse
clinical data pertaining to a medical device and to evaluate whether there is sufficient clinical
evidence to confirm compliance with relevant essential requirements for safety and performance
when using the device according to the manufacturers Instructions for Use.
Note: In exceptional cases where an instruction for use is not required, the collection, analysis and
assessment are conducted taking into account generally recognised modalities of use.
Clinical evidence: the clinical data and the clinical evaluation report pertaining to a medical
device. [GHTF SG5/N2R8:2007]
Clinical investigation: systematic investigation in one or more human subjects, undertaken to

assess the safety or performance of a medical device.
Note: 'clinical trial' or ' clinical study' are synonymous with ' clinical investigation'.
[EN ISO 14155:2011]
Clinical investigation plan: document that states the rationale, objectives, design and proposed
analysis, methodology, monitoring, conduct and record-keeping of the clinical investigation.
[EN ISO 14155:2011]
Clinical performance: behaviour of a medical device or response of the subject(s) to that medical
device in relation to its intended use, when correctly applied to appropriate subject(s). [EN ISO
14155:2011]
Device registry: an organised system that uses observational study methods to collect defined
clinical data under normal conditions of use relating to one or more devices to evaluate specified

outcomes for a population defined by a particular disease, condition, or exposure and that serves
predetermined scientific, clinical or policy purpose(s).
Note: The term device registry should not be confused with the concept of device registration and
listing.
[MEDDEV 2.12/2 rev2]
Clinical safety: freedom from unacceptable clinical risks, when using the device according to the
manufacturers Instructions for Use. [MEDDEV 2.7/2 revision 2]
Note: In exceptional cases where an instruction for use is not required, the collection, analysis and
assessment are conducted taking into account generally recognised modalities of use.
Clinical use: use of a medical device in or on living human subjects.

Note: Includes use of a medical device that does not have direct patient contact.
Equivalent device: a device for which equivalence to the device in question can be demonstrated.
[Derived from Art. 1.2.k MDD]
Feasibility study: a clinical investigation that is commonly used to capture preliminary information
on a medical device (at an early stage of product design) to adequately plan further steps of device
development, including needs for design modifications or parameters for a pivotal study. [MEDDEV
2.7/2 revision 2]
Harmonised standards: standards whose references have been published in the Official Journal
of the European Communities. [Derived from article 5 of Directive 90/385/EEC and article 5 of
Directive 93/42/EEC]
Hazard: potential source of harm. [EN ISO 14971:2012]
Hazard due to substances and technologies: for the purpose of this MEDDEV document, a
hazard that is seen with products that share specific characteristics.
Note: This includes products that contain the same materials and substances, material
combinations, use the same technologies, produce similar abrasion, are used with the same type
of surgical approach, share the same manufacturing procedures or impurities, or share other
characteristics.
Incident: any malfunction or deterioration in the characteristics and/or performance of a device, as

well as any inadequacy in the labelling or the instructions for use which, directly or indirectly, might
lead to or might have led to the death of a patient, or user or of other persons or to a serious
deterioration in their state of health. [MEDDEV 2.12/rev 8]
Information materials supplied by the manufacturer: for the purpose of this document, this
refers to the labelling, instructions for use and the manufacturer's promotional materials for the
device under evaluation.
[Derived from MDD Art. 1.2.g, MDD Annex I section 13, AIMDD Art. 1.2.f, AIMDD Annex I sections
14 and 15]

Intended purpose: the use for which the device is intended according to the data supplied by the
manufacturer on the labelling, in the instructions and/or in promotional materials.
[MDD Art. 1.2.g, AIMDD Art. 1.2.f]
Investigator: individual member of the investigation site team designated and supervised by the
principal investigator at an investigation site to perform critical clinical-investigation-related
procedures or to make important clinical investigation-related decisions. [EN ISO 14155:2011]
PMCF plan: the documented, proactive, organised methods and procedures set up by the
manufacturer to collect clinical data based on the use of a CE-marked device corresponding to a
particular design dossier or on the use of a group of medical devices belonging to the same
subcategory or generic device group as defined in Directive 93/42/EEC. The objective is to confirm
clinical performance and safety throughout the expected lifetime of the medical device, the
acceptability of identified risks and to detect emerging risks on the basis of factual evidence.
[MEDDEV 2.12/2 rev.2]
PMCF study: a study carried out following the CE marking of a device and intended to answer
specific questions relating to clinical safety or performance (i.e. residual risks) of a device when
used in accordance with its approved labelling. [MEDDEV 2.12/2 rev.2]
Risk: combination of the probability of occurrence of harm and the severity of that harm.
[EN ISO 14971:2012]
Risk management: systematic application of management policies, procedures and practices to

the tasks of analysing, evaluating, controlling and monitoring risk. [EN ISO 14971:2012]
Serious adverse event: adverse event that

a) led to death,
b) led to serious deterioration in the health of the subject, that either resulted in
1) a life-threatening illness or injury, or
2) a permanent impairment of a body structure or a body function, or
3) in-patient or prolonged hospitalization, or
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent
impairment to a body structure or a body function,
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP
[Clinical Investigation Plan], without serious deterioration in health, is not considered a serious
adverse event.
[EN ISO 14155:2011]
Sufficient clinical evidence: an amount and quality of clinical evidence to guarantee the scientific
validity of the conclusions.

5. Abbreviations
AIMDD: Active implantable medical device directive (Council Directive 90/385/EEC amended by
Directive 2007/47/EC)
CEAR: Clinical Evaluation Assessment Report
CER: Clinical Evaluation Report
ER: Essential Requirement
IFU: Instructions For Use
MDD: Medical Device Directive (Council Directive 93/42/EEC amended by Directive
2007/47/EC)
PMS: Post Market Surveillance
PMCF: Post Market Clinical Follow-Up
6. General principles of clinical evaluation
6.1. What is clinical evaluation?

Clinical evaluation is a methodologically sound ongoing procedure to collect, appraise and analyse
clinical data pertaining to a medical device and to analyse whether there is sufficient clinical
evidence to confirm compliance with relevant essential requirements for safety and performance
when using the device according to the manufacturers instructions for use.
In exceptional cases where an instruction for use is not required, the collection, appraisal, and
analysis are conducted taking into account generally recognised modalities of use.
The requirements for clinical evaluation apply to all classes of medical devices. The evaluation
should be appropriate to the device under evaluation, its specific properties, and its intended
purpose.
Benefits and risks should be specified, e.g. as to their nature, probability, extent, duration and
frequency. Core issues are the proper determination of the benefit/risk profile in the intended target
groups and medical indications, and demonstration of acceptability of that profile based on current
knowledge/ the state of the art in the medical fields concerned.
Clinical evaluation is a responsibility of the manufacturer and the clinical evaluation report is an
element of the technical documentation of a medical device.
For compliance with European medical device directives,

the clinical evaluation addresses the following Essential Requirements:
- Annex 1 sections 1, 2, 5 of AIMDD (for active implantable medical devices), or
- Annex I sections 1, 3, 6 of MDD (for medical devices);
see Appendix A7 (Analysis of the clinical data - compliance to specific Essential
Requirements);
the evaluation must follow defined and methodologically sound procedures as described in:
- Annex 7 of AIMDD (for active implantable medical devices), or
- Annex X of MDD (for medical devices);

where demonstration of conformity with essential requirements based on clinical data is not
deemed appropriate, an adequate justification has to be given. The justification is included
in the clinical evaluation report with contents according to:
- Annex 7 section 1.5 of AIMDD (for active implantable medical devices), or
- Annex X section 1.1d of MDD (for medical devices).
Conformity to the Essential Requirements can only be assumed when the following items are
aligned with each other:
- the information materials supplied by the manufacturer (the labelling, instructions for
use, available promotional materials, including accompanying documents foreseen by
the manufacturer)
- the clinical evaluation (the device description used for the clinical evaluation, other
contents of the clinical evaluation report)
- the available clinical data (such as results of Clinical Investigations, publications, PMS
studies, etc.).
Particularly, evaluators should address if the following points are adequately supported by
sufficient clinical evidence:
- the intended purpose described in the information materials supplied by the
manufacturer (including for all medical indications);
- the clinical performance and benefits described in the information materials supplied by
the manufacturer (including, for example, any claims on product performance and
safety);
- measures for risk avoidance and risk mitigation described in the information materials
supplied by the manufacturer (including, for example the declaration of the residual risks,
contraindications, precautions, warnings, instructions for managing foreseeable
unwanted situations);
- the usability of the device for the intended users and the suitability of the information
materials supplied by the manufacturer for the intended users (including, if applicable,
for lay or disabled persons);
- instructions for target population groups (including, for example, pregnant women,
paediatric populations).
6.2. When is clinical evaluation undertaken and why is it important?

Clinical evaluation is conducted throughout the life cycle of a medical device, as an ongoing
process.
Usually, it is first performed during the development of a medical device in order to identify data
that need to be generated for market access. Clinical evaluation is mandatory for initial CE-marking
and it must be actively updated thereafter.
Clinical evaluation is necessary and important because it ensures that the evaluation of safety and
performance of the device is based on sufficient clinical evidence throughout the lifetime that the
medical device is on the market. This ongoing process enables manufacturers to provide notified
bodies and competent authorities with sufficient clinical evidence for demonstration of conformity of
the device with the Essential Requirements throughout its lifetime (for example for CE marking,
fulfilment of post-market surveillance and reporting requirements, or during surveillance
procedures).

6.2.1. Clinical evaluation undertaken for the development of a medical device
Premarket research and development are guided by clinical evaluation and risk management.
Typically, manufacturers carry out clinical evaluations to
define needs regarding clinical safety and clinical performance of the device;
in case of possible equivalence to an existing device, evaluate if there are clinical data
available and determine equivalence; for additional information, see Appendix A1
(Demonstration of equivalence);
carry out a gap analysis and define which data still need to be generated with the device
under evaluation, whether clinical investigations are necessary and if so, to define the study
design; for additional information, see Section 10 (Analysis of the clinical data) and
Appendix A2 (When should additional clinical investigations be carried out?).
As the initial clinical evaluation identifies the questions to be answered by a clinical investigation,
the clinical evaluation process should generally commence in advance of any clinical
investigation1.
6.2.2. Clinical evaluation for initial CE-marking

Clinical evaluation is required to be carried out for the conformity assessment process leading to
the CE-marking and placing on the market of a medical device. The purpose is to:
document that there is sufficient clinical evidence to demonstrate conformity with the
Essential Requirements covering clinical performance and clinical safety;
identify aspects that need to be addressed systematically during post-market surveillance
(PMS), e.g. in post market clinical follow-up studies (PMCF Studies) required under the
medical device directives. Typically, these aspects include estimation of residual risks and
uncertainties or unanswered questions (such as rare complications, uncertainties regarding
long-term performance, safety under wide-spread use).
6.2.3. Updating the clinical evaluation
a. Frequency of updates
The manufacturer should define and justify the frequency at which the clinical evaluation needs
to be actively updated.
When doing so, the manufacturer should typically consider:
whether the device carries significant risks
(e.g. based on design, materials, components, invasiveness, clinical procedures, high-risk
anatomical locations, high-risk target populations (e.g. paediatrics, elderly), severity of
disease/ treatment challenges).
whether the device is well established, taking into consideration:
- innovation;
1
Including for the planning of clinical investigations and production of documents described in standard EN
ISO 14155

- relevant changes in clinical sciences, materials sciences or other sciences related to the
device under evaluation;
- the current level of confidence in the evaluation of clinical performance and clinical
safety of the device; the manufacturer should consider
- the data available from clinical investigations, PMCF studies, registries or other
systematic studies (including the number of devices used, if that usage was
representative of the usage in the market, the results to date);
- the total number of devices used so far in the market, and expected reporting rates
under the vigilance system.
whether there are risks and uncertainties or unanswered questions, in the medium or long-
term, that would influence the frequency of updates.
design changes or changes to manufacturing procedures (if any).
The clinical evaluation is actively updated:

when the manufacturer receives new information from PMS that has the potential to change
the current evaluation;
if no such information is received, then
- at least annually if the device carries significant risks or is not yet well established; or
- every 2 to 5 years if the device is not expected to carry significant risks and is well
established, a justification should be provided.
When involvement of notified bodies is required, updates are usually coordinated with the
notified body. Typically, they are aligned with the timetable for surveillance audits and the
renewal of the certificates.
b. General considerations on updating the clinical evaluation

Manufacturers are required to implement and maintain a PMS system that routinely monitors
the clinical performance and clinical safety of the device as part of their quality management
system2. The scope and nature of such PMS should be appropriate to the device and its
intended purpose.
PMS regularly generates new data (e.g. safety reports, results from published literature,
registries, PMCF studies, and other data about device usage). Those data need to be evaluated
for information that has a potential to change the evaluation of the risk/benefit profile, and the
clinical performance and clinical safety of the device. Those data are required to be fed into the
clinical evaluation process in a timely manner.
In accordance with the Directives, the clinical evaluation and the clinical evaluation report must
be actively updated with data obtained from post-market surveillance3.
When updating the clinical evaluation, the evaluators should verify:

if the benefit/risk profile, undesirable side-effects (whether previously known or newly
emerged) and risk mitigation measures are still
2
AIMDD Annexes 2, 4, and 5
MDD Annexes II, IV, V, VI, and VII
3
MDD Annex X letter 1.1.c

- compatible with a high level of protection of health and safety and acceptable according
to current knowledge/ the state of the art;
- correctly addressed in the information materials supplied by the manufacturer of the
device;
- correctly addressed by the manufacturer's current PMS plan;
if existing claims are still justified;
if new claims the manufacturer intends to use are justified.
While clinical evaluation requires data from PMS activities, it also generates new information
that have to be fed into the PMS and risk management process. Clinical evaluation can
therefore result in changes to the manufacturers risk management documents, instructions for
use (IFU) and PMS activities.
If the manufacturer concludes there is not sufficient clinical evidence to be able to declare
conformity with the Essential Requirements, the manufacturer will need to :
stop placing the devices on the market until conformity is restored, and
take necessary corrective and preventive action.
6.3. How is a clinical evaluation performed?

The clinical evaluation is based on a comprehensive analysis of available pre- and post-market
clinical data relevant to the intended purpose of the device in question, including clinical
performance data and clinical safety data.
There are discrete stages in performing a clinical evaluation:
Stage 0: Define the scope, plan the clinical evaluation (also referred to as scoping and the
clinical evaluation plan).
Stage 1: Identify pertinent data.
Stage 2: Appraise each individual data set, in terms of its scientific validity, relevance and
weighting.
Stage 3: Analyse the data, whereby conclusions are reached about
- compliance with Essential Requirements (including ER1, ER3, ER6) on performance
and safety of the device, including its benefit/risk profile,
- the contents of information materials supplied by the manufacturer (including the label,
IFU of the device, available promotional materials, including accompanying documents
possibly foreseen by the manufacturer),
- residual risks and uncertainties or unanswered questions (including on rare
complications, long term performance, safety under wide-spread use), whether these are
acceptable for CE-marking, and whether they are required to be addressed during PMS.
Stage 4: Finalise the clinical evaluation report
The clinical evaluation report summarises and draws together the evaluation of all the
relevant clinical data documented or referenced in other parts of the technical
documentation. The clinical evaluation report and the relevant clinical data constitute the
clinical evidence for conformity assessment.
Each of these stages is covered in separate sections later in this document (see the figure below).
During the course of a clinical evaluation the stages are often iterative. Indeed, the appraisal and
analysis stage may uncover new information and raise new questions, with a need to widen the

scope of the evaluation, refine the clinical evaluation plan, and to retrieve, appraise and analyse
additional data.
Figure: Stages of a clinical evaluation and references to sections and appendices of this
document.
6.4. Who should perform the clinical evaluation?

The clinical evaluation should be conducted by a suitably qualified individual or a team.
The manufacturer should take the following aspects into consideration:
The manufacturer defines requirements for the evaluators that are in line with the nature of
the device under evaluation and its clinical performance and risks.
The manufacturer should be able to justify the choice of the evaluators through reference to
their qualifications and documented experience, and to present a declaration of interest for
each evaluator.
As a general principle, the evaluators should possess knowledge of the following:
- research methodology (including clinical investigation design and biostatistics);

- information management (e.g. scientific background or librarianship qualification;
experience with relevant databases such as Embase and Medline);
- regulatory requirements; and
- medical writing (e.g. post-graduate experience in a relevant science or in medicine;
training and experience in medical writing, systematic review and clinical data appraisal).
With respect to the particular device under evaluation, the evaluators should in addition
have knowledge of:
- the device technology and its application;
- diagnosis and management of the conditions intended to be diagnosed or managed by
the device, knowledge of medical alternatives, treatment standards and technology (e.g.
specialist clinical expertise in the relevant medical specialty).
The evaluators should have at least the following training and experience in the relevant
field:
- a degree from higher education in the respective field and 5 years of documented
professional experience; or
- 10 years of documented professional experience if a degree is not a prerequisite for a
given task.
There may be circumstances where the level of evaluator expertise may be less or different; this
should be documented and duly justified.
7. Definition of the scope of the clinical evaluation (Stage 0)

Before a clinical evaluation is undertaken the manufacturer should define its scope, based on the
Essential Requirements that need to be addressed from a clinical perspective and the nature and
history of the device. This is also referred to as scoping.
The scope serves as a basis for further steps, including the identification of pertinent data. The
manufacturer sets up a description of the device under evaluation, and a clinical evaluation plan.
A clinical evaluation is required to be critical4. Therefore, it needs to identify, appraise and analyse
both favourable and unfavourable data.
Depending on the stage in the lifecycle of the product, considerations for setting up a clinical
evaluation plan should include different aspects. Typical examples are listed below.
Aspects Before For CE

(not an exhaustive list) CE- marked
marking devices
The device description. X X

For additional information, see Appendix A3 (Device description - typical
contents)
Whether there are any design features of the device, or any indications or X X
target populations, that require specific attention. The clinical evaluation
should cover any design features that pose special performance or safety
4
Sections 1.1.1., 1.1.2, 1.1.3 MDD and AIMDD.

concerns (e.g. presence of medicinal, human or animal components), the
intended purpose and application of the device (e.g. target treatment
group and disease, proposed warnings, contraindications, precautions,
and method of application) and the specific claims made by the
manufacturer about the clinical performance and clinical safety of the
device.
Information needed for evaluation of equivalence, if equivalence may X

possibly be claimed.
The risk management documents of the device, e.g. the hazard X X

identification list, clinical risks identified from the risk analysis. The scope
of the clinical evaluation will need data from and cross references to the
manufacturers risk management documents. The risk management
documents are expected to identify the risks associated with the device
and how such risks have been addressed. The clinical evaluation is
expected to address the significance of any clinical risks that remain after
design risk mitigation strategies have been employed by the
manufacturer.
The current knowledge/ state of the art in the corresponding medical field, X X
such as applicable standards and guidance documents, information
relating to the medical condition managed with the device and its natural
course, benchmark devices, other devices and medical alternatives
available to the target population.
Data source(s) and type(s) of data to be used in the clinical evaluation. X X

Data relevant to the clinical evaluation may be generated and held by the
manufacturer or available from scientific literature.
For additional information, see Section 8.1 (Data generated and held by
the manufacturer), and Appendix A4 (Sources of literature).
Whether the manufacturer has introduced/ intends to introduce any X

relevant5 changes, including
- design changes,
- changes to materials and manufacturing procedures,
- changes to the information materials supplied by the manufacturer
(label, IFU, available promotional materials including accompanying
documents possibly foreseen by the manufacturer) or other claims,
- and whether the claim of equivalence to an existing device is still
appropriate.
Whether there are any specific clinical concerns that have newly emerged X
and need to be addressed.
PMS aspects that need6 regularly updating in the clinical evaluation X

report:
5
Many changes are not clinically relevant (such as administrative changes to the labelling) and need not
be considered for setting up a Clinical Evaluation plan.

- new clinical data7 available for the device under evaluation;
- new clinical data available for the equivalent device (if equivalence is
claimed);
- new knowledge about known and potential hazards, risks8,
performance, benefits9 and claims10, including
- data on clinical hazards seen in other products (hazard due to
substances and technologies);
- changes concerning current knowledge/ the state of the art, such
as changes to applicable standards and guidance documents, new
information relating to the medical condition managed with the
device and its natural course, medical alternatives available to the
target population;
- other aspects identified during PMS.
Needs for planning PMS activities. X
It is important to recognise that there is considerable diversity in the types and history of
technologies used in medical devices and the risks posed by them. Many devices are developed or
modified by increments, so they are not completely novel. It may be possible to draw on the clinical
experience and literature reports of the safety and performance of an equivalent device to establish
the clinical evidence, thereby reducing the need for clinical data generated through clinical
investigation of the device under evaluation. Similarly, it may be possible to use compliance with
harmonised standards to satisfy the clinical evidence requirements for devices based on
technologies with well established safety and performance characteristics.
8. Identification of pertinent data (Stage 1)
8.1. Data generated and held by the manufacturer

Data generated and held by the manufacturer typically include the following items (not a complete
list):
All pre market clinical investigations
All clinical data generated from risk management activities and the PMS programmes which
the manufacturer has implemented in Europe and in other countries, including the following
items (not a complete list):
- PMCF studies, such as post market clinical investigations and any device registries
sponsored by the manufacturer
6
Requirement according to letter 1.1.c of Annex X MDD, and section 1.4 AIMDD: "The Clinical Evaluation
and its documentation must be actively updated with data obtained from the post-market surveillance."
7
References: Annex 1, Essential Requirements 1, 2, 5, 5a, and Annex 7 AIMDD; and Annex I, Essential
Requirements 1, 3, 6, 6a, and Annex X MDD.
8
For further detail, refer to standard EN ISO 14971 and other harmonised standards.
9
For further detail, refer to standard EN ISO 14971 and other harmonised standards.
10
Claims made by the manufacturer on the clinical performance and clinical safety of the device under
evaluation.

- PMS reports, including vigilance reports and trend reports
- the literature search and evaluation reports for PMS
- incident reports sent to the manufacturer (including the manufacturers own evaluation
and report)
- complaints regarding performance and safety sent to the manufacturer, including the
manufacturers own evaluation and report
- analysis of explanted devices (as far as available)
- details of all field safety corrective actions
- use as a custom made device
- use under compassionate use/ humanitarian exemption programs
- other user reports
Relevant pre-clinical studies (e.g. bench test reports including verification and validation
data)
With regard to those data:

All data generated and held by the manufacturer need to be identified.
Complete data need to be entirely disclosed and made available to the evaluators; this
includes data from Europe and other countries; it includes clinical studies as well as use
data.
All data sets should be documented (adequately summarised11, appraised, analysed and
referenced) in the clinical evaluation report.
8.2. Data retrieved from literature

Literature searching is used to identify data not held by the manufacturer that are needed for the
clinical evaluation.
Literature searching identifies potential sources of clinical data for establishing:
Clinical data relevant to the device under evaluation, which are data that relate either to the
device under evaluation or to the equivalent device (if equivalence is claimed).
Current knowledge/ the state of the art.
Includes applicable standards and guidance documents, data that relate to benchmark
devices, other devices, critical components and medical alternatives or to the specific
medical conditions and patient populations intended to be managed with the device. The
data are typically needed in order to
- describe the clinical background and identify the current knowledge/ state of the art in
the corresponding medical field,
- identify potential clinical hazards (including hazards due to substances and technologies,
manufacturing procedures and impurity profiles),
- justify the validity of criteria used for the demonstration of equivalence (if equivalence is
claimed),
- justify the validity of surrogate endpoints (if surrogate endpoints are used).
The following aspects should be considered for literature searching:
11
to the extent that it can be critically reviewed by others

The searching strategy should be thorough and objective, i.e. it should identify all relevant
favourable and unfavourable data.
greater part (if not all) of the clinical evidence. Thus, when conducting a literature review a
comprehensive search should be conducted. If a comprehensive search is not deemed
necessary, reasons should be documented.
Several searches with different search criteria or focus are usually necessary to obtain the
necessary data. For additional information, see Appendix A4 (Sources of literature).
A literature search and other retrieval of data are carried out based on a search protocol.
The search protocol documents the planning of the search before execution. For additional
information, see Appendix A5 (Literature search and literature review protocol, key
elements) and Appendix A6 (Appraisal of clinical data - examples of studies that lack
scientific validity for demonstration of adequate clinical performance and/or clinical safety).
Once the searches have been executed, the adequacy of the searches should be verified
and a literature search report should be compiled to present details of the execution, any
deviations from the literature search protocol, and the results of the search.
It is important that the literature search is documented to such degree that the methods can
be appraised critically, the results can be verified, and the search reproduced if necessary.
Abstracts lack sufficient detail to allow issues to be evaluated thoroughly and independently, but
may be sufficient to allow a first evaluation of the relevance of a paper. Copies of the full text
papers and documents should be obtained for the appraisal stage.
The literature search protocol(s), the literature search report(s), and full text copies of relevant
documents, become part of the clinical evidence and, in turn, the technical documentation for the
medical device.
9. Appraisal of pertinent data (Stage 2)
9.1. General considerations

In order to determine the value of the data identified in stage 1, the evaluators should appraise
each individual document in terms of its contribution to the evaluation of the clinical performance
and clinical safety of the device.
Uncertainty arises from two sources: the methodological quality of the data, and the relevance of
the data to the evaluation of the device in relation to the different aspects12 of its intended purpose.
Both sources of uncertainty should be analysed to determine a weighting for each data set.
The evaluators should therefore:
identify information contained in each document,
evaluate the methodological quality of work done by the authors and from that, the scientific
validity of the information,
determine the relevance of the information to the clinical evaluation, and
systematically weight the contribution of each data set to the clinical evaluation.
12
For example different medical indications, target populations, intended users.

9.2. The appraisal plan
To ensure systematic and unbiased appraisal of the data, the evaluators should set up an
appraisal plan that describes the procedure and the criteria to be used for the appraisal.
The appraisal plan typically includes:
- criteria for determining the methodological quality and the scientific validity of each data
set.
- criteria for determining the relevance to the clinical evaluation (relevance to the device
and to the different aspects of its intended purpose).
- criteria for weighting the contribution of each data set to the overall clinical evaluation.
The appraisal should be thorough and objective, i.e. it should identify and attribute
adequate weighting both to favourable and unfavourable contents of each document.
The criteria adopted for the appraisal should reflect the nature, history and intended clinical
use of the device. They should be documented and justified on the basis of current
knowledge / the state of the art, applying accepted scientific standards.
There are many acceptable ways, both qualitative and quantitative, by which the appraisal
can be carried out13. For many well established devices and lower-risk devices, qualitative
data may be adequate to fulfil the requirements of the MDD and AIMDD. The evaluation
criteria should be adjusted accordingly.
The appraisal plan should be documented in the clinical evaluation report.
9.3. Conduct of the appraisal

The evaluators should
follow the pre-defined appraisal plan strictly and apply its criteria consistently throughout the
appraisal;
base their appraisal on the full text of publications and of other documents (not abstracts or
summaries), so as to review all of the contents, the methodology employed, the reporting of
results, the validity of conclusions drawn from the investigation or report, and evaluate any
limitations and potential sources of error in the data;
document the appraisal in the clinical evaluation report to the extent that it can be critically
reviewed by others.
9.3.1. How to evaluate methodological quality and scientific validity

The evaluators should examine the methods used to generate/ collect the data and evaluate the
extent to which the observed effect (performance or safety outcomes) can be considered to be due
to intervention with the device or due to
- confounding influences (e.g. the natural course of the underlying medical condition /
regression to the mean, concomitant treatments)
13
For an example, refer to Appendix D of the GHTF SG5 document N2R8:2007 on Clinical Evaluation
(Appendix D: A Possible Method of Appraisal)

- bias
- random error
- inadequate disclosure of information
- misinterpretation
Some papers considered unsuitable for demonstration of adequate performance because of poor
elements of the study design or inadequate analysis may still contain data suitable for safety
analysis or vice versa.
Examples of aspects that can be taken into consideration for evaluating the methodological quality
and the scientific validity of the evidence are detailed below.
a. Study design of pre-market and post-market clinical investigations

Considerations may need to include:
adequacy of the sample size and power calculation
adequacy and relevance of endpoints (including validity of surrogate endpoints, if used)
adequacy of applied controls (including choice of the study type and of comparators, if
applicable)
prospective randomisation of patients (in case of multiple treatment arms)
adequacy of inclusion and exclusion criteria, and of stratification of patients (e.g. in respect
to age, medical indication, severity of the condition, gender, other prognostic factors)
distribution of prognostic factors (in case of multiple groups, were the groups comparable
for these factors?)
blinding of patients (may include use of sham devices or sham surgery), professional users,
outcome assessors (blinded endpoints)
adequacy of the follow-up period, including if follow-up was long enough for outcomes to
occur, and if follow-up was frequent enough to detect temporary side effects and
complications (such as prolonged wound healing)
reliability of the methods used for quantifying symptoms and outcomes (including validation
of the methods)
adequate recording and reporting of serious adverse events and device deficiencies
adequate handling of medications and concomitant interventions
adequacy of procedures for retrieving complete information (e.g. procedures to be applied
when contacts with patients are lost, disclosure of reasons for patients leaving the study,
conduct of sensitivity analysis for determining if missing data affect conclusions)
The evaluators should verify whether clinical investigations have been defined in such a way as
to confirm or refute the manufacturer's claims for the device; and whether these investigations
include an adequate number of observations to guarantee the scientific validity of the
conclusions.
b. Additional aspects for appraisal of the quality of clinical investigations generated and held by the
manufacturer
Where a clinical investigation has been carried out by or on behalf of a manufacturer, it is
expected that documentation relating to the design, ethical and regulatory approvals, conduct,
results and conclusions of the investigation needed for the clinical evaluation will be available
for consideration, as appropriate. These may include:

- the clinical investigation plan;
- clinical investigation plan amendments and the rationale for these changes;
- case report form templates, monitoring and audit records;
- the relevant ethics committee documentation;
- regulatory authority approvals as required by applicable regulations;
- the signed and dated clinical investigation report (for investigations that are terminated);
- the latest intermediate report available and the latest collation on serious adverse events
(for investigations that are ongoing);
- when a clinical investigation is conducted outside of the EU, an analysis whether the
results are transferable to the European population;
- a gap analysis, when a clinical investigation is conducted to standards different from EN
ISO 14155; the gap analysis should contain sufficient information to be read and
understood by an independent party.
The clinical investigation plan sets out how the study was intended to be conducted. It contains
important information about the study design such as the selection and assignment of
participants to treatment, masking (blinding of participants and investigators) and measurement
of responses to treatment, which may be important sources of bias that can be assessed and
possibly discounted when trying to determine the actual performance of the device. In addition
the clinical investigation plan sets out the intended participant follow-up, approaches to
statistical analyses and methods for recording outcomes, which may impact on the quality,
completeness and validity of results obtained for performance and safety outcomes.
Also, by having the clinical investigation plan, its amendments and the clinical investigation
report available, the evaluators will be able to assess the extent to which the investigation was
conducted as planned and, where deviations from the original plan have occurred, the impact
those deviations had on the veracity of the data generated and the conclusions that can be
drawn from the investigation about the performance and safety of the device.
The clinical investigation report should be signed by the sponsor and the coordinating or
principal investigator to provide assurance that the report is an accurate reflection of the
conduct and results of the clinical investigation.
Another important consideration of the evaluation will be to assess whether the conduct of the
investigation was in accordance with applicable regulations, and in accordance with the current
applicable ethical standards that have their origin in the Declaration of Helsinki. Clinical
investigations not in compliance with applicable ethical standards, medical device standards (for
example EN ISO 14155 or comparable standards) or regulations should not be used for
demonstration of performance and/or safety of the device. The reasons should be noted in the
report.
c. Information derived from vigilance data, device registry data, case series, patient dossiers, and
other use data
Evaluators need to consider significant differences between sources of information in respect to:
procedures used for retrieving information about outcomes
quality aspects of registers and patient dossiers
In case of information based on vigilance reporting, evaluators should consider that expected
undesirable side-effects and complications of devices are not reportable under the vigilance
reporting system. Under-reporting or lack of reporting of expected side effects or complications
by users is common. Therefore, the vigilance system does not typically deliver adequate
information about the true frequency of expected undesirable side-effects and complications.
Systematic scientific data are needed for such purposes. Vigilance data, including trend
analysis, should be used for identification of unexpected risks.

In case of information based on device registries, case series, retrospective analyses of patient
dossiers, and other use data, the retrieval of information about outcomes may be incomplete
and unreliable (have all the patients been considered? are the patients representative of the use
of the device? did the register/ professional lose contact with patients if they moved on to
different professionals? was there a passive or active follow-up of patients by the professionals
involved? for how long?). Significant differences may exist between device registries. For
instance, they may offer an important or limited coverage of a country. The evaluators should
take into account the possibility of patients leaving the coverage of a registry or the follow-up of
a professional when experiencing serious adverse outcomes. In routine practice, there are also
significant differences in the duration of the follow-up of patients by surgeons and other
professionals, and in the quality of patient dossiers and data retrieval.
For clinical experience data it is important that any reports or collations of data (e.g. the
manufacturers PMS reports) contain sufficient information for the evaluators to be able to
undertake a rational and objective evaluation of the information and make a conclusion about its
significance with respect to the performance and safety of the device in question.
Reports of clinical experience that are not adequately supported by data, such as anecdotal
reports or opinions, may contribute to the evaluation, e.g. for the identification of unexpected
risks, but should not be used as proof of adequate clinical performance and clinical safety of the
device.
d. Data processing and statistics

Aspects to consider may include:
suitability of methods for data processing (transforming data that are suitable for analysis),
converting data to a consistent format, reconstructing missing statistics from other statistics,
dealing with missing data;
exclusions from the analysis and their implications (including disclosure and adequacy of
the intention-to-treat and per-protocol populations, disclosure of results from both the
intention-to-treat and the per-protocol populations);
adequacy of statistical methods.
e. Quality assurance
compliance with Good clinical practice (GCP), such as EN ISO 14155 or equivalent
standards;
compliance with the clinical investigation plan, independent monitoring and auditing;
compliance with legal requirements.
While a publication in a renowned peer reviewed scientific journal is generally accepted as an
indicator of scientific quality, such publication is not considered an acceptable reason for
bypassing or reducing appraisal activities.
f. Report quality
Evaluators should consider:
adequacy of disclosure of methods used
adequacy of disclosure of data, including
- completeness of the reporting of adverse events and outcomes
- sufficient description about the distribution of prognostic factors in the study population
and in different study arms
- disclosure of all the results the study was originally designed to generate
validity of conclusions drawn by the authors (example: conclusions not in line with the
results section of the document)

Possible conflicts of interest of the authors of the publications should also be taken into
consideration.
It is recognised that, where manufacturers source clinical investigation data reported in the
scientific literature, the documentation readily available to the manufacturer for inclusion in the
clinical evaluation is likely to be no more than the published paper itself. In case of missing
information, the rating of the methodological quality of a publication may need to be
downscaled.
For additional information see Appendix A6 (Appraisal of clinical data - examples of studies that
lack scientific validity for demonstration of adequate clinical performance and/or clinical safety).
9.3.2. How to determine the relevance of a data set for the clinical evaluation
When evaluating the relevance of collected data it is important to consider whether the data are
intended to directly demonstrate adequate clinical performance and clinical safety of the device
(often referred to as pivotal data), or whether the data serves an indirect supportive role.
a. Pivotal data
Pivotal data must have the data quality necessary for demonstration of adequate clinical
performance and clinical safety of the device under evaluation (see Appendix A6, Appraisal
of clinical data - examples of studies that lack scientific validity for demonstration of
adequate clinical performance and/or clinical safety);
be generated either with the device under evaluation or with an equivalent device used in
its intended purpose (for an equivalent device, equivalence must be demonstrated; see
Appendix A1, Demonstration of equivalence).
b. Other data
Data that are not pivotal are generally appraised and weighted for their contribution for
purposes such as:
identifying and defining the current knowledge/ state of the art in the corresponding medical
field, so as to define acceptability criteria for the evaluation of the benefit/risk profile and of
specific side-effects of the device under evaluation;
identifying hazards (including hazards due to substances and technologies), individual case
reports may be used for identification of new and previously unknown hazards that are
associated with the device;
justifying the validity of criteria used for the demonstration of equivalence (if equivalence is
claimed);
justifying the validity of surrogate endpoints (if surrogate endpoints are used).
providing input for the planning of pivotal studies.
The corresponding information is, in general, summarised in a literature review section of the
clinical evaluation report.
c. Aspects to consider when determining relevance

The table below shows examples of aspects that could be used for determining if and in what
respect data are relevant to the clinical evaluation.

Description Examples
To what extent are the data generated - device under evaluation

representative of the device under - equivalent device
evaluation?
- benchmark device
- other devices and medical alternatives
- data concerning the medical conditions that
are managed with the device
What aspects are covered? - pivotal performance data

- pivotal safety data
- claims
- identification of hazards
- estimation and management of risks
- establishment of current knowledge/ the
state of the art
- determination and justification of criteria for
the evaluation of the risk/benefit relationship
- determination and justification of criteria for
the evaluation of acceptability of
undesirable side-effects
- determination of equivalence
- justification of the validity of surrogate
endpoints
Are the data relevant to the intended - representative of the entire intended
purpose of the device or to claims purpose with all patient populations and all
about the device? claims foreseen for the device under
evaluation
- concerns specific models/ sizes/ settings, or
concerns specific aspects of the intended
purpose or of claims
- does not concern the intended purpose or
claims
If the data are relevant to specific

aspects of the intended purpose or
claims, are they relevant to a specific
- model, size, or setting of the - smallest / intermediate / largest size

device? - lowest / intermediate / highest dose
- etc.
- user group? - specialists

- general practitioners
- nurses

- adult healthy lay persons
- disabled persons
- children
- etc.
- medical indication (if - migraine prophylaxis

applicable)? - treatment of acute migraine
- rehabilitation after stroke
- etc.
- age group? - pre-term infants / neonates / children /

adolescents / adults / old age
- gender? - female/ male
- type and severity of the - early / late stage

medical condition? - mild / intermediate / serious form
- acute / chronic phase
- etc.
- range of time? - duration of application or use

- number of repeat exposures
- duration of follow-up
9.3.3. How to weight the contribution of each data set

Based on their scientific validity and relevance, the data should be weighted according to their
relative contributions.
Due to the diversity of medical devices, there is no single, well established method for weighting
clinical data:
the evaluators should identify appropriate criteria to be applied for a specific evaluation;
these pre-defined criteria should be followed strictly by the evaluators.
Typically, clinical data should receive the highest weighting, when generated through a well
designed and monitored randomized controlled clinical investigation (also called randomised
controlled trial), conducted with the device under evaluation in its intended purpose, with patients
and users that are representative of the target population.
Note: It is acknowledged that randomized clinical investigations may not always be feasible and/or
appropriate and the use of alternative study designs may provide relevant clinical information of
adequate weighting.
When rejecting evidence, the evaluators should document the reasons (both for studies and
reports that have been generated and are held by the manufacturer, and for other documents
identified during Stage 1).

10.1. General considerations

The goal of the analysis stage is to determine if the appraised data sets available for a medical
device collectively demonstrate compliance with each of the Essential Requirements pertaining to
the clinical performance and clinical safety of the device, when the device is used according to its
intended purpose.
In order to demonstrate compliance, the evaluators should
use sound methods;
make a comprehensive analysis;
determine if additional clinical investigations or other measures are necessary;
determine PMCF needs.
10.2. Specific considerations
a. Use sound methods

A literature review that describes current knowledge/ the state of the art should be prepared
with relevant literature identified during Stage 1 and appraised during Stage 2.
Weighting criteria developed and assigned during the appraisal stage can be used to identify
those sets of data, which may be considered to be pivotal.
The methods available for analysing clinical data generally are either qualitative or quantitative.
Depending on the nature of the medical device and the circumstances, it is likely that qualitative
(i.e. descriptive) methods will need to be used for some devices. Reliance on qualitative
methods should be justified. Generally, available clinical data such as numbers of incidents in
the post market phase should be assessed quantitatively in relation to current knowledge/ the
state of the art.
The results of the pivotal datasets should be explored, looking for consistency of results across
particular device performance characteristics and identified risks. If the different datasets report
similar outcomes, confidence in the robustness increases. If different results are observed
across the datasets, it will be helpful to determine the reason for such differences. Regardless,
all data sets should be considered and included. The reviewers should take into account the
weighting attributed to data sets during Stage 2 when addressing conflicting information. Where
relevant, a rationale should be given for the lack of value of a data set to the evaluation.
In general, data that are not methodologically sound (such as single patient reports) should not
be used for demonstration of adequate clinical performance and clinical safety of a device.
For additional information, see Appendix A6 (Appraisal of clinical data - examples of studies that
lack scientific validity for demonstration of adequate clinical performance and/or clinical safety).
In exceptional situations, when an evaluation is based on limited data, this shall be described
and justified in the clinical evaluation report. See additional information and specific
considerations in Appendix A8 (Devices for unmet medical needs - aspects to consider).
b. Make a comprehensive analysis

The evaluators should:

Determine compliance with each of the Essential Requirements pertaining to the clinical
performance and clinical safety of the device. For detailed information concerning specific
Essential Requirements, see Appendix A7 (Analysis of the clinical data - compliance to
specific Essential Requirements).
The evaluation includes
- the adequacy of pre-clinical testing (e.g. bench testing, animal testing) to verify safety
- risks to patients, users or other persons associated with the intended purpose of the
device
- benefits to patients
- confirmation that the device achieves the performance(s) intended by the manufacturer,
including all claims made by the manufacturer
- confirmation of usability, that the design adequately reduces the risk of use error as far
as possible, and that the design is adequate for the intended users (lay, professional,
disabled or other users, if applicable)
- adequacy of the information materials supplied by the manufacturer, including if risk
mitigation measures are correctly addressed in the IFU (handling instructions,
description of risks, warnings, precautions, contraindications, instructions for managing
foreseeable unwanted situations)
Take into consideration all products covered by the clinical evaluation and all aspects of
their intended purpose. Any gaps in evidence need to be identified, including in respect to
information relevant to:
- understanding the interaction between the device and the body;
- the comprehensiveness of the available data, taking into account:
- the entire range of products/ models/ sizes/ settings covered by the evaluation
- the entire range of conditions of use and of the intended purpose
- the estimated number of patients exposed to the device
- the type and adequacy of patient monitoring
- the number and severity of adverse events
- the adequacy of the estimation of associated risk for each identified hazard
- the severity and natural history of the condition being diagnosed or treated
- current standards of care, including the availability and the benefit/risk profiles of other
devices and medical alternatives
Assess if there is consistency and alignment between the clinical evaluation, the
information materials supplied by the manufacturer, and the risk management
documentation for the device under evaluation; any discrepancies should be identified in
order to ensure that all the hazards and other clinically relevant information have been
identified and analysed appropriately.
Assess if there is consistency between the documents mentioned above and current
knowledge/ the state of the art.
c. Determine if additional clinical investigations or other measures are necessary

The evaluators should identify additional clinical investigations or other measures that are
necessary in order to generate any missing data and eliminate compliance issues.
Data needed to address the identified gaps should be determined so that conclusions can be
drawn with confidence in relation to conformity with the essential requirements, including:
- evaluation of the safety, performance and the benefit/risk profile
- compatibility with a high level of protection of health and safety (that can be determined
by considering current knowledge/ the state of the art, with reference to standards and
available alternatives, risk minimisation, patient needs and preferences)
- the acceptability of any undesirable side-effects

- the risk of use error and the adequacy of the IFU to the intended users,
- consistency between available information
See Appendix A2 for detailed information on when additional clinical investigations should be
carried out.
d. Determine PMCF needs

In order to determine needs, the evaluators should describe residual risks and any uncertainties
or unanswered questions. The evaluators should also include aspects such as rare
complications, uncertainties regarding medium- and long-term performance, or safety under
wide-spread use.
10.3. Where demonstration of conformity based on clinical data is not deemed

appropriate
Where demonstration of conformity with Essential Requirements based on clinical data is not
deemed appropriate, adequate justification for any such exclusion has to be given:
The justification must be based on the output of the risk management process. This should
include an evaluation of background clinical data identified from the literature, and an
appraisal of their relevance to the device under evaluation.
The device/body interaction, the clinical performances intended and the claims of the
manufacturer have to be specifically considered.
Adequacy of demonstration of conformity with the Essential Requirements based on
performance evaluation, bench testing and pre-clinical evaluation in the absence of clinical
data has to be duly substantiated.
A clinical evaluation is still required and the above information and evidence-based
justification should be presented in the clinical evaluation report.
11. The clinical evaluation report (CER, Stage 4)

A clinical evaluation report shall be compiled to document the clinical evaluation and its output.
The clinical evaluation report should contain sufficient information to be read and understood by an
independent party (e.g. regulatory authority or notified body). Therefore, it should provide sufficient
detail for understanding the search criteria adopted by the evaluators, data that are available, all
assumptions made and all conclusions reached.
The contents of the clinical evaluation report shall be cross-referenced to the relevant documents
that support them. It should be clear which statements are substantiated by which data, and which
reflect the conclusions or opinions of the evaluators. The report should include references to
literature-based data and the titles and investigational codes (if relevant and available) of any
clinical investigation reports, with cross-references to the location in the manufacturers technical
documentation.
The amount of information may differ according to the history of the device or technology. Where a
new device or technology has been developed, the report would need to include an overview of the
developmental process and the points in the development cycle at which all clinical data have
been generated.

It is important that the report outlines the different stages of the clinical evaluation:
Stage 0, scope of the clinical evaluation:
- explains the scope and context of the evaluation, including which products/ models/
sizes/ settings are covered by the clinical evaluation report, the technology on which the
medical device is based, the conditions of use and the intended purpose of the device;
- documents any claims made about the devices clinical performance or clinical safety.
Stage 1, identification of pertinent data:
- explains the literature search strategy;
- presents the nature and extent of the clinical data and relevant pre-clinical data that
have been identified.
Stage 2, appraisal of pertinent data:
- explains the criteria used by the evaluators for appraising data sets;
- summarises the pertinent data sets (methods, results, conclusions of the authors);
- evaluates their methodological quality, scientific validity, the relevance for the evaluation,
the weighting attributed to the evidence, and any limitations;
- presents justifications for rejecting certain data or documents.
Stage 3, analysis of the clinical data:
- explains if and how the referenced information, such as confirmation of compliance with
clinical data requirement from applicable harmonised standards and the clinical data,
constitute sufficient clinical evidence for demonstration of the clinical performance and
clinical safety of the device under evaluation;
- explains whether there are adequate data for all aspects of the intended purpose and for
all products/ models/ sizes/ settings covered by the clinical evaluation.
- describes the benefits and risks of the device (their nature, probability, extent, duration
and frequency);
- explains the acceptability of the benefit/risk profile according to current knowledge/ the
state of the art in the medical fields concerned, with reference to applicable standards
and guidance documents, available medical alternatives, and the analysis and
conclusions of the evaluators on fulfilment of all Essential Requirements pertaining to
clinical properties of the device (MDD ER1, ER3, ER6; AIMDD ER1, ER2, ER5);
- analyses if there is consistency between the clinical data, the information materials
supplied by the manufacturer, the risk management documentation for the device under
evaluation;
- whether there is consistency between these documents and the current knowledge/ the
state of the art;
- identifies any gaps and discrepancies;
- identifies residual risks and uncertainties or unanswered questions (such as rare
complications, uncertainties regarding medium- and long term performance, safety
under wide-spread use) that should be further evaluated during PMS, including in PMCF
studies.
The evaluators should check the clinical evaluation report, provide verification that it includes an
accurate statement of their analysis and opinions, and sign the report. They should provide their
CV and their declaration of interests to the manufacturer.
The clinical evaluation report should be dated and version controlled.
A suggested format for the clinical evaluation report is located at Appendix A9 (Clinical evaluation
report - proposed table of contents, examples of contents).
Suggestions for aspects that should be checked for the release of a clinical evaluation report are
summarised in Appendix A10 (Proposed checklist for the release of the clinical evaluation report).

Information on declaration of interests can be found in Appendix A11 (Information on declarations
of interests).
12. The role of the notified body in the assessment of clinical

evaluation reports
The notified body plays a key role in the assessment and verification of clinical evaluation reports
and supporting documentation provided by medical device manufacturers to support demonstration
of conformity of a device with the Essential Requirements of the relevant Directive.
Detailed recommendations for notified bodies are given in Appendix A12 (Activities of notified
bodies). These include:
guidance for notified bodies on the assessment of clinical evaluation reports provided by
medical device manufacturers as part of technical documentation (including design
dossiers) and
guidance for notified body in development of their internal procedures for assessment of
clinical aspects relating to medical devices.
In addition, documents of the Notified Bodies Operations Group (NBOG) should also be consulted.
NBOG documents include best practice guides, checklists and forms.
Pursuant to section 6a of Annex I MDD and to section 5a of Annex 1 AIMDD, the demonstration of
conformity with the Essential Requirements must include a clinical evaluation conducted in
accordance with Annex X of Directive 93/42/EEC or with Annex 7 AIMDD. This is applicable for all
classes of medical device.
Where demonstration of conformity with Essential Requirements based on clinical data is not
deemed appropriate this must be adequately justified by the manufacturer and based on the output
of the risk management process. The device-body interaction, the intended purpose and the claims
of the manufacturer have to be specifically considered. The adequacy of demonstration of
conformity based on performance evaluation, bench testing and pre-clinical evaluation in the
absence of clinical data must be duly substantiated. The notified body must review the
manufacturers justification, the adequacy of data presented and whether or not conformity is
demonstrated. Nevertheless a clinical evaluation is still required and the above information and an
evidenced justification should be presented as the clinical evaluation for the device in question.

Appendices
A1. Demonstration of equivalence

Pursuant to Annex X of Directive MDD and Annex 7 AIMDD, the evaluation of clinical data (i.e. the
clinical evaluation), where appropriate taking account of any relevant harmonised standards, must
follow a defined and methodologically sound procedure based on:
1. either a critical evaluation of the relevant scientific literature currently available relating to
the safety, performance, design characteristics and intended purpose of the device, where:
- there is demonstration of equivalence of the device to the device to which the data
relates, and
- the data adequately demonstrate compliance with the relevant Essential Requirements.
2. or a critical evaluation of the results of all clinical investigations made.
3. or a critical evaluation of the combined clinical data provided from 1 and 2.
Clinical, technical and biological characteristics shall be taken into consideration for the
demonstration of equivalence:
Clinical:
- used for the same clinical condition (including when applicable similar severity and stage
of disease, same medical indication), and
- used for the same intended purpose, and
- used at the same site in the body, and
- used in a similar population (this may relate to age, gender, anatomy, physiology,
possibly other aspects), and
- not foreseen to deliver significantly different performances (in the relevant critical
performances such as the expected clinical effect, the specific intended purpose, the
duration of use, etc.).
Technical:
- be of similar design, and
- used under the same conditions of use, and
- have similar specifications and properties (e.g. physicochemical properties such as type
and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength,
surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions
such as nitrocarburising, oxidability), and
- use similar deployment methods (if relevant), and
- have similar principles of operation and critical performance requirements.
Biological: Use the same materials or substances in contact with the same human tissues
or body fluids.
Exceptions can be foreseen for devices in contact with intact skin and minor components of
devices; in these cases risk analysis results may allow the use of similar materials taking
into account the role and nature of the similar material. Different aspects of equivalence
and compliance to different Essential Requirements can be affected by materials.
Evaluators should consider biological safety (e.g. in compliance to ISO 10993) as well as
other aspects necessary for a comprehensive demonstration of equivalence. A justification
explaining the situation should be provided for any difference.

For assuming equivalence,
equivalence can only be based on a single device14;
all three characteristics (clinical, technical, biological) need to be fulfilled;
similar means that no clinically significant difference in the performance and safety of the
device would be triggered by the differences between the device under evaluation and the
device presumed to be equivalent;
the differences between the device under evaluation and the device presumed to be
equivalent need to be identified, fully disclosed, and evaluated; explanations should be
given why the differences are not expected to significantly affect the clinical performance
and clinical safety of the device under evaluation;
the manufacturer should investigate if the medical device presumed to be equivalent has
been manufactured via a special treatment (e.g. a surface modification, a process that
modifies material characteristics); if this is the case, the treatment could cause differences
in respect to technical and biological characteristics; this should be taken into account for
the demonstration of equivalence and documented in the CER;
if measurements are possible, clinically relevant specifications and properties should be
measured both in the device under evaluation and the device presumed to be equivalent,
and presented in comparative tabulations;
comparative drawings or pictures should be included in order to compare shapes and sizes
of elements that are in contact with the body;
the manufacturer is expected to:
- include the supporting non-clinical information (e.g. pre-clinical study reports) in the
technical documentation of the device, and
- in the clinical evaluation report, summarise the information and cite its location in the
technical documentation;
for the evaluation of the technical characteristics, devices that achieve the same therapeutic
result by different means cannot be considered equivalent;
for the evaluation of the biological characteristics:
- when a detailed chemical characterisation of materials in contact with the body is
needed, ISO 10993-18 Annex C can be used to show toxicological equivalence but this
is just a part of the evaluation of the biological criteria;
- sourcing and manufacturing procedures may adversely affect impurity profiles; analytical
methods chosen to characterise medical devices should appropriately take into
consideration knowledge concerning expected impurity profiles (tests may have to be
repeated when production methods or sourcing are changed);
- it may be necessary to show from histopathological studies that the same host response
is achieved in vivo in the intended application and the intended duration of contact;
- for animal tests, differences between species may limit the predictive value of the test;
the choice of the test and its predictive value should be justified;
- abrasion, if relevant, and host response to particles may also need to be considered.
the only clinical data that are considered as relevant are the data obtained when the
equivalent device is a CE-marked medical device used in accordance with its intended
purpose as documented in the IFU.
14
Evaluators may wish to refer to several devices that are equivalent. In such a situation, equivalence of
every single device to the device under evaluation should be fully investigated, demonstrated, and
described in the clinical evaluation report.

Note: Exceptions can be considered. When the equivalent device is not a CE-marked
device, information concerning the regulatory status of the equivalent device and a
justification for the use of its data should be included in the clinical evaluation report. The
justification should explain if the clinical data is transferrable to the European population,
and an analysis of any gaps to good clinical practices (such as ISO 14155) and relevant
harmonised standards.
A2. When should additional clinical investigations be carried out?

a. How should manufacturers and evaluators decide if there is sufficient clinical evidence?
When clinical data are required in order to draw conclusions as to the conformity of a device to
the Essential Requirements, the data need to be in line with current knowledge/ the state of the
art, be scientifically sound, cover all aspects of the intended purpose, and all products/ models/
sizes/ settings foreseen by the manufacturer.
If gaps are present that cannot be addressed by other means, clinical investigations should be
planned and carried out.
b. Considerations
Implants and high-risk devices, those based on technologies where there is little or no
experience, and those that extend the intended purpose of an existing technology (i.e. a new
clinical use) are most likely to require clinical investigation data.
For compliance with Annex X section 1.1.a MDD and Annex 7 AIMDD, clinical investigations
with the device under evaluation are required for implantable and class III devices unless it can
be duly justified to rely on existing clinical data alone.
The need for clinical investigations depends on the ability of the existing data to adequately
address the benefit/risk profile, claims, and side-effects in order to comply with the applicable
Essential Requirements. Clinical investigations may therefore also be required for other
devices, including for devices in class I and class IIa, and for class IIb devices that are not
implantable.
When deciding if additional clinical investigations need to be carried out, the manufacturer
should perform a detailed gap analysis. The gap analysis should determine whether the existing
data are sufficient to verify that the device is in conformity with all the Essential Requirements
pertaining to clinical performance and clinical safety.
Special attention should be given to aspects such as:
- new design features, including new materials,
- new intended purposes, including new medical indications, new target populations (age,
gender, etc.),
- new claims the manufacturer intends to use,
- new types of users (e.g. lay persons),
- seriousness of direct and/or indirect risks,
- contact with mucosal membranes or invasiveness,
- increasing duration of use or numbers of re-applications,
- incorporation of medicinal substances,
- use of animal tissues (other than in contact with intact skin),

- issues raised when medical alternatives with lower risks or more extensive benefits to
patients are available or have become newly available15,
- issues raised when new risks are recognised (including due to progress in medicine,
science and technology)
- whether the data of concern are amenable to evaluation through a clinical investigation,
- etc.
Data on the safety and performance of other devices and alternative therapies, including
benchmark devices and equivalent devices, should be used to define the state of the art or
identify hazards due to substances and technologies. This will allow the clinical data
requirements to be established more precisely in relation to the intended purpose of a device.
Precision in this analysis and the choice of selected medical indications and target populations
may reduce the amount of clinical data needed from additional clinical investigations.
A3. Device description - typical contents

The description should be detailed enough to allow for a valid evaluation of the state of compliance
with Essential Requirements, the retrieval of meaningful literature data and, if applicable, the
assessment of equivalence to other devices described in the scientific literature:
name, models, sizes, components of the device, including software and accessories
device group to which the device belongs (e.g. biological artificial aortic valve)
whether the device is being developed/ undergoing initial CE-marking/ is CE-marked
whether the device is currently on the market in Europe or in other countries, since when,
number of devices placed on the market
intended purpose of the device
- exact medical indications (if applicable)
- name of disease or condition/ clinical form, stage, severity/ symptoms or aspects to be
treated, managed or diagnosed
- patient populations (adults / children / infants, other aspects)
- intended user (use by health care professional / lay person)
- organs / parts of the body / tissues or body fluids contacted by the device
- duration of use or contact with the body
- repeat applications, including any restrictions as to the number or duration of re-
applications
- contact with mucosal membranes/ invasiveness/ implantation
- contraindications
- precautions required by the manufacturer
- single use / reusable
- other aspects
general description of the medical device including
- a concise physical and chemical description
- the technical specifications, mechanical characteristics
- sterility
- radioactivity
15
See Appendix A7.2 (Conformity assessment with requirement on acceptable benefit/risk profile)

- how the device achieves its intended purpose
- principles of operation
- materials used in the device with focus on materials coming in contact (directly or
indirectly) with the patient/ user, description of body parts concerned
- whether it incorporates a medicinal substance (already on the market or new), animal
tissues, or blood components, the purpose of the component
- other aspects
whether the device is intended to cover medical needs that are otherwise unmet/ if there
are medical alternatives to the device / if the device is equivalent to an existing device, with
a description of the situation and any new features
if the device is intended to enter the market based on equivalence:
- name, models, sizes, settings components of the device presumed to be equivalent,
including software and accessories
- whether equivalence has already been demonstrated
Intended performance, including the technical performance of the device intended by the
manufacturer, the intended clinical benefits, claims regarding clinical performance and
clinical safety that the manufacturer intends to use
For devices based on predecessor devices: Name, models, sizes of the predecessor
device, whether the predecessor device is still on the market, description of the
modifications, date of the modifications.
The current version number or date of the information materials supplied by the
manufacturer (label, IFU, available promotional materials and accompanying documents
possibly foreseen by the manufacturer).
A4. Sources of literature

There are different sources of clinical literature that can be searched for clinical evaluation. A
comprehensive search strategy is required, normally involving multiple databases. The search
strategy should be documented and justified. Important sources include the following:
Scientific literature databases

- MEDLINE or Pubmed can provide a good starting point for a search. However, with
possibly incomplete coverage of European Journals and reduced search features,
comprehensiveness may not necessarily be guaranteed.
- Additional databases may need to be used to ensure adequate coverage of devices and
therapies in use in Europe, to identify relevant clinical trials and publications of user
experience16, and to facilitate searches by device name and manufacturer (e.g.
EMBASE/Excerpta Medica, the Cochrane CENTRAL trials register, etc.).
- Information coverage and search features available in scientific databases can change
with time. Criteria for selecting adequate databases therefore need to be defined and re-
evaluated on a regular basis.
Internet searches
16
Studies yielding negative results or user experience (such as publications about risks that are based on a
case or a case series) may not qualify for publication in high impact medical journals. Low impact journals
available to European users and other sources may therefore need to be searched.

Searches provide important data, examples include information on:
- harmonised standards and other standards applicable to the device in question and
containing information on clinical performance and clinical safety.
- Field safety corrective actions for the equivalent and/or other devices. These can be
found on manufacturers web sites, internet sites of European Competent authorities, the
U.S. Food and Drug Administration (FDA), possibly other sites.
- Implant registry reports.
- Documents available in systematic review databases (e.g. the Cochrane Database of
Systematic Reviews, Prospero international prospective register of systematic reviews).
- Expert documents produced by professional medical associations that are important for
assessment of current knowledge/ the state of the art, including clinical practice
guidelines and consensus statements.
- Meta-analyses and reviews of health technology assessment (HTA) institutes and
networks.
- Identification of studies via the WHO International Clinical Trials Registry Platform
(ICTRP) and ClinicalTrials.gov.
Non-published data
Non published data are important for many devices and retrieval of such data should be
considered, including for monitoring of any changes, e.g.
- The label and IFU of the equivalent device (if equivalence is claimed by the
manufacturer) and/or of benchmark devices and other devices.
- Data provided to manufacturers from implant registries.
- Data presented at congresses.
Citations referenced in scientific literature can be important and should be screened.

Literature found to be relevant is likely to cite other literature that is of direct interest to the
manufacturer. Additionally, it may be necessary to retrieve some of the referenced literature
in order to appraise the scientific quality of a document.
A5. Literature search and literature review protocol, key elements

The output of the literature search and literature review are:
Literature on the device in question and the equivalent device.
Note: If the manufacturer holds own clinical data for the device in question (e.g. own pre-
market clinical investigations, PMCF Studies, other PMS data), the literature is considered
together with those data for consistent appraisal and overall analysis.
A review of the current knowledge/ the state of the art needed for the proper conduct of the
appraisal and analysis of the clinical data of the device under evaluation and the equivalent
device (i.e. applicable standards and guidance documents, information on the medical
conditions that are relevant to the clinical evaluation, therapeutic/ management/ diagnostic
options available for the intended patient population, etc.).
The literature collected may relate directly to the device in question (e.g. publications of clinical
investigations of the device in question that have been performed by third parties, its side effects or
complications, incidence reports) and/or to equivalent device, benchmark devices, other devices
and medical alternatives available to the intended patient population.

The literature search and literature review protocol should address the background to and the
objective of the review, specifying the literature review questions and the methods for identification,
selection, collection and appraisal of the relevant publications needed to address them. It should
include the literature search methodology (literature search protocol).
The selection of literature should be objective and justified, i.e. include all relevant data, both
favourable and unfavourable. With respect to the clinical evaluation, it is important that the clinical
evaluators are able to assess the degree to which the selected papers reflect the intended
application/ use of the device.
Objective, non-biased, systematic search and review methods should be used. Examples are:
- PICO (patient characteristics, type of intervention17, control, and outcome queries)
- Cochrane Handbook for Systematic Reviews of Interventions
- PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses)
Statement
- MOOSE Proposal (Meta-analysis Of Observational Studies in Epidemiology)
The protocol should specify the elements described below, addressing the background, objective,
and methods for identification, selection, and collection of the relevant publications to address the
literature review questions.
A5.1. Background to the literature search and the literature review

This section documents the importance of and rationale for the literature review and includes, but
is not limited to:
- Device name/model
- Importance of literature review to risk management process. The literature review will
provide data on current interventions18 for the intended patient population (state of the
art) in order to give input to the assessments of acceptable benefit/risk profiles, what is
currently considered as providing a high level of protection of health and safety and what
are considered acceptable side-effects.
- Previous literature reviews
- Importance of review to risk management process
- Previous literature searches conducted by the manufacturer
- If including equivalent or benchmark devices, name and model of the devices.
- The CER will need to establish equivalence to the device under evaluation or the
relevance of benchmark devices to the clinical evaluation.
A5.2. Objective
This section documents the research question(s), which should be consistent with the scope of the
clinical evaluation and carefully constructed using a process (e.g. PICO):
17
The term Intervention includes therapies, diagnostic measures, measures for the management of
diseases or medical conditions.
18
Includes therapies, diagnostic measures, measures for the management of diseases or medical
conditions.

- Population(s)/disease(s) or condition(s)
- Intervention(s)
- Comparator group(s)/control(s)
- Outcome(s)/endpoint(s)
The inputs for the review question(s) (e.g. PICO) are the device description and the intended
performance of the device including any claims on clinical performance and clinical safety which
the manufacturer wants to use. Also information from the risk management process is needed as
an input.
A5.3. Methods
The methods section of the protocol documents the plans for literature search, study selection,
data collection, and analysis methods. It defines the literature search strategy and the
inclusion/exclusion criteria for the documents found.
The protocol should include:

the literature search methodology
The purpose of a literature search protocol is to plan the search before execution. It should
be developed and executed by persons with expertise in information retrieval, having due
regard to the scope of the clinical evaluation set out by the manufacturer. The involvement
of information retrieval experts will help to optimize literature retrieval to identify all relevant
published literature.
The importance of a literature search protocol is for critical appraisal of the methods. The
search strategy should be based on carefully constructed review questions.
the sources of data that will be used and a justification for their choice (see Appendix A4,
Sources of literature)
the extent of any searches of scientific literature databases (the database search strategy);
attempts to identify all published literature
which electronic databases are to be searched, with justification
the extent of any Internet searching and searching non-published information, including the
search strategy and justification
exact search terms and any limits
limits for start and end dates of each search
the selection/criteria (such as inclusion/exclusion criteria) to be applied to published
literature and justification for their choice
strategies for addressing the potential for duplication of data across multiple publications;
strategies for avoiding retrieving publications of data generated and already held by the
manufacturer
the data collection plan that defines data management practices to ensure data integrity
during extraction (e.g. quality control/second review of extracted data by additional
reviewer)
the appraisal plan, which defines the methods for appraising each publication, including the
relevance of the data to the intended clinical use and the methodological quality of the data
the analysis plan, which defines the methods for analysing the data including data
processing and transformation

Any deviations from the literature search protocol should be noted in the literature search report.
A6. Appraisal of clinical data - examples of studies that lack scientific

validity for demonstration of adequate clinical performance and/or
clinical safety
a. Lack of information on elementary aspects:
This includes reports and publications that omit disclosure of
- the methods used
- the identity of products used
- numbers of patients exposed
- what the clinical outcomes were
- all the results the clinical study or investigation planned to investigate
- undesirable side-effects that have been observed
- confidence intervals/ calculation of statistical significance
- if there are intent-to-treat and per protocol populations: definitions and results for the two
populations
b. Numbers too small for statistical significance

Includes publications and reports with inconclusive preliminary data, inconclusive data from
feasibility studies, anecdotal experience, hypothesis papers and unsubstantiated opinions.
c. Improper statistical methods

This includes
- results obtained after multiple subgroup testing, when no corrections have been applied
for multiple comparisons.
- calculations and tests based on a certain type of distribution of data (e.g. Gaussian
distribution with its calculations of mean values, standard deviations, confidence
intervals, t-tests, others tests), while the type of distribution is not tested, the type of
distribution is not plausible, or the data have not been transformed. Data such as
survival curves, e.g. implant survival, patient survival, symptom-free survival, are
generally unlikely to follow a Gaussian distribution.
d. Lack of adequate controls

In the following situations, bias or confounding are probable in single arm-studies and in other
studies that do not include appropriate controls:
- when results are based on subjective endpoint assessments (e.g. pain assessment).
- when the endpoints or symptoms assessed are subject to natural fluctuations (e.g.
regression to the mean when observing patients with chronic diseases and fluctuating
symptoms, when natural improvement occurs, when the natural course of the disease in
a patient is not clearly predictable).
- when effectiveness studies are conducted with subjects that are likely to take or are
foreseen to receive effective co-interventions (including over-the-counter medication and
other therapies).
- when there may be other influencing factors (e.g. outcomes that are affected by
variability of the patient population, of the disease, of user skills, of infrastructure
available for planning/ intervention/ aftercare, use of prophylactic medication, other
factors).

- when there are significant differences between the results of existing publications,
pointing to variable and ill controlled influencing factors.
In the situations described above, it is generally not adequate to draw conclusions based on
direct comparisons with external or historic data (such as drawing conclusions by comparing
data from a clinical investigation with device registry data or with data from published literature).
Different study designs may allow direct comparisons and conclusions to be drawn in these
situations, such as randomised controlled design, cross-over design, or split-body design.
e. Improper collection of mortality and serious adverse events data

Demonstration of adequate benefits and safety is sometimes based on mortality data or
occurrence of other serious outcomes that limit a subjects ability to live in his home and be
available for follow-up contacts. In this type of study,
- consent of the subjects for contacting reference persons/ institutions for retrieval of
medical information should be obtained during recruitment; when subjects can no longer
be found, outcomes should be investigated with the reference persons/ institutions;
- the consequences of missing data on the results should be analysed (e.g. with a
sensitivity analysis); alternatively, when patients can no longer be found and their
outcomes cannot be identified, they should be considered to meet the SAE endpoint
under investigation (e.g. the mortality endpoint of a study).
In mortality studies (and other studies addressing serious outcomes) procedures for
investigating serious patient outcomes, numbers of subjects lost to follow-up, reasons why
subjects leave the study, and the results of sensitivity analysis should be fully disclosed in
reports and publications.
f. Misinterpretation by the authors

Includes conclusions that are not in line with the results section of the report or publication, such
as
- reports and publications not correctly addressing lack of statistical significance/
confidence intervals that encompass the null hypothesis.
- effects too small for clinical relevance.
g. Illegal activities
Includes clinical investigations not conducted in compliance with local regulations. Clinical
investigations are generally expected to be designed, conducted and reported in accordance
with EN ISO 14155 or to a comparable standard, and in compliance with local regulations and
the Declaration of Helsinki.
A7. Analysis of the clinical data - compliance to specific Essential

Requirements
While this appendix describes the needs for the clinical evaluation (MDD ER1, ER3, ER6; AIMDD
ER1, ER2, ER5), there may be additional essential requirement(s) that need support of sufficient
clinical evidence for the conformity assessment.

A7.1. Conformity assessment with requirement on safety
(MDD ER1 / AIMDD ER1)

The information materials supplied by the manufacturer (including label, IFU, available promotional
materials including accompanying documents possibly foreseen by the manufacturer), should be
reviewed to ensure they are consistent with the relevant clinical data appraised in stage 2 and that
all the hazards, information on risk mitigation and other clinically relevant information have been
identified appropriately.
Input from the risk management and the use of standards:
- Risk management documents should determine if all identified hazards are fully covered by
harmonised standards or other relevant standards or if there are gaps needed to be
covered by clinical data.
- Risk management documents should determine if all identified risks relating to patient
treatment, method of operation of the device or risks relating to usability have been
minimised or if there are question regarding clinical risks that need to be solved.
- Harmonised standards are generally expected to be applied in full in order to confer a
presumption of conformity.
- If technical developments provide a higher level of safety than current harmonised
standards, then the higher level of safety should be prioritised in order to meet the Essential
Requirements on reducing the risks as far as possible, that risks must be compatible with a
high level of protection of health and safety, and that side effects must be acceptable (MDD
ER2 and ER3 and ER6; AIMDD ER1 and ER5).
Examples:
- Electrical hazards should be covered by compliance to EN 60601-1 and applicable
collateral standards regarding medical electrical equipment, so that the device will not
compromise the safety and health of patients or users. Under these circumstances, residual
risks regarding electrical hazards are acceptable and additional clinical data are not needed
unless negative issues are detected during PMS activities.
- Harmonised standards on usability (EN 62366 and if applicable EN 60601-1-6) are
expected to be applied to ensure that usability aspects are taken into consideration during
the device development. However, they do not give guidance on a detailed level of design,
while usability aspects are known to cause or contribute to a large portion of incidents.
Therefore, clinical data may be needed to prove that the risk of use error, due to the
ergonomic features of the device and the environment in which the device is intended to be
used, has been reduced as far as possible.
A7.2. Conformity assessment with requirement on acceptable benefit/risk profile

It is expected,
that the clinical evaluation demonstrates that any risks which may be associated with the
intended purpose are minimised and acceptable when weighed against the benefits to the
patient and are compatible with a high level of protection of health and safety; and
that the IFU correctly describe the intended purpose of the device as supported by sufficient
clinical evidence; and
that the IFU contain correct information to reduce the risk of use error, information on
residual risks and their management as supported by sufficient clinical evidence (e.g.

handling instructions, description of risks, warnings, precautions, contraindications,
instructions for managing foreseeable unwanted situations).
a. Evaluation of the description of the intended purpose of the device

The information materials supplied by the manufacturer (including label, IFU, available
promotional materials including accompanying documents possibly foreseen by the
manufacturer) should be reviewed. The evaluators should evaluate if the description provided
by the manufacturer correctly identifies those medical conditions and target groups for which
conformity with the relevant Essential Requirements has been demonstrated through sufficient
clinical evidence. When reading the IFU, there should be no uncertainty for users as to when a
given medical condition or medical indication or target population is covered by the CE marking
or when it falls entirely under the user's own responsibility (off label use).
b. Evaluation of the devices benefits to the patient

Positive impacts of a device on the health of an individual should be meaningful (relevant for the
patient) and measurable. The nature, extent, probability and duration of benefits should be
considered. Benefits may include:
positive impact on clinical outcome (such as reduced probability of adverse outcomes, e.g.
mortality, morbidity; or improvement of impaired body function),
the patient's quality of life (significant improvements, including by simplifying care or
improving the clinical management of patients, improving body functions, providing relief
from symptoms),
outcomes related to diagnosis (such as allowing a correct diagnosis to be made, provide
earlier diagnosis of diseases or specifics of diseases, or identify patients more likely to
respond to a given therapy),
positive impact from diagnostic devices on clinical outcomes, or
public health impact (such as to the ability of a diagnostic medical device to identify a
specific disease and therefore prevent its spread, to identify phases, stages, location,
severity or variants of disease, predict future disease onset).
c. Quantification of benefit(s) to the patients

Defining specified endpoints is indispensable for setting up clinical investigations and properly
performing the identification, appraisal, and analysis of the clinical data.
Benefit(s) are often evaluated along a scale or according to specific endpoints or criteria
(types of benefits), or by evaluating whether a pre-identified health threshold was achieved.
The change in subjects condition or clinical management as measured on that scale, or as
determined by an improvement or worsening of the endpoint, determines the magnitude of
the benefit(s) in subjects. Variation in the magnitude of the benefit across a population may
also be considered.
The clinical relevance of these changes should be discussed and justified.
Ideally, these parameters should be directly clinically relevant.
In certain cases benefits can be assumed when validated surrogate endpoints are met
(such as obtaining certain results with laboratory tests or measurements of anatomical or
physiological properties).

Based on the current state of medical knowledge, the evaluators shall justify and document
the clinical relevance of endpoints used for the clinical evaluation of a device and
demonstrate the validity of all surrogate endpoints (if surrogate endpoints have been used).
The probability of the patient experiencing one or more benefit(s) is another important aspect of
evaluating benefits and the clinical performance of a device.
Based on the clinical data provided and on a sound statistical approach, a reasonable
prediction of the proportion of "responders" out of the target group or subgroups should be
made.
The data may show that a benefit may be experienced only by a small proportion of
patients in the target population, or, on the other hand, that a benefit may occur frequently
in patients throughout the target population. It is also possible that the data will show that
different patient subgroups are likely to experience different benefits or different levels of
the same benefit.
If the subgroups can be identified, the device may be indicated for those subgroups only.
In some cases, however, the subgroups may not be identifiable. Magnitude and probability
of clinical benefits will have to be put together when weighing benefits against risks.
A large benefit experienced by a small proportion of subjects may raise different
considerations than does a small benefit experienced by a large proportion of subjects. For
example, a large benefit, even if experienced by a small population, may be significant
enough to outweigh risks, whereas a small benefit may not, unless experienced by a large
population of subjects.
The duration of effect(s) (i.e. how long the benefit can be expected to last for the patient, if
applicable to the device)
The duration should be characterised (for example as a statistical distribution) on the basis
of sound clinical data and appropriate statistical approaches.
PMCF will be decisive to refine and corroborate reasonable predictions over time.
The mode of action may play an important role: Some treatments are curative, whereas,
some may need to be repeated frequently over the patients lifetime.
To the extent that it is known, the duration of a treatments effect may directly influence how
its benefit is defined. Treatments that must be repeated over time may introduce greater
risk, or the benefit experienced may diminish each time the treatment is repeated.
The evaluation of the duration of effect should take into consideration current knowledge/
the state of the art and available alternatives.
d. Evaluation of the clinical risks of devices

The risk management documents are expected to identify the risks associated with the device
and how such risks have been addressed. The clinical evaluation is expected to address the
significance of any risks that remain after design risk mitigation strategies have been employed
by the manufacturer.
PMS reports are compiled by the manufacturer and often include details of the devices
regulatory status (countries in which the device is marketed and date of commencement of
supply), regulatory actions undertaken during the reporting period (e.g. recalls, notifications), a
tabulation of incidents (particularly serious adverse events/ incidents, including deaths, stratified
into whether the manufacturer considers them to be device-related or not) and estimates of the
incidence of incidents.

Post-marketing data about incidents are generally more meaningful when related to usage but
caution is needed. The extent of user reporting in the medical devices vigilance system may
vary considerably between countries, users, and type of incident. Considerable under-reporting
by users is expected. However, the analyses of data within these reports may, for some
devices, provide reasonable assurance of both clinical safety and performance.
It may be helpful to provide a table summarising device-related incidents, paying particular
attention to serious adverse events/ incidents, with comments on whether observed device-
related incidents are predictable on the basis of the mode of action of the device.
To demonstrate the extent of the probable risk(s)/ harm(s), the following factors - individually
and in the aggregate - should be addressed:
Nature severity, number and rates of harmful events associated with the use of the device:
- Device-related serious adverse events/ incidents: Those events that may have been or
were attributed to the use of the device and produce an injury or illness that is life-
threatening, results in permanent impairment or damage to the body, or requires medical
or surgical intervention to prevent permanent harm to the body.
- Device-related non-serious/ non-reportable harmful events: Those events that may have
been or were attributed to the use of the device and that do not meet the criteria for
classification as a device-related serious adverse events/ incidents.
- Procedure-related incidents: Harm to the patient that results from use of the device but is
not caused by the device itself. For example, anaesthetic-related complications
associated with the implantation of a device.
Probability of a harmful event: The proportion of the intended population that would be
expected to experience a harmful event; whether an event occurs once or repeatedly may
be factored into the measurement of probability.
Duration of harmful events (i.e., how long the adverse consequences last): Some devices
can cause temporary, minor harm; some devices can cause repeated but reversible harm;
and other devices can cause permanent, debilitating injury. The severity of the harm should
be considered along with its duration.
Risk from false-positive or false-negative results for diagnostic medical devices :
- if a diagnostic device gives a false-positive result, the patient might, for example, receive
an unnecessary treatment and incur all the risks that accompany that treatment, or might
be incorrectly diagnosed with a serious disease;
- if a diagnostic device gives a false-negative result, the patient might not receive an
effective treatment (thereby missing out on the benefits that treatment would confer), or
might not be diagnosed with the correct disease or condition;
- other risks associated with false-positives and false-negatives.
It is also important to look at the totality of the harmful events associated with the device.
The number of different types of harmful events that can potentially result from using the
device and the severity of their aggregate effect has to be considered. When multiple
harmful events occur at once, they have a greater aggregate effect.
Comment specifically on any clinical data that identifies hazards not previously considered
in the risk management documentation, outlining any additional mitigation required (e.g.
design modification, amendment of information materials supplied by the manufacturer
such as inclusion of contraindications in the IFU).
e. Evaluation of acceptability of the benefit/risk profile

Evaluate if the clinical data on benefits and risks are acceptable for all medical conditions
and target populations covered by the intended purpose when compared with the current

state of the art in the corresponding medical field and whether limitations need to be
considered for some populations and/or medical conditions.
The current knowledge/ state of the art therefore needs to be identified and defined,
possibly also relevant benchmark devices and medical alternatives available to the target
population. Typically, documentation of the clinical background shall include the following
information:
- clinical background
- information on the clinical condition(s) to be treated, managed, or diagnosed
- prevalence of the condition(s)
- natural course of the condition(s)
- other devices, medical alternatives available to the target population, including evidence
of clinical performance and safety
- historical treatments
- medical options available to the target population (including conservative,
surgical and medicinal)
- existing devices, benchmark devices
Sufficient detail of the clinical background is needed so that the state of the art can be
accurately characterised in terms of clinical performance, and clinical safety profile. The
selection of clinical data that characterises the state of the art should be objective and not
selective of data on the basis of being favourable for the device under evaluation.
Information should be provided on alternative approaches that have been used or
considered and their benefits and drawbacks. Deficiencies in current therapies should be
identified from a critical and comprehensive review of relevant published literature. The
literature review should demonstrate if the device addresses a significant gap in healthcare
provision. Where there is no such clinical need, the design solution needs to show an
improved or at least equivalent benefit/risk profile compared to existing products or
therapies.
If or when treatment comparability versus accepted therapy is not available at the time of
placing on the market, this should be clearly described in the device IFU.
Even if a device cannot compete with an agreed first-line treatment or the best in class, it
may add to the portfolio of acceptable treatments, as even a first-line treatment will likely
have contraindications or non-responders.
Devices, that might not be best-in-class, might provide sufficient clinical evidence for an
acceptable benefit/risk-profile for specific, defined subgroups or even superior clinical
performance under specific conditions (e.g. emergency outdoor conditions).
The position within the treatment portfolio has to be specified properly in the clinical
evaluation report and other relevant documentation.
Example: A system for deep brain stimulation has a proven effectiveness for the treatment
of depression. However, the implantation of electrodes in the brain is associated with major
risks. Less invasive treatment options are available to patients suffering from depression.
Taking into account the available treatment portfolio, the manufacturer has limited the
medical indication of the device to "therapy resistant depression", which is reflected in the
IFU and in other relevant documentation.

A7.3. Conformity assessment with requirement on performance
The devices must achieve the performances intended by the manufacturer. The ability of a medical
device to achieve its intended purpose as claimed by the manufacturer needs to be demonstrated,
including any direct or indirect medical effects on humans as well as the clinical benefit on patients
resulting from the technical or functional, including diagnostic characteristics of a device, when
used as intended by the manufacturer.
Clinical performance includes any claims about clinical properties and safety of the device that the
manufacturer intends to use. It is expected:
that the devices achieve their intended performances during normal conditions of use, and
that the intended performances are supported by sufficient clinical evidence.
Evaluation of clinical performance can vary widely between device groups, especially between
therapeutic and diagnostic devices. The following list gives examples of performance data relevant
particularly to diagnostic devices:
Reproducibility of independent acquisition of images (same patient, same machine,
different operator and interpreter).
Reproducibility of independent reporting of images (same patient, same machine, same
images, different interpreter/analyser).
Diagnostic sensitivity and specificity of the test for major clinical indications; positive and
negative predictive values according to varying pre-test probabilities.
Comparisons of performance of new iterations of diagnostic software against previous
software versions.
Normal values by age and gender, covering all groups in which the diagnostic system may
be used.
A7.4. Conformity assessment with requirement on acceptability of undesirable side-effects

Any undesirable side-effect must constitute an acceptable risk when weighed against the
In order to evaluate the acceptability of the side-effects of a device:
there needs to be clinical data for the evaluation of the nature, severity and frequency of
potential undesirable side-effects;
the clinical data should contain an adequate number of observations (e.g. from clinical
investigations or PMS) to guarantee the scientific validity of the conclusions relating to
undesirable side-effects and the performance of the device;
in order to evaluate if undesirable side-effects are acceptable, consideration has to be given
to the state of the art, including properties of benchmark devices and medical alternatives
that are currently available to the patients, and reference to objective performance criteria
from applicable standards and guidance documents.
If there is lack of clinical data or an insufficient number of observations, conformity with the
requirement on acceptability of undesirable side-effects is not fulfilled.
Example:

A reasonable probability (80%) of observing at least one event of an undesirable side-effect when
15 subjects are studied requires a side-effect with an actual probability of 10%. If only 15 patients
have been studied, from a statistical point of view, there could be serious side-effects with an
actual probability of 10% that have not had a reasonable chance to be detected. The device would
only be acceptable (for any type and severity of undesirable side-effects), if that magnitude is
acceptable when weighted against the performance of the device and the current state of the art.
The table below shows corresponding numbers for undesirable side-effects with an actual
probability of 10%, 5% and 1%.
Case 1 Case 2 Case 3
Chance of observing at least 1 event (P) 80% 80% 80%
Actual probability of event 10% 5% 1%
Number of subjects studied (n) 15 32 161
The threshold proposed as acceptable for any new device will depend on the severity and
detectability of side effects concerned.
A8. Devices for unmet medical needs - aspects to consider

Like all medical devices, medical devices for unmet medical needs must fully comply with the
Essential Requirements in order to be CE-marked. The evaluators should assess whether devices
deliver clinical benefits to patients for
medical conditions that are life threatening, or cause permanent impairment of a body
function, and
for which current medical alternatives are insufficient or carry significant risks.
Corresponding devices are referred to as "breakthrough products" in this Appendix.
a. Breakthrough products
In exceptional cases, major benefits may justify relatively high levels of uncertainty, and access
to the market may be granted on the basis of limited clinical evidence such as
experience available from compassionate use/ humanitarian exemption programs, use of
custom-made devices, results of feasibility studies;
limited long-term data.
In addition to general aspects described in this MEDDEV document, the evaluators should fully
disclose the situation and address the following items in the clinical evaluation report:
the exact intended purpose, including the medical indication (if applicable to the device), the
product was developed for and whether residual risks and uncertainties or unanswered
questions are considered acceptable in this indication (often a niche indication);
explanations of why current medical alternatives are considered to be insufficient or to carry
significant risks;
explanations of the benefits delivered by the device under evaluation;

whether the IFU clearly describe
- the exact intended purpose (including medical indications) and any limitations,
- the limited clinical experience,
- uncertainties or unanswered questions about residual risks and benefits to patients19;
the need to set up a stringent PMCF plan with information on
- the type and quality of data that needs to be generated in the post-market phase in order
to further evaluate the clinical performance and clinical safety of the device;
- how to generate data in a timely manner and aspects thereof, including projections on
the numbers of patients that will be managed with the device per year;
- in the following cases, the manufacturer should aim at including all patients in PMCF
studies:
- a device that carries significant risks (i.e. expected to cause serious adverse
events), or
- a device for rare diseases.
the need to actively update the clinical evaluation report when new significant information
become available, and in accordance with Section 6.2.3 b of the present document.
In these exceptional cases, notified bodies should perform annual assessments of the updated
clinical evaluation reports and the results of PMCF studies.
b. Subsequent products
Devices that enter the market subsequent to a therapeutic/ diagnostic breakthrough can not be
judged by the same criteria as listed above for breakthrough devices. When performing a
clinical evaluation for these devices, the following considerations should be taken into account:
when a device enters the market subsequent to a therapeutic/diagnostic breakthrough,
clinical evidence is likely to have evolved rapidly since the first breakthrough device
became available
with the evolving body of evidence, entering the market with large uncertainty may no
longer be legitimate
if PMCF data are required, PMCF Studies should also be foreseen for devices that enter
the market subsequent to a therapeutic/ therapeutic breakthrough
A9. Clinical evaluation report - proposed table of contents, examples of

contents
Examples of contents that are shown in the table are for illustration. The contents of the clinical
evaluation report will vary according to the nature and history of the device under evaluation.
19
Example: No serious long-term adverse effects have been reported to date. This would be an
inadequate description of limited experience and of uncertainties as to residual risks.

Table of contents Example of contents
1. Summary Executive summary, summary for external purposes.

This section should summarise the determination of the
benefit/risk profile in the intended target groups and medical
indications, and the demonstration of acceptability of that profile
based on the state of the art in the medical fields concerned.
2. Scope of the clinical See Section 7 and Appendix A3.

evaluation Identification of devices covered by this clinical evaluation report,
products, models, sizes, software versions, accessories, their
proprietary names, code names assigned during device
development. Name and address of the manufacturer.
Whether this clinical evaluation is submitted to the AIMDD as
amended by directive 2007/47/EC, or to the MDD as amended by
directive 2007/47/EC.
Concise physical and chemical description, including materials.
Whether the device incorporated medicinal substances (already
on the market or new), tissues, or blood products. Mechanical and
physicochemical characteristics; others (such as sterile vs. non-
sterile, radioactivity etc.); picture or drawing of the device.
Technologies used, whether the device is based on a new
technology, a new clinical application of an existing technology, or
the result of incremental change of an existing technology.
Description of innovative aspects of the device.
Device group the device belongs to. How the device achieves its
intended purpose. Positioning in relation to available treatment/
management/ diagnostic options.
Exact description of the intended purpose as described in the
device's IFU20, with exact medical indications (if applicable) and
contraindications; claims made in available promotional materials.
Name of disease or condition, clinical form, stage, severity,
symptoms or aspects to be treated/ managed/ diagnosed, target
patient population, target user group. Intended application of the
device, single use/reusable, invasive/non invasive, implantable,
duration of use or contact with the body, maximum number of
repeat applications. Identification of organs, tissues or body fluids
contacted by the device. Precautions.
Claims on clinical performance and clinical safety foreseen by the
manufacturer.
Whether the device is already CE marked, whether it is on the
market, since when, in what regions, history of the device,
including date of past modifications with reasons and description,
sales volumes.
Changes since the last report, whether the device has been
20
In exceptional cases where an instruction for use is not required, describe the generally recognised
modalities of use

modified, identification of new products, models, sizes, software,
accessories, new intended purposes, new claims, new events
related to the device with an impact on clinical evaluation.
Identification of the sections of the clinical evaluation report that
are concerned with the new information and have been modified.
Other aspects.
3. Clinical background, See Sections 8-10 and Appendices A4-A5.

current knowledge, state Identification of medical fields concerned/ relevant medical
of the art conditions.
Brief summary and justification of the literature search strategy
applied for retrieval of information on current knowledge/ the state
of the art, including sources used, search questions, search
terms, selection criteria applied to the output of the search, quality
control measures, results, number and type of literature found to
be pertinent. Appraisal criteria used.
Applicable standards and guidance documents.
Description, natural course and consequences of the medical
conditions concerned. Whether there are different clinical forms,
stages and severities of the conditions. Frequency in the general
population, by age group, gender, ethnicity, familiar
predispositions, genetic aspects.
Description of available therapeutic/ management/ diagnostic
options, historical context and developments, summary of
advantages and disadvantages of the different options, benefit/
risk profiles and limitations in relation to the different clinical
forms, stages, and severities of the medical conditions and in
relation to different target populations. Description of the benefits
and risks (nature, extent, probability, duration, frequency),
acceptability of undesirable side-effects and other risks (including
the nature, severity, probability and duration of acceptable harm).
Hazards due to substances and technologies that could be
relevant to the device under evaluation. The mechanisms of
harm, clinical aspects of minimisation and management of side
effects and other risks.
Types of users. Diverging opinions of professionals as to the use
of the different medical options. Unmet medical needs.
4. Device under evaluation
4.1. Type of evaluation Whether the clinical evaluation is based on

- scientific literature currently available, and/or
- clinical investigations made
or
- whether demonstration of conformity with essential requirements
based on clinical data is not deemed appropriate.
If clinical data is not deemed appropriate, include considerations
according to Section 10.3.
4.2. Demonstration of See Appendix A1.

equivalence (only when Identification of the equivalent device and its manufacturer. Exact
equivalence is claimed) name, models, sizes, software versions, accessories, etc. Name
of the manufacturer. Relationship to the device under evaluation
(predecessor/ successor, others). Regulatory status. If the device
is not CE-marked, justification for the use of the data.
Comparison of clinical, biological and technical characteristics
(see Appendix A1 for details). Justification of equivalence,
description of relevant clinical, biological and technical
characteristics that affect clinical properties of the device,
differences between the intended purpose of the device under
evaluation and the equivalent device (indications,
contraindications, precautions, target patient groups, target users,
mode of application, duration of use/ number of re-applications,
others), type of device-body interaction. Choice, justification and
validity of parameters and models for non-clinical determination of
characteristics.
Identification of pre-clinical studies carried out and literature used,
concise summaries of studies and literature (methods, results,
conclusions of the authors), evaluation of the methodological
quality of the study or document, the scientific validity of the
information.
Comparative tabulations for the device under evaluation versus
the equivalent device showing parameters relevant to the
evaluation of the three characteristics. Comparative drawings or
pictures of the device and the equivalent device showing the
elements in contact with the body.
Identification of differences, evaluation if differences are expected
or not to influence the clinical performance and clinical safety of
the device, reasons for assumptions made.
Conclusions concerning equivalence. Whether the comparison
carried out covers all products/ models/ sizes/ settings/
accessories and the entire intended purpose of the device under
evaluation, or only certain products/ models/ sizes/ settings/
accessories, or selected aspects of the intended purpose, which
ones.
Conclusions whether equivalence is demonstrated or not; if it is
demonstrated, confirmation that the differences are not expected
to affect the clinical performance and clinical safety of the device
under evaluation; description of any limitations and gaps.
4.3. Clinical data generated See Section 8.1.

and held by the Identification of clinical data generated and held by the
manufacturer manufacturer.
4.4. Clinical data from See Section 8.2 and Appendices A4-A5.
literature Brief summary and justification of the literature search strategy
applied for retrieval of clinical data, including objectives, sources
used, search questions, search terms, selection criteria applied to
the output of the search, quality control measures, results,
number and type of literature found to be pertinent.
4.5. Summary and appraisal See Section 9 and Appendix A6.

of clinical data - Feasibility Studies
- Pivotal clinical investigations
- PMCF Studies
- Other use data
Summaries of clinical data generated and held by the
manufacturer and of scientific literature found to be pertinent.
Including brief summary of the studies or references (methods,
results, conclusion of the authors), evaluation of their
methodological quality, scientific validity of contents, relevance to
the clinical evaluation, weighting attributed to the data, contents
used (performance data, safety data, both) reasons for rejecting a
study or document, reasons for rejecting some of its contents.
4.6. Analysis of the clinical

data
4.6.1. Requirement on See Section 10 and Appendix A7.1.

safety (MDD ER1 Summary of conformity assessment with requirement on safety
/ AIMDD ER1) (MDD ER1 / AIMDD ER1).
Analysis whether there are special design features that pose
special safety concerns (e.g. presence of medicinal, human or
animal components) that where identified in the device risk
management documentation and that required evaluation from a
clinical perspective, and whether these have been adequately
addressed.
Whether the risks identified in the risk management
documentation and literature have been adequately addressed.
Whether all the hazards and other clinically relevant information
(e.g. clinical precautions for reduction of risks, clinical
management of risks) have been identified appropriately.
Whether the safety characteristics and intended purpose of the
device requires training of the end-user or other precautions, if
users foreseen are adequate, if training requirements and other
precautions are described in the IFU.
Whether there is full consistency between current knowledge/ the
state of the art, the available clinical data, the information
materials supplied by the manufacturer, and the risk management
documentation for the device.
4.6.2. Requirement See Section 10 and Appendix A7.2.

on acceptable Summary of conformity assessment with requirement on
benefit/risk acceptable benefit/risk profile (MDD ER1 / AIMDD ER1).
profile Summary of the total experience with the device, including
(MDD ER1 / estimated numbers and characteristics of patients exposed to the
AIMDD ER1) device in clinical investigations, PMCF, from other user
experience, and in the market; duration of follow-up. Nature,
extent/severity, probability/frequency, duration of benefits to the
patients and of undesirable side-effects and other risks. For each
aspect of the intended purpose, whether the benefit/risk profile
including its uncertainties or unanswered questions is compatible
with a high level of protection of health and safety, corresponding
justifications.

on Summary of conformity assessment with requirement on
performance performance (MDD ER3 / AIMDD ER2). Description of clinical
(MDD ER3 / performance. For each intended performance, extent to which
AIMDD ER2) evaluation of benefits is possible based on available data,
limitations of the data, description of gaps, uncertainties or
unanswered questions, and assumptions. whether available data
allows adequate evaluation of performance, limitations of the
data, gaps, uncertainties or unanswered questions. Whether there
is sufficient clinical evidence for every intended performance.

on Summary of conformity assessment with requirement on
acceptability of acceptability of undesirable side-effects (MDD ER6 / AIMDD
side-effects ER5). Whether the data available is of sufficient amount and
(MDD ER6 / quality for the detection of undesirable side-effects and their
AIMDD ER5) frequency, limitations of the data, description of gaps,
uncertainties or unanswered questions, and assumptions.
Whether the undesirable side-effects are acceptable and
corresponding justifications.
5. Conclusions See Section 11.

Clear statement concerning compliance to Essential
requirements.
Acceptability of the benefit/risk profile according to current
knowledge/ the state of the art in the medical fields concerned
and according to available medical alternatives.
Adequacy of the information materials supplied by the
manufacturer, whether the intended purpose and risk reduction
measures are adequate; discrepancies.
Suitability of the device, including its IFU, for the intended users
and usability aspects; discrepancies.
Adequacy of claims foreseen by the manufacturer; discrepancies.
If there is consistency between the clinical data, the information
materials supplied by the manufacturer, the risk management
documentation for the device under evaluation; discrepancies.
Whether there is consistency between these documents and the
current knowledge/ the state of the art; discrepancies. Description
of residual risks and uncertainties or unanswered questions,
whether these are acceptable for CE-marking, how these should
be followed during PMS (uncertainties regarding medium- and
long term performance, safety under wide-spread use, residual
risks such as undesirable side-effects and complications
occurring at rates below detection possibilities of currently
available clinical data, others). Whether these are already being
addressed in ongoing PMS activities, e.g. in currently ongoing
PMCF studies. Whether new or additional PMS activities,
including PMCF studies, should be foreseen.
6. Date of the next clinical See Section 6.2.3.

evaluation

Suggested date, justification of the date.
7. Dates and signatures See Section 11.

Date of the clinical evaluation report.
Statement that the evaluators agree with the contents of the
report. Dates, names and signatures of the evaluators.
Final release by the manufacturer. Date, name and signature.
8. Qualification of the See Section 6.4.

responsible evaluators
9. References See Section 11.
A10. Proposed checklist for the release of the clinical evaluation report
The following aspects should be checked for the release of a clinical evaluation report:
Can the report be read and understood by a third party, does it provide sufficient detail for
understanding the data that are available, all assumptions made and all conclusions
reached?
If clinical data have been generated and are held by the manufacturer, are all data
mentioned and adequately summarised in the report?
If equivalence is claimed,
- is demonstration of equivalence included in the report?
- does the report disclose all the differences between the device under evaluation and the
equivalent device?
- does it explain why the differences are not expected to affect the clinical performance
and clinical safety of the device?
If the product is already in the market in Europe or elsewhere, has the latest PMS/ PMCF
data been taken into consideration and has it been summarised and referenced in the
report?
In respect to current knowledge/ the state of the art,
- has the report been updated?
- is current knowledge/ the state of the art summarised in the report and is it adequately
substantiated by literature?
- does the content of the report fully correspond to current knowledge/ the state of the art?
- does the report explain why the benefit/risk profile and the undesirable side-effects are
acceptable in relation to current knowledge/ the state of the art?
If the report covers several models/ sizes/ settings and/or different clinical situations, is
there sufficient clinical evidence and are the reports conclusions correct for
- all the devices?
- all its sizes, models and settings?
(including the smallest/ largest size, highest/ lowest dose, etc.)
- every medical indication?
(as described in the IFU/ not excluded with contraindications in the IFU)
- the entire target population?
(from pre term infants to old age, for males and females, etc., if not restricted in the IFU)
- every form, stage and severity of the medical condition, as applicable?

(including the most severe/ most benign forms, acute/ chronic stage, if not excluded in
the IFU)
- all intended users?
(including lay persons, if not excluded in the IFU, and any unusual user group)
- the whole duration of product use, including the maximal number of repeated exposure?
(as allowed by the IFU)
- if there are any discrepancies as to the above, are they identified in the reports
conclusions?
Is conformity to each of the relevant Essential Requirements (AIMDD ER1,2,5 / MDD
ER1,3,6 ) clearly stated and are all discrepancies identified in the reports conclusions?
Do the information materials supplied by the manufacturer correspond with the contents of
the report and are all discrepancies identified in the reports conclusions?
Do the reports conclusions identify all residual risks and uncertainties or unanswered
questions that should be addressed with PMS/ PMCF studies?
Is the report dated?
Is the qualification of the evaluators included in the report and correct?
Does the manufacturer hold a CV and declaration of interests of each of the evaluators and
are these up-to-date?
A11. Information on declarations of interests

Declarations of interests of the evaluators should be held by the manufacturer and cover relevant
financial interests outside the current work as an evaluator.
Declarations of interests should contain statements that clarify the extent of the declaration.
For example:
- the time span included (e.g. grants, sources of revenue or benefits paid or promised to
be paid over the 36 months prior to the evaluation)
- whether financial interests of family members are included or not (namely spouse or
partner living in the same residence as the evaluator, children and adults for whom the
evaluators is legally responsible)
Typical contents:
- employment by the manufacturer
- participation as an investigator in clinical studies of the device, or in pre-clinical testing of
the device
- ownership/ shareholding possibly affected by the outcome of the evaluation
- grants sponsored by the manufacturer
- benefits such as travelling or hospitality (if beyond what is reasonably necessary for the
work as an employee or external evaluator)
- interests in connection with the manufacturing of the device or its constituents
- interests in connection with intellectual property, such as patents, copyrights and
royalties (whether pending, issued or licensed) possibly affected by the outcome of the
evaluation
- other interests or sources of revenues possibly affected by the result of the evaluation
The declaration of interests should be dated and signed by the evaluator and the manufacturer.

A12. Activities of notified bodies
A12.1. Notified body assessment of clinical evaluation by conformity assessment route

The notified body assessment of clinical Evaluation reports and the supporting data presented by
manufacturers is required for all medical devices. The timing and frequency of the notified body
reviews will vary according to the risk carried by the device, how well established the device is (see
Section 6.2.3) and the conformity assessment procedure that is applied.

- the notified body assesses the manufacturers procedure for clinical evaluation, PMS plan
and PMCF plan and (if applicable) results of PMCF.
- as part of the representative sampling of devices21; for review of their technical
documentation the notified body assesses the clinical evaluation report presented for class
IIa22 and IIb devices as presented below for a design dossier.
A design dossier (Annex II, section 4) or type examination dossier (Annex III) assessment:
- the notified body assesses the data presented in the clinical evaluation report,
- assesses the validity of the conclusions drawn by the manufacturer, and
- the conformity of the device to relevant essential requirements.

- the notified body assesses the data presented in the clinical evaluation report,
- assesses the validity of the clinical evaluation report and the conclusions drawn by the
manufacturer, and
- the conformity of the device to relevant essential requirements.
The notified body should also have documented procedures to address the review of updates to
clinical evaluation reports during their scheduled surveillance activities and at the time of changes
to or extensions of EC design-examination/EC type-examination certificates. The review should
take into account aspects described in Section 6.2.3. This arises from the obligation placed on the
manufacturer to actively update the clinical evaluation with data obtained from PMS e.g. PMCF
and ongoing literature reviews/surveys.
In addition, notified bodies should refer to guidance, checklists and other documents available on
the assessment of clinical evaluations by notified bodies from the Notified Body Operations Group
(NBOG). These should be considered in addition to this guidance. Any such checklists are
intended only as an aide memoire for assessment and should not replace the Clinical Evaluation
Assessment Report (CEAR) outlined below.
21
In accordance with NBOG BPG 2009-4
22
Alternatively Annex VII coupled with Annex IV, V or VI could apply rather than Annex II.3

A12.2. Examination of a design dossier (Annex II.4; Annex 2.4) or of a type examination
dossier (Annex III; Annex 3)
The notified body examines the clinical evaluation documentation submitted (relevant
documentation referenced in previous sections of this MEDDEV), assesses the manufacturers
identification, appraisal and analysis of that data, and validates the conclusions drawn by the
manufacturer. In order to do so, the notified body should possess enough knowledge and
experience in clinical evaluation as stated in previous sections of this document.
A12.2.1. Decision-making by the notified body

In reviewing the evaluation of clinical data submitted by the manufacturer, the notified body verifies
and concludes whether or not the manufacturer has adequately:
- supplied clinical evaluation documentation (as referenced in previous sections);

- followed relevant procedures (as addressed by previous sections);
aspects;
- performed an appropriate risk analysis and estimated the undesirable side-effects which
are aligned with the clinical evaluation;
- involved appropriate clinical expertise in the clinical evaluation and in the compilation of the
risk analysis to ensure risks and benefits associated with real clinical use are adequately
defined;
- provided a solid justification as the basis for their estimations of benefits, risks, undesirable
side-effects, indications and contraindications of the device in question;
- justified the chosen route(s) of clinical data retrieval (according to previous sections);
- identified, appraised, analysed and assessed the clinical data (according to previous
sections) and demonstrated the relevance and any limitations of the clinical data identified
- identified all clinical data, favourable and unfavourable, that is relevant to the device and
using an appropriately robust, reproducible and systematic search strategy;
- provided sufficient clinical evidence relating to the safety, including benefits to the patients,
the clinical performance intended by the manufacturer (including any clinical claims for the
device the manufacturer intends to use), design characteristics and intended purpose of the
device, in order to demonstrate conformity with each of the relevant essential requirements;
- conducted and provided a critical evaluation of relevant scientific literature and data relating
to the safety, benefits, performance, design characteristics and intended purpose of the
device;
- demonstrated the equivalence of the device under evaluation to the device to which the
data relates in all necessary areas, i.e. clinical, technical, biological and that the data
available adequately addresses conformity to each of the relevant essential requirements (if
a critical evaluation of relevant scientific literature is provided as the only source of clinical
data);
- designed appropriate clinical investigations, when necessary, to address specific questions
arising from the critical review of the scientific literature and address each of the relevant
essential requirements;

- provided specific justification if a specific clinical investigation was not performed for class
III or implantable devices;
- provided evidence that clinical investigations presented are in compliance with applicable
regulatory and ethical requirements e.g. scientific validity, ethics committee approval,
competent authority approval;
- provided detail of the PMS plan in place for the particular device and justified the
appropriateness and adequacy of this plan;
- clearly identified which areas in the clinical evaluation and related data need to be further
addressed and confirmed in the post-market phase, with specific alignment to the PMCF;
- justified the appropriateness of the planned PMCF;
- justified and documented if PMCF is not planned as part of the PMS plan for the device;
- identified the sources of clinical data which will be gathered from the manufacturers PMS
system and PMCF;
- concluded that the contents of the IFU are supported by clinical evidence (description of the
intended purpose, handling instructions, type and frequency of risks, warnings, precautions,
contraindications, others) and are in line with the risk analysis and clinical evaluation;
- concluded on the basis of documented evidence:
a. that the risks are acceptable when weighed against the intended benefits and are
compatible with a high level of protection of health and safety,
b. that the intended clinical performances described by the manufacturer are achieved by
the device, and
c. that any undesirable side-effect constitutes an acceptable risk when weighed against
the performances intended.
The assessment carried out by the notified body will in addition typically confirm the following
aspects of the manufacturers clinical evaluation:
- appraisal to determine suitability and any limitations of the data presented to address the
essential requirements in particular relating to the safety, and performance of the device as
outlined in previous sections;
- characterisation and evidence-based proof of the clinical performance of the device
intended by the manufacturer and the expected benefits for the defined patient group(s);
- the application of all relevant harmonised standards or appropriate justifications if not;
- identified hazards to be addressed through analysis of clinical data as described in Section
10;
- characterising the severity of the hazard;
- estimating and characterising the probability of occurrence of harm, impairment of health
or loss of benefit of the treatment (documented and discussed based on scientifically
valid clinical data);
- the adequate description and estimation of the current state of the art in the
corresponding medical field;
- a justifiable and reasoned basis for estimation of risks and hazards.
Where a device incorporates, as an integral part, a substance which, if used separately, may be
considered to be a medicinal product, the notified body is responsible for verifying the usefulness

of the medicinal substance as part of the device prior to the submission of an application for
scientific opinion from a medicines authority.
For drug-device combination products and products incorporating stable human blood derivatives,
where a scientific opinion from a medicinal competent authority or from the European Medicines
Agency (EMA) has been sought, the notified body should consider any comments or
considerations raised in the medicinal clinical assessment when making its final decision on the
device. In the case of devices with a human blood derivative the notified body may not deliver a
positive decision to issue a certificate if the EMA's scientific opinion is unfavourable.
A12.2.2. The report of the notified body

The notified body should write a Clinical Evaluation Assessment Report (CEAR) based on its
assessment of the submitted clinical evaluation report and supporting documentation.
If a design dossier report is applicable to the device, the CEAR may be incorporated into this report
or referenced from it. The report should clearly identify the notified bodys assessment, verification
on each of the critical elements and overall conclusions.
The CEAR at a minimum should address the notified bodys assessment of manufacturers
application relating to the following:
- device description and product specification
- intended purpose of the device
- classification proposed for the device
- pre-clinical evaluation data presented by the manufacturer
- risk analysis and risk management and alignment with the clinical evaluation report
- clinical evaluation process
- clinical evaluation report authors
- equivalence assessment if data from equivalent is used
- clinical investigation plans and reports
- justification if no clinical investigation has been performed
- instructions for use, labelling and, when necessary, the training plan for users
- justification if no PMCF is planned
- PMS
- PMCF
- planned frequency/ criteria for updates to the clinical evaluation
- summary of review
- conclusion on clinical benefit/risk profile
- conformance of the device to the relevant Essential Requirements
The CEAR should also provide details relating to the submission and notified body review
(including staff and experts involved in the review and the aspects assessed by each, signatures of
responsible reviewers, etc.)
The notified body should justify and document each step of the decision making process referred in
section A12.2.1 above.

The CEAR at a minimum should include a summary of the information provided by the
manufacturer relating to the following:
- Record whether the clinical evaluation documentation is complete in accordance with this
document and adequate to demonstrate conformance to the Essential Requirements of the
relevant Directive.
- Record the notified body's verification of each step of the clinical evaluation process, from
the planning of the clinical evaluation, choice of route(s), identification, appraisal, analysis
and overall assessment of the clinical data, to concluding and reporting
- Record the notified bodys assessment of the clinical investigation data and/or literature
review assembled, relevant procedures and compliance to relevant standards
- Verify that the device has met the claimed performance/ intended purpose and benefits,
and that undesirable side-effects and risks have been properly evaluated
- Record the notified bodys assessment of the clinical safety, clinical performance and
benefit/risk profile
- Record the notified bodys assessment of the overall conclusions drawn by the
manufacturer from the clinical data presented
- Record the notified bodys assessment of the validity of the clinical evaluation and its steps
- Record the notified bodys conclusions on the clinical evaluation, documenting each step in
the decision making process as per Section A12.2.1.
A12.2.3. Clinical data from an equivalent device and other products
a. Equivalent devices
The notified body should clearly document its assessment of clinical data presented from an
equivalent device as part of a clinical evaluation. This should critically review and conclude on
the equivalence or not of the device under assessment to the devices presented as equivalent
in terms of their technical, biological and clinical characteristics. The relevance of each dataset
from an equivalent device should be clearly evident and assessed by the notified body.
The notified body should also assess and document the level of access to the technical and
clinical data from an Equivalent device that the manufacturer has. Relevant information may be
commercially sensitive/ confidential and not available to the manufacturer. The notified body
should challenge the ability of the manufacturer to access information that are relevant to the
demonstration of equivalence. Demonstration of equivalence might be difficult or impossible in
case of limited access to the technical documentation of the devices.
b. Other products
For hazard identification and when assessing the benefit/risk profile of the device, the notified
body should consider current knowledge/ the state of the art.
The notified body should assess the appropriateness of the use of data from benchmark
devices, other devices, and medical alternatives.

A12.3. Evaluation as part of quality system related procedures23
A12.3.1. Review of the manufacturers procedures

The notified body shall, as part of the review of the manufacturers quality system, assess the
establishment, maintenance and application of the manufacturers documented procedures for the
evaluation of clinical data. This should cover:
a. the proper assignment of responsibilities to suitably qualified persons involved in the clinical
evaluation (e.g. clinical evaluator(s), information retrieval expert(s), expert(s) in clinical
research);
b. the integration of clinical evaluation into the quality system as a continuous process, to be
specifically inter-related to, and informed by, pre clinical evaluation and risk management;
c. standard operating procedures to assure proper planning, conduct, evaluation, control and
documentation planning of the clinical evaluation, identification of clinical data (previous
section), literature searching (previous section), collection of clinical experience (previous
section), clinical investigation (previous section and EN ISO 14155), appraisal of clinical data
(previous section), analysis of clinical data (previous section), concluding, reporting (previous
section) and update of clinical evaluation, procedures, reporting and updating based on data
from the PMS system and from PMCF (MEDDEV 2.12/2 rev.2);
d. document control as part of overall documentation of procedures, reporting, qualifications and

technical documentation/design dossier(s);
e. identification and evaluation of undesirable side-effects and of clinical performance(s). This

involves identification of known or reasonably foreseeable hazards and verification of
unfavourable and favourable outcome(s), qualification of their severity/magnitude and of their
probability of occurrence. (It is part of the manufacturers documented risk analysis based on
both favourable and unfavourable data identified as relevant in order to give a balanced view).
A12.3.2. Review of the technical documentation of representative samples

The notified body is required to assess the technical documentation for class IIa and class IIb
devices on a representative basis. The clinical evaluation report should be assessed by the notified
body for at least one representative sample for each device subcategory for class IIa devices and
at least one representative sample for each generic device group for class IIb devices. Further
representative samples have to be assessed as part of the annual surveillance assessment cycle.
Regarding the choice of representative sample(s) the notified body will consider the novelty of the
technology, similarities in design, technology, manufacturing and sterilisation methods, the
intended purpose, and the results of previous relevant assessments. Assessment of representative
samples includes assessment of the clinical evaluation report and available clinical data in
accordance with the review procedure in this document rather than solely confirming that the
manufacturer has a clinical evaluation procedure in place or that the clinical evaluation report is
available.
23
According to Article 11 MDD (Annex II.3 MDD, or Annex III MDD coupled with Annex IV, V or VI), and
Article 9 AIMDD.

When performing the assessment on samples of a manufacturers clinical evaluation, the notified
body will follow the steps indicated in previous sections of this document.
A clinical evaluation assessment report should be completed and available for each device
sampled and assessed.
A12.4. Notified body specific procedures and expertise

A notified body should have formal procedures in place controlled by their quality system relating to
the assessment of clinical evaluation reports and associated data provided by medical device
manufacturers. These procedures should also cover the review of updates to the clinical evaluation
report during their scheduled surveillance activities and at the time of changes to or extensions of
EC design-examination/EC type-examination certificates.
Notified bodies should establish and implement internal policies and procedures for the
assessment of clinical evaluation reports and associated data in order to:
a. Ensure that suitable resources, especially clinical competence necessary for such assessment,
are available within24 the notified body to conduct and manage assessments of clinical
evaluations for the notified body, normally a qualified medical doctor.
Such expertise should be sufficient to conduct a complete review of the clinical data and clinical
evaluation presented for a particular device, to identify and estimate the risks and benefits
associated with the use of the medical devices and to identify what, if any, specific clinical
expertise is required for the full assessment of the device.
The assessment team should be able to assess a risk analysis, the risk management strategy
performed by the manufacturer, and the scientific validity of clinical investigations and
publications.
The assessment team should have sufficient expertise in the device technology as the
associated medical procedures.
Such an assessment requires input from a qualified medical practitioner (for example physician,
dentist, nurse, etc.), as appropriate for the particular device, who has clinical experience in
using the device or similar devices, the pathology of the condition being treated, the usual
treatment, other medical alternatives, etc.
The notified body clinical assessor may work with external clinical experts. The notified body
clinical assessor should ensure that any experts are appropriately aware of the relevant
legislation, guidance and standards and to identify specific aspects of the clinical data
evaluation for their specific review.
Notified bodies should have robust procedures around the recruitment, selection, training,
conflict of interest and interaction with external clinical experts including clear procedures
around how the expert opinion is documented and integrated with the notified body assessment
and considered as part of the overall certificate decision.
When examining the results of clinical investigations, the assessment team shall have
knowledge in planning, conduct and interpretation of clinical investigations. All assessors should
be appropriately trained and qualified.
24
Annex XI.3 of Directive 93/42/EEC. This presupposes the availability of sufficient scientific staff within the
organisation who possess experience and knowledge sufficient to assess the medical functionality and
performance of devices for which it has been notified, having regard to the requirements of this Directive
and, in particular, those set out in Annex I.

assessment procedure(s), relevant guidance, standards and the context of the assessment they
are providing. The notified body should be responsible for reviewing the opinion of these
experts, taking account of their level of knowledge of the provisions of the Directives.
The opinion of an external clinical expert may form part of the assessment conducted by the
notified body. The opinion and conclusions of the notified body, in part based on this external
opinion, should be clearly documented.
The impartiality and the potential for conflict of interest of an external expert reviewer should be
assessed and documented by the notified body.
b. Review the clinical evaluation report and clinical data provided by the manufacturer. The
notified body should verify the validity of key statements made in the clinical evaluation report.
The notified body should consider
- statements based on published literature using the full text version of publications;
- statements based on clinical data generated from PMS systems in particular PMCF and
source verification of such data;
- statements regarding equivalence to other devices using the original full text version of
pre-market study reports assessing parameters of interest.
- statements regarding results of own clinical investigations of the manufacturer using the
original full text version of the clinical investigation plan and the clinical investigation
report.
The review of the notified body should consider the scientific validity of the clinical data set
presented as part of the clinical evaluation and decide as to whether it provides evidence that
the clinical benefit outweighs all associated risks.
The data presented by the manufacturer should be scientifically robust and well presented, it
should be complete and clear in its reasoning and should be of sufficient quality and validity to
demonstrate the conclusions which are being drawn.
All clinical data relevant to the device in question, both favourable and unfavourable, should be
considered, appraised and assessed by the manufacturer and likewise by the notified body. An
absence of unfavourable data relating to a medical device should be carefully examined.
Clinical evaluation reports which are based on incomplete, unclear or uncertain datasets should
not be accepted.
Clinical Evaluation reports which are based on incomplete clinical investigations or clinical
investigations which were halted or terminated earlier than their intended duration should be
carefully examined and a robust justification for halting or termination should be sought. The
original endpoints, objectives and statistical basis for the manufacturers clinical investigation
are unlikely to remain valid in circumstances when an investigation is completed prior to its
original planned duration and so it is unlikely that scientific conclusions can be drawn.
c. Document the opinion with rationale of all experts involved.
d. Document the result of their assessment. This is achieved through a specific clinical evaluation
assessment report which may be part of, or may be referenced, in the overall audit report,
design / type examination report (as per A12.2.2 of this document) or the report on the
assessment of representative samples documentation.
e. Preserve confidentiality of the information and data received from the manufacturer, especially
within the terms for contracting external experts.

f. Clearly identify how data from PMS conducted by manufacturers, vigilance and market
surveillance information from competent authorities, PMCF data, and data from other relevant
sources (e.g. clinical literature) is identified and reviewed by the notified body. This should
clearly describe how, when and what criteria are used by the notified body to judge when a re-
assessment of the benefit/risk profile of a particular device is deemed necessary.

EUROPEAN COMMISSION
Consumer goods
MEDDEV 2.7.1
Appendix 1
December 2008
EVALUATION OF CLINICAL DATA

- A GUIDE FOR MANUFACTURERS AND NOTIFIED BODIES -
Appendix 1 :
Clinical Evaluation of Coronary Stents
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-Directives on medical Devices.
They are legally not binding. The Guidelines have been carefully drafted through a process of intensive consultation of the
various interest parties (competent authorities, Commission services, industries, other interested parties) during which
intermediate drafts where circulated and comments were taken up in the document. Therefore, this document reflects positions
GUIDELINE ON
CLINICAL EVALUATION OF CORONARY STENTS
I. OBJECTIVE AND PURPOSE
This document provides guidance to manufacturers on the clinical evaluation of coronary stents,
thus assisting them in their clinical investigation(s) and the subsequent evaluation of all clinical
data required under Directive 93/42/EEC concerning medical devices (MDD), as amended. It
should further be used by Notified Bodies as part of their Design Dossier review or Type Test
certification and any subsequent significant change notifications. It is also aimed at assisting
Member States authorities when verifying that the device meets the essential requirements laid
down in Annex I of the MDD during post market surveillance.
This guideline should be read in conjunction with MEDDEV 2.7.1 Evaluation of Clinical Data: A
Guide for Manufacturers and Notified Bodies which covers evaluation of clinical data. It
describes the main requirements for the clinical evaluation of coronary stents based on current
state-of-the-art and on experience drawn from the most recent reviews of clinical studies. It does
not attempt to exhaustively cover the clinical evaluation of coronary stents. Furthermore, this
guideline is subject to the evolution of the state-of-the-art.
II. BACKGROUND AND LEGAL BASIS
II-1 Background
Cardiac intervention without surgery has profoundly changed the management of cardiac
patients, particularly those with coronary artery disease. The first interventional procedure
involved percutaneous transluminal coronary angioplasty (PTCA), but was soon considered to be
in need of further development in view of relative early re-stenosis and recurrence of symptoms.
This led to the development of bare metal stents (BMS), in an attempt to prevent re-stenosis.
However, re-stenosis continued to occur in some patients however as BMS are not perfectly
suited to address the process of intimal thickening. This results from the cascade of events
initiated by the trauma of the intervention in combination with the underlying arterial disease with
inflammation, smooth muscle cell migration, proliferation and sometimes thrombus formation
occurring.
Currently, the majority of coronary artery dilatation procedures involve the deployment of a stent.
This consists of the placing of a mechanical scaffold at the site of the treated segment in order to
increase the radial support of the vessel wall. In addition, pressing the stenotic structure (plaque)
against the arterial inner wall tends to prevent disruption of plaque and dissected flaps and hence
reducing the risk of embolization and further dissection. This aims to restore local perfusion and
coronary perfusion reserve. The stent itself will, however, confer new properties into the treated
segment of artery and may induce subsequent biological responses, for example intimal
hyperplasia which may, to some extent, undermine the initial advantages of stent placement.
Stenting may also lead to mechanical damage of the arterial wall through over-expansion of
angioplasty balloons or abrasion of the arterial wall by the stent during deployment. The damage
imposed may lead to biomechanical and biochemical actions causing localized inflammation,
thrombus formation or arterial inflammation. Redevelopment of arterial obstructions can
significantly affect medical outcomes with partial or complete stenosis leading to reduced local or
global heart muscle perfusion and potentially infarction.
In an attempt to reduce re-stenosis and as a result of research into the underlying processes,
drug eluting stents (DES) were developed.
3
II-2 Legal basis
Coronary stents fall within the scope of the MDD. In DES, the medicinal substance(s)
incorporated in the stent has/have an ancillary action to that of the stent within in the meaning of
Article 1.4 of the MDD. In view of the above and pursuant to Article 9 of the MDD, the applicable
classification rules for these devices are Annex IX, Chapter III, Section 2.4 (rule 8) and for DES
also Annex IX, Chapter III, Section 4.1 (rule 13). Both rules lead to classifying all coronary stents
as class III medical devices.
Confirmation of conformity with the requirements concerning the characteristics and performance
under normal conditions of use of the device and evaluation of side-effects and of the
acceptability of the benefit/risk profile must be based on an evaluation of clinical data1. In
accordance with Annex X, section 1.1, this clinical evaluation must consist of either a critical
evaluation of the relevant (both positive and negative) scientific literature currently available
supporting the safety, performance, design characteristics and intended purpose of the device
(where there is demonstration of equivalence of the device in question to the device to which the
data relates, and where the data adequately demonstrate compliance with the relevant essential
requirements) or a critical evaluation of the results of all clinical investigations made or a
combination of both. The objectives of a clinical investigation must be to verify a positive
benefit/risk profile of the device for the indications and limitations of use as specified by the
manufacturer.
For coronary stents incorporating a medicinal substance, the Notified Body shall refer to a
member state designated competent authority for medicinal products or to the European
Medicines Agency (EMEA) for their scientific opinion. The opinion of the Competent Authority for
medicinal products or EMEA on the quality and safety of the substance is based on the clinical
data from the evaluation of the DES, pharmacological properties of the substance and data on
the usage of the substance in other applications in accordance with Annex I, Section 7.4 of the
MDD and with the EMEA/CHMP/EWP/110540/2007 guideline.
III. RELEVANT DOCUMENTS
Council Directive 93/42/EEC concerning medical devices, last amended by Directive

2007/47/EC of the European Parliament and of the Council.
EMEA/CHMP/EWP/110540/2007: Guideline on the clinical and non clinical evaluation during

the consultation procedure on medicinal substances contained in drug-eluting (medicinal
substance-eluting) coronary stents.
EN 14299:2004 Non active surgical implants Particular requirements for cardiac and vascular
implants Specific requirements for arterial stents.
EN 12006-3:1998 Non-active surgical implants Particular requirements for cardiac and
vascular implants Part 3: Endovascular devices.
EN ISO 10993 Biological evaluation of medical devices.
EN ISO 14155-1:2003 Clinical investigation of medical devices for human subjects Part 1:
General requirements.
EN ISO 14155-2:2003 Clinical investigation of medical devices for human subjects Part 2:
Clinical investigation plans.
EN ISO 14630:2005 Non-active surgical implants General requirements.
EN ISO 14971:2007 Medical devices Application of risk management to medical devices.
GHTF SG5 N2R8:2007 Guidance on clinical evaluation.
ISO/DIS 25539-2 Cardiovascular implants Endovascular devices Part 2: Vascular stents.
MEDDEV 2.1/3 (2001) Interface with other directive Medical devices/medicinal products.
MEDDEV 2.7.1(2003) Evaluation of clinical data: A guide for manufacturers and notified bodies.
MEDDEV 2.12-2 (2004) Guidelines on post market clinical follow-up.
1
See Annex X, section 6a of the MDD, as amended.
4
IV. PRECLINICAL ASSESSMENT
Prior to undertaking a clinical investigation of a stent, pre-clinical testing is necessary and should
include the following; (conformity to the standards referenced in brackets are considered to fulfil the
relevant requirements of Directive 93/42/EEC).
biocompatibility testing (EN-ISO 10993 series);

bench testing in line with EN 14299;
animal studies (EN 14299, EN ISO 14630, EN 12006-3);
in the case of DES, appropriate testing of the medicinal substance including interaction
between the medicinal substance and the device, pharmacodynamics and characterisation of
time-release profiles (see EMEA guideline);
for rare and serious risks associated with the use of coronary stents (such as risk of late
thrombosis), specific tests shall be considered (e.g. endothelization testing, tissue
measurements, assessment of any late inflammatory response, etc); in case of DES, see
EMEA guideline.
Note: the ISO Standard (ISO 25539-2) on coating durability/stability, analysis of the uniformity of
the drug distribution is currently under development.
V. CLINICAL INVESTIGATION
In order to evaluate whether the device is suitable for the purpose(s) and the population(s) for
which it is intended, the objectives of a clinical investigation according to Annex X, Section 2.1 of
the MDD are:
to verify that under normal condition of use the performance of the device is in
accordance with the manufacturers claimed intended purpose, and
to determine any undesirable side effects, under normal condition of use and assess
whether they constitute risks when weighed against the intended performance of the
device.
Coronary artery disease covers a wide spectrum of different pathological changes in terms of size
and/or length of vessel involved, numbers of lesions, sites of lesions, clinical presentation (acute
coronary syndrome versus chronic stable angina pectoris). Also, coronary artery disease may be
complicated by other co-existent pathologies such as diabetes and/or hypertension. It is therefore
important that in evaluating safety and performance of coronary stents these populations and
pathologies are reflected in the instructions for use.
For BMS, clinical evaluation shall be conducted in line with MEDDEV 2.7.1 and relevant
standards (EN ISO 14155-1 and -2 and relevant parts of EN 12006-3, EN 14299 and EN 14630).
In addition to the above-mentioned requirements:

- for DES, the usefulness of the drug shall always be supported by appropriate clinical
investigation data;
- for innovative stents2, the clinical investigation must be designed appropriately to assess the
novel feature(s) of the device (e.g. bio-absorbability, biological coating, etc.).
It is important that generic claims are not made for devices that have been studied in limited
patient populations. Specific claims must be backed up by specific clinical data.
2
An " innovative stent" is a stent incorporating unique characteristics dissimilar to any currently CE-marked coronary stents, e.g. a
stent with a novel active coating, biodegradable stents, requiring novel clinical techniques for placement or incorporating completely
new design concepts.
5
V.1 Clinical investigation design
The design of the clinical investigation must be based on the claims made by the manufacturer
and as part of the demonstration of compliance with the essential requirements of the MDD.
Controlled randomized studies shall be conducted when necessary to substantiate claims made
by the manufacturer.
The demonstration of the benefit-risk profile of the stent system under investigation may require a
randomized comparative study design. In such a case the choice of the comparator shall be
justified and, in particular, the validity of the comparator should have been established previously
by (an) appropriately conducted clinical investigation(s).
V. 2 Definition of population under clinical investigations
It is important for the population being studied that there are well-defined eligibility criteria, taking
into account the safety and performance claims and any other future marketing claims. Criteria
such as the specific site of the lesion, length of lesion, type of lesion, diameter of vessels, as well
as risk factors including but not limited to diabetes, multiple lesions, bifurcated lesions and a post-
myocardial infarction situation must be considered.
All patients should be on well-defined medically recommended anti-thrombotic medication unless

otherwise justified.
V.3. Number of patients for enrolment.
The number of patients to be enrolled shall be justified on the basis of a sound scientific rationale,
through the use of statistical calculation to support the hypotheses.
The design of a study without control group (either prospective or historical) shall be specifically
justified. When such a study is designed to measure performance and safety, it shall include a
sufficient number of patients completing the study to allow the primary performance and safety
end-points specified in the clinical investigation plan to be estimated with a 95% confidence
interval.
V.4. Duration of the clinical investigation
Timelines for acceptable evaluation of the performance and safety will depend upon the
characteristics of the stent as well as the coronary pathologies and/or medical conditions for
which it is intended. Timelines should always be justified. Appropriate endpoints should take into
consideration the time-frame of expected complications:
for a BMS, generally a minimum of 6 months;
3
for a DES and other innovative stents , generally a minimum of 12 months. Moreover, a
long-term follow-up of patients included in the investigation should be performed and a
post market clinical follow-up shall be considered and conducted unless duly justified as
mentioned in section VII below.
Longer timeline may be required.
V.5. Analysis
Where angiographic, intra-vascular ultrasound (IVUS) and other imaging endpoints are specified
in premarket studies, these should be analysed by an independent core laboratory. If possible a
blinded adjudication of clinical events should be utilised.
3
Other relevant EU legislation should be accounted for in designing clinical investigations, e.g. Council Directive 97/43/Euratom on
health protection of individuals against the dangers of ionizing radiation in relation to medical exposure, when appropriate.
6
V.6 Performance Endpoints
V.6.1 Device and Procedural Success Endpoints.
These acute endpoints may be divided into Device Success Endpoints and Procedure Success
Endpoints. These endpoints should include but are not limited to:
successful delivery of the stent to the targeted lesion site in the coronary artery;
appropriate balloon expansion (if applicable);
appropriate stent deployment;
successful removal of delivery system after release of the stent;
safe removal of the device in case of deployment failure.
Device Success includes the above. Procedure Success includes the above with additional
criteria related to the clinical outcome of the procedure with the use of both investigational and
non-investigational devices.
For example, acute success is classified according to the following definitions:
Clinical device success.

Successful delivery and deployment of the investigational stent(s) at the intended target
lesion (this includes successful delivery and deployment of multiple overlapping stents)
and successful withdrawal of the stent delivery system with attainment of a final residual
stenosis of less than 50% of the target lesion as observed by Quantitative Coronary
Angiography (QCA) or by visual estimation if QCA is not available and without use of a
device outside the assigned treatment strategy. Standard pre-dilation catheters and post-
dilatation catheters (if applicable) may be used.
Clinical procedural success.
Successful delivery and deployment of the investigational stent(s) at the intended target
lesion (this includes successful delivery and deployment of multiple overlapping stents, if
applicable) and successful withdrawal of the stent delivery system with attainment of a
final residual stenosis of less than 50% of the target lesion as observed by QCA or by
visual estimation if QCA is not available and/or using any adjunctive device without the
occurrence of ischemia-driven major adverse cardiac event (ID-MACE) during the
hospital stay to a maximum of first seven days post index procedure.
In case of multiple lesions treatment, all treated lesions must meet the clinical procedural
success.
V.6.2 Clinical Endpoints.
These should include but are not limited to:

death (cardiac, non cardiac);
myocardial infarction (MI);
target lesion revascularisation (TLR, edges included, i.e. +/- 5 mm);
target vessel revascularization (TVR);
non target vessel revascularization (Non-TVR);
pre-defined composite endpoints of the above-mentioned events;
clinical events related to stent thrombosis.
7
4
The Academic Research Consortium Publication recommends using composite endpoints which
include target vessel failure/major adverse cardiac events (TVF/ MACE), a composite endpoint
which may vary from investigation to investigation; its components should therefore be specified.
The manuscript differentiates between two types of composite end-points depending on the
development stage of a device:
Device-oriented composite, in hierarchical order:

cardiac death;
myocardial infarction (not clearly attributable to a non-target vessel);
target lesion revascularisation.
Patient-orientated composite, in hierarchical order:

all-cause of mortality;
any MI (includes non-target vessel territory);
any repeat revascularization (includes all target and non-target vessel).
V.6.3 Angiographic and intra-vascular ultrasound (IVUS) endpoints.
Should include but are not limited to:

rate of binary in-stent and in-segment re-stenosis where re-stenosis is
defined by coronary angiography as stenosis of greater than 50% of the
luminal diameter;
late loss: in-stent and in-segment luminal loss (defined as the difference
between the Minimal Luminal Diameter [MLD], immediately after the
procedure and the MLD at the defined follow-up time);
intra-vascular ultrasound (if performed): in-stent % volume obstruction, in-
stent neo-intimal hyperplasia volume (mm3).
V.7. Safety Endpoints
V.7.1 Peri-procedural safety endpoints.
In terms of procedures and deployment, these include:

vessel dissection;
distal embolisation;
peri-procedural myocardial infarctions (MIs).
V.7.2 Post procedural or follow-up safety endpoints.
V.7.2.1 Clinical safety endpoints:

see paragraph V.6.2
V.7.2.2 Long term follow-up angiographic and/or IVUS safety endpoints:

persistent dissection;
coronary aneurysm;
presence of thrombus;
if using Intra-vascular ultrasound (IVUS, initial or acquired): stent mal-apposition.
V.7.2.3 Clinical event related to antiplatelet therapy:

major bleeding complications
4
Reference: Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions. Donald E. Cutlip, Stephan
Windecker, Roxana Mehran, Ashley Boam, David J.Cohen, Gerrit-Anne van Es, P. Gabriel Steg, Marie-angle Morel, Laura Mauri,
PascalVranckx, Eugene McFadden, Alexandra Lansky, Martial Hamon, Mitchell W. Krucoff, Patrick W. Serruys and on behalf of the
Academic Research Consortium Circulation 2007;115:2344-2351.
8
Note: relevant medication administered to the patient, e.g. dosage, duration and discontinuation
of antiplatelet therapy must be taken into account when determining all endpoints.
VI. EVALUATION OF CLINICAL DATA SUPPORTING CE MARKING
Evaluation of clinical data to support CE marking should be carried out in line with the
methodology laid out in the MDD and the relevant guidance (see section III).
Prior to CE marking, a literature review in accordance with MEDDEV 2.7.1 is necessary. Scientific
literature in this area is highly targeted and specific. It would be expected that a critical evaluation
of literature with an appropriate summary performed by a suitably qualified person is performed.
The literature summary should include explanations dealing with both negative as well as positive
publications.
The objective of the literature review is:
to identify all data generated from clinical investigations or studies of the device in
question and/or of equivalent devices;
to demonstrate, where applicable, equivalence with a similar device already on the

market where equivalence in this context is defined in MEDDEV 2.7/1, i.e.:
a) clinical equivalence:
when used for the same clinical condition or purpose, at the same site in
the body, in a similar population (including age, anatomy, physiology) and
have similar relevant critical performance according to expected clinical
effect for specific intended purpose;
b) technical equivalence:
used under similar conditions of use, have similar specifications and
properties (e.g. tensile strength, viscosity, surface characteristics), be of
similar design, use similar deployment methods (if relevant), and have
similar principles of operation;
c) biological equivalence:
use of the same materials in contact with the same human tissues or body
fluids;
to identify relevant gaps in the literature which should be addressed by a specifically

designed clinical investigation.
The intended purpose of the device, including clinical indications, contra-indications, and claims
shall be based on the result of the evaluation of all available clinical data i.e. all claims must be
supported by clinical data.
Side effects and adverse effects observed during clinical investigation as well as those identified
by the risk management process) shall be reflected in the information supplied with the device.
A Post Market Clinical Follow up (PMCF) is important for coronary stents in order to evaluate long
term safety and performance (pursuant to Annex X, section 1.1c of the MDD and MEDDEV 2.12-
2).
VII. POST-MARKET CLINICAL FOLLOW-UP (PMCF)
An appropriate post-market clinical follow-up programme in accordance with MEDDEV 2.12/2

shall be performed for all DES and innovative stents and for all BMS unless duly justified.
9
Such a programme must be planned and can take the form of a clinical investigation (where the
CE marked device is used according to its intended use) and/or registry All comer registries, to
include those cases treated off-label, should be conducted to better provide clinical safety and
performance data in "real world" clinical practice. Any data gathered from real world usage by
manufacturers should be used to feedback directly into device labelling.
A clinical investigation or a registry should include:

a clearly stated objective;
a scientifically sound design with an appropriate rationale and statistical analysis plan
designed appropriately to address the objectives of the study and scientifically sound to allow
for valid conclusions to be drawn;
a study plan which should justify the patient population (to include a representative population
with risk factors such as diabetes and hypertension), the selection of sites and investigators,
the endpoints and statistical considerations, the number of subjects involved (to ensure
capture of the true incidence of late complications), the duration of the study for a minimum of
3 years (taking into account the lifespan of the device and the time of occurrence of late
complications), the data to be collected, the analysis planning including any interim reporting,
and the procedures for early study termination.
VIII. MODIFICATIONS TO STENT OR INDICATIONS FOR USE
When subsequent modifications of claims or design iterations occur to an already marketed

coronary stent it is essential to evaluate, based on a risk analysis, the impact of the modifications.
The results of this evaluation will determine the need for any new or additional pre-clinical testing
or clinical investigation.
Each claim modification should be approved by the Notified Body. The Notified Body should be
provided with documentary supporting evidence enabling them to adequately evaluate and risk
assess the manufacturer's desired modification to the product labelling. Particular attention is
required with regards to planned extension to the current indications. Claim modifications may
also include highlighting the particular suitability (or not) of selected patients cohorts, lesion and
arterial morphology, implantation technique e.g. direct stenting.
Each modification influencing the specified drug characteristics and/or drug delivery
characteristics requires a consultation by the Notified Body of the relevant Member State-
designated Competent Authority for medicinal products or of the EMEA.
For example, in case of modification of a DES the modification may concern:
the bare stent and the delivery system: here it is necessary to validate with current
standards and to provide specific information in the instructions for use when the
modification concerns the surface treatment of the stent;
the carrier: where there is no influence on the kinetics of the medicinal substance,
the same standard of validation as for a BMS or a BMS with treated surface may be
applied;
the medicinal substance, the medicinal substance kinetics or a change in the
characteristics of the carrier which influences the kinetics of the medicinal substance:
a new evaluation of the benefit/risk profile by a comparative clinical investigation and
a PMCF is required.
Fin- 26 09 08
EUROPEAN COMMISSION
Consumer goods
MEDDEV 2.7.2
December 2008
GUIDE FOR COMPETENT AUTHORITIES

IN MAKING AN ASSESSMENT OF CLINICAL INVESTIGATION
NOTIFICATION
Note
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully
drafted through a process of intensive consultation of the various interest parties (competent authorities,
Fin- 26 09 08
MEDICAL DEVICES DIRECTIVES - CLINICAL INVESTIGATION-
GUIDELINES FOR COMPETENT AUTHORITIES IN MAKING AN

ASSESSMENT OF CLINICAL INVESTIGATION NOTIFICATION
INTRODUCTION
Roles of Competent Authorities may vary between Member States in relation to assessment
of clinical investigation notifications under the provisions of article 10 of Council Directive
90/385/EEC1 and of article 15 of Council Directive 93/42/EEC2, as amended.
It is important however that everybody responsible for raising no grounds for objection to a
clinical investigation progressing ensures that the information submitted in the notification
pursuant to annex 6 of Directive 90/385/EEC or annex VIII of Directive 93/42/EEC contains all
the following items listed below (if appropriate) and is adequate in detail. It is equally
important to note that any change to clinical investigation plan or other amendments and
updates to the original document, must be equally submitted in a timely manner to the
relevant Regulatory Bodies.
The information requested below is in line with the requirements of the harmonised standard
EN ISO 14155.
CHECKLIST
NOTE: The following is a list of items that must be covered although the information may be
provided in different documents or in different formats as required by individual Competent
Authorities. Competent Authorities may also require additional documentation for their
assessment needs.
1. General Information
1.1 Sponsors and/or manufacturers name and contact points for communication
(similarly for authorised representative in the EU if relevant).
1.2 Whether first submission or resubmission.
1.3 If resubmission with regard to same device, previous date(s) and reference
number(s) of earlier submission(s).
1.4 Other Member States and non European countries participating in clinical
investigation as part of a multicentre/multinational study at the time of filing.
1.5 A signed statement (by the managing director or regulatory affairs manager or
manager responsible for compliance with the essential requirements)to the effect that
the device in question complies with the essential requirements except with regard to
those aspects of the device which are to be investigated; and that, in respect of those
aspects, every precaution has been taken to protect the health and safety of the
subject.
1.6 Copy of the Ethics committee opinion as soon as available according to national
requirements.
1
2
Fin- 26 09 08
2. INVESTIGATOR BROCHURE: Devices Identification
2.1 Details allowing device to be identified
2.2 Trade name of device.
2.3 Generic name of device.
2.4 Model name of device.
2.5 Model number(s) including revision number(s), if any (or reference from apparent
model number if appropriate).
3. INVESTIGATOR BROCHURE: Other Device Details
3.1 Classification.
3.2 Description of the intended clinical performance (ISO 14 155).
3.3 A description of device including a list of accessories, principles of operation and

devices designed to be used in combination for purpose of the investigation, if
applicable.
3.4 Identification of any features of design that are different from a previously similar
marketed product (if relevant).
3.5 Details of any new or previously untested features of the device including, where
applicable, function and principles of operation.
3.6 Summary of experience with any similar devices made by same manufacturer
including length of time on market and a review of performance related problems,
complaints any actions taken to address. Clinical data on device in question or
similar device, if available. Reference should be made as to how experience with
previous device models has affected the current iterations of design, if applicable.
3.7 Benefit/Risk analysis to include identification of hazards and estimated risks

actions have been taken to minimise or eliminate the identified risks. (Note: may
also be included in the clinical investigation plan).
3.8 Summary and analysis of pre-clinical testing and experimental data including results
of design calculations, mechanical tests, electrical tests, tests for validation of
software, reliability checks and any performance and safety tests in animals.
3.9 Description of materials coming into contact with the body, rationale for choice of
materials and which Standards apply (if relevant).
3.10 Description of how biocompatibility and biological safety have been addressed
including identification of the risks and hazards associated with the use the device
and how these have been addressed.
Fin- 26 09 08
3.11 Identification of any pharmacological components of device with description of

intended purpose and previous experience with the use this substance (see attached
annex).
3.12 Design drawings, if necessary for the understanding of the functioning of the device.
3.13 Description of software, logic and constraints (if relevant).
3.14 Method of sterilisation and validation (method, justification, if ETO-residuals) (if

applicable) and methods of cleaning, disinfection and sterilisation for reusable
devices.
3.15 Identification of any tissues of animal origin incorporated within the device together
manufacturing operation; and details with regard to validation of manufacturing
procedures employed for the reduction or inactivation of unconventional agents. This
is also applicable in circumstances of genetically produced material.
3.16 Identification of any special manufacturing conditions required and if so, how such
3.17 List of relevant Standards applied in full or in part, or description of solutions adapted
to meet the essential requirements of the Directive if relevant standards have not
been fully applied.
3.18 Instructions for use/labelling including risks, contra indications and warnings (if
available).
3.19 What provisions, if any have been made by the manufacturer for the recovering of the
device (if applicable, i.e. implantable devices, multiple use devices) and subsequent
4. CLINICAL INVESTIGATION PLAN (CIP): General Information
4.1 Name(s), qualifications, professional positions, address(es) of clinical investigator(s),

of principle clinical investigator and co-ordinating investigator (if relevant) from
multicentre clinical investigation at the time of filing. NOTE: this can be provided
separately from the CIP.
4.2 Name(s), address(es) of the institution(s) in which the clinical investigation(s) will be
conducted; identification of the Sponsor and other institutions playing a critical role in
the trial, ie centralised laboratories. NOTE: this can be provided separately from the
CIP.
4.3 Name(s), address(es) of the Sponsor and Manufacturer.
4.4 Synopsis of the clinical investigation plan; reference to GCP standards followed, ie
Declaration of Helsinki and ISO 14155.
4.5 A summary of necessary training experience for use of device in question, if

applicable.
4.7 Copy of informed consent or the draft informed consent submitted in parallel to the
Ethics Committee. NOTE: this can be a separate document
4.8 Copy of draft Clinical Research Form (CRF) if required. NOTE: this can be a
separate document.
Fin- 26 09 08
4.9 Rationale and justification of the clinical investigation; Summary of background to

study with reference to important relevant scientific literature (if any) with analysis and
bibliography; pre-clinical testing and previous clinical experience overview in support
of justification for conducting the clinical investigation; device and investigation risk
analysis and risk assessment.
5 CLINICAL INVESTIGATION PLAN: Investigation Parameters and Design
5.1 Objectives of clinical investigation.
5.2 Investigation design, eg randomised, controlled, including clear statement of the

endpoints corresponding to the objectives of the clinical investigation, variables to be
used, methods and timing of the assessments.
5.3 Numbers of subjects (with justification).
5.4 Duration of study with estimated start and finish dates and proposed follow up period
(with justification).
5.5 Criteria for subject selection.
5.6 Criteria for withdrawal from study
5.7 Description and justification of hazards caused by invasive procedures that are not
medically required (if applicable).
5.8 Description of general methods of diagnosis or treatment of the medical condition for
which the investigation testing is being proposed.
5.9 Monitoring arrangements during the clinical investigation including request for direct
access to source documents including extent of source data verification.
6 CLINICAL INVESTIGATION PLAN: Data Collection/Analysis/Statistics
6.1 Description of endpoints to demonstrate safety and performance and the data
recorded to achieve the endpoints, method of subjects follow up, assessment and
monitoring arrangements during investigation.
6.2 Description and justification of statistical design, method and analytical procedures.
Statistical considerations including statistical design and methods describing how to
reach endpoints to demonstrate safety and performance. Level of significance and
the power of the clinical investigation, any criteria for termination of the clinical
investigation (if applicable) with statistical justifications.
6.3 Procedures for data collection, review, cleaning, and issuing and resolving queries, if
appropriate.
6.4 Recording and reporting procedures of clinical investigation plan deviations, if

appropriate
Fin- 26 09 08
7 CLINICAL INVESTIGATION PLAN : Safety Reporting
7.1 Definitions of adverse events and adverse device effects.
7.2 Definitions of serious adverse events and serious adverse device effects.
7.3 Details of procedures of those events to be reported to the relevant Ethics

Committees and Competent Authority, including timelines.
7.4 List of foreseeable adverse events and adverse device effects, likely incidence,
mitigation and/or treatment.
7.5 Emergency contact details for reporting serious adverse events and serious adverse
device effects to the Sponsor.
8 CLINICAL INVESTIGATION PLAN : Other
8.1 Reference to Insurance coverage in case of injury
8.2 Device accountability procedures.
8.3 Ethics and informed consent procedures
8.4 Procedure for early termination or suspension of the investigation giving criteria and
risk analysis.
8.5 Procedure for clinical investigation plan amendments
8.6 Final report and publication policy.

Fin- 26 09 08
ANNEX
GUIDANCE NOTES ON MEDICAL DEVICES INCORPORATING A MEDICINAL

SUBSTANCE HAVING ANCILLARY ACTION
Additional information required with regard to the medicinal substance.

- (medicinal substance specifications eg, summary of the European Drug

Master File, reference to European Pharmacopoeia or national monograph of
a European Member State).
- Manufacturers may wish to cross-reference a granted Clinical Trial
Exemption (CTE).

Pharmokinetic characteristics (local/systemic exposure patterns, duration and

individual variability).
- New active substances should address the release of the substance from the
device, its subsequent distribution and elimination.

conventional application) eg, the results of EN/ISO 10993 testing, or a review o
NOTE: Referral to MEDDEV 2.1.3, Section B3, which describes the documentation to be
provided by the Notified Body to the Medicinal Product Competent Authority for medicinal
products as part of the consultation procedure may be helpful.
EUROPEAN COMMISSION
September 2015
GUIDELINES FOR COMPETENT AUTHORITIES

FOR MAKING A VALIDATION/ASSESSMENT OF A
CLINICAL INVESTIGATION APPLICATION
Note
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully drafted
through a process of intensive consultation of the various interested parties (competent authorities,
taken by representatives of interest parties in the medical devices sector. These guidelines incorporate
changes introduced by Directive 2007/47/EC amending Council Directive 90/385/EEC and Council
page 1 of 68
GUIDELINES FOR COMPETENT AUTHORITIES FOR MAKING A

VALIDATION/ASSESSMENT OF A
CLINICAL INVESTIGATION APPLICATION
Index
0. PREFACE
1. INTRODUCTION
2. SCOPE
3. REFERENCES
4. DEFINITIONS
5. ETHICAL CONSIDERATIONS
6. VALIDATION
7. ASSESSMENT
8. DECISION ON APPROVAL/AUTHORIZATION
9. INFORMATION TO BE EVALUATED DURING THE CONDUCT OF A
CLINICAL INVESTIGATION AND AT THE END
9.1 Suspension of a Clinical Investigation
9.2 Termination, Temporary Halt, Clinical Investigation
Report
9.3 Follow-up
APPENDICES
1a: List of the standards applied in full or in part
1b: Matrix of Essential Requirements applicable to IMD
2: Guidance notes on medical devices incorporating a medicinal substance
having ancillary action
3: Guidance on medical devices which require sterilization
4: Guidance on clinical investigations of active devices
5: Guidance on clinical investigations of software
6: Guidance on medical devices incorporating tissues of animal origin
7: Clinical investigation application form
8: Clinical investigation validation checklist
9: Clinical investigation assessment checklist
page 2 of 68
0. PREFACE:
These guidelines on the validation/assessment of a clinical investigation application are part

of a set of Medical Device Guidelines that, according to the relevant Annexes of the Medical
Devices Directives, promote a common approach in clinical investigation validation and
assessment procedures by Competent Authorities charged with safeguarding public health.
The guidelines are regularly updated according to regulatory developments. The latest
version of the guidelines should always be used. This revision of the previous version has:
modified the structure to align with the structure of other Medical Device Guidelines
and to better reflect the relevant Directives and take note of the harmonized standard
EN ISO 14155;
provided some basic criteria to promote a harmonized approach in clinical
investigation assessment among Member States and further the understanding of the
requirements of Directive 93/42/EEC concerning medical devices and Directive
90/385/EEC relating to active implantable medical devices as amended by Directive
2007/47/EC;
rephrased some paragraphs to reflect the above listed changes;
introduced new Appendices to standardize specific procedures or provide checklists.
example as a result of scientific developments, an alternative approach may be possible or
from National Competent Authorities, it is anticipated that the guidelines will be followed within
the Member States and, therefore, support uniform application of relevant EU Directive
provisions and common practices within Member States.
However, only the text of the Directives constitutes legal requirements. On certain issues not
addressed in the Directives, national legislation may be different from these guidelines.
1. INTRODUCTION
These guidelines are addressed to Competent Authorities responsible for
validation/assessment of clinical investigation applications referred to in article 10 of Council
1 2
Directive 90/385/EEC and in article 15 of Council Directive 93/42/EEC , as amended.
However roles of Competent Authorities (CAs) may vary between Member States, and other
bodies, such as Ethics Committees, are involved in the assessment/approval process of
clinical investigations mentioned above, according to national regulations. Competent
Authorities shall encourage the use of these guidelines by all the Ethics Committees and
other possible national bodies involved in the assessment of clinical investigational
application, according to national law.
Competent Authorities shall ensure that the information submitted in the application pursuant
to annex 6 of Directive 90/385/EEC or annex VIII of Directive 93/42/EEC, contains the items
listed below (if appropriate) and is adequate in detail.
It is also important to ensure that the clinical investigation plan shall include documented
procedures and a study design in accordance with the provisions of Section 2 of Annex 7 of
Directive 90/385/EEC or Section 2 of Annex X of Directive 93/42/EEC. Furthermore it is
important that the clinical investigation plan correctly reflects the clinical evaluation as
planned by the manufacturer/sponsor.
1
2
page 3 of 68
It is equally important to note that any substantial modifications to the clinical investigation
plan or other substantial amendments and updates to the original documents, also need to be
submitted in a timely manner to the Competent Authorities in accordance with applicable
national legislation.
The clinical investigations described above are generally expected to be designed, conducted
and reported in accordance with harmonized standard EN ISO 14155 Clinical investigation
of medical devices for human subjects- good clinical practice- or to comparable standards,
and in compliance with the Declaration of Helsinki and national regulations.
2. SCOPE
The primary purpose of this document is to provide guidance to Competent Authorities

when validating/assessing a clinical investigation application according to Article 10 of
Directive 90/385/EEC or Article 15 of Directive 93/42/EEC provided by
manufacturers/sponsors from the initial application up to the end of the investigation.
This document provides guidance on:

description of the documents to be validated and/or assessed;
criteria to be applied for general validation/assessment;
description of events that may occur during the carrying out of the investigation and
possible measures to be adopted;
specific aspects of assessment (criteria in Appendices).
vitro diagnostics.
Furthermore, the guidance is intended to provide advice on the format and content of the
information to be submitted in an application for clinical investigations and for substantial
modifications.
NOTE: Post market clinical follow-up studies (PMCF-studies), where the IMD is a CE-marked medical
device according to Directive 93/42/EEC and is used within its intended purpose and the study is not
considered interventional as per national regulations, shall be excluded from the scope of this MEDDEV
and are covered by MEDDEV 2.12/2.
3. REFERENCES
Council Directive 90/385/EEC of 20 June 1990 concerning active implantable medical devices
Commission Regulation (EU) No 722/2012 - OJ 212/3 of 9.08.2012 concerning medical
devices manufactured utilising tissues of animal origin
Commission Decision of 19 April 2010 No. 2010/227/EU on the European Databank on
Medical Devices (EUDAMED)
Harmonized and International standards
EN ISO 14155:2011 Clinical investigation of medical devices for human subjects Good
clinical practice
EN ISO14971:2012 Medical devices application of risk management to medical
devices.
page 4 of 68
MEDDEV 2.7/1 Clinical Evaluation: a guide for manufacturers and notified bodies
MEDDEV 2.7/3 Clinical investigations: serious adverse event reporting
MEDDEV 2.7/4 Guidelines on Clinical investigations: a guide for manufacturers and
notified bodies
MEDDEV 2.12/2 Guidelines on post-market clinical follow up studies: a guide for
manufacturer and notified body
MEDDEV 2.1/3 Borderline products, drug-delivery products and medical devices
incorporating, as integral part, an ancillary medicinal substance or an
MEDDEV 2.1/2 Field of application of directive "active implantable medical devices"
MEDDEV 2.1/2.1 Field of application of directive "active implantable medical devices"
Treatment of computers used to program implantable pulse
generators
MEDDEV 2.1/6 Qualification and Classification of stand alone software
MEDDEV 2.4/1 Classification of medical devices
Manual on borderline and classification in the Community regulatory

framework for medical devices
4. DEFINITIONS3
Adverse Event: any untoward medical occurrence, unintended disease or injury, or untoward
clinical signs (including abnormal laboratory findings) in subjects, users or other persons,
whether or not related to the investigational medical device.
NOTE 1: This definition includes events related to the investigational medical device or the comparator.
NOTE 2: This definition includes events related to the procedures involved.
NOTE 3: For users or other persons, this definition is restricted to events related to investigational
medical devices.
Adverse Device effect: adverse event related to the use of an investigational medical
device.
NOTE 1: this definition includes adverse events resulting from insufficient or inadequate instructions for
use, deployment, implantation, installation, or operation, or any malfunction of the investigational
medical device.
NOTE 2: this definition includes any event resulting from use error or from intentional misuse of the
investigational medical device.
Clinical Data: safety and/or clinical performance information that are generated from the use
of a medical device in humans.
Clinical Evaluation: a methodologically sound procedure to collect and analyse clinical data
pertaining to a medical device and to assess whether there is sufficient clinical evidence to
confirm compliance with relevant essential requirements for safety and performance.
4
Clinical Evidence : clinical data of an amount and quality as to prove the validity and
accuracy of a claim or a statement.
Clinical Evaluation Report: the documentation of the clinical evaluation.
Clinical Investigation: any systematic investigation or study in or on one or more human

subjects, undertaken to assess the safety or performance of a medical device.
NOTE: Clinical Trial or clinical study are synonymous with clinical investigation.
3
Definitions to be adjusted when revision of MEDDEV 2.7.1 is finalised.
4
Definition to be adjusted when revision of MEDDEV 2.7.1 is finalised.
page 5 of 68
Clinical Investigation Plan CIP: document that state(s) the rationale, objectives, design and
proposed analysis, methodology, monitoring, conduct and record-keeping of the clinical
investigation.
NOTE: The term protocol is synonymous with CIP. However, protocol has many different meanings,
some not related to clinical investigation, and these can differ from county to country. Therefore, the
term CIP is used in this MEDDEV.
Clinical Performance: behaviour of a medical device or response of the subject(s) to that

medical device in relation to its intended use, when correctly applied to appropriate subject(s).
Clinical Safety: freedom from unacceptable risk, when using the device according to the
manufacturers Instructions for Use.
Conformity Assessment: the systematic examination of evidence generated and

procedures undertaken by the manufacturer, under requirements established by the
Regulatory Authority, to determine that a medical device is safe and performs as intended by
the manufacturer and, therefore, conforms to the Essential Requirements.
Device Deficiency: inadequacy of a medical device with respect to its identity, quality,
durability, reliability, safety or performance.
NOTE Device deficiencies include malfunctions, use errors, and inadequate labelling.
Ethics Committee (EC): independent body whose responsibility it is to review clinical

investigations in order to protect the rights, safety and well-being of human subjects
participating in a clinical investigation.
NOTE: For the purposes of this MEDDEV, ethics committee is synonymous with research ethics
committee, independent ethics committee or institutional review board. The regulatory requirements
pertaining to ethics committees or similar institutions vary by country or region.
Feasibility Study: a clinical investigation that is commonly used to capture preliminary

information on a medical device (at an early stage of product design) to adequately plan
further steps of device development, including needs for design modifications or parameters
for a pivotal study.
Investigator: individual member of the investigation site team designated and supervised by
the principal investigator at an investigation site to perform critical clinical-investigation-related
procedures or to make important clinical-investigation-related decisions.
NOTE: An individual member of the investigation site team can also be called sub-investigator or co-
investigator.
Investigators brochure (IB): compilation of the current clinical and non-clinical information
on the investigational medical device(s) relevant to the clinical investigation.
Pivotal study: a clinical investigation adequately designed and powered to collect definitive
evidence of benefits to the patients, clinical risks, clinical performance, and/or clinical aspects
of the usability of a device for a specified intended use.
Principal Investigator: qualified person responsible for conducting the clinical investigation
at an investigation site.
NOTE 1: If a clinical investigation is conducted by a team of individuals at an investigation site, the

principal investigator is responsible for leading the team.
NOTE 2: Whether this is the responsibility of an individual or an institution can depend on national
regulations.
page 6 of 68
Serious Adverse Event: an adverse event that
a) led to death;
b) led to serious deterioration in the health of a subject, that either resulted in:
1. a life threatening illness or injury, or
2. a permanent impairment of a body structure or body function;
3. in-patient hospitalisation or prolongation of existing hospitalisation
4. medical or surgical intervention to prevent life-threatening illness or injury or
permanent impairment to a body structure or a body function;
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without
serious deterioration in health, is not considered a serious adverse event.
Harmonised Standards: standards, the titles of which are published by the European
Commission deemed to offer a presumption of conformity to the Essential or other
Requirements of the Directives.
5. ETHICAL CONSIDERATIONS
In their sections 2.2 of Annex 7/Annex X, directives 90/385/EEC and 93/42/EEC require that:
Clinical investigations must be carried out in accordance with the Helsinki Declaration
adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964, as last amended
by the World Medical Assembly. It is mandatory that all measures relating to the protection of
human subjects are carried out in the spirit of the Helsinki Declaration. This includes every
step in the clinical investigation from first consideration of the need and justification of the
study to publication of the results.
As a general principle, the rights, safety and wellbeing of clinical investigation subjects shall
be protected consistent with the ethical principles laid down in the Declaration of Helsinki (EN
ISO 14155).
It is ethically important when deciding to conduct a clinical investigation that it should

generate new data and answer specific safety and/or performance questions that remain
unanswered by the current body of knowledge.
The desire to protect human subjects from unnecessary or inappropriate experimentation

must be balanced with the need to protect public health through the use of clinical
investigations where they are indicated. In all cases, however, care must be taken to ensure
that the necessary data are obtained through a scientific and ethical investigational process
that does not expose subjects to undue/avoidable risks or discomfort. The rights, safety and
well-being of subjects are paramount and appropriate clinical investigation design and
conduct is essential to generate meaningful data.
The following procedures/documents/information will have primary - but not exclusive-

importance for validation and decision making with regard to ethical considerations:
seeking research ethics committee favourable opinion;
the confirmation of insurance of subjects for the purpose of the study;
the process and documents used to obtain informed consent (usually CAs request
these documents to be (also) available in national language(s));
procedures with regard to protection of vulnerable groups and individuals;
justification of the clinical investigation under ethical and scientific aspects;
appropriate risk management and benefit/risk determination;
qualification of Clinical Investigators and suitability of clinical investigation sites;
appropriate choice of control group(s);
National and/or regional regulations usually play a major role in ethical considerations.
page 7 of 68
6. VALIDATION
The Validation of a clinical investigation application as an administrative review has to assure
whether:
the investigational product falls under one of the medical device directives
90/385/EEC or 93/42/EEC (qualification);
a notification (preferably in an up-loadable format) is present with basic information
on the clinical investigation to be uploaded to the EUDAMED database and to provide
the correct CIV ID code; (see Appendix 7)
a rationale is given for the classification of the investigational medical device (under
Directive 93/42/EEC only: class III or implantable or long-term-invasive device under
classes IIa or IIb);
the statement together with the relevant documentation requested in Annex 6
respectively. VIII are present, according to national provisions;
relevant information in accordance with additional national requirements has been
provided.
Validation should be based on the following considerations:
6.1. Information to be supplied in applications
6.1.1. Cover letter
The applicant should submit and sign a letter with the application cover. Its heading should
contain the sponsor protocol number with a title of the clinical investigation. The text should
draw attention to any special issues related to the application such as special clinical
investigation populations, first-in-human investigation, high-risk medical device, unusual
clinical investigation designs, sub-group analyses etc.
In addition, it should be mentioned whether an application for a clinical investigation with the
same medical device has previously been submitted in that or any other Member State.
6.1.2. An application form
Containing basic data on clinical investigations, to be included in the EUDAMED CI module

by the MS, will have to be provided and should be preferably in an xml-format, to facilitate the
upload by MS. A template is provided in Appendix 7 (MSs may require additional data in their
own national application forms in accordance with national regulations)
Decision 2010/227/EU requests the following information to be provided:
a) manufacturer, where applicable authorised representative:

(i) Name; (ii) Street; (iii) Locality; (iv) Postcode; (v) Country; (vi) Phone and E-mail;
(vii) Role.
b) device:
(i) Internationally recognised nomenclature code;
(ii) Device Name/Make or, where not available, generic name.
c) title of investigation;
d) protocol number;
e) primary objective.
6.1.3. Additional documents/information usually required for the application

dossier:
1 sponsors and manufacturers name (if the manufacturer is not the sponsor) and
contact points for communication (similarly for authorised representative in the EEA if
applicable);
page 8 of 68
2 whether first submission or resubmission5;
3 if resubmission with regard to same device, previous date(s) and reference number(s)
of earlier submission(s);
4 Member States and other countries participating in this clinical investigation as part of
a multicentre/multinational study at the time of filing and the opinion available of the
Member State or other countries;
5 a EUDAMED Clinical Investigation identification number (CIV ID), when available;
6 the application form signed by the sponsor confirming that:
the information provided is complete;
that submitted documents contain an accurate account of the information
available;
that the clinical investigation will be conducted in accordance with the clinical
investigation plan;
that serious adverse events, device deficiencies and related updates will be
reported, in accordance with the applicable legislation (see MEDDEV 2.7.3);
that appropriate safety measures have been taken for study participants/users
and other persons;
that the applicable fee for submission is accepted.
7 copy of the Ethics committee opinion as soon as available according to national
requirements;
8 title of the clinical investigation;
9 other relevant documentation according to national requirements;
10 description of the current legal status of the investigational medical device and its
intended use within the clinical investigation:
6
CE marked and within intended use (esp. Directive 90/385/EEC or if national
provision); manufacturer should give indication on amount and time of market
exposure since first placing on the market;
CE marked and not within intended use;
not CE marked;
if national provisions allow: simplified dossier, if the investigational medical device
has previously been part of a clinical investigation in the Member State and
investigational medical device and its use have not been modified since then at
all.
6.1.4. Rationale for Qualification (both Directives) and Classification (Directive

93/42/EEC only):
A rationale must be given, that the device under investigation falls under Directive 93/42/EEC
resp. Directive 90/385/EEC.
Reference concerning qualification must address Art.1 of Directive 90/385/EEC resp.

Directive 93/42/EEC. Helpful Guidance is contained in relevant MEDDEVs (e.g. MEDDEV
2.1/3) and the Manual on borderline and classification in the Community Regulatory
framework for medical devices.
For Classification rationale, Art. 9 and Annex IX of Directive 93/42/EEC provide the legal
basis; helpful guidance may be found in relevant MEDDEVs (e.g. 2.4/1) and in the Manual on
borderline and classification in the community regulatory framework for medical devices.
6.1.5. Statement and Documentation according to Annex 6 of Directive

90/385/EEC respectively Annex VIII of Directive 93/42/EEC:
Directives 90/385/EEC and 93/42/EEC request specific information to be provided or made

available to CAs by manufacturers or Authorised Representatives, serving as sponsors. MS
5
Resubmission: application of a clinical investigation previously submitted reporting the
same title, the same identification number/code and same EUDAMED code (CIV ID) where
the previous one has been rejected or withdrawn.
6
See note in chapter 2
page 9 of 68
may vary in their requests to provide the content of the statement or the documentation
mentioned below without further notice at the time of application or may have a policy to
request the content of the statement immediately and the more detailed information of the
7
documentation if needed in the specific cases . Subsequent information requests may trigger
clock-stop procedures, according to national provisions.
Annex 6 of Directive 90/385/EEC and Annex VIII of Directive 93/42/EEC request the following
content of a statement for devices intended for clinical investigations covered by Annex 7
(MDD 90/385/EEC), respectively Annex X (MDD 93/42/EEC) to be provided:
data allowing identification of the device in question;
the clinical investigation plan;
the investigator's brochure;
the confirmation of insurance of subjects;
the documents used to obtain informed consent (usually CAs request translation into
national language(s));
a statement indicating whether or not the device incorporates, as an integral part, a
substance or human blood derivative referred to in Section 10 of Annex 1 of Directive
90/385/EEC respectively section 7.4 of Annex I of Directive 93/42/EEC;
a statement indicating whether or not the device is manufactured utilising tissues of
animal origin as referred to in Commission Regulation 722/2012/EC;
the opinion of the ethics committee concerned and details of the aspects covered by
its opinion8;
the name of the medical practitioner or other authorized person and of the institution
responsible for the investigations;
the place, starting date and scheduled duration for the investigation;
a statement that the device in question conforms to the essential requirements apart
from the aspects covered by the investigation and that, with regard to these aspects,
every precaution has been taken to protect the health and safety of the patient.
For devices intended for clinical investigations, annex 6 of Directive 90/385/EEC and annex
VIII of Directive 93/42/EC request that the documentation must contain:
a general description of the product and its intended use;
design drawings, methods of manufacture envisaged, in particular as regards
sterilisation, and diagrams of components, sub-assemblies, circuits, etc.;
the descriptions and explanations necessary to understand the abovementioned
drawings and diagrams and the operation of the product;
the results of the risk analysis and a list of the standards referred to in Article 5,
applied in full or in part, and descriptions of the solutions adopted to meet the
essential requirements of this Directive if the standards referred to in Article 5 have
not been applied;
if the device incorporates, as an integral part, a substance or human blood derivative
referred to in Section 10 of Annex 1 of Directive 90/385/EEC resp. Section 7.4 of
Annex I of Directive 93/42/EEC, the data on the tests conducted in this connection
which are required to assess the safety, quality and usefulness of that substance or
human blood derivative, taking account of the intended purpose of the device;
if the device is manufactured utilising tissues of animal origin as referred to in COM
Regulation 722/2012/EC, the risk management measures in this connection which
have been applied to reduce the risk of infection;
the results of the design calculations, and of the inspections and technical tests
carried out, etc.
The relevant annexes mentioned above also request that:
"The manufacturer must take all the measures necessary to ensure that the manufacturing
process produces products which are manufactured in accordance with the documentation
referred to in the first paragraph of this Section."
7
MSs should make available that information to sponsors prior to the submission.
8
Some MSs accept parallel submission.
page 10 of 68
"The manufacturer must authorise the assessment, or audit where necessary, of the
effectiveness of these measures."
"The information contained in the declarations concerned by these Annexes mentioned

9
above shall be kept for a period of time of at least five years. In the case of implantable
10
devices the period shall be at least 15 years."
6.1.6. Specific information may be added to the application/notification based on national

regulations, mainly on ethical or local issues (e.g. on qualification of clinical investigators or
11
suitability of clinical investigation sites; liability issues; protection of vulnerable subjects etc).
6.1.7 A checklist for validation is provided in Appendix 8.
6.2 Outcome of the Validation:
Validation usually leads to a statement of the CA to the Sponsor/manufacturer/Authorised

Representative that:
a valid application has been submitted and (if applicable) the clock is ticking for the
assessment phase within a certain time frame12, according to national provisions; or
a valid application has been submitted and the Sponsor/MF/AR now may commence
the clinical investigation, on condition that the relevant Ethics Committee has issued a
favorable opinion, if the Member States has so decided; or
an incomplete/invalid application has been submitted, which must be
completed/adjusted (possibly within a time frame); or
an incomplete/invalid application has been submitted, which has not been
completed/adjusted within a legal time frame or after (a) reasonable attempt(s) of the
CA to have the application repaired, and the clinical investigation is rejected; or
no favorable opinion of a relevant Ethics Committee, according to national
regulations, has been obtained, and the clinical investigation is rejected; or
the application submitted does not fall under the medical device regime.
7. ASSESSMENT:
7.1. General aspects:
Assessment is a detailed ethical, technical, scientific and clinical review of documents/ and
information submitted in an application (possibly after a further information request) and of
other relevant information, usually performed by experts, to ascertain, whether
the Essential Requirements, applicable to the investigational medical device in
question, apart from those, which are to be examined in this clinical investigation, are
correctly identified and fulfilled, e.g. by use of relevant harmonized standards or
equivalent solutions (see Appendices 1a and 1b, with templates as a help to outline
this information),
all applicable safety measures and risk mitigation have been taken with regard to the
aspects under investigation (under consideration of the risk management provisions
in Annexes 1/I, point I.2 of the Directives and the harmonized standard EN ISO
14971),
9
Necessary adjustment.
10
MS may have deviating time frames.
11
Usually indicated at homepages of CAs; list of relevant CA contact points at URL:
http://ec.europa.eu/growth/sectors/medical-devices/contacts/index_en.htm
12
In the case of devices under Directive 90/385/EEC or devices falling within Class III and implantable and long-term
invasive devices falling within Class IIa or IIb of Directive 93/42/EEC, the manufacturer may commence the relevant
clinical investigation at the end of a period of 60 days after notification, unless the competent authorities have notified
him within that period of a decision to the contrary based on considerations of public health or public policy.
page 11 of 68
the benefit/risk estimation has been correctly performed and is acceptable according
to the state of the art in medicine (see MEDDEV 2.7.1),
scientific aspects and methodology have been duly considered and warrant, that the
clinical data generated will be robust and reliable and are appropriate with regard to
the clinical evaluation plan,
ethical requirements of the Declaration of Helsinki and, if applicable, relevant national
requirements are met (see chapter 5).
This assessment is usually primarily based on the information delivered in the Clinical
Investigation Plan (CIP) and the Investigators Brochure (IB), which are extensively
covered by the harmonized Standard EN ISO 14155:2011, in its Annexes A and B.
Considerations for the review of the CIP and IB as given by the Annexes to the
harmonized standard are given below under points 7.2 and 7.3.
NOTE: The following is a list of items that should be covered although the information may be provided
in different documents or in different formats, as required by individual Competent Authorities.
Competent Authorities may also require additional documentation for their assessment needs.
NOTE: Where the harmonized Standard EN ISO 14155:2011 is not followed or only partly followed, a
justification for that and for the alternative solutions taken should be provided.
Ethical Considerations are usually covered by the documentation discussed under chapter 5.
Depending on national provisions, the roles of EC and the CA in this detailed ethical,
technical and scientific review will have to be considered.
A tentative checklist of relevant points to consider for assessment can be found in

Appendix 9.
7.2. Clinical Investigation Plan (CIP):
N.B.: The numbering follows the one in Annex A of EN ISO 14155:2011 for easy
reference and coherence and adds comments or additional specific considerations.
A.1.3: The following information should be considered under Annex A.1.3 of EN ISO
14155:2011
Consideration: Name(s), address(es) and contact points for communication of the Sponsor
and Manufacturer (if the manufacturer is not the sponsor). Similarly for the Authorised
13
Representative, if applicable .
A.2: the following information should be considered under Annex A.2 of EN ISO
14155:2011
Consideration: When the handling of the specific device is complex or unfamiliar to the
investigator: Have risks associated with learning been properly mitigated (such as training
prior to the first use, support during the first cases). In addition, when inadequate handling of
a complex or unfamiliar device can cause serious adverse events (SAE): Supervision of every
investigator by an experienced person during the first use(s) should be foreseen and properly
described in the CIP (or IB)
A.3: the following information should be considered under Annex A.3- of EN ISO
14155:2011
Consideration: There should be a clear reference to the Clinical Evaluation and the position
and justification of this clinical investigation within, based on a proper scientific literature
13
This would normally be checked during validation
page 12 of 68
review, the related gap analysis, the benefit/risk estimation before the background of the state
of the art in medicine in the relevant field (see MEDDEV 2.7.1). It should be made clear in the
rationale for the clinical investigation whether the current application is for an exploratory (eg.
FIM, feasibility, pilot or proof of concept clinical investigation) or a confirmatory (pivotal)
clinical investigation or a combined one. These may have different risk management and
statistical approaches and procedures, e.g. see considerations under A.4. Also the possible
conclusions from the clinical investigation with regard to demonstration of safety and clinical
performance and to creation of clinical evidence will differ.
14155:2011
Considerations: The sponsor should review a subjects relevant clinical data, relevant
information related to the device (functioning, method, usability) and continuously evaluate
the risk/benefit of the study and potential remediation through the SAE's or USADE's process.
If deemed necessary by the sponsor, a temporary suspension, interval time of exposure may
be decided.
In light of this and considering FIM-studies, especially for high-risk devices, it shall be shown
how unexpected risk will be addressed and mitigated and whether a need for improvement is
identified before the next subject is treated, allowing a sufficient interval of time between
treatment/exposure of subsequent subjects:
a. the sponsor should review a subjects relevant clinical data, relevant information related
to the device (functioning, method, usability) and evaluate the need for improvement before
the next subject is exposed to the device.
b. clear definition of the scope of an exploratory study: how many devices/subjects should
reasonably be taken into account for this phase. This will certainly impact and limit the time
for product development.
In FIM studies, the existing experience e.g. with the specific kind of technology, design,
materials used or application shall be considered.
Consideration: Blended trials (exploratory/confirmatory; especially FIM/pivotal): FIM and
pivotal phases normally should not be combined unless the sponsor presents adequate
justification for the need to do so and explains how to mitigate the foreseen risks (special
attention should be given to high risk class devices).
a) the sponsor should always properly separate a FIM-cohort, and produce an interim
report of FIM patients that includes an adequate duration of follow-up. Based on FIM
experience, the sponsor shall analyse if clinical development can be continued as
originally planned or if there is a need to adapt the device or the CIP;
b) CAs should consider to request the sponsor to send the FIM report to the CA and/or
the ethics committee for evaluation before recruitment is extended to the pivotal
cohort with or without CIP/IB and possibly other document (informed consent, case
report forms) modifications as a result of the FIM. (as part of an approval with
conditions);
c) combining FIM and pivotal phases in one investigation should not be permissible for
devices with significant high or unknown risks.
Consideration: description and justification of hazards caused by procedures that are

specifically required by the clinical investigation, in particular with regard to invasive and
innovative ones (if applicable).
A.6.1: the following information should be considered under Annex A.6.1 of EN ISO
14155:2011
Consideration: Is the duration of the follow up sufficient?

a) long enough to gather data necessary for ensuring the safety of participating subjects
and take remedial action if necessary, under consideration of the specific standards,
to the type of studies and to the shelf life of the medical device;
b) long enough to fully achieve study objectives;
page 13 of 68
c) observations should cover at least entire duration of clinical healing phase/ recovery
phase connected to use of investigational devices. Longer observations are
necessary if required by a or b (e.g. for implants if long term side-effects can be
expected).
A.6.4: the following information should be considered under Annex A.6.4 of EN ISO
14155:2011
Considerations for implants:

a) retrieval analyses: Retrievals (failed implants removed in a revision intervention)
should be collected and assessed in a structured process by the manufacturer;
b) comprehensive documentation should be available for inspection;
c) retrieval collection and analysis plan including further investigation scheduled for
retrievals in case of failure, including in-house possibilities/capabilities and external
expertise (conflict of interest);
d) workflow of retrieval assessment, including forms for documentation, and institutions
involved;
e) arrangements for long-term follow-up of subjects beyond primary endpoint e.g. for
long term implantable devices.
Consideration: Description and justification of hazards caused by procedures that are

specifically required by the clinical investigation, in particular with regard to invasive and
innovative ones (if applicable).
14155:2011
Consideration: Patients lost to follow-up

a) there should be clear procedures on how patients lost to follow-up are handled.
b) if study endpoints include death or outcomes that can cause disability / loss of
autonomy:
if a study subject cannot be contacted, the procedure should foresee that the
centre should contact other persons or institutions (in certain countries the family
doctor). Such contacts should take place rapidly, especially in FIM studies of
devices with relevant risks, in order to enable the sponsor to promptly identify
undue risks and take measures that are necessary for preserving the health and
safety of study subjects (i.e. temporary stop of recruitment in order to review the
design of the device);
the consent form should name the persons or institutions to be contacted and
clearly state that the subject allows exchange of medical information with these
persons or institutions. (see also 4.7.4.j of EN ISO 14155:2011).
14155:2011
Consideration: what provisions, if any have been made by the manufacturer for the recovering
of the device (if applicable, i.e. implantable devices, multiple use devices) and subsequent
14155:2011
Consideration: besides the process described in A.13 the copy of informed consent or the
draft informed consent intended for the Ethics Committee shall be examined. Persons
responsible for reviewing the (draft) informed consent should be clarified.
NOTE: These can be separate documents.
Check for a reference to insurance coverage in case of injury: confirmation that the sponsor
has an insurance in place for the study to cover the patients enrolled as per the CIP.
page 14 of 68
14155:2011
Consideration: principles applied to clarify relationship of events to investigational procedures

should be captured.
14155:2011
Consideration: the Chapter "Research Registration and Publication and Dissemination of

Results" (points 35 and 36) of the Declaration of Helsinki shall be considered here, as this is
mandated by the Directives reference to the Declaration of Helsinki.
7. 3.Investigators Brochure (IB):
N.B: the numbering follows the one in Annex B of EN ISO 14155:2011 for easy
reference and coherence and adds comments or additional specific issues
B.2: the following information should be added to/considered under Annex B.2 of EN
ISO 14155:2011
Devices Identification
2.1 details allowing device(s) to be identified;

2.2 trade name of device(s);
2.3 generic name of device(s);
2.4 model name of device(s) and/or trade name or generic name of the investigational
device(s);
2.5 model number(s) including revision number(s), if any (or reference from apparent
model number if appropriate);
2.6 copy of device(s) labels and IFU(s) [including version nr and date of issue] including
risks, contraindications and warnings (if available);
2.7 A description of the device including a list of accessories, principles of operation and
devices designed to be used in combination for the purpose of the investigation, if
applicable;
2.8 identification of any features of design that are different from a previously similar
marketed product (if relevant);
2.9 details of any new or previously untested features of the device including, where
applicable, function and principles of operation;
2.10 description of software, functionality and constraints, version (if relevant);
2.11 design drawings, if necessary for the understanding of the functioning of the device;
2.12 identification of any special manufacturing conditions required and if so, how such
Consideration: device(s) classification: the rationale for device classification could also be
provided as a separate document, see chapter 6 Validation.
ISO 14155:2011
3.1 description of materials coming into contact with the body, body fluids, rationale for
choice of materials and which standards apply (if relevant);
3.2 identification of any medicinal substance or human blood derivatives incorporated into
the device with description of intended purpose and previous experience with the use
of substance(s) (see Appendix 2);
page 15 of 68
3.3 method of sterilisation and its validation (method, justification, if ETO-residuals) (if
applicable) and methods for cleaning, disinfection and sterilisation for devices
indicated as reusable (see Appendix 3);
3.4 identification of any tissues of animal origin incorporated within the device together
manufacturing operation and other relevant information on the origin of tissue(s) (e.g.:
copy of TSE certificate of suitability, if available); and details with regard to
validation of manufacturing procedures employed for the reduction or inactivation of
(un)conventional agents as well as details concerning the manufacturers risk analysis
and risk management process and the justification for the use of animal tissues or
derivatives, taking into consideration lower risk tissues or synthetic alternatives. This
is also applicable in circumstances of genetically produced material (see Appendix 6).
In case of devices falling under Commission Regulation (EU) No 722/2012 the
relevant requirements have to be observed.
ISO 14155:2011
4.1 summary of experience with any similar devices made by same manufacturer
including length of time on market and a review of safety and clinical performance
related problems and complaints together with any corrective or preventive actions
taken to address these issues;
4.2 summary of existing clinical data, in particular:
of the relevant scientific literature available relating to the safety, clinical
performance, design characteristics and intended purpose of the device and/or of
equivalent devices;
of previous clinical investigations, relating to the device in question and/or to
equivalent devices, if available;
4.3 reference should be made as to how experience with previous device models has
affected the current iterations of design, if applicable. The modifications should be
described, documented and improvement evaluated against the expected effect.
ISO 14155:2011
5.1 benefit/risk analysis to include identification of hazards and estimated risks

actions have been taken to minimise or eliminate the identified risks. (NOTE: may
also be included in the clinical investigation plan);
5.2 description of how biocompatibility and biological safety have been addressed
including identification of the risks and hazards associated with the use of the device
and how these have been addressed;
5.3 list of applicable Essential Requirements and of relevant Standards applied in full or
in part, or description of solutions adopted to meet the essential requirements of the
Directive if relevant standards have not been fully applied (Appendices 1a and 1b
show examples of lists with all relevant elements. Competent authorities may
encourage manufacturers to use the templates).
8. DECISION ON APPROVAL/AUTHORIZATION
Based on the outcome of Validation and/or Assessment by the entitled parties (primarily CA,
14
EC ), the following decisions may be taken according to national provisions:
1. Approval of the Clinical Investigation;

2. Approval with conditions;
(1+2: See template letter of no objection in 8.1)
14
others, e.g. hospital owners, health insurance providers, according to national provisions, may also play a role.
page 16 of 68
3. Tacit approval;
4. Rejection of/Objection to the Clinical Investigation
(4: See template letter of objection in 8.2)
8.1. Letter of no objection
Letters of no objection/decisions of Competent Authorities should contain the following

information:
1. the name of the sponsor of the Clinical Investigation (according to national

provisions);
2. the name of the authorised representative, if applicable;
3. the name of the manufacturer of the investigational device (if the manufacturer is not
the sponsor);
4. the title of the clinical investigation, the CIP code and version date;
5. the name of the investigational device(s);
6. the EUDAMED CIV-ID;
7. the date;
8. the decision;
9. any conditions imposed (i.e. recruitment limited to a subgroup (e.g. FIM cohort), need
to submit an interim report in order to extend recruitment beyond the subgroup,
approval from the Ethics Committee;
10. summary of duties (such as serious adverse event reporting, reporting of serious
violations of the CIP, amendments, reports required as a condition of approval.
8.2. Letter of objection
Letters of objection/decisions of Competent Authorities should contain the following

information:
1. the name of the sponsor;

2. the name of the authorised representative, if applicable;
3. the name of the manufacturer of the investigational device (if the manufacturer is not
the sponsor);
4. the title of the clinical investigation, the CIP code and version date;
5. the name of the investigational device(s), if available;
6. the EUDAMED CIV-ID;
7. the date;
8. the decision;
9. detailed reason(s) for the objection to include all grounds for objection being raised;
10. description of legal remedies open to the applicant under national legislation,
including timelines.
11. Specific information required in a resubmission in order to address the grounds for
objection.
9. ACTIONS TO BE PERFORMED DURING THE CONDUCT OF A

CLINICAL INVESTIGATION AND AT THE END
9.1 Suspension of a clinical investigation
After the commencement of the investigation, the Competent Authority may call for a
significant modification or temporary interruption of a clinical investigation where it has
objective grounds for considering that the conditions in the authorisation are not being met or
has doubts about the safety or scientific validity of the clinical trial, due to suspicion of an
page 17 of 68
15
unacceptable risk to subjects arisen during the clinical investigation . Before they reach their
decision, they must inform the manufacturer, or the sponsor when this does not coincide with
the manufacturer, except where there is imminent risk for the subjects involved, and ask the
sponsor and/or the investigator for their opinion. The sponsor should immediately investigate
the grounds for suspension and provide a report/response addressing the issues raised in a
timely manner. A preliminary report may be requested by the MS and be provided within one
week.
When the Competent Authority suspends a trial, they must inform the ethics committee
concerned and the other Competent Authorities concerned about its action and the grounds
for the actions taken.
To restart the trial following a suspension, the sponsor should make the request as a
substantial amendment to the Competent Authority and the Ethics Committees concerned
providing evidence that it is safe to restart the clinical investigation.
If the sponsor decides not to recommence a temporarily halted clinical investigation he should
notify the Competent Authorities and the ethics committees concerned within 15 days of his
decision and provide a brief explanation of the reasons for ending the investigation early.
9.2 Termination, Temporary Halt, Clinical Investigation Report
The manufacturer/sponsor shall notify the Competent Authorities of the Member States
concerned and the Ethics committee involved the termination of the clinical investigation.
The manufacture/sponsor should also make a report of the clinical investigation preferably
within one year after the termination of the investigation and keep it at the disposal of the
competent Authorities according to Annex 7 and Annex X of Directives 90/385/EEC and
93/42/EEC. A guidance to produce a clinical investigation report is contained in the ISO
14155:2011 (Annex D) and, for some aspects in the MEDDEV 2.7/1.
If the manufacture/sponsor halts the clinical investigation temporarily he should notify

immediately the competent Authorities concerned and at least within 15 days from when the
clinical investigation is halted. This should be notified as a substantial amendment and clear
explanations should be provided.
Whenever a clinical investigation is terminated early the sponsor must notify the Competent
Authorities and the Ethics committees concerned immediately and at least within 15 days
from the premature termination. This time frame will be shorter for halt or termination for
safety reasons.
9.3 Follow-up
If a new event occurs after the termination of the investigation that is likely to change the
risk/benefit analysis of the medical device and could still have an impact on the investigation
participants, the sponsor should notify the Competent Authority and ethics committee
concerned and provide a proposed course of action.
The following Appendices are provided as guidance. The format or document stated in
the Appendices can be modified, according to MS provisions.
15
Doubts about the validity of the ongoing investigation may arise from SAE reports, new data from human
experience with the investigational medical device, new interpretation of existing data from human experience with
the investigational medical device or type of medical devices, results from other trials, data demonstrating lack of
efficacy.
page 18 of 68
APPENDIX 1a:
List of the standards applied in full or in part

Investigational device (name, size, model):
Manufacturer:
Date:
Standard Version/ Compliance

(identifier and title) Year (with the exception of clinical requirements that will be assessed during
the clinical investigation)
Full Partial Description of all deviations and of the

alternative solutions adopted to meet the
essential requirements of directive 90/385/EEC
or 93/42/EEC
page 19 of 68
APPENDIX 1b:
Matrix of Essential Requirements16, being applicable or not to an
Investigational Medical Device, with rationale
Does
ER Standards Evidence of
ESSENTIAL REQUIREMENT apply used in conformance Justification/comment in
(ER) ? full or in to standard; case of deviation
(Yes/ part documentation
No)
I. GENERAL REQUIREMENTS
1. The devices must be
designed and manufactured
in such a way that, when
used under the conditions
and for the purposes
intended, they will not
compromise the clinical
condition or the safety of
patients, or the safety and
health of users or, where
applicable, other persons,
provided that any risks which
may be associated with their
use constitute acceptable
risks when weighed against
the benefits to the patient
and are compatible with a
high level of protection of
health and safety. This shall
include:
reducing, as far as
possible, the risk of
use error due to
ergonomic features
of the device and the
environment in which
the device is
intended to be used
(design for patient
safety), and
consideration of the
technical knowledge,
experience,
education and
training and where
applicable the
medical and physical
conditions of
intended users
(design for lay,
professional,
disabled or other
users).
16
For Directive 93/42/EEC
page 20 of 68
Does
No)
2. The solutions adopted by the
manufacturer for the design
and construction of the
devices must conform to
safety principles, taking
account of the generally
acknowledged state of the
art.
In selecting the most
appropriate solutions, the
manufacturer must apply the
following principles in the
following order:
eliminate or reduce
risks as far as
possible (inherently
safe design and
construction),
where appropriate
take adequate
protection measures
including alarms if
necessary, in relation
to risks that cannot
be eliminated,
inform users of the
residual risks due to
any shortcomings of
the protection
measures adopted.
3. The devices must achieve
the performances intended
by the manufacturer and be
designed, manufactured, and
packaged in such a way that
they are suitable for one or
more of the functions
referred to in Article 1 (2) (a),
as specified by the
manufacturer.
4. The characteristics and
performances referred to in
Sections 1, 2 and 3 must not
be adversely affected to
such a degree that the
clinical conditions and safety
of the patients and, where
applicable, of other persons
are compromised during the
lifetime of the device as
indicated by the
page 21 of 68
Does
No)
manufacturer, when the
device is subjected to the
stresses which can occur
during normal conditions of
use.
5. The devices must be
designed, manufactured and
packed in such a way that
their characteristics and
performances during their
intended use will not be
adversely affected during
transport and storage taking
account of the instructions
and information provided by
the manufacturer.
6. Any undesirable side effect
must constitute an
acceptable risk when
weighed against the
6a. Demonstration of conformity
with the essential
requirements must include a
clinical evaluation in
accordance with Annex X.
II. REQUIREMENTS REGARDING DESIGN AND CONSTRUCTION
7. Chemical, physical and biological properties
7.1 The devices must be
in such a way as to
guarantee the characteristics
and performances referred
to in Section I on the
General requirements.
Particular attention must be
paid to:
the choice of
materials used,
particularly as
regards toxicity and,
where appropriate,
flammability,
the compatibility
between the
materials used and
biological tissues,
cells and body fluids,
taking account of the
page 22 of 68
Does
No)
intended purpose of
the device.
where appropriate,
the results of
biophysical or
modelling research
whose validity has
been demonstrated
beforehand.
designed, manufactured and
packed in such a way as to
minimize the risk posed by
contaminants and residues
to the persons involved in
the transport, storage and
use of the devices and to the
patients, taking account of
the intended purpose of the
product. Particular attention
must be paid to the tissues
exposed and to the duration
and frequency of exposure.
in such a way that they can
be used safely with the
materials, substances, and
gases with which they enter
into contact during normal
use or during routine
procedures; if the devices
are intended to administer
medicinal products they
must be designed and
manufactured in such a way
as to be compatible with the
medicinal products
concerned according to the
provisions and restrictions
governing these products
and that their performance is
maintained in accordance
with the intended use.
7.4 Where a device
incorporates, as an integral
part, a substance which, if
used separately, may be
considered to be a medicinal
product as defined in Article
1 of Directive 2001/83/EC
page 23 of 68
Does
No)
and which is liable to act
upon the body with action
ancillary to that of the
device, the quality, safety
and usefulness of the
substance must be verified
by analogy with the methods
specified in Annex I to
For the substances
referred to in the first
paragraph, the notified
body shall, having
verified the usefulness of
the substance as part of
the medical device and
taking account of the
intended purpose of the
device, seek a scientific
opinion from one of the
competent authorities
designated by the
Member States or the
European Medicines
Agency (EMA) acting
particularly through its
committee in accordance
with Regulation (EC) No
726/2004 (*) on the
quality and safety of the
substance including the
clinical benefit/risk profile
of the incorporation of
the substance into the
device. When issuing its
opinion, the competent
authority or the EMA
shall take into account
the manufacturing
process and the data
related to the usefulness
of incorporation of the
substance into the
device as determined by
the notified body.
Where a device
incorporates, as an
integral part, a human
blood derivative, the
notified body shall,
having verified the
usefulness of the
page 24 of 68
Does
No)
substance as part of the
medical device and
taking into account the
intended purpose of the
device, seek a scientific
opinion from the EMEA,
acting particularly
through its committee,
on the quality and safety
of the substance
including the clinical
benefit/risk profile of the
incorporation of the
human blood derivative
into the device. When
issuing its opinion, the
EMEA shall take into
account the
manufacturing process
and the data related to
the usefulness of
substance into the
the notified body.,
Where changes are
made to an ancillary
substance incorporated
in a device, in particular
related to its
manufacturing process,
the notified body shall be
informed of the changes
and shall consult the
relevant medicines
competent authority (i.e.
the only involved in the
initial consultation), in
order to confirm that the
quality and safety of the
ancillary substance are
maintained. The
competent authority shall
take into account the
data related to the
usefulness of
substance into the
the notified body, in
order to ensure that the
changes have no
negative impact on the
page 25 of 68
Does
No)
established benefit/risk
profile of the addition of
the substance in the
medical device.
When the relevant
medicines competent
authority (i.e. the one
involved in the initial
consultation) has
obtained information on
the ancillary substance,
which could have an
impact on the
medical device, it shall
provide the notified body
with advice, whether this
information has an
impact on the
medical device or not.
The notified body shall
take the updated
scientific opinion into
account in reconsidering
its assessment of the
conformity assessment
procedure.
in such a way as to reduce
to a minimum the risks
posed by substances leaking
from the device. Special
attention shall be given to
substances which are
carcinogenic, mutagenic or
toxic to reproduction, in
accordance with Annex I to
Directive 67/548/EEC of 27
June 1967 on the
approximation of laws,
regulations and
administrative provisions
relating to the classification,
packaging and labeling of
dangerous substances.
page 26 of 68
Does
No)
If parts of the device (or
device itself) intended to
administer and/or
remove medicines, body
liquids or other
substances to or from
the body, or devices
intended for transport
and storage of such
body fluids or
substances, contain
phthalates which are
classified as
carcinogenic, mutagenic
or toxic to reproduction,
of category 1 or 2, in
accordance with Annex
1 to Directive
67/548/EEC, these
devices must be labelled
on the device itself
and/or on the packaging
for each unit, or, where
appropriate, on the sale
packaging as a device
containing phthalates.
If the intended use of
such devices includes
treatment of children or
treatment of pregnant or
nursing women, the
manufacturer must
provide a specific
justification for the use of
these substances with
regard to compliance
with the essential
requirements, in
particular of this
paragraph, within the
technical documentation
and within the
instructions of use
information on residual
risks for these patient
groups and, if applicable,
on appropriate
precautionary measures.
7.6 Devices must be designed
and manufactured in such a
way as to reduce, as much
as possible, risks posed by
page 27 of 68
Does
No)
the unintentional ingress of
substances into the device
taking into account the
device and the nature of the
environment in which it is
intended to be used.
8 Infection and microbial contamination
8.1 The devices and
manufacturing processes
must be designed in such
a way as to eliminate or
reduce as far as possible
the risk of infection to the
patient, user, and third
parties. The design must
allow easy handling and,
where necessary,
minimize contamination
of the device by the
patient or vice versa
during use.
8.2 Tissues of animal origin
must originate from
animals that have been
subjected to veterinary
controls and surveillance
adapted to the intended
use of the tissues.
Notified bodies shall
retain information on the
geographical origin of the
animals. Processing,
preservation, testing, and
handling of tissues, cells,
and substances of animal
origin must be carried out
so as to provide optimal
security. In particular,
safety with regard to
viruses and other
transmissible agents
must be addressed by
implementation of
validated methods of
elimination or viral
inactivation in the course
of the manufacturing
process.
8.3 Devices delivered in a
sterile state must be
designed, manufactured,
page 28 of 68
Does
No)
and packed in a non-
reusable pack and/or
according to appropriate
procedures to ensure that
they are sterile when
placed on the market and
remain sterile, under the
storage and transport
conditions laid down, until
the protective packaging
is damaged or opened.
8.4 Devices delivered in a
sterile state must have
been manufactured and
sterilized by an
appropriate, validated
method.
8.5 Devices intended to be
sterilized must be
manufactured in
appropriately controlled
(e.g. environmental)
conditions.
8.6 Packaging systems for
non-sterile devices must
keep product without
deterioration at the level
of cleanliness stipulated
and, if the devices are to
be sterilized prior to use,
minimize the risk of
microbial contamination;
the packaging system
must be suitable, taking
account of the method of
sterilization indicated by
the manufacturer.
8.7 The packaging and/or
label of the device must
distinguish between
identical or similar
products sold in both
sterile and non-sterile
condition.
9 Construction and environmental properties
9.1 If the device is intended for
use in combination with other
devices or equipment, the
whole combination, including
the connection system must
page 29 of 68
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No)
be safe and must not impair
the specified performances
of the devices. Any
restrictions on use must be
indicated on the label or in
the instructions for use.
way as to remove or
minimize as far as is
possible:
the risk of injury, in
connection with their
physical features,
including the
volume/pressure
ratio, dimensional
and, where
appropriate,
ergonomic features;
risks connected with
reasonable
foreseeable
environmental
conditions, such as
magnetic fields,
external electrical
influences,
electrostatic
discharge, pressure,
temperature or
variations in
pressure and
acceleration,
risks of reciprocal
interference with
other devices
normally used in the
investigations or for
the treatment given,
risks arising where
maintenance or
calibration is not
possible (as with
implants), from aging
of materials used or
loss of accuracy of
any measuring or
control mechanism.
page 30 of 68
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No)
way as to minimize the risks
of fire or explosion during
normal use and in single
fault condition. Particular
attention must be paid to
devices whose intended
use includes exposure to
flammable substances or to
substances that could
cause combustion.
10 Devices with a measuring function
10.1 Devices with a measuring
function must be designed
way as to provide sufficient
accuracy and stability within
appropriate limits of
accuracy and taking
account of the intended
purpose of the device. The
limits of accuracy must be
indicated by the
manufacturer.
10.2 The measurement,
monitoring and display
scale must be designed in
line with ergonomic
principles, taking account of
the intended purpose of the
device.
10.3 The measurements made
by devices with a
measuring function must be
expressed in legal units
conforming to the
provisions of Council
11 Protection against radiation
11.1 General
11.1.1 Devices shall be
designed and
manufactured in such a
way that exposure of
patients, users, and
other persons to
radiation shall be
reduced as far as
possible compatible with
the intended purpose,
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while not restricting the
application of
appropriate specified
levels for therapeutic
and diagnostic purposes.
11.2 Intended radiation
11.2.1 Where devices are
designed to emit
hazardous levels of
radiation necessary for a
specific medical purpose
the benefit of which is
considered to outweigh
the risks inherent in the
emission, it must be
possible for the user to
control the emissions.
Such devices shall be
designed and
manufactured to ensure
reproducibility and
tolerance of relevant
variable parameters.
11.2.2 Where devices are
intended to emit
potentially hazardous,
visible and/or invisible
radiation, they must be
fitted, where practicable,
with visual displays
and/or audible warnings
of such emissions
11.3 Unintended radiation
11.3.1 Devices shall be
designed and
way that exposure of
patients, users and other
persons to the emissions
of unintended, stray or
scattered radiation is
reduced as far as
possible.
11.4 Instructions
11.4.1 The operating
instructions for devices
emitting radiation must
give detailed information
as to the nature of the
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emitted radiation, means
of protecting the patient
and the user and on
ways of avoiding misuse
and of eliminating the
risks inherent in
installation.
11.5 Ionizing radiation
11.5.1 Devices intended to emit
ionizing radiation must
be designed and
way as to ensure that,
where practicable, the
quantity, geometry and
quality of radiation
emitted can be varied
and controlled taking into
account the intended
use.
11.5.2 Devices emitting ionizing
radiation intended for
diagnostic radiology
shall be designed and
way as to achieve
appropriate image
and/or output quality for
the intended medical
purpose whilst
minimizing radiation
exposure of the patient
and user.
11.5.3 Devices emitting ionizing
radiation intended for
therapeutic radiology
shall be designed and
way as to enable reliable
monitoring and control of
the delivered dose, the
beam type and energy
and where appropriate
the quality of radiation.
12 Requirements for devices connected to or equipped with an
energy source
12.1 Devices incorporating
electronic programmable
systems must be designed
to ensure the repeatability,
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reliability, and performance
of these systems according
to the intended use. In the
event of a single fault
condition (in the system)
appropriate means should
be adopted to eliminate or
reduce as far as possible
consequent risks.
12.1a. For devices which
incorporate software or
which are medical
software in themselves,
the software must be
validated according to the
state of the art taking into
the account the principles
of development lifecycle,
risk management,
validation and verification.
12.2 Devices where the safety of
the patients depends on an
internal power supply must
be equipped with a means
of determining the state of
the power supply.
12.3 Devices where the safety of
the patients depends on an
external power supply must
include an alarm system to
signal any power failure.
12.4. Devices intended to monitor
one or more clinical
parameters of a patient
must be equipped with
appropriate alarm systems
to alert the user of
situations which could lead
to death or severe
deterioration of the patients
state of health.
12.5. Devices must be designed
way as to minimize the risks
of creating electromagnetic
fields which could impair
the operation of other
devices or equipment in the
usual environment.
12.6. Protection against electrical
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risks:
Devices must be designed
and manufactured in such
a way as to avoid, as far as
possible, the risk of
accidental electric shocks
during normal use and in
single fault condition,
provided the devices are
installed correctly.
12.7. Protection against mechanical and thermal risks
12.7.1. Devices must be
designed and
way as to protect the
patient and user against
mechanical risks
connected with, for
example, resistance,
stability and moving
parts.
designed and
way as to reduce to the
lowest possible level the
risks arising from
vibration generated by
the devices, taking
account of technical
progress and of the
means available for
limiting vibrations,
particularly at source,
unless the vibrations are
part of the specified
performance.
designed and
way as to reduce to the
lowest possible level the
risks arising from the
noise emitted, taking
account of technical
progress and of the
means available to
reduce noise, particularly
at source, unless the
noise emitted is part of
the specified
page 35 of 68
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performance.
12.7.4. Terminals and
connectors to the
electricity, gas or
hydraulic and pneumatic
energy supplies which
the user has to handle
must be designed and
constructed in such a
way as to minimize all
possible risks.
12.7.5. Accessible parts of the
devices (excluding the
parts or areas intended
to supply heat or reach
given temperatures) and
their surroundings must
not attain potentially
dangerous temperatures
under normal use.
12.8. Protection against the risks posed to the patient by energy
supplies or substances
12.8.1. Devices for supplying the
patient with energy or
substances must be
designed and
constructed in such a
way that the flow-rate
can be set and
maintained accurately
enough to guarantee the
safety of the patient and
of the user.
12.8.2. Devices must be fitted
with the means of
preventing and/or
indicating any
inadequacies in the flow-
rate which could pose a
danger. Devices must
incorporate suitable
means to prevent, as far
as possible, the
accidental release of
dangerous levels of
energy from an energy
and/or substance source.
12.9. The function of the
controls and indicators
must be clearly specified
page 36 of 68
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on the devices. Where a
device bears instructions
required for its operation
or indicates operating or
adjustment parameters
by means of a visual
system, such information
must be understandable
to the user and, as
appropriate, to the
patient.
13. Information supplied by the manufacturer
13.1. Each device must be
accompanied by the
information needed to
use it safely and
properly, taking account
of the training and
knowledge of the
potential users, and to
identify the
manufacturer. This
information comprises
the details on the label
and the data in the
instruction for use. As
far as practicable and
appropriate, the
information needed to
use the device safely
must be set out on the
device itself and/or on
the packaging for each
unit or, where
appropriate, on the sales
packaging. If individual
packaging of each unit is
not practicable, the
information must be set
out in the leaflet supplied
with one or more
devices. Instructions for
use must be included in
the packaging for every
device. By way of
exception, no such
instructions for use are
needed for devices in
Class I or IIa if they can
be used completely
safely without any such
instructions.
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13.2. Where appropriate, this
information should take
the form of symbols.
Any symbol or
identification color used
must conform to the
harmonized standards.
In areas for which no
standards exist the
symbols and colors must
be described in the
documentation supplied
with the device.
13.3. The label must bear the following particulars:
(a) the name or trade
name and address of
the manufacturer.
For devices imported
into the Community,
in view of their
distribution in the
Community, the
label, or the outer
packaging, or
instructions for use,
shall contain, in
addition, the name
and address of the
authorized
representative where
the manufacturer
does not have a
registered place of
business in the
Community.
(b) the details strictly
necessary to identify
the device and the
contents of the
packaging especially
for the users;
(c) where appropriate,

the word STERILE;
(d) where appropriate,
the batch code,
preceded by the
word LOT, or the
serial number;
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(e) where appropriate,

an indication of the
date by which the
device should be
used, in safety,
expressed as the
year and month;
(f) where appropriate, an

indication that the
device is for single
use. A
manufacturers
indication of single
use must be
consistent across the
Community
(g) if the device is
custom-made, the
words custom-made
device;
(h) if the device is
intended for clinical
investigations, the
words exclusively for
clinical
investigations;
(i) any special storage

and/or handling
conditions;
(j) any special operating
instructions;
(k) any warnings and/or

precautions to take;
(l) year of manufacture
for active devices
other than those
covered by (e). This
indication may be
included in the batch
or serial number;
(m) where applicable,
method of
sterilization.
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(n) in the case of a
device within the
meaning of Article
1(4a), an indication
that the device
contains a human
blood derivative
13.4. If the intended purpose
of the device is not
obvious to the user, the
manufacturer must
clearly state it on the
label and in the
instructions for use.
13.5. Whenever reasonable
and practicable, the
devices and detachable
components must be
identified, where
appropriate in terms of
batch, to allow all
appropriate action to
detect any potential risk
posed by the devices
and detachable
components.
13.6. Where appropriate, the
instructions for use must
contain the following
particulars:
(a) the details referred to
in section 13.3, with
the exception of (d)
and (e);
(b) the performances
referred to in Section
3 and any
undesirable side-
effects;
(c) if the device must be
installed with or
connected to other
medical devices or
equipment in order
to operate as
required for its
intended purpose,
sufficient details of
its characteristics to
identify the correct
page 40 of 68
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No)
devices or
equipment to use in
order to obtain a
safe combination;
(d) all the information
needed to verify
whether the device is
properly installed
and can operate
correctly and safely,
plus details of the
nature and
frequency of the
maintenance and
calibration needed to
ensure that the
devices operate
properly and safely
at all times;
(e) where appropriate,
information to avoid
certain risks in
connection with
implantation of the
device;
(f) information regarding
the risks of reciprocal
interference posed
by the presence of
the device during
specific
investigations or
treatment;
(g) the necessary

instructions in the
event of damage to
the sterile packaging
and, where
appropriate, details
of appropriate
methods of re-
sterilization;
(h) if the device is

reusable, information
on the appropriate
processes to allow
reuse, including
cleaning,
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disinfection,
packaging and,
where appropriate,
the method of
sterilization of the
device to be re-
sterilized, and any
restriction on the
number of reuses.
Where devices are
supplied with the
intention that they be
sterilized before use,
the instructions for
cleaning and
sterilization must be
such that, if correctly
followed, the device
will still comply with
the requirements in
Section I.
If the device bears
an indication that the
device is for single
use, information on
known
characteristics and
technical factors
known to the
manufacturer that
could pose a risk if
the device would be
re-used. If in
accordance with
Section 13.1 no
instructions for use
are needed, the
information must be
made available to
the user upon
request;
(i) details of any further
treatment or
handling needed
before the device
can be used (for
example,
sterilization, final
assembly, etc.):
(j) in the cases of
devices emitting
radiation for medical
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purposes, details of
the nature, type,
intensity and
distribution of this
radiation.
The instructions for use
must also include details
allowing the medical staff
to brief the patient on
any contraindications
and any precautions to
be taken. These details
should cover in
particular:
(k) precautions to be
taken in the event of
changes in the
performance of the
device;
(l) precautions to be
taken as regards
exposure, in
reasonably
foreseeable
environmental
conditions, to
magnetic fields,
external electrical
influences,
electrostatic
discharge, pressure
or variations in
pressure or
acceleration, thermal
ignition sources, etc.;
(m) adequate
information regarding
the medicinal
product or products
which the device in
question is designed
to administer,
including any
limitations in the
choice of substances
to be delivered;
(n) precautions to be
taken against any
special, unusual
risks related to the
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disposal of the
device;
(o) medicinal
substances, or
human blood
derivatives
incorporated into the
device as an integral
part in accordance
with section 7.4;
(p) degree of accuracy
claimed for devices
with a measuring
function
(q) date of issue or the
latest revision of the
page 44 of 68
APPENDIX 2:
Guidance Notes on Medical Devices Incorporating a Medicinal

Substance or Human Blood Derivative Having Ancillary Action
Additional information may be required with regard to the medicinal substance and/or the
human blood derivative:
Information if it is an authorized medicinal substance, or not. If yes, its authorized on

the EU market? Since how long? The approved indication(s) must be mentioned and
the EU SPC must be included; reference to applicable pharmaceutical legislation
(EU, nationally).

Clinical documentation (clinical data demonstrating the usefulness of the medicinal

substance).
Additional information required with regard to the medicinal substance only:
- medicinal substance specifications e.g., summary of the European Drug Master

File, reference to European Pharmacopoeia or national monograph of a
European Member State.
- Manufacturers may wish to cross-reference a granted Clinical Trial Authorisation
(CTA)

Pharmacokinetic characteristics (local/systemic exposure patterns, duration and

individual variability, area under the curve (AUC), in the context of the device).
Notably, for new active substances the release of the substance from the device, its
subsequent distribution and elimination should be addressed.

conventional application) e.g., the results of EN/ISO 10993 testing, or a review of
NOTE: Reference is made to MEDDEV 2.1.3, Section C 3, which describes the

documentation to be provided by the Notified Body to the Medicinal Product Competent
page 45 of 68
Authority for medicinal products as part of the consultation procedure, which may be helpful
here also.
Additional information required with regard to the human blood derivative only:
- Control of plasma source e.g. summary of the European Plasma Master File
- Production of the blood derivative
page 46 of 68
For Appendices 3-5 reference is made to the harmonized standards applicable for each
section in light of the presumption of conformity given by those standards with the
Essential requirements, the intent of the appendices being to emphasize key
considerations of the standards
APPENDIX 3: Guidance on medical devices which require sterilization
Additional information may be required for sterile devices, which are either provided sterile or
sterilized at the point of use:
Documentation to demonstrate that the method of sterilization renders the device sterile.
If provided sterile, this should include where appropriate:

the method of sterilization
details of the sterilization facility, name, location, process
proof of validation to demonstrate that the sterilization process can be delivered
effectively and reproducibly to the specified devices in the sterilization load, e.g.
results, certificates and justification for the choice of sterilization process
details of the records for product release (indicator testing, dosimetric release,
parametric release), this should include the results and outcomes
data relating to bio burden, e.g. nature, frequency and outcome
details of any environmental precautions undertaken on the device during
manufacture or sterilization. Information to include; nature, frequency of monitoring
and outcome
details of any standards applied to any of the sterilization processes.
If devices are to be sterilized at the point of use, this should include where appropriate:
a copy of the instructions for decontamination (i.e. cleaning, disinfection and/or
sterilization) including details of any special precautions for handling
appropriate validation data to demonstrate that the processes can be delivered
effectively and reproducibly to the specified devices must be provided.
Important points to note

documentation should be provided for each investigational device which requires
sterilization. This includes any instruments or accessories.
where devices are sterilized at the point of use, and specifically moist heat (steam) is
chosen as the method of sterilization, particular attention should be taken with
regards to the standard sterilization parameters applicable within the country where
the devices are to be processed and sterilized. The appropriate sterilization
qualification and validation reports should take account of these standard
requirements and of relevant harmonized standards.
page 47 of 68
APPENDIX 4: Guidance on clinical investigations of active devices (excluding
Software, see Appendix 5)
Additional information to support claims of compliance with the essential requirements of the
Council Directive, e.g. 93/42/EEC or 90/385/EEC.
General
1. Essential requirements checklist detailing how these requirements have been
addressed, including references to harmonised standards as appropriate.
Note: The application of harmonised standards is voluntary and applicants may choose
alternative methods of demonstrating compliance with the essential requirements. For
example, compliance with international, national or in-house standards. This should be
supported by a risk benefit analysis, preferably to EN ISO 14971.
2. Documentary evidence supporting compliance with any of the standards referenced.

This may include certification by an independent body, or test house. Alternatively,
self-certification is acceptable, providing this is supported with evidence of design
input and subsequent in-house verification.
3. For those applicants choosing self-certification against EN 60601-1 (which includes

protection against electric shock hazards, mechanical hazards, fault conditions,
constructional requirements etc.) a checklist for that standard, or equivalent, should
be provided. This should be completed and signed by a competent engineer. Where
clauses are considered not applicable, a justification should be given. Where
measurements of leakage currents are made, the values should be recorded.
4. When the medical device is to be used with other devices as part of a system, e.g.
connection to laptop computers, etc. an additional EN 60601-1-1 checklist or
equivalent covering the whole system under investigation should also be provided.
Specialist technologies including: infra-red, laser, microwave, MRI, RF ultrasound,

ultraviolet, X-ray etc.
5. Details of how this technology has been incorporated in the design and what steps
have been taken to assure the safe application in the device. Information pertaining to
output power, justification of safety limits used and reference to appropriate standards
should be included, e.g. the relevant part 2 of the EN 60601 series.
Active Implants
6. A summary of the Failure Mode, Effects [and Criticality] Analysis (FMEA/FMECA).
7. The results of animal studies.
8. Performance statistics and adverse incident data of earlier model, when device is the
next generation of an earlier design.
page 48 of 68
APPENDIX 5: Software and programmable devices
Where the device includes a software component or is software the following should be
addressed in the notification:
Describe any standards used in the development of the software (e.g. IEC 62304, IEC 80002,
IEC 80001-1).
Describe the role of the software including whether:

the normal operation, initial setting up, maintenance, calibration, adjustment, or
monitoring of the medical device, depend on software;
the correct operation of the medical device depends on the execution of the software
within a limited time i.e. real time software is used;
any part of the medical devices software can be run independently on hardware not
directly connected to the medical device.
Describe the relationship of software to safety including:

whether essential performance depends on software (essential performance is the
performance whose absence would pose a threat of harm to the patient);
which risk control measures depend on software;
what opportunities there are for informed intervention by clinical staff or the patient to
prevent harm in the event of a software failure.
Describe the risk management of software including:

a risk management process that includes software items;
identification of causative sequences of events that includes software defects;
whether hardware risk control measures are used to prevent the consequences of
software defects;
whether the software development process is used as a risk control measure;
whether software verification or software validation is used as a risk control measure
(verification = did we do the right thing right, validation = did we do the right thing?).
Describe the software development processes including:

whether the system and software architecture is documented in such a manner that it
is possible to reason about the contribution of each component and software item to
safety;
whether software units (the lowest level of software decomposition) were tested
before being integrated into larger software items.
Describe the purpose of the clinical investigation with regard to:

whether the clinical investigation is intended to evaluate the performance and/or
safety of the software or to evaluate the fitness for clinical purpose of any part of the
software and, if so, how this will be done;
detail of any specific protocols designed to evaluate the operation of the software in
the clinical context.
Describe the human interface including:
the user interfaces (mechanisms intended to allow humans to interact with the
software) that the software has (including user interfaces for the patient, clinical
technician, physician, service engineer, etc.);
the target population for each type of user interface (for example, age, expertise,
language etc.) and whether this is documented;
the tests that have been done prior to the clinical investigation to evaluate the
effectiveness of the user interfaces for each target population, or how this will be
evaluated in the study;
the measures used to ensure that only appropriate people are allowed to operate
each different type of user interface.
page 49 of 68
Describe how the software is protected including:
protection from accidental or unauthorised change;
identification of roles which have the authority to make software changes during the
clinical trial;
the rationale and/or measures that are in place to ensure that software changes do
not adversely affect the clinical investigation.
page 50 of 68
APPENDIX 6: Devices utilizing animal tissue which is rendered non-viable or non-
viable products derived from animal tissue:
Regulation No. 722/2012/EC lays down particular requirements in relation to the placing on
the market and/or putting into service of medical devices, including active implantable medical
devices, manufactured utilizing animal tissue which is rendered non-viable or non-viable
products derived from animal tissue. This Regulation applies to animal tissues, as well as
their derivatives, originating from bovine, ovine and caprine species, deer, elk, mink and cats.
It does not apply to certain tallow derivatives, processed under conditions at least as vigorous
as those laid down in Section 3 of Annex I of that Regulation nor to medical devices, which
are not intended to come into contact with the human body or which are intended to come into
contact with intact skin only.
For devices intended for clinical investigation which fall under that Regulation, the statement
of the manufacturer or of his authorized representative and the documentation in accordance
with Annex 6 to Directive 90/385/EEC or Annex VIII to Directive 93/42/EEC, respectively,
shall also address compliance with the particular requirements set out in section 1 of Annex I
to that Regulation.
Harmonized standard series EN ISO 22442 on medical devices utilizing animal tissues and
their derivatives will be additionally useful in providing important information to support or
assess applications for clinical investigations of that kind of devices.
page 51 of 68
APPENDIX 7:
Clinical Investigation Application form to National Competent
Authority for Medical Devices
Member State concerned:
.
A. Clinical Investigation (CI):
A.1.First notification to an authority within the EEA: yes no

A.1.1.EUDAMED CIV ID, when available:
A.2.Full title of the trial (local language/English):
A2.1.local language:
A2.2.english:
A.2.3. Short title:
A.2.4. Protocol number: A.2.4.1.version: A.2.4.2.date:
A.2.5. Is this a resubmission? yes no
A.2.5.1. If Yes, indicate NCAs reference(s):
A.2.6. Objective of the investigation:
A.2.7. Inclusion criteria:
17
A.2.8. Exclusion criteria:
A.2.9. Study-specific measures (procedures, medications, diagnostics):
A.2.10. Type of clinical investigation (CI):
A.2.10.1. First-in-Man (FIM)
Pilot/proof-of-concept CI
Confirmatory (pivotal) CI
A.2.10.2. CI with medical device and medicinal product (combined study)
A.2.10.2.1 If yes EudraCT number:
A.2.11. Mononational CI or multinational CI
A.2.11.1 Other Member States concerned
A.2.12. Planned number of subjects to be enrolled:
In the Member State: In the EEA: Outside the EEA:
A.2.13. Planned number of sites:
In the Member State: In the EEA: Outside the EEA:
A.2.14. Planned start date DD/MM/YYYY: Planned end date DD/MM/YYYY:
B. Contact Information
B.1. Sponsor:
B.1.1. Name of organisation:
B.1.2. Name of the person to contact:
B.1.3. Address:
B.1.3.1. ZIP code/place:
B.1.3.2. country:
17
A.2.7. and A.2.8. optional
page 52 of 68
B.1.4.Telephone number:
B.1.5. Fax number:
B.1.6. e-mail:
B.1.7. Status of the sponsor: commercial Non-Commercial
B.2. Legal Representative of the sponsor in the Community for this trial (if different from the
sponsor)
B.2.3. Address:
B.2.3.2. country:
B.2.4. Telephone number:
B.2.5. Fax number:
B.2.6. e-mail:
B.3. Billing Address (if not identical with the Sponsor)

B.3.3. Address:
B.3.3.2. country:
B.3.4. Telephone number:
B.3.5. Fax number:
B.3.6. e-mail:
C. Description of the Investigational Medical Device

C.1. Name:
C.2. Description and Type (local language/English)
C.2.1. local language:
C.2.2.english:
C.3. GMDN Code:
C.4. Information on the use of the device
C.4.1.Intended use(s) of the medical device in the CI:
C.4.2. Indication as defined by the manufacturer:
C.4.3. Contraindication(s) as defined by the manufacturer:
C.4.4. Patient population as defined by the manufacturer:
C.4.5. Medical device bears a CE mark
C.4.5.1. and will be used in accordance with the intended use as given by the
manufacturer1819
18
see NOTE in chapter 2 concerning PMCF-studies conducted with investigational CE-
marked medical devices acc. to Directive 93/42/EEC, which are covered by MEDDEV 2.12/2
19
MS may request data on countries where device is placed on the market and since when
page 53 of 68
C.4.5.2. and will not be used in accordance with the intended use as given by the
manufacturer
C.4.5.3. the medical device and/or its intended use has been modified in relation
to the CE mark
C.5. Manufacturer of the medical device:

C.5.1. Name of organisation:
C.5.2. Address:
C.5.2.1. ZIP code/place:
C.5.2.2. country:
Ca/b. Description of comparator devices, placebo or other comparator/control, if any

Ca.0. Description of comparator device, if applicable
Ca.1. Name of comparator device:
Ca.2. Description and Type (local language/English)
Ca.2.1. local language:
Ca.2.2.english:
Ca.3. GMDN Code:
Ca.4. Information on the use of the device
Ca.4.1.Intended use(s) of the medical device in the CI:
Ca.4.2. Indication(s) as defined by the manufacturer:
Ca.4.3. Contraindication(s) as defined by the manufacturer:
Ca.4.4. Patient population as defined by the manufacturer:
Ca.4.5. Medical device bears a CE mark
Ca.4.5.1. and will be used in accordance with the intended use as given by the
manufacturer
Ca.4.5.2. and will not be used in accordance with the intended use as given by the
manufacturer
Ca.4.5.3. the medical device and/or its intended use has been modified in relation
to the CE mark
Ca.5. Manufacturer of the medical device:

Ca.5.1. Name of organisation:
Ca.5.2. Address:
Ca.5.2.1. ZIP code/place:
Ca.5.2.2. country:
Cb.0. Description of other comparator/control than a device, including placebo, if any
Cb.1. Name of (non-device) comparator:
Cb.2. Description and Type (local language/English)
Cb.2.1. Local language:
page 54 of 68
Cb.2.2. English:
Cb.3. Information on the use of the non-device comparator:
Cb.3.1. Intended use(s) of the non-device comparator in the CI:

Cb.3.2. Indication(s) as defined by the manufacturer of the comparator:
Cb.3.3. Contraindication(s) as defined by the manufacturer:
Cb.3.4. Patient population as defined by the manufacturer:

Cb.4. Manufacturer of the non- device comparator:
Cb.4.1. Name of organisation:
Cb.4.2. Address:
Cb.4.2.1. Street Address:
Cb.4.2.2. Postcode:
Cb.4.2.3. Town/City:
Cb.4.2.4. Country:
Cb.4.3.. Telephone number:
Cb.4.4. E-mail:
Repeat if necessary, add more button should be available
D. Classification of the Medical Device
D.1. Active implantable medical device (AIMD) (device according to Directive 90/385/EEC)
D.2. Medical device by risk class (device according to Directive 93/42/EEC)
D.2.1 Class I according to rule (Annex IX, Dir/93/42/EC)
D.2.2. Class IIa according to rule (Annex IX, Dir/93/42/EC)
D.2.2.1. invasive, intended for long-term use
D.2.3. Class IIb according to rule (Annex IX, Dir/93/42/EC)
D.2.3.1. invasive, intended for long-term use
D.2.4. Class III according to rule (Annex IX, Dir/93/42/EC)
D.3. Medical device is an implant
D.3.1. if yes, which type:
D.3.2. is the implant intended to remain permanently in the patient yes no
D.4. Medical device is manufactured using tissue of animal origin (COM RegNo. 722/2012/EC)
D.4.1. if yes, which:
D.5. Medical device contains human blood or blood plasma component(s) (Dir/2000/70/EC or
Dir/2001/104/EC)
D.6. Medical device contains/incorporates, as an integral part, a substance which, if used
separately, can be considered to be a medicinal product, as defined in Article 1 of
Dir/2001/83/EC
page 55 of 68
D.7. Medical device is used in combination with accessories
D.8. Medical device contains medicinal product components with supportive function
D.9. Specific additional software application is required for the medical device
E. List of Investigational Sites
E.1.1. Investigator Coordinator:

E.1.2. Principal investigator:
E.1.3. Investigator:
E.2.1. Organisation:
E.2.2. Address:
E.2.3. Telephone number:
E.2.4. e-mail:
Repeat if necessary add more button should be available; a new site would get E.2.sequence fields
page 56 of 68
F. Ethics Committee
F.1. Concerned ethics committee:
F.1.1. Responsible for Investigational site(s):
F.2. Favourable Opinion yes no pending
F.2.1. If no: Submission date:
Repeat if necessary add more button should be available; a new ethics committee would get
F.2.sequence fields
G. The following documentation is contained in the dossier:

G.1. Clinical Investigation Plan/Protocol
G.2. Investigators Brochure
G.3. Manufacturers instructions (in appropriate local language) for CE marked medical
devices
G.4. Declaration of Compliance with Essential Requirements20 or Declaration of Conformity
by the manufacturer21, as applicable
G.5. Certificate of the Notified Body/Bodies
G.6. Documentation on construction/manufacture (manufacturing process, sterilization etc.)
G.7. Results of studies or technical tests (i.e. Biocompatibility22, electrical safety23, etc.)
G.8. List of harmonized standards applied in full or in part/List of ER
G.9. Documentation on the safety of animal 24 or human25 derived components, if applicable
G.10. Risk assessment
G.11. Agreements between Sponsor, Monitor and clinical investigator outlining their
respective responsibilities
G.12. Documentation on Investigator Qualification
G.13. Informed Consent Form (in local language)
G.14. Insurance certificate
G.15. CRF, Case Report Form
G.16. Opinion of the ethics committee(s) concerned
G.17. further documentation: G.17.1. List documentation:
20 See Annex 6.2.2 of Directive 90/385/EEC resp. Annex VIII.2.2 of Directive 93/42/EEC
21 For CE-marked investigational devices
22
See EN ISO 10993
23
See standard series EN 60601
24
See COM Reg (EU) Nr. 722/2012
25
See Dir/2000/70/EC, Dir/2001/104/EC
page 57 of 68
H. Declaration and Signature
H.1. I hereby confirm that /confirm on behalf of the sponsor (delete which is not applicable) that:
the information provided is complete
the attached documents contain an accurate account of the information available
the clinical investigation will be conducted in accordance with the protocol
serious adverse events and result-related information will be reported, in accordance
with the applicable legislation
I confirm that the medical device(s) conform(s) to the essential requirements of all
applicable directives and regulations except for those which are the scope of this CI
I confirm that appropriate safety measures have been taken for study participants/users
I accept the applicable fee(s)
H.2.1. Signature of the sponsor/legal representative:

H.2.2. Print name:
H.2.3. Date:
page 58 of 68
APPENDIX 8: Clinical Investigation Validation Checklist:
Checklist Validation (Verification of Submission requirements)

Comment: Validation check for presence of document only, unless stated differently)
Application document in electronic form (xml or pdf-file; fields include EUDAMED
required information)(check for provision of required fields)
Clinical Investigation Plan
Investigators Brochure
Patient Information and Informed Consent Form
Case Report Forms (CRFs)
Proof of qualification of the clinical investigator(s)
Information on the device:
o For CE-marked medical devices:
instructions for use
Certificate(s) of notified bodies
Declaration of conformity of the manufacturer
o For non CE-marked devices: Written confirmation that the medical device
complies with the essential requirements of the applicable Directive in all
aspects except those that will be assessed in the clinical investigation
construction and manufacture of the device, especially sterilisation
Results of construction calculations, assessments, technical tests,
preclinical and clinical studies etc.
Results of the risk analysis
Rationale for Qualification (both Directives) and Classification (Directive 93/42/EEC
only)
List of standards applied in full or in part/List of applicable ER and how addressed
Billing address (Company, contact, Street, ZIP code/place, country, Phone, Fax,
Email)
26 27
Documentation on the safety of animal or human derived components, if applicable
Documentation on medicinal substances having ancillary action
Optional (depending on country specific requirements)

Opinion of the competent ethics committee(s)
Confirmation of insurance coverage for the subjects enrolled in the clinical
investigation
Written agreements or draft agreements between the sponsor, monitor, and clinical
investigator establishing each partys responsibilities
Declaration and signature
26
See COM Reg (EU) 722/2012
27
See RL 2000/70/EG bzw. RL 2001/104/EG
page 59 of 68
APPENDIX 9: Clinical investigation assessment checklist
(CIP, IB, Ethical aspects)
Investigational device :
Manufacturer/Sponsor:
Title of clinical investigation :
Date:
Version:
CIV/ID:
Clinical Investigation Plan (CIP)
Requirement Fulfilled? Comment

General
Identification of CIP
Title and ref.nr of CI; version/issue complete/sufficient
nr/date of CIP; summary revision
Incomplete/insufficient
history;
Identification of sponsor, MF, AR,
principal or other investigators; sufficient/adequate
investigation sites
insufficient/inadequate
provided elsewhere (eg IB)
The justification for the need of the

proposed CI adequate/sufficient
inadequate/insufficient
Overall Synopsis of the clinical

investigation sufficient/adequate
Identification and description of the IMD

Identification and description of the
investigational device(s) sufficient/adequate
provided elsewhere (eg IB)
Benefit/risk considerations for CI and IMD

Anticipated clinical benefits
adequate/sufficient
Anticipated ADE, SAE, SADE, DD,

including those considered critical adequate/sufficient
Results of risk analysis

adequate/sufficient
Steps to control or mitigate risks.

adequate/sufficient
Risk management according to EN

ISO 14791? Yes
No
page 60 of 68
partly
equivalent solutions provided
Justification of the Design of the Clinical Investigation

Rationale in relation to preclinical
and clinical evaluation: sufficient/adequate
based on evaluation of preclinical data
to justify use on human subjects and
on results of clinical evaluation to
determine and justify optimal design of
CI and help identify relevant endpoints
and confounders
General design aspects:
Specification if the CI has been sufficient/adequate
planned as exploratory, confirmatory
study or a combined one; planned for
CE-marking?; phase of device
development; Type of CI with
rationale; measures to avoid bias
Investigational device and
comparators: sufficient/adequate
Exposure to IMD and comparator, if
any; justification for choice of
comparator(s); other concomitant
treatments;
Subjects:
Inclusion-exclusion criteria; adequate/sufficient
representative to target population?
Criteria and procedures for subject
withdrawal or discontinuation;
expected duration of CI and for
subjects; number of subjects
Statistical considerations
Design, method and analytical
procedures adequate/sufficient
non adequate/insufficient
Sample size, level of significance and

power of the CI adequate/sufficient
non adequate/insufficient
Particular justification for descriptive

statistical analysis and small sample adequate/sufficient
size (e.g. for exploratory, FIM study)
Provisions for subgroup analysis or

interim reports, if any adequate/sufficient
NA
Procedures for missing data, drop-

outs and lost to follow-ups adequate/sufficient
Objectives, endpoints and hypothesis

Description of primary and secondary
objectives and endpoints of CI, that adequate/sufficient
must be consistent with the rationale
of the CI and appropriate to the
device; rationale for selection and
measurement of endpoints; methods
page 61 of 68
and timing for assessing, recording
and analysing variables; equipment
used for assessing
Description of the hypothesis of the CI,
that must be consistent with the adequate/sufficient
selected objectives and with the
statistical plan
Identification of the variables to be
evaluated and/or measured during the adequate/sufficient
CI, in order to accept or reject the
hypothesis of the CI
Design of CI
Description and justification of the
type and of the design of the CI adequate/sufficient
Choice of controls, if any (e.g.,

comparator, cohort, sham, historical) adequate/sufficient
NA
Description and identification of the

comparator, if used, and justification of adequate/sufficient
its choice
NA
Identification of any medical device,

medical treatment or medication to be adequate/sufficient
used during the CI
NA
Number of investigational medical

devices and comparators (if adequate/sufficient
applicable) to be used
Expected duration of CI
adequate/sufficient
Expected duration of CI for each

subject adequate/sufficient
Procedures and follow-up

Description of the medical/surgical
procedures involved in the use of the adequate/sufficient
investigational device and
identification of the innovative aspects
of these procedures;
known or foreseeable factors to
compromise outcome or interpretation
of results
Description of all the medical
procedures that subjects undergo adequate/sufficient
during the CI
Proposed follow up:

- long enough to demonstrate the adequate/sufficient
page 62 of 68
safety and performance of the
investigational device and of the inadequate/insufficient
procedures
- consistent with the objectives of the
CI
Description of procedures for follow up
of subjects who have withdrawn their adequate/sufficient
consent and for subjects lost to follow
up
Training of investigators
Description of the training and
experience of the investigator/s adequate/sufficient
regarding the use of the investigational
device
Mitigation of the risks due to the
learning curve. adequate/sufficient
For FIM with high risk class,
innovative, invasive device:
- procedure supervision of each
investigator by an experienced
person during the first use(s).
- sufficient interval between the
treatment/exposure of each of
study subjects to be able to
evaluate need for improvement.
Monitoring plan
General description of the monitoring
plan sufficient /adequate
non adequate /insufficient
incomplete/absent
Data management
Description of procedures for data
management adequate/sufficient
A DSMB is presented, or its

Yes
absence justified?
No
Deviation from or Amendments to the CIP

Description of the procedures to
manage, report and prevent the adequate/sufficient
deviation from CI
Statement that deviating without

request from CIP is not allowed, adequate/sufficient
except in justified emergency
circumstances
Description of the procedures to

amend the CIP adequate/sufficient
Device Accountability
Procedures for device accountability
adequate/sufficient
Description of the procedures for the

adequate/sufficient
page 63 of 68
traceability of the device during the
CI (including before the use, example, inadequate/insufficient
storage and distribution circuit in the
Centre) and after the CI;
Statements of Compliance
Ethical principles of DoH; conformity
with relevant legislation; with relevant adequate/sufficient
standards or equivalent; waiting for
approval/favourable opinion and
observing conditions acc. to nat.
provisions; liability and insurance acc.
to nat. provisions
AE, SAE, ADE, SADE, DD
Definition of terms (e.g. adverse
events, adverse effects, SAE, SADE, adequate/sufficient
adverse events related to
investigational procedures, device
deficiencies)
List of foreseeable adverse events and
anticipated device effects weighed on adequate/sufficient
their likely incidence, mitigation or
treatment
Identification of anticipated adverse

events related to IMDs adequate/sufficient
Identification of anticipated adverse

events related to investigational adequate/sufficient
procedures.
Procedures for recording and

analysing AE, ADE and DD adequate/sufficient
Procedures and time frames for

reporting SAE, SADE, DD and adequate/sufficient
updates
Informed consent process

Description of general process for
obtaining the informed consent, adequate/sufficient
specifying procedures for subjects
unable to give it and for cases of
emergency treatment. considered under Ethical
Aspects
Vulnerable population
Description of vulnerable population to
be included in CI, justification for adequate/sufficient
including, and description of particular
procedures and medical care planned
for them considered under Ethical
Aspects
Suspension premature termination of the CI

Description of the procedure to
suspend terminate prematurely the adequate/sufficient
CI
Description of procedures for follow up

of subjects following completion, adequate/sufficient
suspension or early termination of the
page 64 of 68
clinical investigation .
Publication policy and transparency

Description of publication policy, that
shall be in line with the provisions of adequate/sufficient
Declaration of Helsinki
Statement of compliance to DoH with

regard to registration requirements in adequate/sufficient
a public CI registry or database before
commencing the CI
Conclusions:
Investigators Brochure (IB)
Requirement Fulfilled? Comment

General requirements
Identification of the IB
adequate/sufficient
Identification of Sponsor/MF/AR
adequate/sufficient
provided elsewhere (eg in CIP)

Investigational device information
Scientific rationale for design and
intended use adequate/sufficient
provided elsewhere (eg in CIP)

Risk classification of IMD and
adequate/sufficient
application rule(s)
Description of the device (included
components, software, materials, adequate/sufficient
substances used and accessories)
together with its intended use in the
study population
Description of the intended clinical
performance, mechanism of action, adequate/sufficient
technical and functional features of the
investigational device,
Description of the manufacturing,
related validation processes, adequate/sufficient
maintenance, storage and handling of
the device
Description and rationale of the choice
of materials and substances coming adequate/sufficient
into contact with the body and body
fluids, together with the evaluation of
the benefit/risk ratio related to their
use.
Description of the innovative aspects
of the investigational device and adequate/sufficient
reference to previous and similar
generations of the device.
page 65 of 68
Description of method of cleaning,
28
disinfection and sterilization and adequate/sufficient
validation
Instructions of use and labels of
investigational device
29 adequate/sufficient
Identification and description of any
medicinal substance incorporated into adequate/sufficient
the investigational device, together
with the justification of their use and
the evaluation of the risk/benefit ratio N.A.
30
related to their use.
tissues of animal origin incorporated adequate/sufficient
within the device, together with the
justification of their use, risk mitigation
and the evaluation of the risk/benefit N.A.
31
ratio related to their use.
human blood derivatives incorporated adequate/sufficient
into the investigational device,
together with the justification of their
use and the evaluation of the N.A
risk/benefit ratio related
32
to their use.
Preclinical testing
Preclinical evaluation based on
relevant in vivo, in vitro, ex vivo, bench adequate/sufficient
and performance testing and
experimental data
Biocompatibility evaluation following
EN ISO 10993 series? yes, in full or in part with
equivalent solutions
adequate/sufficient
Software validation
adequate/sufficient
Existing clinical data
Evaluation of existing clinical data for
IMD or similar devices, incl. for other adequate/sufficient
indications;
Analysis of ADE, history of
modification or recall adequate/sufficient
Risk Management
Synthesis of risk/benefit analysis and
the risk management: description of adequate/sufficient
actions taken to minimize or eliminate
the identified risks; identification of
residual risks
Anticipated risks, contraindications,
warnings etc. for IMD adequate/sufficient
28
See Appendix 3 Guidance on medical devices which require sterilization
29
This information could be provided as a separate document
30
See Appendix 2 Guidance notes on medical devices incorporating a medicinal substance or human blood
derivative having ancillary action
31
See Appendix 6 Guidance on Medical Devices incorporating tissues of animal origin
32
See Appendix 2 Guidance notes on medical devices incorporating a medical substance or human blood derivate
having ancillary action
page 66 of 68
Regulatory, normative and other references
List of applicable essential
requirements of the directives and of adequate/sufficient
relevant Harmonized Standards
applied in full or in part and description
of other solutions adopted to meet the Info provided elsewhere
essential requirements (App. 1a and 1b)
Statement of conformity with
national/regional regulations, where adequate/sufficient
appropriate; list of references
Conclusions:
Ethical Aspects33
Requirement Fulfilled Comment

Copy of the competent Ethics
committee opinion available
pending
favorable/positive
not favorable/negative
Justification for CI and its design

adequate/sufficient
Process and documents for informed

consent adequate/sufficient
Provisions for liability and insurance for

subjects and investigator(s) adequate/sufficient
Vulnerable population and individuals:

possible inclusion with justification and adequate/sufficient
specific protection
Benefit/Risk estimation feasible and

risk management acceptable against adequate/sufficient
state of the art in medicine
Suitability of Clinical Investigators

(Principal, Coordinating or others) adequate/sufficient
Suitability of Clinical Investigation

Site(s) adequate/sufficient
Statement on prior registration of

clinical investigation in public CI adequate/sufficient
registry (like WHO ICTRP or clinical
33
usually depends largely on national provisions
page 67 of 68
trials.gov)
(=p. 35 of DoH) inadequate/insufficient
Statement on publication policy (p. 36

of DoH) adequate/sufficient
Conclusions:
Abbr.:
AE Adverse Event
ADE Adverse Device Effect
AR Authorized Representative
CA Competent Authority
CI Clinical Investigation
CIP Clinical Investigation Plan
DD Device Deficiency
DoH Declaration of Helsinki
DSMB Data Safety Monitoring Board
FIM First-In-Man study
IB Investigator Brochure
ICTRP International Clinical Trial Registry Platform
IMD Investigational Medical Device
MF Manufacturer
SADE Serious Adverse Device Effect
SAE Serious Adverse Event
WHO World Health Organization
page 68 of 68
EUROPEAN COMMISSION
DIRECTORATE GENERAL for HEALTH and CONSUMERS
Consumer Affairs
MEDDEV 2.7/3
December 2010
CLINICAL INVESTIGATIONS:
SERIOUS ADVERSE EVENT REPORTING
UNDER DIRECTIVES 90/385/EEC AND 93/42/EEC.
The present guidelines are part of a set of guidelines relating to questions of application of EU-Directives on
MEDICAL DEVICEs. They are legally not binding. The guidelines have been carefully drafted through a
process of intensive consultation of the various interested parties (competent authorities, Commission
services, industries, other interested parties) during which intermediate drafts were circulated and comments
were taken up in the document. Therefore, this document reflects positions taken by representatives of
interested parties in the medical devices sector.
These guidelines incorporate changes introduced by Directive 2007/47/EC amending Council Directive
90/385/EEC and Council Directive 93/42/EEC.
1. OBJECTIVE
This guidance defines Serious Adverse Event (SAE) reporting modalities and includes a
summary tabulation reporting format1. Its objective is to contribute to the notification of
SAEs to all concerned National Competent Authorities (NCAs2) in the context of clinical
investigations in line with the requirements of Annex 7 of Directive 90/385/EEC and
Annex X of Directive 93/42/EEC, as amended by Directive 2007/47/EC.
According to annex 7 of Directive 90/385/EEC and to annex X of Directive 93/42/EEC:

All serious adverse events must be fully recorded and immediately notified to all
competent authorities of the Member States in which the clinical investigation is
being performed."
2. SCOPE
The reporting modalities and format set out in this guidance apply to pre-market3 clinical
investigations4-5 conducted with:
a. Non-CE marked devices,
b. CE marked devices used outside the intended use(s) covered by the CE
marking.
The tabular format featured in the Appendix needs to be updated for each reportable
event or for new findings/updates to already reported events. It shall be transmitted to all
NCAs where the clinical investigation is being performed.
3. DEFINITIONS (from ISO/FDIS 14155)
Adverse Device Effect (ADE)

Adverse event related to the use of an investigational medical device.
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies
in the instructions for use, the deployment, the implantation, the installation, the
operation, or any malfunction of the investigational medical device.
NOTE 2- This includes any event that is a result of a use error or intentional misuse.
Adverse Event (AE)
1 A template for individual reporting of SAEs is under preparation to harmonize individual SAE forms in case NCAs require
individual reporting for the SAEs occurring within their jurisdictions. Further revisions of these template documents may
become necessary in line with the forthcoming corresponding GHTF-Guidance.
2
For the purpose of this guidance," NCAs" encompass the National Competent Authorities of the EU, the EEA and of
Switzerland and Turkey.
3
A specific guidance on Post Market Clinical Follow-Up Studies is in preparation.
4
- This includes pre-market clinical investigations:
which started prior to 21 March 2010 and are continued after that date. [Note: reporting of SAE as covered in this guidance
only started on 21 March 2010 with the implementation of Directive 2007/47/EC and is not retrospective.to SAEs that
occurred prior to 21 March 2010].
- For pre-market clinical investigations involving CE marked comparator devices, SAEs occurring in or to subjects that are in
the comparator arm of an investigation shall also be reported in accordance with these guidelines.
5
Where the right to bear the CE marking has been obtained before the end of the clinical investigation, the SAE reporting
continues until completion of the investigation, according to the clinical investigation plan.
Page 2 of 6
Any untoward medical occurrence, unintended disease or injury or any untoward clinical
signs (including an abnormal laboratory finding) in subjects, users or other persons
whether or not related to the investigational medical device.
NOTE 1: This includes events related to the investigational device or the comparator.
NOTE 2: This includes events related to the procedures involved (any procedure in the
clinical investigation plan).
NOTE 3: For users or other persons this is restricted to events related to the
investigational medical device.
Device deficiency
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety
or performance, such as malfunction, misuse or use error and inadequate labeling.
Investigational medical device

Medical device being assessed for safety or performance in a clinical investigation
NOTE: This includes medical devices already on the market that are being evaluated for
new intended uses, new populations, new materials or design changes.
Serious Adverse Device Effect (SADE)

Adverse device effect that has resulted in any of the consequences characteristic of a
serious adverse event.
Serious Adverse Event (SAE)

Adverse event that:
a) led to a death,
b) led to a serious deterioration in health that either:
1) resulted in a life-threatening illness or injury, or
2) resulted in a permanent impairment of a body structure or a body function, or
3) required in-patient hospitalization or prolongation of existing hospitalization, or
4) resulted in medical or surgical intervention to prevent life threatening illness or
injury or permanent impairment to a body structure or a body function.
c) led to fetal distress, fetal death or a congenital abnormality or birth defect.
NOTE 1: This includes device deficiencies that might have led to a serious adverse event
if a) suitable action had not been taken or b) intervention had not been made or c) if
circumstances had been less fortunate. These are handled under the SAE reporting
system.
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure required by
the Clinical Investigation Plan, without a serious deterioration in health, is not considered
to be a serious adverse event.
Unanticipated Serious Adverse Device Effect (USADE)

Serious adverse device effect which by its nature, incidence, severity or outcome has not
been identified in the current version of the risk analysis report.
NOTE: Anticipated: an effect which by its nature, incidence, severity or outcome has
been previously identified in the risk analysis report
Page 3 of 6
4. REPORTABLE EVENTS UNDER ANNEX 7 AND ANNEX X OF DIRECTIVES 90/385/EEC
AND 93/42/EEC RESPECTIVELY.
For the purpose of this guidance and based on the definitions above, the following events
are considered reportable events in accordance with Annex 7, section 2.3.5 and Annex X,
section 2.3.5 of the above mentioned Directives:
- any SAE,
- any Investigational Medical Device Deficiency that might have led to a SAE if a)
suitable action had not been taken or b) intervention had not been made or c) if
circumstances had been less fortunate
- new findings/updates in relation to already reported events.
Reportable events occurring in Third Countries6 in which a clinical investigation is performed

under the same clinical investigation plan, have to be reported in accordance with this
guidance.
5. REPORT BY WHOM.
Reportable events have to be reported by the sponsor of the clinical investigation, which
could be the manufacturer (MFR), the authorized representative (AR) or another person or
entity7-8.
6. REPORT TO WHOM.
Reportable events must be reported at the same time to all NCAs where the clinical
investigation has commenced9-10 using the summary tabulation featured in the Appendix.
A list of clinical investigation contact points within the NCAs is published at the
Commission's homepage.
7. REPORTING TIMELINES
7.1 Report by sponsor to NCAs.

The sponsor must report to the NCAs where the clinical investigation has commenced:
a SAE which indicates an imminent risk of death, serious injury, or serious illness and
that requires prompt remedial action for other patients/subjects, users or other
persons11 or a new finding to it: immediately, but not later than 2 calendar days after
6
Countries other than Switzerland, Turkey and those belonging to the EU and the EEA.
7
Note: Member States may also require separate reporting by clinical investigators/medical professionals.
8
Note: SAEs concerning CE marked devices (e.g. comparators) which meet the vigilance reporting criteria may also need to
be handled under the post-market surveillance/vigilance system.
9
For the purpose of this guidance, an investigation is considered to have commenced in an individual Member State when the
sponsor is authorised to start the investigation in accordance with the notification procedures in that Member State.
10
Note: Member States may also require separate reporting to the Ethics Committee(s) and/or separate reporting to the other
clinical investigators/study centers involved in the clinical investigation.
11
This includes:
- events that are of significant and unexpected nature such that they become alarming as a potential public health hazard,
e.g. human immunodeficiency virus (HIV) or Creutzfeldt-Jacob Disease (CJD). These concerns may be identified by
either the NCA or the MFR.
- the possibility of multiple deaths occurring at short intervals.
Page 4 of 6
awareness by sponsor of a new reportable event or of new information in relation with
an already reported event.
any other reportable events as described in section 4 or a new finding/update to it:
immediately, but not later than 7 calendar days following the date of awareness by
the sponsor of the new reportable event or of new information in relation with an
already reported event.
7.2 Report by the investigator to the sponsor

The sponsor shall implement and maintain a system to ensure that the reporting of the
reportable events will be provided by the investigator to the sponsor in acceptable timely
conditions, but not later than within 3 calendar days after the occurrence of the event.
In some cases, a different periodicity or different modalities12 may be agreed by the

participating NCAs according to the investigational design and to the pathology under clinical
investigation. This would allow adequate provision for clinical investigations (e.g. palliative
oncology) in which SAE frequency is expected to be high due to progression of the disease.
This needs to be agreed between the sponsor and relevant NCAs.
8. REPORTING FORM
The reporting form template for the summary SAE tabulation is given in the Appendix of
this document.
The table gives a cumulative overview of the reportable events per clinical investigation
and will be updated and transmitted to participating NCAs each time a new reportable
event or a new finding to an already reported event is to be reported. More detailed
information has to be provided on request of an NCA.
The sponsor shall identify the new/updated information in the status column of the
tabular form featured in the Appendix as:
a = added = new reportable event;
m = modified = new finding/update to an already reported event;
u = unchanged.
Changes in a line should be highlighted in bold and/or color in the respective column.
The reporting form is study specific and covers only a given clinical investigation, defined
by a distinct clinical investigation plan. English is the recommended language for the
reporting form. The report should be sent by email preferably in Excel or equivalent
format to the participating NCAs.
REFERENCES:
1. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member
States relating to active implantable medical devices, last amended by Directive 2007/47/EC.
2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, last amended by
3. ISO/FDIS 14155:2010 Clinical investigation of medical devices for human subjects Good clinical
practice
12
in line with Annex 7.2.3.5 of Directive 90/385/EEC and Annex X.2.3.5 of Directive 93/42/EEC
Page 5 of 6
APPENDIX REPORTING FORM
MEDDEV 2.7/3 SAE Report Table- V1

EUDAMED - ID:
Title of Clinical
Investigation:
CIP Number:
Contact person Device type:
(Name, Address,
E-Mail, Telephone
Number)
MS+NCA Reference
Reference Member
Numbers State:
for all participating
Countries:
No. of Patients No. of

enrolled to date Invest.
(date of report): Devices
used to date
Date of Report:
Assessment
Treatment
of
Assessment of Arm:
Date Relationship Event Status:
Relationship Investigational
Sponsor Date of Date of Event: action/ to Resolved/ Date of
Status: Study Patient ID Description to Procedure: Unanticipated Device/
received Country Procedure/ Event Organ treatment/patient Investigational Resolved with Event
a, m, u Center Code of event Yes SADE yes/No Control
Report of First Use Onset System outcome Device: Sequelae/ Resolution
No Group/
SAE Yes Ongoing/Death
Possibly blinded/
No
n.a.
Possibly
Note: Submission of this report does not, in itself, represent a conclusion by the sponsor or the competent authority that the content of this report is complete or that the device(s) listed failed in any manner
and/or that the device(s) caused or contributed to the alleged death or deterioration in the state of the health of any person.
Page 6
EUROPEAN COMMISSION
May 2015
CLINICAL INVESTIGATIONS:
SERIOUS ADVERSE EVENT REPORTING
UNDER DIRECTIVES 90/385/EEC AND 93/42/EEC.
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of EC-Directives on medical Devices.
They are legally not binding. The Guidelines have been carefully drafted through a process of intensive consultation of the
various interested parties (competent authorities, Commission services, industries, other interested parties) during which
intermediate drafts where circulated and comments were taken up in the document. Therefore, this document reflects positions
taken by representatives of interest parties in the medical devices sector. These guidelines incorporate changes introduced by
Directive 2007/47/EC amending Council Directive 90/385/EEC and Council Directive 93/42/EEC.
1
GUIDELINES FOR ADVERSE EVENT REPORTING

UNDER DIRECTIVES 90/385/EEC AND 93/42/EEC
Index
1. INTRODUCTION
2. SCOPE
3. DEFINITIONS
4. REPORTABLE EVENTS
5. REPORT BY WHOM
6. REPORT TO WHOM
8. CAUSALITY ASSESSMENT
9. REPORTING FORM
Appendix Summary Reporting Form
2
1. INTRODUCTION
This guidance defines Serious Adverse Event (SAE) reporting modalities and
includes a summary tabulation reporting format. Individual reporting should be
performed in accordance with national requirements. The objective of this guidance is
to contribute to the notification of SAEs to all concerned National Competent
1
Authorities (NCAs ) in the context of clinical investigations in line with the
requirements of Annex 7 of Directive 90/385/EEC and Annex X of Directive
93/42/EEC, as amended by Directive 2007/47/EC. According to Annex 7 of Directive
90/385/EEC and to Annex X of Directive 93/42/EEC: All serious adverse events
must be fully recorded and immediately notified to all competent authorities of
the Member States in which the clinical investigation is being performed."
2. SCOPE
2
The reporting modalities and format set out in this guidance apply to pre-market
clinical investigations 3-4 conducted with:
a. Non-CE marked devices,
b. CE marked devices used outside the intended use(s) covered by the CE-
marking.
The tabular format featured in the Appendix needs to be updated for each reportable
event or for new findings/updates to already reported events. It shall be transmitted to
all NCAs where the clinical investigation is being performed.
1
For the purpose of this guidance," NCAs" encompasses the National Competent Authorities of the EU, the EEA
and of Switzerland and Turkey.
2
A specific guidance on Post Market Clinical Follow-Up Studies is available as MEDDEV 2.12/2 rev. 2:
http://ec.europa.eu/health/medical-devices/files/meddev/2_12_2_ol_en.pdf .
3
This includes pre-market clinical investigations:
- which started prior to 21 March 2010 and are continued after that date. [Note: reporting of SAE as
covered in this guidance only started on 21 March 2010 with the implementation of Directive
2007/47/EC and is not retrospective.to SAEs that occurred prior to 21 March 2010].
- for pre-market clinical investigations involving CE marked comparator devices, SAEs occurring in or to
subjects that are in the comparator arm of an investigation shall also be reported in accordance with
these guidelines.
4
Where the right to bear the CE marking has been obtained before the end of the clinical investigation, the SAE
reporting continues until completion of the investigation, according to the clinical investigation plan.
3
3. DEFINITIONS (in line with EN ISO 14155)
Investigational medical device

Medical device being assessed for safety or performance in a clinical investigation
NOTE: This includes medical devices already on the market that are being evaluated
for new intended uses, new populations, new materials or design changes.
Adverse Event (AE)

Any untoward medical occurrence, unintended disease or injury or any untoward
clinical signs (including an abnormal laboratory finding) in subjects, users or other
persons whether or not related to the investigational medical device.
NOTE 1: This definition includes events related to the investigational device or the
comparator.
NOTE 2: This definition includes events related to the procedures involved.
NOTE 3: For users or other persons, this definition is restricted to events related to
investigational medical devices.
Serious Adverse Event (SAE)

Adverse event that:
a) led to a death,
b) led to a serious deterioration in health of the subject, that either resulted in:
- a life-threatening illness or injury, or
- a permanent impairment of a body structure or a body function, or
- in-patient hospitalization or prolongation of existing hospitalization, or
- in medical or surgical intervention to prevent life threatening illness or
- injury or permanent impairment to a body structure or a body function.
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required
by the Clinical Investigation Plan, without a serious deterioration in health, is not
considered a serious adverse event.
Device deficiency
Inadequacy of an investigational medical device related to its identity, quality,
durability, reliability, safety or performance. This may include malfunctions, use error,
or inadequacy in the information supplied by the manufacturer.
4
Adverse Device Effect (ADE)
Adverse event related to the use of an investigational medical device.
NOTE 1- This includes any adverse event resulting from insufficiencies or
inadequacies in the instructions for use, the deployment, the implantation, the
installation, the operation, or any malfunction of the investigational medical device.
NOTE 2- This includes any event that is a result of a use error or intentional
abnormal use of the investigational medical device.
Serious Adverse Device Effect (SADE)

Adverse device effect that has resulted in any of the consequences characteristic of a
serious adverse event.
Unanticipated Serious Adverse Device Effect (USADE)

Serious adverse device effect which by its nature, incidence, severity or outcome has
not been identified in the current version of the risk analysis report.
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity
or outcome has been previously identified in the risk analysis report
4. REPORTABLE EVENTS UNDER ANNEX 7 AND ANNEX X OF

DIRECTIVES 90/385/EEC AND 93/42/EEC RESPECTIVELY
For the purpose of this guidance and based on the definitions above, the following
events are considered reportable events in accordance with Annex 7, section 2.3.5
and Annex X, section 2.3.5 of the above mentioned Directives 5 :
- any SAE,
- any Device Deficiency that might have led to a SAE if:
a) suitable action had not been taken or
b) intervention had not been made or
c) if circumstances had been less fortunate
- new findings/updates in relation to already reported events.
5
The definition of the term SAE has changed over time. A distinction between SAE and device deficiencies was
introduced with the adoption of standard ISO 14155 in 2011. While this MEDDEV document uses terminology
according to the international standard, please be aware that the European medical device directives pre-date
the split in the terminology. In order to fulfil reporting requirements under the European medical device
directives, device deficiencies as well as SAE need to be documented during the course of the clinical
investigation and reported to competent authorities as described in this chapter.
5
6
Reportable events occurring in Third Countries in which a clinical investigation is
performed under the same clinical investigation plan have to be reported to the
NCA(s) in accordance with this guidance. This includes events occurring in third
Countries after European sites have closed.
5. REPORT BY WHOM.
Reportable events have to be reported by the sponsor of the clinical investigation,
which could be the manufacturer, the authorized representative or another person or
entity 7-8.
6. REPORT TO WHOM.
Reportable events must be reported at the same time to all NCAs where the clinical
9-10
investigation has commenced using the summary tabulation featured in the
Appendix.
A list of clinical investigation contact points within the NCAs is published at the
Commission's homepage.
7.1 Report by sponsor to NCAs.

The sponsor must report to the NCAs where the clinical investigation has
commenced:
- for all reportable events as described in section 4 which indicate an imminent
risk of death, serious injury, or serious illness and that requires prompt
6
Countries other than Switzerland, Turkey and those belonging to the EU and the EEA.
7
Note: Member States may also require separate reporting by clinical investigators/medical professionals.
8
Note: SAEs concerning CE marked devices (e.g. comparators) which meet the vigilance reporting criteria may
also need to be handled under the post-market surveillance/vigilance system.
9
For the purpose of this guidance, an investigation is considered to have commenced in an individual Member
State when the sponsor is authorized to start the investigation in accordance with the notification procedures
in that Member State.
10
Note: Member States may also require separate reporting to the Ethics Committee(s) and/or separate
reporting to the other clinical investigators/study centers involved in the clinical investigation.
6
11
remedial action for other patients/subjects, users or other persons or a new
finding to it: immediately, but not later than 2 calendar days after awareness
by sponsor of a new reportable event or of new information in relation with an
already reported event.
- any other reportable events as described in section 4 or a new finding/update
to it: immediately, but not later than 7 calendar days following the date of
awareness by the sponsor of the new reportable event or of new information in
relation with an already reported event.
7.2 Report by the investigator to the sponsor

The sponsor shall implement and maintain a system to ensure that the reporting of
the reportable events as defined under chapter 4 will be provided by the investigator
to the sponsor immediately, but not later than 3 calendar days after investigational
site study personnels awareness of the event.
12
In some cases, a different periodicity or different modalities may be agreed by the
participating NCAs according to the investigational design and to the pathology under
clinical investigation. This would allow adequate provision for clinical investigations
(e.g. palliative oncology), in which SAE frequency is expected to be high due to
progression of the disease. This needs to be agreed between the sponsor and
relevant NCAs.
8. CAUSALITY ASSESSMENT
13
The relationship between the use of the medical device (including the medical -
surgical procedure) and the occurrence of each adverse event shall be assessed and
categorized.14 During causality assessment activity, clinical judgement shall be used
and the relevant documents, such as the Investigators Brochure, the Clinical
Protocol or the risk Analysis Report shall be consulted, as all the foreseeable serious
11
This includes:
A) events that are of significant and unexpected nature such that they become alarming as a potential public
health hazard, e.g. human immunodeficiency virus (HIV) or Creutzfeldt-Jacob Disease (CJD). These concerns
may be identified by either the NCA or the manufacturer.
B) the possibility of multiple deaths occurring at short intervals.
12
In line with Annex 7.2.3.5 of Directive 90/385/EEC and Annex X.2.3.5 of Directive 93/42/EEC
13
Intended as both medical device investigated in the investigation and comparator.
14
Procedure related events refers to the procedure related to the initial application of the investigational
medical device only and therefore not to any other procedures or treatments applied later throughout the
clinical investigation, for instance to treat (serious) adverse events.
7
adverse events and the potential risks are listed and assessed there. The presence
of confounding factors, such as concomitant medication/treatment, the natural history
of the underlying disease, other concurrent illness or risk factors shall also be
considered.
The above considerations apply also to the serious adverse events occurring in the
comparison group.
For the purpose of harmonising reports, each SAE will be classified according to five
different levels of causality. The sponsor and the investigators will use the following
definitions to assess the relationship of the serious adverse event to the
investigational 15 medical device or procedures.
1) Not related: relationship to the device or procedures can be excluded when:

- the event is not a known16 side effect of the product category the device
belongs to or of similar devices and procedures;
- the event has no temporal relationship with the use of the
investigational device or the procedures;
- the serious event does not follow a known response pattern to the
medical device (if the response pattern is previously known) and is
biologically implausible;
- the discontinuation of medical device application or the reduction of the
level of activation/exposure - when clinically feasible - and
reintroduction of its use (or increase of the level of activation/exposure),
do not impact on the serious event;
- the event involves a body-site or an organ not expected to be affected
by the device or procedure;
- the serious event can be attributed to another cause (e.g. an underlying
or concurrent illness/ clinical condition, an effect of another device,
drug, treatment or other risk factors);
- the event does not depend on a false result given by the investigational
device used for diagnosis 17, when applicable;
15
Investigational device: any device object of the clinical investigation, including the comparators.
16
When the event is not a known side effect of the product category the device belongs to or of similar devices
and procedures, generally is considered not related. Yet, the unexpected effect shall not be excluded from
evaluation and reporting.
8
- harms to the subject are not clearly due to use error;
- In order to establish the non-relatedness, not all the criteria listed above
might be met at the same time, depending on the type of
device/procedures and the serious event.
2) Unlikely: the relationship with the use of the device seems not relevant and/or
the event can be reasonably explained by another cause, but additional
information may be obtained.
3) Possible the relationship with the use of the investigational device is weak but
cannot be ruled out completely. Alternative causes are also possible (e.g. an
underlying or concurrent illness/ clinical condition or/and an effect of another
device, drug or treatment). Cases were relatedness cannot be assessed or no
information has been obtained should also be classified as possible.
4) Probable the relationship with the use of the investigational device seems
relevant and/or the event cannot reasonably explained by another cause, but
additional information may be obtained.
5) Causal relationship: the serious event is associated with the investigational
device or with procedures beyond reasonable doubt when:
- the event is a known side effect of the product category the device
belongs to or of similar devices and procedures;
- the event has a temporal relationship with investigational device
use/application or procedures;
- the event involves a body-site or organ that
o the investigational device or procedures are applied to;
o the investigational device or procedures have an effect on;
- the serious event follows a known response pattern to the medical
device (if the response pattern is previously known);
- the discontinuation of medical device application (or reduction of the
level of activation/exposure) and reintroduction of its use (or increase of
17
If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an
unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly
diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment (thereby
missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease
or condition.
9
the level of activation/exposure), impact on the serious event (when
clinically feasible);
- other possible causes (e.g. an underlying or concurrent illness/ clinical
condition or/and an effect of another device, drug or treatment) have
been adequately ruled out;
- harm to the subject is due to error in use;
- the event depends on a false result given by the investigational device
used for diagnosis 17, when applicable;
- In order to establish the relatedness, not all the criteria listed above
might be met at the same time, depending on the type of
device/procedures and the serious event.
The sponsor and the investigators will distinguish between the serious adverse
events related to the investigational device and those related to the procedures (any
procedure specific to the clinical investigation). An adverse event can be related both
to procedures and the investigational device. Complications of procedures are
considered not related if the said procedures would have been applied to the patients
also in the absence of investigational device use/application.
In some particular cases the event may be not adequately assessed because
information is insufficient or contradictory and/or the data cannot be verified or
supplemented. The sponsor and the Investigators will make the maximum effort to
define and categorize the event and avoid these situations. Where the sponsor
remains uncertain about classifying the serious event, it should not exclude the
relatedness and classify the event as possible.
Particular attention shall be given to the causality evaluation of unanticipated serious

adverse (device) events. The occurrence of unanticipated events related to the use of
the device (USADE) could suggest that the clinical investigation places subjects at
increased risk of harm than was to be expected beforehand.
10
9. REPORTING FORM
The reporting form template for the summary SAE tabulation is given in the Appendix
of this document.
The table gives a cumulative overview of the reportable events per clinical
investigation and will be updated and transmitted to participating NCAs each time a
new reportable event or a new finding to an already reported event is to be reported.
More detailed information has to be provided on request of an NCA, if so requested
by using the individual reporting form. The sponsor shall identify the new/updated
information in the status column of the tabular form featured in the Appendix as:
a = added = new reportable event;
m = modified = new finding/update to an already reported event;
u = unchanged.
Changes in a line should be highlighted in bold and/or colour in the respective

column.
The reporting form is study specific and covers only a given clinical investigation,
defined by a distinct clinical investigation plan. English is the recommended language
for the reporting form. The report should be sent by email in Excel to the participating
NCAs, or an equivalent format which allows using the inserted filters.
Appendix Summary Reporting Form
11
REFERENCES:
1. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the
Member States relating to active implantable medical devices, last amended by Directive
2007/47/EC.
2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, last amended
by Directive 2007/47/EC.
3. EN ISO 14155:2011 Clinical investigation of medical devices for human subjects Good
clinical practice
12
EUROPEAN COMMISSION
Consumer Affairs
MEDDEV 2.7/4
December 2010
GUIDELINES ON CLINICAL INVESTIGATION:

BODIES
Note
Directives on medical Devices. They are legally not binding. The Guidelines have been carefully drafted
through a process of intensive consultation of the various interest parties (competent authorities,
Page 1 of 10
CONTENTS
1 Introduction........................................................................................................... 3
2 Scope ................................................................................................................... 3
3 References ........................................................................................................... 4
4 Definitions............................................................................................................. 5
5 General Principles When Considering the Need for a Clinical Investigation ........ 6
6 General Principles of Clinical Investigation Design .............................................. 7
7 Ethical Considerations for Clinical Investigations ............................................... 10
Page 2 of 10
1 Introduction
These guidelines are based on the guidance document SG5/N3:2010 of the Global
Harmonization Task Force. They are adapted to the requirements on clinical
investigations laid out in annex 7 of directive 90/385/EEC and in annex X of directive
93/42/EEC as amended by directive 2007/47/EC. The clinical investigations shall be
performed as described in these annexes.
They reflect the consensus view of the various interested parties with regard to
clinical investigations under the above-mentioned medical devices directives.
What is a clinical investigation?
A clinical investigation is defined as any systematic investigation or study in or on

one or more human subjects, undertaken to assess the safety and/or performance
of a medical device. (SG5/N1:2007).
The undertaking of a clinical investigation is a scientific process that represents one

method of generating clinical data.
What is the objective of a clinical investigation?
The objective of a clinical investigation is to assess the safety and clinical

performance of the device in question and evaluate whether the device is suitable
for the purpose(s) and the population(s) for which it is intended (EN ISO 14155-
1:2009).
How is a clinical investigation conducted?
EN ISO 14155-1:2009 Clinical Investigation of Medical Devices for Human Subjects

- General Requirements details the general requirements for the conduct of clinical
investigations and EN ISO 14155-2:2009 Clinical Investigation of Medical Devices
for Human Subjects - Clinical Investigation Plan contains detailed information about
the procedure and contents of a clinical investigation plan. Clinical investigations
must take into account scientific principles underlying the collection of clinical data
along with accepted ethical standards surrounding the use of human subjects. The
clinical investigation objectives and design should be documented in a clinical
investigation plan.
2 Scope
The primary purpose of this document is to provide guidance in relation to:
when a clinical investigation should be undertaken for a medical device to

demonstrate compliance with the relevant Essential Requirements; and
Page 3 of 10
the general principles of clinical investigations involving medical devices.
Given the wide diversity of medical devices and their associated risks, this document
is not intended to provide comprehensive guidance for clinical investigations of
specific medical devices.
generally and to combination products regulated as medical devices. It is not
intended to cover in vitro diagnostic medical devices. Additionally, this document
was drafted primarily to address the use of Clinical Investigations to support clinical
evaluation and a conformity assessment procedure. Some aspects of this document
may apply to studies conducted following commercial release of a device. A
separate guidance document specifically addresses post-market clinical follow-up
(MEDDEV 2.12/2: Clinical Evaluation - Post Market Clinical Follow-up).
3 References
Directive 90/385/EEC, as amended by Directive 2007/47/EC
Directive 93/42/EEC, as amended by Directive 2007/47/EC
Interpretative Documents
MEDDEV 2.7.1 Rev. 3; December 2009
Clinical Evaluation: A Guide for Manufacturers and Notified
Bodies
MEDDEV 2.7.1, Appendix 1; December 2008

Evaluation of Clinical Data A Guide for Manufacturers and
Notified Bodies Appendix 1: Clinical Evaluation of Coronary
Stents
MEDDEV 2.7.2; December 2008

Guide for Competent Authorities in Making an Assessment of
Clinical Investigations Notification
MEDDEV 2.12/2; May 2004

Clinical Evaluation - Post Market Clinical Follow-up

SG5/N1:2007 Clinical Evidence Key definitions and Concepts
SG5/N2:2007 Clinical Evaluation
Harmonized/International standards
EN ISO 14155-1: 2009
Clinical investigation of medical devices for human subjects Part
1 General requirements
EN ISO 14155-2: 2009

Clinical investigation of medical devices for human subjects Part
2 Clinical investigation plans
Page 4 of 10
EN ISO 14971: 2009
Application of risk management to medical devices
Other References
World Medical Association Declaration of Helsinki - Ethical
principles for medical research involving human subjects
4 Definitions
Clinical Data:
The safety and/or performance information that is generated from
the use of a device. Clinical data are sourced from:
clinical investigation(s) of the device concerned; or
clinical investigation(s) or other studies reported in the
scientific literature, of a similar device for which equivalence
to the device in question can be demonstrated; or
published and/or unpublished reports on other clinical
experience of either the device in question or a similar device
for which equivalence to the device in question can be
demonstrated.
Clinical Evaluation:
The assessment and analysis of clinical data pertaining to a medical
device to verify the clinical safety and performance of the device
when used as intended by the manufacturer.
Clinical Evidence:
The clinical data and the clinical evaluation report pertaining to a
medical device.
Clinical Investigation:
Any systematic investigation or study in or on one or more human
subjects, undertaken to assess the safety and/or performance of a
medical device.
Clinical Investigation Plan:

Document that states the rationale, objectives, design and proposed
analysis, methodology, monitoring, conduct and record-keeping of
Clinical Performance:
The ability of a medical device to achieve its intended purpose as
Clinical Safety:
The absence of unacceptable clinical risks, when using the device
according to the manufacturers Instructions for Use.
Page 5 of 10
Conformity Assessment:
The systematic examination of evidence generated and procedures
undertaken by the manufacturer, according to Article 9 of directive
90/385/EEC and Article 11 of directive 93/42/EEC, to determine that
a medical device is safe and performs as intended by the
manufacturer and, therefore, conforms to the Essential
Requirements according to Annex 1 of directive 90/385/EEC and
Annex I of directive 93/42/EEC.
Device intended for Clinical Investigation:

any device intended for use by a duly qualified medical practitioner
when conducting investigations as referred to in Sections 2.1 of
Annex 7 of directive 90/385/EEC and section 2.1 of Annex X of
directive 93/42/EEC in an adequate human clinical environment.
Endpoint: Indicators measured or determined to assess the objectives of a

clinical investigation, prospectively specified in the clinical
investigation plan. (EN ISO 14155_2:2009, modified)
Residual Risk: Risk remaining after risk control measures has been taken (EN ISO
14971:2009).
Risk Management:
The systematic application of management policies, procedures and
practices to the tasks of analysing, evaluating, controlling and
monitoring risk (EN ISO 14971:2009).
5 General Principles When Considering the Need for a Clinical

Investigation
Clinical Evaluation
According to Annex 1.I.5a of directive 90/385/EEC and Annex I.I.6a of directive

93/42/EEC demonstration of conformity with the essential requirements must
include a clinical evaluation in accordance with Annex 7/Annex X of the respective
directive.
As a general rule, confirmation of conformity with the requirements concerning the

characteristics and performances referred to in sections I.1 and I.3 of annex I of
directive 90/385/EEC and in sections I.1 and I.2 of annex I of directive 93/42/EEC
under the normal conditions of use of the device, and the evaluation of the side-
effects and of the acceptability of the benefit/risk ratio referred to in Section I.5/I.6 of
Annex I of directives 90/385/EEC and 93/42/EEC respectively, must be based on
clinical data.
The kind and amount of clinical data needed will primarily depend on the specifics of
the clinical claims with regard to clinical performance, considerations of clinical
safety, including determination of undesirable side-effects and on risk management
output, namely determination of residual risks and favorable benefit/risk ratio.
Some factors that may typically influence the specificity/extent of clinical data
Page 6 of 10
requirements are listed in section 6 of this guidance.
Different clinical claims/intended purposes of a device may often necessitate
different clinical data. For example, in the case of the closure of the heart defect
patent foramen ovale, clinical performance/safety data and benefit/risk-
considerations may vary in different intended purposes such as stroke prevention or
migraine crisis prevention.
Conducting a proper clinical evaluation will demonstrate which clinical data are
necessary, which clinical data can be adequately supplemented by other methods,
such as literature search, prior clinical investigations, clinical experience or by using
suitable clinical data from equivalent1 devices, and which clinical data remain to be
delivered by clinical investigations (see MEDDEV 2.7.1 Rev.3: Clinical Evaluation: A
Guide for Manufacturers and Notified Bodies).
The clinical evaluation and its documentation must be actively updated with data
obtained from the post-market surveillance. New such data as well as considerations
for new or changed intended purposes need updating of the clinical evaluation and
may indicate necessity of additional clinical investigations.
When must/should a clinical investigation be undertaken?
The Conformity Assessment process for active implantable medical devices as well
as for class III and implantable medical devices requires that a clinical investigation
is undertaken unless it is duly justified to rely on existing data (section 1.2 of Annex
7 of directive 90/385/EEC and section I.1a of Annex X of directive 93/42/EEC ). Any
such justification will have to be based on a proper clinical evaluation.
Depending on clinical claims, risk management outcome and on the results of the
clinical evaluation, clinical investigations may also have to be performed for non-
implantable medical devices of classes I, IIa and IIb.
Additional clinical investigations may be feasible to corroborate the existing clinical

evidence with regard to aspects of clinical performance, safety, benefit/risk-ratio or
to determine relative effectiveness and safety with suitable comparators.
6 General Principles of Clinical Investigation Design
Any clinical investigation must:

be part of the clinical evaluation process;
follow a proper risk management procedure to avoid undue risks;
be compliant with all relevant legal and regulatory requirements;
be appropriately designed (see below);
follow appropriate ethical principles (see Section 7).
1
The concept of equivalency encompasses technical, biological and clinical equivalency.
Page 7 of 10
Basic legal and administrative provisions given in directives 90/385/EEC and
93/42/EEC
Art. 4 of the two directives require that Member States shall not create any obstacle
to devices intended for clinical investigation being made available to medical
practitioners or authorized persons for that purpose if they meet the conditions laid
down in Article 10/15 and in Annex 6/VIII of the respective directives. These devices
shall not bear the CE marking.
Art. 10/15 of the directives contain the administrative provisions for clinical
investigations, Annex 6/VIII respectively the contents and provisions for the
statement and documentation required.
Annexes 7/X, sections 2.2 relate to ethical provisions, sections 2.3 specify basic
methodological aspects of clinical investigations.
Further legal and regulatory/administrative requirements may be valid at
national/regional level.
Factors to Influence Clinical Data Requirements

The design of the clinical investigation, including the study objectives and statistical
considerations, should provide the clinical data necessary to address relevant
aspects of clinical performance, safety, including undesirable side-effects as well as
the residual risks identified in the risk management process. Some factors that may
influence the extent of clinical data requirements include, but are not limited to, the
following:
type of device and/or regulatory classification;
novel technology/relevant previous experience;
clinical application/indications;
nature of exposure to the product, e.g.: surface contact, implantation,

ingestion;
risks inherent in the use of the product, e.g.: risk associated with the
procedure;
performance claims made in the device labeling (including instructions for

use);
component materials and substances;
disease process (including severity) and patient population being treated;
demographic, geographic and cultural considerations (e.g.: age, race, gender,

etc.);
potential impact of device failure;
period of exposure to the device;
Page 8 of 10
expected lifetime of the device;
availability of alternative treatments and current standard of care; and
ethical considerations.
Considerations for Device Study Designs

Some of the factors that need to be considered in the study design include, for
example:
clear statement of objectives
appropriate subject population(s)
minimization of bias (e.g., randomization, blinding)
identification of confounding factors (e.g., concurrent medications, co-

morbidities)
choice of appropriate controls (e.g., cohort, sham, historical), where

necessary
design configuration (e.g., parallel, crossover, factorial)
type of comparison (e.g., superiority, non-inferiority, equivalence)

Investigations should be planned in such a way as to maximize the clinical relevance
of the data while minimizing confounding factors. Possible study designs include:
randomized controlled trials
cohort studies
case-control studies
case series
These are further explained in Appendix C of the document MEDDEV 2.7.1 Rev. 3
on Clinical Evaluation.
In designing the study, statistical considerations should be prospectively specified
and should be based on sound scientific principles and methodology. Care must be
taken in developing a statistical plan that includes consideration of, for example, the
following:
endpoints that are clinically relevant, clearly defined and assessed at a

2
specified time point
a testable hypothesis
statistical significance levels, power
sample size justification
2
See e.g. critical aspects of end point definition for regulatory trials [D.B. Kramer et al, American Journal of
Therapeutics 17, 2-7 (2010)]
Page 9 of 10
analysis methodology (including sensitivity and poolability analysis)
The design should ensure that the statistical evaluation derived from the
investigation reflects a meaningful, clinically significant outcome.
Discussion with a competent authority or a notified body may be appropriate when
there is uncertainty as to whether the proposed clinical investigation plan is
sufficient.
Conduct of Clinical Investigations

A properly conducted clinical investigation, including compliance to the clinical
investigation plan and local laws and regulations, ensures the protection of subjects,
the integrity of the data and that the data obtained is acceptable for the purpose of
demonstrating conformity to the Essential Requirements. EN ISO 14155 outlines
good clinical practice for clinical investigations of medical devices.
Final Study Report

The outcome of a clinical investigation has to be documented in a final study report
(Annex 7/X, section 2.3.7 of directives 90/385/EEC and 93/42/EEC) This then forms
part of the clinical data that is included in the clinical evaluation process and
ultimately becomes integrated into the clinical evaluation report (see MEDDEV 2.7.1
Rev. 3) for the purposes of conformity assessment. The structure of a final study
report is proposed in EN ISO 14155-1:2009.
7 Ethical Considerations for Clinical Investigations

In their sections 2.2 of Annex 7/Annex X, directives 90/385/EEC and 93/42/EEC
require: Clinical investigations must be carried out in accordance with the Helsinki
Declaration adopted by the 18th World Medical Assembly in Helsinki, Finland, in
1964, as last amended by the World Medical Assembly. It is mandatory that all
measures relating to the protection of human subjects are carried out in the spirit of
the Helsinki Declaration. This includes every step in the clinical investigation from
first consideration of the need and justification of the study to publication of the
results.
As a general principle, the rights, safety and wellbeing of clinical investigation

subjects shall be protected consistent with the ethical principles laid down in the
Declaration of Helsinki (EN ISO 14155-1:2009).
It is ethically important in deciding to conduct a clinical investigation that it should

generate new data and answer specific safety and/or performance questions that
remain unanswered by the current body of knowledge. The desire to protect human
subjects from unnecessary or inappropriate experimentation must be balanced with
the need to protect public health through the use of clinical investigations where they
are indicated. In all cases, however, care must be taken to ensure that the
necessary data are obtained through a scientific and ethical investigational process
that does not expose subjects to undue risks or discomfort. The rights, safety and
well-being of subjects are paramount and appropriate trial design and conduct is
essential to generate meaningful data.
Page 10 of 10
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.10-2 Rev 1
April 2001
(NOTE: For attachment 1 to 4 see separate documents)
DESIGNATION AND MONITORING OF

NOTIFIED BODIES
WITHIN THE FRAMEWORK OF
EC DIRECTIVES ON MEDICAL DEVICES
These guidelines aim at promoting a common approach by, the notified bodies involved in the conformity
assessment procedures according to the relevant annexes of the Medical Devices Directives and by the
Competent Authorities charged with safeguarding public health.
They have been carefully drafted through a process of consultation with various interested parties during which
intermediate drafts were circulated and comments were taken up in the document. Therefore, this document
reflects positions taken in particular by representatives of Competent Authorities, Commission services,
Notified Bodies, industry and other interested parties in the medical sector.
These guidelines are not legally binding. It is recognised that under given circumstances an alternative approach
may be possible to comply with the legal requirements.
Due to the participation of the aforementioned interested parties and of experts from Competent Authorities, it is
anticipated that these guidelines will be followed within the Member States and, therefore, ensure uniform
application of relevant Directive provisions.It is intended that this document will also be useful to Regulatory
Authorities, Designating Authorities and Conformity Assessment Bodies in the context of mutual recognition
agreements with third parties.
Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel - Belgium - Office: SC15 3/133.
Telephone: direct line (+32-2)295 93 39, switchboard 299.11.11. Fax: 296 70 13.
-1-
TABLE OF CONTENTS
I. INTRODUCTION 4
II. CRITERIA FOR THE DESIGNATION AND OPERATION OF NOTIFIED BODIES 5
1. General requirements 5
2. Independence requirements 6
3. Impartiality requirements 7
4. Competence requirements 7
5. Internal procedures and facilities - requirements 10
6. Confidentiality requirements 10
7. Liability insurance requirements 11
8. Subcontracts requirements 11
9. Notified Bodys quality system requirements 13
III. RELATIONSHIP BETWEEN COMPETENT AUTHORITY RESPONSIBLE FOR

DESIGNATION AND NOTIFIED BODIES 16
1. Reporting 16
2. Designation of Notified Bodies operations by the Competent Authority responsible for designation. 16
3. Monitoring of Notified Bodies operations by the Competent Authority responsible for designation. 17
-2-
APPENDICIES
- Appendix A Additional requirements for the specific annexes under which a notified
body offers its services.
- Appendix B CERTIF Documents
- Appendix C MEDDEV Documents
- Appendix D References for harmonized standards
ATTACHMENTS ( on separate documents)

- Attachment 1 Guidance on the preparation of a curriculum vitae for a Medical Device
Expert; example of a form
- Attachment 2 Example of a training course format
- Attachment 3 The responsibilities of the Notified Body under the Medical Device
Directives Document
- Attachment 4 Special Rules of accreditation for Certification Bodies of Quality Systems
(scope Sterile Medical Devices)
-3-
I. INTRODUCTION
These guidelines describe in more detail the criteria and conditions for the designation of
Notified Bodies in the framework of EC Directives on medical devices.
This guideline does not address the specific requirements for Notified Bodies dealing with in
vitro diagnostic medical devices. It is intended that this guideline will be revised in due course
to address the requirements of the directive relating to in vitro diagnostic medical devices.
Directive 98/79/EEC of 7 December 1998 relating to in vitro diagnostic medical devices
(IVMDD)1
Relevant legal requirements are laid down in :
Directive 90/385/EEC of 20 June 1990 relating to active implantable medical devices

(AIMD)2 Article 11; Annex 8
Directive 93/42/EEC of 14 June 1993 relating to medical devices (MDD)3 Article 16;
Annex XI
Ammendments to Article 16 in 93/42/EEC described in Directive 98/79/EEC of 7

December 1998 relating to in vitro diagnostic medical devices (IVMDD)4
Associated responsibilities are described in annexes 2,3,4 and 5 of the active implantable
directive and annexes II, III, IV, V and VI of the medical devices directive.
Further provisions on the same subject are contained in Council Decision 93/465/EEC of 22
July 19936 concerning the modules for notification monitoring, co-ordination and operation of
Notified Bodies as well as in the Guide to the implementation of directives based on New
Approach and Global Approach;September 19997 and other documents of the "High Officials
for Standardization Policy" (Appendix B). Special aspects for medical devices are addressed in
the MEDDEV-documents (Appendix C). Furthermore reference is made to the European
standards of the EN 45000 series where definitions of terms and principles of accreditation are
laid down. Further European standards relevant to the subject are listed in Appendix D.
1 OJ L 331 of 7 Dec 1998

2 OJ L 189 of 20 July 1990
3 OJ L 169 of 12 July 1993
4 OJ L 331 of 7 Dec 1998
6 OJ L 22 of 30 August 1993
7 http://europa.eu.int/comm/enterprise/newapproach/legislation.htm
-4-
Where, in this document, reference is made to the Competent Authority responsible for
designation, this includes any appointed body, in particular accreditation body to which, in
accordance with the national system, given tasks are assigned.
II. CRITERIA FOR THE DESIGNATION AND OPERATION OF NOTIFIED BODIES
1. General requirements
a) Resources: The Notified Body shall provide the resources for conformity assessment of
medical devices as specified in the directives in a competent, transparent, neutral,
independent and impartial manner.
A body may be designated to offer the services set out in one or more of the relevant
annexes of the directives.
The applicant must be capable of taking full responsibility for all tasks required of a
Notified Body in relation to the (or those) annexe(s) of the directives and the medical
devices for which it is being designated.
Once designated, the Notified Body shall, without delay, inform the Competent
Authority responsible for designation of any change regarding availability of resources,
including sub-contractors, and compliance with designation conditions which may have
an impact on the maintenance of the designation and of the assignment of tasks.
b) The Notified Body shall be a legally defined entity and shall make available to the
Competent Authority responsible for designation on request:
i. documentation clearly identifying its legal status;
ii. documentation which clearly shows both the authority and the responsibility of
individuals within, and the reporting structure within the Notified Body;
iii. documentation about its financial situation.
c) If the Notified Body is a legal entity, which is part of a larger organisation, the links
and relationship between the Notified Body and the larger organisation shall be clearly
documented.
Guidance
a) Where the Notified Body uses the services of a subcontractor, the Notified Body is
responsible for all contracted actions of its subcontractor and shall be liable for them as
if the Notified Body itself performed the action (see also clause 8 Subcontractor
requirements).
b) Where subcontractors are already notified/accredited in respect of the relevant

requirements by the Competent Authority responsible for designation or the authorized
national accreditation body, this may be taken into account by the Notified Body. They
may be assumed to fulfil the requirements.
-5-
2. Independence requirements
a) The Notified Body and the assessment and verification staff shall not be the designer,
manufacturer, supplier, installer or user * of medical devices, nor the authorised
representative of any of those parties engaged in these activities. The assessment and
verification staff including subcontractors shall be impartial and free from engagements
and influences, which could affect their objectivity, and in particular shall not be:
involved in the design, construction, marketing, installation, servicing or supply

of the devices within the scope of the audit;
involved in the design, construction, implementation or maintenance of the

quality system being audited;
nor represent the parties engaged in these activities.
* NB The term user in this context is not meant to exclude the use of individual
clinicians as assessment and verification staff.
b) Links with manufacturers: The directors, executives and personnel (whether directly
employed or subcontracted) responsible for carrying out the evaluation and verification
activities shall be independent of both the manufacturers for whom the Notified Body
conducts assessments and the commercial competitors of those manufacturers, during
their employment by the Notified Body. They shall not have been involved in the
design, construction, marketing or maintenance of the devices.
c) Consultancy: Notified Body personnel (whether directly employed or subcontracted)

shall not offer or provide (or have offered or provided) consultancy or advice to the
manufacturer, the authorised representative, a supplier or their commercial competitor
as regards the design, construction, marketing or maintenance of the products under
assessment. 8(see also clause 3 Impartiality requirements ).
Guidance
a) The Notified Body should have documented procedures for the identification, review
and resolution of all cases where conflict of interests is suspected or proven. Records
of such reviews and decisions should be kept.
b) The Notified Body should require all staff acting on its behalf to declare any potential
conflict of interest. Records of such declarations should be kept.
c) Marketing material produced by the Notified Body should not give any impression that
consultancy activities are offered.
d) If the Notified Body is linked to any organisation which itself provides consultancy
services, then the documented quality system of the Notified Body should include a
policy statement and documented procedures ensuring that assessment and consultancy
8 Guide to the implementation of the directives based on new approach and global approach - dated September 1999.
-6-
services are separate. The Notified Body should ensure, by means of a documented
agreement, that its subcontractors are aware of this guidance.
e) Notified Bodies should refrain from offering to manufacturers, with whom they
maintain a Notified Body relationship, additionalmarkings unless these marks fulfil a
different function from that of CE marking. Thus they should provide an added value in
signifying conformity with objectives that are different from those to which CE
marking relates. Such additional marks should not create confusion with the CE mark
from the point of view of the parties who are likely to come into contact with them.9.
f) The requirements of this clause do not preclude exchange of technical information and
guidance between a Notified Body and a company seeking their assessment.
g) In relation to consultancy the notified body should take into account the period of time
which has elapsed since any consultancy was offered on the design, construction,
marketing or maintenance of the products in question. It is envisaged that after 5 years
the relevance of the consultancy will be minimal but that this should be evaluated on a
case by case basis by the notified body management and records kept (see also
guidance a).
3. Impartiality requirements
a) The Notified Body shall guarantee the impartiality of all assessment and verification
personnel and ensure that the remuneration of personnel shall not depend on the number
of inspections and verifications that they carry out, nor on the results of their activities.
b) The Notified Body shall ensure by implementation of documented procedures that

personnel are free from pressures and inducements, particularly financial, which might
influence their judgement during any assessment or inspection that they perform.
Guidance
a) The Notified Body should document the means by which it ensures that the principle of
impartiality is made known and safeguarded throughout its organisation.
4. Competence requirements
a) The Notified Body shall employ within the organisation the necessary administrative,
technical, medical and scientific personnel, which possess satisfactory knowledge and
experience relating to the medical devices, technologies and conformity assessment
9 Guide to the implementation of the directives based on new approach and global approach - dated September 1999.
-7-
procedures assigned to them. Knowledge and experience related to the scope of
assignment of tasks shall include in particular:
- regulatory requirements and enforcement policies;
- European and international standardization activities;
- methodology of risk analysis and risk management regarding relevant medical

technology, production methods and the applicable verification procedures; the
personnel shall be capable of assessing the medical function and performance of
devices and the processes to determine compliance with essential requirements
especially for those cases where no specific standards are available;
- clinical evaluation, conduct of clinical investigations and normal conditions of

use of relevant medical devices.
b) The Notified Body shall have documented the competence and training requirements
for assessment and verification staff. Records shall be available to demonstrate that
personnel have the appropriate experience and have received appropriate training
relevant to the Notified Bodys scope.
c) Notified Bodies shall participate in co-ordination activities at European and/or national

level in order to attain maximum coherence in performing conformity assessment.
d) Notified Bodies carrying out assessments under annexes 2 and 5 of the active
implantable medical devices directive, and annexes II, V and VI of the medical devices
directive shall require that such quality system audits are conducted by a team that
includes at least one member who is experienced in the evaluation of the technologies
used by the manufacturer.
Guidance
a) The management of the Notified Body should satisfy themselves that personnel who
administered and perform assessment and verification operations are competent to fulfil
the tasks required of them.
b) One or more members of an assessment team involved in conformity assessment should

be trained and/or experienced in each of the following skills, as relevant to the
assessment being made. This includes in particular:
i. the assessment of design documentation and clinical evaluation data to

determine that all aspects of the design are in compliance with the requirements
of the regulations ( relevant to annexes 2(AIMDD)/II(MDD) and
3(AIMDD)/III(MDD);
ii. for sterile medical devices, microbiological assessment, including

environmental control, and validation and routine control of sterilization
process according to harmonised standards;
-8-
iii. for devices in contact with human bodies, biocompatibility assessment (relevant
to annexes 2(AIMDD)/II(MDD) and 3(AIMDD)/III(MDD)) according to
harmonised standards;
iv. for devices manufactured from animal tissues, assessment of all aspects related
in particular to sourcing of raw material, processing and
inactivation/elimination of transmissible agents;
v. for active devices, assessment of safety and performance of programmable

electronic systems including software;
vi. the application of statistical controls to device verification (relevant to all

annexes);
vii. medicinal products.
c) Personnel involved in the assessment of quality systems (i.e. procedures

accordingtoannexes2(AIMDD)/II(MDD), 5(AIMDD)/V(MDD) and VI(MDD)) should
be qualified and capable of functioning in accordance with Guidelines for regulatory
auditing of quality systems of medical device manufacturers: Part 1 general
requirements . The management of quality systems assessments should be in
accordance with Guidelines for regulatory auditing of quality systems of medical
device manufacturers: Part 1 general requirements 10.
d) For each assessor, an up to date record11 should be maintained and include the
following information:
i. name of assessor;
ii. designated areas of competence and responsibility within the scope of activities
for which the Notified Body has been notified;
iii. educational and professional qualifications, skills, languages;
iv. work experience (relevant to the activities being performed);
v. audits conducted;
vi. details of training12 received relating to assessment activities, including training

in the requirements of the directive(s), relevant standards and other appropriate
documents.
10 Available from the following sources http://www.ghtf.org document reference SG4(99)28 or appendix C MEDDEV
2.5/2
11 Form for the preparation of a curriculum vitae for a Medical Device Expert is enclosed at Attachment 1.
12 An example of a training course format is enclosed in Attachment 2.
-9-
vii. for all auditors, including sub-contractors, documentation to confirm that there
has been no conflict of interest concerning the manufacturers audited .
5. Internal procedures and facilities - requirements
a) The Notified Body shall have appropriate structures and procedures to ensure that
conduct of conformity assessment and issuing of certificates is subject to a review
process. Relevant procedures shall in particular address obligations and responsibilities
in relation to suspension and withdrawal of certificates, imposition of corrective
measures to manufacturers and reporting to Competent Authority.
b) The Notified Body shall have available the appropriate facilities to enable it to carry out
the assessment and verification activities for which it has been notified.
Guidance
a) The facilities should enable the Notified Body to perform the technical and
administrative tasks connected with evaluation and verification, whether those tasks are
carried out by the Notified Body itself or under its responsibility (see also clause 8).
The Notified Body shall apply appropriate procedures of quality control in relation to
services provided.
If verification and testing procedures require use of technical equipment normally

controlled and used by the manufacturer, the Notified Body should be able to
demonstrate that it both had access to, and full control of, the equipment during the
relevant procedures. In addition, the Notified Body should be able to demonstrate that
the technical equipment was appropriately maintained, serviced and in calibration at the
time when verification and testing procedures are conducted.
6. Confidentiality requirements
a) The Notified Body shall have made adequate arrangements to ensure confidentiality of
the information obtained in the course of carrying out its tasks under the regulations.
These arrangements shall ensure that no details, records, results or information of any
kind are disclosed to any other party except the relevant Competent Authorities and the
manufacturer.
Guidance
a) Documented procedures should describe the means by which the Notified Body
maintains confidentiality between itself and the manufacturer. These should include
the mechanism through which assessment personnel are made aware of confidentiality
requirements. For example staff may be required to give a written undertaking not to
divulge any information gained about clients to third parties.
- 10 -
b) Guidance subclause 6(a) does not relate to :
i. the provision of access to certification information requested by other Notified

Bodies or Competent Authorities in accordance with the directives, or,
ii. the requirement to communicate information relating to the issue, refusal,

suspension or withdrawal of certificates to Competent Authorities and other
Notified Bodies, or;
iii. information pertaining to devices that when correctly put into service and used
in accordance with their intended purpose have been found to compromise the
health and/or safety of patients or users.
7. Liability insurance requirements
a) Provisions for misadventure : the Notified Body shall take out appropriate liability
insurance to provide for claims and litigation in the event of misadventure, unless
liability is assured under the domestic legislation of the Member State responsible for
the designation of the Notified Body.
Guidance
a) The scope and overall financial value of liability insurance should correspond to the
level of activities of the Notified Body. The liability insurance should in particular
cover cases where the Notified Body may be obliged to withdraw or suspend
certificates.
b) The coverage of liability insurance should be notified to the Competent Authority.
c) The coverage of liability insurance should be notified to the manufacturer on request.
8. Subcontracts requirements
a) Contract requirements: where specific tasks relating to conformity assessment are

carried out by subcontractors, the Notified Body shall ensure that these subcontractors
conform to all the requirements of the regulations that would apply, had the task been
performed by its own personnel. The manufacturers approval shall be obtained before
activities are subcontracted.
b) Limitation to scope: the Notified Body shall not subcontract the overall responsibility
for reviewing the outcome of assessment and verification activities, which are the
essential tasks for which it was notified. Subcontractors shall fulfil only an objective
role, that is, one, which is restricted to factual reporting and/or supported
recommendations, on the basis of which the Notified Body shall make assessments and
judgements in relation to the requirements of the regulations.
c) Documented agreement: a documented agreement shall be drawn up between the

Notified Body and the subcontractor reflecting these requirements, including
- 11 -
confidentiality and the provision of access for the Competent Authority. This
agreement shall also prohibit subcontractors from further subcontracting their duties.
d) Subcontractors documentation: the Notified Body shall ensure that the subcontracted
activities are carried out according to detailed documented procedures which are the
same as, or judged by the Notified Body to be equivalent to, those followed by the
Notified Body itself in the context of conformity assessment.
e) Competence: the competence of subcontractors may be assumed where they are

accredited by the Competent Authority or the authorised national accreditation body
according to Annex XI of 93/42/EEC or Annex 8 of 90/385/EEC and EN 45001 for the
scope under consideration..
f) Register: the Notified Body shall inform the Competent Authority of its intention to
subcontract duties in relation to the scope for which it was appointed. The Notified
Body shall keep an up to date register of all its subcontractors, which shall be provided
to the Competent Authority responsible for the designation on request. The Notified
Body shall maintain documentary evidence that the subcontractor has the necessary
technical competence and facilities to carry out the subcontracted activities.
Guidance
a) A Notified Body, which subcontracts duties in relation to the scope for which it was
notified remains in all cases responsible for all activities, covered by the notification.
The Notified Body should determine and specify in advance the tasks to be carried out
(e.g. test plans). Subcontracting does not entail the delegation of powers of
responsibilities. The subcontractor register maintained by the Notified Body should
include the following information:
i. the name of the subcontractor,
ii. its legal status and details of any relationship with a parent company, group of
companies, or any other organisation to which the subcontractor is linked,
iii. names of staff carrying out the subcontracted activities and evidence that they
are competent to do so (see also clause 4);
iv. the precise duty performed by the subcontractor (e.g. auditing, testing, etc.) and
details of the procedures used in carrying out the subcontracted duties
b) A Notified Body which subcontracts duties should document the means by which it
ensures that the principle of impartiality is made known to subcontractors and
safeguarded by the subcontractor carrying out tests or audits on behalf of the Notified
Body.
c) The conditions of this clause apply to any subcontractor whether or not it is located on
Community territory. Subcontractors are not necessarily resident in the Community but
their activities are defined by contract, which is interpreted under the law of the
Member State responsible for the designation of the Notified Body.
- 12 -
9. Notified Bodys quality system requirements
a) The Notified Body shall establish and maintain up to date documented procedures and
records which, together, demonstrate its compliance with the regulations. As
appropriate, this documentation shall include the following.
i. a description of the legal status of the Notified Body, including the links and
relationship with parent organisation, if relevant,
ii. documentation showing the responsibilities and reporting structure of the Notified
Body,
iii. a rationale for defining the scope of the responsibilities for each of the assessment
personnel,
iv. the names of assessment personnel, both internal and subcontracted, their assessment
responsibilities, and records of their relevant training and experience (see also clause
4);
v. procedures for the identification review and resolution of all cases where conflict of
interests is suspected or proven;
vi. a description of the application process by which manufacturers can obtain third party
approval by the Notified Body. The document shall specify which languages are
acceptable for submissions and correspondence from manufacturers relating to their
demonstration of compliance with the requirements of the directives,
vii. procedures to review applications in respect to the manufacturers classifications of his

medical devices,
viii. procedures to review the completeness of application against the details provided in the
annex under which approval has been sought,
ix. procedures to evaluate and verify manufacturers compliance with their chosen
annexes,
x. procedures detailing the rationale for fixing time limits for completion of evaluation
and verification activities,
xi. procedures for the demarcation between other Directives such as 65/65/EEC,
xii. procedures for the assessment of clinical data: if applicable, where the results have
been derived from clinical investigations the Notified Body shall ensure that the
conclusions drawn by the manufacturer are valid in the light of the plan of clinical
investigation submitted to the Competent Authority.
xiii. procedures to take account of information on medical devices subject to pre-existing

national law, regulations or administrative provisions,
xiv. records to demonstrate the conclusions of the assessment including a reasoned

evaluation of the manufacturers compliance with the requirements of the relevant
- 13 -
directive. For quality assessments, records should be available which provide a
discernible audit trail (e.g. procedures, processes, records, products etc that were
assessed),
xv. procedures for the consideration of appeals against decisions made by the Notified
Body regarding :
* the interpretation of classification rules, including referral to the Competent

Authority where necessary;
* a manufacturers compliance with the requirements of the directives.
xvi. procedures relating to the issue, expiration, withdrawal and suspension of certificates,
including action to be taken in the event of the Notified Body learning that a CE mark
has been wrongly affixed to a device or to a product outside the scope of medical
devices directives. These procedures shall include a requirement to inform the
Competent Authority forthwith of any such action taken,
xvii. details of obligations regarding communications with other organisations, including

Competent Authorities, the Commission and other Notified Bodies (ie about all
certificates suspended or withdrawn and on request about certificates issued or refused
and any additional relevant information), and the means adopted for these
communications. The documentation shall also include records of all communications
with the Commission and action taken as a result of such communications. (e.g. in
respect to safeguard issues) These records shall be made available to the Competent
Authority on request,
xviii. procedures for assessing and monitoring the competence of subcontractors, if used,
xix. details of record keeping facilities including means to ensure security and
confidentiality,
xx. details about liability insurance,
xxi. documentation about its financial situation, including accounts,
xxii. details about fees and financial conditions for the conduct of conformity assessment,
xxiii procedure for the provision of information in relation to the EUDAMED database.
b) Control: a system shall be maintained to control all quality system documentation and
to ensure that current issues of procedures are available at all relevant locations
c) The Notified Body shall ensure that the defined quality system procedures are
effectively implemented
- 14 -
Guidance
a) The description of the application process, subclause 9a(vi.), may be the description of
the certification system required to be made available in published form by the
EN45000 series of standards
- 15 -
III. RELATIONSHIP BETWEEN COMPETENT AUTHORITY RESPONSIBLE FOR
DESIGNATION AND NOTIFIED BODIES
1. Reporting
Notified Bodies shall without delay inform the Competent Authority responsible for their
designation of any changes/additions to personnel, facilities or subcontractors which might
effect their ability to cover the Annexes and product range which they have been designated
(e.g. change in management, replacement/addition/loss of specific expertise, change in
facilities).
Information on Certificates suspended or withdrawn must be forwarded without delay to the

Competent Authority and other Notified Bodies for information and also forwarding to
EUDAMED. On request, the Notified Body shall provide information about certificates issued
or refused and shall also make available all additional relevant information.
2. Designation of Notified Bodies operations by the Competent Authority responsible for

designation.
Pre assessment prior to designation by the Competent Authority.
Scope: Prior to designation by the Competent Authority there will be a pre-assessment

to ensure that the candidate Notified Body fulfils the requirements detailed in
section II of this document. The Competent Authority will obtain evidence
about the competence and independence of the candidate Notified Body and its
subcontractors by an assessment of relevant documentation. If successful the
Competent Authority will inform the Commission and Member States ref.
article 11 of the AIMDD, and article 16 of the MDD.
Timing: The pre-assessment of the candidate Notified Body should take place within six
months after their application to the Competent Authority for designation.
Personnel: Assessment personnel shall be competent for the functions they perform. They
shall have knowledge and experience in Medical Devices Directive regulations,
the EN 45000 and EN46000 series and other harmonized standards, and the
application of this document.
Reference document: Section II and the relevant Appendices of this document. Annex
8 of the AIMDD and Annex X1 of the MDD
- 16 -
3. Monitoring of Notified Bodies operations by the Competent Authority responsible for
designation.
A. Initial and Surveillance Audits
Initial and surveillance audits are performed by the Competent Authority at a Notified Bodys,
and if applicable its subcontractors, facilities
Scope: Initial audits are intended to cover all the operational activities set out in section
II and the relevant Appendices of this document in order to check compliance
against the Directive/Regulations/Standards and the bodys own procedures.
Surveillance audits are intended to cover specific operational activities set out in
section II and the relevant Appendices of this document in order to check
compliance against Directive/Regulations/Standards and the bodys own
procedures. Special attention should be focused on case review of the
certification process under all the Annexes within the notified bodys scope
including initial application by the manufacturer to the Notified Body,
assessment, certification and ongoing manufacturer surveillance.
Frequency: Initial audits are the first audits performed by the Competent Authority.
Surveillance audits of the Notified Body site should take place at least every 18
months unless the Notified Body has performed no assessments since the
previous surveillance. However such audits could be brought forward if
considered necessary for example
- Major problems at initial or previous surveillance audit.
- Extension to scope
- Significant vigilance or regulatory compliance cases for a manufacturer covered

by the Notified Body
- Complaints received on a Notified body
- Large volume of work
Subcontractors who are solely carrying out a testing function need not be audited if they have
national accreditation for those tests and fulfil the relevant criteria of Annex 8 of 90/385/EEC
or Annex XI of 93/42/EEC. However it may be necessary to perform random surveillance
audits on sub-contractors carrying out tests for which they have no such accreditation.
Personnel: Audit personnel shall be competent for the functions they perform. The team
should consist of assessors with knowledge and experience in Medical Devices
Directive regulations, the EN 46000 series and harmonized standards, and the
application of this document with related medical expertise and medical devices
specialists if review of design dossiers or testing is involved.
- 17 -
Duration: This will depend on the scope of Annexes and products covered, along with the
number of clients for which certification has been granted. A minimum of 3
man days should be applied for initial audits and a minimum of one man day
should be appliedfor surveillance audits.
Reference document: section II and the relevant Appendices of this document
B. Observed audits
Observed audits are performed by the Competent Authority during a Notified Body Quality
Assurance audit of a manufacturer during the process of an Annex 2(AIMDD) /II(MDD),
5(AIMDD)/V(MDD)/ and VI(MDD) approval or where design dossier review or NB testing is
carried out by the Notified Body at the manufacturers site.
Scope: Observed audits are intended to cover specific operational activities in order to
check the Notified Bodys compliance against the Directive/Regulations/
Standards and the bodys own procedures. Where a pre-assessment is
performed as part of the overall assessment this should also be observed
(Note: wherever possible relevant observed audits should be conducted during a
full Notified Body assessment rather than a more limited interim assessment by
the Notified Body)
Frequency: observed audits of the Notified Body may be considered under the following
circumstances but at least every 18 months:
- one of the Notified Bodys first QA assessments following designation;
- the number of certificates granted
- where relevant in conjunction with, or as a result of, an initial or surveillance

audit
- extension to scope
- significant vigilance or regulatory compliance cases for a manufacturer covered

by the Notified Body
- complaints received on a Notified Body
- where testing is carried out by the Notified Body at the manufacturers site.
- significant growth involving new personnel, training methods, etc
- large volume of work
- 18 -
Personnel: The assessor should have knowledge and experience in Medical devices directives
regulations, the EN 46000 series and harmonised standards and the application of
this document see also initial and surveillance audits.
Duration: dictated by Notified Bodys audit plan
Reference Documents:
Guidelines for regulatory auditing of quality systems of medical device manufacturers: Part 1
general requirements.
The responsibilities of the Notified Body under the Medical Device Directives Document,
Attachment 3,
Special rules of accreditation for Certification Bodies of Quality Systems (scope Sterile
Medical Device"), Attachment 4.
C. Spot checks
Competent Authorities should follow up with Notified Bodies specific cases, which
have been reported to them (eg Vigilance reports, regulatory compliance cases,
information received from other Competent Authorities)
- 19 -
APPENDIX - A
A1. Introduction
The following requirements are detailed in the specific annexes of the Directives under which
Notified Bodies offer their services. Further details can be found in the relevant annexes of
the particular directives. A document detailing the responsibilities of the Notified Body under
Medical Device Directive 93/42/EEC is at attachment 3.
A2. Annex 2 of AIMDD and Annex II of MDD
a) Quality system
i. Notified Bodies have to approve the quality system, which must ensure that the medical
devices conform to the provisions of the relevant Directive, which apply to them at
every stage, from design to final inspection. Based on relevant technical
documentation, Notified Bodies shall review the elements, requirements and provisions
adopted by the manufacturer including those in relation to fulfilling the essential
requirements including the risk analysis. This shall be performed in reference to the
class of the device. The documentation samples shall be chosen to reflect the risks
associated with the intended use for the device, the complexity of the manufacturing
technologies, the range of devices produced and any available post market surveillance
data;
ii Notified Bodies shall ensure that personnel (whether directly employed or

subcontracted) carrying out quality assurance audits are appropriately trained and
experienced in the application of the Medical Devices Regulations and relevant
harmonised standards;
iii. Notified Bodies and/or their subcontractors shall have appropriate facilities for
conducting quality systems audits on manufacturers premises. They shall ensure that
the outcome of the evaluation, notified to the manufacture after the inspection, includes
a reasoned evaluation;
iv. The Notified Body shall have documented procedures for dealing with notifications
from manufacturers of proposed changes in their certified quality systems or the
product-range covered. They shall ensure that manufacturers are informed as to whether
the modified quality system will meet the requirements of the relevant directive. This
decision shall include a reasoned evaluation.
b) Design dossier
i. The Notified Body shall have procedures, sufficient expertise and facilities for the
examination of design dossiers, relating to active implantable medical devices or class
- 20 -
III medical devices.Appropriately qualified personnel shall carry out examination of
design dossiers.
ii. For dossiers covering devices which incorporate a medicinal product acting in a manner
ancillary to that of the device, the Notified Body shall have procedures to identify such
devices and, in consideration of the application, enable consultation with the relevant
authority for medicinal products. The Notified Body shall ensure its final decision is
communicated to the authority consulted. A description of the consultation process is
given in MED DEV 2.1/3.
iii. The Notified Body shall have procedures for the production of EC design examination
certificates. The certificates should include their conditions of validity, the data needed
for identification of the approved design, and (where appropriate) a description of the
intended use of the product.
iv. The Notified Body shall have procedures for checking the significance of changes to
the design dossier notified by the manufacturer: this shall include an evaluation of
whether appropriate changes have been made to the manufacturers quality system.
Approval shall be given in the form of a addendum to the EC design-examination
certificate.
c) Surveillance
i. The Notified Body shall have procedures, which define how and when surveillance
inspections and evaluations of manufacturers quality systems are to be carried out and
how unannounced visits to manufacturers are to be conducted. Manufacturers shall be
supplied with evaluation reports following all inspections.
d) Administration procedures
i The Notified Body shall have facilities for communicating all relevant information on
approvals of quality systems issued, refused, suspended or withdrawn to the Competent
Authority and other Notified Bodies on request.
A3. Annex 3 of AIMDD & Annex III of MDD
a) Type examination
i. The Notified Body must carry out or arrange for the appropriate inspections and the
tests necessary to verify whether the solutions adopted by the manufacturer meets the
essential requirements of the Directive. All relevant and critical parameters shall be
verified by the Notified Body or subcontractor under its responsibility.
ii. Notified Bodies and/or their subcontractors shall have suitable facilities and procedures
to examine and evaluate the documentation, to verify that the type has been
manufactured in accordance with the documentation, and for performing the
- 21 -
appropriate inspections and tests to verify compliance with the essential requirements,
including risk analysis, of the relevant directive.
iii. The Notified Body shall make provision to issue an EC type-examination certificate to
the manufacturer where the type meets the provisions of the relevant directive. It shall
contain the name and address of the manufacturer, the conclusions of the control, the
conditions under which the certificate is valid and the information necessary for
identification of the type approved. The relevant parts of the documentation must be
annexed to the certificate.
iv. For devices which incorporate a medicinal product acting in a manner ancillary to that
of the device, the Notified Body shall have procedures to identify such devices and, in
consideration of the application, enable consultation with the relevant authority for
medicinal products. The Notified Body shall ensure its final decision is communicated
to the authority consulted
v. The Notified Body shall have documented procedures for reviewing changes to the
approved product. When the change is considered to be satisfactory, they shall issue to
the manufacturer a supplement to the initial EC type-examination certificate.
b) Administration procedures
i. The Notified Body shall have facilities for communicating all relevant information on
EC type-examination certificates and supplements issued, refused, suspended or
withdrawn to the Competent Authority and other Notified Bodies when requested.
A4. Annex 4 of AIMDD and Annex IV of MDD
i. The Notified Body must carry out the appropriate examinations and tests in order to
verify the conformity of the product with the requirements of the Directive. Relevant
and critical parameters shall be tested by the Notified Body or under its responsibility.
ii. Notified Bodies and/or their subcontractors shall have available suitable facilities and
procedures for examination and testing of products to verify that they conform to the
requirements of the relevant directive.
iii. The Notified Body shall make provision for examining and testing products on a
statistical sampling basis for each homogeneously produced batch or, in addition for the
medical devices directive on an individual product basis, and draw up a written
certificate of conformity relating to the tests carried out
iv. The Notified Body shall have procedures to ensure that any rejected product or batch of
products is prevented from being placed on the market and in the case of frequent
rejection of batches to suspend statistical verification.
A5. Annex 5 of AIMDD and Annex V-VI of MDD
- 22 -
a) Quality system
i. Notified Bodies have to approve the quality system for the manufacture and final
inspection of the products concerned. The quality system must ensure that the medical
devices conform to the type described in the EC type-examination certificate or the
technical documentation, respectively. Based on relevant technical documentation
Notified Bodies shall review the elements, requirements and provisions adopted by the
manufacturer including those in relation to fulfilling the essential requirements
including the risk analysis. The documentation samples shall be chosen to reflect the
risks associated with the intended use for the device, the complexity of the
manufacturing technologies, the range of devices produced and any available post
market surveillance data;
ii. Notified Bodies shall ensure that personnel (whether directly employed or
subcontracted) carrying out quality assurance audits are appropriately trained and
experienced in the application of relevant harmonised standards.
iii. Notified Bodies and/or their subcontractors shall have appropriate facilities for
conducting quality systems audits on manufacturers premises. They shall ensure that
the outcome of the evaluation, notified to the manufacture after the inspection, includes
a reasoned evaluation.
iv. The Notified Body shall have documented procedures for dealing with notifications
from manufacturers of proposed changes in their certified quality systems. They shall
ensure that manufacturers are advised as to whether the modified quality system would
meet the requirements of the relevant directive. This decision shall include a reasoned
evaluation.
b) Surveillance
i The Notified Body shall have procedures, which define how and when surveillance
audits and evaluations of manufacturers quality systems are to be carried out and how
unannounced visits to manufacturers are to be conducted. Manufacturers shall be
supplied with evaluation reports following all audits.
c) Administration procedures
i. The Notified Body shall have facilities for communicating all relevant information on
approvals of quality systems issued, refused, suspended or withdrawn to the Competent
Authority and other Notified Bodies on request.
- 23 -
APPENDIX - B
13
Certif-Document ( ):
96/03 rev 4 Procedure for designation of conformity assessment bodies(CABs) under mutual
recognition agreements (MRAs) with non member countries.
(13)
(Certif.Documents are working documents of the Senior Officials Group for Standardisation, chaired by the European
Commission - DG ENTERPRISE -Directorate G. They can be request at CEC-DG ENTR/G/1 - tel.+32-2-295 13 04)
- 24 -
APPENDIX - C
LIST OF GUIDANCES DOCUMENTS ON MEDICAL DEVICES
""" see last Updated Guidance in web site Unit G/4"""
APPENDIX - D
Council directive 93/42/EC in relation to Medical Devices.
Harmonized standards
Collated list of harmonised standards available at the following web address:

http://www.europa.eu.int/comm/enterprise/newapproach/standardization/harmstds/
OJ C 245 of 23 August 1996
OJ C 149 of May 17 1997
OJ C 338 of November 8 1997
OJ C 362 of December 6 1997
OJ C 144 of May 9 1998
OJ C 268 of August 27 1998
OJ C 181 of June 26 1999
OJ C 277 of August 10 1999
OJ C 288 October 9 1999
-----------((()))----------
Attachments 1 to 4 : See on separate documents
- 25 -
Attachment 1
Antragsteller
Applicant
Verfahrensnummer
Procedure number
Attachment1
MEDDEV 2.10-2 Rev 1
April 2001
Qualifikation des Personals

Qualification of personnel
1 Angaben zur Person

personal data
Titel, Name, Vorname

title, name, first name
Geburtsdatum
date of birth
Nationalitt
nationality
Sprachen
languages
Anmerkung
Die benennende Behrde erklrt, da die Daten nur zu Zwecken des Akkreditierungs- und
Benennungsverfahrens verwendet werden.
Note
The Designating Authority declares, that any data is only used in relation with the accreditation and designation process.
MEDDEV 2.10/2 Attachment 1 12/99 1/11

Verfahrensnummer
Procedure number
2 Einsatzgebiet
field of operation
Die oben bezeichnete Person ist

The above named person is
G voll-/teilzeitbeschftigter Mitarbeiter des Antragstellers
a full-time/part-time employee of the applicant
G Mitarbeiter auf Honorarbasis
an employee on freelance-basis
G Unterauftragnehmer (Werkvertrag)
subcontractor
und wird eingesetzt als
and will be engaged as
G Auditor
auditor
G Leitender Auditor
lead auditor
G Fachexperte im Auditteam
technical expert in an auditing team
G Fachexperte Prfung
expert in testing
G Fachzertifizierer
expert in certification
Sie verfgt ber spezielle Kenntnisse auf den Gebieten
The person has special knowledge in the field of
G Konformittsbewertungsverfahren nach Medizinprodukterecht und
Richtlinie 93/42/EWG oder 90/385/EWG
conformity assessment procedures according to the medical device law and the Directives 93/42/EEC or
90/385/EEC
G Qualittswesen (DIN EN ISO 9001 ff, DIN EN 46001 f, ISO 13485/88 ...)
quality systems (ISO 9001 ff, EN 46001 ff, ISO 13485 ...)

Verfahrensnummer
Procedure number
ber spezielle Kenntnisse auf den Gebieten

and special knowledge in the field of
G Bewertung von Risiken und Nebenwirkungen
evaluation of risks and side effects
G Chemische Prfung und Bewertung
chemical testing and evaluation
G Physikalische Prfung und Bewertung
physical testing and evaluation
G Biologische Prfung und Bewertung
biological testing and evaluation
G Klinische Prfung und Bewertung
clinical testing and evaluation
G Mikrobiologie, Hygiene und Sterilisation
microbiology, hygiene and sterilization
G Verarbeitung, Konservierung, Prfung und Behandlung von Geweben, Zellen und
Stoffen tierischen Ursprungs
processing, preservation, testing and treatment of tissues, cells and substances of animal origin
G Verarbeitung, Konservierung, Prfung und Behandlung von Geweben, Zellen und
Stoffen menschlichen Ursprungs
processing, preservation, testing and treatment of tissues, cells and substances of human origin
G Wechselwirkung mit Arzneimitteln
interaction with medicinal products
G Werkstoff- und Fertigungstechnik
material and manufacturing techniques
G Umgebungsberwachung
environmental control
G Produkt- und Verpackungsstabilitt
product and packaging stability
G .........................................................................................................................
G .........................................................................................................................
ber Kenntnisse und Erfahrungen in folgenden Verfahrens-/Fertigungstechniken
knowledge and experience in the following manufacturing technologies
G Dnn-, Dickschichttechnik
thin and thick film technology
G Feinmechanik, Optik
precision mechanics and optics
G Fertigung in Reinrumen
cleanroom manufacturing
G Aseptische Bereitung
aseptic processing
G Fgetechnik
welding techniques
G Keramische Fertigungstechniken
manufacturing techniques for ceramics
G Kunststoffverarbeitung (Extrusion, Spritzgu, ...)
polymer processing (extrusion, injection moulding, ...)
G Metallverarbeitung (Urform-, Umformtechnik, ...)
metall processing (prototyping, reshaping, ...)
G Textil-/Faserverarbeitung, Webtechniken
textile/fiber processing, weaving technologies
G Verfahrenstechnik
process techniques
G Verpackungstechnologien
packaging technologies
G

Verfahrensnummer
Procedure number
und Kenntnisse ber folgende Medizinprodukte sowie deren

Produktionstechniken/Herstellungsverfahren und Anwendung Produkt Produk- Anwen-
and knowledge of the following medical devices and/or their production techniques/ tion dung
manufacturing processes and application product production application
Nichtaktive Medizinprodukte
non-active medical devices
Implantate und medizinische Einmalprodukte

implants and disposable medical devices
Skelettimplantate G G G
orthopaedic implants
Weichteilimplantate G G G
soft tissue implants
Funktionsimplantate G G G
function implants
Medizinische Einmalprodukte G G G
disposable medical devices
Nichtaktive medizinische Instrumente zur Mehrfachverwendung
reusable non-active medical instruments
Produkte zur Ansthesie G G G
anesthetic products
Produkte zur Orthopdie und Rehabilitation G G G
orthopaedic and rehabilitation products
Nichtenergetische medizinische Metechnik G G G
non-energy medical instrumentation
Produkte zur Wundversorgung
products for wound care
Verbandmittel, Wundauflagen G G G
bandages and dressings
Naht- und Klammermaterial G G G
suture material and clamps
Sonstige Medizinprodukte zur Wundversorgung G G G
other medical devices for wound care
Zahnrztliche Hilfsmittel und Werkstoffe
dental accessories and materials
Zahnrztliche Ausrstung und Instrumente G G G
dental equipment and instruments
Werkstoffe fr die Zahnheilkunde G G G
dental materials
Dentalimplantate G G G
dental implants
Sonstige
others
G G G
G G G
G G G
G G G
G G G
G G G
G G G

Verfahrensnummer
Procedure number
und Kenntnisse ber folgende Medizinprodukte sowie deren

Produktionstechniken/Herstellungsverfahren und Anwendung Produkt Produk- Anwen-
and knowledge of the following medical devices and/or their production techniques/ tion dung
manufacturing processes and application product production application
Aktive Medizinprodukte
active medical devices
Gerte zur berwachung und Bestimmung von Vitalparametern G G G

monitoring devices
Gerte fr extrakorporale Kreislufe, Infusionen sowie zur G G G
Hmopherese
diveces for extracorporal circulation, infusion und haemophoreses
Beatmungs-, Sauerstofftherapie- und Inhalationsnarkosegerte G G G
respiratory devices, devices for oxygen therapy and others
Chirurgiegerte und Chirurgiehilfsgerte G G G

surgical devices
Gerte fr bildgebene Verfahren
devices for imaging processing
1. Gerte mit ionisierenden Strahlen G G G
devices for ionizing rays
2. Gerte mit nicht ionisierenden Strahlen G G G
equipment for non-ionizing rays
Strahlentherapiegerte
devices for stimulation
1. Gerte mit ionisierenden Strahlen G G G
devices for ionizing rays
2. Gerte mit nicht ionisierenden Strahlen G G G
equipment for non-ionizing rays
Gerte zur Stimulation G G G
devices for stimulation
Opthalmologische Gerte G G G
opthalmic devices
Dentalgerte G G G
dental devices
Gerte zur Desinfektion und Sterilisation G G G
devices for disfection and sterilisation
Rehabilitationsgerte und aktive Prothesen G G G
rehabilitation devices and active prothesis
Patientenlagerungs- und Transporteinrichtungen G G G
devices for patient positioning and transport
Medizinische Versorungseinheiten G G G
medical supply units
Aktive Implantate G G G
active implantable medical devices
Sonstige G G G
Others
G G G
G G G
G G G
G G G
G G G

Verfahrensnummer
Procedure number
3 Ausbildung
education
von - bis Schul-/ Fachrichtung Abschlu
Hochschulausbildung
from to college/university subject(s) degree/qualification
Weitere Qualifikationen (insbesondere Qualittswesen, Konformittsbewertung nach

EG-Richtlinien 93/42/EWG und 90/385)
Additional qualifications (especially quality management, conformity assessment according to EC directives 93/42/EEC and
90/385/EEC)
von - bis Schulungsorganisation Titel des Schulungskurses Erreichter Abschlu/
Qualifikation
from to training organization title of course degree/qualification

Verfahrensnummer
Procedure number
4 Beruflicher Werdegang
curriculum vitae (professional)
von - bis Arbeitgeber Abteilung / Position Verantwortlichkeiten im Produkt-/
Technologiebereich/Qualittswesen
from - to employer branch / position responsibilities with respect to products/
technologies/quality assurance/quality
management

Verfahrensnummer
Procedure number
5 Beschreibung der derzeitigen Ttigkeit

description of the present working activities
G im Qualittswesen und/oder
in quality assurance/quality management and/or
G in den vorgenannten Produktbereichen sowie
with respect to the aforementioned products and
G Darlegung der Technologieerfahrung
explanation of the technology experience

Verfahrensnummer
Procedure number
6 Sonstige Erfahrungen
other experience
6.1 Mitarbeit in nationalen und internationalen Normungsorganisationen

participation in national and international standardization organizations
6.2 Mitarbeit in Gremien der Europischen Kommission, der Benennenden Behrden,

in wissenschaftlichen Gesellschaften, und in sonstigen Organisationen, die sich
mit Medizinprodukten, speziellen Fachgebieten oder dem Qualittswesen
befassen
participation in committees of the European Commission, Designating Authorities, scientific societies, and other
organizations working with medical devices, other special fields or quality assurance
6.3 Eigene relevante Verffentlichungen

own relevant publications

Verfahrensnummer
Procedure number
7 Teilnahme an externen Audits in den letzten zwei Jahren

participation in external audits within the last two years
Datum und auditiertes Unternehmen Leitender Auditor (LA) Nach welchem Regelwerk wurde
Dauer audited company oder Auditor (A) auditiert?
date and lead auditor (LA) or basis of the audit (e.g. ISO 9000,
duration auditor (A) EN 46000, MDD, GMP, ...)

Verfahrensnummer
Procedure number
8 Ttigkeit als Auditor

activity as auditor
8.1 Gesamtzahl Audits

Total number of audits
Bislang wurden ............ externe Audits
Until now external audits
mit insgesamt ............ Audittagen vor Ort durchgefhrt.
with a total number of days at the manufacturers facilities have been performed.
8.2 Anzahl der Audits nach EG-Richtlinie 93/42/EWG

Total number of audits according to Directive 93/42/EEC
Bislang wurden ............ externe Audits nach Richtlinie 93/42/EWG
Until now external audits according to Directive 93/42/EEC
mit insgesamt ............ Audittagen vor Ort durchgefhrt.
with a total number of days at the manufacturers facilities have been performed.
8.3 Datum der Berufung zum leitenden Auditor

Date of appointment as lead auditor
Vor der Berufung zum leitenden Auditor am ............................... wurden
Prior to the appointment as a lead auditor dated a total number of
......... externe Audits mit insgesamt ......... Audittagen vor Ort durchgefhrt.
external audits with a total number of days at the manufacturers facilities have been performed.
9 Beratung von Unternehmen

Consultation of companies
von - bis Unternehmen Art der Beratung
from - to company type of consultation
Fr die Vollstndigkeit und Richtigkeit der Angaben

For completeness and correctness
________________ ________________
Datum/date Datum/date
________________________ ________________________
Unterschrift Auditor/Fachexperte Unterschrift Antragsteller
signature auditor/expert signature applicant

Attachment 2
Attachment 2
MEDDEV 2.10-2 Rev 1
April 2001
Day 1
07:45 Registration.
08:00 Session 1.1 Welcome & Introductions
Aims & Objectives of the Course
08.30 Session 1.2 Development of Directives & Quality Management Systems
- Directives
- Consumer Protection
- Medical Device Directives
- Regulatory Systems
- Quality Systems & Global Harmonisation
- Medical Device Directive Overview
9:45 Session 1.3 Role of Product and System Standards ( Hierarchy of 'Horizontal' & 'Vertical'
Standards )
Harmonisation of Standards
10:15 Session 1.4 Duality System R 1 Requirements

- ISO 9001/2, EN 46001/2, ISO 13485/8
FDAcGMP (QSR)
- ISO 9000-2; EN 50103; EN 724, EN 928;
IS014969 (draft); EN1441,
11:30 Session 1.5 Workshop 1; Assessments in the Context of the Directives;

Whatabout Class 1 devices?
(Team Exercise)
12:00 Session 1.6 Workshop 1: Report back
12:15 Session 1.7. Risk Analysis.
2:00 Session 1.8. Case Study: Workshop 2, Risk Analysis
3:00 Session 1.9 Case Study: Workthoo, 2: Report back.

3:30 Session 1.10Practical Applications, 1
- Regulatory Structures
- Competent Authorities 1 Notified Bodies
4:00 CLOSE
Day 2
8:00 Session 2.1 Practical Applications 2
- Classification
- Conformity Assessment Routes
9:00 Session 2.2 Practical Applications 3

- Design Control for Existing Products
- Private Labeling
9:45 Session 2.3 Case Study: Workshop 3

- Technical Documentation and Essential Requirements (Team Exercise)
11:00 Session 2.4 Case Study: Workshop 3: Report Back
12:30 Session 2.5 Tech. Documentation, Design Dossier

Declaration of Conformity
1:00 Session 2.6 Essential Requirements & Administrative Issues
1:30 Session 2.7 Clinical Evaluation/investigation

- EN540.&Annex X
- Post Market Surveillance and Vigilance
2:15 Session 2.8 Labelling and 'Instructions for Use'
3:15 Session 2.9 Compliance with the Directive and National Requirements
4:00 CLOSE
program new us. 149
Day 3
8:00 Session 3.1 New Provisions of MDD in Article 21 of IVDD (98/79/EEC)
8:30. Session 3.2 Process Validation - Sterilization as an Example
9:45 Session 3.3 Workshop 5: Course Review/Delegate Issues
10:15 Session 3.4 Examination (optional)
1:00 END OF COURSE
(At the delegates' request Day 3 can be started at 7:30 am and the programme advanced by a 1/2 hour
to enable an earlier finish)
------ ooo -----

Attachment 3
Attachment 3
MEDDEV 2.10-2 Rev 1
April 2001
UK MEDICAL DEVICES NOTIFIED BODY GROUP
UK POSITION PAPER (Nov 1997 plus Annex IV)
The Responsibilities of the Notified Body

Under Medical Device Directive 93/42/EEC
1. Scope
To define the responsibilities of the Notified Body when undertaking certification

to Annexes II, III, IV, V and VI, and then to indicate the level of competency
required by the assessment team.
2. Background
These outline responsibilities are those directly required of the Notified Body by
the directive disregarding any current national practice. They were agreed by
joint meetings of the UK Competent Authority, UK manufacturers (ABHI) and
delegates representing all UK Notified Bodies.
3. Requirements of the Notified Body
3.1 General
3.1.1 To check the manufacturer has followed his declared procedures and
those required by the directive. The manufacturer through the EC
Declaration of Conformity takes the ultimate responsibility for device
safety and product liability. The Notified Body has a responsibility to
monitor the manufacturers system for producing the Declaration of
Conformity for all Classes of device except Class 1 (non sterile/non
measuring).
3.1.2 To agree the device classification with the manufacturer and whether
the application is within the scope of the directive. The manufacturer
will be asked to submit a classification of his device or device category
at the application stage for consideration by the Notified Body. The
final responsibility for classification remains with the manufacturer.
3.1.3 To refer to the Competent Authority instances where previously agreed

clinical trial protocols have not been followed.
3.1.4 To check the correct use of the CE mark.
1 of 5
3.1.5 To ensure the manufacturer has informed the Notified Body of any
significant changes to its products, processes or QA systems since the
last audit.
3.1.6 To check the manufacturers procedure for reviewing experience in the

post-production phase.
Note: 3.1.1, 3.1.5 and 3.1.6 do not normally apply for certification under Annex III and
IV.
3.2 Annex II
3.2.1 To audit the quality systems to the requirements of Annex II using the
current EN 46001 as a basis for the audit (EN 46001:1996 as of 6/97)
plus regulatory requirements of 93/42/EEC. There is no requirement in
the Directive for the Annex II assessment to be different depending on
whether Class IIa or IIb devices are involved.
3.2.2 If sterilisation or sterility are involved to include a technical evaluation

by a suitably competent person.
3.2.3 To assess that the procedures for process control, inspection and
testing are appropriate for that type of device and are in conformity
with those indicated in the technical documentation.
3.2.4 To assess the procedures for controlling, monitoring and verifying the
design of the device and its compliance with the requirements of the
directive. To assess the capability of the manufacturer to use and
interpret in the design process the essential requirements and the
relevant standards for all product technologies used by the
manufacturer. This includes checking the procedures for producing
the Declaration of Conformity, and checking the content of the
Declarations themselves on a sample basis to gain confidence that
they are in the correct format and properly specify the products to
which they apply. There is no requirement to check technical files for
every device, but some should be checked on a sample basis as part
of the audit of the design process (including use of clinical data, risk
analysis and other technical assessments) in order to gain confidence
that the products meet the ERs.
3.2.5 For Class 3 devices to undertake an EC Design Examination. The

objective is to confirm that the product conforms to the relevant
provisions of the Directive by verifying the items listed below.
- the conclusions of the risk analysis;
- that the applicable essential requirements have been addressed;
2 of 5
- that relevant standards have been applied or that the solutions
adopted, in the absence of standards, meet the essential
requirements;
- the conclusions of the clinical data.
- The Notified Body may require further tests or other data during
this procedure.
3.2.6 - For Class III devices only, the Notified Body must also approve
changes which could affect the products conformity with the
Essential Requirements or the conditions of use.
3.3 Annex III
3.3.1 To verify that the device is in conformity with the technical

documentation.
3.3.2 To agree with the manufacturer which standards or protocols are

applicable and which tests are required to verify compliance with the
3.3.3 To test or inspect to verify the solutions satisfy the Essential

Requirements:
- using standards referred to in Article 5 where it is agreed that

these apply;
- or using other standards or protocols designed by the

manufacturer where it is agreed that these verify compliance with
the Essential Requirements.
3.3.4 To verify conclusions drawn from clinical data, risk analysis and other
technical assessments.
3.3.5 To issue, if relevant an EC type-examination certificate with five-year

validity.
3.3.6 When a manufacturer informs the Notified Body that a device

previously granted an EC type Examination Certificate has undergone
a significant change, to reassess the device prior to the manufacturer
placing the changed device on the market.
3.4 Annex IV
3.4.1 To verify that the type is in conformity with the technical

documentation.
3 of 5
3.4.2 Prepare a plan to ensure sufficient and consistent application of tests
and inspections.
3.4.3 To test each product or, where the batch size exceeds 50 and the
manufacturer does not choose otherwise, random samples taken from
a homogeneous batch according to the sampling plan described in
Annex IV.
3.4.4 If relevant, to prepare an Annex IV verification certificate specific to the

product and limited to the batch or samples subjected to the
verification process.
3.4.5 To ensure that the identification number of the Notified Body appears
adjacent to the CE mark.
3.4.6 To take measures to prevent non-conforming samples or batches from

being placed on the market.
3.4.7 For products supplied sterile1, to ensure that the appropriate parts of
Annex V have been applied.
3.4.8 As a non-statutory duty, the Notified Body may wish to examine the
declaration of conformity, the technical documentation and the
undertakings of the manufacturer.
3.5 Annex V
3.5.1 To audit the quality systems to the requirements of Annex V using the
current EN 46002 as a basis for the audit (EN 46002:1996 as of 6/97)
plus the regulatory requirements of 93.42.
3.5.2 For Class 2b and 3 devices, to check the validity of the EC Type
Examination Certification and that production conforms to the type
certificated. There is no responsibility to check the validity of the
design solution, test reports, clinical date etc. This is the responsibility
of the Notified Body that undertakes the EC Type Examination.
3.5.3 For Class 2a devices, to check procedures for controlling technical

documentation and production conformity. Although there is no
requirement to check all technical files for Class IIa devices, their
content should be checked on a sample basis to gain confidence that
the manufacturer is following the appropriate procedures and the
Declarations are in the correct format. This should be checked on a
sample basis for every product technology used by the manufacturer.
3.5.4 As for 3.2.2.
3.5.5 As for 3.2.3.
1
The Annex IV conformity route is of limited application for sterile products.
4 of 5
3.6 Annex VI
3.6.1 To audit the quality system to the requirements of Annex VI using ISO
9003:1994 as a basis for the audit (when an EN 46003 is issued the
current version will be the basis for the audit).
3.6.2 Unless 100% testing is carried out, to check that production is

homogenous enough to allow sample inspection/testing. To check
that final testing/inspection demonstrates continuing conformance to
the EC Type Examination certificate or the relevant technical
documentation.
3.6.3 To check the validity of the EC Type Examination certificate or

technical documentation including user instructions and labelling.
4. Competency Criteria for Assessment Teams
4.1 Annex II
4.1.1 The assessment team shall include experience in:
- EN 46000 and the directive;
- the assessment of medical device manufacturers;
- the technology involved including relevant harmonised

standards.
4.1.2 For sterile devices the assessment team shall include a suitably
competent assessor/expert.
4.1.3 The assessment team shall include a member with knowledge of the
design criteria and solutions and harmonised standards appropriate to
the device under assessment.
4.1.4 For Class 3 devices relevant experience of design reviews will be

necessary.
4.2 Annex III and IV
4.2.1 The Notified Body must possess the relevant product specific
expertise and competence and have access to the appropriate testing
and inspection capability.
4.3 Annex V and VI
4.3.1 As for 4.1.1 and 4.1.2.
5 of 5
Attachment 4
Attachment 4
MEDDEV 2.10-2 Rev 1
April 2001
Special Rules of Accreditation

for Certification Bodies of Quality Systems
Scope "Sterile Medical Devices"
Inofficial Translation of
Spezielle Akkreditierungsregeln fr Zertifizierungsstellen fr Qualittssicherungssysteme
Geltungsbereich Sterile Medizinprodukte"
Zentralstelle der Lnder fr Gesundheitsschutz bei Arzneimitteln und Medizinprodukten (ZLG)
Contents
1 Scope
2 Accreditation requirements
2.1 Certification personnel
2.1.1 Senior executive and deputy of certification body
2.1.2 Audit team
2.1.3 "Certifiers"
2.2 Independence
3 Certification procedures
3.1 Checking of documents
3.2 Auditing of manufacturing and sterilization processes
3.2.1 Manufacturing processes
3.2.2 Sterilization processes
4 Evaluation and decision making
Annexes (not enclosed)

1 Microbiological-hygienic examinations as part of the surveillance of manufacturing
processes (HS 52/97)
2 Contents of the validation report according to DIN EN 550 for sterilization with ethylene
oxide (HS 25/97)
3 "Recommendation for validation and routine control of sterilization processes with moist
heat for medical devices" of DGKH
MEDDEV 2.10/2 Attachment 4 ZLG 07/98 1/6

4 Resolutions 2, 6, 7, 9 and 11 of the exchange of experiences circle of the bodies notified
according to the Medical Devices Act (EK-Med)
1 Scope "Sterile medical devices"

The approval of quality systems has to be conducted in accordance with the provisions of
directive 93/42/EEC annexes II, V, VI, taking into account the classification of devices ( 13
Medical Devices Act (MPG) or 93/42/EEC, Article 9). Active implantable medical devices are to
be treated in an analogous way, taking account of directive 90/385/EEC.
The approval of quality systems of manufacturers who sterilize CE-marked medical devices for
the purpose of placing them on the market is issued in accordance with 93/42/EEC, article 12
(3) or 10 (3) MPG.
Conformity Assessment Procedures
Annex III VII combined IV V VI or II

with
Class
I sterile l (m) l (m)
IIa l m l m l
IIb l m l m l
III l m l l
Art. 12 (3) m l m
all classes
l compulsory m applicable not applicable

(m) applicable in theory, but not relevant to practice
2 Accreditation Requirements
In addition to the Accreditation Rules II-A-3, the special accreditation regulations cited in the
following apply to certification bodies which approve quality systems for sterile medical devices.
2.1 Certifying Personnel

Certification bodies may only be accredited for this scope if their personnel fulfil the following
requirements:
2.1.1 Senior Executive and Deputy of Certification Body

Successfully completed studies in medicine, natural science or engineering at a
university or higher technical college, or equivalent knowledge in special cases.

A minimum of three years full-time professional experience with at least two years'
work in testing and/or certification activities in testing/calibration laboratories, -
inspection or certification bodies in accordance with EN 45 000 or in comparable
institutions and in areas related to the applied scope of accreditation
Knowledge of quality management procedures in the field of testing, surveillance
and/or certification, based on practical experience and successful participation in
relevant courses
2.1.2 Audit Team

As a rule, the audit team shall comprise at least two persons1, who together have the following
qualifications:
Quality Auditor
Qualification criteria according to ISO 10 011 Part 2, as well as provable knowledge of the rele-
vant EC directives, the Medical Device Act and the related statutory ordinances.
Experts with technological experience

Successfully completion of studies in medicine, natural science or engineering at a
university or higher technical college, or equivalent knowledge and skills in special
cases
A minimum of three years' full-time professional experience with at least two years'
work in areas directly related to the production technology to be assessed, or ade-
quate experience in general process engineering
Experts in sterilization
Successfully completion of studies in medicine, natural science or engineering at a
university or higher technical college, or equivalent knowledge in special cases
Knowledge in the areas of
- hygiene
- microbiology and/or
- sterilization process engineering
At least three years' professional experience with at least two years' work in areas
directly related to the sterilization technology to be assessed2
as well as
- special experience and/or training in clean room technology, determination of
bioburden, validation of cleaning, disinfection and sterilization processes, and
in sterile packaging
- proof of successful participation in at least one course in the validation of
ethylene oxide sterilization and/or sterilization by irradiation and/or sterilization
by moist heat according to EN 550, EN 552, EN 554 as well as in require-
ments for medical devices labelled sterile according to EN 556
- proof of participation in at least two sterilization validations based on every
harmonised standard for which an authorization is requested. As of 1 July
1
MedDev 1/94: Guidelines for auditing quality systems of medical device manufacturers
2
Instead of two years work in areas directly related to the sterilization technology to be assessed, the
following will also be recognised: an appropriate training programme/futher education in connection with
attendance at at least three sterilization process audits, the validation of which is based on the
respective harmonized standard, under the supervision of an appropriately qualified specialist.
1998, the sitting in on validations is to be carried out with one of the testing
laboratories accredited for this scope.
2.1.3 "Certifiers"
The persons entrusted with in the evaluation must have obtained an adequate qualification in
order to evaluate the testing results with highest competence. The independence required must
be observed.
2.2 Independence and Impartiality

If persons employed to less than 100% by the certification body are included in the conformity
assessment, resolution 9 of the exchange of experiences circle of the bodies designated ac-
cording to the Medical Devices Act (EK-Med) (4) must be observed.
3 Certification Procedures
Certification bodies must have documented procedures to enable the assessment, certification
and surveillance of quality systems to be carried out in accordance with the following require-
ments:
Proposal Assessment Certification
Audit
Production Process
Checking of Evaluation
Documents and
Decision
Audit
Sterilization/
Irradiation Process
3.1 Checking of Documents

During document evaluation the following points in particular are to be taken into account
suitability of the sterilization process for the medical device
application of EN 550, EN 552 or EN 554 or of a suitable validation procedure devi-
ating from these
competence of the body which has carried out the validation and routine control of
sterilization
As a result of the check of documents crucial points of the audit are to be determined. In par-
ticular it has to be decided if subcontractors who sterilize/irradiate medical devices on behalf of
the manufacturer must be audited.

Note
Provided the sterilization/irradiation of the medical devices concerned is assigned to a subcon-
tractor, auditing of this subcontractor may be omitted if the notified body receives proof of the
following alternative requirements concerning the commissioning:
a) The validation and routine control of sterilization are carried out by a testing laboratory
accredited for EN 550, EN 552 and EN 554 respectively.
The requested summarised commissioning report and also, where appropriate, the
report on the performance qualification have been issued by this laboratory.
b) The sterilization/irradiation plant has a quality system according to directive 93/42/EEC
approved by a notified body for medical devices that are sterilized with the same equipment.
A summarized commissioning report may be requested if required.
c) The sterilization/irradiation plant has a certified quality system according to EN ISO 9001/2
and EN 46001/2 which is under surveillance by a notified body or by the inclusion of ex-
perts from a notified body. In addition, this notified body attests that the commissioning of
the sterilization equipment fulfils the requirements according to EN 550, EN 552 or EN 554.
A summarised commissioning report may be requested if required.
The physical and where necessary microbiological performance qualification remain unaf-
fected by this.
If these conditions are not or only partially fulfilled, an auditing of the sterilization / irradiation
plant is to be carried out. This also applies to sterilization/irradiation plants in countries outside
Europe.
Deviations from this are to be justified and comprehensibly documented.
3.2 Auditing of manufacturing and sterilization processes
3.2.1 Manufacturing processes

Sterile medical devices must be manufactured and sterilized according to a suitably validated
procedure under appropriately monitored conditions.
During production, requirements are to be laid down in accordance with EN 46001/2 among
others regarding personal hygiene, monitoring of the surrounding area during manufacture and
the cleanliness of the finished products. The results of the check are to be documented.
The audit team checks the conformity of the manufacturing process with the requirements of
Annexes II or V of the directive 93/42/EEC or the directive 90/385/EEC, taking account of EN
46001/2, EN 724 or EN ISO 9001/2.
During this check it must also to be considered whether:
the microbiological-hygienic inspections (e.g. bioburden control, examinations of
room air, water, surfaces, sterile work benches, validation of cleaning processes)
were carried out expertly and skilfully.
For this, the recommendations in Annex 1 are to be observed.
suitable sterile packaging and packaging technology was selected for the steriliza-
tion procedure applied and whether these ensure that sterility is maintained until the
product is used.
the labelling, when relevant, corresponds to the basic requirements of the directives
and, if applicable, EN 980.

The suitability of the sterile packaging is to be verified taking into account the storing
and transport conditions indicated by the manufacturer.
If no expiry date is given, it must be assumed that the product shelf life is infinite.
Accordingly proof should be furnished of the sterile packaging not undergoing any
ageing process which could endanger the integrity of the packaging.
3.2.2 Sterilization processes

During the special processes all control parameters are to be recorded. The validation has to be
carried out and evaluated by qualified personnel using the required technical methods. The
validation report must show by means of appropriate examinations, that the requirements of
EN 550, EN 552 or EN 554 are fulfilled or that a comparable validation procedure was applied in
order to check the compliance of the product with the specifications in EN 556.
The audit team must check the compliance of the sterilization installation as well as the
sterilization documentation kept on site with the details set out in the validation report.
The minimum data needed to evaluate formal compliance with the requirements of EN 550 in a
validation report are given in Annex 2.
Minor requirements for validation reports on sterilization with moist heat can be found in the
DGKH "Recommendation for the validation and routine surveillance of sterilization processes
with moist heat for medical devices" (Annex 3). The annexes 2 and 3 are intended as a recom-
mendation3.
Note
It is appropriate to carry out the specialist check of the validation report before the audit and
then to pass on any points that have arisen for the on-site inspection. Where the check of the
validation report only takes place during the audit, this must be taken into account by an appro-
priate period of time in the audit plan.
4 Evaluation and decision-making

The decision on certification is taken on the basis of the documents to be submitted in accord-
ance with the certification procedure by specialist personnel not involved in the audit. (see
2.1.3).
The documents submitted (e.g. check lists, specialist appraisals, audit report) must be suffi-
ciently informative to enable those responsible for the certification as well as the responsible
authorities to retrace the relevant circumstances at the time of the audit.
When the decision is taken, it may also be necessary to lay down surveillance measures. This
may include not only surveillance audits, but also specific examinations, such as sterility tests,
microbiological and physical tests (see resolution 11 of the exchange of experiences circle of
the bodies notified according to the Medical Devices Act (EK-Med); Annex 4).
For the approval of quality systems the resolutions 2, 6 and 7 of the exchange of experiences
circle of the bodies notified according to the Medical Devices Act (EK-Med); (Annex 4) are to be
observed.
3
The working group for radiation sterilization of the main sterilization working party of the ZLG does not
consider specifications for validation reports necessary in the case of radiation sterilization.
EUROPEAN COMMISSION
Consumer goods
Competitiveness in pharmaceuticals, medical devices, cosmetics
MEDDEV. 2.11/1 rev.1

April 2005
APPLICATION OF COUNCIL DIRECTIVE 93/42/EEC TAKING INTO

ACCOUNT THE COMMISSION DIRECTIVE 2003/32/EC FOR MEDICAL
DEVICES UTILISING TISSUES OR DERIVATIVES ORIGINATING FROM
ANIMALS FOR WHICH A TSE RISK IS SUSPECTED
Note
The present Guide lines are part of a set of Guidelines relating to questions of
application of EC -Directives on medical devices. They are legally not binding. The
Guidelines have been carefully drafted through a process of intensive consultation
of the various interest par ties (competent authorities, Commission services,
industries, other interested parties) during which intermediate drafts were
circulated and comments were taken up in the document. Therefore, this document
reflects positions taken by representatives of int erest parties in the medical devices
sector.
1/7
This guidance is based on Commission Directive 2003/32/EC, OJ EC N L 105, 26.4.2003, p.18.
Application of Council Directive 93/42/EEC taking into account
Commission Directive 2003/32/EC for medical devices utilising tissues or
derivatives originating from animals for which a TSE risk is suspected
1.0 - Introduction
1.1 - Commission Directive 2003/32/EC makes provision for the management of risks arising from
medical devices that utilise tissues or derivatives originating from animals for which a TSE risk is
suspected. The Directive requires that such devices, whether new or already on the market, be
subject to a risk management scheme which incorporates a risk assessment. For all new and existing
devices within the scope of the Directive the manufacturer is required to submit the risk assessment
to a Notified Body for an evaluation prior to certification.
1.2 - Member States are responsible for ensuring that those Notified Bodies that are verified 1 to
evaluate devices utilising animal tissues or derivatives, are appropriately experienced and qu alified
to evaluate the risk control measures adopted by the manufacturer and to verify conformity with
Commission Directive 2003/32/EC. In addition, Member States are responsible for facilitating
verification of the Notified Body's evaluation of the manu facturers risk management activities. Such
verification is not necessary when the suitability of all the susceptible starting materials has been
certified by the European Directorate for the Quality of Medicines (EDQM).
1.3 - It should be kept in mind th at the requirement in this Commission Directive 2003/32/EC does
not alter the provisions of the Medical Devices Directive 93/42/EEC and both are applicable to
relevant products to achieve conformity with the regulations.
2.0 Scope
2.1 - Commission D irective 2003/32/EC is applicable to medical devices which utilise tissue from
bovine, ovine and caprine species, or deer, elk, mink or cats rendered non -viable or non-viable
products derived from such tissue. These may comprise a major part of the device (e.g. bovine
cardiac valves, bovine bone for orthopaedic surgery or collagen as a wound dressing) a
coating/impregnation of the product (e.g. gelatin impregnated vascular graft), an aid to the
manufacturing stages of production (e.g. fetal calf serum, bovi ne serum albumin, enzymes, culture
media) or they may be used for channelling, processing or storing blood, body liquids, cells, or
tissues, liquids or gases for subsequent infusion, administration or introduction into the body .
2.2 - Products that do not come into contact with the human body and those that are intended to
come into contact with intact skin only are excluded by Article 1.4 Directive 2003/32/EC. In-vitro
diagnostic medical devices and products such as leather orthopaedic footwear, are excluded from this
Directive. Nonetheless the application of a risk management scheme by the manufacturer is
appropriate under all circumstances.
1
The Commission intends to place a list of the Notified Bodies verified for this subject on its website.
2/7
2.3 - The provisions of the Animal By Product Regulation 2 are relevant to medical devices within the
scope of Commission Directive 2003/32/EC. The import, export, transit, and trade of raw and
starting materials intended for medical device manufacture must therefore comply with this
Regulation. A Commission guidance document 3 confirms that the Regulation is ap plicable to
intermediate products but it is not applicable to finished medical devices 4. As defined in the
Regulation, materials used for the manufacture of medical devices shall be category 3 material or
equivalent, i.e. from animals fit for human consum ption (however see 2.4).
2.4 Tallow derivatives (e.g. stearates) are used, for example, as a plasticiser or mould releasing agent
in the production of some medical devices (e.g. blood bags). Tallow used as the starting material for
the manufacture of tal low derivatives shall be Category 3 material or equivalent, as defined by
Regulation No 1774/2002 , as amended. Tallow derivatives manufactured from tallow by rigorous
processes have been subject to specific consideration 5. Materials manufactured under cond itions at
least as vigorous as those in the Annex should be considered compliant with the regulatory
expectations of this Commission Directive. Whilst these are considered excluded from this Directive,
the requirements of Directive 93/42/EEC and the applic ation of a risk management scheme by the
manufacturer is still relevant. Other tallow derivatives produced using other manufacturing
conditions should demonstrate compliance with this Commission Directive.
3.0 - Purpose
3.1 The purpose of this guidanc e is to aid the common application of Commission Directive
2003/32/EC by clarifying some aspects of its interpretation. In particular it addresses the evaluation
performed by the Notified Body, the activities of the coordinating Competent Authority and the
verification role of the other Competent Authorities.
4.0 - Evaluation by the Notified Body

4.1 The Notified Bodys evaluation is expected to focus on the primary aim of the Commission
Directive, namely the justification for the use of non -viable animal tissue or derivatives from a TSE -
susceptible species. Such a justification should be based on an overall risk:benefit assessment for the
product that compares the risks and benefits arising from the use of the animal -derived material with
2
Regulation (EC) No 1774/2002 of the European Parliament and of the Council laying downhealth rules concerning
animal by-products not intended for human consumption (OJ L 273, 10.10.2002, p.1), last amended by Commission
Regulation 92/2005.
3
http://europa.eu.int/comm/food/food/biosafety/animalbyproducts/guidance_faq_en.pdf
4
Quote from above-mentioned Commission Guidance: The Animal By Product Regulation only applies to cosmetics,
medicinal products (pharmaceuticals) and medical devices (including laboratory reagents) as far as the source and
starting materials of animal origin that are used in the manufacture of such products are concerned. It requires that such
starting materials must derive from "Category 3 materials" i.e. materials from animals fit for human consumption
following veterinary checks. When such starting materials are to be imported into the EU, they must meet the minimum
conditions set out in the Regulation, ensuring their safety vis--vis animal and public health. There were similar provisions
in the animal waste Directive 90/667/EEC and the Balai Directive 92/118/EC (Annex I, Chapters 7 and 10), which have
now been repealed by the Animal By Products Regulation.
5
Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and
veterinary medicinal products (EMEA/410/01 Rev. 2 - October 2003) adopted by the Committee for Proprietary Medicinal
Products (CPMP) and by the Committee for Veterinary Medicinal products (CVMP)
Official Journal C 024 , 28/01/2004 P. 0006 - 0019
3/7
those relating to the available alternatives. The risk analysis should thus consider both similar
materials sourced from non -TSE-susceptible species and any synthetic materials. The Notified Body
should ensure that the overall risk assessment for the product takes in to account the TSE risk and
that this risk assessment has been undertaken as part of a documented risk management process.
4.2 In reaching a decision on the suitability of the product for its intended use and the acceptability
of the TSE risk, Notified Bo dies should take into account at least the following information, where
applicable:
a critical analysis of pre -clinical and clinical data to support any specific advantages
claimed;
an evaluation of alternative materials (e.g. materials of animal origin that are not
susceptible to TSE infection and synthetic materials) to determine their ability to achieve
the desired product characteristics and intended purpose;
an evaluation of the measures adopted to minimise the risk of infection, including

sourcing and veterinary controls 6, feeding restrictions, harvesting practices, significant
processing stages, elimination and/or inactivation studies, or of literature searches;
whether or not the product complies with relevant standards 7;
confirmation that any collagen, gelatin or tallow used meets the requirements fit for
human consumption 8 ;
any evaluation and certification of the suitability of raw materials by the European
Directorate for the Quality of Medicines (EDQM).
4.3 The Notified Body should document the key elements of its evaluation as a Summary Evaluation
Report. T he purpose of this report is to provide confirmation that the relevant supporting documentation
has been evaluated by the Notified Body and is deemed sufficient to demonstrate c ompliance with the
TSE-relevant parts of Commission Directive 93/42/EEC and the whole of Council Directive 2003/32/EC.
The Summary Evaluation Report should briefly characterise the TSE hazard, estimate the risk and outline
applicable risk control measures . It should include:
a product description, including information on intended use and composition. This

should include information on the nature of the starting tissue 9, the species and
geographical origin;
6
Essential Requirements laid down in Annex I, 8.2 of the MDD (93/42/EEC) requires Notified Bodies to retain
information on the geographical origin of the animals, and these materials originate from animals subject to veterinary
controls and surveillance.
7
EN ISO 14971, Medical devices - the application of risk management to medical devices and EN 12442, Animal tissues
and their derivatives utilized in the manufacture of medical devices Parts 1, 2 & 3, are considered to be relevant.
8
The material of animal origin intended for utilisation in the medical device should have originated from animals
confirmed by a veterinarian as being fit for human consumption. For species not usually consumed by humans a status
equivalent to "fit for human consumption" is required. Tallow should be prepared by a recognised processing method, see
Regulation (EC) 1774/2002, as amended.
9
The infectivity classification table of materials for sheep and goats should continue to be considered indicative for the
selection of source materials from other species (e.g. deer, elk, mink, cat) known to be susceptible to TSEs. See WHO
Guideline on Transmissible Spongiform Encephalopathies in Relation to Biological and Pharmaceutical Products
(February 2003).
4/7
a description of the key elements adopted to minimise the risk of infection;
a qualitative or quantitative estimate of the TSE risk arising from the use of the product,
taking into account the likelihood of contamination of the product, the nature and
duration of patient exposure;
a justification for the use of animal tissues or derivatives in the medical device,
including a rationale for the acceptability of the overall TSE risk 10 estimate which takes
into account the evaluation of alternative materials 11 and the expected clinical benefit 12
;
the approach to the auditing of source establishments and/or third party suppliers for the
animal material used by the medical device manufacturer,
a conclusion statement.
4.4 Where there are EDQM TSE Certificate(s) of Suitability for the starting mate rial(s) the Notified
Body shall document the complete audit trail leading to the decision for the complementary
certification. The evaluation process of the medical device by the Notified Body should document
and verify the indents of Section 4.3, except t he first two.
5.0 - Verification by the Competent Authorities

5.1 The role of the Competent Authorities is to verify that:
the procedures set out in Commission Directive 2003/32/EC have been followed and that sound
judgements 13 have been made;
5.2 If the medical device utilises only EDQM certified starting materials, the Notified Body is not
required to approach its National Competent Authority for an opinion of the Competent Authorities
of the other Member States. However, an exchange of information between the concerned parties
(Notified Body and National Competent Authority) may be foreseen in the interest of gaining
increased experience in relation to medical devices utilising EDQM certified materials 14.
5.3 Some Competent Authorities may choose to approach other Member States or a relevant
National Authority (e.g. a national committee of specialists) for assistance. Where this is the case, it
will be necessary for the Competent Authority to ensure that there are no conflicts of interest, that a ll
10
This must take into account any evaluation and certification by EDQM, to demonstrate conformity with relevant
monographs on the reduction of TSE risk in respect of starting materials.
11
Such as similar materials of animal origin not susceptible to TSE or other synthetic alternatives that achieve the
desired product characteristics and intended purpose.
12
The justification should identify the specific advantages expected and include an analysis of the supporting data. For
instance the device may provide an improvement in the treatment or prevention of a disease or injury, it may eliminate or
reduce an existing treatment so limiting the potential for certain adverse effects, or it may provide beneficial treatment in a
specific group of patients within the population.
13
The verification of the review process by the Notified Body, the presentation of the summary data, the adoption of key
principles for minimising the risk of TSE and the relevance of the risk factors to the risk assessment form the basis of a
sound judgement which builds confidence in the safety of the product.
14
This is outside of the certification process as detailed in the Directive.
5/7
data are maintained in confidence and that the consultation is carried out in a timely manner.
5.4 National Competent Authorities are requested to provide an update on the progress of these
conformity assessments at the Medical Devices Experts Group me etings.
6.0 - Coordinating Competent Authority
6.1 The Notified Body is required to approach its National Competent Authority, who will then seek
the opinion of the Competent Authorities of the other Member States on the evaluation and
conclusions in the Summary Evaluation Report 15. As the designating authority, the Notified Bodys
National Competent Authority is also responsible for verifying that the Notified Body has sufficient
knowledge to assess conformity for these devices.
6.2 The role of the Coor dinating Competent Authority is thus to ensure that:
The opinions of the Competent Authorities of the other Member States are sent to the
Notified Body within twelve weeks of the date of the receipt of information from the
Notified Body.
Notified Bodies undertaking the evaluation of products subject to Commission Directive

2003/32/EC have appropriate knowledge and experience to perform the risk assessment.
6.3 The Coordinating Competent Authority should acknowledge receipt of any request for an
opinion, act as a channel for all communications between Competent Authorities and the Notified
Body, collate the opinions of the National Authorities, including their own, and pass them on to the
Notified Body. Competent Authorities should complete their review on the evaluation and
conclusions in the Summary Evaluation Report within nine weeks of its receipt from the
Coordinating Competent Authority. This should allow sufficient time to collate the opinions and pass
them directly to the relevant Notified Body.
6.4 The designating Competent Authority should amend the scope of activities of any Notified Body
not deemed to possess the knowledge and experience necessary for assessing conformity of these
products.
7.0 - Review of the opinions from the Competent A uthorities

7.1 The Notified Body is required to give due consideration to any comments received through their
National Competent Authority. The Notified Body should document the final decision on the
certification of the product and t he rationale for any deviation from the opinion of any Competent
Authority. Where this occurs the Notified Body should consult with their device Competent
Authority. This decision should be notified to the manufacturer and the National Competent
Authority, and will be made ava ilable to other Competent Authorities upon request.
7.2 If the Notified Body receives no opinions within 12 weeks of the confirmed receipt of the
Summary Evaluation Report by its Competent Authority, it can finalise its decision on the
certification of the product, without further reference to the Competent Authority.
15
This Report (circa 3-5 pages) should be in English and is to be sent by e-mail between all the relevant parties.
6/7
Annex Examples of Rigorous Processes for Tallow Derivatives are :
- Trans-esterification or hydrolysis at not less than 200C for not less than 20 minutes under
pressure (glycerol, fa tty acids and fatty acid esters production),
- Saponification with NaOH 12 M (glycerol and soap production)
- Batch process: at not less than 95C for not less than 3 hours
- Continuous process: at not less than 140C, under pressure for not less than 8 minutes
or equivalent,
- Distillation at 200C.
7/7
Summary Evaluation Report
on the Assessment of a Medical Device by the Notified Body
for Conformity with Council Directive 93/42/EEC and Commission Directive 2003/32/EC.
Template Document - enter text directly to expandable box.
Reporter Reference
1. Report sent by : 2. Notified Body No : 3. Country :
4. Sent by: 5. Contact person: 6. Telephone:
7. Fax: 8. E-mail: 9. Client Reference :
10. Our Designating Competent Authority has confirmed the scope of our activities meets the provisions
of Article 16 of Council Directive 93/42/EEC and Article 4 of Commission Directive 2003/32/EC.
Medical Device Data

11. Product description and composition:
12. Information on intended use:
13. Nature of the starting tissue(s), animal species(s) and geographical source(s):
14. A description of the key elements adopted to minimise the risk of infection:
15. An estimate of the TSE risk arising from the use of the product, taking into account the likelihood of
contamination of the product, the nature and duration of patient exposure:
16. A justification for the use of animal tissues or derivatives in the medical device, including a rationale for the
acceptability of the overall TSE risk estimate, the evaluation of alternative materials and the expected clinical
benefit:
17. The approach to the auditing of source establishments and/or third party suppliers for the animal material used
by the device manufacturer:
Notified Body Statement
18. Conclusion of this assessment:
Based on the evaluation of data and the assessment process it is our preliminary decision this application meets the
requirements of conformity with Council Directive 93/42/EEC and Commission Directive 2003/32/EC.
Distribution Record
19. This report was sent on ............................. to the Coordinating Competent Authority of ............................................
to seek an opinion from the Competent Authorities of the other Member States.
EUROPEAN COMMISSION
Consumer goods
Cosmetics and medical devices

January 2008
APPLICATION OF COUNCIL DIRECTIVE 93/42/EEC TAKING I NTO

ACCOUNT THE COMMISSION DIRECTIVE 2003/32/EC FOR MEDICAL
DEVICES UTILISING TISSUES OR DERIVATIVES ORIGINATING FROM
ANIMALS FOR WHICH A TSE RISK IS SUSPECTED
Note

application of EC -Directives on medical devices. They are legally not binding. The
Guidelines have been carefully drafted through a process of intensive consultation
of the various interest parties (competent auth orities, Commission services,
industries, other interested parties) during which intermediate drafts were
circulated and comments were taken up in the document. Therefore, this document
reflects positions taken by representatives of interest parties in the medical devices
sector.

MEDEV 2.11/1 REV. 2
F INAL D RAFT
Application of Council Directive 93/42/EEC taking into account
Commission Directive 2003/32/EC for medical devices utilising tissues or
derivatives originating from animals susceptible for TSE
1.0 - Introduction
1.1 - Commission Directive 2003/32/EC makes provision for the management of risks arising from
medical devices that utilise tissues or derivatives originating from animals for which a TSE risk is
suspected. The Directive requires that such devices, whether new or alr eady on the market, be
subject to a risk management scheme which incorporates a risk assessment. For all new and existing
devices within the scope of the Directive the manufacturer is required to submit the risk assessment
to a Notified Body for an evaluat ion prior to certification.
1.2 - Member States are responsible for ensuring that those Notified Bodies that are verified 1 to
evaluate devices utilising animal tissues or derivatives, are appropriately experienced and qualified
to evaluate the risk cont rol measures adopted by the manufacturer and to verify conformity with
Commission Directive 2003/32/EC.
In addition, all the Member States are responsible for facilitating verification of the Notified Body's
evaluation of the manufacturers risk managem ent activities (see section 6.1). Such verification is
not necessary when the suitability of all the susceptible starting materials has been certified by the
European Directorate for the Quality of Medicines (EDQM ) (see section 5.2).
1.3 - It should be kept in mind that the requirement in this Commission Directive 2003/32/EC does
not alter the provisions of the Medical Devices Directive 93/42/EEC and both are applicable to
relevant products to achieve conformity with the regulations.
2.0 Scope
2.1 - Commission Directive 2003/32/EC is applicable to medical devices which utilise tissue from
bovine, ovine and caprine species, or deer, elk, mink or cats rendered non -viable or non-viable
products derived from such tissue. These may comprise a major part o f the device (e.g. bovine
cardiac valves, bovine bone for orthopaedic surgery or collagen as a wound dressing) a
coating/impregnation of the product (e.g. gelatin impregnated vascular graft), an aid to the
manufacturing stages of production (e.g. fetal cal f serum, bovine serum albumin, enzymes, culture
media) or they may be used for channelling, processing or storing blood, body liquids, cells, or
tissues, liquids or gases for subsequent infusion, administration or introduction into the body .
2.2 - Products that do not come into contact with the human body and those that are intended to
come into contact with intact skin only are excluded by Article 1.4 Directive 2003/32/EC. In-vitro
diagnostic medical devices and products such as leather orthopaedic footwear, are excluded from this
Directive. Nonetheless the application of a risk management scheme by the manufacturer is
appropriate under all circumstances.
1
The Commission intends to place a list of the Notified Bodies verified for this subject on its website.
2/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
2.3 - The provisions of the Animal By Product Regulation 2 are relevant to medical devices with in the
scope of Commission Directive 2003/32/EC. The import, export, transit, and trade of raw and
starting materials intended for medical device manufacture must therefore comply with this
Regulation. A Commission guidance document 3 confirms that the Regu lation is applicable to
intermediate products but it is not applicable to finished medical devices 4. As defined in the
Regulation, materials used for the manufacture of medical devices shall be category 3 material or
equivalent, i.e. from animals fit for human consumption (however see 2.4).
2.4 Tallow derivatives (e.g. stearates) are used, for example, as a plasticiser or mould releasing agent
in the production of some medical devices (e.g. blood bags). Tallow used as the starting material for
the manufacture of tallow derivatives shall be Category 3 material or equivalent, as defined by
Regulation No 1774/2002, as amended. Tallow derivatives manufactured from tallow by rigorous
processes have been subject to specific consideration 5. Materials manufacture d under conditions at
least as vigorous as those in Annex 1 (below) should be considered compliant with the regulatory
expectations of this Commission Directive. Whilst these are considered excluded from this Directive,
the requirements of Directive 93/42/ EEC and the application of a risk management scheme by the
manufacturer is still relevant. Other tallow derivatives produced using other manufacturing
conditions should demonstrate compliance with this Commission Directive.
2.5 The specific reference in this document to cell culture media is applicable to both Working
Cell Banks and Master Cell Banks. The principles and practices on this specific subject by the
medicinal sector should be adapted for the purposes of the medical device sector. (Reference s:Note
for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via
human and veterinary medicinal products, adopted by CPMP/CVMP, EMEA/410/01 rev2 October
2003; O.J.E.C. 28.01.2004. Position paper on re -establishment o f working seeds and working cell
banks using TSE compliant materials. EMEA/22314/02 10 September 2002).
2.6 The management by Member States of the applications for the safety and quality of clinical
investigations of medical devices utilising material of TSE susceptible species is the responsibility of
the Competent Authority where the application is submitted. The Competent Authority should take
into account the principles of the Annex in Commission Directive 2003/32/EC.
3.0 - Purpose
3.1 The purpose of this guidance is to aid the common application of Commission Directive
2003/32/EC by clarifying some aspects of its interpretation. In particular it addresses the evaluation
performed by the Notified Body, the activities of the coordinating Competent Auth ority and the
verification role of the other Competent Authorities.
2
Regulation (EC) No 1774/2002 of the European Parliament and of the Council laying down health rules concerning
animal by-products not intended for human consumption (OJ L 273, 10.10.2002, p.1), last amended by Commission
Regulation 92/2005.
3
http://europa.eu.int/comm/food/food/biosafety/animalbyproducts/guidance_faq_en.pdf
4
Quote from above-mentioned Commission Guidance: The Animal By Product Regulation only applies to cosmetics,
medicinal products (pharmaceuticals) and medical devices (including laboratory reagents) as far as the source and
starting materials of animal origin that are used in the manufacture of such products are concerned. It requires that such
starting materials must derive from "Category 3 materials" i.e. materials from animals fit for human consumption
following veterinary checks. When such starting materials are to be imported into the EU, they must meet the minimum
conditions set out in the Regulation, ensuring their safety vis--vis animal and public health. There were similar provisions
in the animal waste Directive 90/667/EEC and the Balai Directive 92/118/EC (Annex I, Chapters 7 and 10), which have
now been repealed by the Animal By Products Regulation.
5
Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and
veterinary medicinal products (EMEA/410/01 Rev. 2 - October 2003) adopted by the Committee for Proprietary Medicinal
Products (CPMP) and by the Committee for Veterinary Medicinal products (CVMP)
Official Journal C 024 , 28/01/2004 P. 0006 - 0019
3/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
4.0 - Evaluation by the Notified Body

4.1 The Notified Bodys evaluation is expected to focus on the primary aim of the Commission
Directive, namely the justification for the use of n on-viable animal tissue or derivatives from a TSE -
susceptible species. Such a justification should be based on an overall benefit/risk assessment for the
product that compares the risks and benefits arising from the use of the animal -derived material with
those relating to the available alternatives. The risk analysis should thus consider both similar
materials sourced from non -TSE-susceptible species and any synthetic materials. The Notified Body
should ensure that the overall risk assessment for the pro duct takes into account the TSE risk and
that this risk assessment has been undertaken as part of a documented risk management process.
4.2 In reaching a decision on the suitability of the product for its intended use and the acceptability
of the TSE risk, Notified Bodies should take into account at least the following information, where
applicable:
a critical analysis of pre -clinical and clinical data to support any specific advantages
claimed;
an evaluation of alternative materials (e.g. materials of animal origin that are not
susceptible to TSE infection and synthetic materials) to determine their ability to achieve
the desired product characteristics and intended purpose;
an evaluation of the measures adopted to minimise the risk of infection, inclu ding
sourcing and veterinary controls 6, feeding restrictions, harvesting practices, significant
processing stages, elimination and/or inactivation studies, or of literature searches;
whether or not the product complies with relevant horizontal and produc t standards7;
confirmation that any collagen, gelatin or tallow used meets the requirements fit for
human consumption 8 ;
any evaluation and certification of the suitability of raw materials by the European
Directorate for the Quality of Medicines (E DQM).
4.3 The Notified Body should document the key elements of its evaluation as a Summary Evaluation
Report. T he purpose of this report is to provide confirmation that the relevant supporting documentation
has been evaluated by the Notified Body and is deemed sufficient to demonstrate compliance with the
TSE-relevant parts of Co uncil Directive 93/42/EEC and the whole of Commission Directive 2003/32/EC.
The Summary Evaluation Report should briefly characterise the TSE hazard, estimate the risk and outl ine
applicable risk control measures. It should include:
6
Essential Requirements laid down in Annex I, 8.2 of the MDD (93/42/EEC) requires Notified Bodies to retain
information on the geographical origin of the animals, and these materials originate from animals subject to veterinary
controls and surveillance.
7
EN ISO 14971, Medical devices - the application of risk management to medical devices and EN 22442, Medical Devices
utilizing animal tissues and their derivatives , Parts 1, 2 & 3, are considered to be relevant.
8
The material of animal origin intended for utilisation in the medical device should have originated from animals
confirmed by a veterinarian as being fit for human consumption. For species not usually consumed by humans a status
equivalent to "fit for human consumption" is required. Tallow should be prepared from raw material fit for human
consumption and using a recognised processing method, see Regulation (EC) 1774/2002, as amended.
4/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
a product description, including information on intended use and composition. This
should include information on the nature of the starting tissue 9, the species and
geographical origin 10;
a description of the key elements adopted to minimise the risk of infection;
a qualitative or quantitative estimate of the TSE risk arising from the use of the product,
taking into account the likelihood of contamination of the product, the nature and
duration of patient exposure;
a justification for the use of animal tissues or derivatives in the medical device,
including a rationale for the acceptability of the overall TSE risk 11 estimate which takes
into account the evaluation of alternative materials 12 and the expected clinical benefit 13
;
the approach to the auditing of source establishments and/or third party suppliers for the
animal material used by the medical device manufacturer,
a conclusion statement.
4.4 Where there are EDQM TSE Certificate(s) of Suitability for the starting material(s) the Notified
Body shall document the complete audit trail leading to the decision for the complementary
certification. The evaluation process of the medical device by the Notified Body should document
and verify the indents of Section 4.3, except the first two.
4.5 The device manufacturer has the responsibility to verify the validity of the EDQM certificate
underlying a medical device design examination certificate at least on an annual basis, e.g. by
verifying with the supplier of the TSE material and on the EDQM website. This validity will be
verified by the responsible Notified Body during the on -going regulatory audits of the medical
device manufacturer.
5.0 - Verification by the Competent Authorities

5.1 The role of the Competent Authorities is to verify that:
the procedures set out in Commission Directive 2003/32/EC have been followed and that sound
9
The infectivity classification table of materials for sheep and goats should continue to be considered indicative for the
selection of source materials from other species (e.g. deer, elk, mink, cat) known to be susceptible to TSEs. See WHO
Guideline on Transmissible Spongiform Encephalopathies in Relation to Biological and Pharmaceutical Products
(February 2003).
10
Commission Regulation (EC) N 722/2007 of 25th June 2007, amending Regulation 999/2001, replaced the four
category GBR assessment procedure with a system of three country categories according to their BSE risk based on the
international OIE Standards. Commission Decision N2007/453/EC of 29 June 2007 establishes the BSE status of
different Member States or third countries according to their BSE risk. Relevant parties in the device sector are expected to
apply this information from the date of entry into force.
11
This must take into account any evaluation and certification by EDQM, to demonstrate conformity with relevant
monographs on the reduction of TSE risk in respect of starting materials.
12
Such as similar materials of animal origin not susceptible to TSE or other synthetic alternatives that achieve the
desired product characteristics and intended purpose.
13
The justification should identify the specific advantages expected and include an analysis of the supporting data. For
instance the device may provide an improvement in the treatment or prevention of a disease or injury, it may eliminate or
reduce an existing treatment so limiting the potential for certain adverse effects, or it may provide beneficial treatment in a
specific group of patients within the population.
5/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
14
judgements have been made;
5.2 If the medical device utilises only EDQM certified starting materials, the Notified Body is not
required to approach its National Competent Authority for an opinion of the Competent Authorities
of the other Member States (see section 4.4). However, an exchange of information between the
concerned parties (Notified Body and N ational Competent Authority) may be foreseen in the interest
of gaining increased experience in relation to medical devices utilising EDQM certified materials 15.
5.3 Some Competent Authorities may choose to approach other Member States or a relevant
National Authority (e.g. a national committee of specialists) for assistance. Where this is the case, it
will be necessary for the Competent Authority to ensure that there are no conflicts of interest, that all
data are maintained in confidence and that the c onsultation is carried out in a timely manner.
5.4 National Competent Authorities are requested to provide an update on the progress of these
conformity assessments at the Medical Devices Experts Group meetings.
6.0 - Coordinating Competent Authority
6.1 The Notified Body is required to approach its National Competent Authority, who will then seek
the opinion of the Competent Authorities of the other Member States on the evaluation and
conclusions in the Summary Evaluation Report 16.
6.2 As the designa ting authority, the Notified Bodys National Competent Authority is also
responsible for verifying that the Notified Body has sufficient knowledge to assess conformity for
these devices.
6.3 The role of the Coordinating Competent Authority is thus to ensu re that:
The opinions of the Competent Authorities of the other Member States are sent to the
Notified Body within twelve weeks of the date of the receipt of information from the
Notified Body.
Notified Bodies undertaking the evaluation of products subj ect to Commission Directive
2003/32/EC have appropriate knowledge and experience to perform the risk assessment.
6.4 The Coordinating Competent Authority should acknowledge receipt of any request for an
opinion, act as a channel for all communications be tween Competent Authorities and the Notified
Body, collate the opinions of the National Authorities, including their own, and pass them on to the
Notified Body. Competent Authorities should complete their review on the evaluation and
conclusions in the Summary Evaluation Report within nine weeks of its receipt from the
Coordinating Competent Authority. This should allow sufficient time to collate the opinions and pass
them directly to the relevant Notified Body.
6.5 The designating Competent Authority shou ld amend the scope of activities of any Notified Body
not deemed to possess the knowledge and experience necessary for assessing conformity of these
products.
14
The verification of the review process by the Notified Body, the presentation of the summary data, the adoption of key
principles for minimising the risk of TSE and the relevance of the risk factors to the risk assessment form the basis of a
sound judgement which builds confidence in the safety of the product.
15
This is outside of the certification process as detailed in the Directive.
16
This Report (circa 3-5 pages) should be in English and is to be sent by e-mail between all the relevant parties.
6/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
6.6 The Coordinating Competent Authority should inform the other Member States on the final
decision by the Notified Body on the certification of the product (e.g. confirmation the certificate
was issued or refused by the Notified Body).
7.0 - Review of the opinions from the Competent Authorities

7.1 The Notified Body is required to give due con sideration to any comments received through their
National Competent Authority.
7.2 For uniformity and consistency the principle activities by which the Notified Body should review
the opinions received from their Coordinating Competent Authority are to :
collate all correspondence from their Coordinating Competent Authority;

identify all the opinions raised, which may be in different formats;
document their response, or corrective actions, to each point;
add additional information from manufacturers da ta file where necessary;
decide if they disagree with or deviate from any of the opinions from any Member State 17
;
consult with their device Competent Authority, if this was the case 18;
record their final decision on the complementary certification of the pr oduct;
notify the manufacturer and the National Competent Authority of this decision.
7.3 If the Notified Body receives no opinions within 12 weeks of the confirmed receipt of the
Summary Evaluation Report by its Competent Authority, it can finalise its decision on the
certification of the product, without further reference to the Competent Authority.
8.0 - Significant changes

8.1 Information related to any changes to the sourcing, collection and handling or inactivation /
elimination that may modify t he result of the manufacturers risk assessment dossier must be
transmitted to the Notified Body for the purposes of an additional approval prior to its
implementation (e.g. the use of a different abattoir for the primary raw material, a reclassification of
BSE status of the country ). These ongoing activities are to be performed by the Manufacturer and the
Notified Body. Any new information on TSE risk collected by the manufacturer, and relevant for
their devices, must be sent to their Notified Body.
8.2 Any product involving a significant change that is assessed by the Notified Body, after
consultation with their Competent Authority, as increasing the overall TSE risk will be regarded as a
new product needing a renewed consultation procedure that reference s the previous consultation.
9.0 - Renewal of TSE Certificates

9.1 At the renewal of the Certificate 19 the Notified Body shall perform a reassessment to verify its
conformity with the requirements of the relevant Directives (i.e. Council Directive 93/42/E EC and
Commission Directive 2003/32/EC). In the updated design dossier, there should be information on:
17
Where a Member State stated there was no mention of a relevant standard in the SER or there was no review of the
clinical data to support the performance of the product, and the Notified Body can demonstrate it was contained in the
manufacturers submission/file, it should not be viewed as a disagreement.
18
This approach is similar to the procedures in MEDDEV 2.1/3 for the situation of a negative opinion from a medicinal
authority on a medicinal substance when its action is ancillary to the medical device.
7/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
- the updated risk analysis;
- the updated clinical evaluation;
- the test data and/or rationales in relation to applicable new harmonized standards;
- the evidence on the file to be state of art in relation to TSE risks, scientific knowledge, a
reclassification of BSE status of the country etc.
- the justification for the use of animal tissue or derivative in the medical device (including
comparison with alternatives).
9.2 The Notified Body needs to verify if aspects of the updated design dossier should be regarded as
a significant increase in risk. If that is the case, the consultation process as describe d for significant
changes will need to be followed, including the pre -evaluation on the increase of the TSE risk (see
section 8.0).
10.0 - Medical device with ancillary medicinal substance utilising material from TSE species
10.1 The combination of a me dical device with an ancillary medicinal substance (i.e. utilising
material from a TSE species) is within the scope of the Medical Devices Directive and the TSE
Directive. The Notified Body should perform their review according to the existing procedures,
including liaison with the relevant medicinal authorities in relation to the consultation for the
medicinal component. The consultation procedure in MEDDEV 2.1/3 should be followed. Thereafter
the Notified Body should proceed with the consultation procedu re (see section 4.3). For medical
devices incorporating pharmaceutical substances utilising non -EDQM CEP TSE certified materials
the notified bodies and competent authorities should take account that the drug regulatory body
would have covered the safety a nd quality of the medicinal substance, including TSE issues.
10.2 This regulatory approach provides confidence in the safety of the final product as there are
aspects of the TSE Directive (e.g. evaluation of alternative materials, justification rationale ) which
are not covered by the existing procedures alone.
11.0 - Discoveries
11.1 This relates to where a manufacturer of an existing medical device has verified their product to
be outside the scope of Directive 2003/32/EC but is then informed by a t hird party the product, or its
components, utilises material of TSE susceptible species. The manufacturer should explain the full
details of the discovery and seek advice from their Notified Body 20. Before the start of any
assessment process the Notified Body and its Competent Authority shall define the full regulatory
process for these special circumstances. The Competent Authority should keep the other Member
States informed of their activities.
19
Conformity assessments are typically valid for five years and may be renewed on application (Article 11, MDD).
20
Where applicable, this may involve the manufacturers Competent Authority.
8/9
MEDEV 2.11/1 REV. 2
F INAL D RAFT
ANNEX 1
Examples of Rigorous Processes for Tallow Derivatives are :
- Trans-esterification or hydrolysis at not less than 200C for not less than 20 minutes under
pressure (glycerol, fatty acids and fatty acid esters production),
- Saponification with NaOH 12 M (glycerol and soap production)
- Batch process: at not less than 95C for not less than 3 hours
- Continuous process: at not less than 140C, under pressure for not less than 8 minutes
or equivalent,
- Distillation at 200C.
9/9
EUROPEAN COMMISSION
DG ENTERPRISE AND INDUSTRY
Directorate F-Consumer Good
Unit F3- Cosmetic and Medical Devices
MEDDEV 2.12-1 rev 5
April 2007
GUIDELINES
ON A MEDICAL DEVICES VIGILANCE SYSTEM
These guidelines will enter into force on 1 st January 2008. The transitional period allowing a
gradual implementation of the guidelines will therefore end on 31st December 2007.
Note : This document is a revision of an earlier document published in April 2001 as

MEDDEV 2.12/1 - rev. 4
1
TABLE OF CONTENTS
TABLE OF CONTENTS ................................................................................................................................2
1 FOREWORD...........................................................................................................................................4
2 INTRODUCTION ...................................................................................................................................4
3 SCOPE.....................................................................................................................................................5
3.1 GENERAL PRINCIPLES ...............................................................................................................6
3.1.1 FOR MANUFACTURERS ........................................................................................................6
3.1.2 FOR MANUFACTURERS OF IVDS ........................................................................................7
3.1.3 FOR NATIONAL COMPETENT AUTHORITIES ...................................................................7
3.1.4 FOR USERS..............................................................................................................................8
4 DEFINITIONS.........................................................................................................................................8
4.1 ABNORMAL USE...........................................................................................................................8
4.2 AUTHORISED REPRESENTATIVE.............................................................................................8
4.3 CORRECTIVE ACTION ................................................................................................................8
4.4 DRUG / DEVICE COMBINATION PRODUCT ............................................................................9
4.5 EUDAMED ......................................................................................................................................9
4.6 FIELD SAFETY CORRECTIVE ACTION (FSCA) ......................................................................9
4.7 FIELD SAFETY NOTICE (FSN)..................................................................................................10
4.8 HARM............................................................................................................................................10
4.9 IMMEDIATELY............................................................................................................................10
4.10 INCIDENT .....................................................................................................................................10
4.11 INDIRECT HARM........................................................................................................................10
4.12 INTENDED PURPOSE .................................................................................................................11
4.13 MANUFACTURER .......................................................................................................................11
4.14 MEDICAL DEVICE......................................................................................................................11
4.15 OPERATOR ..................................................................................................................................11
4.16 PERIODIC SUMMARY REPORTING........................................................................................11
4.17 SERIOUS PUBLIC HEALTH THREAT......................................................................................12
4.18 TREND REPORTING...................................................................................................................12
4.19 UNANTICIPATED ........................................................................................................................12
4.20 USE ERROR..................................................................................................................................12
4.21 USER..............................................................................................................................................12
5 MANUFACTURERS ROLE................................................................................................................12
5.1 INCIDENT REPORTING SYSTEM.............................................................................................13
5.1.1 CRITERIA FOR INCIDENTs TO BE REPORTED BY MANUFACTURERS TO
COMPETENT AUTHORITIES.............................................................................................13
5.1.2 CONDITIONS FOR PERIODIC SUMMARY REPORTING UNDER THE MEDICAL
DEVICE VIGILANCE SYSTEM ...........................................................................................15
5.1.2.1 INCIDENTS DESCRIBED IN A FIELD SAFETY NOTICE ............................................................... 15
5.1.2.2 COMMON AND WELL-DOCUMENTED INCIDENTS ..................................................................... 15
5.1.3 CONDITIONS WHERE REPORTING UNDER THE MEDICAL DEVICE VIGILANCE
SYSTEM IS NOT USUALLY REQUIRED ............................................................................16
5.1.3.1 DEFICIENCY OF A DEVICE FOUND BY THE USER PRIOR TO ITS USE ..................................... 16
5.1.3.2 EVENT CAUSED BY PATIENT CONDITIONS ................................................................................ 16
5.1.3.3 SERVICE LIFE OR SHELF-LIFE OF THE MEDICAL DEVICE EXCEEDED ................................... 17
5.1.3.4 PROTECTION AGAINST A FAULT FUNCTIONED CORRECTLY ................................................. 17
5.1.3.5 EXPECTED AND FORESEEABLE SIDE EFFECTS.......................................................................... 18
5.1.3.6 NEGLIGIBLE LIKELIHOOD OF OCCURRENCE OF DEATH OR SERIOUS DETERIORATION IN
STATE OF HEALTH ......................................................................................................................... 19
5.1.4 TREND REPORTS..................................................................................................................19
5.1.5 REPORTING OF USE ERROR AND ABNORMAL USE........................................................20
5.1.5.1 REPORTABLE USE ERRORS ........................................................................................................... 20
5.1.5.2 USE ERROR WHERE REPORTING UNDER THE MEDICAL DEVICE VIGILANCE SYSTEM IS
NOT USUALLY REQUIRED............................................................................................................. 20
2
5.1.5.3 CONSIDERATION FOR HANDLING ABNORMAL USE ................................................................. 20
5.1.6 DETAILS TO BE INCLUDED IN MANUFACTURER REPORTS........................................21
5.1.7 TIMESCALE FOR THE INITIAL REPORTING OF AN INCIDENT ...................................21
5.1.8 TO WHOM TO REPORT ........................................................................................................21
5.2 HANDLING OF USER REPORTS SUBMITTED TO THE MANUFACTURER BY A
NATIONAL COMPETENT AUTHORITY.................................................................................22
5.3 INVESTIGATIONS......................................................................................................................22
5.3.1 PRINCIPLES ..........................................................................................................................22
5.3.2 ACCESS TO THE DEVICE SUSPECTED TO BE INVOLVED IN THE INCIDENT ...........22
5.4 OUTCOME OF AN INVESTIGATION AND FOLLOW-UP .....................................................23
5.4.1 PRINCIPLES ................................................................................................................................23
5.4.2 FOLLOW-UP REPORT ..........................................................................................................23
5.4.3 FINAL REPORT.....................................................................................................................23
5.4.4 FIELD SAFETY CORRECTIVE ACTION .............................................................................23
5.4.4.1 NOTIFICATION TO NATIONAL COMPETENT AUTHORITIES ..................................................... 24
5.4.4.2 CONTENT OF THE FIELD SAFETY NOTICE .................................................................................. 25
6. RESPONSIBILITIES OF NATIONAL COMPETENT AUTHORITY...............................................26
6.1 ACTIONS ON A REPORT FROM USERS OR OTHER SYSTEMS..........................................26
6.2 RISK EVALUATION AND SUBSEQUENT ACTIONS ..............................................................27
6.2.1 RISK EVALUATION BY THE NATIONAL COMPETENT AUTHORITY ............................27
6.2.2 MONITORING OF MANUFACTURERS SUBSEQUENT ACTIONS ...................................27
6.2.3 NATIONAL COMPETENT AUTHORITY ACTIONS.............................................................28
6.3 CO-ORDINATION BETWEEN COMPETENT AUTHORITIES ...............................................28
6.3.1 CIRCUMSTANCES WHERE A COORDINATING NATIONAL COMPETENT AUTHORITY
IS NEEDED...........................................................................................................................28
6.3.2 DETERMINATION OF THE COORDINATING NATIONAL COMPETENT AUTHORITY 29
6.3.3 THE TASKS OF THE CO-ORDINATING NATIONAL COMPETENT AUTHORITY ..........29
6.3.4 SAFEGUARD CLAUSE..........................................................................................................30
6.3.5 DISSEMINATION OF INFORMATION BETWEEN National COMPETENT
AUTHORITIES .....................................................................................................................30
6.3.6 DISSEMINATION OF INFORMATION OUTSIDE National COMPETENT AUTHORITIES
by a National Competent Authority ........................................................................................31
6.4 COMPLETION OF THE INVESTIGATION ...............................................................................31
7 THE ROLE OF THE NOTIFIED BODIES..........................................................................................32
8 THE ROLE OF THE COMMISSION ..................................................................................................32
9 USERS ROLE WITHIN THE VIGILANCE SYSTEM .......................................................................32

10.1 ANNEX 1 EXAMPLES OF INCIDENTS WHICH THE MANUFACTURER SHOULD REPORT
.......................................................................................................................................................34
10.2 ANNEX 2 EXTRACTS FROM DIRECTIVES RELATING TO "MEDICAL DEVICES
VIGILANCE" ...............................................................................................................................36
10.3 ANNEX 3 REPORT FORM FOR MANUFACTURERS TO THE NATIONAL COMPETENT
AUTHORITY................................................................................................................................39
10.4 ANNEX 4 EUROPEAN FIELD SAFETY CORRECTIVE ACTION REPORT FORM .............44
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE ........................................................47
10.6 ANNEX 6 SUGGESTED NATIONAL COMPETENT AUTHORITY REPORT FORMAT...49
10.7 ANNEX 7 TITLES OF GLOBAL HARMONISATION TASK FORCE STUDY GROUP 2
DOCUMENTS USED IN THE DEVELOPMENT OF THIS MEDDEV AND/OR CITED.....52
10.8 ANNEX 8 LIST OF THE USED ABBREVIATIONS ...................................................................53
10.9 ANNEX 9 GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS IN THE
VIGILANCE SYSTEM.................................................................................................................54
3
1 FOREWORD
These guidelines on the Medical Device Vigilance System are part of a set of Medical Device
Guidelines that promote a common approach by MANUFACTURERs and Notified Bodies
involved in the conformity assessment procedures according to the relevant annexes of the
directives, and by the National Competent Authorities charged with safeguarding public
health.
parties during which intermediate drafts were circulated and comments were taken up in the
documents. Therefore, it reflects positions taken in particular by representatives of National
Competent Authorities and Commission Services, Notified Bodies, industry and other
interested parties in the MEDICAL DEVICEs sector.
carefully considered and transposed into the European context the Global Harmonisation
Task Force (GHTF)1 international regulatory guidance documents on vigilance and post
market surveillance;
addressed the introduction of European medical device database EUDAMED;
amended the document in light of experience with previous clauses.
Nevertheless, due to the participation of the aforementioned interested parties and of ex perts
within the Member States and, therefore, work towards uniform application of relevant
directive provisions and common practices within Member States.
However, only the text of the Directives is authentic in law. On certain issues not addressed
in the Directives, national legislation may be different from these guidelines.
2 INTRODUCTION
These guidelines describe the European system for the notification and evaluation of
INCIDENTs and FIELD SAFETY CORRECTIVE ACTIONS (FSCA) involving MEDICAL
DEVICEs, known as the Medical Device Vigilance System.
The principal purpose of the Medical Device Vigilance System is to improve the protection of
health and safety of patients, USERs and others by reducing the likelihood of reoccurrence
of the INCIDENT elsewhere. This is to be achieved by the evaluation of reported INCIDENTs
and, where appropriate, dissemination of information, which could be used to prevent such
repetitions, or to alleviate the consequences of such INCIDENTs.
These guidelines are intended to facilitate the uniform application and implementation of the
Medical Device Vigilance System requirements contained within:
1
A list of the used abbreviations is listed in annex 8
4
the Directive for Active Implantable Medical Devices (AIMD), 90/385/EEC
the Directive for Medical Devices (MDD), 93/42/EEC
the In Vitro Diagnostic Medical Devices Directive (IVDD), 98/79/EC.
FIELD SAFETY CORRECTIVE ACTION (FSCA), FIELD SAFETY NOTICE (FSN), USE
ERROR and ABNORMAL USE are new concepts introduced in this revision of the guideline
to enhance and clarify the European Medical Device Vigilance System while promoting
harmonisation with GHTF provisions.
The Medical Device Vigilance System is intended to facilitate a direct, early and harmonised
implementation of FIELD SAFETY CORRECTIVE ACTION across the Member States where
the device is in use, in contrast to action taken on a country by country basis.
Corrective action includes, but may not be confined to: a device recall; the issue of a FIELD
SAFETY NOTICE; additional surveillance/modification of devices in use; modification to
future device design, components or manufacturing process; modification to labelling or
3 SCOPE
These guidelines describe the requirements of the Medical Device Vigilance System as it
applies to or involves:
MANUFACTURERs2
National Competent Authorities (NCA)
the European Commission
Notified Bodies
USERs and others concerned with the continuing safety of MEDICAL DEVICEs
These guidelines cover the actions to be taken once the MANUFACTURER or National
Competent Authority receives information concerning an INCIDENT involving a MEDICAL
DEVICE. Information on INCIDENTs which should be reported under the Medical Device
Vigilance System may come to the attention of MANUFACTURERs via the systematic
procedure to review experience gained from devices in the post-production phase, or by
other means (see annexes II, IV, V, VI, VII of MDD and annexes III, IV, VI and VII of IVDD).
The term "post-marketing surveillance" as referred to in Annexes 2, 4, 5 in AIMD has the
same meaning as the aforementioned "systematic procedure".
These guidelines cover Article 8 (AIMD), Article 10 (MDD) and Article 11 (IVDD) outlining the
obligations of Member States upon the receipt of INCIDENT reports, from
MANUFACTURERs or other sources, concerning any MEDICAL DEVICE. They also include
guidance to National Competent Authorities about the issue and receipt of information from
National Competent Authorities outside Europe who are involved in the GHTF National
Competent Authority Report (NCAR) exchange programme.
These guidelines are relevant to INCIDENTs occurring within the Member States of the
European Economic Area (EEA) and Switzerland with regard to:
a) devices which carry the CE-mark
2
including their Authorised Representatives and persons responsible for placing on the
market, see section 4 on definitions.
5
b) devices that do not carry the CE-mark but fall under the directives scope (e.g. custom
made devices)
c) devices that do not carry the CE mark because they were placed on the market before
the entry into force of the medical devices directives.
d) devices that do not carry the CE-mark but where such INCIDENTs lead to
CORRECTIVE ACTION(s) relevant to the devices mentioned in a), b) and c).
These guidelines cover FIELD SAFETY CORRECTIVE ACTION relevant to CE-marked

devices which are offered for sale or are in use within the EEA and Switzerland.
These guidelines make no recommendations on the structure of the systems by which

MANUFACTURERs gather information concerning the use of devices in the post-production
phase, of which the Medical Device Vigilance System is an integral part. Such
recommendations are outside the scope of this document.
3.1 GENERAL PRINCIPLES
3.1.1 FOR MANUFACTURERS
The MANUFACTURER or his AUTHORISED REPRESENTATIVE shall notify the

relevant National Competent Authority about INCIDENTs and FIELD SAFETY
CORRECTIVE ACTIONs when the reporting criteria are met (see section 5.1 and 5.4).
The MANUFACTURER has the responsibility for investigating INCIDENTs and for taking
any CORRECTIVE ACTION necessary (see section 5.2 and 5.3).
The MANUFACTURER should ensure that these guidelines are made known to their
AUTHORISED REPRESENTATIVEs within the EEA and Switzerland, persons
responsible for placing devices on the market and any other agents authorised to act on
their behalf for purposes related to medical devices vigilance, so that the
MANUFACTURERs' responsibilities may be fulfilled.
The MANUFACTURER should ensure that their AUTHORISED REPRESENTATIVE
within the EEA and Switzerland, persons responsible for placing devices on the market
and any other agents authorised to act on their behalf for purposes relating to medical
devices vigilance, are kept informed of INCIDENT reports as appropriate.
Where an INCIDENT occurs as a consequence of the combined use of two or more
separate devices (and/or accessories) made by different MANUFACTURERs, each
MANUFACTURER should submit a report to the relevant National Competent Authority
(see section 5.1)
MANUFACTURERs must keep the Notified Body advised of issues occurring in the post
production phase affecting the certification (see the relevant annexes of the relevant
directives and section 7 of this document). This would include relevant changes derived
from the vigilance system.
The act of reporting an INCIDENT to a National Competent Authority is not to be construed

as an admission of liability for the INCIDENT and its consequences. Written reports may
carry a disclaimer to this effect.
When placing on the market of a particular model of MEDICAL DEVICE ceases, the
MANUFACTURERs vigilance reporting obligations under the Medical Device Directives
remain. However, a MANUFACTURERs legal trading arrangements change with mergers
and acquisitions etc. Where the vigilance and other post market surveillance obligations are
being transferred to another legal entity it is important that post market surveillance activities
6
continue and that Competent Authorities are appraised of the implications and provided with
new contact details as soon as possible, so that any detrimental effects on the functioning of
the vigilance system are minimised.
For a complete description of the MANUFACTURERs role in the Medical Device Vigilance
System, see section 5 of these guidelines.
3.1.2 FOR MANUFACTURERS OF IVDS
Vigilance reporting for IVDs may be more difficult since IVDs do not generally come into
contact with patients. Therefore, it can be difficult to demonstrate direct HARM to patients,
unless the device itself causes deterioration in state of health. HARM to patients is more
likely to be indirect - a result of action taken or not taken on the basis of an incorrect result
obtained with an IVD. Whether as a result of direct or INDIRECT HARM, INCIDENTs should
be reported.
It may be difficult to determine if a serious deterioration in the state of a patients health was
or could be the consequence of an erroneous result obtained with an IVD, or if the HARM
was the consequence of an error by the USER or third party. There should be a
predisposition to report under such circumstances (see section 5.1).
In the case of potential errors by USERs or third parties, labelling and instructions for use
should be carefully reviewed for any possible inadequacy. This is particularly true for devices
used for self-testing where a medical decision may be made by the patient. Inadequacies in
the information supplied by the MANUFACTURER that led or could have led to HARM to
USERs, patients or third parties should be reported.
In particular, it can be extremely difficult to judge events in which no HARM was caused, but
where HARM could result if the event was to occur again elsewhere.
3.1.3 FOR NATIONAL COMPETENT AUTHORITIES

For the purposes of Medical Devices Vigilance System, Member States are represented by
appointed National Competent Authorities, their vigilance contact points being listed on the
European Commission web site:
http://ec.europa.eu/enterprise/medical_devices/contact_links_en.htm
The National Competent Authority monitors the investigation of the INCIDENT carried out
by the MANUFACTURER.
The National Competent Authority should take any further action that may be necessary
to supplement the actions of the MANUFACTURER.
Depending on the outcome to the investigation, any information necessary for the
prevention of further INCIDENTs (or the limitation of their consequences) should be
disseminated by the National Competent Authority.
Member States should ensure that organisations and individuals involved in purchasing
MEDICAL DEVICEs and in the provision of health-care are aware that their co-operation
is vital in providing the first link in the vigilance chain. In order to enhance the efficiency of
the Medical Device Vigilance System, National Competent Authorities should encourage
the reporting of INCIDENTs by the USER and other professionals involved in the
distribution, the delivery or putting in to service of the device. This includes organisations
and individuals responsible for providing calibration and maintenance for MEDICAL
DEVICEs. Such reports may be made directly to the MANUFACTURER or to the National
Competent Authority as well depending on national practice.
7
Information held by National Competent Authorities in connection with the Medical Device
Vigilance System is to be held in confidence, as defined by the relevant articles of the
directives3. However, any INCIDENT report should be available on request, and in
confidence, to the other European Competent Authorities and to other National Competent
Authorities participating in the GHTF exchange programme.
For a complete description of the National Competent Authoritys role in the Medical Device
Vigilance System, see section 6 of this guideline.
3.1.4 FOR USERS

USERs should report INCIDENTs with MEDICAL DEVICEs to the MANUFACTURER or
to the National Competent Authority depending on national practice.
Once corrective (or other) action is identified, hospital administrators, medical
practitioners and other health-care professionals, and USER representatives responsible
for the maintenance and the safety of MEDICAL DEVICEs, can take the necessary steps.
Such steps should, where practicable, be taken in co-operation with the
MANUFACTURER.
For a complete description of the USERs role in the Medical Device Vigilance System, see
section 9 of this guideline.
4 DEFINITIONS
4.1 ABNORMAL USE
Act or omission of an act by the OPERATOR or USER of a MEDICAL DEVICE as a result of

conduct which is beyond any means of risk control by the MANUFACTURER.
Reference: EN IEC 60601-1-6
4.2 AUTHORISED REPRESENTATIVE
Any natural or legal person established in the Community who, explicitly designated by the
MANUFACTURER, acts and may be addressed by authorities and bodies in the Community
instead of the MANUFACTURER with regard to the latters obligations under the directive.
4.3 CORRECTIVE ACTION
Action to eliminate the cause of a potential nonconformity or other undesirable situation.
NOTE1: There can be more than one cause for non-conformity.
NOTE 2: Corrective action is taken to prevent recurrence whereas preventive action is taken
to prevent occurrence.
Reference: EN ISO 9000:2000, 3.6.5
3
AIMD 15, MDD 20 and IVDD 20
8
4.4 DRUG / DEVICE COMBINATION PRODUCT
A MEDICAL DEVICE incorporating a medicinal product or substance where the action of the
medicinal product or substance is ancillary to that of the device. In this case, the lead
directive are the Medical Devices Directives (AIMD, MDD).
4.5 EUDAMED
The European database for MEDICAL DEVICEs EUDAMED is to centralise:

data relating to registration of MANUFACTURERS and MEDICAL DEVICES placed on
the Community market,
data relating to certificates issued, modified, supplemented, suspended,,withdrawn or
refused,
data obtained in accordance with the vigilance procedure.
Reference: Article 14a of MDD and article 10 of IVDD.
4.6 FIELD SAFETY CORRECTIVE ACTION (FSCA)
A FIELD SAFETY CORRECTIVE ACTION is an action taken by a MANUFACTURER to

reduce a risk of death or serious deterioration in the state of health associated with the use of
a MEDICAL DEVICE that is already placed on the market. Such actions should be notified
via a FIELD SAFETY NOTICE.
NOTE 1:
The FSCA may include

- the return of a MEDICAL DEVICE to the supplier;
- device modification;
- device exchange;
- device destruction;
- retrofit by purchaser of MANUFACTURER's modification or design change;
- advice given by MANUFACTURER regarding the use of the device (e.g. where the
device is no longer on the market or has been withdrawn but could still possibly be in use
e.g. implants or change in analytical sensitivity or specificity for diagnostic devices)
A device modification can include:

- permanent or temporary changes to the labelling or instructions for use;
- software upgrades including those carried out by remote access;
- modification to the clinical management of patients to address a risk of death or serious
deterioration in state of health related specifically to the characteristics of the device. For
example:
- For implantable devices it is often clinically unjustifiable to explant the device.
Corrective action taking the form of special patient follow-up, irrespective of
whether any affected un-implanted devices remain available for return, constitutes
FSCA.
- For any diagnostic device (e.g. IVD, imaging equipment or devices) the recall of
patients for retesting or the retest or review of previous results constitutes FSCA.
9
- advice relating to a change in the way the device is used e.g. IVD MANUFACTURER
advises revised quality control procedure -use of third party controls or more frequent
calibration or modification of control values for IVDs.
NOTE 2: This guideline uses the definition of FSCA as synonym for recall mentioned in
article 10(1), paragraph 1b) of the MDD and Article 11 IVD Directive since there is no
harmonised definition of recall.
4.7 FIELD SAFETY NOTICE (FSN)
A communication to customers and/or USERs sent out by a MANUFACTURER or its

representative in relation to a Field Safety Corrective Action.
4.8 HARM
Physical injury or damage to the health of people, or damage to property or the environment.
Reference: ISO/IEC Guide 51:1999
4.9 IMMEDIATELY
For purposes of this guideline, IMMEDIATELY means without any delay that could not be
justified.
4.10 INCIDENT
Any malfunction or deterioration in the characteristics and/or performance of a device, as

well as any inadequacy in the labeling or the instructions for use which, directly or indirectly,
might lead to or might have led to the death of a patient, or USER or of other persons or to a
serious deterioration in their state of health.
Reference: Article 10 of the MDD
Note 1: There is a similar definition in Article 8 of the AIMD and Article 11 IVD Directive with
minor wording differences.
Note 2: A description of serious deterioration in the state of health is given in section 5.1.1.
(C) of this document.
4.11 INDIRECT HARM
Some diagnostic devices and all IVDs do not act directly on the individual. HARM may occur
as a consequence of the medical decision, action taken/not taken on the basis of information
or result(s) provided by the device.
Examples include
misdiagnosis,
delayed diagnosis,
10
delayed treatment,
inappropriate treatment,
transfusion of inappropriate materials.
For self-testing devices, a medical decision may be made by the USER of the device who is also
the patient.
4.12 INTENDED PURPOSE
The use for which the device is intended according to the data supplied by the
MANUFACTURER on the labelling, in the instructions and/or in promotional materials.
Reference: Article 1.2 (h) of the IVDD and Article 1.2 (g) of the MDD
4.13 MANUFACTURER
The natural or legal person with responsibility for the design, manufacture, packaging and
labelling of a device before it is placed on the market under his own name, regardless of
whether these operations are carried out by that person himself or on his behalf by a third
party.
Reference: Article 1.2 (f) of the IVDD and Article 1.2 (f) of the MDD
4.14 MEDICAL DEVICE
For the purpose of the Medical Devices Directives 90/385/EEC, 93/42/EEC and 98/79/EEC,
any instrument, apparatus, appliance, material or other Article, whether used alone or in
combination, including the software necessary for its proper application intended by the
MANUFACTURER to be used for human beings for the purpose of:

- diagnosis, monitoring, treatment, alleviation of or compensation for an injury or
handicap,
- investigation, replacement or modification of the anatomy or of a
physiological process,
and which does not achieve its principal intended action in or on the human body by
pharmacological, immunological or metabolic means, but which may be assisted in its
function by such means.
4.15 OPERATOR
Person handling equipment.
4.16 PERIODIC SUMMARY REPORTING
PERIODIC SUMMARY REPORTING is an alternative reporting regime that is agreed

between the MANUFACTURER and the National Competent Authority for reporting similar
11
INCIDENTs with the same device or device type in a consolidated way where the root cause
is known or an FSCA has been implemented.
4.17 SERIOUS PUBLIC HEALTH THREAT
Any event type which results in imminent risk of death, serious deterioration in state of
health, or serious illness that requires prompt remedial action.
This would include:

events that are of significant and unexpected nature such that they become alarming
as a potential public health hazard, e.g. human immunodeficiency virus (HIV) or
Creutzfeldt-Jacob Disease (CJD). These concerns may be identified by either the
National Competent Authority or the MANUFACTURER.
the possibility of multiple deaths occurring at short intervals.
Reference: GHTF SG2 N33R11
4.18 TREND REPORTING
A reporting type used by the MANUFACTURER when a significant increase in events not
normally considered to be INCIDENTs according to section 5.1.3. occurred and for which
pre-defined trigger levels are used to determine the threshold for reporting.
NOTE: GHTF SG2 document N36 'MANUFACTURER's TREND REPORTING of Adverse

INCIDENTs' provides useful guidance (see annex 7).'
4.19 UNANTICIPATED
A deterioration in state of health is considered UNANTICIPATED if the condition leading to

the event was not considered in a risk analysis.
NOTE: Documented evidence in the design file is needed that such analysis was used to
reduce the risk to an acceptable level, or that this risk is well known by the intended USER.
4.20 USE ERROR
Act or omission of an act, that has a different result to that intended by the
MANUFACTURER or expected by the OPERATOR of the MEDICAL DEVICE.
4.21 USER
The health care institution, professional, carer or patient using or maintaining MEDICAL
DEVICES.
5 MANUFACTURERS ROLE
12
5.1 INCIDENT REPORTING SYSTEM
The MANUFACTURER or their AUTHORISED REPRESENTATIVE must submit an initial

INCIDENT report to the National Competent Authority for recording and evaluation. Each
initial report must lead to a final report unless the initial and the final report are combined into
one report. But not every INCIDENT report will lead to a corrective action.
As a general principle, there should be a pre-disposition to report rather than not to report in
case of doubt on the reportability of an INCIDENT.
Reference to the following considerations may be made in the report, or should be kept on
file by the MANUFACTURER in the case of a decision not to report.
INCIDENTs which occurred outside the EEA and Switzerland and do not lead to a FIELD
SAFETY CORRECTIVE ACTION relevant to these geographic areas do not need to be
reported. Incidents which occurred outside the EEA and Switzerland and led to a FIELD
SAFETY CORRECTIVE ACTION relevant to the above-mentioned geographical areas must
be reported as a FIELD SAFETY CORRECTIVE ACTION.
Where appropriate, MANUFACTURERs should notify their AUTHORISED

REPRESENTATIVE, persons responsible for placing devices on the market and any other
agents (e.g. distributors) authorised to act on their behalf of INCIDENTs and FSCA reported
under the Medical Device Vigilance System.
If the MANUFACTURER is located outside the EEA and Switzerland, a suitable contact point
within should be provided. This may be the MANUFACTURER's AUTHORISED
REPRESENTATIVE, persons responsible for placing devices on the market or any other
agent authorised to act on their behalf for purposes relating to Medical Devices Vigilance.
Any report should not be unduly delayed because of incomplete information.

COMPETENT AUTHORITIES
Any event which meets all three basic reporting criteria A C listed below is considered as
an INCIDENT and must be reported to the relevant National Competent Authority. The
criteria are that:
A: An event has occurred
This also includes situations where testing performed on the device, examination of the
information supplied with the device or any scientific information indicates some factor that
could lead or has led to an event.
Typical events include, but are not limited to:
a) A malfunction or deterioration in the characteristics or performance.
A malfunction or deterioration should be understood as a failure of a device to perform in

accordance with its INTENDED PURPOSE when used in accordance with the
MANUFACTURERs instructions.
13
b) False positive or false negative test result falling outside the declared performance of the
test.
c) Unanticipated adverse reaction or unanticipated side effect
d) Interactions with other substances or products
e) Degradation/destruction of the device (e.g. fire)
f) Inappropriate therapy
g) An inaccuracy in the labelling, instructions for use and/or promotional materials.

Inaccuracies include omissions and deficiencies. Omissions do not include the absence of
information that should generally be known by the intended USERs.
NOTE: see ISO TS 19218 adverse event type and cause/effect coding for further details on
events.
B: The MANUFACTURERs device is suspected to be a contributory cause of the

INCIDENT
In assessing the link between the device and the INCIDENT the MANUFACTURER should
take account of:
the opinion, based on available evidence, of healthcare professionals;

the results of the MANUFACTURER's own preliminary assessment of the INCIDENT;
evidence of previous, similar INCIDENTs;
other evidence held by the MANUFACTURER.
This judgement may be difficult when there are multiple devices and drugs involved. In
complex situations, it should be assumed that the device may have caused or contributed to
the INCIDENT and the MANUFACTURERs should err on the side of caution.
C: The event led, or might have led, to one of the following outcomes:
death of a patient, USER or other person

serious deterioration in state of health of a patient, USER or other person
A serious deterioration in state of health can include:
a) life-threatening illness
b) permanent impairment of a body function or permanent damage to a body structure
c) a condition necessitating medical or surgical intervention to prevent a) or b)
Examples: - clinically relevant increase in the duration of a surgical procedure
- a condition that requires hospitalisation or significant prolongation of
existing hospitalisation
d) any indirect harm (see definition under 4.11) as a consequence of an incorrect
diagnostic or IVD test results when used within MANUFACTURERs instructions for
use
e) foetal distress, foetal death or any congenital abnormality or birth defects
NOTE :
14
Not all INCIDENTs lead to death or serious deterioration in health. The non-occurrence of
such a result might have been due to other fortunate circumstances or to the intervention of
healthcare personnel.
It is sufficient that:
an INCIDENT associated with a device happened, and

the INCIDENT was such that, if it occurred again, it might lead to death or
serious deterioration in health.
Examples of reportable INCIDENTs are given in Annex 1.
5.1.2 CONDITIONS FOR PERIODIC SUMMARY REPORTING UNDER THE

MEDICAL DEVICE VIGILANCE SYSTEM
There are a number of occasions when a National Competent Authority may accept from a
MANUFACTURER or AUTHORISED REPRESENTATIVE periodic summary or trend
reports, after one or more initial reports have been issued and evaluated by the manufacturer
and the National Competent Authority. This should be agreed between MANUFACTURERs
and individual National Competent Authorities and submitted in an agreed format and
frequency for certain types of device and INCIDENT.
When a MANUFACTURER has received the agreement of a National Competent Authority to

switch to periodic summary reporting or trend reports, he shall inform the other concerned
CAs of the agreement and of its modalities. Periodic summary reporting can only be
extended to other competent authorities upon agreement of the individual national competent
authority.
5.1.2.1 INCIDENTS DESCRIBED IN A FIELD SAFETY NOTICE
INCIDENTs specified in the FIELD SAFETY NOTICE that occur after the MANUFACTURER
has issued a FIELD SAFETY NOTICE and conducted a field safety corrective action need
not be reported individually. Instead, the MANUFACTURER can agree with the coordinating
National Competent Authority on the frequency and content of the Periodic Summary Report.
The Periodic Summary Report must be sent to all affected National Competent Authorities
and the coordinating National Competent Authority.
Example:
A MANUFACTURER issued a FIELD SAFETY NOTICE and conducted a FIELD SAFETY

CORRECTIVE ACTION of a coronary stent that migrated due to inadequate inflation of an
attached balloon mechanism. Subsequent examples of stent migration were summarised in
quarterly reports concerning the FIELD SAFETY CORRECTIVE ACTION and individual
INCIDENTs did not have to be reported.
5.1.2.2 COMMON AND WELL-DOCUMENTED INCIDENTS
Common and well-documented INCIDENTs (identified as such in the risk analysis of the
device and which have already led to incident reports assessed by the MANUFACTURER
and the relevant National Competent Authority) may be exempted from reporting individually
by the National Competent Authority and changed to PERIODIC SUMMARY REPORTING.
However, these INCIDENTs shall be monitored and trigger levels determined. Trigger levels
15
for interim reporting should also be agreed with the relevant National Competent Authority.
An interim report should be made whenever trigger levels are exceeded.
Periodic summary reporting can only be extended to other competent authorities when it has
the agreement of individual national CA's.
5.1.3 CONDITIONS WHERE REPORTING UNDER THE MEDICAL DEVICE

VIGILANCE SYSTEM IS NOT USUALLY REQUIRED
5.1.3.1 DEFICIENCY OF A DEVICE FOUND BY THE USER PRIOR TO ITS USE
Regardless of the existence of provisions in the instructions for use provided by the
MANUFACTURER, deficiencies of devices that are always detected (that could not go
undetected) by the USER prior to its use do not need to be reported under the vigilance
system.
This is without prejudice to the fact that the user should inform the MANUFACTURER of any
deficiency identified prior to the use of a MEDICAL DEVICE.
Examples:
The packaging of a sterile single use device is labelled with the caution 'do not
use if the packaging is opened or damaged'. Prior to use, obvious damage to
the packaging was observed, and the device was not used.
Intravenous administration set tip protector has fallen off the set during
distribution resulting in a non-sterile fluid pathway. The intravenous
administration set was not used.
A vaginal speculum has multiple fractures. Upon activating the handle, the
device fell apart. The device was not used.
In an IVD testing kit a bottle labelled lyophilised is found to be fluid, this is

discovered by the USER prior to use.
5.1.3.2 EVENT CAUSED BY PATIENT CONDITIONS
When the MANUFACTURER has information that the root cause of the event is due to
patient condition, the event does not need to be reported. These conditions could be pre-
existing or occurring during device use.
To justify no report, the MANUFACTURER should have information available to conclude

that the device performed as intended and did not cause or contribute to death or serious
deterioration in state of health. A person qualified to make a medical judgement would accept
the same conclusion. It is recommended that the MANUFACTURER involves a clinician in
making the decision.
Examples:
Early revision of an orthopedic implant due to loosening caused by the patient

developing osteolysis, which is not considered a direct consequence of the
implant failure. This conclusion would need to be supported by the opinion of a
medical expert.
16
A patient died after dialysis treatment. The patient had end-stage-renal disease
and died of renal failure, the MANUFACTURERs investigations revealed the
device to be functioning as claimed and the INCIDENT was not attributed to the
device.
5.1.3.3 SERVICE LIFE OR SHELF-LIFE OF THE MEDICAL DEVICE EXCEEDED
When the only cause for the event was that the device exceeded its service life or shelf-life
as specified by the MANUFACTURER and the failure mode is not unusual, the INCIDENT
does not need to be reported.
The service life or shelf-life must be specified by the device MANUFACTURER and included
in the master record [technical file] and, where appropriate, the instructions for use (IFU) or
labelling, respectively. Service life or shelf-life can include e.g.: the time or usage that a
device is intended to remain functional after it is manufactured, put into service, and
maintained as specified. Reporting assessment shall be based on the information in the
master record or in the IFU.
Examples:
Loss of sensing after a pacemaker has reached end of life. Elective

replacement indicator has shown up in due time according to device
specification. Surgical explantation of pacemaker required.
Insufficient contact of the defibrillator pads to the patient was observed. The
patient could not be defibrillated due to insufficient contact to the chest. The
shelf life of the pads was labelled but exceeded.
A patient is admitted to hospital with hypoglycaemia based on an incorrect

insulin dosage following a blood glucose result. The investigation found that
the test strip was used beyond the expiry date specified by the
MANUFACTURER.
5.1.3.4 PROTECTION AGAINST A FAULT FUNCTIONED CORRECTLY
Events which did not lead to serious deterioration in state of health or death, because a
design feature protected against a fault becoming a hazard (in accordance with relevant
standards or documented design inputs), do not need to be reported. As a precondition,
there must be no danger for the patient to justify not reporting. If an alarm system is used,
the concept of this system should be generally acknowledged for that type of product.
Examples:
An infusion pump stops, due to a malfunction, but gives an appropriate alarm

(e.g. in compliance with relevant standards) and there was no injury to the
patient.
Microprocessor-controlled radiant warmers malfunction and provide an audible

appropriate alarm. (e.g., in compliance with relevant standards) and there was
no deterioration in state of health of the patient.
17
During radiation treatment, the automatic exposure control is engaged.
Treatment stops. Although patient receives less than optimal dose, patient is
not exposed to excess radiation.
A laboratory analyser stops during analysis due to a malfunction of the sample

pipetting module, but the appropriate error message was provided for the
OPERATOR. No results were reported.
5.1.3.5 EXPECTED AND FORESEEABLE SIDE EFFECTS
Expected and foreseeable side effects which meet all the following criteria:
clearly identified in the MANUFACTURER's labelling;

clinically well known* as being foreseeable and having a certain qualitative** and
quantitative predictability when the device is used and performs as intended;
documented in the device master record, with an appropriate risk assessment, prior
to the occurrence of the INCIDENT and
clinically acceptable in terms of the individual patient benefit
are ordinarily not reportable.
It is recommended that the MANUFACTURER involves a clinician in making this decision.
If the MANUFACTURER detects a change in the risk-benefit-ratio (e.g. an increase of

frequency and/or severity) based on reports of expected and foreseeable side effects that led
or might lead to death or serious deterioration of state of health, this must be considered as a
deterioration in the characteristics of the performance of the device. A trend report must be
submitted to the NCA where the MANUFACTURER or its AUTHORISED
REPRESENTATIVE has his registered place of business.
Rationale: At the moment side effects are not covered by the INCIDENT definition in
the directive unless the change in the risk-benefit-ratio is considered as a
deterioration in the performance of the device.
NOTES:
* Some of these events are well known in the medical, scientific, or technology field; others
may have been clearly identified during clinical investigation or clinical practice and labelled
** The conditions that lead to the side effect can be described but they may sometimes be
difficult to predict numerically.
Conversely, side effects which were not documented and foreseeable, or which were not
clinically acceptable in terms of individual patient benefit should continue to be reported.
Examples:
A patient who is known to suffer from claustrophobia experiences severe

anxiety in the confined space of a MRI machine which subsequently led to the
patient being injured. Potential for claustrophobia is known and documented in
the device product information.
18
A patient receives a second-degree burn during the use in an emergency of an
external defibrillator. Risk assessment documents that such a burn has been
accepted in view of potential patient benefit and is warned in the instructions
for use. The frequency of burns is occurring within range specified in the
device master record.
A patient has an undesirable tissue reaction (e.g. nickel allergy) previously

known and documented in the device product information.
Patient who has a mechanical heart valve developed endocarditis ten years
after implantation and then died. Risk assessment documents that endocarditis
at this stage is clinically acceptable in view of patient benefit and the
instructions for use warn of this potential side effect.
Placement of central line catheter results in anxiety reaction and shortness of

breath. Both reactions are known and labelled side effects.
5.1.3.6 NEGLIGIBLE LIKELIHOOD OF OCCURRENCE OF DEATH OR SERIOUS

DETERIORATION IN STATE OF HEALTH
INCIDENTs where the risk of a death or serious deterioration in state of health has been
quantified and found to be negligibly small need not be reported if no death or serious
deterioration in state of health occurred and the risk has been characterised and documented
as acceptable within a full risk assessment.
If an INCIDENT resulting in death or serious deterioration in state of health has happened,

the INCIDENT is reportable and a reassessment of the risk is necessary. If reassessment
determines that the risk remains negligible small previous INCIDENTs of the same type do
not need to be reported retrospectively. Decisions not to report subsequent failures of the
same type must be documented. Changes in the trend, usually an increase, of these non-
serious outcomes must be reported.
Example:
MANUFACTURER of a pacemaker released on the market identified a

software bug and quantified the probability of occurrence of a serious
deterioration in state of health with a particular setting to be negligible. No
patients experienced adverse health effects.
Mislabelling of IVD reagents that is an isolated INCIDENT and where it

would have no effect on the final result as the result itself would be invalid.
5.1.4 TREND REPORTS
On identifying a significant increase or trend of events or INCIDENTs that are usually

excluded from individual reporting as per chapter 5.1.3 a report should to be made to the
relevant National Competent Authority. To enable this, the MANUFACTURER should have
suitable systems in place for proactive scrutiny of trends in complaints and INCIDENTs
occurring with their devices. GHTF SG2 document N36 'MANUFACTURER's TREND
REPORTING of Adverse INCIDENTs' provides useful guidance (see annex 7).
19
A trend report to the National Competent Authority where the MANUFACTURER or its
AUTHORISED REPRESENTATIVE has its registered place of business should be made
where there is a significant increase in the rate of:
already reportable INCIDENTs

INCIDENTs that are usually exempt from reporting
events that are usually not reportable
irrespective of whether PERIODIC SUMMARY REPORTING has been agreed.
5.1.5 REPORTING OF USE ERROR AND ABNORMAL USE
As with all reported device complaints, all potential USE ERROR events, and potential
ABNORMAL USE events dealt with in paragraph 5.1.5.3, should be evaluated by the
MANUFACTURER. The evaluation is governed by risk management, usability engineering,
design validation, and corrective and preventive action processes.
Results should be available, upon request, to regulatory authorities and conformity

assessment bodies.
5.1.5.1 REPORTABLE USE ERRORS
USE ERROR related to MEDICAL DEVICEs, which did result in death or serious
deterioration in state of health or SERIOUS PUBLIC HEALTH THREAT, should be reported
by the MANUFACTURER to the National Competent Authority.
USE ERRORs become reportable by the MANUFACTURER to the National Competent

Authority when a MANUFACTURER:
- notes a significant change in trend (usually an increase in frequency), or a significant
change in pattern (see annex 7 GHTF SG2 N36) of an issue that can potentially lead
to death or serious deterioration in state of health or public health threat)
- or initiates corrective action to prevent death or serious deterioration in state of health
or SERIOUS PUBLIC HEALTH THREAT
5.1.5.2 USE ERROR WHERE REPORTING UNDER THE MEDICAL DEVICE

VIGILANCE SYSTEM IS NOT USUALLY REQUIRED.
USE ERROR related to MEDICAL DEVICEs, which did not result in death or serious
deterioration in state of health or SERIOUS PUBLIC HEALTH THREAT, need not be
reported by the MANUFACTURER to the National Competent Authority. Such events should
be handled within the MANUFACTURERs quality and risk management system. A decision
to not report must be justified and documented.
5.1.5.3 CONSIDERATION FOR HANDLING ABNORMAL USE
ABNORMAL USE needs not be reported by the MANUFACTURER to the National

Competent Authority under the reporting procedures. ABNORMAL USE should be handled
by the health care facility and appropriate regulatory authorities under specific appropriate
schemes not covered by this document.
20
If MANUFACTURERs become aware of instances of ABNORMAL USE, they may bring this
to the attention of other appropriate organisations and healthcare facility personnel.
5.1.6 DETAILS TO BE INCLUDED IN MANUFACTURER REPORTS
Annex 3 comprises the essential details of an INCIDENT to be included in any report made
by a MANUFACTURER, AUTHORISED REPRESENTATIVE or person(s) responsible for
placing on the market on their behalf to a National Competent Authority and should be used
for Initial, Follow-up and Final Incident Reports. In the interests of efficiency, reporting by
electronic means (email, on-line database system, xml etc.) is encouraged.
If the initial report is made by oral means (e.g. telephone), it should always be followed as
soon as possible by a written report by the MANUFACTURER or the AUTHORISED
REPRESENTATIVE.
The report may also include a statement to the effect that the report is made by the
MANUFACTURER without prejudice and does not imply any admission of liability for the
INCIDENT or its consequences.
5.1.7 TIMESCALE FOR THE INITIAL REPORTING OF AN INCIDENT
Upon becoming aware that an event has occurred and that one of its devices may have
caused or contributed to that event, the MEDICAL DEVICE MANUFACTURER must
determine whether it is an INCIDENT.
The following time lines apply in a case of:
Serious public health threat: IMMEDIATELY (without any delay that could not be justified)
but not later than 2 calendar days after awareness by the MANUFACTURER of this threat.
Death or UNANTICIPATED serious deterioration in state of health: IMMEDIATELY

(without any delay that could not be justified) after the MANUFACTURER established a link
between the device and the event but not later than 10 elapsed calendar days following the
date of awareness of the event.
Others: IMMEDIATELY (without any delay that could not be justified) after the
MANUFACTURER established a link between the device and the event but not later than 30
elapsed calendar days following the date of awareness of the event.
If after becoming aware of a potentially reportable INCIDENT there is still uncertainty about
whether the event is reportable, the MANUFACTURER must submit a report within the
timeframe required for that type of INCIDENT.
All report times refer to when the National Competent Authority must first be notified. The
relevant contact points are available from the Commissions web site.
5.1.8 TO WHOM TO REPORT
In general, the report should be made to the National Competent Authority in the country of
occurrence of the INCIDENT unless specified differently in this guideline.
21
5.2 HANDLING OF USER REPORTS SUBMITTED TO THE MANUFACTURER
BY A NATIONAL COMPETENT AUTHORITY
If the MANUFACTURER receives a USER report from a National Competent Authority he

shall check this report against the reporting criteria of chapter 5.1 and
- submit an Initial INCIDENT (or Follow-up/Final) Report to the relevant National

Competent Authority, if the event fulfils the relevant reporting criteria or
- if the MANUFACTURER considers the event not to fulfil the reporting criteria, provide the
National Competent Authority with a justification why this is not reportable to the National
Competent Authority with details of what use will be made of the information. (e.g. added
to complaints file).
5.3 INVESTIGATIONS
5.3.1 PRINCIPLES
The MANUFACTURER normally performs the investigation, while the National Competent
Authority monitors progress. Timeframe(s) for follow up and/or final reports should be
defined.
If the MANUFACTURER is not able to perform the investigation of an INCIDENT then he

should inform the National Competent Authority without delay.
The National Competent Authority may intervene, or initiate independent investigation if

appropriate. This should be in consultation with the MANUFACTURER where practicable.
Note: The above principles are generalised and do not take account of interventions by
judicial or other agencies.
5.3.2 ACCESS TO THE DEVICE SUSPECTED TO BE INVOLVED IN THE

INCIDENT
A MANUFACTURER may consult with the USER on a particular INCIDENT before a report
has been made to the National Competent Authority (see section 6.1). The
MANUFACTURER may also need to have access to the device suspected to have
contributed to the INCIDENT for the purpose of deciding whether the INCIDENT should be
reported to the National Competent Authority. The MANUFACTURER should in such cases
make reasonable efforts to gain access to the device and may request support from the
Competent Authorities to gain access to the device so that testing can be performed as soon
as possible. Any delay can result in loss of evidence (e.g. loss of short term memory data
stored in the device software; degradation of certain devices when exposed to blood)
rendering future analysis of the root cause impossible.
If the MANUFACTURER gains access to the device, and his initial assessment (or cleaning
or decontamination process) will involve altering the device in a way which may affect
subsequent analysis, then the MANUFACTURER should inform the National Competent
Authority before proceeding. The National Competent Authority may then consider whether
to intervene. Due to the frequency of these requests, a statement introduced in the Initial
Vigilance report should cover this requirement, e.g. The MANUFACTURER will assume
destructive analysis can begin 10 days following issuance of this Initial INCIDENT Report,
22
unless the National Competent Authority contacts the MANUFACTURER within this time
frame opposing a destructive analysis of the device.
NOTE: This section also applies to samples and any other useful information associated with
the INCIDENT.
5.4 OUTCOME OF AN INVESTIGATION AND FOLLOW-UP
5.4.1 PRINCIPLES
The MANUFACTURER shall take the action necessary following the investigation, including
consultation with the National Competent Authority and performing any FSCA - see section
5.4.
The National Competent Authority may take any further action it deems appropriate,
consulting with the MANUFACTURER where possible - see section 6.2.3.
5.4.2 FOLLOW-UP REPORT
The MANUFACTURER shall provide a follow-up-report to the National Competent Authority

if the investigation time reaches the time line given to the National Competent Authority
within the initial report.
5.4.3 FINAL REPORT
There shall be a final report which is a written statement of the outcome of the investigation
and of any action.
Examples of actions may include:
no action;
additional surveillance of devices in use;
preventive action on future production;
FSCA.
The report is made by the MANUFACTURER to the National Competent Authority(ies) to

whom the MANUFACTURER sent the initial report.
If the National Competent Authority performs the investigation then the MANUFACTURER
shall be informed of the result.
A recommended format for the MANUFACTURER's final report is given in annex 3.
5.4.4 FIELD SAFETY CORRECTIVE ACTION
The Medical Device Directives require the MANUFACTURER to report to the National
Competent Authority any technical or medical reason leading to a systematic recall of
devices of the same type by the MANUFACTURER. Those reasons are any malfunction or
deterioration in the characteristics and/or performance of a device, as well as any
23
inadequacy in the instructions for use which might lead to or might have led to the death of a
patient or USER or to a serious deterioration in his state of health.
The term "withdrawal" used in the AIMD is interpreted in the same way. This guideline uses
the definition of a FIELD SAFETY CORRECTIVE ACTION as a synonym for recall or
withdrawal since there is no longer a harmonised definition of these terms.
Removals from the market for purely commercial non-safety related reasons are not
included.
In assessing the need for the FSCA the MANUFACTURER is advised to use the
methodology described in the harmonised Risk Management standard EN ISO 14971: 2000.
In case of doubt, there should be a predisposition to report and to undertake a FIELD
SAFETY CORRECTIVE ACTION.
FSCA taken on a basis of INCIDENTs occurred outside the EEA and Switzerland and
affecting devices covered by the MDD are included in this guideline.
FSCA should be notified to the customers via a FIELD SAFETY NOTICE.
Where a Notified Body was involved in the conformity assessment procedure of the device, it
is recommended to inform them about the FIELD SAFETY CORRECTIVE ACTION.
5.4.4.1 NOTIFICATION TO NATIONAL COMPETENT AUTHORITIES
The MANUFACTURER should issue a notification (see below) to the Competent Authorities
of all countries affected at the same time and also to the National Competent Authority
responsible for the MANUFACTURER or AUTHORISED REPRESENTATIVE. Use the
format recommended in annex 4.
This notification should include all relevant documents necessary for the National Competent
Authority to monitor the FSCA, e.g.
Relevant parts from the risk analysis
Background information and reason for the FSCA (including description of the device
deficiency or malfunction, clarification of the potential hazard associated with the
continued use of the device and the associated risk to the patient, USER or other
person and any possible risks to patients associated with previous use of affected
devices.)
Description and justification of the action (corrective/preventive)
Advice on actions to be taken by the distributor and the USER (include as
appropriate:
identifying and quarantining the device,
method of recovery, disposal or modification of device
recommended patient follow up, e.g implants, IVD
a request to pass the FIELD SAFETY NOTICE to all those who need
to be aware of it within the organisation and to maintain awareness
over an appropriate defined period.
a request for the details of any affected devices that have been
transferred to other organisations, to be given to the
MANUFACTURER and for a copy of the FIELD SAFETY NOTICE to
be passed on to the organisation to which the device has been
transferred.)
Affected devices and serial / lot / batch number range
24
In the case of an action concerning lots or parts of lots an explanation why the other
devices are not affected
Identity of the MANUFACTURER/AUTHORISED REPRESENTATIVE.
MANUFACTURERs should also include a copy of the FIELD SAFETY NOTICE to the
Competent Authorities along with the notification. This should be done before or at the same
time as FSCA is being issued.
The MANUFACTURER or other responsible on his behalf should inform the coordinating
Competent Authority once the FSCA has been completed in both, the EEA and Switzerland.
This should include information on the effectiveness of the action per country involved (e.g.,
percentage of devices recalled)
It is recommended that MANUFACTURERs should provide a draft of the Field Safety

Notification to a relevant National Competent Authority, e.g. where the MANUFACTURER or
the AUTHORISED REPRESENTATIVE has his registered place of business, where most of
the affected devices are on the market or any other appropriate National Competent
Authority.
Normally, the MANUFACTURER should allow a minimum of 48 hours for receipt of comment
on the Field Safety Notification unless the nature of the FSCA dictates a shorter timescale
e.g. for SERIOUS PUBLIC HEALTH THREAT.
It is recommended to copy the FIELD SAFETY NOTICE to the Notified Body involved in the
conformity assessment procedure of that device.
5.4.4.2 CONTENT OF THE FIELD SAFETY NOTICE
Unless duly justified by the local situation, a uniform and consistent FIELD SAFETY NOTICE
should be offered by the MANUFACTURER to all affected EEA member states and
Switzerland.
The MANUFACTURER should use a distribution means ensuring the appropriate

organisations have been informed, e.g. by confirmation of receipt.
The FIELD SAFETY NOTICE should be on a company letterhead, be written in the

language(s) accepted by the National Competent Authority(s) and include the following:
1. A clear title, with Urgent FIELD SAFETY NOTICE followed by the commercial name of
the affected product, an FSCA-identifier (e.g. date) and the type of action (e.g. see
chapter 4 definition of a FSCA).
2. Specific details to enable the affected product to be easily identified e.g. type of device,
model name and number, batch/lot or serial numbers of affected devices and part or
order number.
3. A factual statement explaining the reasons for the FSCA, including description of the
device deficiency or malfunction, clarification of the potential hazard associated with the
continued use of the device and the associated risk to the patient, USER or other person
and any possible risks to patients associated with previous use of affected devices.
4. Advice on actions to be taken by the USER.

Include as appropriate:
25
recommended review of patients previous results or patient follow up, e.g
implants, IVD
timelines.
5. A request to pass the FIELD SAFETY NOTICE to all those who need to be aware of it
within the organisation and to maintain awareness over an appropriate defined period.
6. If relevant, a request for the details of any affected devices that have been transferred to
other organisations, to be given to the MANUFACTURER and for a copy of the FIELD
SAFETY NOTICE to be passed on to the organisation to which the device has been
transferred.
7. If relevant, a request that the recipient of the FIELD SAFETY NOTICE alerts other
organisations to which incorrect test results from the use of the devices have been sent.
For example failure of diagnostic tests.
8. Confirmation that the relevant National Competent Authorities have been advised of the
FSCA.
9. Any comments and descriptions that attempt to

a) serve to play down the level of risk in an inappropriate manner
b) advertise products or services
should be omitted.
10. Contact point for customers how and when to reach the designated person.
An acknowledgment form for the receiver might also be included (especially useful for
MANUFACTURERs control purposes).
By following the recommendations above the clarity of FIELD SAFETY NOTICEs will be
improved. This will reduce the likelihood of Competent Authorities either requesting
MANUFACTURERs issue revised FIELD SAFETY NOTICEs or issuing separate National
Competent Authority communications.
A template for a FIELD SAFETY NOTICE is provided in annex 5.
6. RESPONSIBILITIES OF NATIONAL COMPETENT AUTHORITY
The National Competent Authority should send an acknowledgement of receipt of the report
to the sender.
The National Competent Authority shall evaluate the report in consultation with the
MANUFACTURER, if practicable (see section 5.2 and 5.3), advise as appropriate and
intervene if necessary.
6.1 ACTIONS ON A REPORT FROM USERS OR OTHER SYSTEMS
A report which appears to meet the criteria of section 5.1.1, received by a National
Competent Authority from a USER reporting system or other source, shall be copied by the
26
National Competent Authority to the MANUFACTURER without delay or translation. In doing
so, patient confidentiality should be maintained.
Once the MANUFACTURER has been so informed and has determined that the event fulfils
the three basic reporting criteria of section 5.1.1, the subsequent procedure is the same, as
far as practicable, as that described in section 5 of these guidelines.
6.2 RISK EVALUATION AND SUBSEQUENT ACTIONS
6.2.1 RISK EVALUATION BY THE NATIONAL COMPETENT AUTHORITY
The risk assessment of an INCIDENT or FSCA reported may include where relevant:
Acceptability of the risk, taking into account criteria such as: causality, technical/other
cause, probability of occurrence of the problem, frequency of use, detectability,
probability of occurrence of HARM, severity of HARM, INTENDED PURPOSE and
benefit of the product, requirements of harmonised European standards, the Medical
Device Directives safety principles (see annex I, clause 2 of the directives 93/42/EEC
and 98/79/EC and clauses 5 and 6 of directive 90/385/EEC), potential USER(s),
affected populations etc.
Need for (what) corrective action
Adequacy of measures proposed or already undertaken by the MANUFACTURER
This assessment should be carried out in cooperation with the MANUFACTURER.
6.2.2 MONITORING OF MANUFACTURERS SUBSEQUENT ACTIONS
The National Competent Authority normally monitors the investigation being carried out by
the MANUFACTURER. However, the National Competent Authority may intervene at any
time. Such intervention shall be in consultation with the MANUFACTURER where
practicable.
Aspects of the MANUFACTURER's investigation which may be monitored include, for

example:
course (direction the investigation is taking);

conduct (how the investigation is being carried out);
progress (how quickly the investigation is being carried out);
outcome (whether the results of device analysis are satisfactory ).
Facts which may be needed include, for example:
the number of devices involved;

the length of time they have been on the market;
details of design changes which have been made.
Liaison may be needed with:
27
Notified Bodies (involved in the attestation leading to the CE marking);
USER(s);
other Competent Authorities;
other independent bodies, test houses etc.
Competent Authorities may also monitor experience with the use of devices of the same kind
(for instance, all defibrillators or all syringes), but made by different MANUFACTURERs.
They may then be able to take harmonised measures applicable to all devices of that kind.
This could include, for example, initiating USER education or suggesting re-classification.
6.2.3 NATIONAL COMPETENT AUTHORITY ACTIONS
For drug device combination products regulated under the medical device directives, the
National Competent Authority receiving the INCIDENT report should establish a link with any
other relevant National Competent Authority or the EMEA, if required.
The National Competent Authority should take coordinating action to ensure that an
investigation is carried out if several MANUFACTURERs are involved.
National Competent Authoritys actions as a result of a report of the MANUFACTURER or

AUTHORISED REPRESENTATIVE may include, for example:
no further action;
gathering more information (for example by commissioning independent reports);
making recommendations to MANUFACTURERs (for example to improve information
provided with the device);
keeping the Commission and other Competent Authorities informed (for example on
FSCA and other actions to be taken). The information may be in the format of a National
Competent Authority Report (see annex 6) or similar;
consulting with the relevant Notified Body on matters relating to the conformity
assessment;
consulting the Commission (for example if it is considered that re-classification of the
device is necessary);
further USER education;
further recommendations to USER(s);
any other action to supplement MANUFACTURER action.
6.3 CO-ORDINATION BETWEEN COMPETENT AUTHORITIES
6.3.1 CIRCUMSTANCES WHERE A COORDINATING NATIONAL COMPETENT

AUTHORITY IS NEEDED
Competent Authorities should determine a single coordinating National Competent Authority

under the following circumstances:
INCIDENTs of similar types occurring in more than one country within the EEA and
Switzerland;
FSCA conducted in more than one country within the EEA and Switzerland, whether or
not a reportable INCIDENT has occurred.
28
information available on a FSCA conducted outside the EEA and Switzerland where
there is uncertainty whether the FSCA affects the member states within the EEA and
Switzerland or not, e.g. a Competent Authority Report issued outside EEA and
Switzerland (GHTF SG2) or information published on a CA website outside the EEA and
Switzerland.
6.3.2 DETERMINATION OF THE COORDINATING NATIONAL COMPETENT

AUTHORITY
The co-ordinating Competent Authority should be the one that is responsible for the
MANUFACTURER or his AUTHORISED REPRESENTATIVE, unless otherwise agreed
between Competent Authorities e.g. the National Competent Authority:
which has a particular high interest in consulting other Competent Authorities or is

already undertaking investigation on INCIDENTs and therefore initiates the co-
ordination.
in the State where the Notified Body which made the attestation leading to CE-
marking, is situated.
6.3.3 THE TASKS OF THE CO-ORDINATING NATIONAL COMPETENT

AUTHORITY
The coordinating National Competent Authority should, where relevant:
inform the MANUFACTURER, the other affected Competent Authorities as described in

6.3.1 and the Commission about taking the lead;
coordinate and monitor the investigation with the MANUFACTURER on behalf of other
Competent Authorities;
consult with the Notified Body which made the attestations which led to the CE marking
and coordinate with other National Competent Authorities within the EEA and
Switzerland;
discuss with the MANUFACTURER the principles, need for and circumstances of
corrective actions to be taken within the EEA and Switzerland;
reach agreement, where possible, with MANUFACTURER and amongst National
Competent Authorities about implementing a uniform FSCA in all affected European
countries;
Feedback to the Competent Authorities and the Commission the conclusion from
inquiries within the EEA member states and Switzerland e.g. with respect to multiple
INCIDENTs in different countries which do not lead to corrective actions at the latest with
the closure of the file; MANUFACTURER will be informed according to section 6.4;
Agree with the MANUFACTURER about content and periodicity of PERIODIC
SUMMARY REPORTING for INCIDENTs covered by FSCA
Distribute the closure information.
Such an arrangement would not affect the rights of an individual National Competent
Authority to perform its own monitoring or investigation, or to instigate action within its
Member State in accordance with the provisions of the relevant directives. In doing so, the
coordinating National Competent Authority and the Commission should be kept informed
about these activities.
29
6.3.4 SAFEGUARD CLAUSE
The application of the Medical Device Vigilance System does not affect the responsibilities of
the Member States laid down in the Safeguard Clause (Article 7 of AIMD, Article 8 of MDD
and Article 8 of IVDD).
The Safeguard Clause procedures remain applicable regardless of the Medical Devices
Vigilance System.

AUTHORITIES
Information shall be disseminated between National Competent Authorities and copied to the
Commission when:
A) a FSCA is performed by the MANUFACTURER;

B) a National Competent Authority requires the MANUFACTURER to perform an FSCA or
to make changes in an FSCA that the MANUFACTURER has already initiated;
C) there is a serious risk to the safety of patients or other USERs, but where no corrective
action has yet been established, although measures are under consideration;
D) the MANUFACTURER does not provide a final report in a timely manner.
This information is called National Competent Authority Report (NCAR).
National Competent Authorities should use their discretion where corrective action is taken
by a MANUFACTURER which is not considered to be essential to protect the safety of
patients or other USERs. Under these circumstances a National Competent Authority Report
may not be necessary. In cases of doubt there should be a pre-disposition on the part of
National Competent Authorities to disseminate the NCAR.
The NCAR concerning A) above should be disseminated by the National Competent

Authority responsible for the MANUFACTURER or its AUTHORISED REPRESENTATIVE.
The NCAR concerning B), C) and D) above should be disseminated by the National
Competent Authority requesting the FSCA or changes within the FSCA, or identifying the
serious risk and considering measures, or expecting the final report, respectively.
This NCAR should be distributed by the NCA IMMEDIATELY (without any delay that could
not be justified) but not later than 14 calendar days after being informed by the
MANUFACTURER.
The recommended format for dissemination of information between National Competent

Authorities and the Commission is given in Annex 6 and is the GHTF SG2 N79 with minor
changes. The MANUFACTURER's report may be circulated with the Competent Authority
Report. Member states are encouraged to use EUDAMED as a preferred means to
exchange NCARs.
The appropriate "reason for report" should be identified on the National Competent Authority Report.
National Competent Authorities receiving reports should pay particular attention to the "reason for
report" and any "recommendations" given by the National Competent Authority issuing the report. A
number of reports may not require any immediate further action. Wherever possible, National
Competent Authorities should direct enquiries relating to the investigation arising from the report to the
National Competent Authority providing the notification, who will co-ordinate communication with
the MANUFACTURER or Notified Body.
30
National Competent Authority Reports are intended for dissemination between National
Competent Authorities and the Commission only, and are not for onward distribution to
USERs or other interested parties unless otherwise subject to national provisions and
practices (Article 20 of MDD and Article 19 of IVDD).
Competent Authorities must, where appropriate, consult the MANUFACTURER when

preparing a NCAR, and must inform the MANUFACTURER when one is issued.
6.3.6 DISSEMINATION OF INFORMATION OUTSIDE National COMPETENT

AUTHORITIES by a National Competent Authority
Careful consideration should be given to the mode of communication, the drafting and the
dissemination of information by the National Competent Authorities. The possible positive
and negative effects of the information to be disseminated should be considered when
drafting advisory notifications and when selecting the means and medium by which the
message is transmitted.
When the MANUFACTURER has informed one or multiple National Competent Authorities in
advance of the start of an FSCA (see section 5.4) this information should be held confidential
by the National Competent Authority until the information becomes public.
In general, preference should be given to notification communicated directly to medical

practitioner or health-care facilities concerned, over communication to the public.
In some cases dissemination of information directly to the public may be needed e.g. to
suggest that patients or USERs contact their medical practitioner for further, more specific
advice.
Where appropriate, it is recommended that the communication includes a statement

indicating that medical practitioners or other health-care professionals should be consulted
and that the information is intended for medical professionals only.
Consideration should be given to the preparation of a press statement for use by all National
Competent Authorities.
The above considerations apply also to dissemination of information by the

MANUFACTURER in consultation with the National Competent Authorities.
Interfaces with communication media should be coordinated wherever practicable between

the MANUFACTURER and the National Competent Authorities.
6.4 COMPLETION OF THE INVESTIGATION
The National Competent Authority shall place the MANUFACTURER's final report on file and
make any other observations necessary. The files investigation may then be endorsed as
"complete".
If a National Competent Authority itself conducts an investigation, the MANUFACTURER

(and, where appropriate, other National Competent Authorities) shall be informed of progress
and of the results.
31
The MANUFACTURERs final report shall also be copied to any National Competent
Authorities who were informed by a National Competent Authority of the initial report.
The National Competent Authority should inform the MANUFACTURER when the
investigation is complete, or if no investigation by the MANUFACTURER is required by the
National Competent Authority (Note: this does not preclude the MANUFACTURER
investigating as part of their ongoing quality assurance procedures).
Records of INCIDENT reports shall be retained to enable the investigation to be reopened if

necessary, and to facilitate systems for trend analysis.
7 THE ROLE OF THE NOTIFIED BODIES
Even though the Notified Bodies do not play a key operational role in the Medical Device
Vigilance System, the overall performance of the Medical Device Vigilance System is
supported by the Notified Body activity in the following areas:
Assessment of vigilance procedures

Audit of the implementation of the vigilance procedures, and link with other systems
e.g. Corrective and Preventive Action (CAPA) , FSCA
Assessment of the impact of vigilance issues on the certification granted
Liaise with the National Competent Authority if required, e.g. specific
investigations/audits based on a request of the National Competent Authority
Further guidance on these areas is provided by Notified Bodies Operation Group documents
or Notified Body recommendations.
8 THE ROLE OF THE COMMISSION
The Commission shall ensure that appropriate coordination and cooperation is put into place
between the Competent Authorities of all Member States to allow the Medical Device
Vigilance System to deliver the high level of protection for the health and safety of patients
and USERs.
In order to reinforce a common understanding and a common approach towards the

identification and resolution of vigilance cases, the Commission shall:
facilitate the exchange of experience and best practices between the National
Competent Authorities of the Member States,
facilitate the transmission of relevant data through the appropriate data exchange
system,
when appropriate, in cooperation with National Competent Authorities, develop and
organise training programs.
9 USERS ROLE WITHIN THE VIGILANCE SYSTEM
There is no legal requirement within the directives obliging USERs to have an active role in
the Vigilance System. Yet for the successful operation of the vigilance system their
involvement is vital. It is through the USERs that suspected INCIDENTs are made known to
32
the MANUFACTURERs and it is with their close involvement and co-operation that the
implementation of FSCAs is made possible.
The involvement of USERs is promoted and encouraged through the relationship the
MANUFACTURER develops with his customer (the USER). Annex 9 details some key areas
that the MANUFACTURER should promote with the USER. These areas may also be
reinforced by separate advice from National Competent Authorities.
33
ANNEXES
10.1 ANNEX 1 EXAMPLES OF INCIDENTs WHICH THE MANUFACTURER
SHOULD REPORT
The following examples are for illustrative purposes only, and are for the guidance of the
MANUFACTURER in determining whether a report should be made to a National Competent
Authority. The examples are intended to show that there is a considerable judgmental
element in the decision on whether to report.
1. A patient dies after the use of a defibrillator and there is an indication of a problem with the
defibrillator. The INCIDENT should be reported.
2. A patient receives a burn during the use, in accordance with the MANUFACTURER's
instructions, of surgical diathermy. If the burn is significant, this should be reported as such a
serious deterioration in state of health is not normally expected.
3. An infusion pump stops, due to a malfunction of the pump, but fails to give an appropriate
alarm; there is no patient injury. This should be reported as in a different situation it could
have caused a serious deterioration in state of health.
4. An infusion pump delivers the wrong dose because of an incompatibility between the
pump and the infusion set used. If the combination of pump and set used was in accordance
with the instructions for use for either pump or set, then the INCIDENT should be reported.
5. An aortic balloon catheter leaked because of inappropriate handling of the device in use,
causing a situation which was potentially dangerous to the patient. It is believed that the
inappropriate handling was due to inadequacies in the labelling.
6. A catheter fractured during insertion, with no suggestion of inappropriate handling. The

fracture occurred in such a position that the broken part could easily be withdrawn. However,
this was clearly a fortunate circumstance as if the catheter had fractured in a slightly different
position then surgical intervention would have been necessary to retrieve the broken end.
7. Glass particles are found in a contact lens vial.
8. A defect is discovered in one (hitherto unopened) sample of a batch (lot) of a contact lens
disinfecting agent that could lead to incidence of microbial keratitis in some patients. The
MANUFACTURER institutes a FSCA of this batch. The FSCA should be reported.
9. Loss of sensing after a pacemaker has reached end of life. Elective replacement indicator
did not show up in due time, although it should have according to device specification. This
INCIDENT should be reported.
10. On an X-ray vascular system during patient examination, the C arm had uncontrolled
motion. The patient was hit by the image intensifier and his nose was broken. The system
was installed, maintained, and used according to MANUFACTURERs instructions. This
11. The premature revision of an orthopedic implant is required due to loosening. Although
no cause is yet determined, this INCIDENT should be reported.
12. The MANUFACTURER of a pacemaker has identified a software bug in a pacemaker

that has been placed on the market. The initial risk assessment identified the risk of a serious
34
deterioration in state of health as remote. Subsequent failure results and the new risk
assessment carried out by the MANUFACTURER indicate that the likelihood of occurrence
of a serious deterioration in state of health is not remote. This should be reported.
13. Fatigue testing performed on a commercialised heart valve bioprosthesis demonstrates

premature failure, which resulted in a risk to public health.
14. MANUFACTURER provides insufficient details on cleaning methods for reusable surgical
instruments used in brain surgery, despite obvious risk of transmission of CJD.
15. A batch of out-of-specification blood glucose test strips is released by

MANUFACTURER. A patient uses the strips according to the MANUFACTURERs
instructions, but the readings provide incorrect values leading to incorrect insulin dosage,
resulting in hypoglycemic shock and hospitalization. This INCIDENT should be reported.
16. A customer reports a wrong assignment of analytical results to patient codes by an

automated analyzer. An evaluation could reproduce the effect and indicated that under
specific conditions a data mismatch could occur. Due to the data mismatch a patient suffered
from wrong treatment. This INCIDENT should be reported.
17. During maintenance of a self-testing analyzer for patients it was detected that a screw
which places the heating unit of the analyzer in exact position had come loose. Due to this
fact, it may happen that the heating unit leaves its position and the measurement is
performed under non exact temperature, which would lead to wrong results. As this could
lead to wrong treatment of the patient this should be reported.
18. During stability testing of a CRP test the internal quality control found that after several
months of storage false increased values are measured with neonatal samples. This could
lead to the wrong diagnosis of the existence of an inflammatory illness and to a wrong
treatment of the patient. This should be reported.
35
10.2 ANNEX 2 EXTRACTS FROM DIRECTIVES RELATING TO "MEDICAL
DEVICES VIGILANCE"
I. COUNCIL DIRECTIVE 90/385/EEC OF 20 JUNE 1990 ON THE APPROXIMATION OF THE LAWS OF

THE MEMBER STATES RELATIVE TO ACTIVE IMPLANTABLE MEDICAL DEVICES
A. Article 8
1. Member States shall take the necessary steps to ensure that information brought to their
knowledge regarding the incidents mentioned below involving a device is recorded and
evaluated in a centralised manner:
a) any deterioration in the characteristics and performances of a device, as well as

any inaccuracies in the instruction leaflet which might lead to or might have led to
the death of a patient or to a deterioration in his state of health;
b) any technical or medical reason resulting in withdrawal of a device from the

market by the manufacturer.
2. Member States shall, without prejudice to Article 7, forthwith inform the Commission and
the other Member States of the incidents referred to in paragraph 1 and of the relevant
measures taken or contemplated.
B. Annexes 2, 4 and 5
Extracts :
An undertaking by the manufacturer to institute and keep up-dated a post-marketing

surveillance system. The undertaking shall include an obligation for the manufacturer to
notify the competent authorities of the following incidents immediately on learning of them :
a) any deterioration in the characteristics or performances, and any inaccuracies in

the instruction leaflet for a device which might lead to or have led to the death of a
patient or a deterioration in his state of health;

II. COUNCIL DIRECTIVE 93/42/EEC OF 14 JUNE 1993 CONCERNING MEDICAL DEVICES
A. Article 10 : Information on incidents occurring following placing of devices on the

market
1. Member States shall take the necessary steps to ensure that any information brought to
their knowledge in accordance with the provisions of this directive, regarding the incidents
mentioned below involving a Class I, IIa, IIb or III device is recorded and evaluated centrally :
a) any malfunction or deterioration in the characteristics and/or performance of a

device, as well as any inadequacy in the labelling or the instructions for use which
might lead to or might have led to the death of a patient or user or to a serious
deterioration in his state of health;
36
b) any technical or medical reason in relation to the characteristics or performance
of a device for the reasons referred to in subparagraph (a), leading to systematic
recall of devices of the same type by the manufacturer.
2. Where a Member State requires medical practitioners or the medical institutions to inform
the competent authorities of any incidents referred to in paragraph 1, it shall take the
necessary steps to ensure that the manufacturer of the device concerned, or his authorized
representative established in the Community, is also informed of the incident.
3. After carrying out an assessment, if possible together with the manufacturer, Member
States shall, without prejudice to Article 8, immediately inform the Commission and the other
Member States of the incidents referred to in paragraph 1 for which relevant measures have
been taken or are contemplated.
B. Annexes II, IV, V, VI and VII
Extracts :
An undertaking by the manufacturer to institute and keep up to date a systematic procedure

to review experience gained from devices in the post-production phase and to implement
appropriate means to apply any necessary corrective action. This undertaking must include
an obligation for the manufacturer to notify the competent authorities of the following
incidents immediately on learning of them :

device, as well as any inadequacy in the instructions for use which might lead to or
might have led to the death of a patient or user or a serious deterioration in his state
of health;
b) any technical or medical reason connected with the characteristics or

performance of a device leading for the reasons referred to in subparagraph (i) to
systematic recall of devices of the same by the manufacturer.
III. COUNCIL DIRECTIVE 98/79/EC OF 27 OCTOBER 1998 ON IN VITRO DIAGNOSTIC MEDICAL

DEVICES
A. Article 11 : Vigilance Procedure
their knowledge, in accordance with the provisions of this directive, regarding the
incidents mentioned below involving devices bearing the CE marking is recorded and
evaluated centrally:
a) any malfunction, failure or deterioration in the characteristics and/or performance

of a device, as well as any inadequacy in the labelling or the instructions for use
which, directly or indirectly, might lead to or might have led to the death of a patient,
or user or of other persons or to a serious deterioration in their state of health;

2. Where a Member State requires medical practitioners, the medical institutions or the
organisers of external quality assessment schemes to inform the competent authorities of
any incidents referred to in paragraph 1, it shall take the necessary steps to ensure that
37
the manufacturer of the device concerned, or his AUTHORISED REPRESENTATIVE, is
also informed of the incident.
States shall, without prejudice to Article 8, immediately inform the Commission and the
other Member States of the incidents referred to in paragraph 1 for which appropriate
measures, including possible withdrawal, have been taken or are contemplated.
4. Where, in the context of notification referred to in Article 10, a device notified, bearing the
CE marking, is a new product, the manufacturer shall indicate this fact on his
notification. The Competent Authority so notified may at any time within the following two
years and on justified grounds, require the manufacturer to submit a report relating to the
experience gained with the device subsequent to its being placed on the market.
5. The Member States shall on request inform the other Member States of the details
referred to in paragraphs 1 to 4. The procedures implementing this Article shall be
adopted in accordance with the procedure referred to in Article 7(2).
B. Annexes II, IV, VI and VII
Extracts :
The manufacturer shall institute and keep up to date a systematic procedure to review
experience gained from devices in the post-production phase and to implement appropriate
means to apply any necessary corrective actions, taking account of the nature and risks in
relation to the product. He shall notify the competent authorities of the following incidents
immediately on learning of them:

which, directly or indirectly, might lead to, or might have led to, the death of a patient
or user or other persons or to a serious deterioration in his or their state of health;
b) any technical or medical reason connected with the characteristics or the

performance of a device for the reasons referred to in subparagraph (i) leading to
systematic recall of devices of the same type by the manufacturer.
38
10.3 ANNEX 3 REPORT FORM FOR MANUFACTURERS TO THE NATIONAL
COMPETENT AUTHORITY
V. 05/07
Report Form
Manufacturers Incident Report
Medical Devices Vigilance System
(MEDDEV 2.12/1 rev 5)
1. Administrative information
Recipient
Name of national competent authority (NCA)
Address of national competent authority
Date of this report
Reference number assigned by the manufacturer
Reference number assigned by NCA to whom sent (if known)
Type of report
Initial report
Follow-up report
Combined initial and final report
Final report
Classification of incident
Death or unanticipated serious deterioration in state of health, serious public health threat
All other reportable incidents
Identify to what other NCAs this report was also sent
2 Information on submitter of the report

Status of submitter
Manufacturer
Authorised representative within EEA and Switzerland
Others (identify the role):
3 Manufacturer information
Manufacturer name
Manufacturers contact person
Address
Postal code City
Phone Fax
E-mail Country
4 Authorised Representative information

Name of the authorised representative
39
The authorised representatives contact person
Address
Postal code City
Phone Fax
E-mail Country
5 Submitters information (if different from section 3 or 4)

Submitters name
Name of the contact person
Address
Postal code City
Phone Fax
E-mail Country
6 Medical device information

Class
AIMD Active implants
MDD Class III IVD Annex II List A
MDD Class IIb IVD Annex II List B
MDD Class IIa IVD Devices for self-testing
MDD Class I IVD General
Nomenclature system (preferable GMDN)
Nomenclature code
Nomenclature text
Commercial name/brand name/make
Model and/or catalogue number
Serial number(s) and/or lot/batch number(s)
Software version number (if applicable)
Manufacturing date/expiry date (if applicable)
Accessories/associated device (if applicable)
Notified body (NB) ID- number
40
7 Incident information
User facility report reference number, if applicable
Manufacturers awareness date
Date of incident occurred
Incident description narrative
Number of patients involved (if known) Number of medical devices involved (if known)
Medical device current location/disposition (if known)
Operator of the medical device at the time of incident (select one)

health care professional
patient
other
Usage of the medical device (select from list below)
initial use reuse of a single use medical device
reuse of a reusable medical device re-serviced/refurbished
other (please specify): problem noted prior use
8 Patient information
Patient outcome
Remedial action taken by the healthcare facility relevant to the care of the patient
Age of the patient at the time of incident, if applicable
Gender, if applicable
Female Male
Weight in kilograms, if applicable
9 Healthcare facility information

Name of the healthcare facility
Contact person within the facility
Address
Postal code City
Phone Fax
E-mail Country
10 Manufacturers preliminary comments (Initial/Follow-up report)

Manufacturers preliminary analysis
Initial corrective actions/preventive actions implemented by the manufacturer
41
Expected date of next report
11 Results of manufacturers final investigation (Final report)

The manufacturers device analysis results
Remedial action/corrective action/preventive action/Field Safety Corrective Action

NOTE: In the case of a FSCA the submitter needs to fill in the form of Annex 4
Time schedule for the implementation of the identified action
Final comments from the manufacturer
Further investigations
Is the manufacturer aware of similar incidents with this type of medical device with a similar root cause?
Yes No
If yes, state in which countries and the report reference numbers of the incidents
For final report only. The medical device has been distributed to the following countries:
Within EEA and Switzerland:
AT BE BU CH CY CZ DE DK EE ES
FI FR GB GR HU IE IS IT LI LT
LU LV MT NL NO PL PT RO SE SI
SK
Candidate Countries:
CR TR
All EEA, Candidate Countries and Switzerland
Others:
12 Comments
I affirm that the information given above is correct to the best of my knowledge.
Signature
Name City Date
Submission of this report does not, in itself, represent a conclusion by the manufacturer and/or authorized
representative or the national competent authority that the content of this report is complete or accurate, that the
42
medical device(s) listed failed in any manner and/or that the medical device(s) caused or contributed to the
alleged death or deterioration in the state of the health of any person.
43
10.4 ANNEX 4 EUROPEAN FIELD SAFETY CORRECTIVE ACTION REPORT
FORM
V. 05/07
Report Form
Field Safety Corrective Action
Destination
Date of this report
Incidence reference number and name of the co-ordinating national competent authority (if applicable)
Identify to what other national competent authorities this report was also sent

Status of submitter
Manufacturer
Authorised representative within EEA
Manufacturer name
Address
Postal code City
Phone Fax
E-mail Country
4 Authorised representative information

Address
Postal code City
Phone Fax
E-mail Country
44
5 National contact point information
National contact point name
Address
Postal code City
Phone Fax
E-mail Country

Class

Nomenclature code
Nomenclature text
Model number
7 Description of FSCA
Background information and reason for the FSCA
Advice on actions to be taken by the distributor and the user
Attached please find

Field Safety Notice (FSN) in English
FSN in national language
45
Others (please specify):
Time schedule for the implementation of the different actions
These countries within the EEA and Switzerland are affected by this FSCA
AT BE BU CH CY CZ DE DK EE ES
SK
CR TR
Others:
These countries outside the EEA and Switzerland are affected by this FSCA
8 Comments
Signature
Name City Date
46
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE
---------------------------------------------------------------------------------------------------------------------------
Urgent Field Safety Notice
Commercial name of the affected product,
FSCA-identifier (e.g. date)
Type of action (e.g. chapter 4 definition of a FSCA).
---------------------------------------------------------------------------------------------------------------------------
Date:
Attention: ///////////////
Details on affected devices:

Specific details to enable the affected product to be easily identified e.g. type of device ,
model name and number, batch/ serial numbers of affected devices and part or order
number.
Insert or attach list of individual devices.
(Possible reference to a manufacturer web site.)
Description of the problem:

A factual statement explaining the reasons for the FSCA, including description of the device
deficiency or malfunction, clarification of the potential hazard associated with the continued
use of the device and the associated risk to the patient, user or other person.
Any possible risk to patients associated with previous use of affected devices.
Advise on action to be taken by the user:

Include ,as appropriate:
timelines.
Confirmation form to be sent back to the manufacturer if an action is required (
e.g. return of products)
Transmission of this Field Safety Notice: (if appropriate)
This notice needs to be passed on all those who need to be aware within your organisation
or to any organisation where the potentially affected devices have been transferred. (If
appropriate)
Please transfer this notice to other organisations on which this action has an impact. (If
appropriate)
Please maintain awareness on this notice and resulting action for an appropriate period to
ensure effectiveness of the corrective action. (if appropriate)
47
Contact reference person:
Name / organisation, address, contact details.
The undersign confirms that this notice has been notified the appropriate Regulatory Agency
(Closing paragraph)
Signature
48
10.6 ANNEX 6 SUGGESTED NATIONAL COMPETENT AUTHORITY REPORT
FORMAT
GLOBAL/EUROPEAN MEDICAL DEVICES COMPETENT AUTHORITY REPORT

Form N9R11
This form should be used for the exchange of information between National Competent Authorities (NCA)
and the Commission only
1. Is this report confidential? Yes [ ] No [ ]

Reference and Reporter Data
2. NCA report ref. no.: 3. Local NCA case no.: 4. Related NCA report nos. (if
any):
5. Manufacturer Ref/FSCA no.: 6. Sent by (Name and 7. Contact person (if different
Organization): from 6):
8. Tel: 9. Fax: 10. E-mail
Device Data
11a. Generic name/ kind of device: 11b. Category: 20. CAB/Notified Body no.:
12. Nomenclature id: 13. No.:

GMDN
14. Trade Name and Make and Model: 21a. Device approval status:
15. Software version: [ ] CE mark
16. Serial no.: 17. Lot/batch no.: 21b. Risk Class:
18. Manufacturer: 19. Authorized rep (if different Action taken:
Country: from 18): [ ] None
Full Address: Country: [ ] FSCA/Recall
Contact: Full Address: [ ] Safeguard Clause
Tel: Contact: [ ] Other (specify)
Fax: Tel:
E-mail: Fax:
E-mail:
Event Data
23a. Background information and reason for this report:
23b. Is the investigation of the report complete?: [ ]Yes [ ] No
24a. Conclusions:
24b. [ ] is willing to take the lead and co-ordinate the investigation
25a. Recommendation to receivers of this report:
25b. Device known to be in the market in:

25c. Device also marketed as (trade name):
49
Report Distribution
26. This report is being distributed to:
[ ] the GHTF NCAR Secretariat for further distribution to all non EEA GHTF NCAR participants
(AU CA JP NZ US).
[ ] EEA states, EC and Switzerland
[ ] The following targeted NCAs:
[ ] The manufacturer / authorized rep.:
The form can be downloaded as well from http://www.ghtf.org/sg2/sg2-final.html.
Instructions for Filling in National Competent Authority Report
Field:
1 - Please be sure to check Yes or No for confidentiality. This tells the recipient NCA if the
information provided can be released publicly or must be held strictly confidential.
2 - Use the rules for numbering NCARs, which incorporates a two-letter code of the issuing
country to fill in this item. For example: DE-2004-10-19-004 is a report from Germany sent 19
October 2004 and is the 4th report for 2004.
3 - Insert any local reference number used by your NCA relevant to this report here.
4 - If there have been previous NCARs exchanged relating to this one, regardless of source,
insert their NCA exchange numbers here.
5 - Insert the manufacturers reference/FSCA number here, if applicable.
6 - Identify person and organization sending the NCAR.
7 - Identify contact person for any information / technical discussion of the topic.
8-10 Telephone, Fax and e-mail of person in (7) above.
11 - Kind of device or generic descriptor.
12 - Identify the nomenclature system (e.g. GMDN, MHW, NKKN, UMDNS, Product
Code, Preferred Name Code, etc.) used, but note that GMDN is expected and therefore
prefilled.
13 - Number or code to identify the device based on the nomenclature system identified in
(12).
14 - Trade name / Brand name AND Model number
15-17 Self explanatory
18 - Manufacturer of device - full address, including country, fax, phone numbers and e-
mail.
19 - Identify the authorized representative in reporting country (who is legally responsible for
placing the subject device on the market where the incidents occurred), full address,
including country, fax, phone numbers and e-mail.
20 - Indicate name or code number of the Notified Body involved, if applicable.
21 - a.) Self explanatoryb.) Device risk class
22 - Identify any regulatory, legal or company-initiated action taken in advance of sending out
the report. This could for instance refer to a FSCA or the use of Safeguard action.
23a - Provide a description of what has happened, including consequences to patients or
users. With reference to the criteria for reporting describe the reason for the report and why
you want to inform other NCAs about these events. Such information will lead to a better
understanding by the recipient on what is considered to be appropriate follow-up.
23b - Indicate if the investigation of the report is complete or not.
50
24a - Describe the outcome or conclusion of the investigation, to date. If useful, include a
copy of any manufacturer or NCA advisory notice(s) associated with the NCAR and make
reference to them within the NCAR.
24 b Indicate whether originating NCA is willing to take the lead in co-ordination of the
investigation.
25a - Recommendations to receivers of this report
25b - List countries known to have received the device. Put considerable care and effort
into obtaining accurate information from the manufacturer for this field.
25c - List the marketed trade name(s) in other countries, if different.
26a - Indicate to whom the report has been sent. Care should be taken to indicate the
correct distribution for the NCAR. If the report will be send via the GHTF NCAR Secretariat
for distribution within GHTF NCAR program, stick first box. NCAs outside the exchange
program that are being sent the NCAR by the originating NCAR participant should be listed
right after the third tick box.
51
10.7 ANNEX 7 TITLES OF GLOBAL HARMONISATION TASK FORCE STUDY
GROUP 2 DOCUMENTS USED IN THE DEVELOPMENT OF THIS
MEDDEV AND/OR CITED
SG2/N31R8 Medical Device Postmarket Vigilance and Surveillance: Proposal for

Reporting of USE ERRORs with Medical Devices by their Manufacturer or Authorized
Representative
SG2/N32R5 Medical Device Postmarket Vigilance and Surveillance: Universal Data Set
for Manufacturer Adverse Event Reports
SG2-N36R7 Manufacturer's Trend Reporting of Adverse Events
SG2-N9R11 Global Medical Device Competent Authority Report
SG2-N33R11 Medical Device Postmarket Vigilance and Surveillance: Timing of Adverse
Event Reports
SG2-N20R10 Medical Devices: Post Market Surveillance: National Competent Authority
Report Exchange Criteria
SG2-N7R1 Minimum Data Set for Manufacturer Reports to Competent Authority
SG2-N8R4 Guidance on How to Handle Information Concerning Vigilance Reporting
Related to Medical Devices
SG2-N21R8 Adverse Event Reporting Guidance for the Medical Device Manufacturer or
its Authorized Representative
NOTE: All these documents can be downloaded from http://www.ghtf.org/sg2/sg2-final.html
52
10.8 ANNEX 8 LIST OF THE USED ABBREVIATIONS
AIMD Directive for Active Implantable Medical Devices
CAPA Corrective and Preventive Action
EEA European Economic Area
FSCA FIELD SAFETY CORRECTIVE ACTION
FSN FIELD SAFETY NOTICE
GHTF Global Harmonisation Task Force
IVD In Vitro Diagnostic Device
IVDD In Vitro Diagnostic Medical Devices Directive
MDD Directive for Medical Devices
NB Notified Body
NCA National Competent Authority
NCAR National Competent Authority Report
53
10.9 ANNEX 9 GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS
IN THE VIGILANCE SYSTEM
Reporting Guidance
What: Encourage users or those given specific responsibility for reporting incidents that have
occurred with medical devices and that meet the criteria within these guidelines to report the
incidents to the Manufacturer and or to the Competent Authority in accordance with national
guidance.
When: Encourage users to report all adverse incidents as soon as possible. Serious cases
ought be reported by the fastest means possible. Initial incident reports should contain as
much relevant detail (e.g. equipment type, make and model) as is immediately available, but
reporting ought not be delayed for the sake of gathering additional information.
How: Encourage the user the use reporting forms in accordance with national guidance and
to provide contact details when reporting to the manufacturer or the Competent Authority.
What to do with the device: All items, together with relevant packaging materials, ought to
be quarantined; they ought not be repaired, or discarded. The device should be returned to
the manufacturer in accordance with their instructions unless otherwise required by national
or other legal requirements. In some member states the Competent Authority may be
required to be given opportunity then to carry out its own investigation. Medical devices
ought not to be sent to Competent Authorities unless it has been specifically requested.
Users ought to contact the manufacturer to obtain information relating to the procedure for
returning the suspect device. The device should be appropriately decontaminated, securely
packaged, and clearly labelled, including the CA or manufacturer reference number if
needed.
Further local information: Encourage reporters to cooperate with the manufacturer and the
Competent Authority by providing further information concerning incidents should they
become available e.g. relevant outcomes of internal investigations concerning the device or
patient outcomes e.g. subsequent death.
Field Safety Corrective Action Guidance
Importance of FSNs: Field Safety Notices are an important means of communicating safety
information to medical device users in all healthcare areas. Field Safety Notices may also be
used to provide updated information and request feedback.
It is therefore important that users are encouraged to develop effective closed loop systems
that ensure the dissemination of the Field Safety notices and the timely completion of the
actions outlined. .
Distribution: Healthcare organisations should be encouraged to help ensure that the FSN
reaches all in the organisation that needs to be aware and/or take the recommended action.
Action: encourage users responsible for the maintenance and the safety of medical devices
to take the actions advised in the manufacturers field safety notice. These actions ought to
be taken in co-operation with the manufacturer where required. They may also include
associated actions recommended by the Competent Authority in connection with the FSCA,
including providing any requested feedback.
54
Access to devices: Encourage users responsible for the maintenance and the safety of
medical devices to a) facilitate manufacturer access to the device if this is required, and b)
work with the manufacturer when needing to balance the individual risks and benefits for any
dependent patients using affected devices.
55
EUROPEAN COMMISSION
DG ENTERPRISE AND INDUSTRY
Directorate F-Consumer Good
Unit F3- Cosmetic and Medical Devices
MEDDEV 2.12-1 rev 6
December 2009
GUIDELINES
Revision 6 of MEDDEV 2.12-1 incorporates technical modifications to Annex 3 (Report Form

- Manufacturer's Incident Report). The April 2007 version of MEDDEV 2.12-1 remains
otherwise unchanged. The revised Annex 3 will be applicable as of 20 March 2010.
1
TABLE OF CONTENTS
TABLE OF CONTENTS ................................................................................................................................. 2
1 FOREWORD .................................................................................................................................... 4
2 INTRODUCTION.............................................................................................................................. 4
3 SCOPE............................................................................................................................................. 5
3.1 GENERAL PRINCIPLES ...................................................................................................... 6
3.1.1 FOR MANUFACTURERS .................................................................................................. 6
3.1.2 FOR MANUFACTURERS OF IVDS ................................................................................... 7
3.1.3 FOR NATIONAL COMPETENT AUTHORITIES................................................................ 7
3.1.4 FOR USERS ....................................................................................................................... 8
4 DEFINITIONS................................................................................................................................... 8
4.1 ABNORMAL USE ................................................................................................................. 8
4.2 AUTHORISED REPRESENTATIVE ..................................................................................... 8
4.3 CORRECTIVE ACTION ........................................................................................................ 8
4.4 DRUG / DEVICE COMBINATION PRODUCT...................................................................... 9
4.5 EUDAMED............................................................................................................................. 9
4.6 FIELD SAFETY CORRECTIVE ACTION (FSCA) ................................................................ 9
4.7 FIELD SAFETY NOTICE (FSN).......................................................................................... 10
4.8 HARM .................................................................................................................................. 10
4.9 IMMEDIATELY.................................................................................................................... 10
4.10 INCIDENT............................................................................................................................ 10
4.11 INDIRECT HARM................................................................................................................ 10
4.12 INTENDED PURPOSE........................................................................................................ 11
4.13 MANUFACTURER .............................................................................................................. 11
4.14 MEDICAL DEVICE.............................................................................................................. 11
4.15 OPERATOR ........................................................................................................................ 11
4.16 PERIODIC SUMMARY REPORTING ................................................................................. 11
4.17 SERIOUS PUBLIC HEALTH THREAT............................................................................... 12
4.18 TREND REPORTING.......................................................................................................... 12
4.19 UNANTICIPATED ............................................................................................................... 12
4.20 USE ERROR ....................................................................................................................... 12
4.21 USER................................................................................................................................... 12
5 MANUFACTURERS ROLE .......................................................................................................... 12

5.1 INCIDENT REPORTING SYSTEM ..................................................................................... 13
COMPETENT AUTHORITIES .......................................................................................... 13
DEVICE VIGILANCE SYSTEM ........................................................................................ 15
5.1.2.1 INCIDENTS DESCRIBED IN A FIELD SAFETY NOTICE...................................... 15
5.1.2.2 COMMON AND WELL-DOCUMENTED INCIDENTS ............................................ 15
SYSTEM IS NOT USUALLY REQUIRED ........................................................................ 16
5.1.3.1 DEFICIENCY OF A DEVICE FOUND BY THE USER PRIOR TO ITS USE.......... 16
5.1.3.2 EVENT CAUSED BY PATIENT CONDITIONS ...................................................... 16
5.1.3.3 SERVICE LIFE OR SHELF-LIFE OF THE MEDICAL DEVICE EXCEEDED ......... 17
5.1.3.4 PROTECTION AGAINST A FAULT FUNCTIONED CORRECTLY........................ 17
5.1.3.5 EXPECTED AND FORESEEABLE SIDE EFFECTS.............................................. 18
DETERIORATION IN STATE OF HEALTH................................................................................ 19
5.1.4 TREND REPORTS ........................................................................................................... 19
5.1.5 REPORTING OF USE ERROR AND ABNORMAL USE .................................................. 20
5.1.5.1 REPORTABLE USE ERRORS ............................................................................... 20
5.1.5.2 USE ERROR WHERE REPORTING UNDER THE MEDICAL DEVICE VIGILANCE
SYSTEM IS NOT USUALLY REQUIRED. ................................................................................. 20
2
5.1.5.3 CONSIDERATION FOR HANDLING ABNORMAL USE ........................................ 20
5.1.6 DETAILS TO BE INCLUDED IN MANUFACTURER REPORTS .................................... 21
5.1.7 TIMESCALE FOR THE INITIAL REPORTING OF AN INCIDENT.................................. 21
5.1.8 TO WHOM TO REPORT .................................................................................................. 21
NATIONAL COMPETENT AUTHORITY ............................................................................ 22
5.3 INVESTIGATIONS .............................................................................................................. 22
5.3.1 PRINCIPLES..................................................................................................................... 22
5.3.2 ACCESS TO THE DEVICE SUSPECTED TO BE INVOLVED IN THE INCIDENT......... 22
5.4 OUTCOME OF AN INVESTIGATION AND FOLLOW-UP ................................................ 23
5.4.1 PRINCIPLES ........................................................................................................................ 23
5.4.2 FOLLOW-UP REPORT .................................................................................................... 23
5.4.3 FINAL REPORT................................................................................................................ 23
5.4.4 FIELD SAFETY CORRECTIVE ACTION ......................................................................... 23
5.4.4.1 NOTIFICATION TO NATIONAL COMPETENT AUTHORITIES............................. 24
5.4.4.2 CONTENT OF THE FIELD SAFETY NOTICE........................................................ 25
6. RESPONSIBILITIES OF NATIONAL COMPETENT AUTHORITY .............................................. 26

6.1 ACTIONS ON A REPORT FROM USERS OR OTHER SYSTEMS................................... 26
6.2 RISK EVALUATION AND SUBSEQUENT ACTIONS ....................................................... 27
6.2.1 RISK EVALUATION BY THE NATIONAL COMPETENT AUTHORITY ......................... 27
6.2.2 MONITORING OF MANUFACTURERS SUBSEQUENT ACTIONS ............................... 27
6.2.3 NATIONAL COMPETENT AUTHORITY ACTIONS ........................................................ 28
6.3 CO-ORDINATION BETWEEN COMPETENT AUTHORITIES........................................... 28
AUTHORITY IS NEEDED................................................................................................. 28
6.3.2 DETERMINATION OF THE COORDINATING NATIONAL COMPETENT AUTHORITY29
6.3.3 THE TASKS OF THE CO-ORDINATING NATIONAL COMPETENT AUTHORITY ....... 29
6.3.4 SAFEGUARD CLAUSE ................................................................................................... 30
AUTHORITIES.................................................................................................................. 30
6.3.6 DISSEMINATION OF INFORMATION OUTSIDE NATIONAL COMPETENT
AUTHORITIES BY A NATIONAL COMPETENT AUTHORITY ...................................... 31
6.4 COMPLETION OF THE INVESTIGATION ......................................................................... 31
7 THE ROLE OF THE NOTIFIED BODIES ...................................................................................... 32
8 THE ROLE OF THE COMMISSION .............................................................................................. 32
9 USERS ROLE WITHIN THE VIGILANCE SYSTEM ..................................................................... 32
10.1 ANNEX 1 EXAMPLES OF INCIDENTs WHICH THE MANUFACTURER SHOULD

REPORT.............................................................................................................................. 34
VIGILANCE" ....................................................................................................................... 36
AUTHORITY........................................................................................................................ 39
10.4 ANNEX 4 EUROPEAN FIELD SAFETY CORRECTIVE ACTION REPORT FORM ......... 44
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE................................................... 48
10.6 ANNEX 6 SUGGESTED NATIONAL COMPETENT AUTHORITY REPORT FORMAT ... 50
DOCUMENTS USED IN THE DEVELOPMENT OF THIS MEDDEV AND/OR CITED ...... 53
10.8 ANNEX 8 LIST OF THE USED ABBREVIATIONS............................................................ 54
10.9 ANNEX 9 GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS IN THE
VIGILANCE SYSTEM ......................................................................................................... 55
3
1 FOREWORD
health.
2 INTRODUCTION
1
4
3 SCOPE
MANUFACTURERs2
Notified Bodies
European Economic Area (EEA) and Switzerland with regard to:
2
5
made devices)

devices which are offered for sale or are in use within the EEA and Switzerland.


AUTHORISED REPRESENTATIVEs within the EEA and Switzerland, persons
within the EEA and Switzerland, persons responsible for placing devices on the market
and any other agents authorised to act on their behalf for purposes relating to medical
devices vigilance, are kept informed of INCIDENT reports as appropriate.
(see section 5.1)

6
be reported.

7
3.1.4 FOR USERS

MANUFACTURER.
4 DEFINITIONS
4.1 ABNORMAL USE

3
8
4.5 EUDAMED

refused,
data obtained in accordance with the vigilance procedure.

NOTE 1:

- device exchange;
- advice given by MANUFACTURER regarding the use of the device (e.g. where the
device is no longer on the market or has been withdrawn but could still possibly be in use
e.g. implants or change in analytical sensitivity or specificity for diagnostic devices)

deterioration in state of health related specifically to the characteristics of the device. For
example:
Corrective action taking the form of special patient follow-up, irrespective of
whether any affected un-implanted devices remain available for return, constitutes
FSCA.
patients for retesting or the retest or review of previous results constitutes FSCA.
9
advises revised quality control procedure -use of third party controls or more frequent
calibration or modification of control values for IVDs.
NOTE 2: This guideline uses the definition of FSCA as synonym for recall mentioned in
article 10(1), paragraph 1b) of the MDD and Article 11 IVD Directive since there is no
harmonised definition of recall.

4.8 HARM
4.9 IMMEDIATELY
justified.
4.10 INCIDENT

4.11 INDIRECT HARM
or result(s) provided by the device.
Examples include
misdiagnosis,
delayed diagnosis,
10
delayed treatment,
For self-testing devices, a medical decision may be made by the USER of the device who is also
the patient.
4.13 MANUFACTURER
party.
4.14 MEDICAL DEVICE

handicap,
4.15 OPERATOR

11
is known or an FSCA has been implemented.
This would include:

Reference: GHTF SG2 N33R11
NOTE: GHTF SG2 document N36 'MANUFACTURER's TREND REPORTING of Adverse

INCIDENTs' provides useful guidance (see annex 7).'
4.19 UNANTICIPATED

4.20 USE ERROR
4.21 USER
DEVICES.
12

INCIDENTs which occurred outside the EEA and Switzerland and do not lead to a FIELD
SAFETY CORRECTIVE ACTION relevant to these geographic areas do not need to be
reported. Incidents which occurred outside the EEA and Switzerland and led to a FIELD
SAFETY CORRECTIVE ACTION relevant to the above-mentioned geographical areas must
be reported as a FIELD SAFETY CORRECTIVE ACTION.

If the MANUFACTURER is located outside the EEA and Switzerland, a suitable contact point
within should be provided. This may be the MANUFACTURER's AUTHORISED

criteria are that:

13
test.

events.

INCIDENT
take account of:


serious deterioration in state of health of a patient, USER or other person
a) life-threatening illness
b) permanent impairment of a body function or permanent damage to a body structure
c) a condition necessitating medical or surgical intervention to prevent a) or b)
Examples: - clinically relevant increase in the duration of a surgical procedure
existing hospitalisation
use
e) foetal distress, foetal death or any congenital abnormality or birth defects
NOTE :
14



authority.
Example:

15

system.
Examples:


Examples:

medical expert.
16
device.
Examples:


MANUFACTURER.
Examples:

patient.

17

OPERATOR. No results were reported.


NOTES:
Examples:

18




Example:

Mislabelling of IVD reagents that is an isolated INCIDENT and where it

would have no effect on the final result as the result itself would be invalid.
5.1.4 TREND REPORTS

excluded from individual reporting as per chapter 5.1.3 a report should to be made to the
occurring with their devices. GHTF SG2 document N36 'MANUFACTURER's TREND
REPORTING of Adverse INCIDENTs' provides useful guidance (see annex 7).
19


assessment bodies.

change in pattern (see annex 7 GHTF SG2 N36) of an issue that can potentially lead
to death or serious deterioration in state of health or public health threat)
- or initiates corrective action to prevent death or serious deterioration in state of health
or SERIOUS PUBLIC HEALTH THREAT


20
REPRESENTATIVE.

21


5.3 INVESTIGATIONS
5.3.1 PRINCIPLES
defined.



INCIDENT
22
the INCIDENT.
5.4.1 PRINCIPLES
5.4.

5.4.3 FINAL REPORT
and of any action.
no action;
FSCA.

23
included.
FSCA taken on a basis of INCIDENTs occurred outside the EEA and Switzerland and
devices.)
appropriate:
transferred.)
24
Competent Authority once the FSCA has been completed in both, the EEA and Switzerland.
This should include information on the effectiveness of the action per country involved (e.g.,
percentage of devices recalled)

Authority.
should be offered by the MANUFACTURER to all affected EEA member states and
Switzerland.


order number.

25
implants, IVD
timelines.
transferred.
FSCA.

should be omitted.
to the sender.
26
practicable.

example:


27
USER(s);

no further action;
assessment;

AUTHORITY IS NEEDED

INCIDENTs of similar types occurring in more than one country within the EEA and
Switzerland;
FSCA conducted in more than one country within the EEA and Switzerland, whether or
not a reportable INCIDENT has occurred.
28
information available on a FSCA conducted outside the EEA and Switzerland where
there is uncertainty whether the FSCA affects the member states within the EEA and
Switzerland or not, e.g. a Competent Authority Report issued outside EEA and
Switzerland (GHTF SG2) or information published on a CA website outside the EEA and
Switzerland.

AUTHORITY

ordination.

AUTHORITY

and coordinate with other National Competent Authorities within the EEA and
Switzerland;
corrective actions to be taken within the EEA and Switzerland;
countries;
inquiries within the EEA member states and Switzerland e.g. with respect to multiple
INCIDENTs in different countries which do not lead to corrective actions at the latest with
the closure of the file; MANUFACTURER will be informed according to section 6.4;
29
Vigilance System.

AUTHORITIES
Commission when:


MANUFACTURER.
The recommended format for dissemination of information between National Competent

Authorities and the Commission is given in Annex 6 and is the GHTF SG2 N79 with minor
changes. The MANUFACTURER's report may be circulated with the Competent Authority
Report. Member states are encouraged to use EUDAMED as a preferred means to
exchange NCARs.
The appropriate "reason for report" should be identified on the National Competent Authority Report.
National Competent Authorities receiving reports should pay particular attention to the "reason for
report" and any "recommendations" given by the National Competent Authority issuing the report. A
number of reports may not require any immediate further action. Wherever possible, National
Competent Authorities should direct enquiries relating to the investigation arising from the report to the
National Competent Authority providing the notification, who will co-ordinate communication with
the MANUFACTURER or Notified Body.
30



advice.



"complete".

and of the results.
31



and USERs.

system,
32
MANUFACTURER develops with his customer (the USER). Annex 9 details some key areas
that the MANUFACTURER should promote with the USER. These areas may also be
33
ANNEXES
10.1 ANNEX 1 EXAMPLES OF INCIDENTs WHICH THE MANUFACTURER
SHOULD REPORT
serious deterioration in state of health is not normally expected.
have caused a serious deterioration in state of health.
inappropriate handling was due to inadequacies in the labelling.

7. Glass particles are found in a contact lens vial.
MANUFACTURER institutes a FSCA of this batch. The FSCA should be reported.
did not show up in due time, although it should have according to device specification. This
11. The premature revision of an orthopedic implant is required due to loosening. Although

34
of a serious deterioration in state of health is not remote. This should be reported.
13. Fatigue testing performed on a commercialised heart valve bioprosthesis demonstrates

premature failure, which resulted in a risk to public health.
14. MANUFACTURER provides insufficient details on cleaning methods for reusable surgical
instruments used in brain surgery, despite obvious risk of transmission of CJD.

instructions, but the readings provide incorrect values leading to incorrect insulin dosage,
resulting in hypoglycemic shock and hospitalization. This INCIDENT should be reported.
16. A customer reports a wrong assignment of analytical results to patient codes by an

automated analyzer. An evaluation could reproduce the effect and indicated that under
specific conditions a data mismatch could occur. Due to the data mismatch a patient suffered
from wrong treatment. This INCIDENT should be reported.
lead to wrong treatment of the patient this should be reported.
treatment of the patient. This should be reported.
35
10.2 ANNEX 2 EXTRACTS FROM DIRECTIVES RELATING TO "MEDICAL
DEVICES VIGILANCE"

A. Article 8


2. Member States shall, without prejudice to Article 7, forthwith inform the Commission and
the other Member States of the incidents referred to in paragraph 1 and of the relevant
measures taken or contemplated.
Extracts :



A. Article 10 : Information on incidents occurring following placing of devices on the

market

36
Extracts :


of health;


DEVICES


37
B. Annexes II, IV, VI and VII
Extracts :


38
10.3 ANNEX 3 REPORT FORM FOR MANUFACTURERS TO THE NATIONAL
COMPETENT AUTHORITY
Report Form V.12/09

1 Administrative information
Recipient Stamp box for the Competent
Name of National Competent Authority (NCA) Authority (~ 60 x 40 mm)
Address of National Competent Authority
Date of this report
Type of report
Initial report
Follow-up report
Combined Initial and final report
Final report
Does the incident represent a serious public health threat?
Yes
No
death
unanticipated serious deterioration in state of health, serious public health threat

Status of submitter
Manufacturer
Authorised Representative within EEA and Switzerland
39
Others: (identify the role)
Manufacturer name
Address
Postal code City
Phone Fax
2)
E-mail Country

Name of the Authorised Representative
The Authorised Representatives contact person
Address
Postal code City
Phone Fax
2)
E-mail Country

Submitters name
Address
Postal code City
Phone Fax
2)
E-mail Country

Class
40

Nomenclature code
Nomenclature text
Commercial name/ brand name / make
Device Manufacturing date, Expiry date
Implant date (for implants only) Explant date (for implants only)
IDuration of implantation (to be filled is the exact implant or explant dates are unknown)
Accessories/ associated device (if applicable)
Notified Body (NB) ID-number
Date the incident occurred
41
health care professional patient
other
other (please specify) problem noted prior use
Patient outcome
Female Male

Name of the health care facility
Address
Postcode City
Phone Fax
2)
E-mail Country


Remedial action/corrective action/preventive action / Field Safety Corrective Action
42
NOTE: In the case of a FSCA the submitter needs to fill in the form of Annex
4
Time schedule for the implementation of the identified actions
Yes No
Number of similar incidents.
If yes, state in which countries and the report reference numbers of the incidents.
For Final Report only: The medical device has been distributed to the following countries:
- within the EEA and Switzerland:
AT BE BU CH CY CZ DE DK EE ES FI FR GB GR HU IE
IS IT LI LT LU LV MT NL NO PL PT RO SE SI SK
- Candidate Countries CR TR
ALL EEA -, Candidate Countries and Switzerland
- others:
10 Comments
Submission of this report does not, in itself, represent a conclusion by the manufacturer and / or
authorized representative or the National Competent Authority that the content of this report is
complete or accurate, that the medical device(s) listed failed in any manner and/or that the medical
device(s) caused or contributed to the alleged death or deterioration in the state of the health of any
person.
Name City date
43
10.4 ANNEX 4 EUROPEAN FIELD SAFETY CORRECTIVE ACTION REPORT
FORM
V. 04/07
Report Form
Destination Stamp box for the Competent
Name of National Competent Authority Authority (~ 60 x 40 mm)
Date of this report
Incident reference number and name of the co-ordinating NCACompetent Authority (if applicable):
Identify to what other Competent Authorities this report was also sent

Status of submitter
Manufacturer
Authorised Representative within EEA
Others: (identify the role):
Manufacturer name
Address
Postal code City
Phone Fax
2)
E-mail Country
44
Name of the Authorised Representative
The Authorised Representatives contact person
Address
Postal code City
Phone Fax
2)
E-mail Country

Address
Postal code City
Phone Fax
2)
E-mail Country

Class
AIMD Active implant

Nomenclature code
Nomenclature text
Model number
Serial number(s) or lot/batch number(s)
45
Manufacturing date/ Expiry date (if applicable)
Background information and reason for the FSCA,
Advice on actions to be taken by the distributor and the user.

Field Safety Notice (FSN) in English FSN in national language
Others (please specify)
These countries within the EEA and Switzerland are affected by this FSCA:
- within the EEA and Switzerland:
AT BE BU CH CY CZ DE DK EE ES FI FR GB GR HU IE
IS IT LI LT LU LV MT NL NO PL PT RO SE SI SK
- Candidate Countries CR TR
ALL EEA -, Candidate Countries and Switzerland
- others:
These countries outside the EEA and Switzerland are affected by this FSCA:
8 Comments
46
Name City date
Submission of this report does not, in itself, represent a conclusion by the manufacturer and / or authorized
representative or the National Competent Authority that the content of this report is complete or accurate, that the
47
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE
---------------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------------
Date:
Attention: ///////////////

number.


timelines.
appropriate)
appropriate)
48
(Closing paragraph)
Signature
49
10.6 ANNEX 6 SUGGESTED NATIONAL COMPETENT AUTHORITY REPORT
FORMAT

Form N9R11
This form should be used for the exchange of information between National Competent Authorities (NCA)
and the Commission only

any):
Device Data
11a. Generic name/ kind of device: 11b. Category: 20. CAB/Notified Body no.:

GMDN
14. Trade Name and Make and Model: 21a. Device approval status:
18. Manufacturer: 19. Authorized rep (if different 22. Action taken:
Fax: Tel:
E-mail: Fax:
E-mail:
Event Data
24a. Conclusions:

50
Report Distribution
(AU CA JP NZ US).
[ ] EEA states, EC and Switzerland
Field:
4 - If there have been previous NCARs exchanged relating to this one, regardless of source,
12 - Identify the nomenclature system (e.g. GMDN, MHW, NKKN, UMDNS, Product
Code, Preferred Name Code, etc.) used, but note that GMDN is expected and therefore
prefilled.
(12).
18 - Manufacturer of device - full address, including country, fax, phone numbers and e-
mail.
51
investigation.
52
10.7 ANNEX 7 TITLES OF GLOBAL HARMONISATION TASK FORCE STUDY
MEDDEV AND/OR CITED
SG2/N31R8 Medical Device Postmarket Vigilance and Surveillance: Proposal for

Reporting of USE ERRORs with Medical Devices by their Manufacturer or Authorized
Representative
SG2/N32R5 Medical Device Postmarket Vigilance and Surveillance: Universal Data Set
for Manufacturer Adverse Event Reports
SG2-N36R7 Manufacturer's Trend Reporting of Adverse Events
SG2-N9R11 Global Medical Device Competent Authority Report
SG2-N33R11 Medical Device Postmarket Vigilance and Surveillance: Timing of Adverse
Event Reports
SG2-N20R10 Medical Devices: Post Market Surveillance: National Competent Authority
Report Exchange Criteria
SG2-N7R1 Minimum Data Set for Manufacturer Reports to Competent Authority
SG2-N8R4 Guidance on How to Handle Information Concerning Vigilance Reporting
SG2-N21R8 Adverse Event Reporting Guidance for the Medical Device Manufacturer or
its Authorized Representative
53
10.8 ANNEX 8 LIST OF THE USED ABBREVIATIONS
NB Notified Body
54
10.9 ANNEX 9 GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS
IN THE VIGILANCE SYSTEM
Reporting Guidance
guidance.
needed.
actions outlined. .
55
56
V.12/09
Report Form
Recipient
Date of this report
Type of report
Initial report
Follow-up report
Final report
Yes
No
Death
Unanticipated serious deterioration in state of health, serious public health threat

Status of submitter
Manufacturer
Authorised representative within EEA and Switzerland
Manufacturer name
Address
Postal code City
Phone Fax
E-mail Country

Address
Postal code City
Phone Fax
E-mail Country

Submitters name
Address
Postal code City
Phone Fax
E-mail Country

Class
Nomenclature code
Nomenclature text
Device manufacturing date Expiry date
Implant date (For implants only) Explant date (For implants only)
Duration of implantion (For implants only. To be filled if the exact implant and explant dates are unknown)

Date of incident occurred

health care professional
patient
other
other (please specify): problem noted prior use
Patient outcome
Female Male

Address
Postal code City
Phone Fax
E-mail Country


Remedial action/corrective action/preventive action/Field Safety Corrective Action

Time schedule for the implementation of the identified action
Yes No
Number of similar incidents
If yes, state in which countries and the report reference numbers of the incidents
For final report only. The medical device has been distributed to the following countries:
AT BE BG CH CY CZ DE DK EE ES
SK
HR TR
Others:
12 Comments
Signature
Name City Date
medical device(s) listed failed in any manner and/or that the medical device(s) caused or contributed to the alleged
death or deterioration in the state of the health of any person.
V.05/07
Report Form
Destination
Date of this report
Incidence reference number and name of the co-ordinating national competent authority (if applicable)
Identify to what other national competent authorities this report was also sent

Status of submitter
Manufacturer
Authorised representative within EEA
Manufacturer name
Address
Postal code City
Phone Fax
E-mail Country

Address
Postal code City
Phone Fax
E-mail Country
Address
Postal code City
Phone Fax
E-mail Country

Class

Nomenclature code
Nomenclature text
Model number

Field Safety Notice (FSN) in English
These countries within the EEA and Switzerland are affected by this FSCA
SK
HR TR
Others:
These countries outside the EEA and Switzerland are affected by this FSCA
8 Comments
Signature
Name City Date
List of vigilance contact points within the National/Competent Authorities
AUSTRIA - BELGIUM - BULGARIA - CYPRUS - CZECH REPUBLIC - DENMARK - ESTONIA - FINLAND -
Shortcuts FRANCE - GERMANY - GREECE - HUNGARY - ICELAND - IRELAND - ITALY - LATVIA - LIECHENSTEIN -
-
LITHUANIA - LUXEMBOURG - MALTA - NETHERLANDS NORWAY - POLAND - PORTUGAL -
ROMANIA - SLOVENIA - SLOVAKIA - SPAIN - SWEDEN - SWITZERLAND - TURKEY - UNITED KINGDOM
Country and name Dir. Contact person E-mail/ Web site Address Phone/Fax
AIMDD
Austria sterreichische Agentur
Phone :
Institut Inspektionen, inspektionen@ages.at fr Gesundheit und
+43 50 555-36420
Medizinprodukte und MDD Ernhrungssicherheit
Dr. Ronald Bauer
Hmovigilanz GmbH
ronald.bauer@ages.at Fax :
AGES PharmMed Schnirchgasse 9, A-1030
+43 50 555-36409
Vienna
IVDMD
Belgium
Federal Public
Service AIMDD
Health, Food Chain Head of Unit Place Victor Horta 40, Phone :
Safety and Mr. Th. Roisin meddev@fagg.be bote 40 +32 2 524 81 13
Environment. 1060 Brussels Fax :
www.fagg.be
Directorate General Belgium +32 2 524 81 20
Dr. C. Duerinck
Public Health
Protection : Medicinal MDD
Products Medical
Devices Unit
Belgium Anne.VanNerom@iph.fgov.be
Dr. Anne Van Nerom Phone :
I
J. Wytsmanstraat, 14 +32 2 642 53 92
Scientific Institute
IVDMD latifa.elbali@iph.fgov.be B-1050 Brussels
Public Health Mrs. Latifa El Bali Fax :
Belgium
Department of Clinical +32 2 642 56 45
Biology website CA IVD-BE
AIMDD Bulgarian Drug Agency

Head of office: lyubomir.dimitrov@bda.bg
Dr. Lyubomir Dimitrov Department Medical Phone :
Bulgaria devices +359 2 890 35 11
MDD roumena.kambourova@bda.bg
Bulgarian Drug Rumena Kamburova
Agency darakchiev@bda.bg 8 Damyan Gruev Str. Fax:
Todor Darakchiev
www.bda.bg BG-1303 Sofia +359 2 890 34 34
IVDMD Bulgaria
AIMDD
Prodromou 1 & Chilonos Phone :
Cyprus Dr. Stelios Christofides cymda@mphs.moh.gov.cy 17 Corner +357 22 605 572
Medical Devices MDD web site: under construction 1449 Nicosia +357 22 605574
Competent Authority Andrie Stylianou Cyprus Fax:
+357 22 468427
IVDMD
Czech Republic Dr. Irena Vchov irena.vichova@sukl.cz State Institute for Drug
AIMDD
State Institute for Control, robrova 48, 100 Phone :
Drug Control MDD 41 Prague 10, Czech +420 272 185 705
Republic
Fax:
IVDMD +420 272 185 764
AIMDD
Danish Medicines Agency Phone :
Denmark med-udstyr@dkma.dk Axel Heides Gade 1 +45 44 88 95 95
MDD
The Danish Medical device section www.medicinskudstyr.dk DK-2300
Medicines Agency www.medicaldevices.dk Koebenhavn S Fax :
Denmark +45 44 88 95 99
IVDMD
AIMDD State Agency of Medicines Phone :

Medical Devices +372 737 41 40
Estonia info@ravimiamet.ee Department (common)
(common)
State Agency of Dr Sulev Jaksman
MDD
Medicines 1 Nooruse st., Fax :
www.ravimiamet.ee
50411 Tartu +372 737 41 42
IVDMD Estonia (common)
Phone :
Finland +358-9-7729 2187
Valvira MDD Phone :
Mr. Hannu Seitsonen Lintulahdenkuja 4
National Supervision laitevaarat@valvira.fi +358-5 0563 8532
P.O. Box 210,
Authority for Welfare AIMDD Phone :
FI-00531 Helsinki
and Health Mr. Jari Knuuttila http://www.valvira.fi +358-9 772 920
Finland
IVDMD
Fax :
+358-9-7729 2155
AIMDD AFSSAPS Phone :

France
143 / 147 Boulevard +33 1 55873706
Agence Francaise de dedim.ugsv@afssaps.sante.fr Anatole France
Securite MDD Mrs Sandrine Colas
F-93285 Saint - Denis
Sanitaire des www.afssaps.fr Fax:
Cedex
Produits de Sante IVDMD +33 1 55873702
France
Federal Institute for Drugs

Germany and Medical Devices, Phone :
Federal Institute for Medical Devices Division +49-228 207.53.84
Drugs and Medical AIMDD
Dr. Ekkehard Stlein medizinprodukte@bfarm.de Kurt-Georg-Kiesinger-
Devices (BfArM) MDD
Allee 3 Fax:
D-53175 Bonn +49-228 207.53.00
Germany
IVDMD1
and Medical Devices, Phone :
Medical Devices Division +49-228 207.53.60
Prof. Dr. Rdiger medizinprodukte@bfarm.de
Kurt-Georg-Kiesinger-Allee
Siekmeier Fax:
3
D-53175 Bonn +49-228 207.53.00
Germany
Paul Ehrlich Institute
Dr. Markus Funk pharmacovigilance2@pei.de Phone :
Section Pharmacovigilance
+49-6103-77-3115
2
Dr. Jochen Halbauer
Paul-Ehrlich-Strasse 51-59
Fax:
D-63225 Langen
+49-6103-77-1268
Germany
1 exmost Annex II devices
AIMDD
Vigilance Department
Phone :
National Organization for
Greece
Medicines (EOF) +30- 210 65 07 528
National Organization MDD Dr. Dimitris Panidis vigilancematerial@eof.gr
284 Messogion Avenue Fax :
for Medicines
155.62 Athens +30-210 65 49 585
Greece
IVDMD
Hungary Budapest 1245 Phone :

Authority for Medical AIMDD amd@eekh.hu Pf. 987. +36 1 302 5060
Devices Mr. Peter Bunyitai Hungary Fax :
MDD +36 1 269 1255
IVDMD Mrs. Regina Kormendy
AIMDD
Austurstrond 5 Phone :
Iceland
Mrs. Anna Bjorg IS 170 Seltjarnarnes +354 510 1900/1905
(EFTA) MDD annabara@landlaeknir
Aradottir Iceland Fax :
Directorate of Health
+354 510 1919
IVDMD
AIMD
Irish Medicines Board Phone .:
Ireland
Ms. Anne Tobin vigilance@imb.ie Earlsfort Centre +353-1-676.49.71
Irish Medicines Board
MDD Earlsfort Terrace
Medical Devices Ms. Andrea Hanson Fax :
www.imb.ie Dublin 2
Department +353-1-6344033
Ireland
IVDMD
Italy Ministry of Labour, Health Phone :

AIMDD Dr Monica Capasso m.capasso@sanita.it and Social Affairs,
Ministry of Health +39-06-5994-3783
Department of Innovation
Directorate General of Fax :
Medicine and Medical +39-06-5994-3812
Devices
MDD Head of Unit 5
via Giorgio Ribotta 5,
00144 Roma
Italy
Ministry of Labour, Health
and Social Affairs,
Directorate General of Phone :
Medicine and Medical +39-6-5994-3390
IVDMD Dr. Giovanna Nistic g.nistico@sanita.it
Devices Fax :
Head of Unit 4 +39-06-5994-3226
via Giorgio Ribotta 5,
00144 Roma
Italy
Latvia
State Agency of AIMDD Tel: +37167078466
Mrs. Daiga Lagzdina 15 Jersikas street,
Medicines Daiga.Lagzdina@zva.gov.lv Fax: +37167078428
Riga,
MDD Mrs. Nellija Kangare Latvia, LV-1003
nellija.kangare@zva.gov.lv Tel: +37167078466
Medical Devices Fax: +37167078428
Evaluation IVDMD
Department for Latvia
AIMDD
Liechenstein Amt fr Gesundheit Phone :
(EFTA) info@ag.llv.li ulestrasse 51 +423 236 73031
MDD FL-9490 Vaduz
Amt fr Gesundheit
http://www.llv.li Fax :
Liechenstein +423 236 75 64
IVDMD
AIMDD Phone :
Lithuania
Ms. Jolanta jolanta.karavackaite@vaspvt.gov.lt
+370 5 2122346
State Health Care Zalgirio str.92
Karavackaite +370 5 2629607
Accreditation Agency julius.tertelis@vaspvt.gov.lt LT-09303 Vilnius
MDD Mr. Julius Tertelis +370 5 2615177
under Ministry of Lithuania
Health of the Republic vaspvt@vaspvt.gov.lt)
Fax:
of Lithuania http://vaspvt.gov.lt +370 5 2127310
IVDMD
AIMDD
Phone :
Luxembourg Villa Louvigny + 352- 2478 56 34
Ministere de la Sante MDD Dr. Gerard Scharll gerard.scharll@ms.etat.lu Alle Marconi
Direction de la Sante L-2120 Luxembourg Fax :
+352-262 03296
IVDMD
AIMDD Regulatory Affairs
Directorate -
Second Floor Phone :
Dr David Pulis david.pulis@msa.org.mt
Malta MDD Evans Building +356 2395 2000
Malta Standards tristan- Merchants Street
Authority charles.camilleri@msa.org.mt Valletta VL T1179 Fax:
Dr. Tristan Camilleri
Malta +356 2124 2406
IVDMD
Healthcare Inspectorate
AIMDD IGZ Information Office/ Phone :
IGZ-Loket +31-88-1205000
IGZ-Loket Loket@igz.nl
PO Box 2680 Fax :
NL- 3500 GR Utrecht +31-88-1205001
MDD The Netherlands
Netherlands Healthcare Inspectorate

Health Care
Inspectorate Postal address :
P.O. Box 2860 Phone . :
NL-3500 GR Utrecht +31-88-1205000
IVDMD Ms L.M. de Vries Loket@igz.nl The Netherlands
Fax :
Visitors address : +31 88-1205001
St. Jacobsstraat 16
3511 BS Utrecht
The Netherlands
AIMDD Mr. Tore Bernt Berg
Norway Phone :
PO Box 7000
(EFTA) +47 810 20 050
St. Olavs plass
Norwegian MDD Mr. Tore Bernt Berg meddev-no@helsedir.no
N-0130 Oslo
Directorate of Health Fax :
Norway
+47-24 16 30 21
Mr. Bjrn Kristian
IVDMD
Berge
AIMDD
Phone :
Poland Mr. Andrzej Karczewicz 41 Zabkowska str, + 48 22 492 11 68
Office for Registration (Head of Department) incydenty@urpl.gov.pl 03-736 Warsaw
MDD + 48 22 492 11 90
of Medicinal Product, Poland
Medical Devices and Mrs. Beata www.urpl.gov.pl
Fax:
Biocidal Products Kozioemska
+ 48 22 492 11 29
IVDMD
Portugal
AIMDD
Unidade de Vigilncia
Parque de Saude de
de Produtos de Phone :
Lisboa;
Sade +351-21 798 7297
MDD Av. do Brasil, 53,
+351-21 798 7145
(Healthcare Products Dr. Raquel Alves dvps@infarmed.pt Pav. 17A
Vigilance Unit) 1749 - 004 Lisboa
Fax :
INFARMED, I. P. +351-21 798 7367
Portugal
IVDMD
AIMDD
1-3, Cristian Popisteanu Phone :
atanase@ms.ro Street, Sector 1 +40 21 307 25 81
Romania
MDD Ms Ana Tanase
Ministry of Health www.ms.ro 010024, Bucharest Fax:
Romania +40 21 307 25 85
IVDMD
Slovenia Zaloska 7 Phone :

University Medical AIMDD SI-1525 Ljubljana +386 (0)1 522 86 19
Centre MDD Dr Martin Mozina martin.mozina@kclj.si
Ljubljana IVDMD Fax:
Center of Poisoning Slovenia +386 (0)1 522 23 48
Slovenia Phone :
Agency for Medicinal Ptujska ulica 21 +386 (0)8 2000 500
Products and Medical AIMDD SI-1000 Ljubljana
Fax: +386 (0)8 2000
Devices of the MDD Dr Petra Marinko meddev.vigilance@jazmp.si
510
Republic of Slovenia IVDMD Slovenia
(serious adverse or +386 (0)8 2000
incidents) 557
Slovakia Mr. Marek Slvik slavik@sukl.sk State Institute for Phone :

State Institute for AIMDD +421 2 50701307
DrugControlMedical
Drug Control, Mrs.Gabriela Buzkov buzakova@sukl.sk Devices Section +421 2 50701215
Medical Devices
Section MDD Kvetna 11, Fax:
825 08 Bratislava 26 +421 2 55565151
www.sukl.sk
IVDMD Slovak Republic
Spain AIMDD
Parque Empresarial Las Phone :
Ministerio de Sanidad
psvigilancia@aemps.es Mercedes. +34 91 8225255
y Consumo Mrs. C. Valls
MDD Edificio 8. C/ Campezo 1
Agencia Espaola de Mrs C. Abad
www.aemps.es 28022 Madrid Fax:
Medicamentos y
Spain +34 91 8225289
Productos Sanitarios
IVDMD
AIMDD PO Box 26,

SE - 751 03 Uppsala Phone :
Sweden +46-18 17 46 00
Mr Arne Kardell www.lakemedelsverket.se Visiting address:
Medical Products MDD
Agency (MPA) meddev.central@mpa.se Dag Hammarskjlds vg Fax :
42, Uppsala +46-18 50 31 15
IVDMD Sweden
Switzerland margit.widmann@swissmedic.ch Medical Devices Division Phone :

AIMDD Hallerstrasse 7 +41 (0)31 324 91 80
(EFTA) Mrs Margit Widmann
Swissmedic MDD PO Box +41 (0)31 322 77 01
materiovigilance@swissmedic.ch
Swiss Agency CH-3000 Bern 9 Fax :
for Therapeutic andreas.schlegel@swissmedic.ch Switzerland +41 (0)31 322 76 46
Products IVDMD Mr. Andreas Schlegel
Turkey AIMDD
(Candidate)
Ministry of Health mehtap.cakmak@saglik.gov.tr Phone :
Ms. Mehtap Cackmak Atatrk Bulvar No: 65
General Directorate of + 90 312 3240248
Barsbay Kat: 7
Pharmacy and MDD Fax :
Shhiye/ANKARA
Pharmaceuticals, + 90 312 3240378
www.tibbicihaz.saglik.gov.tr TURKEY
Biomedical
Engineering
Department IVDMD
Phone :
AIMDD MHRA Adverse Incident +44 (0) 20 7084
Center 3080 (for any general
United Kingdom
MDD Market Towers enquiries on
Medicines and
Mr Tony Sant aic@mhra.gsi.gov.uk 1 Nine Elms Lane notification)
Healthcare products
IVDMD London
Regulatory Agency Fax :
SW8 5NQ
United Kingdom +44 (0) 20 7084
3109
List of contact points within the National/Competent Authorities
AUSTRIA - BELGIUM - BULGARIA - CYPRUS - CZECH REPUBLIC - DENMARK - ESTONIA - FINLAND

FRANCE - GERMANY - GREECE - HUNGARY - ICELAND - IRELAND - ITALY - LATVIA - LIECHENSTEIN
Shortcuts LITHUANIA - LUXEMBOURG - MALTA - NETHERLANDS - NORWAY - POLAND - PORTUGAL - ROMANIA -
SLOVENIA - SLOVAKIA - SPAIN - SWEDEN - SWITZERLAND - TURKEY - UNITED KINGDOM
Dir. E-mail &

Country Name Contact person Phone Fax
Website
Address
AIMDD Federal Ministry of Health meddev@bmgf.gv.at

Dept. Pharmaceuticals and Dr. Wolfgang Ecker +43 1 711 00 42 06
Austria Medical Devices Dr. Martin Renhardt
+43 1 711 00 44 87 +43 1 7134404
MDD +43 1 711 00 46 02 2183
Ing. Andreas Gutruf (Secretariat)
Radetzkystrasse 2; www.bmgf.gv.at
IVDMD A-1030 Vienna
Austria
Federal Agency for Medicines Head of the Medical

Device Unit : meddev@fagg.be
and Health Products
Health Products Division Mr Wim Penninckx +32 2 52 48322
Belgium AIMDD (Frdrique +32 2 52 48120
Meulders)
Eurostation II Co-ordinator of MD
Unit : Mrs.
Place Victor Horta 40 b40 Frdrique
www.fagg.be
B-1060 Brussels Meulders
Belgium
MDD
Scientific Institute Public Dr. Pharm. Jean- jean-claude.libeer@

Health Claude Libeer iph.fgov.be
Department of Clinical Biology
IVDMD +32 2 642 55 40 +32 2 642 56 45
J. Wytsmanstraat, 14
B-1050 Brussels anne.vannerom@
Belgium Dr. Anne Van iph.fgov.be
Nerom, DVM
website CA IVD-BE
AIMDD
Head of Department: lyubomir.dimitrov@bda.bg,
Bulgarian Drug Agency Dr. Lyubomir
Dimitrov roumena.kambourova@bda.bg
Department Medical devices
Bulgaria Mrs. Rumena darakchiev@bda.bg
MDD 8 Damyan Gruev Str.
+359 2 890 35 11 +359 2 890 34 34
Kamburova
BG-1303 Sofia
Bulgaria Mr. Todor
Darakchiev
IVDMD www.bda.bg
AIMDD Cyprus Medical Devices
Competent
Dr. Stelios
+357 22 605 572
Cyprus Christofides cymda@mphs.moh.gov.cy +357 22 468 467
MDD AuthorityProdromou 1 & +357 22 605 574
Chilonos 17 Corner
Andrie Stylianou
1449 Nicosia
Cyprus
IVDMD
AIMDD danuse.drahotova@mzcr.cz +420 224 972 735
Ministry of Health pavel.sroub@mzcr.cz

Mrs. Danue
Czech
Palackho nmst 4 Drahotov +420 224 916 002
Republic MDD +420 224 972 738
128 01 Prague 2 Mr. Pavel Sroub
Czech Republic
www.mzcr.cz
IVDMD +420 224 972 363
The Danish Medicines Mrs Ellen Jespersen med-udstyr@dkma.dk

Denmark AIMDD Agency +45 44 88 95 95 +45 44 88 95 99
Mr Hans-Kristian
Axel Heides Gade 1 Andersen www.medicinskudstyr.dk
DK-2300 www.medicaldevices.dk
MDD Kbenhavn S
Denmark
IVDMD
AIMDD State Agency of Medicines

info@ravimiamet.ee
Medical Devices Department
+37 27 37 41 40 +37 27 37 41 42
Estonia
Dr. Andrei Knuut (common) (common)
MDD 1 Nooruse st.,
50411 Tartu
www.ravimiamet.ee
Estonia
IVDMD
AIMDD Valvira Jussi.holmalahti@valvira.fi

National Supervision Authority
for Welfare and Health kirjaamo@valvira.fi
MDD Dr. Jussi Holmalahti
Finland +358 9 772 920 +358 9 772 2138
Lintulahdenkuja 4 Director
P.O. Box 210,
FI-00531 Helsinki
IVDMD Finland www.valvira.fi
Agence francaise de scurit dedim.ugsv@

France AIMDD +33 1 55 87 37 45 +33 1 55 87 37 42
sanitaire des produits de Dr. Jean-Claude afssaps.sante.fr
sant (AFSSAPS) Ghislain
MDD www.afssaps.fr
143-147 boulevard Anatole
France
93285 Saint Denis Cedex
IVDMD France
Federal Ministry of Health medizinprodukte@ + 49(0) 228 941-

Mr. Wilfried Reischl bmgs.bund.de 1180
AIMDD (W. Reischl) + 49 228
Germany Am Propsthof 78a Dr. Matthias + 49(0) 228 941- 941-4946
Legislation
D-53123 Bonn Neumann 2636
Germany www.bmgs.bund.de (Dr. M. Neumann)
Zentralstelle der Lnder fr

zlg@zlg.nrw.de
Gesundheitsschutz bei
AIMDD Dr. Rainer
Arzneimitteln und + 49 228 97794-0 + 49 228 97794-44
Designating Edelhaeuser
Medizinprodukten (ZLG)
www.zlg.de
Germany

medizinprodukte@
and Medical Devices
bfarm.de
AIMDD Dr. Ekkehard
+49 228 207 5384 + 49 228 207 5300
CA Kurt Georg Kiesinger Allee 3 Stlein
D53175 Bonn
www.bfarm.de
Germany
Mr. Wilfried Reischl bmgs.bund.de 1180 (W. Reischl)
MDD + 49 228
Am Propsthof 78a Dr. Matthias + 49(0) 228 941-
941-4946
Legislation 2636
D-53123 Bonn Neumann
(Dr. Neumann)
Germany www.bmgs.bund.de

zlg@zlg.nrw.de
MDD Dr. Rainer
www.zlg.de
Germany

medizinprodukte@
and Medical Devices
bfarm.de
MDD
Dr. Dirk Wetzel +49 228 207 5235 +49 228 207 5300
CA Kurt Georg Kiesinger Allee 3
D53175 Bonn
www.bfarm.de
Germany

1180
Mr. Wilfried Reischl bmgs.bund.de
IVDMD (W. Reischl) + 49 228
Am Propsthof 78a Dr. Matthias + 49(0) 228 941- 941-4946
Legislation
D-53123 Bonn Neumann 2636
Germany www.bmgs.bund.de (Dr. Neumann)

zlg@zlg.nrw.de
IVDMD Dr. Rainer
www.zlg.de
Germany
medizinprodukte@
and Medical Devices
bfarm.de
IVDMD 1
Dr. Rdiger
+ 49 228 207 5360 + 49 228 207 5300
CA Kurt Georg Kiesinger Allee 3 Siekmeier
D53175 Bonn
www.bfarm.de
Germany
Paul Ehrlich Institute

pharmacovigilance2@pei.de +49- 6103
Section Pharmacovigilance
Dr.. Markus Funk 77 3115
IVDMD 2
2 +49- 6103
(Dr. Funk) or
CA Paul-Ehrlich-Strasse 51-59 77 1268
Jochen Halbauer 77 3114
D-63225 Langen (J. Halbauer)
www.pei.de
Germany
1
ex those Annex II devices
2
Annex II products as far as related to infection diseases or immuno haematology or tissue typing
AIMDD perpiraki@eof.gr
National Organization for
Medicines vsafra@eof.gr +30 21 06 50 74 07
Mrs. Maria Perpiraki
+30 21 06 50 74
Greece MDD 50
284 Mesogion Ave
Mrs. Virginia Safra +30 21 06 50 73 24
155 62 Holargos-Athens
Greece www.eof.gr
IVDMD
Hungary Authority for Medical Devices amd@eekh.hu

AIMDD Mr. Peter Bunyitai +36 1 302 5060 +36 1 269 1255
Budapest 1245
MDD Pf. 987. http://www.eekh.hu
Hungary
IVDMD
AIMDD annabara@landlaeknir.is
Directorate of Health
Iceland Mrs. Anna Bjorg +354 510
MDD Austurstrond 5, 1900/1905
+354 510 1919
(EFTA) Aradottir
IS-170 Seltjarnarnes
Iceland
www.landlaeknir.is
IVDMD
IIrish Medicines Board.Kevin

AIMDD OMalley House Medical
Devices Department medicaldevices@imb.ie
Earlsfort Centre Ms. Ann O'Connor

Ireland MDD Earlsfort Terrace +353-1-6764971 +353-1-6344033
Dublin 2
Ireland www.imb.ie
IVDMD
AIMDD Ministry of Labour, Health 0039 06 5994 3809 0039 06 5994
MD and AIMD
and Social Affairs, 3292
Head of
Unit 3
Directorate General of
Dr.Annamaria 0039 06 5994 3390
Medicine and Medical an.donato@sanita.it
Donato 0039 06 5994
Italy MDD Devices 3266
g.nistico@sanita.it
IVDMD
via Giorgio
Head of
Ribotta 5,
Unit 4
00144 Roma
Dr.Giovanna Nistic
IVDMD Italy
AIMDD
State Agency of Medicines
Director
Latvia MDD 15 Jersikas street, info@zva.gov.lv +371 67078424 +371 67078428
Inguna Adovia
Riga, LV-1003,
Latvia
IVDMD
Liechenstein Amt fr Gesundheit +423 236 +423 236

AIMDD R. Kieber reto.kieber@ag.llv.li 66 33 75 64
(EFTA)
ulestrasse 51
Postfach 684
MDD FL-9490 Vaduz
IVDMD Liechenstein
juozas.galdikas@vaspvt.gov.lt
AIMDD The State Health Care
Accreditation Agency under Common email:
the Ministry of Health of the Director: vaspvt@vaspvt.gov.lt
Lithuania Republic of Lithuania Prof. Juozas
+370 5 261 51 77 +370 5 212 73 10
MDD Galdikas
Zalgirio str. 92
LT- 09303 Vilnius
Lithuania
IVDMD www.vaspvt.gov.lt
AIMDD Ministre de la Sant - gerard.scharll@ms.etat.lu

Direction de la Sant
Luxembourg MDD Dr Grard Scharll +352 478 56 34 +352 26 20 32 96
Villa Louvigny - alle Marconi
L-2120 Luxembourg www.etat.lu/MS/
IVDMD
Malta Malta Standards Authority Dr. David Pulis david.pulis@msa.org.mt

AIMDD +356 2395 2000 +356 2124 2406
Second Floor, tristan-
Evans Building, Dr. Tristan Camilleri charles.camilleri@msa.org.mt
MDD Merchants Street,
Valletta VLT 1179
Malta www.msa.org.mt
IVDMD
Vigilance
AIMDD Dutch Healthcare
Inspectorate Mr. Jan Moleveld
loket@igz.nl
Postal address:
MDD P.O. Box 2680 Mr. Jan Moleveld
Netherlands 3500 BS Utrecht +31 88 120 5000 +31 88 120 5001
The Netherlands
Ms. Laura de Vries www.igz.nl
IVDMD Visitors address:
St. Jacobstraat 16
3511 BS Utrecht
The Netherlands
Notification/Registration
AIMDD CIBG
Farmatec-BMC
Medische_hulpmiddelen@minvws.nl
Postal address:
PO box 16114
MDD 2500 BC Ms. Joan Deckers +31 70 340 5200 +31 70 340 7426
IVDMD The Hague PhD
The Netherlands www.farmatec.nl
Visitors address:
Wijnhaven 16
2511 GA Den Haag
The Netherlands
AIMDD Mrs. Ingeborg

Directorate of Health Hagerup-Jenssen
meddev-no@shdir.no
Norway P.O.Box 7000 Mr. Bjrn Kristian
MDD ST. Olavs plass Berge +47 810 20 050 +47 24 16 30 21
(EFTA)
N-0130 Oslo
www.shdir.no
Norway
IVDMD Mrs. Sissel Dyrnes
Legislation
Designation of NBs s.migdalski@mz.gov.pl
MDD
Mr. Sebastian
AIMD Ministry of Health +48 22 6349324 +48 22 8316557
Migdalski
IVDMD Miodowa 15
00-952 Warsaw www.mz.gov.pl
Poland
Poland
Competent Authority
joanna.kilkowska@urpl.gov.pl
Mrs.Joanna
Office for Registration of
Kilkowska +48 22 4921170 +48 22 4921199
MDD Medicinal Products, Medical andrzej.karczewicz@urpl.gov.pl
AIMD Devices and Biocidal
IVDMD Products +48 22 4921190 +48 22 4921199
Mr. Andrzej
Zabkowska 41
Karczewicz
03 736 Warsaw www.urpl.gov.pl
Poland
AIMDD Infarmed
National Authority of infarmed@infarmed.pt
Medicines and Health + 351 21 798 7100 + 351 21 798 7316
Mrs. Judite Neves,
Products, IP daps@infarmed.pt
MDD Pharm.D.,
Portugal
Director of Health 351 21 798 7235 + 351 21 798 7281
Parque de Saude de Lisboa
Products Directorate
Av. do Brasil, n. 53
1749-004 Lisboa www.infarmed.pt
IVDMD Portugal
AIMDD Ministry of Health
atanase@ms.ro
1-3, Cristian Popisteanu
Romania MDD Street, Mrs. Ana Tanase +40 21 307 25 81 +40 21 307 25 85
Sector 1
010024, Bucharest www.ms.ro
IVDMD Romania
AIMDD Agency for Medicinal

Products and Medical meddev@jazmp.si
Devices of the Republic of petra.marinko@jazmp.si +386 (0)8 2000
510
Slovenia MDD Slovenia
Dr. Petra Marinko +386 (0)8 2000 500 or
+386 (0)8 2000
Ptujska ulica 21 557
SI-1000 Ljubljana www.jazmp.si
IVDMD Slovenia
AIMDD State Institute for Drug

Control
Medical Devices Section slavik@sukl.sk
Slovakia
MDD Mr. Marek Slvik +421 2 50701307
+421 2 55565151
Kvetna 11,
825 08 Bratislava 26
IVDMD Slovakia
Ministerio Sanidad y
AIMDD
Consumo
Agencia Espaola de
sgps@aemps.es
Medicamentos y Productos
Sanitarios
Spain MDD Mrs. Carmen Abad +34918225261 +34918225289
Parque Empresarial Las
www.msc.es
Mercedes.
http://www.aemps.es/
Edificio 8. C/ Campezo 1
28022 Madrid
IVDMD Spain
AIMDD Medical Products Agency

meddev.central@mpa.se
Medical Devices
Dr. Lennart Philipson
Sweden +46 18 17 46 00 +46 18 50 31 15
MDD Box 26
Mr. Lars Johansson
SE-751 03 Uppsala
http://www.lakemedelsverket.se/
Sweden
IVDMD
AIMDD Swissmedic margit.widmann@swissmedic.ch

Medical Devices Division Dr. Margit Widmann
MDD medical.devices@swissmedic.ch
Switzerland +41 31 323 22 51 +41 31 322 76 46
(EFTA) Erlachstr. 8
CH 3000 Bern 9 andreas.schlegel@swissmedic.ch
Switzerland Dr. Andreas
IVDMD materiovigilance@swissmedic.ch
Schlegel
www.swissmedic.ch/md.asp
Ministry of Health bilgehan.karadayi@saglik.gov.tr

General Directorate of Mr. Bilgehan
Pharmacy and Karadayi olgun.sener@saglik.gov.tr
AIMDD Parmaceuticals Biomedical
Turkey
MDD Mr. Olgun Sener mehtap.cakmak@saglik.gov.tr
Engineering Department + 90 312 3240248 +903123240378
(Candidate)
IVDMD
Atatrk Bulvar No: 657. Kat Mrs. Mehtap
Shhiye 06343 Cakmak Barsbay www.tibbicihaz.saglik.gov.tr
Ankara/TURKEY
Medicines and Healthcare

products Regulatory Agency
(MHRA) steve.owen@mhra.gsi.gov.uk
AIMDD
United + 44 (0) 20 7084 + 44 (0) 20 7084
MDD 8th Floor Mr. Steve Owen 3184 3112
Kingdom
IVDMD Market Towers
1 Nine Elms Road www.mhra.gov.uk
London SW8 6NQ
United Kingdom
EUROPEAN COMMISSION
DG Health and Consumers (SANCO)
Directorate B-Consumer Affairs
Unit B2- Health Technology and Cosmetics
MEDDEV 2.12-1 rev 7
March 2012
GUIDELINES
Revision 7 of MEDDEV 2.12-1 incorporates two new Report Forms (Annex 6-Manufacturer's
Periodic Summary Report and Annex 7- Manufacturer's Trend Report Form) and updates
two existing Report Forms (Annex 3 and Annex 4). The revised guidance will be applicable
as of 15 June 2012.
1
TABLE OF CONTENTS
1 FOREWORD .................................................................................................................................... 4
2 INTRODUCTION .............................................................................................................................. 4
3 SCOPE ............................................................................................................................................. 5
3.1.2 FOR MANUFACTURERS OF IVDS ................................................................................... 7
3.1.4 FOR USERS ....................................................................................................................... 8
4 DEFINITIONS ................................................................................................................................... 8
4.1 ABNORMAL USE ................................................................................................................. 8
4.4 DRUG / DEVICE COMBINATION PRODUCT ...................................................................... 9
4.5 EUDAMED............................................................................................................................. 9
4.7 FIELD SAFETY NOTICE (FSN) .......................................................................................... 10
4.8 HARM .................................................................................................................................. 10
4.9 IMMEDIATELY .................................................................................................................... 10
4.10 INCIDENT ............................................................................................................................ 10
4.11 INDIRECT HARM ................................................................................................................ 10
4.13 MANUFACTURER .............................................................................................................. 11
4.14 MEDICAL DEVICE .............................................................................................................. 11
4.15 OPERATOR ........................................................................................................................ 11
4.17 SERIOUS PUBLIC HEALTH THREAT ............................................................................... 12
4.18 TREND REPORTING .......................................................................................................... 12
4.19 UNANTICIPATED ............................................................................................................... 12
4.20 USE ERROR ....................................................................................................................... 12
4.21 USER ................................................................................................................................... 12

5.1.3.1 DEFICIENCY OF A DEVICE FOUND BY THE USER PRIOR TO ITS USE .......... 16
5.1.3.4 PROTECTION AGAINST A FAULT FUNCTIONED CORRECTLY ........................ 17
5.1.3.5 EXPECTED AND FORESEEABLE SIDE EFFECTS .............................................. 18
5.1.4 TREND REPORTS ........................................................................................................... 19
2
5.1.7 TIMESCALE FOR THE INITIAL REPORTING OF AN INCIDENT .................................. 21
5.1.8 TO WHOM TO REPORT .................................................................................................. 21
5.3 INVESTIGATIONS .............................................................................................................. 22
5.3.1 PRINCIPLES..................................................................................................................... 22
5.3.2 ACCESS TO THE DEVICE SUSPECTED TO BE INVOLVED IN THE INCIDENT ......... 22
5.4.1 PRINCIPLES ........................................................................................................................ 22
5.4.2 FOLLOW-UP REPORT .................................................................................................... 23
5.4.3 FINAL REPORT................................................................................................................ 23

6.1 ACTIONS ON A REPORT FROM USERS OR OTHER SYSTEMS ................................... 26
6.3 CO-ORDINATION BETWEEN COMPETENT AUTHORITIES ........................................... 28
AUTHORITIES .................................................................................................................. 29
10.1 ANNEX 1 EXAMPLES OF INCIDENTs AND FIELD SAFETY CORRECTIVE ACTIONS

WHICH THE MANUFACTURER SHOULD REPORT ........................................................ 33
VIGILANCE" ....................................................................................................................... 35
AUTHORITY ........................................................................................................................ 38
10.4 ANNEX 4 REPORT FORM FOR FIELD SAFETY CORRECTIVE ACTION ...................... 43
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE ................................................... 46
10.6 ANNEX 6 MANUFACTURER'S PERIODIC SUMMARY REPORT FORM ........................ 48
10.7 ANNEX 7 MANUFACTURER'S TREND REPORT FORM
52
10.8 ANNEX 8 NATIONAL COMPETENT AUTHORITY REPORT FORMAT
56
10.10 ANNEX 10 LIST OF THE USED ABBREVIATIONS .......................................................... 60
10.11 ANNEX 11GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS IN THE
3
1 FOREWORD
health.
2 INTRODUCTION
1
4
3 SCOPE
MANUFACTURERs2
Notified Bodies
European Economic Area (EEA), Switzerland and Turkey with regard to:
made devices)
2
5

devices which are offered for sale or are in use within the EEA, Switzerland and Turkey.


AUTHORISED REPRESENTATIVEs within the EEA, Switzerland and Turkey, persons
within the EEA, Switzerland and Turkey, persons responsible for placing devices on the
market and any other agents authorised to act on their behalf for purposes relating to
medical devices vigilance, are kept informed of INCIDENT reports as appropriate.
(see section 5.1)

6
be reported.

7
3.1.4 FOR USERS

MANUFACTURER.
4 DEFINITIONS
4.1 ABNORMAL USE

3
8
4.5 EUDAMED

refused,
data obtained in accordance with the vigilance procedure,
data concerning clinical investigations.

NOTE 1:

- device exchange;
- advice given by MANUFACTURER regarding the use of the device and/or the follow
up of patients, users or others (e.g. where the device is no longer on the market or
has been withdrawn but could still possibly be in use e.g. implants or change in
analytical sensitivity or specificity for diagnostic devices).

- deterioration in state of health related specifically to the characteristics of the device. For
- example:
- Corrective action taking the form of special patient follow-up, irrespective of
- whether any affected un-implanted devices remain available for return, constitutes
- FSCA.
- patients for retesting or the retest or review of previous results constitutes FSCA.
- 10
- advises revised quality control procedure -use of third party controls or more frequent
9
- calibration or modification of control values for IVDs.
NOTE 2:
This guideline uses the definition of FSCA as synonym for recall mentioned in article 10(1),
paragraph 1b) of the MDD and Article 11 IVD Directive since there is no harmonised
definition of recall.

4.8 HARM
4.9 IMMEDIATELY
justified.
4.10 INCIDENT

4.11 INDIRECT HARM
or result(s) provided by the device,
Examples include
misdiagnosis,
delayed diagnosis,
delayed treatment,
10
For self-testing devices, a medical decision may be made by the USER of the device who is
also the patient.
4.13 MANUFACTURER
party.
4.14 MEDICAL DEVICE

handicap,
4.15 OPERATOR

is known or an FSCA has been implemented..
11
This would include:

Reference: GHTF SG2 N54
NOTE: Appendix C of GHTF SG2 document N54 '" Global Guidance for Adverse Event
Reporting for Medical Devices" provides useful guidance.
4.19 UNANTICIPATED

4.20 USE ERROR
4.21 USER
DEVICES.

12
INCIDENTs which occurred outside the EEA, Switzerland and Turkey do not lead to a
FIELD SAFETY CORRECTIVE ACTION relevant to these geographic areas do not need to
be reported. Incidents which occurred outside the EEA , Switzerland and Turkey led to a
FIELD SAFETY CORRECTIVE ACTION relevant to the above-mentioned geographical
areas must be reported as a FIELD SAFETY CORRECTIVE ACTION.

If the MANUFACTURER is located outside the EEA, Switzerland and Turkey, a suitable
contact point within should be provided. This may be the MANUFACTURER's AUTHORISED

criteria are that:

test.
13

events.

INCIDENT
take account of:


serious deterioration in state of health of a patient, USER or other person.
a) life-threatening illness,
b) permanent impairment of a body function or permanent damage to a body structure,
c) a condition necessitating medical or surgical intervention to prevent a) or b).
Examples: - clinically relevant increase in the duration of a surgical procedure,
existing hospitalisation.
use.
e) foetal distress, foetal death or any congenital abnormality or birth defects.
NOTE :

14


authority.
A form for Periodic Summary Reporting is provided in Annex 6 .
Example:

15
system.
Examples:


Examples:

medical expert.
device.
16
Examples:


MANUFACTURER.
Examples:

patient.



USER. An intervention by the user or an immediate remote intervention by the
manufacturer allowed the analyser to resume the analysis, resulting in correct
results.
17


NOTES:
Examples:



18



Example:

5.1.4 TREND REPORTS

excluded from individual reporting as per chapter 5.1.3 a report should be made to the
occurring with their devices.

A form for Trend Reporting is provided in Annex 7 .
19

assessment bodies.

change in pattern (see appendix C of GHTF SG2 N54) of an issue that can potentially
lead to death or serious deterioration in state of health or public health threat)
- or initiates a FSCA to prevent death or serious deterioration in state of health or
SERIOUS PUBLIC HEALTH THREAT


REPRESENTATIVE.
20




21
5.3 INVESTIGATIONS
5.3.1 PRINCIPLES
defined.



INCIDENT
the INCIDENT.
5.4.1 PRINCIPLES
5.4.
22

5.4.3 FINAL REPORT
and of any action.
no action;
FSCA.

included.
FSCA taken on a basis of INCIDENTs occurred outside the EEA, Switzerland and Turkey
23
devices.)
appropriate:
transferred.)
Competent Authority once the FSCA has been completed in both, the EEA, Switzerland and
Turkey. This should include information on the effectiveness of the action per country
involved (e.g., percentage of devices recalled)

Authority.
24
should be offered by the MANUFACTURER to all affected EEA member states, Switzerland
and Turkey.


order number.

implants, IVD
timelines.
transferred.
FSCA.
25
should be omitted.
to the sender.
26
practicable.

example:



USER(s);

no further action;
27
assessment;

AUTHORITY IS NEEDED

INCIDENTs of similar types occurring in more than one country within the EEA,
Switzerland and Turkey;
FSCA conducted in more than one country within the EEA, Switzerland and Turkey,
whether or not a reportable INCIDENT has occurred.
information available on a FSCA conducted outside the EEA, Switzerland and Turkey
where there is uncertainty whether the FSCA affects the member states within the EEA,
Switzerland and Turkey or not, e.g. a Competent Authority Report issued outside EEA
Switzerland and Turkey (GHTF SG2) or information published on a CA website outside
the EEA , Switzerland and Turkey.

AUTHORITY

ordination.

AUTHORITY
28
and coordinate with other National Competent Authorities within the EEA, Switzerland
and Turkey;
corrective actions to be taken within the EEA, Switzerland and Turkey ;
countries;
inquiries within the EEA member states, Switzerland and Turkey e.g. with respect to
multiple INCIDENTs in different countries which do not lead to corrective actions at the
latest with the closure of the file; MANUFACTURER will be informed according to section
6.4;
Vigilance System.

AUTHORITIES
Commission when:

29

MANUFACTURER.
The format for dissemination of information between National Competent Authorities and the
Commission is given in Annex 8 and is the GHTF SG2 N79 format with minor changes. The
MANUFACTURER's report may be circulated with the Competent Authority Report. The use
of Eudamed to exchange NCARs is mandatory.
The appropriate "reason for report" should be identified on the National Competent Authority
Report. National Competent Authorities receiving reports should pay particular attention to
the "reason for report" and any "recommendations" given by the National Competent
Authority issuing the report. A number of reports may not require any immediate further
action. Wherever possible, National Competent Authorities should direct enquiries relating to
the investigation arising from the report to the National Competent Authority providing the
notification, who will co-ordinate communication with the MANUFACTURER or Notified Body.



advice.
30


"complete".

and of the results.


31
and USERs.

system,
MANUFACTURER develops with his customer (the USER). Annex 11 details some key
areas that the MANUFACTURER should promote with the USER. These areas may also be
32
ANNEXES
v.12/11
10.1 ANNEX 1- EXAMPLES OF INCIDENTS AND FIELD SAFETY

CORRECTIVE ACTIONS WHICH THE MANUFACTURER SHOULD
REPORT
EXAMPLES OF REPORTABLE INCIDENTS
serious deterioration in state of health is not normally expected. The INCIDENT should be
reported.
have caused a serious deterioration in state of health. The INCIDENT should be reported.
inappropriate handling was due to inadequacies in the labelling. The INCIDENT should be
reported.

The INCIDENT should be reported.
7. Glass particles are found by the user in a contact lens vial. The INCIDENT should be
reported.
did not show up in due time, although it should have according to device specification. The
10. The premature revision of an orthopaedic implant is required due to loosening. Although
33
11. User discovers that insufficient details are provided on cleaning methods for reusable
surgical instruments used in brain surgery, despite obvious risk of transmission of CJD. The

instructions, but the readings provide incorrect values leading to incorrect insulin dosage.
This INCIDENT should be reported.
13 A customer reports a wrong assignment of analytical results to patient codes by an

automated analyzer. An evaluation could reproduce the effect and indicated that a data
mismatch could occur. Due to the data mismatch a patient may obtain a wrong diagnosis /
treatment. This INCIDENT should be reported.
lead to wrong treatment of the patient this incident should be reported.
EXAMPLES OF REPORTABLE FSCA.

of a serious deterioration in state of health is not remote. The FSCA should be reported.
16. Fatigue testing performed on a commercialised heart valve bio prosthesis demonstrates
premature failure, which resulted in a risk to public health. The FSCA should be reported.
MANUFACTURER initiates a FSCA of this batch. This should be reported as an FSCA..
treatment of the patient. The MANUFACTURER issues information to the field that a reduced
onboard stability has to be taken into account. The FSCA should be reported.
19. A MANUFACTURER has noticed that starting from control lot XX a lower recovery is
obtained and re-assigns the control value. Users are informed of this new value by means of
warning stickers and a customer communication. The FSCA should be reported.
20. A MANUFACTURER of an immunohematology analyzer received complaints of an ABO

blood grouping system results being attributed to the wrong patient identification. The error
proved to be due to the analyzers software, which was subsequently updated. The FSCA his
should be reported.
34
v.12/11
10.2 ANNEX 2- EXTRACTS FROM DIRECTIVES RELATING TO "MEDICAL

DEVICES VIGILANCE"

A. Article 8
Extracts :


necessary steps to ensure that the manufacturer of the device concerned, or his authorised
representative, is also informed of the incident.
3. After carrying out an assessment, if possible together with the manufacturer or his
authorised representative, Member States shall, without prejudice to Article 7, immediately
inform the Commission and the other Member States of measures that have been taken or
are contemplated to minimise the recurrence of the incidents referred to in
paragraph 1, including information on the underlying incidents.
Extracts :
The manufacturer shall make an application for evaluation of his quality system to a notified
body. The application shall include:



35
A. Article 10: Information on incidents occurring following placing of devices on the
market
Extracts :


Extracts :


of health;


DEVICES
36


B. Annex III
Extracts :


37
10.3 ANNEX 3 - REPORT FORM FOR MANUFACTURERS TO THE NATIONAL
COMPETENT AUTHORITY
Report Form V.12/11

Date of this report
Reference number assigned by NCA
Type of report
Initial report
Follow-up report
Final report
Yes
No
Death
Unanticipated serious deterioration in state of health
2. Information on submitter of the report
38
Status of submitter
Manufacturer
Authorised Representative within EEA, Switzerland and Turkey
Others: (identify the role) :
3. Manufacturer information
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
4. Authorised Representative information

Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
5. Submitters information (if different from section 3 or 4)

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
6. Medical device information

Class

IVD Annex II List A
39
MDD Class III IVD Annex II List B
MDD Class IIb IVD Devices for self-testing
MDD Class IIa IVD General
MDD Class I
Nomenclature system (preferable GMDN) Nomenclature code
Nomenclature text
Model number Catalogue number
Serial number(s) (if applicable) Lot/batch number(s) (if applicable)
Device Manufacturing date Expiry date
Duration of implantation (to be filled is the exact implant or explant dates are unknown)
7. Incident information
other
40
other (please specify)
problem noted prior use
8. Patient information
Patient outcome
Female Male
9. Healthcare facility information

Address
Postcode City
Phone Fax
E-mail Country
10. Manufacturers preliminary comments (Initial/Follow-up report)

11. Results of manufacturers final investigation (Final report)

41
Yes No
Within EEA, Switzerland and Turkey:
SK TR
HR
All EEA, Candidate Countries, Switzerland and Turkey
Others:
12. Comments
person.
Name City date
42
10.4 ANNEX 4 - REPORT FORM FOR FIELD SAFETY CORRECTIVE ACTION
Report Form
Manufacturers Field Safety Corrective Action Report
v.12/11
To which NCA(s) is this report being sent?
Type of report
Initial report
Follow up report
Final report
Date of this report
FSCA reference number assigned by NCA
Incidence reference number assigned by NCA
Name of the co-ordinating national competent authority (if applicable)

Status of submitter
Manufacturer
Authorised representative within EEA, Switzerland and Turkey
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
43
Address
Postcode City
Phone Fax
E-mail Country

Address
Postal code City
Phone Fax
E-mail Country

Class

IVD Annex II List A
MDD Class I
Nomenclature text
Serial number(s) lot/batch number(s)
44
Progress of FSCA , together with reconciliation data (Mandatory for a Final FSCA)
Attached please find FSN Status

Draft
Field Safety Notice (FSN) in English Final
These countries within the EEA and Switzerland and Turkey are affected by this FSCA
SK TR
HR
Others:
8 Comments
Signature
Name City Date
45
10.5 ANNEX 5 - Template for a Field Safety Notice
v.12/11
---------------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------------
Date:
Attention: ///////////////

number.


timelines.
appropriate)
appropriate)
46
(Closing paragraph)
Signature
47
10.6 ANNEX 6 - Manufacturers PERIODIC SUMMARY REPORT FORM
Report Form
Manufacturers Periodic Summary Report (PSR)
Medical Devices Vigilance System (MEDDEV 2.12/1 rev 7)
v.12/11
1. Administration Information
Date of this report
Type of report
Initial report
Follow up report Follow up Number s
Final report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
48
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
6. Medical Device Information
Class
AIMD Active Implants IVD Annex II List A
MDD Class I
49
Nomenclature text
Notified Body (NB) ID Number
Model number(s) or Family Name Catalogue number(s)
7. PSR Information
PSR Type:
Incidents described in a Field Safety Notice Common and well documented incidents
If Incidents described in a Field Safety Notice,

Manufacturers reference number for FSN/FSCA
Stage of PSR reporting based on:
Observed Failure mode Root cause
Nature of problem agreed for PSR reporting
Summary period agreed:

Every month Every 2 months Every 3 months Every 6 months Every 12 months
The figures in the table below relate EEA + All PSR recipients NCAs Single Member State
to: CH+ TR identified in Section 1 Please name:-
Date of PSR New incidents Total number Total number Total number in
this period incidents via PSR resolved progress
8. Manufacturers comments / investigation results

Investigation update for this period
Initial corrective actions / preventive actions implemented by the manufacturer

50
Recommended actions for this period, if any
Expected date of next PSR report
9. Distribution
The medical device has been distributed to the following Countries
SK TR
HR
Others:
10. Comments
person.
Name City date
51
10.7 ANNEX 7- MANUFACTURERS TREND REPORT FORM
Report Form
Manufacturers Trend Report
v.12/11
Recipient (Name of National Competent Authority NCA)
Date of this report
Type of report
Trend Initial
Trend Follow up
Trend Final
Do these incidents / trend represent a serious public health threat?

Yes
No

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
52
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Class
MDD Class I
Nomenclature text
Model number(s) or Family name Catalogue number(s)
Serial number range (if applicable) Lot/batch number range(if applicable)
53
Accessories / associated devices (if applicable)
7. Information on Trend Report

Date the trend was identified
Description narrative for identified trend
Time period of trend analysis
Established trigger level
Have any of the trended events been submitted individually as reportable events under vigilance?
Yes No
If yes, please list how many and to which Competent Authority
8. Manufacturers preliminary comments

Manufacturers preliminary analysis into causes of trend
9. Results of manufacturers final investigation into trend

The manufacturers trend analysis results
Remedial action / corrective action / preventive action / Field Safety Corrective Action
Time scheduled for the implementation of the identified actions
Further investigation
10. The medical device has been distributed to the following Countries
SK TR
HR
Others:
54
11. Comments
person.
Name City date
55
10.8 ANNEX 8 - NATIONAL COMPETENT AUTHORITY REPORT FORMAT
v.12/11

Form N9R11
This form should be used for the exchange of information between National Competent Authorities
(NCA) and the Commission only

any):
Device Data
11a. Generic name/ kind of 11b. Category: 20. CAB/Notified Body no.:
device:

GMDN
14. Trade Name and Make and Model: 21a. Device approval
status:
18. Manufacturer: 19. Authorized rep (if different 22. Action taken:
Fax: Tel:
E-mail: Fax:
E-mail:
Event Data
24a. Conclusions:

56
Report Distribution
(AU CA JP NZ US).
[ ] EEA states, EC, Switzerland and Turkey
Field:
4 - If there have been previous NCARs exchanged relating to this one, regardless of
source, insert their NCA exchange numbers here.
12 - Identify the nomenclature system (e.g. GMDN, MHW, NKKN, UMDNS, Product Code,
Preferred Name Code, etc.) used, but note that GMDN is expected and therefore prefilled.
(12).
18 - Manufacturer of device - full address, including country, fax, phone numbers and e-mail.
57

investigation.
58
10.9 ANNEX 9 - TITLES OF GLOBAL HARMONISATION TASK FORCE
STUDY
MEDDEV AND/OR CITED
SG2-N8 Guidance on How to Handle Information Concerning Vigilance Reporting

SG2-N79 Medical Devices: Post Market Surveillance: National Competent Authority
Exchange Criteria and Report Form.
SG2-N54 Global Guidance for Adverse Event Reporting for Medical Devices :
59
10.10 ANNEX 10- LIST OF THE USED ABBREVIATIONS
NB Notified Body
60
10.11 ANNEX 11- GUIDANCE TO MANUFACTURERS WHEN INVOLVING
USERS IN THE VIGILANCE SYSTEM
v.12/11
Reporting Guidance
guidance.
needed.
actions outlined.
61
62
Report Form
Manufacturer's Incident Report
Version 2.24en
2012-05-25
Recipient (Name of NCA)
Date of this report
Type of report
o Initial report
o Follow-up report
o Combined initial and final report
o Final report
Oyes
Ono
o Death
o Unanticipated Serious Deterioration in State of Health
o All other reportable incidents
Identify to what other NCAts this report was also sent
Status of submitter
o Manufacturer
OAuthorised Representative within EEA and Switzerland and Turkey
o Others: (identify the role)
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
DE - Germany
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
DE- Germany
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
DE-Germany
Class
OAIMD Active implants
o MDD Class III o IVD Annex 11 List A
OMDD Class lib o IVD Annex 11 List B
o MDD Class lIa o IVD Devices for self-testing
OMDD Class I o IVD General
GMDN
Nomenclature text
Device Mfr Date Expiry date
Duration of Implantation (For implants only. To be filled if the exact implant and explant dates are unknown)
Incident description n"rrative
Manufacturer's awareness date
Number of patients involved (if known) I~umber of medical devices involved (if known)
0
o Healthcare Professional
o Patient
o Other
o initial use
o reuse of a single use medical device
o reuse of a reusable medical device
Ore-serviced/refurbished
Oother
o problem noted prior use
Patient outcome
Remedial action taken by the health care facility relevant to the care of the patient
OFemale OMale
o months Odays
Address
Postcode City
Phone Fax
E-mail Country
DE-Germany
Manufacturer'S preliminary analysis
The manufacturer's device analysis results
Is the manufacturer aware of si incidents with this type root cause?

OYes ONo
o
For final reports only. The medical device has been distributed to the following countries:
within the EEA and Switzerland and Turkey
DAT DBE OBG OCH OCY DCZ ODE DDK

DEE DES OFI OFR OGB OGR OHU DIE
OIS OIT OLl OLT OLU OLV OMT ONL
ONO OPL OPT ORO OSE OSI OSK OTR
Candidate Countries
OHR
OAII EEA, candidate countries and Switzerland and Turkey
Others:
Submission of this report does not, in itself, represent a conclusion by the manufacturer and/or authorised
representative or the National Competent Authority that the content of this report is complete or accurate,
that the medical device(s) listed failed in any manner and/or that the medical device(s) caused or
contributed to the al/eged death or deterioration in the state of the health of any person.
Signature
I affirm that the information given above is correct

to the best of my knowledge
How to use the Manufacturer Incident Report (MIR) Form
1. Acrobat version: Use the Acrobat Reader or Acrobat Professional

version 9 or higher.
2. Identification of the type of report: Mandatory field depending on the

type of report (Initial, Follow-up or Final Report) can be identified by
hitting the button Highlight Fields in the right upper corner of the
Reader.
3. When the author of the report is the manufacturer or the authorised

representative (identified via the radio buttons in section 2), the
information from section 3 or 4 will be copied line by line into section
6.
4. The option to produce templates is implemented. Fill all areas of

interest (usually administrative data) and store the template under an
individual name.
5. By hitting the button new next to the headline in sections 2-6 and 9,
all data of the specific sections will be deleted.
6. Date format is YYYY-MM-DD.
7. Hitting the button send xml-data per Email:

9 checks that all mandatory data are filled,
9 produces the xml file containing all entered data
9 and opens the local E-mail client.
The xml file is attached and the mail is ready to be sent. The body of
the email may be modified. Recipients may be added or deleted .
PLEASE DO NOT CHANGE THE ATTACHED XML FILE.
8. The form is locked once the button send XML by Email is hit. Store
the copy in your file system and add it to the email.
Sending the xml file is sufficient as the information will be loaded back
into the form.
V 03/03/2011
Report Form
v.12/11
Type of report
Initial report
Follow up report
Final report
Date of this report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
1
Postcode City
Phone Fax
E-mail Country

Address
Postal code City
Phone Fax
E-mail Country

Class

IVD Annex II List A
MDD Class I
Nomenclature text
2

Draft
SK TR
HR
Others:
8 Comments
Signature
Name City Date
3
Report Form
v.12/11
Date of this report
Type of report
Trend Initial
Trend Follow up
Trend Final

Yes
No

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
1
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Class
MDD Class I
Nomenclature text
2

Yes No


SK TR
HR
Others:
11. Comments
3
person.
Name City date
4
v.12/11
Date of this report
Type of report
Initial report
Final report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
1
Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
Class
MDD Class I
Nomenclature text
2
7. PSR Information
PSR Type:



9. Distribution
3
SK TR
HR
Others:
10. Comments
person.
Name City date
4
MEDDEV 2 12-1 rev. 8 Vigilance
EUROPEAN COMMISSION
DG Health and Consumers (SANCO)
Directorate B-Consumer Affairs
Unit B2- Health Technology and Cosmetics
MEDDEV 2.12-1 rev 8
January 2013
GUIDELINES
Revision 8 of MEDDEV 2.12-1 explicitly includes IVF/ART devices within the scope of the
vigilance system and provides clarity in relation to devices that are not intended to act
directly on the individual. The revised guidance will be applicable as of July 2013.
1
TABLE OF CONTENTS
1 FOREWORD .................................................................................................................................... 4
2 INTRODUCTION .............................................................................................................................. 4
3 SCOPE ............................................................................................................................................. 5
3.1.2 FOR MANUFACTURERS OF DEVICES THAT ARE NOT INTENDED TO ACT
DIRECTLY ON THE INDIVIDUAL ...................................................................................... 7
3.1.4 FOR USERS ....................................................................................................................... 8
4 DEFINITIONS ................................................................................................................................... 8
4.1 ABNORMAL USE ................................................................................................................. 8
4.4 DRUG / DEVICE COMBINATION PRODUCT ...................................................................... 9
4.5 EUDAMED............................................................................................................................. 9
4.7 FIELD SAFETY NOTICE (FSN) .......................................................................................... 10
4.8 HARM .................................................................................................................................. 11
4.9 IMMEDIATELY .................................................................................................................... 11
4.10 INCIDENT ............................................................................................................................ 11
4.11 INDIRECT HARM ................................................................................................................ 11
4.13 MANUFACTURER .............................................................................................................. 12
4.14 MEDICAL DEVICE .............................................................................................................. 12
4.15 OPERATOR ........................................................................................................................ 12
4.17 SERIOUS PUBLIC HEALTH THREAT ............................................................................... 13
4.18 TREND REPORTING .......................................................................................................... 13
4.19 UNANTICIPATED ............................................................................................................... 13
4.20 USE ERROR ....................................................................................................................... 13
4.21 USER ................................................................................................................................... 13

5.1.3.1 DEFICIENCY OF A DEVICE FOUND BY THE USER PRIOR TO ITS USE .......... 17
5.1.3.4 PROTECTION AGAINST A FAULT FUNCTIONED CORRECTLY ........................ 18
5.1.3.5 EXPECTED AND FORESEEABLE SIDE EFFECTS .............................................. 19
5.1.4 TREND REPORTS ........................................................................................................... 20
2

5.1.7 TIMESCALE FOR THE INITIAL REPORTING OF AN INCIDENT .................................. 22
5.1.8 TO WHOM TO REPORT .................................................................................................. 22
5.3 INVESTIGATIONS .............................................................................................................. 23
5.3.1 PRINCIPLES..................................................................................................................... 23
5.3.2 ACCESS TO THE DEVICE SUSPECTED TO BE INVOLVED IN THE INCIDENT ......... 23
5.4.1 PRINCIPLES ........................................................................................................................ 23
5.4.2 FOLLOW-UP REPORT .................................................................................................... 24
5.4.3 FINAL REPORT................................................................................................................ 24

6.1 ACTIONS ON A REPORT FROM USERS OR OTHER SYSTEMS ................................... 27
6.3 CO-ORDINATION BETWEEN COMPETENT AUTHORITIES ........................................... 29
AUTHORITIES .................................................................................................................. 30
10.1 ANNEX 1 EXAMPLES OF INCIDENTs AND FIELD SAFETY CORRECTIVE ACTIONS

WHICH THE MANUFACTURER SHOULD REPORT ........................................................ 34
VIGILANCE" ....................................................................................................................... 37
AUTHORITY ........................................................................................................................ 40
10.4 ANNEX 4 REPORT FORM FOR FIELD SAFETY CORRECTIVE ACTION ...................... 45
10.5 ANNEX 5 TEMPLATE FOR A FIELD SAFETY NOTICE ................................................... 48
10.6 ANNEX 6 MANUFACTURER'S PERIODIC SUMMARY REPORT FORM ........................ 50
10.7 ANNEX 7 MANUFACTURER'S TREND REPORT FORM
52
10.8 ANNEX 8 NATIONAL COMPETENT AUTHORITY REPORT FORMAT
56
10.10 ANNEX 10 LIST OF THE USED ABBREVIATIONS .......................................................... 62
10.11 ANNEX 11GUIDANCE TO MANUFACTURERS WHEN INVOLVING USERS IN THE
3
1 FOREWORD
health.
2 INTRODUCTION
1
4
ERROR and ABNORMAL USE are concepts used in this guideline to enhance and clarify the
European Medical Device Vigilance System while promoting harmonisation with GHTF
provisions.
3 SCOPE
MANUFACTURERs2
Notified Bodies
European Economic Area (EEA), Switzerland and Turkey with regard to:
made devices)
2
5

devices which are offered for sale or are in use within the EEA, Switzerland and Turkey.


AUTHORISED REPRESENTATIVEs within the EEA, Switzerland and Turkey, persons
within the EEA, Switzerland and Turkey, persons responsible for placing devices on the
market and any other agents authorised to act on their behalf for purposes relating to
medical devices vigilance, are kept informed of INCIDENT reports as appropriate.
(see section 5.1)

6
3.1.2 FOR MANUFACTURERS OF DEVICES THAT ARE NOT INTENDED TO

ACT DIRECTLY ON THE INDIVIDUAL
Vigilance reporting may be more difficult for medical devices which do not generally come
into contact with patients. For example, for the majority of diagnostic devices, IVDs and
IVF/ART medical devices, due to their intended use, it can be difficult to demonstrate direct
HARM to patients, unless the device itself causes deterioration in state of health. HARM to
patients is more likely to be indirect - a result of action taken or not taken on the basis of an
incorrect result obtained with an IVD, a diagnostic device or as a consequence of the
treatment of cells (e.g. gametes and embryos in the case of IVF/ART devices) or organs
outside of the human body that will later be transferred to a patient. Software qualified as
medical devices may also lead to indirect HARM (incorrect information generated by
software).
Any event which meets all three basic reporting criteria A C listed under section 5.1.1 is
considered an INCIDENT and must be reported to the relevant National Competent
Authority. Where the manufacturer of an IVD, IVF/ART or diagnostic medical device identifies
such an event that has or could result in INDIRECT HARM (as defined in section 4.11) and
that led or might have led to death or serious deterioration in state of health, they should
submit a Manufacturers INCIDENT Report (in accordance with section 5.1.6) to the relevant
Competent Authority.
Any action taken by the manufacturer to reduce a risk of death or serious deterioration in the
state of health associated with the use of a MEDICAL DEVICE that is already placed on the
market should be reported through a Field Safety Corrective Action Report (as defined in
section 5.4.4). Such actions, whether associated with direct or indirect harm, should be
reported.
or could be the consequence of an erroneous result obtained with an IVD or a diagnostic
device, the consequence of an inappropriate treatment of reproductive cells with an IVF/ART
device or the consequence of an error by the USER or third party. In cases of doubt a report
should be submitted (see section 5.1).

7
3.1.4 FOR USERS

MANUFACTURER.
4 DEFINITIONS
4.1 ABNORMAL USE

3
8
4.5 EUDAMED

refused,
data obtained in accordance with the vigilance procedure,
data concerning clinical investigations.

a MEDICAL DEVICE that is already placed on the market. Such actions, whether associated
with direct or indirect harm, should be reported and should be notified via a FIELD SAFETY
NOTICE.
NOTE 1:

- device exchange;
- advice given by MANUFACTURER regarding the use of the device and/or the follow
up of patients, users or others (e.g. where the device is no longer on the market or
9
has been withdrawn but could still possibly be in use e.g. implants or change in
analytical sensitivity or specificity for diagnostic devices).
NOTE 2
A MANUFACTURER can as part of ongoing quality assurance or an investigation at the
manufacturing site identify a failure of a device to perform according to the characteristics
specified in the information for use provided by the MANUFACTURER. If the failure might
lead to or might have led to death or serious deterioration in the state of health associated
with the use of a MEDICAL DEVICE and has an impact on a product that has already been
placed on the market the MANUFACTURER must initiate a FSCA.
Examples of failure modes may include software anomalies (e.g. incorrect correlation
between patient sample and the obtained result), invalid controls, invalid calibrations or
reagent failures (e.g. contamination, transcription errors and reduced stability).
NOTE 3
permanent or temporary changes to the labelling or instructions for use.
For example:
- advice relating to a change in the way the device is used e.g. MANUFACTURER
advises revised quality control procedure such as use of third party controls or more
frequent calibration or modification of control values for the device.
- changes to storage conditions for sample to be used with an IVD
- advice issued to users relating to a change in the stated shelf life of an IVF/ART
device e.g. IVF/ART MANUFACTURER informs users of an error on the labelling of
their device which indicates a shelf life longer than the validated shelf life for the
product.
software upgrades following the identification of a fault in the software version already
in the field. (This should be reported regardless of whether the software update is being
implemented by customers, field service engineers or by remote access)
NOTE 4
Advice given by the manufacturer may include modification to the clinical management of
patients/samples to address a risk of death or serious deterioration in state of health related
specifically to the characteristics of the device.
For example:
- for implantable devices it is often clinically unjustifiable to explant the device.
Corrective action taking the form of special patient follow-up, irrespective of whether
any affected un-implanted devices remain available for return, constitutes FSCA.
- for diagnostic devices (e.g. IVD, imaging equipment or devices), corrective action
taking the form of the recall of patients or patient samples for retesting or the
review of previous results constitutes FSCA.
NOTE 5:
This guideline uses the definition of FSCA as synonym for recall mentioned in article 10(1),
paragraph 1b) of the MDD and Article 11 IVD Directive since there is no harmonised
definition of recall.

10
4.8 HARM
4.9 IMMEDIATELY
justified.
4.10 INCIDENT

4.11 INDIRECT HARM
In the majority of cases, diagnostic devices IVDs and IVF/ART medical devices will, due to
their intended use, not directly lead to physical injury or damage to health of people (HARM
see section 4.8). These devices are more likely to lead to indirect harm rather than to direct
harm. HARM may occur as a consequence of the medical decision, action taken/not taken on
the basis of information or result(s) provided by the device or as a consequence of the
treatment of cells (e.g. gametes and embryos in the case of IVF/ART devices) or organs
outside of the human body that will later be transferred to a patient.
Examples of indirect harm include

misdiagnosis,
delayed diagnosis,
delayed treatment,
absence of treatment
Indirect harm may be caused by

imprecise results
inadequate quality controls
inadequate calibration
false positive or
false negative results.
11
For self-testing devices, a medical decision may be made by the USER of the device who is
also the patient.
4.13 MANUFACTURER
party.
4.14 MEDICAL DEVICE

handicap,
4.15 OPERATOR

is known or an FSCA has been implemented..
12
This would include:

Reference: GHTF SG2 N54
NOTE: Appendix C of GHTF SG2 document N54 '" Global Guidance for Adverse Event
Reporting for Medical Devices" provides useful guidance.
4.19 UNANTICIPATED

4.20 USE ERROR
4.21 USER
DEVICES.

13
INCIDENTs which occurred outside the EEA, Switzerland and Turkey do not lead to a
FIELD SAFETY CORRECTIVE ACTION relevant to these geographic areas do not need to
be reported. Incidents which occurred outside the EEA , Switzerland and Turkey led to a
FIELD SAFETY CORRECTIVE ACTION relevant to the above-mentioned geographical
areas must be reported as a FIELD SAFETY CORRECTIVE ACTION.

If the MANUFACTURER is located outside the EEA, Switzerland and Turkey, a suitable
contact point within should be provided. This may be the MANUFACTURER's AUTHORISED

criteria are that:

b) For IVDs where there is a risk that an erroneous result would either (1) lead to a patient
management decision resulting in an imminent life-threatening situation to the individual
being tested, or to the individuals offspring, or (2) cause death or severe disability to the
individual or fetus being tested, or to the individuals offspring, all false positive or false
negative test results shall be considered as events.
For all other IVDs, false positive or false negative results falling outside the declared
performance of the test shall be considered as events.
14

events.

INCIDENT
take account of:


serious deterioration in state of health of a patient, USER or other person.
A serious deterioration in state of health can include (non exhaustive list):
a) life-threatening illness,
b) permanent impairment of a body function or permanent damage to a body structure,
c) a condition necessitating medical or surgical intervention to prevent a) or b).
Examples: - clinically relevant increase in the duration of a surgical procedure,
existing hospitalisation.
d) any indirect harm (see definition under section 4.11) as a consequence of an
incorrect diagnostic or IVD test result or as a consequence of the use of an IVF/ART
device when used within MANUFACTURERs instructions for use (use errors
reportable under section 5.1.5.1 must also be considered).
e) foetal distress, foetal death or any congenital abnormality or birth defects.
NOTE :
15



authority.
A form for Periodic Summary Reporting is provided in Annex 6 .
Example:

16

system.
Examples:


Examples:

medical expert.
device.
17
Examples:


MANUFACTURER.
Examples:

patient.



USER. An intervention by the user or an immediate remote intervention by the
18
manufacturer allowed the analyser to resume the analysis, resulting in correct

results.


NOTES:
Examples:


19




Example:

5.1.4 TREND REPORTS

excluded from individual reporting as per chapter 5.1.3 a report should be made to the
occurring with their devices.

A form for Trend Reporting is provided in Annex 7 .
20

assessment bodies.

change in pattern (see appendix C of GHTF SG2 N54) of an issue that can potentially
lead to death or serious deterioration in state of health or public health threat)
- or initiates a FSCA to prevent death or serious deterioration in state of health or
SERIOUS PUBLIC HEALTH THREAT


21
REPRESENTATIVE.




22
5.3 INVESTIGATIONS
5.3.1 PRINCIPLES
defined.



INCIDENT
the INCIDENT.
5.4.1 PRINCIPLES
5.4.
23

5.4.3 FINAL REPORT
and of any action.
no action;
FSCA.

included.
FSCA taken on a basis of INCIDENTs occurred outside the EEA, Switzerland and Turkey
24
devices.)
appropriate:
transferred.)
Competent Authority once the FSCA has been completed in both, the EEA, Switzerland and
Turkey. This should include information on the effectiveness of the action per country
involved (e.g., percentage of devices recalled)

Authority.
25
should be offered by the MANUFACTURER to all affected EEA member states, Switzerland
and Turkey.


order number.

implants, IVD
timelines.
transferred.
FSCA.

26
should be omitted.
to the sender.
27
practicable.

example:



USER(s);

no further action;
28
assessment;

AUTHORITY IS NEEDED

INCIDENTs of similar types occurring in more than one country within the EEA,
Switzerland and Turkey;
FSCA conducted in more than one country within the EEA, Switzerland and Turkey,
whether or not a reportable INCIDENT has occurred.
information available on a FSCA conducted outside the EEA, Switzerland and Turkey
where there is uncertainty whether the FSCA affects the member states within the EEA,
Switzerland and Turkey or not, e.g. a Competent Authority Report issued outside EEA
Switzerland and Turkey (for example via the GHTF NCAR Exchange Program) or
information published on a CA website outside the EEA , Switzerland and Turkey.

AUTHORITY

ordination.

AUTHORITY

29
and coordinate with other National Competent Authorities within the EEA, Switzerland
and Turkey;
corrective actions to be taken within the EEA, Switzerland and Turkey ;
countries;
inquiries within the EEA member states, Switzerland and Turkey e.g. with respect to
multiple INCIDENTs in different countries which do not lead to corrective actions at the
latest with the closure of the file; MANUFACTURER will be informed according to section
6.4;
Vigilance System.

AUTHORITIES
Commission when:

30

MANUFACTURER.
The format for dissemination of information between National Competent Authorities and the
Commission is given in Annex 8 and is the GHTF SG2 N79 format with minor changes. The
MANUFACTURER's report may be circulated with the Competent Authority Report. The use
of Eudamed to exchange NCARs is mandatory.
The appropriate "reason for report" should be identified on the National Competent Authority
Report. National Competent Authorities receiving reports should pay particular attention to
the "reason for report" and any "recommendations" given by the National Competent
Authority issuing the report. A number of reports may not require any immediate further
action. Wherever possible, National Competent Authorities should direct enquiries relating to
the investigation arising from the report to the National Competent Authority providing the
notification, who will co-ordinate communication with the MANUFACTURER or Notified Body.



advice.
31



"complete".

and of the results.


32
and USERs.

system,
MANUFACTURER develops with his customer (the USER). Annex 11 details some key
areas that the MANUFACTURER should promote with the USER. These areas may also be
33
ANNEXES
10.1 ANNEX 1- EXAMPLES OF INCIDENTS AND FIELD SAFETY

CORRECTIVE ACTIONS WHICH THE MANUFACTURER SHOULD
REPORT
EXAMPLES OF REPORTABLE INCIDENTS
serious deterioration in state of health is not normally expected. The INCIDENT should be
reported.
have caused a serious deterioration in state of health. The INCIDENT should be reported.
inappropriate handling was due to inadequacies in the labelling. The INCIDENT should be
reported.

The INCIDENT should be reported.
7. Glass particles are found by the user in a contact lens vial. The INCIDENT should be
reported.
did not show up in due time, although it should have according to device specification. The
10. The premature revision of an orthopaedic implant is required due to loosening. Although
34
11. User discovers that insufficient details are provided on cleaning methods for reusable
surgical instruments used in brain surgery, despite obvious risk of transmission of CJD. The

instructions, but the readings provide incorrect values leading to incorrect insulin dosage.
This INCIDENT should be reported.
13 A customer reports a wrong assignment of analytical results to patient codes by an

automated analyzer. An evaluation could reproduce the effect and indicated that a data
mismatch could occur. Due to the data mismatch a patient may obtain a wrong diagnosis /
treatment. This INCIDENT should be reported.
lead to wrong treatment of the patient this incident should be reported.
15. A user discovers that an IVF culture medium is contaminated resulting in degeneration of
the cells. This INCIDENT should be reported.
EXAMPLES OF REPORTABLE FSCA.

of a serious deterioration in state of health is not remote. The FSCA should be reported.
16. Fatigue testing performed on a commercialised heart valve bio prosthesis demonstrates
premature failure, which resulted in a risk to public health. The FSCA should be reported.
MANUFACTURER initiates a FSCA of this batch. This should be reported as an FSCA.
treatment of the patient. The MANUFACTURER issues information to the field that a reduced
onboard stability has to be taken into account. The FSCA should be reported.
19. A MANUFACTURER has noticed that starting from control lot XX a lower recovery is
obtained and re-assigns the control value. Users are informed of this new value by means of
warning stickers and a customer communication. The FSCA should be reported.
20. A MANUFACTURER of an immunohematology analyzer received complaints of an ABO

blood grouping system results being attributed to the wrong patient identification. The error
proved to be due to the analyzers software, which was subsequently updated. The FSCA
should be reported.
35
21. IVF/ART MANUFACTURER informs users of an error on the labelling of their device
which indicates a shelf life longer than the validated shelf life for the product. The FSCA
should be reported.
36
10.2 ANNEX 2- EXTRACTS FROM DIRECTIVES RELATING TO "MEDICAL

DEVICES VIGILANCE"

A. Article 8
Extracts :


necessary steps to ensure that the manufacturer of the device concerned, or his authorised
representative, is also informed of the incident.
3. After carrying out an assessment, if possible together with the manufacturer or his
authorised representative, Member States shall, without prejudice to Article 7, immediately
inform the Commission and the other Member States of measures that have been taken or
are contemplated to minimise the recurrence of the incidents referred to in
paragraph 1, including information on the underlying incidents.
Extracts :



37
A. Article 10: Information on incidents occurring following placing of devices on the

market
Extracts :


Extracts :


of health;


DEVICES
38


B. Annex III
Extracts :


39
10.3 ANNEX 3 - REPORT FORM FOR MANUFACTURERS TO THE NATIONAL

COMPETENT AUTHORITY
v.01.13
Report Form
Date of this report
Type of report
Initial report
Follow-up report
Final report
Yes
No
Death
Unanticipated serious deterioration in state of health

Status of submitter
Manufacturer
40
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
6. Medical device information

Class

IVD Annex II List A
MDD Class I
Nomenclature text
41
Duration of implantation (to be filled is the exact implant or explant dates are unknown)
7. Incident information

other

other (please specify)
8. Patient information
Patient outcome
42
Female Male
9. Healthcare facility information

Address
Postcode City
Phone Fax
E-mail Country
10. Manufacturers preliminary comments (Initial/Follow-up report)

11. Results of manufacturers final investigation (Final report)

Yes No
43
SK TR
HR
Others:
12. Comments
person.
Name City date
44
10.4 ANNEX 4 - REPORT FORM FOR FIELD SAFETY CORRECTIVE ACTION
Report Form
v.01.13
Type of report
Initial report
Follow up report
Final report
Date of this report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
45
Postcode City
Phone Fax
E-mail Country

Address
Postal code City
Phone Fax
E-mail Country

Class

IVD Annex II List A
MDD Class I
Nomenclature text
46

Draft
SK TR
HR
Others:
8 Comments
Signature
Name City Date
47
10.5 ANNEX 5 - Template for a Field Safety Notice
---------------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------------
Date:
Attention: ///////////////

number.


timelines.
appropriate)
appropriate)
48
(Closing paragraph)
Signature
49
10.6 ANNEX 6 - Manufacturers PERIODIC SUMMARY REPORT FORM

Report Form
v. 01.13
Date of this report
Type of report
Initial report
Final report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
Postcode City
Phone Fax
50
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
Class
MDD Class I
Nomenclature text
51
7. PSR Information
PSR Type:



9. Distribution
52

SK TR
HR
Others:
10. Comments
person.
Name City date
53
10.7 ANNEX 7- MANUFACTURERS TREND REPORT FORM
Report Form
v. 01.13
Date of this report
Type of report
Trend Initial
Trend Follow up
Trend Final

Yes
No

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
54
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Class
MDD Class I
Nomenclature text
55
Yes No


SK TR
HR
Others:
11. Comments
56
person.
Name City date
57
10.8 ANNEX 8 - NATIONAL COMPETENT AUTHORITY REPORT FORMAT

v.01.13
NATIONAL COMPETENT AUTHORITY REPORT

This form should be used for the exchange of medical device information
between NCAR participants only. Completed forms should not be released to
the public.

The form should be completed in English
The NCAR participant filling in and sending the NCAR is responsible for the quality of the content as
well as the appropriateness of sending such a message and the scope of its distribution. Guidance on
which issues should be selected for exchange between NCAR participants is given in Section 5
above. Before releasing any information, careful note should be taken of the SG2 N8 (Guidance on
How to Handle Information Concerning Vigilance Reporting Related to Medical Devices).
58
This form should be completed by NCAR participants only, when exchanging safety information about
relevant measures and/or recommendations relating to the prevention of adverse incidents concerning
medical devices. This form is designed for exchanging information between NCAR participants; it
should not be passed directly on to patients, users, third persons or the public instead, if there is a
need to communicate to this audience another form of notice should be used. It is not to be used for
advising of single incidents, unless those incidents have a clear implication for public health. In such
cases, the implied recommendation is for other NCAs to be aware and take such local actions they
find appropriate.
If the NCAR report concerns a specific manufacturers device, then the manufacturer or authorized
representative should be consulted about the NCARs content and distribution prior to it being sent
preferably by providing a copy for the manufacturer or authorized representative to comment on. This
will help to ensure the accuracy of the NCAR. An appropriate time frame for receiving manufacturers
comments should be communicated. However, this process should not be allowed to cause
unnecessary delay. If an NCAR concerns a range of devices from different manufacturers then the
NCA should make efforts to contact and obtain comment from all relevant manufacturers or authorized
representatives known to be on their markets.
There are differing reporting obligations for various NCAR participants. In general, NCAR participants
shall send reports directly to the NCAR Secretariat for appropriate global distribution. The NCAR
secretariat will include the originator of the NCA report as confirmation of distribution.
The EEA States must exchange reports with each other in accordance with current European
Directives for medical device. They should also send the report to the NCAR Secretariat for further
distribution to all other (non EEA) NCAR participants. There are instances where reports are sent only
to EEA participants of the NCAR program. This may cause a discontinuity in the numbering of reports
received from EEA participants. When an NCAR is not to be distributed to all NCAR participants a note
of this should be made on the next NCAR that is issued by the originating NCA to all NCAR
participants (see Notes on Field 26b).
On the rare occasions-when there are time critical issues of significant public health threat or concern-
in addition to sending the report to the NCAR Secretariat, NCAs may send reports directly to countries
participating in the NCAR exchange who are known to have the subject device in national distribution.
In such circumstances, the issuing NCA should ensure that the form is completed fully and contains the
correct sequential reference, preferably by contacting the NCAR Secretariat.
Field:
1- Please be sure to check Yes or No for confidentiality. This tells the recipient NCA if the
2- Use the rules for numbering NCARs,(* use the ISO 3166 for country codes) which
incorporates a two-letter code of the issuing country to fill in this item. For example: CA-2004-
10-19-004 is a report from Canada sent 19 October 2004 and is the 4th report for 2004. Each
NCAR should be given a new, unique NCAR number. If an NCAR relates to a previously
exchanged NCAR (i.e : is an update), the original NCAR number should be specified in field 4.
3 - Insert any local reference number used by your NCA relevant to this report, here.
4- If there have been previous NCARs exchanged relating to this one, regardless of source,
5 - Insert the manufacturers reference/recall number here, if applicable.
6- Identify person and organization sending the NCAR. This should be the single point of contact,
previously identified to the NCAR Secretariat.
7- Identify contact person for any information / technical discussion of the topic.
8-10 - Telephone, Fax and e-mail of person in (7) above.
59

12 - Identify the nomenclature system used (e.g. GMDN Global medicaldevice nomenclature, etc) .
13 - Number or code to identify the device based on the nomenclature system identified in (12).
15 - Self Explanatory 16-17 If there are many lot/batch numbers or serial numbers (ie: more than 3
or 4), a detailed list should be appended to the bottom of the report.
18 - Manufacturer of device - full address, including country, fax, phone numbers and e-mail.
placing the subject device on the market where the incidents occurred), full address, including
country, fax, phone numbers and e-mail.
20 - Indicate name or code number of Conformity Assessment Body/Notified Body involved, if
applicable.
21 - a.) Identify approval status of the device in the region where the report originates. For
example: CE-marking, approval number or licence number
b.) Device risk class according to the jurisdiction of the issuing NCA can also be included.
22 - Identify any regulatory, legal or company-initiated action taken in advance of sending out the
report. This could, for instance, refer to a Recall or the use of Safeguard action.
23a - .Provide a description of what has happened, including consequences to patients or users. With
reference to the criteria for reporting (SECTION 5 ABOVE), describe the reason for the report
and why you want to inform other NCAs about these events. Such information will lead to a
better understanding by the recipient on what is considered to be appropriate follow-up.

24a - Describe the outcome or conclusion of the investigation, to date. If useful, include a copy of
any manufacturer or NCA advisory notice(s) associated with the NCAR and make reference to
them within the NCAR.
24b - Indicate whether the manufacturers actions have been made public.
24c - Indicate whether originating NCA is willing to take the lead in co-ordination of the investigation.
25a - Recommendations to receivers of this report.
25b - List all countries known to have received the device. Put considerable care and effort into
obtaining accurate information from the manufacturer for this field.
26a - Indicate to whom the report has been sent. Care should be taken to indicate the correct
distribution for the NCAR. Confidential NCARs should only be sent via the NCAR Secretariat
to full NCAR participants not all NCAR participants. EEA European Economic Area , EC
European commission and EFTA European federation trade associates NCAR participants
should indicate direct distribution of the NCAR to EEA states, EC and EFTA NCAs in
accordance European Medical Device Directives. NCAs outside the exchange program that
are being sent the NCAR by the originating NCAR participant should also be listed.
26b - Where NCAR report numbers are not sequential, participants should include the number of
the last report issued to all NCAR participants
Form N79R11 can be downloaded as well from: http://www.imdrf.org/documents/doc-ghtf-sg2.asp
60
10.9 ANNEX 9 - TITLES OF GLOBAL HARMONISATION TASK FORCE

STUDY GROUP 2 DOCUMENTS USED IN THE DEVELOPMENT OF THIS
MEDDEV AND/OR CITED
SG2-N8 Guidance on How to Handle Information Concerning Vigilance Reporting

SG2-N79 Medical Devices: Post Market Surveillance: National Competent Authority
Exchange Criteria and Report Form.
SG2-N54 Global Guidance for Adverse Event Reporting for Medical Devices :
NOTE: All these documents can be downloaded from http://www.imdrf.org/documents/doc-

ghtf-sg2.asp
61
10.10 ANNEX 10- LIST OF THE USED ABBREVIATIONS
AIMD Active Implantable Medical Devices Directive
MDD Medical Devices Directive
NB Notified Body
62
10.11 ANNEX 11- GUIDANCE TO MANUFACTURERS WHEN INVOLVING

USERS IN THE VIGILANCE SYSTEM
Reporting Guidance
guidance.
needed.
actions outlined.
63
64
How to use the Manufacturer Incident Report (MIR) Form
1. Acrobat version: Use the Acrobat Reader or Acrobat Professional

version 9 or higher.
2. Identification of the type of report: Mandatory field depending on the

type of report (Initial, Follow-up or Final Report) can be identified by
hitting the button Highlight Fields in the right upper corner of the
Reader.
3. When the author of the report is the manufacturer or the authorised

representative (identified via the radio buttons in section 2), the
information from section 3 or 4 will be copied line by line into section
6.
4. The option to produce templates is implemented. Fill all areas of

interest (usually administrative data) and store the template under an
individual name.
5. By hitting the button new next to the headline in sections 2-6 and 9,
all data of the specific sections will be deleted.
6. Date format is YYYY-MM-DD.
7. Hitting the button send xml-data per Email:

9 checks that all mandatory data are filled,
9 produces the xml file containing all entered data
9 and opens the local E-mail client.
The xml file is attached and the mail is ready to be sent. The body of
the email may be modified. Recipients may be added or deleted .
PLEASE DO NOT CHANGE THE ATTACHED XML FILE.
8. The form is locked once the button send XML by Email is hit. Store
the copy in your file system and add it to the email.
Sending the xml file is sufficient as the information will be loaded back
into the form.
V 03/03/2011
import XML fix + save
Report Form
Manufacturer's Incident Report
fill with test data Initial Medical Devices Vigilance System
fill with test data I+F (MEDDEV 2.12/1 rev 7)
fill with test data Follow Up
fill with test data Final new case, keep base data
Version 2.26en
2012-12-04
Recipient (Name of NCA) Stamp box
Date of this report
Type of report
Initial report
Follow-up report
Final report
yes
no
Death
Unanticipated Serious Deterioration in State of Health
Status of submitter
Manufacturer
Authorised Representative within EEA and Switzerland and Turkey
3 Manufacturer information new
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
AT - Austria
4 Authorised Representative Information new
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
AT - Austria
5 Submitters information new
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
AT - Austria
6 Medical device information new
Class

GMDN
Nomenclature text
Duration of Implantation (For implants only. To be filled if the exact implant and explant dates are unknown)
7 Incident Information
0 1
Healthcare Professional
Patient
Other
initial use
reuse of a single use medical device
reuse of a reusable medical device
re-serviced/refurbished
other
Patient outcome
Female Male
Age of the patient at the time of incident, if applicable units
Years months days
9 Healthcare facility information new
Address
Postcode City
Phone Fax
E-mail Country
AT - Austria
Manufacturer's preliminary analysis
Yes No
0
For final reports only. The medical device has been distributed to the following countries:
within the EEA and Switzerland and Turkey
AT BE BG CH CY CZ DE DK
EE ES FI FR GB GR HU IE
IS IT LI LT LU LV MT NL
NO PL PT RO SE SI SK TR
Candidate Countries
HR
All EEA, candidate countries and Switzerland and Turkey
Others:
12 Comments
contributed to the alleged death or deterioration in the state of the health of any person.
Signature
print check send XML-data by E-Mail
import XML fix + save
Report Form
fill with test data #1
new case, keep base data Version 2.7en
2012-12-03
Type of report
Initial report
Follow-up report
Final report
Date of this report
Name of the co-ordinating NCACompetent Authority (if applicable)
Status of submitter
Manufacturer
Authorised Representative within EEA and Switzerland
3 Manufacturer information new
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
DE - Germany
4 Authorised Representative Information new
Name
Contact Name
Address
Postcode City
Phone Fax
E-mail Country
DE - Germany
5 National contact point information new
Address
Postcode City
Phone Fax
E-mail Country
DE - Germany
6 Medical device information new
Class

GMDN
Nomenclature text
Serial number(s) Lot/batch number(s)

7 Description of the FSCA
Description and justification of the action (corrective / preventive)

Field Safety Notice (FSN) in English Draft FSN
FSN in national language Final FSN
Others (please specify)
The medical device has been distributed to the following countries:
within the EEA and Switzerland
AT BE BG CH CY CZ DE DK
EE ES FI FR GB GR HU IE
IS IT LI LT LU LV MT NL
NO PL PT RO SE SI SK TR
Candidate Countries
HR
All EEA, candidate countries and Switzerland
Others:
8 Comments
contributed to the alleged death or deterioration in the state of the health of any person.
Signature
print check send XML-data by E-Mail
Report Form

v.12/11
Date of this report
Type of report
Trend Initial
Trend Follow up
Trend Final

Yes
No

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
1
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Class
MDD Class I
Nomenclature text
2

Yes No


SK TR
HR
Others:
11. Comments
3
person.
Name City date
4
v.12/11
Date of this report
Type of report
Initial report
Final report

Status of submitter
Manufacturer
Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

Name
Contact name
Address
Postcode City
Phone Fax
E-mail Country

1
Submitters name
Contact name
Address
Postcode City
Phone Fax
E-mail Country
Class
MDD Class I
Nomenclature text
2
7. PSR Information
PSR Type:



9. Distribution
3
SK TR
HR
Others:
10. Comments
person.
Name City date
4
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
MEDDEV 2.12-2
May 2004
GUIDELINES
ON POST MARKET CLINICAL FOLLOW-UP
The present Guidelines are part of a set of Guidelines relating to questions of application
of EC-Directives on medical devices. They are legally not binding. The Guidelines have
been carefully drafted through a process of intensive consultation of the various
interested parties (competent authorities, Commission services, industries, other
interested parties) during which intermediate drafts were circulated and comments were
taken up in the document. Therefore, this document reflects positions taken by
representatives of interested parties in the medical devices sector.
Page 1
CEC CLINICAL EVALUATION TASK FORCE. May 18, 2004
POST MARKET CLINICAL FOLLOW-UP OF

MEDICAL DEVICES UNDER
THE MEDICAL DEVICES DIRECTIVES
Foreword : Rationale and Goals of PMCF
This document is intended to be a guide for manufacturers and notified bodies on how to
carry out PMCF in order to fulfill post market surveillance obligation according to point 3.
1 of annex II, point 3. of annex IV, point 3 of annex V, point 3.1 of annex VI or point 4 of
annex VII of medical device directive (add ref. AIMDD)
While clinical evidence is an essential element of the premarket conformity assessment

process, it is important to recognize the limitations inherent to these premarket clinical
investigations. The extent of the data that can be gathered in the premarket phase does
not enable the manufacturer to detect infrequent complications or problems only
apparent after widespread use, or /long term performance issues. As part of the
manufacturers quality system, a program of appropriate post market surveillance is key
to identifying and investigating risks associated with the use of medical devices placed
on the market.
Manufacturers should have general systems in place to cover PMS as well as having a
defined PMS strategy for each of their products/product ranges
Therefore, PMCF appears as a method of choice for this purpose. It will, for instance,
enable patients' access to new therapies while establishing a review process for long
term safety follow-up and detection of possible emergent risks that cannot be adequately
detected by relying solely on pre-market clinical investigations (given the relatively short
follow up required) or product experience /vigilance.
Implementation
Post market surveillance may include a number of strategies in addition to complaint
handling and vigilance :
active supervision by customer surveys,

inquiries of users and patients,
literature reviews,
Post market Clinical Follow-up, etc..
Post market clinical follow-up (PMCF) through clinical studies and registries has a great
importance among these strategies.
Post Market Clinical Follow-up (PMCF) should always be considered for devices where
identification of possible emerging risks and the evaluation of long term safety and
performance are critical. In identifying such emerging risk, the following criteria should
be taken into account :
Page 2
innovation, when the design of the device, the material, the principles of
operation, the technology, or the medical indication is new
severity of the disease,
sensitive target population
risky anatomical location
well known risk from the literature
well known risk of similar marketed devices
Identification of an acceptable risk during pre-CE clinical evaluation, which
should be monitored in a longer term and/or through a larger population.
Obvious discrepancy between the premarket follow up timescales and the
expected life of the product
All PMCF should be planned. The PMCF plan can take the form of extended follow-up of
patients enrolled in the pre-market trials, and / or a prospective study of a representative
subset of patients after the device is placed on the market. It can also take the form of
open registries. This plan will need to take into account :
Results of the clinical investigation including Adverse events identified

Average life expectancy of the device
The claims made by the manufacturer for the device
Performances for which equivalence is claimed
New information becoming available
PMCF, when carried out, must always be performed for the use of the product within its
intended indications according to Instructions for use. National regulations on post
market clinical studies must be taken into account.
The involved Notified Body should review the appropriateness of the manufacturer's
general PMS procedures, incorporating PMCF, as relevant, as well their PMCF plan(s)
and results for specific products as part of conformity assessment procedures and
quality management system auditing
The follow up duration should take into account the average life expectancy of the
product in its indication. Therefore, in case of a device subject to short term premarket
follow up and intended to stay in the patient for its lifetime, a longer follow up will be
required.
PMCF will not be required for products for which the long term clinical performance and
safety is already known from previous use of the device. In the case the assessment of a
product is performed through the concept of equivalence , PMCF should always be
considered .
Post Market clinical Requirements (Risk based matrix)
The following table sets out a triage approach and suggests general advice for the
evaluation of products under different circumstances.
Notified bodies should be part of the decision making with the manufacturer if applicable.
Page 3
PMCF Product specificities Required actions
no PMCF Products for which the All received complaints and adverse events data shall be
medium/long term clinical systematically reviewed, and all product related adverse
performance and safety is events such as those described in Annex II 3.1 of the
already known from MDD must be notified to the relevant Competent
previous use of the device Authority (ies). This includes all sources of information
, or from fully transferable known by the manufacturer, including published
experience with equivalent literature.
devices (except **)
Monitoring of postmarket performance should take into
account relevant data publicly available with similar
devices especially when the CE marking was based on
equivalence.
PMCF Always considered for

devices where Same as above ,
identification of possible Plus
emerging risks and the
evaluation of long term Post-Market Clinical Follow-up (PMCF) in the form of
safety and performance follow up of all or a justifiable subset of patients already
are critical enrolled in pre-marketing Clinical Investigations; or on
specific sub-groups and/or prospective study or registry
of a sample of products. A formal protocol should
describe the duration of PMCF; identify patient
(**)Products quoted as population and data to be collected.
"equivalent" devices where
reference product is (NOTE: The manufacturer must justify the design,
subjected to PMCF nature, and duration of post-marketing follow-up, having
regard to any published standards)
PMCF report to be provided to the relevant NB for
review and to competent authority if requested.
*Equivalence has been precisely defined and should be demonstrated according

to the criteria described in the document Evaluation of clinical data: A guide for
manufacturers and notified bodies (see annex 1 of this document).
Page 4
ANNEX 1 : The Demonstration of equivalence
From MEDDEV.2.7.1 : guidelines on medical devices Evaluation of clinical data : a guide

for manufacturers and notified bodies -Section 4.3.1 d)relevance of data
The manufacturer must demonstrate equivalence in all the following essential

characteristics with the device, which is the subject of the published reports.
Equivalence means :
Clinical:
-used for the same clinical condition or purpose;
-used at the same site in the body;
-used in similar population (including age, anatomy, physiology);
-have similar relevant critical performance according to expected
clinical effect for specific intended use.
Technical:
-used under similar conditions of use;
-have similar specifications and properties (e.g. tensile strength,
viscosity, surface characteristics)
-be of similar design;
-use similar deployment methods (if relevant);
-have similar principles of operation
Biological:
-use same materials in contact with the same human tissues or
body fluids;
To be equivalent, the devices should have similarity with regard to the clinical,
technical and biological parameters with special attention to the performance,
principles of operation and materials; or if there are differences identified, an
assessment and demonstration of the significance these might have on safety
and performance must be documented.
For example, where the device under consideration and the device referred to in
the published study has a new principle of operation, then the two devices cannot
be considered equivalent. A new mechanism and action does not necessarily
result in a new clinical benefit and therefore a specifically designed clinical
investigation will be needed to provide data to demonstrate (or otherwise) the
clinical benefit of the new device
Page 5
EUROPEAN COMMISSION
Consumer Affairs
MEDDEV 2.12/2 rev2
January 2012
POST MARKET CLINICAL FOLLOW-UP STUDIES
Note

application of EC-Directives on medical Devices. They are legally not binding. The
Guidelines have been carefully drafted through a process of intensive consultation of
the various interest parties (competent authorities, Commission services, industries,
other interested parties) during which intermediate drafts where circulated and
comments were taken up in the document. Therefore, this document reflects positions
1 CONTENTS
2
3
4
5 1. Introduction ................................................................................................................................ 3
6 2. Scope .......................................................................................................................................... 4
7 3. References .................................................................................................................................. 4
8 4. Definitions.................................................................................................................................. 6
9 5. Circumstances where a post market clinical follow up study in indicated ................................. 8
10 6. Elements of a post-market clinical follow up study................................................................. 10
11 7. The use of study data ................................................................................................................ 12
12 8 The role of the notified body in post-market clinical follow up .............................................. 12
13
14
15 Preface
16 This document is intended to be a guide for manufacturers and Notified Bodies on

17 how to carry out Post-Market Clinical Follow-up (PMCF) studies in order to fulfil
18 Post-Market Surveillance (PMS) obligations according to Section 3.1 of Annex II,
19 Section 3 of Annex IV, Section 3 of Annex V, Section 3.1 of Annex VI or Section 4
20 of Annex VII of the Medical Devices Directive (93/42/EEC) and Section 3.1 of
21 Annex 2, Section 3 of Annex 4, Section 3.1 of Annex 5 of the Active Implantable
22 Medical Devices Directive (90/385/EEC). These Sections refer to requirements of
23 Annex X of Directive 93/42/EEC and Annex 7 of Directive 90/385/EEC, respectively.
24
25 Attention is drawn to paragraph 8 of Article 15 of Directive 93/42/EEC which spells
26 out the provisions of Article 15 that are not applicable to clinical investigations
27 conducted using CE-marked devices within their intended use.
28 Similarly when PMCF studies are conducted using CE marked devices within their
29 intended use, the provisions of section 2.3.5 of Annex X of Directive 93/42/EEC do
30 not apply. However, the provisions of Directive 93/42/EEC concerning information
31 and notification of incidents occurring following placing devices on the market are
32 fully applicable.
.
33 1. Introduction
34
35 While clinical evidence is an essential element of the premarket conformity

36 assessment process to demonstrate conformity to Essential Requirements, it is
37 important to recognise that there may be limitations to the clinical data available in
38 the pre-market phase. Such limitations may be due to the duration of pre-market
39 clinical investigations, the number of subjects and investigators involved in an
40 investigation, the relative heterogeneity of subjects and investigators and/or the
41 controlled setting of a clinical investigation versus the full range of clinical conditions
42 encountered in general medical practice.
43
44 A precondition for placing a product on the market is that conformity to the relevant
45 Essential Requirements, including a favourable benefit/risk ratio, has been
46 demonstrated. The extent of the data that can be gathered in the pre-market phase
47 does not necessarily enable the manufacturer to detect rare complications or problems
48 that only become apparent after wide-spread or long term use of the device. As part of
49 the manufacturers quality system, an appropriate post-market surveillance plan is key
50 to identifying and investigating residual risks associated with the use of medical
51 devices placed on the market. These residual risks should be investigated and assessed
52 in the post-market phase through systematic Post-Market Clinical Follow-up (PMCF)
53 study(ies).
54
55 Clinical data obtained from post-market surveillance and during PMCF studies by the
56 manufacturer are not intended to replace the pre-market data necessary to demonstrate
57 conformity with the provisions of the legislation. However, they are critical to update
58 the clinical evaluation throughout the life-cycle of the medical device and to ensure
59 the long term safety and performance of devices after their placing on the market.
60
61 PMCF studies are one of several options available in post-market surveillance and
62 contribute to the risk management process.
63
64
65
66
67 2. Scope
68
69 The objective of this document is to provide guidance on the appropriate use and
70 conduct of PMCF studies to address issues linked to residual risks. The intention is
71 not to impose new regulatory requirements.
72
73 PMCF studies are an important element to be considered in PMCF or PMS plans. The
74 principles for PMCF studies set out in this guidance are not intended to replace PMCF
75 or PMS plans. They are or may be applicable to PMCF studies conducted for other
76 purposes.
77
78 This document provides guidance in relation to:

79 i) the circumstances where a PMCF study is indicated;
80 ii) the general principles of PMCF studies involving medical devices;
81 iii) the use of study data (for example to update instructions for use and labelling);
82 and
83 iv) the role of a notified body for medical devices in the assessment of PMCF plans
84 and of the results obtained from the plans as part of conformity assessment.
85
86 This document does not apply to in vitro diagnostic devices.

87
88 3. References
89
90 Council Directive 93/42/EEC of 14 June 1993 concerning medical devices as last
91 amended by Directive 2007/47/EC of the European Parliament and of the Council of
92 5 September 2007.
93
94 Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of
95 the Member States relating to active implantable medical devices last amended by
96 Directive 2007/47/EC of the European Parliament and of the Council of 5 September
97 2007.
98
99
100
101 Interpretative Documents
102
103 MEDDEV 2.7.1 Clinical Evaluation: A Guide for Manufacturers and Notified
104 Bodies
105
106 MEDDEV 2.7.1, Appendix 1
107 Evaluation of Clinical Data A Guide for Manufacturers and
108 Notified Bodies Appendix 1: Clinical Evaluation of Coronary
109 Stents
110
111
112 GHTF Final Documents:

113 SG1/N41:2005 Essential Principles of Safety & Performance of Medical Devices
114 SG1/N44:2008 The Role of Standards in the Assessment of Medical Devices
115 SG1/N065:2010 Registration of Manufacturers and Other Parties and Listing of
116 Medical Devices
117 SG2/N47:2005 Review of Current Requirements on Post-Market Surveillance
118 SG5/N1:2007 Clinical Evidence Key Definitions and Concepts
119 SG5/N2:2007 Clinical Evaluation
120 SG5/N3:2010 Clinical Investigations
121
122
123 International Standards:

124 EN ISO 14155:2011 Clinical investigation of Medical Devices for human subjects
125 Good clinical practice; Second edition 2011-02-01
126
127 EN ISO 14971:2009 Application of risk management to medical devices

128
129 Others:
130 US Department of Health and Human Service, Agency for Healthcare Research
131 and Quality:
132 Registries for Evaluating Patient Outcomes: a Users Guide (Executive
133 Summary, April 2007).
134
135
136
137
138 4. Definitions
139
140
141 Clinical Data1:
142 The safety and/or performance information that is generated from the use of a
143 device.
144 Clinical data are sourced from:
145 - clinical investigation(s) of the device concerned; or
146 - clinical investigation(s) or other studies reported in the scientific literature
147 of a similar device for which equivalence to the device in question can be
148 demonstrated; or
149 - published and/or unpublished reports on other clinical experience of either
150 the device in question or a similar device for which equivalence to the
151 device in question can be demonstrated.
152
153 Clinical Evaluation2:

154 The assessment and analysis of clinical data pertaining to a medical device to
155 verify the clinical safety and performance of the device when used as intended
156 by the manufacturer.
157
158 Clinical Evidence2:

159 The clinical data and the clinical evaluation report pertaining to a medical
160 device.
161
162 Clinical Investigation2:

163 Any systematic investigation or study in or on one or more human subjects,
164 undertaken to assess the safety or performance of a medical device.
165
166 Device Registry3:

167 An organised system that uses observational study methods to collect defined
168 clinical data under normal conditions of use relating to one or more devices to
1
Council Directives 90/385/EEC and 93/42/EEC
2
GHTF document SG5/N1R8: 2007: Clinical Evidence Key Definitions and Concepts
3
GHTF document SG5/N4:2010: Post Market Clinical Follow-Up Studies, based on the definition in
Agency for Healthcare Research and Quality, Registries for Evaluating Patient Outcomes: A Users
Guide, as modified.
169 evaluate specified outcomes for a population defined by a particular disease,
170 condition, or exposure and that serves predetermined scientific, clinical or
171 policy purpose(s).
172
173 Note: The term device registry as defined in this guidance should not be
174 confused with the concept of device registration and listing. (See GHTF
175 SG1N065)
176
177 Post-market clinical follow-up (PMCF) study:

178 A study carried out following the CE marking of a device and intended to
179 answer specific questions relating to clinical safety or performance (i.e. residual
180 risks) of a device when used in accordance with its approved labelling.
181
182 PMCF plan:
183 The documented, proactive, organised methods and procedures set up by the
184 manufacturer to collect clinical data based on the use of a CE-marked device
185 corresponding to a particular design dossier or on the use of a group of medical
186 devices belonging to the same subcategory or generic device group as defined
187 in Directive 93/42/EEC. The objective is to confirm clinical performance and
188 safety throughout the expected lifetime of the medical device, the acceptability
189 of identified risks and to detect emerging risks on the basis of factual evidence.
190
191 Residual Risk:

192 Risk remaining after risk control measures has been taken4 .
193
4
EN ISO 14971
194
195 5. Circumstances where a PMCF study is indicated

196
197 Following a proper premarket clinical evaluation, the decision to conduct PMCF
198 studies must be based on the identification of possible residual risks and/or unclarity
199 on long term clinical performance that may impact the benefit/risk ratio.
200
201 PMCF studies may review issues such as long-term performance and/or safety, the
202 occurrence of clinical events (e.g. delayed hypersensitivity reactions, thrombosis),
203 events specific to defined patient populations, or the performance and/or safety of the
204 device in a more representative population of users and patients.
205
206 Circumstances that may justify PMCF studies include, for example:
207 innovation, e.g., where the design of the device, the materials, substances,
208 the principles of operation, the technology or the medical indications are
209 novel;
210 significant changes to the products or to its intended use for which pre-
211 market clinical evaluation and re-certification has been completed;
212 high product related risk e.g. based on design, materials, components,
213 invasiveness, clinical procedures;
214 high risk anatomical locations;
215 high risk target populations e.g. paediatrics, elderly;
216 severity of disease/treatment challenges;
217 questions of ability to generalise clinical investigation results;
218 unanswered questions of long-term safety and performance;
219 results from any previous clinical investigation, including adverse events
220 or from post-market surveillance activities;
221 identification of previously unstudied subpopulations which may show
222 different benefit/risk-ratio e.g. hip implants in different ethnic
223 populations;
224 continued validation in cases of discrepancy between reasonable
225 premarket follow-up time scales and the expected life of the product;
226 risks identified from the literature or other data sources for similar
227 marketed devices;
228 interaction with other medical products or treatments;
229 verification of safety and performance of device when exposed to a larger
230 and more varied population of clinical users;
231 emergence of new information on safety or performance;
232 where CE marking was based on equivalence.
233
234 PMCF studies may not be required when the medium/long-term safety and clinical
235 performance are already known from previous use of the device or where other
236 appropriate post-market surveillance activities would provide sufficient data to
237 address the risks.
238
239
240
241
242
243 6. Elements of a PMCF study

244
245 Post-market clinical follow-up studies are performed on a device within its intended
246 use/purpose(s) according to the instructions for use. It is important to note that PMCF
247 studies must be conducted according to applicable laws and regulations and should
248 involve an appropriate methodology and follow appropriate guidance and standards.
249
250 PMCF studies must be outlined as a well designed clinical investigation plan or study
251 plan, and, as appropriate, include:
252 clearly stated research question(s), objective(s) and related endpoints;
253 scientifically sound design with an appropriate rationale and statistical analysis
254 plan;
255 a plan for conduct according to the appropriate standard(s);
256 a plan for an analysis of the data and for drawing appropriate conclusion(s).
257
258 Objectives of PMCF studies

259 The objective(s) of the study should be stated clearly and should address the residual
260 risk(s) identified and be formulated to address one or more specific questions relating
261 to the clinical safety or clinical performance of the device. A formal hypothesis
262 should be clearly expressed.
263
264 Design of PMCF studies

265 PMCF studies should be designed to address the objective(s) of the study. The design
266 may vary based on the objective(s), study hypothesis research question and endpoints
267 and should be scientifically sound to allow for valid conclusions to be drawn.
268
269 PMCF studies can follow several methodologies, for example:

270 the extended follow-up of patients enrolled in premarket investigations;
271 a new clinical investigation;
272 a review of data derived from a device registry; or
273 a review of relevant retrospective data from patients previously exposed to
274 the device.
275
276 PMCF studies should have a plan describing the design and methodologies
277 appropriate for addressing the stated objectives. The clinical investigation plan/study
278 plan should identify and where needed justify at a minimum:
279 the study population (corresponding to the CE-mark scope);
280 inclusion/exclusion criteria;
281 rational and justification of the chosen study design including use of
282 controls/control groups (where relevant; randomised or not);
283 the selection of sites and investigators;
284 study objectives and related study endpoints and statistical considerations;
285 the number of subjects involved;
286 the duration of patient follow-up;
287 the data to be collected;
288 the analysis plan including any interim reporting where appropriate to
289 ensure continuous risk management based on clinical data; and
290 procedures/criteria for early study termination;
291 ethical considerations;
292 methods of quality control of data where appropriate.
293
294 The points above may not all apply to a retrospective data review.
295
296
297 Implementation of the PMCF study, analysis of data and conclusion(s)

298 The study should:
299 be executed with adequate control measures to assure compliance with the
300 clinical investigation or study plan;
301 include data analysis with conclusions drawn according to the analysis plan by
302 someone with appropriate expertise; and
303 have a final report with conclusions relating back to original objective(s) and
304 hypothesis/hypotheses.
305
306
307
308 7. The use of study data
309
310 The data and conclusions derived from the PMCF study are used to provide clinical
311 evidence for the clinical evaluation process. This may result in the need to reassess
312 whether the device continues to comply with the Essential Requirements. Such
313 assessment may result in corrective or preventive actions, for example changes to the
314 labelling/instructions for use, changes to manufacturing processes, changes to the
315 device design, or public health notifications.
316
317 8 The role of the notified body in PMCF

318 When auditing the quality system of the manufacturer in the framework of one of the
319 conformity assessment annexes of Directive 90/385/EEC or of Directive 93/42/EEC,
320 the Notified Body (NB) shall review the appropriateness of the manufacturers
321 general post-market surveillance procedures and plans, including plans for PMCF, as
322 relevant.
323
324 The Notified Body shall verify that PMCF as part of the overall clinical evaluation is
325 conducted by or on behalf of the manufacturer by appropriately competent assessors
326 (as per section 10.3 of MEDDEV 2.7/1).
327
328 The NB shall verify that clinical investigations conducted as part of PMCF plans are
329 conducted in accordance with the relevant provisions of Annex X (as per Article 15.8
330 of 93/42/EEC), related guidance and relevant standards.
331
332 The NB shall as part of its assessment of a specific medical device5:
333 verify that the manufacturer has appropriately considered the need for
334 PMCF as part of post market surveillance based on the residual risks
335 including those identified from the results of the clinical evaluation and
336 from the characteristics of the medical device in accordance with section 5
337 of the guidance;
338 verify that PMCF is conducted when clinical evaluation was based
339 exclusively on clinical data from equivalent devices for initial conformity
5
in accordance with Annex II.4, Annex II.7, Annex III, Annex V.6 and Annex VI.6 of Directive
93/42/EEC and Annex II.4, Annex II.7, Annex III and Annex V.6 of Directive 90/385/EEC
340 assessment and that PMCF addresses the residual risks identified for the
341 equivalent devices;
342 assess the appropriateness of any justification presented by a manufacturer
343 for not conducting a specific PMCF plan as part of post market surveillance
344 and seek appropriate remedy where the justification is not valid;
345 assess the appropriateness of the proposed PMCF plan in demonstrating the
346 manufacturers stated objectives and addressing the residual risks and issues
347 of long term clinical performance and safety identified for the specific
348 device;
349 verify that data gathered by the manufacturer from PMCF, whether
350 favourable or unfavourable, is being used to actively update the clinical
351 evaluation (as well as the risk management system);
352 consider whether, based on the specific device assessment, data obtained
353 from PMCF should be transmitted to the NB between scheduled assessment
354 activities (e.g. surveillance audit, recertification assessment);
355 consider an appropriate period for certification of the product in order to set
356 a particular time point at which PMCF data will be assessed by the NB or
357 specific conditions relating to certification for subsequent follow up. (This
358 decision may be based on the residual risks, the characteristics presented in
359 section 5 and the clinical evaluation presented at the time of initial
360 assessment. Conditions the NB may consider could include the need for the
361 manufacturer to submit interim reports between certification reviews, of the
362 clinical data generated from the PMCF and post-market surveillance
363 system).
364
MEDDEV 2. 13 rev 1
1.8.98 Offcial Journal of the European Communities C242/5
Commission communication on the application of transitional provision of Directive

93/42/EEC relating to medical devices
(98/C 242/05)
This communication refers to Article 22(4) of Directive To a large extent, devices covered by Directive
93/42/EEC concerning medical devices. It aims at 93/42/EEC are ready for use at the time they are placed
providing clarification on the aforementioned provision in on the market by the manufacturer. In fact, distribution
order to ensure its uniform application throughout the or other manipulations make no difference to their safety
European Community. and performance, provided manufacturers' instructions
have been followed. These devices are considered as
Article 22(4) of Directive 93/42/EEC requires Member being put into set-vice at the same time as they are
States to continue to accept the placing on the market and placed on the market. Therefore, such devices which
the putting into service of devices which conform to the have been made available by the manufacturer up to and
rules in force in their territory on 31 December 1994 including 14 June 1998 may, after that date, continue to
pre-existing national rules) for a period of five years be transferred to end-users and used in accordance with
following the adoption of the aforementioned Directive, pre-existing national rules.
i.e. ending on 14 June 1998.
Some devices, prior to their use, need further processing,
Accordingly, since 1 January 1995, when Directive for instance sterilisation of surgical dressings,
93/42/EEC became first applicable, it has been possible to preparation of dental filling material, soaking and fitting
place medical devices on the market and put them into of contact lenses. Such kind of processing by the
service either in accordance with the pre-existing national end-user, according to its needs, is assigned to products
rules or in compliance with Directive 93/42/EEC. From by the manufacturer as part of the intended use. Relevant
15 June 1998, it will only be possible to place medical devices should be considered as being ready for use,
devices on the market and put them into service if they even if the aforementioned processing by the end-user
comply with Directive 93/42/EEC. has not yet taken place.
The term 'placing on the market' is defined in Article However, devices placed on the market which, in view
1(2)(h) of Directive 93/42/EEC as the 'first making of their first use, need to be assembled or installed in the
available in return for payment or free of charge of a hospital and where these manipulations have an impact
device ... with a view to distribution and/or use on the on safety and/or performances of the devices, are not
Community market regardless of whether it is new or considered as 'put into service', unless the
fully refurbished'. 'Putting into service' means in aforementioned activities have been carried out.
accordance with Article 1(2)(i), 'the stage at which a
device is ready for use on the Community market for the It should be noted that Article 22(4) as well as the
first time for its intended use'. The concepts of placing on
definition of 'putting into service' within the meaning of
the market and putting into service refer to each individual
Directive 93/42/EEC are currently under revision (').
product, and not to a type of device. Once the forthcoming amendment of Article 22(4)
which is currently going through the legislative
The provision of Article 22(4) applies in relation to procedure will become applicable, the present
devices placed on the market prior to 15 June 1998 in interpretation will cease to apply.
compliance with the pre- existing national rules of
Member States. Member States may require evidence on
compliance with such rules and, where no specific rules
exist, on the assurance of an adequate level of safety of ___________________
devices based on general safety considerations. See Article 21(2)(g) of the common position adopted by
the Council on 23 March 1998 with a view to adopting
Regarding the 'putting into service' of those devices, the Directive 98/ ... /EC of the European Parliament and the
Commission considers that a device reaches this stage as Council on in-vitro diagnostic medical devices.
soon as it is ready for use in the Community.
EUROPEAN COMMISSION

MEDDEV. 2.14/1 rev. 1

January 2004
IVD GUIDANCES : Borderline issues
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of
EC-Directives on medical devices. They are legally not binding. The Guidelines have been
carefully drafted through a process of intensive consultation of the various interest parties
Therefore, this document reflects positions taken by representatives of interest parties in the
medical devices sector.
Borderline IVDD Page 1 19/01/2004

IN VITRO DIAGNOSTIC MEDICAL DEVICES: BORDERLINE ISSUES
Foreword
The present Guideline is part of a set of Guidelines relating to questions of application of EC-
Directives on In Vitro Diagnostic Medical Devices. They are not legally binding. The Guideline has
been carefully drafted through a process of intensive consultation of the various interested parties
(Competent Authorities, Commission Services, Manufacturers and other interested parties in both
the IVD and the Medical Device sectors) during which intermediate drafts were circulated and
comments were taken up in the document. Therefore this document reflects positions taken in
particular by the aforementioned interested parties.
Due to the participation of the aforementioned interested parties, including experts from
Competent Authorities, it is anticipated that these guidelines will be followed within the Member
States and, therefore, ensure uniform application of relevant Directive provisions.
1. Introduction
This guideline should be read in association with the scope of Directive 98/79/EC as stated in
article 1 (2) and with particular reference to an in vitro diagnostic medical device (IVD)1 having a
medical purpose, and in relation to Directive 93/42/EEC concerning medical devices. The
guideline provides a practical support for the uniform application of these Directives. It deals with
specific issues in the context of the Directives and is therefore of complementary nature to the
Guide to the implementation of directives based on the New Approach and the Global Approach.
The aim is to establish the demarcation between both legal regimes. The document also aims to
provide guidance in relation to issues that have arisen in relation to other Directives e.g.
Medicinal Products and Biocides or other non-IVD products.
One of the main borderline issues that will arise is the determination of the borderline between
the In Vitro Diagnostic Medical Devices Directive (IVDD) and the Medical Devices Directive
(MDD). This determination is of fundamental importance because the two directives are mutually
exclusive.2 A product cannot be an IVD under
1
IVD in this document should be read as in vitro diagnostic medical devices in the sense of European Directive 98/79/EC.
2
There will inevitably be difficult borderline cases, but the following factors indicate why it is essential to determine whether a particular
device is within the scope of the MDD or that of the IVDD:-
the essential requirements and the conformity assessment procedures of the MDD were developed and adopted on the basis that that
Directive would not apply to IVDs and they are therefore different from those that were eventually developed specifically taking into
account the particular nature of IVDs and their users.
unlike the IVDD, the MDD contains no provision for the development and adoption of common technical specifications and therefore
devices falling within the scope of the MDD cannot be required to comply with any such quasi-mandatory specifications;
harmonised standards published for the purposes of the IVDD would not give rise to the legal presumption of compliance as regards devices
that fall within the scope of the MDD and vice-versa;
notified bodies designated only for the purposes of the MDD will not have (or are unlikely to have) competence in the field of IVDs and
certainly any competence that they may have in that field will not have been assessed by the designating competent authority and vice-
versa.
2
Directive 98/79/EC and a medical device under Directive 93/42/EC as the two directives are
mutually exclusive. A product can only be under one or the other directive. This is so because,
during the development of the MDD, it was decided to develop a Directive establishing the legal
regime for the free movement IVD medical devices later and separately and, consequently,
Article 1.5 of the MDD specifically states that that directive does not apply to IVD
medical devices. Although the legal regime that was eventually developed for application
to IVD medical devices was in the form of a new approach directive and followed very
closely the general structure of the MDD, the IVDD contains many significant differences
especially as regards the essential requirements (including the labelling requirements)3 and
the conformity assessment procedures.
2. Definitions, essential characteristics and medical purpose
2.1 Definitions
A product is an IVD device, if it fulfils the clauses a) and b) of the Article 1.2 of Directive
98/79/EC:
1. intended use and properties as a medical device according to Article 1.2 a) and
2. intended use and properties as a IVD device according to Article 1.2 b)
* thus a product must firstly be determined to be a medical device before determining whether or
not it is an IVD, within the definitions contained in the directive 98/79/EC.
Reference is made in this guidance document to the following relevant definitions, namely:
medical device - Article 1.2(a) of the MDD and of the IVDD

in vitro diagnostic medical device - Article 1.2(b) of the MDD (as amended
by Directive 98 / 79 / EC) and of the IVDD
specimen receptacle - Article 1.2(b) of the IVDD
accessory - Article 1.2(c) of the IVDD
intended purpose - Article 1.2 (h) of the IVDD
2.2 Essential Characteristics
The essential characteristics of an IVD, whether consisting of a single component or a

combination, are that:
> its principal intended purpose is to provide information

- concerning a physiological or pathological state or
- concerning a congenital abnormality or
- to determine the safety and compatibility with potential recipients or
- to monitor therapeutic measures,
> the device is used in vitro for the examination of a specimen derived from the human body, and
> the information thus obtained is to be used for one or more of the medical purposes
specified in Article 1.2 (a, b).
2.3 Medical Purpose
In order for a product to come within the scope of the Medical Device Directives (including the
IVDD) it must be intended by the manufacturer to be used for a medical purpose. If no medical
purpose is intended by the manufacturer then the product is not a medical device. Thus the
intended purpose for a product will be key in determining whether or not the product is a (IVD)
medical device.
3
the labelling requirements of the MDD were developed without reference to the special nature and characteristics of IVDs and without
reference to the specialised information needs of their professional and lay users;
3
It is to be noted that Article 1.2 (h) of the IVDD provides that the intended purpose is the use for
which a device is intended according to the data (presumably, the information) supplied by the
manufacturer on the labelling, in the instructions for use and / or in promotional material.
Examples:
Devices for detection of agents of biological or chemical warfare in the environment are not
IVDs because such products have no medical purpose. On the other hand a device intended
to be used on human specimens in the detection of biological or chemical warfare agents
with medical purpose would fall within the scope of the IVDD (see point 9).
Devices intended to be used only in the course of law enforcement or other non-medical
purposes, for example for detecting drugs of abuse/alcohol, are outside the scope of the
IVDD (see point 10).
If however, the in- vitro examination of human specimens with a medical purpose is one of
the intended uses of a specific product, the IVD Directive will apply.
A product for research use only which has no medical purpose, cannot be a medical device
and, therefore, cannot be an IVD medical device. By definition, these products fall outside the
scope of the IVDD and the other medical devices directives.
3. Specimen receptacles
Article 1.2(b) of the IVD Directive clearly states that specimen receptacles are considered as
IVDs. It defines specimen receptacles for this purpose as those devices that are specifically
intended by the manufacturer to be for the primary containment and preservation of specimens
derived from the human body for the purposes of in vitro diagnostic examination. This applies
whether the product is vacuum type or not.
This specific intended use should be included on the labelling and any associated promotional
literature for the product. The manufacturer must also have evidence and technical
documentation to support this use for the product. A manufacturer cannot place the CE mark on
a piece of general laboratory equipment as a marketing claim, without ensuring that it complies
with all the relevant essential and other requirements of the directive and have evidence to
substantiate this.
It is possible for more that one specimen receptacle to be involved in the collection, transport and
storage of an individual specimen. In such cases the manufacturer of each receptacle must have
evidence of compliance with the directive as above.
During the actual analytical process the receptacles into which the specimen is placed (by
aliquoting or otherwise), may be glass or plastic tubes, cups, cuvetttes or other receptacles.
These are unlikely to be specimen receptacles as defined in the directive. They are usually
considered to be general laboratory equipment, however in some cases they could be considered
accessories to an IVD.
In the context of the definition of specimen receptacle in Art. 1.2 (b), of the IVD Directive it
should be noted that:
(a) the word primary does not necessarily refer to the initial or first container of the specimen
in point of time, but rather to a container that is intended by its manufacturer to mainly come
into direct contact with the specimen and which could therefore affect the specimen, and
(b) the word preservation does not imply that the receptacle has to contain a specimen
preservative, but that the receptacle is one intended to protect the specimen, for example,
from temperature fluctuations, from light, from physical breakage, etc.
Example:
Sample tubes, microbial transportation devices (tubes). Article 1 (2) b applies.
4
Note; Specimen receptacles that come into contact with a patient are considered to fall within the
scope of the MDD and not the IVDD.
Accessory
Note: The second paragraph of the definition of accessory in Art 1.2 (c) of the IVDD states that
invasive sampling devices or those which are directly applied to the human body for the purpose
of obtaining a specimen within the meaning of Directive 93/42/EEC are not to be considered as
accessories to IVDs. Thus, for example, where a manufacturers kit includes lancets or pricking
devices to obtain a blood specimen, they are to be regarded as being devices within the scope of
the MDD and not accessories to the IVD.
4. Products for general laboratory use
Products for general laboratory use (non-IVD products) are not IVDs unless on the basis of its
specific characteristics the manufacturer specifically intends such products to be used for in vitro
diagnostic purposes. Thus such a product must possess specific characteristics to make it
suitable for in vitro diagnostic procedures in order to be classified as an IVD.
Products used in vitro in the preparation of samples that have been obtained for examination, but
not used directly in the actual test can be considered to be IVDs if the manufacturer specifically
states that the product can be used for in vitro diagnostic purposes, otherwise they fall outside
the scope of the directive.
The one qualification provided for in the Directive is where, on the basis of its characteristics
(emphasis added), a manufacturer specifically intends that the product should be used for in vitro
diagnostic examination. In this case, the product becomes an IVD and must comply with the
applicable essential and other requirements of the IVDD and must be CE marked. If, however,
the product does not in fact possess specific characteristics that make it suitable for one or more
identified in vitro diagnostic examination procedures, then the manufacturer is not free to bring it
within the scope of the IVDD merely by affixing the CE marking to it. In other words, a
manufacturer is not able to bring within the scope of the IVDD a product that, in reality, is a piece
of general laboratory equipment simply by affixing the CE mark to it.
Example:
Laboratory products that are not usually considered to fall within the scope of the IVD directive
include: sterilizers, laboratory centrifuges, general purpose automatic pipette, weighing
machines, microtomes, multi purpose tubes, pipettes and flasks etc. where such items have no
specifically intended in vitro diagnostic use. Examples also include items for general purpose use
such as foetal calf serum, culture media and stains, unless the manufacturers intended purpose
falls within the definition of an in vitro diagnostic medical device.
5. Products for research use only
A product for research use only which has no medical purpose, cannot be a medical device and,
therefore, cannot be an IVD medical device. By definition, these products fall outside the scope of
the IVDD and the other medical devices directives.
Recital 8 of Directive 98/79/EC states:

Whereas instruments, apparatus, appliances, materials or other articles, including software,
which are intended to be used for research purposes, without any medical objective, are not
regarded as devices for performance evaluation.
This means that products for research purposes, which have no medical indication and are not
yet established in medical diagnosis, are excluded from the scope of the directive.
5
6. Devices for IVD purposes with an invasive body contact
Some devices may incorporate both specimen collection and analytical functions. These devices
may be borderline between the Medical Device Directive 93/42/EC and the IVD Directive
98/79/EC. Borderline cases such like this should be approached with regard to the principal
intended purpose of the product. Thus if the principal intended purpose is for the product is to be
used in vitro for the examination of specimens derived from the human body for the purposes of
providing information the IVD directive would apply. (Art 2b).
Devices which during their measuring function involve contact with the human system (as defined
in 93/42/EEC Annex IX) in order to obtain a continuous sample are not considered to be IVD
devices.
Example:
A device involving the vacuum suction of saliva into the integrated handle of a device which
contains reagent material (e.g. for the detection of HIV). The use of such a device involves the
penetration of the device into a body orifice for the collection of the specimen and this may
appear to make it a medical device within the scope of the MDD. However, its principal intended
purpose is the provision of relevant information by the in vitro examination of the specimen
derived from the patient. The devices brief contact with the patient or penetration into the
patients body to collect the specimen is subsidiary and incidental to its principal intended
purpose.
Mouth and other swabs having integrated reagents or reagent areas are IVDs because their
principal intended purpose is to provide information relevant to the medical purposes specified in
Article 1.2 (b).
The intended purpose, invasiveness and continuity of sampling are important criteria in deciding
the correct regulatory route for this kind of product.
Example:
A Holter blood glucose monitoring system that includes a subcutaneous catheter to provide a
continuous supply of the patients specimen to an in vitro analysing instrument is a medical
device not an IVD because, during the in vitro measuring function, surgically invasive contact with
the patient is necessary in order to obtain a continuous specimen flow. In this case, the analytical
function is carried out at the same time as the continuous specimen collection process is still
going on. There is no dissociation of the specimen from the patient and therefore the analytical
function cannot properly be regarded as being in vitro. Such a device would therefore be a
medical device within the scope of the MDD. Other examples are continuous pH measurements
during haemodialysis and oxygen saturation devices.
Other Sampling Devices (also see pt. 3)

Sampling devices which are either invasive (needles, lancets etc) or that come into contact with
patients, that are made available together with IVD devices (in kits, procedure packs etc) are not
considered to be accessories to IVD devices, They come within the scope of the MDD and have
to be CE marked as medical devices.
Note: For devices that have key features, which could be considered as being covered by the
MDD as well, the relevant requirements (e.g. biocompatibility, sterility, etc.) of that directive need
to be considered during the conformity assessment procedure.
7. Kits containing IVDs and medicinal products
Medicinal products made available together with IVD devices are to be authorised for marketing
by the normal process for medicinal products and the primary, and if applicable the secondary
packages of the medicinal products are to be labelled according to the rules for medicinal
products. The IVD components of the kits themselves fall within the scope of the IVD Directive
and must therefore comply with its requirements and carry the CE mark, but will not need not be
authorised for marketing as medicinal. This also applies to any MDD components. I.e. each set of
6
regulatory requirements needs to be met for each of the individual medicinal products, medical
device and/or IVD medical device components.
Example:
A Helicobacter pylori breath test kit containing labelled urea (a licensed pharmaceutical product)
to be ingested prior to sampling for analysis, a straw (a medical device) and a sample container
(an IVD).
Note: So far as the medicinal product is concerned, it must have been granted a marketing
authorisation covering the actual use for which it is being included in the IVD kit and it must be
labelled in accordance with the regulations relating to medicinal products. The IVD component of
the kit must comply with all the applicable essential and other requirements of the IVDD (including
the labelling requirements) and it must bear the CE marking. It is important to note that, while the
CE marking of the IVD content of the kit entitles it to free movement within the European
Economic Area (subject to language requirements), that is not so as regards the medicinal
product. That aspect must be considered separately under the relevant medicinal product
legislation as must the extent to which the label of the kit must provide information about the
medicinal product over and above a statement that the kit contains the medicinal product.
8. Control Materials
Some EQA organisations distribute materials for internal control, national calibration materials,
etc. These materials are IVDs and must bear the CE label.
CE Label Remarks
Calibrators/Controls Part of the kit Calibrators and controls
included in the kit with assigned values must
be traceable
Standing alone calibrators CE label Calibrators and controls
and internal quality control with assigned values must
(IQC) materials (assigned be traceable
or not assigned)
Even if these materials
are also used as EQA
materials4
Specific EQA materials No CE label Reference Recital (9) of
98/79/EC
Reference material of No CE label Metrological traceability
higher order required
9. Devices where no specimen is involved
Some medical diagnostic devices function without a specimen is being taken from the patient.
Since it is an essential part of the definition of an in vitro diagnostic medical device that the
manufacturers intention is that the product should be used .. for the examination of
specimens., it follows that a medical device that functions without the need for a patient
specimen cannot be an IVD within the scope of the IVDD. Such products will almost always be a
medical device within the scope of the MDD.
Example
A non-invasive medical device for the detection of blood glucose by energy emission (e.g. near
infra-red energy) is not an IVD because no specimen derived from the human body is involved,
but it would be a medical device for the purposes of the MDD.
4
This part of the table is still subject to discussion and can be changed in the next revision of this Meddev (3 Nov 2003)
7
10. Devices involved in biological or chemical warfare
Devices for detection of agents of biological or chemical warfare in the environment are not IVDs
because such products have no medical purpose. A device used on human specimens with
medical purpose in the detection of biological or chemical warfare agents would be an IVD.
11. Devices to be used in law enforcement
Devices intended to be used only in the course of law enforcement or other non-medical
purposes, for example paternity tests or tests for detecting drugs of abuse/alcohol, are not IVDs.
If however, the in vitro examination of human specimens with a medical purpose is one of the
intended uses of a specific product, the IVD Directive will apply.
12. Boundary with the Biocides Directive 98/8/EC
IVDs according to the Directive 98/78/EC shall be exempted from the Biocides Directive
(amendment not accomplished yet).
Note: Biocidial substances used as a raw material in an IVD may have to fulfil the requirements
of the Biocides directive as well5.
5
This part of the text is still subject to discussion and can be changed in the next revision of this Meddev (3 Nov 2003)
8
EUROPEAN COMMISSION
Consumer Affairs

January 2012

IVD Medical Device Borderline and Classification issues
Foreword
The present Guideline is part of a set of Guidelines relating to questions of application of EC

Directives on medical devices.
This guideline is not legally binding, since only the European Court of Justice can give an
authoritative interpretation of Community law. It has been elaborated by an expert group
including experts from Member States' Competent Authorities, the Commission services, as
well as industry trade associations. It is therefore intended that the document will provide
useful guidance which should assist common positions to be taken throughout the European
Union. Due to the participation of the aforementioned interested parties and of experts from
Competent Authorities, it is anticipated that these guidelines will be followed within the
Member States and, therefore, ensure the uniform application of relevant Directive
provisions.
The present guideline provides non-exhaustive lists of examples of IVD medical devices,
accessories to IVD medical devices and medical devices. Further detailed examples may be
found in the Manual on Borderline and Classification in the Community Regulatory
framework for medical devices, published on the European Commission website1.
Note: This document is a revision of an earlier document published in January 2004 as

MEDDEV 2.14/1 rev 1.
1
http://ec.europa.eu/health/medical-devices/documents/borderline/index_en.htm
1
CONTENT
Introduction
Part A Qualification
1. General principles of qualification
1.1. Definition of an IVD medical device
1.2. Accessories
1.3. Specimen receptacles and products used for the collection of specimens
1.3.1. Specimen receptacles
1.3.2. Products used to obtain specimens
1.4. Products for general laboratory use
1.5. Products for research use only
1.6. IVD kits
1.7. Control Materials
2. Specific cases on qualification
2.1. Microbiological culture media
2.2. Stains
2.3. Devices with an invasive body contact for IVD purposes
2.4. Devices where no specimen is involved
2.5. Devices involved in biological or chemical warfare
2.6. Devices to be used in law enforcement
2.7. Relation with the Biocides Directive 98/8/EC
Part B Classification
1. General principles on Classification
2
1.1. Interpretation of annex II, list A
1.1.1. Interpretation of marker of infection wording
1.1.2. Clarification of rare blood groups and subgroups
1.2. Interpretation of annex II, list B
1.2.1. Classification of Chlamydia detection IVD medical devices
1.2.2. Classification of in vitro diagnostic kits measuring parameters

which can be used for evaluating the risk of trisomy 21
3
1. Introduction
The demarcation between the IVD Medical Device Directive 98/79/EC (IVDD), on the
one hand, and other sectoral legislation, on the other hand, in particular the Medical
Device Directive 93/42/EC (MDD), is crucial for the proper implementation of these
Directives and the correct interpretation and enforcement of national laws.
In particular, the qualification of a product as an IVD or as a medical device will have

an impact on:
- the essential requirements and the conformity assessment procedures to be

followed,
- the appropriate technical specifications giving presumption of conformity (common
technical specifications and harmonised standards),
- the selection of a competent designated notified body to conduct the conformity
assessment procedure.
The demarcation between the IVDD and the MDD is of fundamental importance
because the MDD foresees in its article 1 that this Directive shall not apply to IVD
medical devices.
Therefore, it was recognised that the subject needs to be further explained and
illustrated by practical guidance.
Part A - Qualification
1. General principles of qualification
In deciding on whether a product falls within the scope of the IVD Directive, the
primary consideration are the definitions set up in article 1 (2) of Directive 98/79/EC.
1.1. Definition of an IVD
Article 1(2) (b) of the IVDD defines an IVD as:
in vitro diagnostic medical device means any medical device which is a reagent,
reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or
system, whether used alone or in combination, intended by the manufacturer to be
used in vitro for the examination of specimens, including blood and tissue donations,
derived from the human body, solely or principally for the purpose of providing
information:
4
to determine the safety and compatibility with potential recipients,
or
to monitor therapeutic measures.
The essential characteristics of an IVD are that:
1. The principal intended purpose of an IVD is to provide information on one or

more of the following medical purposes:
* information concerning a physiological state e.g. menopause assay,

ovulation assay, pregnancy test or
* information concerning a pathological state e.g. HIV assay
* information concerning a congenital abnormality e.g. evaluation of the
risk of trisomy 21
* to determine the safety and compatibility with potential recipients e.g.
determination of blood groups of the ABO system
* to monitor therapeutic measures e.g. digitoxin assay
Note that tests for detecting drugs abuse/alcohol, intended to be used in law
enforcement are not IVDs (see 2.6)
2. The IVD may provide this information either alone or in combination with
other devices or products
3. The IVD is used in vitro for the examination of a specimen derived from the
human body and where such specimen is never reintroduced into the body.
Note that if no specimen is involved, or if the examination takes place in or on

the human body (in vivo), the devices intended to be used for this examination
are not IVDs. (see 2.3 and 2.4)
Examples: - a pulse oxymeter emitting light through the fingertip and

absorbing infrared light, to measure the oxy/deoxyhemoglobin
ratio is not an IVD,
- a continuous blood glucose monitoring system where the
analytical function is carried out at the same time as the
continuous specimen collection is not an IVD.
4. The IVD is used in vitro for the examination of a specimen derived from the
human body.
Note that devices for detection of e.g. pathological agents in the environment
are not IVDs.
5
From the definition it follows that in order to be qualified as an IVD the product must
first fulfil the definition of a medical device2 and therefore must be intended by its
manufacturer to be used for a medical purpose3.
According to Article 1.2 (h) of the IVDD, the intended purpose means the use for
which the device is intended according to the data supplied by the manufacturer on
the labelling, in the instructions for use and/or in promotional materials.
There may be cases where claims of a medical nature are made for certain products
where those claims cannot be substantiated by technical, clinical and scientific data.
If there is insufficient clinical, technical and scientific data to support the claims made,
the product does not meet the requirements of the MDD and therefore shall not be
CE marked as a medical device or an IVD.
Products cannot be brought into the scope of the IVDD, merely by mentioning for in
vitro diagnostic use.
On the other hand, a product might have several intended uses. If one of these
intended uses is the in vitro examination of human specimens and if a medical
purpose can be established based on sufficient and broadly agreed scientific,
diagnostic and clinical evidence, then the product must comply with the requirements
of the IVDD before the manufacturer can place it on the market.
Products cannot be placed on the market as Research use only (RUO) products if
these products have a medical intended purpose.
1.2. Accessories
Directive 98/79/CE, article 1.2 (c) defines an accessory as "an article which, whilst
not being an IVD, is intended specifically by its manufacturer to be used together with
a device to enable that device to be used in accordance with its intended purpose.
Directive 98/79/CE, article 1.1 states that This Directive shall apply to in vitro
diagnostic medical devices and their accessories. For the purposes of this Directive,
accessories shall be treated as in vitro diagnostic medical devices in their own right.
Both in vitro diagnostic medical devices and accessories shall hereinafter be termed
devices.
Example: a cleaning solution specifically intended by its manufacturer to be used

with a defined automated IVD instrument
1.3. Specimen receptacles and products used for the collection of specimens
1.3.1. Specimen receptacles
2
It is to be noted that the definition of a medical device in Directive 98/79/EC is not strictly identical to the definition of a medical
device set up in Directive 93/42/EEC. However the definitions of a medical device in both directives are considered to be similar
3
Further information regarding the interpretation of the medical purpose can be found in MEDDEV 2.1/1.
(http://ec.europa.eu/health/medical-devices/files/meddev/2_1-1___04-1994_en.pdf)
6
Article 1(2) (b) of the IVDD states that:
Specimen receptacles are considered to be in vitro diagnostic medical devices.
Specimen receptacles are those devices, whether vacuum-type or not, specifically

intended by their manufacturers for the primary containment and preservation of
specimens derived from the human body for the purpose of in vitro diagnostic
examination.
Notes:
(a) the word primary does not necessarily refer to the initial or first container of the
specimen in point of time, but rather to a container that is intended by its
manufacturer to mainly come into direct contact with the specimen and which could
therefore affect the specimen, and
(b) the word preservation does not imply that the receptacle has to contain a
specimen preservative, but that the receptacle is intended to protect the specimen,
for example, from temperature fluctuations, from light, from physical breakage, etc.
This specific intended use shall be clearly indicated on the labelling and any
associated promotional literature for the product. The manufacturer must also have
evidence and technical documentation to support this use for the product.
It is possible that more than one specimen receptacle is involved in the collection,
transport and storage of an individual specimen. In such cases the manufacturer of
each receptacle must have evidence of compliance with the IVDD.
Other glass or plastic tubes, cups, cuvettes or other receptacles into which the
specimen is placed during the analytical process (by aliquoting or otherwise), are not
considered to be specimen receptacles within the meaning of the IVDD. They are
considered to be general laboratory equipment.
Examples:- Blood collection tubes, urine sample containers are considered as IVDs.
Specimen receptacles with an invasive body contact should be handled in the same
way as described in chapter 1.3.2.b.
1.3.2. Products used to obtain specimens
a) Without intended direct contact with the human body
A product intended to transfer the sample, but which is not specifically intended by its
manufacturer for the primary containment and preservation of specimens derived
from the human body for the purpose of in vitro diagnostic examination, is usually not
considered to be an IVD (e.g. plastic pipettes to transfer blood drop from finger to
rapid test)
b) With intended direct contact with the human body
7
Invasive sampling devices or those which are directly applied to the human body for
the purpose of obtaining a specimen within the meaning of Directive 93/42/EEC shall
not be considered to be accessories to in vitro diagnostic medical devices (Art 1.2.c)
(e.g. needles, lancets, lancing devices, mouthtubes, swabs, urine collection bags for
babies). These products are regarded as being devices within the scope of Directive
93/42/EEC.
1.4. Products for general laboratory use
Article 1(2) (b) of the IVDD states that:
Products for general laboratory use are not in vitro diagnostic medical devices
unless such products, in view of their characteristics, are specifically intended by
their manufacturer to be used for in vitro diagnostic examination.
The qualification provided for in the Directive is where, on the basis of its
characteristics, a manufacturer specifically intends that the product should be used
for in vitro diagnostic examination. In this case, the product becomes an IVD and
must comply with the applicable essential requirements of the IVDD and therefore
must be CE marked.
If, however, the product does not possess specific characteristics that make it
suitable for one or more identified in vitro diagnostic examination procedures, then
the manufacturer is not allowed to qualify its product as an IVD. A manufacturer is
not allowed to affix the CE mark on a piece of general laboratory equipment as a
marketing claim. Merely adding the statement for in vitro diagnostic use to a product
is not sufficient to qualify a product as an IVD.
Products used in vitro in the preparation of samples that have been obtained for
examination are considered neither as IVD nor as accessories and fall outside the
scope of the Directive unless, based on their characteristics, they are specifically
intended for a particular IVD test. The validation of this specific combination shall be
clearly documented in the technical documentation.
Examples of product of general laboratory use and IVD medical devices:
Laboratory use product Covered by IVD Directive

Centrifuges General centrifuges, Hematocrite centrifuge
cytospin
Pipettes General purpose pipettes Blood coagulation pipettes
(e.g. single or multiple with automatic timing
pipettes, plastic pipettes, (Accessory of
Pasteur pipettes) coagulometer)
Tubes and flasks Erlenmeyers, plastic tubes Blood collection tubes,
urine sample containers
Plates Empty ELISA plates, Coated microtiter plates
empty Petri dishes, for the diagnosis of Lymes
disease
8
Nucleic Acid extraction DNA and RNA extraction DNA and RNA extraction
products kits that only provide a kits intended to provide a
specimen without an specimen to be used with
intended IVD detection an IVD device (validation
combination for at least one
combination is to be
provided)
General equipment Scales, balances,
microtomes, incubators,
sterilizers for laboratory
equipment, paraffin
embedding machine,
HPLC products size-exclusion HPLC HPLC columns for IVD
columns purposes: e.g. HbA1c
Detection equipment Mass spectrometer, McFarland bacteria
spectrophotometers, density testing
ELISA readers providing
raw data which is not
readily readable and
understandable by the
user (e.g. peaks, OD).
Others Foetal calf serum, cell
culture media, fixation
solution, mounting media,
buffers (e.g. PBS),
chemicals (e.g. sulphuric
acid, formol, water)
(This table contains a non-exhaustive list of examples).
9
1.5. Products for research use only
For further guidance on RUO, please consult MEDDEV 2.14/2 rev.1: IVD Guidance:
Research Use Only products4
1.6. IVD kits
The definition of an IVD includes kit as being an IVD in itself. The IVDD does not
give a definition of 'kit', but it is generally agreed that a kit consists of more than one
component that are made available together and intended to be used to perform a
specific IVD examination.
A whole product combination, placed on the market as a single product, shall be

treated as a kit and fulfil the requirements of the IVDD, if the principal intended
purpose of the whole product combination falls within the definition of an IVD.
The combined use of the products contained in the kit shall be validated by the
manufacturer of the kit during the conformity assessment procedure.
The kit shall be classified and assessed for its conformity to the requirements of the
IVDD, according to the principal intended purpose of the whole product combination
and must be CE marked and labelled under the IVDD (Annex I, B, ER 8.4).
A kit with a principal intended purpose falling within the definition of an IVD medical
device may contain:
a) IVD medical devices (e.g. antibody, antigen, coated ELISA plates, specimen
receptacles), which may be either:
CE marked under the IVDD in their own right allowing them to be also
marketed separately, or
not CE marked,
a combination of both CE marked and not CE marked.
b) a combination of IVD medical devices and :

medical devices (e.g. lancet, swab), which must be CE marked according to
Directive 93/42/EEC;
other products, such as products for general laboratory use (e.g. pipette for
transferring a patient sample), which shall not be CE marked;
food products (e.g. chewing gum added for inducing a patient reaction in
order to obtain a specific sample), which shall not be CE marked.
Note: while the CE marking of the kit ensures its free movement within the European
Union (subject to language requirements), this is not automatically the case for
medicinal products. This should be considered separately under the relevant
medicinal product legislation.
4
http://ec.europa.eu/health/medical-devices/files/meddev/2_14_2_research_only_product_en.pdf
10
Note: the kit shall fulfil in its own the requirements regarding the Information
supplied by the manufacturer (IVDD, Annex I,B,8) and must be CE marked, but
shall not bear an additional CE marking on the outer packaging for the medical
devices included in the kit.
Note: the qualification either as a procedure pack, according to MDD or as a kit

according to IVDD should be based on the principal intended purpose of the whole
product combination. If the whole product combination is qualified as a procedure
pack, this will comply with the requirements set in the Medical Device Directive
93/42/EEC. When IVD components are included in the procedure pack, they shall
fulfil the requirements of the IVD Directive 98/79/EC.
1.7. Control Materials
IVD Remarks
Calibrators/Controls included Kit is an IVD Calibrators and controls with
in the kit assigned values must be traceable
Stand alone IVD Calibrators and controls
calibrators/controls (either as with assigned values must
part of a kit or provided be traceable
separately) used to If the control material includes
confirm/define the validity control values for parameters listed
criteria of one or several IVD in List A or List B of Annex II, the
assay control material shall be classified
according to the highest
classification
Specific EQA materials Not IVD* Reference Recital (9) of
including materials (stand 98/79/EC
alone calibrators) used for an
external quality assurance
system
Reference material of Not IVD Metrological traceability
higher order required
* When External Quality Assessment organisations make available these EQA materials for
internal control, national calibration materials, etc, outside of the scope of EQA schemes,
these materials are considered as IVD medical devices. In that case, EQA organisations
would be considered as manufacturers and the products must be CE marked under the IVD
Directive.
2. Specific cases on qualification
2.1. Microbiological culture media
In order to be qualified as an IVD, the culture media must be specifically intended,

designed and validated to provide information concerning a physiological or
pathological state, on specimens derived from the human body.
11
Such qualification for culture media includes elements that should be available to the
user, such as:
the type of information provided by the IVD (presence, characteristics and typing of
micro-organisms) for medical purposes;
indication of the appropriate type of human specimens required (general or specific
like blood or urine);
any specific specimen collection, transport and storage requirements (e.g. sterile
collection for blood culture);
manufacturer batch release criteria.
Culture media without any specific medical intended purpose are not qualified as an
IVD.
Powder culture media will also be considered as an IVD if the above mentioned
conditions are fulfilled.
It should be noted that powder bulk components of microbiological culture media are
not considered to fall under the scope of the IVD Directive.
2.2. Stains
In order to be qualified as IVD, stains used in histology and microbiology (e.g.

smears and tissue sections) must be intended to provide information concerning a
physiological or pathological state on specimens derived from the human body.
Claims must be supported by a validation dossier.
Such qualification includes elements that should be made available to the user, such
as:
the type of information provided by the IVD for medical purposes (characteristics
and performance of the stains, specific identification by the stains)
indication of the appropriate type of human specimens required
any specific specimen collection, transport, storage and preparation requirements
A stain without any specific medical intended purpose is not qualified as an IVD.
2.3. Devices with an invasive body contact for IVD purposes
Some devices may in a single product incorporate both specimen collection and
analytical functions. These devices may be borderline between the MDD and the
IVDD because they are in contact with the body and/or are invasive. Their intended
purpose is to be used for the examination of specimens derived from the human
body for the purpose of providing information.
12
These borderline cases should be treated on the basis of their principal intended
purpose. Thus, where the principal intended purpose of the product is to be used in
vitro for the examination of specimens derived from the human body for the purposes
of providing information according to the definition of an IVD, the IVDD would apply.
In that case, due to the invasive characteristics of the IVD, special care has to be
applied for essential requirements 1 and 2 of Directive 98/79/EC which include all
risks for patients. In that respect, the respective essential requirements of MDD
should be taken into account, namely the requirements regarding the sterility,
biocompatibility and toxicity.
Devices which involve contact with the human body in order to obtain continuous
specimen collection are not considered to be IVD.
Examples:
A device involving the vacuum suction of saliva into the integrated handle of a device
which contains reagent material (e.g. for the detection of HIV).
The use of such a device involves the penetration of the device into a body orifice for
the collection of the specimen and this may appear to make it a medical device within
the scope of the MDD. However, its principal intended purpose is the provision of
relevant information by the in vitro examination of the specimen derived from the
patient. The devices brief contact with the patient or penetration into the patients
body to collect the specimen is subsidiary and incidental to its principal intended
purpose.
Mouth and other swabs having integrated reagents or reagent areas are IVDs
because their principal intended purpose is to provide information relevant to the
medical purposes specified in Article 1.2 (b). But in the case they are invasive, they
have to fulfil the relevant essential requirements of the MDD.
If the swab doesnt include the measuring or detection function, it would be
considered as invasive sampling device and therefore qualified as a medical device.
A continuous blood glucose monitoring system (Holter) that includes a subcutaneous

catheter to provide a supply of the patients specimen to an external analysing
instrument is a medical device not an IVD because, during the in vitro measuring
function, a surgically invasive contact with the patient is necessary in order to obtain
a continuous specimen flow. In this case, the analytical function is carried out at the
same time as the continuous specimen collection. There is no dissociation of the
specimen from the patient and therefore the analytical function cannot properly be
regarded as being in vitro. Such a device would therefore be a medical device
within the scope of the MDD.
2.4. Devices where no specimen is involved
Some diagnostic medical devices function without the need of a containable

specimen taken from the patient.
13
The definition of an in vitro diagnostic medical device states that IVD medical devices
are intended by the manufacturer to be used in vitro for the examination of
specimens, derived from the human body. Therefore, if no sample is derived from
the human body the device is not considered to be an IVD. Such products shall be
qualified as medical devices.
Examples:
A non-invasive medical device for the detection of blood glucose by energy emission
(e.g. near infra-red energy) is not an IVD because no specimen derived from the
human body is involved, but is a medical device within the scope of the MDD.
A pulse oxymeter emitting light through the fingertip and absorbing infrared light, to
measure the oxy/deoxyhemoglobin ratio falls within the scope of the MDD. There is
no specimen derived from the patient involved.
2.5. Devices involved in biological or chemical warfare
Devices for detection of agents of biological or chemical warfare in the environment

are not IVD because they do not have a medical purpose.
If however, the in vitro examination of human specimens for the detection of

biological or chemical warfare agents with a medical purpose is one of the intended
uses of a specific product, the IVDD will apply.
2.6. Devices to be used in law enforcement
Devices intended to be used only in the course of law enforcement or other non-
medical purposes, for example paternity tests or tests for detecting drugs
abuse/alcohol, are not qualified as IVD.
If however, the in vitro examination of human specimens with a medical purpose is

one of the intended uses of a specific product, the IVDD will apply.
2.7. Relation with the Biocides Directive 98/8/EC
The products falling within the scope of the IVDD are excluded from the scope of
Directive 98/8/EC. Directive 98/8/EC is currently under revision.
14
Part B Classification
1. General principles on Classification
The in vitro diagnostic medical devices are classified into two main product
classes:
- the large majority of devices does not constitute a direct risk to patients or public
health and are used by competently trained professionals, and the results obtained
can often be confirmed by other means, the conformity assessment procedures can
be carried out, as a general rule, under the sole responsibility of the manufacturer
being this IVD medical devices currently named as general IVD.
IVD intended to be used by lay persons are currently named as self-testing IVD and
have specific requisites in the Directive regarding both the conformity evaluation
procedure, with notified body intervention, and the user information essential
requirements;
- the IVD for which the correct performance is essential to medical practice and the
failure of which can cause a serious risk to individual patients health or public health
were defined as high-risk IVD and are currently listed in annex II, list A and list B, of
the Directive, and have specific requisites in the Directive regarding both the
conformity evaluation procedure, with notified body intervention.
The IVD listed in Annex II list A are mainly used in blood transfusion, for the
prevention of transmission of HIV and certain types of hepatitis and require a
conformity assessment guaranteeing an optimum level of safety and reliability,
having to fulfil the common technical specifications for their performance evaluation
and re-evaluation;
According to Article 1.1 of Directive 98/79/EC, accessories shall be treated as in vitro

diagnostic medical devices in their own right. Therefore the system of classification
described in Annex II of Directive 98/79/EC applies equally to accessories.
1.1. Interpretation of Annex II, list A
1.1.1. Interpretation of marker of infection wording
Annex II list A of Directive 98/79/EC states that "the lists of devices referred to in
article 9(2) and (3) includes .reagents, and reagents products, including calibrators
and control materials for the detection, confirmation and quantification in human
specimens of markers of HIV infection (HIV1 and 2), HTLV I and II, and Hepatitis B,
C and D."
It appears necessary to clarify the meaning of the word "markers of infection".
A "marker of infection" is considered as a substance that can be determined and/or

be measured objectively and is an indicator of an infectious disease process. A target
15
marker may be a biochemical entity, genetic profile, nucleic acid, antigen, antibody,
virus, bacteria or other substance.
1.1.2. Clarification of rare blood groups and subgroups
Annex II List A includes reagents for determining blood groups of ABO system,
rhesus (C, c, D, E, e) and anti-Kell.
Questions have arisen as to the scope of devices and reagents covered and in
particular so called rare blood groups and subgroups.
List A refers to:

Reagents and reagent products, including related calibrators and control materials,
for determining the following blood groups: ABO system, rhesus (C, c, D, E, e) anti-
Kell.
The use of the word system appears to have led to some confusion.
The table below defines reagents and devices that are included within Annex II List
A. These reagents are used for the routine determination of ABO, Rh and K types.
TABLE 1 Reagents Reagents & Devices Corresponding Antigen

covered by Annex II, List A Included* - ISBT Nomenclature
Annex II List A
Terminology
ABO System Anti-A ABO1

Anti-B ABO2
Anti-AB ABO1, ABO2
Reagent red cells for Not relevant
reverse grouping
Rhesus (C, c, D, E, e) Anti-D RH1
Anti-C RH2
Anti-E RH3
Anti-c RH4
Anti-e RH5
Anti-Kell Anti-K K1
* Reagents and devices included:

This column only concerns denomination of markers based on antibody/antigen assays
and does not mean to exclude devices applying other technologies for the determination
of ABO system, rhesus (C, c, D, E, e) anti-Kell.
Other antigens, subgroups and variants of these systems are of minor importance in
transfusion practice. Therefore, reagents for the characterization of these antigens
are not included in Annex II. Blood grouping reagents/devices not listed in Annex II
are regulated as general IVDs.
16
1.2. Interpretation of Annex II, list B
1.2.1. Classification of Chlamydia detection IVD medical devices
Annex II list B in the Directive refers to 'chlamydia' as a human infection.
The Directive does not differentiate between species, it simply states for determining
the following human infections: cytomegalovirus, chlamydia:
reagents and reagent products, including related calibrators and control materials,
for determining the following human infections: cytomegalovirus, chlamydia,
Due to the chlamydia taxonomic reclassification, the former species Chlamydia

pneumoniae, Chlamydia pecorum and Chlamydia psittaci were moved to the new
genus Chlamydophila. The term Chlamydia in Annex II List B of Directive 98/79/EC
should be understood as including the above mentioned species from genus
Chlamydophila and genus Chlamydia.
1.2.2. Classification of in vitro diagnostic kits measuring parameters which

can be used for evaluating the risk of trisomy 21
The manufacturer may choose to put kits intended for the measurement of
parameters which can be used for evaluating the risk of trisomy 21, such as AFP,
hCG, hCG-beta, estriol and PAPP-A, on the market with no intended use of risk
evaluation of trisomy 21.
In that case, such kits shall clearly not be intended for the risk evaluation of trisomy
21, and shall not include information concerning the measured parameter in the risk
evaluation of trisomy 21 in the instructions for use.
These kits are classified as general IVD and are to be placed on the marked
following Annex III.
A consensus has been reached that in that case the insert or the packaging shall
mention "this kit is NOT intended to be used for the risk evaluation of trisomy 21.
For further guidance on this subject, please consult the consensus statement
Requirements for in vitro diagnostic kits measuring parameters which can be used
for evaluating the risk of trisomy 21 available on the European Commission
website5.
5
http://ec.europa.eu/health/medical-devices/files/guide-stds-directives/trisomy_21_en.pdf
17
EUROPEAN COMMISSION


February 2004
IVD GUIDANCE : Research Use Only products
Note
The present Guidelines are part of a set of Guidelines relating to questions of application of
EC-Directives on medical devices. They are legally not binding. The Guidelines have been
carefully drafted through a process of intensive consultation of the various interest parties
Therefore, this document reflects positions taken by representatives of interest parties in the
medical devices sector.
Page 1 of 4
RUO Labelled Products and the IVD Directive 98/79/EC
01. Introduction
This document has been developed as a result of the outcome of initial discussions on
research only products at the Medical Devices Expert Group (MDEG) meeting of July 2003.
It aims to clarify a number of issues raised by Competent Authorities with regard to products
labeled as For Research Use Only (RUO) and their potential misuse by diagnostic
laboratories.
02. Legislation
This document is written in the context of the Directive 98/79/EC of the European Parliament
and of the Council of 27th October 1998 on in-vitro diagnostic medical devices. Reference is
clearly made in recital 8 of the above Directive to research use only products as follows:
whereas instruments, apparatus, appliances materials or other articles, including the

software which are intended to be used for research purposes, without any medical objective
are not regarded as devices for performance evaluation.
In summary for a product to be categorized as an RUO product it must have no intended

medical purpose or objective.
Article 1 point 2.5 of the Directive should also be noted where it states that This Directive
shall not apply to devices manufactured and used only within the same health institution and
on the premises of their manufacture or used on premises in the immediate vicinity without
having been transferred to another legal entity. This does not affect the right of Member
State to subject such activities to appropriate protection requirements.
Examples: enzymes used in Polymerase Chain Reaction, gel component agars, primers
designed by the institution scientific experts used in in-house techniques.
03. Definitions
The following are the key definitions that should be noted:
In-vitro Diagnostic Medical Device means any medical device which is a reagent
product, calibrator, control material, kit, instrument, apparatus, equipment or system,
whether used alone or in combination, intended by the manufacturer to be used in vitro for
the examination of specimens, including blood and tissue donations, derived from the human
body, solely or principally for the purpose of providing information:
- Concerning a physiological or pathological state, or

- Concerning a congenital abnormality, or
Page 2 of 4
- To determine the safety and compatibility with potential recipients, or
- To monitor therapeutic measures.
Article 1, 2 (e) defines a device for performance evaluation as follows:

device for performance evaluation means any device intended by the manufacturer to be
subject to one or more performance evaluation studies in laboratories for medical analyses
or in other appropriate environments outside his own premises;
04. Research Use Products versus Devices for Performance Evaluation
As per EN 13612, Performance Evaluation means an investigation of the performance of

an in-vitro diagnostic medical device based upon data already available, scientific literature
and / or performance evaluation studies.
If a device is in a performance evaluation phase it can be made available to institutions or

laboratories to be subject to one or more evaluation studies intended to gather information
on performance evaluation parameters mentioned in Annex I of the Directive, which would
be used for its conformity assessment.
In this situation the manufacturer has to draw up a statement that the device conforms to
the requirements of the Directive, apart from the aspects covered by the evaluation and
apart from those specifically itemised in the statement, and that every precaution has been
taken to protect the health and safety of the patient, user and other persons.
As per Recital 30 of IVDD 98/79/EC ...it is essential that manufacturers notify the competent
authorities of the placing on the market of new products with regard both to the technology
used and the substances to be analysed or other parameters; whereas this is true in
particular of high-density DNA probe devices (Known as micro-chips) used in genetic
screening.
Therefore new parameters or technologies placed on the market by the manufacturer with
an intended medical purpose are within the scope of the Directive.
Recital 8 of the IVD Directive 98/79/EC states:
Whereas instruments, apparatus, appliances, materials or other articles, including software,

which are intended to be used for research purposes, without any medical objective, are not
regarded as devices for performance evaluation.
Therefore once a medical device is intended by the manufacturer to be used for medical
purposes it must either fall under the category of a product undergoing performance
evaluation for the purpose of CE marking or be a product which is CE marked. For research
use only products do not have an intended medical purpose. When a medical purpose has
been established based on sufficient and broadly agreed upon scientific, diagnostic and
clinical evidence, then the product must comply with the requirements of the Directive before
the manufacturer can place it on the market with an intended IVD use.
Page 3 of 4
05. Potential Situations where RUO Labeled Products could be used
The following are a list of possible situations where RUO products could be used and which
therefore fall outside the scope of the IVD Directive.
(a) RUO products used for Basic Research:

These are products used for research conducted to study all aspects of human life in
an attempt to better understand all underlying mechanisms. In such studies /
experiments animal and / or human models are used. No medical purpose is defined,
as the specimens taken are not being used for the purpose identified in the definition
of an IVD device in the IVD Directive, article 1 2(b). In such practice there is no
potential to misuse RUO products.
(b) RUO products used in Pharmaceutical Research:

This is research conducted to find new drug compounds. The RUO products are
used to verify the reactions to compounds in animal and / or human models. In such
practice there is no potential to misuse RUO products.
(c) RUO products used for a better identification and quantification of individual chemical
substances or ligands in biological specimens:
These products usually react with substances in a specimen through specific bindings
or chemical reactions e.g. monoclonal or polyclonal antibodies. The RUO products
are not sold by the manufacturers with an intended use within the definition of an IVD
as defined by the IVD Directive in article 1 2(b). They may more appropriately fall
under the category of products for general laboratory use. They may be used as an
element in a home brew diagnostic testing plan to determine the possibility of their
potential future use as IVDs.
(d) In house manufacturing of so called home brew kits by a legal entity for the purpose
of research:
This may involve the use of laboratory tools such as primers to improve the
performance of an existing IVD within a healthcare institution. The IVD Directive does
not cover this type of research
06. Other Situations
There are a number of other points which should be clarified, as follows:
(a) Use of raw materials which are labelled for research use only but which are
incorporated into a finished product:
Raw materials, which are used in this manner are a component of the end product
and as such are not regarded as IVDs in their own right. For the finished product to
be placed on the market as an IVD it will have been through conformity assessment in
line with the legislative requirements and will thus bear the CE mark. In this case the
raw material should not be labelled for research use only
Page 4 of 4
(b) So called research use products being tested against a comparator IVD product that
bears the CE mark:
In this case the fact that the so-called research use product is being assessed
against an existing CE marked IVD medical device implies a medical purpose and
therefore in this case the product more rightly is undergoing a performance
evaluation. It should not therefore be classified as an RUO product
(c) Market studies / Feasibility studies:

These are carried out to determine the suitability of the product prior to CE marking
for its intended use i.e. the medical purpose is clearly defined at this point. In case of
a market study the product is undergoing a performance evaluation rather than a
usage for basic research and therefore these studies fall within the scope of the IVD
Directive.
Market studies may also take place after CE marking. As long as the manufacturer
remains within the intended use of the CE marking, there is no issue with such
studies. However a manufacturer may decide to carry out a limited feasibility study
with a view to finding a new or expanded intended use. If the results are to be used
for inclusion in a future performance evaluation study then this study will fall within the
scope of the IVD Directive.
07. Labelling
It is recommended that products which clearly fall within the remit of performance evaluation
should be labelled as such to clearly distinguish them from products that fall outside the
scope of the IVD Directive.
Page 5 of 4
EUROPEAN COMMISSION
Consumer goods

January 2007
IVD GUIDANCES: Supply of Instructions For Use (IFU) and other information for
In-vitro Diagnostic (IVD) Medical Devices
Note
This guideline is part of a set relating to the application of EC Directive 98/79/EC on in vitro
Diagnostic Medical Devices (IVD Directive). It is not legally binding but has been jointly drafted by
various interested parties including Competent Authorities, the European Commission services
and industry. As such it can be taken as reflecting positions taken by those stakeholders in the
medical device sector and it is anticipated that they will be followed within the Member States and
help ensure uniform application of relevant provisions of the Directive.
Page 1 of 6
Commission europenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel - Belgium. Telephone: (32-2) 299 11 11.
1.0 Introduction
Annex I, section 8.1 of the IVD Directive 98/79/EC requires manufacturers, to supply the
information necessary for the safe and proper use of the device but does not provide a lot of
details on how this should be done (Annex I, section 8.1 also indicates that in duly justified and
exceptional cases no such instructions for use are needed for a device if it can be properly and
safely used without them).
Currently most instructions for use (IFU) are provided in paper format. However, these documents
can be very lengthy due to the need to include multiple printed versions in all the required
languages. Also, the cost of using paper can be high to both manufacturers and the environment.
Given that most IVDs are used by healthcare professionals in a clinical environment, with relatively
common access to computers and internet facilities, the possibility of issuing the IFU for
professional users in a format other than paper for example, by CD-Rom or DVD or through
different means of supply, for example, an Internet website, has been raised.
2.0 Scope
This guideline has been developed to advise manufacturers on how to provide IFUs and other
information for the safe and effective use of IVDs while taking into account any limitations or
safeguards to be employed appropriate for the user population and the media or means of supply
chosen. It should be read in association with the labelling requirements of Annex I, section 8 of
the IVD Directive 98/79/EC and with the language requirements of the transpositions of article 4(4)
of the IVD Directive 98/79/EC by the Member States.
3.0 Definitions
Instructions For Use (IFU)

Information provided by the manufacturer to inform the device user of the products proper
use and of any precautions to be taken as outlined in Annex I of the IVD Directive 98/79/EC.
Different media: other than paper form, e.g. CD-Rom, DVD, etc.
Different means of supply: provision of IFU by sales force, fax, internet, etc, rather than by
inclusion of paper IFU with the device itself.
Layperson
An individual who does not have formal training in a specific field or discipline (Source ISO
15197 and GHTF SG1 N043). (Training received by a diabetic patient for the safe use of, for
example, a glucose meter would not constitute formal training in the context of this
definition.
Professional Use
Use by personnel who have received specialised education and training with regard to
procedures utilising in-vitro diagnostic medical devices (Source EN 375).
Point of Care Testing

Testing that is performed near or at the site of a patient with the result leading to a
possible change in the care of a patient. (Source ISO 22870)
Self-Testing
Use in the home or similar environments by a layperson who will relate the results of the test
to him or herself (Source EN 376).
Page 2 of 6
4.0 Provision of the IFU for an IVD
The IVD Directive 98/79/EC clearly states that each IVD must be accompanied by the information
needed to use it safely and properly taking into account the training and the knowledge of the
potential user. The format in which the IFU shall be supplied is not specified in the IVD Directive.
However, the stakeholder consensus is that the appropriate media and means of supply is
dependant on the category of users.
IVDs can be split into two major categories with respect to their user population i.e.:
IVD for self testing

IVD for professional use
4.1 IVDs for Self-Testing
The IVD Directive defines such devices as those intended by the manufacturer for use by
laypersons in a home environment. Such a user need have no formal education and / or training
in using IVD tests. Self-test IVDs may be single use devices e.g. pregnancy tests or may be used
regularly by a layperson to monitor and control a particular disease e.g. glucometers for diabetes.
Typically, the result is used directly by the user who is the patient.
IFUs for IVDs to be used principally by laypersons shall always be provided in a paper format with
the device. This is because the user needs ready access to the IFU but cannot be assumed to
have access to the necessary information technology systems to access an electronic format or to
obtain the IFU by other means.
4.2 IVDs for Professional Use
In general, these IVDs are used in a healthcare institution e.g. medical laboratory, by
professionals who have a formal education and expertise in performing IVD tests and using IVD
instrumentation. These IVD tests are typically carried out repetitively and in a routine setting as
part of a healthcare service to the patient. Test results are interpreted by a healthcare
professional as part of the clinical management of a patient.
The IFU for IVDs intended for professional use can be provided in either paper or non paper form
or be supplied by different means such as:
providing a free of charge telephone number that can be contacted to have the IFU faxed,
mailed or e-mailed
making the IFU available at a fax call in number: fax polling
making it available through a designated internet website
or distribution through local sales organisation
Where the manufacturer elects to supply the IFU in a format other than paper, he shall provide a
free of charge contact number that can be used in order to have the IFU faxed, mailed or e-
mailed to the user.
Exception
IFUs for IVDs that are specifically intended by the manufacturer for use at point of care shall be
provided with each device in paper format. This is because there may not be ready access to
information technology systems at the point of use of the IVD.
5.0 Instructions for Use for Reagents, Reagent Kits, and Specimen Receptacles
for Professional Use
Page 3 of 6
This section outlines the conditions for the provision of the IFU in a format other than paper and
the minimum information that shall accompany an IVD if a manufacturer chooses to provide the
IFU by other means of supply. In all cases the manufacturer shall comply with the labelling
requirements outlined in Annex I, section 8 of IVD Directive 98/79/EC and with the language
requirements of the transpositions of article 4(4) of the IVD Directive 98/79/EC by the Member
States.
Note: Under article 10.2 of the IVD Directive, the manufacturer may be requested by the
Competent Authority to provide information on the labelling and the IFU. The information provided
at that moment should be equal to what is provided to the user irrespective of the media or means
of supply.
5.1 Conditions for the Provision of an IFU by other Media or Different Means of
Supply
1. The device must only be used as outlined in section 4.2
2. The manufacturer must ensure the proper design and function of the IFU for all media and
means of supply and document the verification and validation of same as part of the quality
system. This should be reviewed by a Notified Body, if applicable, as part of the conformity
assessment process.
3. The manufacturer, informed by the views of healthcare professionals, must have carefully
considered as part of his risk management, the risks associated with the provision of the
IFU by other media and means of supply especially in light of the product usage and the
professional users need. This should be reviewed by a Notified Body, if applicable, as part
of the conformity assessment process.
4. The user should be informed via the catalogue and / or the device labeling and / or any
other appropriate communication that the IFU for the device will be supplied by other
means to ensure that the user will have the IFU at the moment of use including any
necessary equipment to read the IFU.
5. Where IFUs are posted on an internet website, manufacturer must comply with the
additional requirements as defined in section 5.3 below.
6. The manufacturer must have a system in place to provide in a timely manner a paper
version of the IFU on request by the user at no additional cost.
7. The manufacturer must comply with the information requirements as defined in section 5.2
below when the IFU is provided by different means of supply.
8. For revisions to the IFU there shall be a clear indication on the device label to indicate to
the user that the IFU has been changed by reference to the latest revision.
9. If a revision to the IFU is necessary due to a field safety corrective action the manufacturer
must ensure that each user of the device, that is already placed on the market, is informed
about the change and provided with either the information on how to obtain the latest
version of the IFU by other means or be provided with the IFU as a paper copy or other
appropriate media.
5.2 Information to be Supplied with IVD when the IFU is Supplied by Different Means of
Supply
Page 4 of 6
The following information shall be supplied with each device when the IFU is provided by other
means:
The name and address of the manufacturer or authorized representative

The various options to obtain, free of charge, the applicable version of the IFU, except when
provided with the initial delivery of the instrument in a controlled way.
A unique reference (and any other information needed by the user) to identify the right
version of the IFU. This reference should allow the user to retrieve the applicable IFU using
any of the options provided.
When the IVD is considered dangerous for the user (e.g. chemical, radioactive and/or
biological risk), the outer container should include the appropriate hazard symbol(s) and the
corresponding risk and safety phrase numbers. But in case of specific biological risk, e.g.
where an IVD reagent includes substances of human or animal origin, or when no symbol is
available, a warning should be given in the additional information supplied with each device
concerning their potentially infectious nature taking into account the risk posed by the nature
or amount of the substances.
Where appropriate, any batch specific related information not provided in the IFU obtained
by other means (e.g. the value of a certain parameter to be used on an instrument or any
specific settings to be used on a particular type of instrument etc).
In case of revision to the IFU a clear indication on the device to alert the user that IFU has
changed. This also applies in situations where the IFU is changed as a result of a safety field
corrective action.
This information can appear on the device label if space permits or can be provided on a separate
sheet included with the device.
The following is an example of how this information may be presented with an IVD when
the IFU is provided by other means of supply:
PRODUCT NAME CATALOG NUMBER

Manufacturer/Authorised Representative Name
Valid edition of the instructions for use: 2003-10
If you do not have this edition, you can obtain it free of charge:
1. from Internet under www.edma-ivd.be/IFU
2. by calling up free of charge the following phone number: +32 2
SAFETY WARNING
The calibrators have been prepared exclusively from the blood of donors tested individually and
shown by official approved methods to be free from HbsAg and antibodies to HIV 1, HIV 2 and HCV.
As the risk of infection cannot be ruled out with certainty, however, the product must be handled just
as carefully as patient specimens.
Note 1: This is only an example and is not binding for format or content.
5.3 Internet Website Additional Requirements for Provision of IFU
In addition to the conditions outlined in section 5.1, the manufacturer shall also meet the following
requirements for the supply of the IFU by Internet website:
Page 5 of 6
Provide clear instruction to the user to readily locate the IFU on a dedicated area of the
Internet website.
Adhere to appropriate data security requirements in terms of:
- Physical security (availability of hardware and software and intrusion protection)
- Server certification (to ensure the user logs on to the appropriate server).
File format - IFU should be available in a generic read-only file format, such as PDF (portable
document format). In any case, the manufacturer must ensure that documents displayed and
printed via this route are identical in content to those included in the IVD kit when made
available in paper format.
Access to the reader of the provided file format is necessary (for example by providing a link
for download).
6.0 Instructions for Use for instruments / Software for Professional Use
Instructions for use for instruments (sometimes also called users guides) shall be provided in a
paper copy or on different media with the initial delivery of an instrument but shall not be provided
by different means of supply at the initial delivery of the instrument.
For changes as part of / an upgrade and / or field corrective action, the manufacturer shall
1. include any changed page of the IFU provided in a paper copy with clear instructions on
how to include them into the initially provided IFU and which old pages to be removed or
2. include a full new paper copy or
3. include a new copy of the IFU on a CD-Rom (or other suitable format other than paper)
with clear instructions to destroy the previous version of the CD-Rom.
Page 6 of 6
Form for the registration of manufacturers and devices
In Vitro Diagnostic Medical Device Directive, Article 10
(Version January 2007)
A. Identification of the Competent Authority

6100 Competent Authority code 1)
6110 Competent Authority name
6120 Country code 2)
6140 City 6150 Postal code
6160 Street, number 6165 PO box
6170 Telephone number 6180 Fax number
6190 E-mail
B. Identification of the registration

6200 Date of registration 3) 6210 Registration number 4)
6220 Indicate if this is a first registration, a change of information, a discontinuation or a withdrawal of a registration: 5)
first change of address discontinuation by manufacturer
significant change of product withdrawal by Competent Authority
6230 If change, discontinuation or withdrawal provide previous registration number
6240 Status of the organization making this registration application: 6)
Manufacturer Authorized representative

City Date
Name Signature...
City ............................................................................. Date ..........................................................................
C. Identification of the Manufacturer 7)

6250 Manufacturer code 8)
6260 Manufacturer name, long
6265 Manufacturer name, short
Contact point
6320 Name 6330 Telephone number
6340 Fax number 6350 E-mail
D. Identification of the authorized representative9)

6370 Representative code 8)
6380 Representative name

Contact point
6400 Name 6410 Telephone number
6420 Fax number 6430 E-mail
City Date
Name Signature...
E. Identification of the concerned device

6440 Classification of the concerned device 10)
Device of List A, Annex II
Device of List B, Annex II
Device for self-testing not listed in Annex II
Other device (all devices except Annex II and self-testing devices)
6445 Notification according article 10(4)
New product 11)
6446 Device Category Code 12)
06
Device Category Term 12)
6447 In local language 13)
6448 In English
In vitro diagnostic devices
E.1 Information related to reagents, reagents products, calibration and control materials:
In terms of common technological characteristics and/or analytes
6450 Nomenclature system used 14)
GMDN EDMS
15)
6460 Local language
6465 Generic Device Group Code Generic Device Group Term16)

6470 In local language 13) 6480 In English
Short description 17)
6490 In local language 13) 6500 In English
E.3 Additional information for Annex II and self-testing devices: Identification of the device
(Note: this form does not contain data related to analytical or diagnostic parameters, or the outcome of
performance evaluations. Instead this will be available in the instructions for use and held on file by the
manufacturer)
6605 Device Type 18)
6610 Conformity checked by Notified Body 6615 Notified Body identification number
6620 In conformity with Common Technical Specifications (for Annex II List A devices)
City Date
Name Signature...
E. Identification of the concerned device

6440 Classification of the concerned device 10)
Device of List A, Annex II
Device of List B, Annex II
Device for self-testing not listed in Annex II
Other device (all devices except Annex II and self-testing devices)
6445 Notification according article 10(4)
New product 11)
6446 Device Category Code 12)
06
Device Category Term 12)
6447 In local language 13)
6448 In English
In vitro diagnostic devices
E.2 Information related to other IVDs: appropriate indications

6550 Nomenclature system used14)
GMDN EDMS
15)
6560 Local language
6565 Generic Device Group Code Generic Device Group Term16)

6570 In local language 6580 In English
Short description17)
6590 In local language 6600 In English
E.3 Additional information for Annex II and self-testing devices: Identification of the device
(Note: this form does not contain data related to analytical or diagnostic parameters, or the outcome of
performance evaluations. Instead this will be available in the instructions for use and held on file by the
manufacturer)
6605 Device Type 18)
6610 Conformity checked by Notified Body 6615 Notified Body identification number
6620 In conformity with Common Technical Specifications (for Annex II List A devices)
City Date
Name Signature...
Notes on completing the form for the registration pursuant to article 10 IVD-Medical Device Directive
1)
Composed of the two-letter country code of ISO 3166 followed by a slash, CA and the number of the
Competent Authority in the state, e.g.: ES/CA01.
2)
Two-letter code of ISO 3166 (1993), e.g.:
AT Austria IE Ireland
AU Australia IS Iceland
BE Belgium IT Italy
BG Bulgaria LI Liechtenstein
CA Canada LT Lithuania
CH Switzerland LU Luxembourg
CY Cyprus LV Latvia
CZ Czech Republic MT Malta
DE Germany NL Netherlands
DK Denmark NO Norway
EE Estonia PL Poland
ES Spain PT Portugal
FI Finland RO Romania
FR France SE Sweden
GB United Kingdom SI Slovenia
GR Greece SK Slovakia
HU Hungary TR Turkey
3)
YYYY-MM-DD
4)
To be assigned by the Competent Authority. Composed of the two-letter country code of ISO 3166
followed by a slash, the code of the Competent Authority, a slash and an internal registration number, e.g.:
ES/CA01/nnn...
5)
"Change" must be marked for all types of reported changes. Only one change may be reported per
notification of change (e.g. either change of address or discontinuation / withdrawal of IVD medical device).
change of address: A notification of change concerning the address must contain the relevant
manufacturer / authorized representative code and the complete address block
to be changed. No further data should be submitted.
significant change of product: In case a significant change of IVD medical device is reported, "change
of product" must be marked and the "previous registration number" must be
given. The form must be filled in completely (the definition of significant change
must be generated)
discontinuation by manufacturer: Discontinuation of placing on the market.
withdrawal by Competent Authority: Withdrawal of devices or group of devices as identified in section E.
6)
References to the IVD MDD 98/79/EC:
Manufacturer (art. 10(1)); authorized representative (art. 10(3)).
7)
The address of the manufacturer should be stated and should be the same as the manufacturers address
stated on the label
8)
Assigned by the manufacturer or the authorized representative. This code is always composed of the two-
letter country code of ISO 3166 followed by a slash and a standardized coding system for manufacturers
and authorized representatives adopted by a state. Only one system has to be used within a state.
9)
To be filled in if the manufacturer has nominated an authorized representative.
10)
Multiple entries are not possible.
For all devices: fill E.1 or E2.
For Annex II and self-testing devices: fill also E.3
11)
According article 10(4), a device is new if:
- there has been no such device continuously available on the Community market during the previous three
years for the relevant analyte or other parameter
- the procedure involves analytical technology not continuously used in connection with a given analyte or
other parameter on the Community market during the previous three years
12)
Device Category , Generic Device Group and Device Type are based on prEN ISO 15225
13)
If available
14)
Generic Device Group code and term have to be taken from the Global Medical Device Nomenclature
(GMDN) when available. If the GMDN is not ready in time, device code and term will have to be taken from
the European Diagnostic Market Statistics Nomenclature (EDMS). The EDMS is available on the following
WEB site: http://www.edma-ivd.be.
15)
Two-letter code of ISO 639 (1988), e.g.:
bg Bulgarian lt Lithuanian
cs Czech lv Latvian
da Danish mt Maltese
de German nl Dutch
el Greek no Norwegian
en English pl Polish
es Spanish pt Portugese
et Estonian ro Romanian
fi Finnish sk Slovak
fr French sl Slovenian
hu Hungarian sv Swedish
is Icelandic tr Turkish
it Italian
Only one Non-English language is permitted to be used in " device term", "short description" and "device
category term" (No. 6470, 6490, 6540).
16)
If Generic Device Group code and term are taken from the European Diagnostic Market Statistics
Nomenclature (EDMS):
IVD Reagents: Level 5 (Method) or if not available Level 4 ("Parameter") has to be used
IVD Instruments: Level 3 ("Subgroup") of the instrument grouping has to be used.
If Generic Device Group code and term are taken from the Global Medical Device Nomenclature (GMDN):
Preferred term has to be used
17)
Only compulsory, if no right device code/term has been given. Please use appropriate terms or a short
phrase. The phrase can include basic features of the product such as, for example, the intended use, the
aspects governing its
18)
Manufacturer product name
EUROPEAN COMMISSION
Directorate B, Unit B2 Health technology and Cosmetics
MEDICAL DEVICES
-
Guideline for the CE marking of blood based in vitro diagnostic medical devices for vCJD based on detection of abnormal PrP
MEDDEV 2.14/4
January 2012
Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices
Foreword
This guideline is not legally binding. This guideline has been produced further to the addition of vCJ D blood screening assay to Annex II List A of Directive 98/79/EC and the
establishment of Common Technical Specifications for these assays.
It has been elaborated by an expert group including experts from Member States' Competent Authorities, National Public Bodies, Notified Bodies, Commission services, as
well as industry trade associations.
The guideline is limited to assays for abnormal PrP in human blood plasma.
1
Introduction
The appearance of cases of a new form of Creutzfeldt-Jakob Disease (CJD) in young adults followed the outbreak of bovine spongiform encephalopathy (BSE) in the United
Kingdom. Compared with sporadic CJD, the new form of the disease, termed variant CJD (vCJD) has a characteristic pathology, including a different tissue distribution pattern,
and clinical presentation. Up to July 2010 there had been 173 cases in the United Kingdom and of the order of 200 world-wide. The pathology and epidemiology of the disease
are novel, and four apparent transmissions of infection by blood transfusion from donors later developing vCJD have been identified (resulting in three clinical and one
asymptomatic disease courses in the recipients at the time of death). Infection is currently undetectable in the preclinical phase so that the effect of precautionary measures is
difficult to judge and studies of prevalence are difficult to carry out. However, a number of in vitro diagnostics (IVD) manufacturers are working on the development of blood
based assays for vCJD. The candidate assays are difficult to validate because of the small number of relevant cases and samples obtained from them and because of the
nature of the disease and the infectious agent. This guideline gives some minimal criteria that such tests should meet and their scientific background.
Prion diseases including vCJD, BSE, scrapie, and others are associated with the accumulation of a normal host protein (PrP) in an abnormal isoform termed PrPres , PrPtse or
PrPsc . In this document, this will be referred to as abnormal PrP. Many assays in development are based on the detection of abnormal PrP in blood but other approaches
might be followed. Current views are that the abnormal protein catalyses the conversion of the normal to the abnormal conformation and is considered as the infectious agent.
However, the exact nature of the infectious agents is still uncertain and it is thus not possible to establish a clear correlation between the number of abnormal PrP molecules
and infectivity. In particular, aggregates consisting of different numbers of molecules of the protein are believed to be different in their infectivity so that the mass of abnormal
PrP alone is not an accurate measure of infectivity. The presence of abnormal PrP should therefore be considered only as a surrogate of infection rather than a direct measure
of it. In addition in an infected individual and between infected individuals, these various forms distribute differently from tissue to tissue, both in quantitative and qualitative
terms. Furthermore, the different aggregated forms are likely to vary in their sensitivity to conditions such as proteolysis or denaturing agents which are used in tests for the
presence of abnormal PrP. As a consequence, the ratio of infectivity to mass of abnormal PrP may depend on the means used to assay it as well as the tissue examined.
Validated blood tests could be used for various objectives such as studies of prevalence, screening and/or monitoring the blood supply, assessing infection in potentially
infected groups, monitoring the effectiveness of therapies or other areas of interest. They could provide a sound basis for policy development. However, it should be
appreciated that these objectives differ in nature and the analytical performance needed from the designed test may thus differ
In Europe, blood screening markers (e.g. HIV, HBV, HCV) are listed in Annex II list A of Directive 98/79/EC (IVD Directive). The IVD Directive defines minimal requirements
for assays to be placed on the European market (CE marking procedure). Blood screening assays undergo a more stringent assessment, including involvement of Notified
Bodies and fulfilment of Common Technical Specifications (CTS). In principal, vCJD blood screening tests should fulfil minimal quality requirements equivalent to other IVDs
qualified for blood screening. Recognizing that the current CTS cannot be adapted easily to vCJD assays, this guideline has been generated to identify basic quality
requirements for vCJD assays.
This guideline defines the minimum desirable properties of a test for vCJD potentially suitable for blood screening. If other applications of the tests are proposed e.g.
confirmatory, diagnostic, monitoring, these tests shall be assessed with similar rigour to screening tests and the evaluation of the performance of the tests shall be specifically
adapted to the intended use.
The use of any test for blood screening is a matter for individual Member States, considering different aspects such as epidemiology, existing precautionary measures,
features of the assays, specific needs.
Scope
This guideline is intended for manufacturers, Notified Bodies and Competent Authorities.
The guideline is limited to assays for abnormal PrP in human blood plasma. For assays based on other approaches be developed or using other blood components as the
testing substrate other considerations will apply.
This guideline deals with test methods using plasma as test matrix and abnormal PrP as the analyte. The principle described could be adapted to other blood components.
The primary but not the sole routine application of such tests is assumed to be the screening of blood donations. As such, the validation criteria proposed in this guideline have
been designed for this primary objective.
Sample preparation
The analyte may be aggregated and have amyloid properties. Handling of the sample may therefore affect the state of the analyte and its detection by a given assay in
unpredictable ways. Consideration should be given to the possible effects of the specimen receptacles, and anticoagulant used. In particular the possible loss of prion protein
through binding to the type of specimen receptacle that will be used if the test is implemented should be considered. Due to the nature of the analyte, particular attention
should be paid to potential effects of pre-analytical procedures on its aggregation state (freezing/thawing, centrifugation).
As the amount of abnormal protein present is likely to be small, a pre-concentration procedure may be required.
Sample selection and characterization
The specific characteristics of samples used to assess the performance characteristics of any assay can have a significant impact on the outcome of the assessment of
performance. In the case of vCJD it has to be recognized that vCJD samples are poorly characterized. In particularly, the commutability of animal samples and spiked human
samples with actual patient samples is unknown. Therefore it is important to ensure that:
The samples used should be traceable and available information on its characteristics and preparation be duly documented
In the case of animal models, it should be clear whether the material was from an infected animal in a clinical or pre-clinical phase.
The final evaluation against the CTS requirements should be state of the art at the time of the evaluation. Samples from animals in the clinical phase can be used for the
assessment of the sensitivity criteria.
Blinding of specimens
There has been previous experience of claims of successful detection of abnormal PrP in non-blinded tests and subsequent failure to correctly detect blinded samples.
Therefore, it is important that a component of the evaluation should include panel of blinded samples.
Comparison with another blood based in vitro diagnostic medical device for vCJD
According to the current CTS GENERAL PRINCIPLE 3.1.4, All performance evaluations shall be carried out in direct comparison with an established device with acceptable
performance. Clearly this will not be possible for the first test applying for CE marking.
Nevertheless, if more than one assay applies for CE marking, it would be desirable to evaluate them in a coordinated manner as it would allow better interpretation of
performance data.
Analytical sensitivity
Analytical sensitivity may be expressed as the limit of detection, i.e. the smallest amount of the target marker, in this case abnormal PrP, that can be precisely detected.
For tests based on the detection of abnormal PrP the target can be an aggregated form of protein, where different tissues (brain, spleen or blood) are likely to have a different
range of aggregated forms and different test procedures may detect different aggregated forms to different sensitivities. Analytical sensitivity established on one source may
therefore be different from analytical sensitivity defined on another.
The form of abnormal PrP in brain homogenates might differ from that in spleen homogenates. The form in blood is likely to be different from both, but an assay that performs
well on the different forms found in spleen and brain might also detect the form found in blood.
The precise level of infectivity in human blood is not known. Based on animal models it is estimated that there are approximately 1 to 10 infectious doses per ml whole blood.
This is consistent with the transmission of infection by blood transfusion. Infected human brain has been titrated in animals and the titre is estimated at approximately 106 to
108 per gram of brain. This figure is uncertain because of the species barrier to infection which would make the titre lower in the experimental animals used for the titration than
in humans by an indeterminate factor.
However, assuming that within a given species the infectivity in brain is in the same form as in blood an assay must be able to detect at least a 1 in 104 dilution of 10%
homogenate of infected brain on one set of extreme assumptions (10 infectious units per ml of blood and 106 infectious units per gram of infected brain) and a 1 in 107 dilution
of 10% homogenate of infected brain 1 on the other (1 infectious unit per ml of blood and 108 infectious units per gram of infected brain). Based on the same reasoning, as
spleen has about one hundred to one thousand fold less infectivity than brain the corresponding extreme figures for 10% homogenate of infected spleen are 1 in 10 and 1 in
105.
In view of the difficulties in defining the meaning of analytical sensitivity for abnormal PrP , it is unreasonable to demand the highest sensitivity where a test has been proven to
identify the marker in blood. The lower figures therefore seem the most suitable as a minimum acceptable requirement, i.e. the test must detect at least a 1 in 104 dilution of a
10% homogenate of vCJD infected human brain and a 1 in 10 dilution of a 10% homogenate of vCJD infected human spleen.
Working reagents of 10% homogenates of brains from patients infected with vCJD have been established by the World Health Organisation (WHO) following an international
collaborative study and are available from the National Institute of Biological Standards (NIBSC) in the United Kingdom. NIBSC also holds and distributes preparations of 10%
homogenates of spleens from patients infected with vCJD. The spleen preparations have no WHO status but have been calibrated in studies at NIBSC against the WHO
working reagents.
1 Reference material WHO number: NHBYO/003

Analytical specificity
Analytical specificity means the ability of the method to determine solely the target marker, in this case abnormal PrP.
As prion diseases are amyloidoses and neurological, other similar diseases may interfere with the tests designed for detection of the vCJD marker. At least 100 blood (plasma)
samples should be tested from the diseases selected and justified by the manufacturer based on the principles of the test and could include the following:
- patients with other diseases involving aggregated misfolded proteins including conditions with systemic amyloidosis
- patients with neurological diseases such as Parkinsons disease, Alzheimers disease, Huntingtons disease
- patients with vascular dementia
- rheumatoid factor positive individuals
- multiparous women
- patients with diabetes.
The 100 samples should not be constituted from only one category, as wide a distribution as possible should be tested.
It is possible that a satisfactory blood test for vCJD will also detect other forms of CJD. If there is less abnormal PrP in blood in the other forms of the disease the test may
discriminate between vCJD and other forms. It is believed that there is greater involvement of peripheral, non neurological tissues in the pathogenesis of vCJD compared to
other prion diseases. At present there is no epidemiological evidence for the presence of infectivity in blood of patients with other forms of CJD but the study design should
reflect this theoretical possibility At least 20 samples from such patients should be tested. Analytical specificity should be known. If other forms of CJD are detected, it would
be preferable that the test can distinguish vCJD from these other forms.
Diagnostic sensitivity
Diagnostic sensitivity is defined as the probability that the device gives a positive result in the presence of the target marker, in this case abnormal PrP. The objective of testing
is to detect infected but asymptomatic individuals. For blood the aim is to prevent infected donations from being transfused and it is possible that an infected donor may not yet
have infectious material in the blood. The diagnostic sensitivity must be demonstrated but the number of relevant samples is currently so small that the statistical significance
will be low.
Considering the rarity of human presumed infected vCJD samples, it would be preferable to demonstrate the sensitivity of the test using animal samples (e.g. sheep, mouse,
hamster, non human primate and finally human samples.
Samples from animal models such as scrapie of sheep or laboratory models including hamsters , mice or transgenic mice may be more readily available but the assays will be
designed to work optimally on human samples, and this is likely to affect both sensitivity and specificity. In such cases, a lower sensitivity than in human samples is acceptable
when justified. Since the specificity might be affected, the panels from animal models should also include negative controls.
It may be necessary to replace components of a vCJD assay (e.g. monoclonal antibodies) for the optimal adaption of the assay to a certain animal model. At the current stage
of knowledge justified modifications should be accepted for providing evidence for the proof of principle.
It is likely but not proven that all humans and most animals in the clinical stage do have infectivity in the blood. Samples of blood or plasma from humans or animal models
(e.g. non-human primates) that are known to be infectious (for example because they have transmitted infection experimentally or through transfusion) are very rare, but a
satisfactory assay should detect such materials at a high rate using as many samples as reasonably possible and available.
- Specimen from appropriate animal models:
As many specimen as reasonably possible and available, and at least 10 specimens, shall be tested. The diagnostic sensitivity should be at least 90%.
- Specimen from humans with known clinical vCJD:
- Where there are ten or more specimen from humans with known clinical vCJD the diagnostic sensitivity should be at least 90%.
- Where there are six to nine specimens from humans with known clinical vCJD there should be no more than one false negative result and all available specimens
shall be tested. This only applies in case where 10 specimens from humans with known clinical vCJD are not available
Once sensitivity at the clinical end stage has been demonstrated and suspected pre-clinical patients are identified via population screening, further studies must be undertaken
to attempt to establish the time in the incubation period when the assay gives a positive signal. There are very few samples from humans known to be infected but
asymptomatic at the time of sampling. No scientifically sound requirement can be formulated to specify when during the incubation period the assay should give a positive
result but studies should be undertaken to show that the assay can detect asymptomatic infection to some unspecified degree. From animal models including transfusion
experiments in sheep, blood may become infectious at about one third through the incubation period. The incubation period for vCJD in humans is not known except for the
cases of transmission of infection through blood, where the incubation periods were approximately six to ten years from transfusion from a donor developing vCJD up to three
years after the donation was given. The level of infectivity in the blood at this stage is not known, nor how it compares to the end stage. Further more as the route of infection
may influence incubation period this can provide only a very approximate guide.
It is possible to prepare samples from animal models such as experimentally infected sheep or primates, where the pathogenesis and incubation periods will be different from
humans. It is known that blood from infective animals become infectious before clinical onset. Therefore studies in animal models should indicate that the assay gives a
positive signal at least some time before clinical onset.
Diagnostic specificity
Diagnostic specificity is defined as the probability that the device gives a negative result in the absence of the target marker, in this case abnormal PrP. The consequences of
a false positive result due to insufficient diagnostic specificity will be severe. It is desirable for any confirmatory test to be based on a different principle. A high specificity for
both primary and confirmatory tests is essential.
A satisfactory assay will achieve a diagnostic specificity greater than or equal to 99.5%. For the future assays, and in the absence of a true confirmatory assay, a higher level of
specificity is desirable. This implies testing of at least of 5000 samples, as it is defined in the CTS for other blood screening markers. It may be preferable to test samples from
areas with no known cases of vCJD or BSE. In practice the assay may detect cases of classical CJD which would arise even in such geographical regions, but it is statistically
unlikely that in an area of low vCJD prevalence a positive donor for either vCJD or classical CJD will be found in this number of samples.
EUROPEAN COMMISSION
DG ENTERPRISE
Directorate G
Unit 4 Pressure Equipment, Medical Devcies, Metrology

MEDDEV 2.15 Rev 2
July 2001
Committees / Working parties relevant for Medical Devices
Committee Set up under the Directive
AIMD
MDD
IVDD
Scientific Committee
MDEG Medicinal Products
and Medical Devices
Steering
GHTF
Committee
Study
NBOG
Groups
Eudamed
MRA Prep. Group
CETF US - CABs
BSE/TSE
Latex
MSOG
(Classification)*
(Drug/Device)*
(IVDD-CTS)*
Committee Directive 98/34 on

Standards and Technical Regulations
* dormant
EUROPEAN COMMISSION
Consumer Goods
MEDDEV. 2.15 Rev 3

December 2008
Committees/Working Groups contributing to the

implementation of the Medical Device Directives
Note
This guideline is giving information on the practical working structures in implementation
of the medical device directives. It is not legally binding but has been jointly drafted by
various interested parties including Competent Authorities, the European Commission
services and industry. As such it can be taken as reflecting positions taken by those
stakeholders in the medical device sector and it is anticipated that they will be followed
within the Member States and help ensure uniform application of relevant provisions of
the Directive.
INTRODUCTION
A number of Committees and Working Groups play a role in the implementation of the
medical device directives (Directives 93/42/EEC on medical devices, 90/385/EEC on
active implantable medical devices and 98/79/EC on in vitro medical devices). This
document gives an overview of the existing groups and their functions, participation in
these groups and their working practices. These groups either have a legally defined role
in the implementation, such as the Committee on Medical Devices, or they contribute to
the harmonized implementation and application of the Directives and support the
Commission in the development of new policies and initiatives in relation to medical
devices.
1. EXISTING GROUPS AND THEIR FUNCTIONS
1.1. Committees
1.1.1. Committee on Medical Devices
The Committee on Medical Devices has specific regulatory powers as set out in the
medical device directives, including for example changing classification rules,
implementation of Eudamed, adoption of Community health monitoring measures or
amendments of non-essential elements relating to the clinical investigation requirements.
Measures taken by the Committee are legally binding. An example of such measure is
the Commission Directive 2005/50/EC on the reclassification of hip, knee and shoulder
joint replacements. The Committee has its own rules of procedure and is composed of
Member States representatives.
1.1.2. Committee under Directive 98/34/EC
The Directives on medical devices also make reference to the Committee set up under
Directive 98/34/EC, dealing with standardization. This is related to the procedures
relating to mandates for standardization and to be used when challenging harmonized
standards, either as such or in the context of safeguard clauses.
(http://ec.europa.eu/enterprise/standards_policy/general_framework/index.htm)
1.1.3. Scientific Committees
The Commission is assisted by Scientific Committees and in relation to medical devices

in particular by the Scientific Committee on emerging and newly identified health
risks (SCENIHR) which provides for independent scientific expertise.
(http://ec.europa.eu/health/ph_risk/committees/committees_en.htm).
1.2. Working Groups1
The Commission and Member States are supported in the implementation of the
Directives of medical devices by a number of Working Groups. These Working Groups
have, inter alia, developed a number of guidance documents, the so-called MEDDEVs,
which are available on the Commission Website
1
The term Working Group is used here as an umbrella term for all types of groups, also those
that are called differently, such as Competent Authority Group, expert group etc.
(http://ec.europa.eu/enterprise/medical_devices/meddev/meddev_en.htm). Similarly, the
Commission has started to publish consensus statements on its website on issues on
which MDEG reached consensus.
These documents do not have regulatory power and can not set legally binding rules. But
they have been jointly drafted by various interested parties including Competent
Authorities, the European Commission services and industry. As such they can be taken
as reflecting positions taken by those stakeholders in the medical device sector and it is
anticipated that they will be followed within the Member States and help ensure uniform
application of relevant provisions of the Directive.
1.2.1. General coordination/Policy and Strategy related Groups
A broad forum for coordination encompassing all stakeholders is the Commission's

Medical Devices Experts Group (MDEG), in which national competent authorities,
representatives of the European standards bodies, Notified Bodies, European trade
federations, representing also Small and Medium Enterprises, and, as the case may be, of
other stakeholders, such as patient organisations participate. MDEG aims at discussion
and coordination of strategic issues and of issues relating to implementation and
enforcement of the medical device Directives, as well as the coordination of and
overseeing the work of other Working Groups. The notes of the MDEG meetings are
published on the Unit's website
(http://ec.europa.eu/enterprise/medical_devices/implementation_en.htm).
Member State representatives meet in the so-called Competent Authority (CA) meetings.
These are organized by Member States on the occasion of their respective, rotating
Council Presidency. Competent Authorities only also meet in the closed sessions of the
Medical Devices Experts Group (MDEG/CA).
1.2.2. Standing Working Groups
There are a number of Working Groups that address issues of implementation that
require constant coordination between Member States. These are in particular the
Compliance and Enforcement Group (COEN) and Notified Bodies Operational Group
(NBOG), which coordinate the implementation of Member States competencies under
the Directive on medical devices. These groups are under the oversight of the Competent
Authorities.
Similarly, the Medical Device Vigilance Experts group, the Medical Device Borderline
and Classification Group, the Working Group on Clinical Investigation and Evaluation
and the IVD Technical Group are working groups dealing with the coordination of
general implementation.
1.2.3. Special Issue Working Groups
The MDEG has in addition set up several working groups, dealing with issues such as
European Database on Medical Devices (EUDAMED), New and Emerging Technologies,
etc.
1.3. Notified Bodies Group
The Commission services have set up the Notified Bodies group (NB-MED) in order to
ensure close cooperation between Notified Bodies active in the medical device field.
Such cooperation is needed for a consistent application of the conformity assessment
procedures.
2. PARTICIPATION
Participation in the Committee on Medical Devices is restricted to Member State

representatives.
The Competent Authority meetings, the Compliance and Enforcement Group (COEN)
and Notified Bodies Operational Group (NBOG) are also restricted to representatives of
the Member States, respectively the Competent Authorities/Designating Authorities.
The other Working Groups are generally open to all invited stakeholders, unless the
meeting is clearly specified as a closed meeting. Stakeholders include in particular
industry representatives, patient and user representatives, and representatives of Notified
Bodies. In order to ensure balanced participation and representation and to maintain a
workable meeting size, participation is however restricted to European umbrella
organizations. Therefore, neither representatives of single manufacturers, patients or
users, nor national trade associations can generally participate in these meetings.
3. FREQUENCY OF MEETINGS
The Committee on Medical Devices only meets when necessary, there is no regular
meeting frequency. The MDEG as well as the CA meetings take place twice a year. The
meeting frequency of the other Working Groups depends on the need, but usually each
Working Groups will meet between 2 and 4 times a year.
4. WORKING PRACTICES
In the interests of having efficient and effective meetings the Working Groups aim to
work in accordance with the following work practices:
Each Group will have clear terms of reference, endorsed by MDEG/CA,
Each Group will have a yearly working program and produce annual activity reports,
Meetings will be forecasted early in advance,
If there are insufficient items for the agenda a meeting will be cancelled or postponed,
A preliminary draft agenda should be set at least one month prior to the meeting,
Reports or updates should be submitted in writing prior to the meeting for discussion
at the meeting,
CIRCA will be further utilised to coordinate meetings and circulate documents,
All papers should be submitted no later than two weeks before a meeting,
The Commission, and, where applicable, in conjunction with the Chair, will make all
documents available on CIRCA at least two weeks prior to a meeting,
Draft notes/operational conclusions should be produced, in principle, within one

month following a meeting.
5. OVERVIEW OF THE COMMITTEE AND WORKING GROUP STRUCTURE
Committee on Medical Devices

Committee 98/34
Scientific Committee
Policy and Strategy/General Coordination

CA Meetings MDEG
(partly Authorities only)
Standing Working Groups
COEN NBOG Vigilance Classification Clinical IVD
and Investigation Technical
Borderline and Evaluation Group
(CIE)
Special Issue Working Groups (WG)
EUDAME New and E- Software MRA WG PVC- BSE/
D WG Emerging labelling WG (inactive) DEHP TSE WG
Medical WG WG (inactive)
Device (inactive)
Technologies
(NET)
NB-MED
Member States
All Stakeholders
(but in some cases
closed sessions
possible)

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MEDICAL DEVICES : Guidance document

GUIDELINES RELATING TO THE APPLICATION OF :

THE COUNCIL DIRECTIVE 90/385/EEC ON ACTIVE IMPLANTABLE MEDICAL DEVICES

THE COUNCIL DIRECTIVE 93/42/EEC ON MEDICAL DEVICES

Definition of "medical devices"

I. FIELD OF APPLICATION - DEFINITIONS

1. Directive 93/42/EE on medical devices

II. CLASSIFICATION OF MEDICAL DEVICES COVERED BY DIRECTIVE

III. CONFORMITY ASSESSMENT PROCEDURES(*):

IV. CUSTOM MADE DEVICES(*):

V. DEVICES INTENDED FOR CLINICAL INVESTIGATIONS(*):

VI. MEDICAL DEVICE VIGILANCE(*):

VII. USE OF LANGUAGES(*):

VIII. TRANSITIONAL PERIOD(*):

I. FIELD OF APPLICATION - DEFINITIONS

1. Directive 93/42/EEC on medical devices

1.1 Definition of "medical devices"

The definition of the term "medical device" together with the

Following the latter directive, accessories are by definition medical

Accessories are therefore following Directive 93/42/EEC to be

Medical devices are defined as articles which are intended to be used

Following this concept, raw materials, components or intermediate

Spare parts supplied for replacement of existing components of a

- sterilisation of medical devices supplied non-sterile

The aforementioned activities are normally not manufacturers

A particular consideration in this context needs to be given for the

d) medical - toiletry purpose

The definition of "medical device" should be understood to include

- tooth brushes, dental sticks, dental floss;

Examples for products, where depending on the circumstances, a

e) aids for handicapped persons

In the case of equipment intended for alleviation of or compensation

- acoustic signals at traffic lights,

The following distinction can be made : software influencing the

Software related to the functioning of a medical device may be part of

In the case of software intended for use with multipurpose informatic

- calculation of anatomical sites of the body,

There is no medical purpose in the case of software used for

Products with a multiple purpose which may be used occasionally in a

- multipurpose PC, printer, scanner, ...

1.2 Definition of "accessory"

The question whether a product is a "device" or a "accessory" has not

The definition of "accessory" requires that the accessory is specifically

Examples for accessories depending on defined circumstances of device-

- sterilizers for use in a medical environment,

1.3 Definition of "manufacturer"

Users in-house manufacturing

The Directive defines a manufacturer as the natural or legal person

MEDICAL DEVICES : Guidance document

MEDDEV 2. 1/2 rev 2

GUIDELINES RELATING TO THE APPLICATION OF :

FIELD OF APPLICATION OF DIRECTIVE 90/385/EEC

I. FIELD OF APPLICATION - DEFINITIONS

II. CLASSIFICATION OF MEDICAL DEVICES COVERED BY DIRECTIVE 93/42/EEC(*):

III. CONFORMITY ASSESSMENT PROCEDURES(*):

IV. CUSTOM MADE DEVICES(*):

I. 2. DIRECTIVE 90/385/EEC ON ACTIVE IMPLANTABLE MEDICAL DEVICES

2.1. Active implantable medical device

a) - implantable pulse generator for pacing including the electrode

b) - implantable drug administration device with or without catheter

2.1.3. An active medical device is defined as "implantable" if it is "totally or partly introduced,

MEDICAL DEVICES : Guidance document