ICH-GCP

Agenda

§History of development of Clinical Trial

Regulations

§The ICH process

§The ICH-GCP Guidelines

 How did these principles evolve?

•The Elixir Sulfanilamide incident

• The infamous Tuskegee Syphilis Study (Alabama, U.S.A.,

1932-1972)

•In 1946, 23 Nazi physicians were put on trial at Nuremberg

for “research atrocities” they had performed on prisoners

•The Thalidomide Tragedy

•The Harvard Fraud

•
Regulations for the Use of Investigational Drugs in

Humans:

Regulations in Clinical Research

The Declaration of Helsinki of the World Medical
Association, Finland 1964

Most well known international regulation

for biomedical research

Establishes the principles and rationale for

research in human subjects
Introduces the concepts of:
Protocol approval by an independent ethics committee
Investigator as responsible for the care of the
participating subjects
Written informed consent

Content has been reviewed in Tokyo, 1975; Italy, 1983;

Hong Kong, 1989; South Africa, 1996; and Edinburgh, 2000
 What is ICH?

Harmonization came in 2 steps:

• In Europe: European Guidelines on GCP 1991

(EU-GCP Guidelines)

• In Europe + USA + Japan 1997

EU + USA + Japan= ICH = International Conference on
Harmonization
 The ICH Process

Membership:
Representatives of Regulatory Authorities and
Pharmaceutical Industries of EU, US and Japan (the 3
regions)
Objective:
Facilitate worldwide drug development through
“harmonization of requirements”
Results:
Have published many guidelines, one of them is the ICH-
GCP guideline
 International Conference
on
Harmonization (ICH)

The International Conference on Harmonisation of

Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) is a unique
project that brings together the regulatory authorities
of Europe, Japan and the United States and experts
from the pharmaceutical industry in the three regions
to discuss scientific and technical aspects of
product registration
 Reduce or obviate the
need to duplicate the
testing of new medicines

Mutual acceptance of
Early availability of
clinical trial data by
drugs in the market
regulatory authorities

Objectives of
ICH

Maintaining safeguards
Less expensive drugs for
on quality, safety and
patients
efficacy
 Expert Working
Groups
SAFETY EFFICACY

QUALITY
MULTIDISCIPLINARY

STEERING
COMMITTEE
 ICH Guidelines
ü Q "Quality" Topics, i.e., those relating to
chemical & pharmaceutical Quality
Assurance. e.g. Q1 Stability Testing, Q3
Impurity Testing
ü S "Safety" Topics, i.e., those relating to in
vitro & in vivo pre-clinical studies. e.g. S1
Carcinogenicity Testing, S2 Genotoxicity
Testing
ü E "Efficacy" Topics, i.e., those relating to
clinical studies in human subject. e.g. E4
Dose Response Studies, Carcinogenicity
Testing, E6 Good Clinical Practices. (Note
Clinical Safety Data Management is also
 ICH
Guidelines
M "Multidisciplinary" Topics, i.e. cross-cutting topics w
do not fit
uniquely into one of the above categories:
M1: Medical Terminology (MedDRA)
M2: Electronic Standards for Transmission of
Regulatory Information (ESTRI)
M3: Timing of Pre-clinical Studies in Relation to Cli
Trials
M4: The Common Technical Document (CTD)
M5: Data Elements & Standards for Drug Dictionar
Participants in a Clinical
Trial

Regulators

GCP

Institute Sponsor
•Investigator
•Ethics
Committee
•Administrator
CRO
Contents of ICH-GCP guidelines
(ICH E6)
Title Page
Table of contents
Introduction
1. Glossary
2. The Principles of ICH-GCP
3. IRB / IEC (responsibilities of…)
4. Investigator (responsibilities of…)
5. Sponsor (responsibilities of …)
6. Clinical Trial Protocol and amendment (s) (contents of …)
7. Investigator’s Brochure (contents of …)
8. Essential Documents for the Conduct of Clinical Trial (what
we need to keep on file and why)
Introduction

GCP is an international ethical and scientific

quality standard for designing, conducting ,
recording and reporting trials that involve the
participation of human subjects.

Objective: To provide a unified standard for the

EU, Japan and the United States to facilitate the
mutual acceptance of clinical data by the
regulatory authorities in these jurisdictions
Principles of ICH / GCP

Clinical trials should be conducted in accordance

with the ethical principles that have their origin in
the Declaration of Helsinki and that are consistent
with GCP and the applicable regulatory
requirements
 Principles of ICH-GCP

SUBJECTS

Subject’s rights,
All foreseeable risks
safety and well
are weighed against
being is of
anticipated benefits
foremost
importance

Informed consent
should be given freely
 Principles of ICH-GCP

MEDICAL
COMMUNITY

Each participating Clinical decision

person should have the making and medical
right qualification, care by qualified
training and experience physicians
(Task-oriented)

Confidentiality of the subject’s identity should be maintained

and such records must be protected (as per applicable rules)
 Principles of ICH-GCP

CLINICAL TRIAL

Trial must be Should be

scientifically sound conducted after
(described in a favorable
detailed protocol) approval of the
IEC/IRB

All information should be recorded, handled, reported and stored

so as to allow its accurate interpretation and verification
 Principles of ICH-GCP

INVESTIGATIONAL
PRODUCT

   IP should be sufficiently
supported
                                 by available
                                
clinical and non-clinical
Manufactured, handled
and stored as per GMP
rules
data

SOPs must be implemented for quality

assurance
The Concept of
Good Clinical Practice
DESIGN

REPORT
International
Scientific &

R E
Ethical quality

CO
Standard

RD
COLLECT

Protection of trial
subject’s rights, Ensure credibility
integrity and and accuracy
confidentiality of data
Institutional Review Board (IRB)/
Independent Ethics Committee
(IEC)
 Definitions

IRB/IEC (ICH 1.27, 1.31)

• An independent body (a review
board or a committee, institutional,
regional, national, or supranational),
constituted of medical professionals
and non-medical members,
• whose responsibility it is to ensure
the protection of the rights, safety
and well-being of human subjects
involved in a trial
• and to provide public assurance of
that protection, by, among other
things, reviewing and approving /
providing favourable opinion on, the
trial protocol, the suitability of the
investigator(s), facilities, and the
methods and material to be used in
 Composition

• The IRB/IEC should consist of a reasonable number

of members, who collectively have the
qualifications and experience to review and
evaluate the science, medical aspects, and ethics
of the proposed trial
• It is recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose primary
area of interest is in a
non scientific area.
(c) At least one member who is independent
of the
institution/trial site.
• Only those IRB/IEC members who are independent
of the investigator and the sponsor of the trial
ROLE AND RESPONSIBILITIES OF
THE INVESTIGATOR
 Definitions

Investigator (ICH 1.34)

§ A person responsible for
the conduct of the trial
at a trial site
§ “Responsible Leader”

Sub Investigator (ICH 1.56)

§ Designated and
supervised by the
investigator
§ Performs critical trial-
related procedures &/
makes important trial-
related decisions
 Qualifications and Agreements (ICH - GCP 4.1)

§ Should comply with GCP, protocol and

Investigator: Responsibilities

regulatory requirements

§ Should maintain a list of appropriately

qualified persons to whom trial related
duties have been delegated

§ Should permit monitoring and auditing

by sponsor/CRO and inspection by the
regulatory authorities
 Adequate Resources (ICH - GCP 4.2)

Resources

− Potential recruitment
Investigator: Responsibilities

− Time

− Qualified and informed

staff

− Facilities
 Medical Care of Trial Subjects (ICH - GCP
4.3)

§ Responsible for all trial-related medical

decisions

§ Should ensure adequate medical care to

Investigator: Responsibilities

the subject for any adverse events and

intercurrent illnesses during the trial

§ Should exert “reasonable efforts” to

ascertain patient’s reasons for
withdrawing
 Communication with IRB/IEC (ICH - GCP 4.4

§ Should obtain written and dated

Ap o

approval for Protocol, ICF and

pr d

other recruitment documents

Investigator: Responsibilities ve

before start of the study

§ Should provide the IRB/EC with the

current/updated copy of the
Investigator’s Brochure

§ Should provide the IRB/EC all documents

 Compliance with Protocol (ICH - GCP 4.5)
Pro
toc
ol
Investigator: Responsibilities

§ Should conduct the trial in compliance

with the protocol

§ Should not implement changes or

deviations to Protocol unless approved
by Sponsor and EC

§ Should document and explain any

deviation from the approved protocol
 Investigational Product(s)- IP (ICH - GCP 4.6

§ May assign duties for IP accountability to

appropriate individual under supervision of the
investigator

§ Designated individual should maintain a record

Investigator: Responsibilities

of delivery, use and return of investigational

product received from the sponsor

§ Investigational product should be stored in a

secure location and under appropriate
conditions (as specified by sponsor)

§ Should ensure that the IP is used only in

accordance with the approved protocol
 Randomization &Unblinding - IP (ICH - GCP
4.7)
•Should follow the trial's randomization
procedures, if any
•Should ensure that the code is broken only in
accordance with the protocol
Investigator: Responsibilities

• If the trial is blinded, the

investigator should promptly
document and explain to the
sponsor any premature unblinding -
(e.g., accidental unblinding,
unblinding due to a serious adverse
event) of the investigational product
(s).
 Informed Consent of Trial Subjects (ICH - GCP
4.8)
§ Should obtain written approval from
xCo
nse
nt For
In t
his m
con stud
d
IRB/EC u
Pro cted , y
you fessor by
X
the will v XX,
la b isit
on t orat
and hree d ory
… ays
X
Investigator: Responsibilities

___
___
__

§ Should obtain written Informed consent

from each study subject prior to inclusion
in the study

§ Should ensure that the ICF is signed and

 Records and Reports (ICH - GCP 4.9)
§ Should ensure that data are
− Accurate CRF Consistent Source
− Complete with Doc
− Legible
− Reported in time

§ Corrections in CRF’s should § Maintain essential documents

Investigator: Responsibilities

be recorded and duly − Keep at least 2 years after

endorsed by the investigator • last marketing application
approval in an ICH region
• or discontinuation of
§ Ensure documentation of development
financial aspects of the study
§ Access to all trial related original
records
 Records and Reports (ICH - GCP 4.9)

Document !
Do
t!
en cu
m
um
en
t!
oc
D
Investigator: Responsibilities

Docu
ment
! Document !

Document !
 Progress Reports (ICH - GCP 4.10)
Investigator: Responsibilities

Investigator

or
IRB/IEC IRB/IEC Sponsor
Written summaries of the Written reports about any changes:
trial status - annually or •which affect trial conduct
more frequently as
requested •which increase risk to subject
 Safety Reporting (ICH - GCP 4.11)

SAEs (Initial +Follow-up

reports)
AEs/Lab abnormalities
Deaths (Autopsy reports)
Investigator: Responsibilities

Investigator

IRB/IEC Sponsor

HA
 Premature termination or suspension
of a trial (ICH - GCP 4.12)
If the trial is prematurely terminated or suspended for any reason,
the investigator/institution should promptly inform the trial subjects,
should assure appropriate therapy and follow-up for the subjects
and should inform the IRB/IEC, Sponsor and
the regulatory authority(ies) (as applicable)
Investigator: Responsibilities

Investigator

IRB/IEC Sponsor
 Final Report (s) (ICH - GCP 4.13)
Investigator: Responsibilities

Investigator

Upon completion of the trial, the investigator, where applicable,

should inform the institution; the investigator/institution
should provide the IRB/IEC with a summary of the trial’s
outcome, and the regulatory authority(ies) with any reports
required
 ICH GCP 5.19

GCP Audits and

Inspections
 GCP Audits and Inspections

… please be aware that

this is a possibility for

any study!!!
 Health Authority (HA)
Inspections

§ Monitoring activities by Health Authorities to

ensure:
§ Scientific integrity and reliability of data
submitted in marketing applications
§ Adequate protection of study subjects
§ Compliance with protocol, GCP
requirements, local laws
§ Assess quality systems in place

§ Can occur during or after completion of the trial

 GCP FDA Inspection Observations

§ Failure to follow protocol

§ Failure to maintain adequate & accurate
medical records
§ Discrepancies between source
documents and CRFs
§ Irregular submission of periodic reports
to Ethics Committee
§ Lack of computer validation
§ Lack of raw data and SOPs
 Documentation

§ Availability of key documents prior to, during,

after the trial
§ Appropriate delegation of activities and
training. Perform only activities for which
training received
§ Clear definition and availability of supportive
source data – paper and/or electronic
§ Follow the protocol, document all deviations,
reasons and corrective actions
§ Document any important correspondence
§ Interact with the monitors who are there to
help……….
 Documentati
on
§ ‘There is one unwritten rule in this work,
GET IT DOWN ON PAPER!

§ ‘If it is not documented, it did not happen!

 And finally…….

Ethics is not separable from scientific, social, and political

questions in clinical research.

Ethics is what all the partners in research can share.

We must insist on ethics having the upper hand in clinical

research.
Thank You