Standard Operating Procedure For The Recording, Management and Reporting of Adverse Events by Investigators

S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Investigator SOP\INV_S05_SOP for AE_SAE Reporting by Inv &
ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 1 of 19
Standard Operating Procedure for the Recording,

Management and Reporting of Adverse Events by
Investigators
SOP Number: JRO/INV/S05/06 Effective Date: 12/12/13
Review Date: 12/12/16

Version Number & Date of Authorisation: V06, 11/11/13
SOP eDocument Kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Investigator

SOP\INV_S05_SOP for AE_SAE Reporting by Inv & ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc
Revision Chronology:
Effective
SOP ID Number Reason for Change Author
Date
Yvanne
CRN/04/S05/00 09/09/2004 N/A
Enever
Administrative changes i.e. email address update.
UCL CRN to UCL Biomedicine R&D Unit. Yvanne
BRD/04/S05/01 20/04/2005
Removal of UCL SAE Follow-up Form. Update of Enever
UCL SAE Reporting Form.
Administrative changes i.e. UCL logo. Additional
text P2 to clarify version number, plus addition of Yvanne
BRD/04/S05/02 25/10/2005
CI expectedness evaluation, changes in staff Enever
titles.
Implementation of the Joint UCL/UCLH
Biomedical Research Unit, clarification of
Farhat
JBRU/07/S07/00 18/06/2007 definitions, inclusion of pregnancy, unblinding,
Gilani
update SAE report form, overdose reporting and
a new numbering system.
Update SOP in response to MHRA Inspection to
ensure all AE/Rs are recorded and reported Farhat
JBRU/07/S07/01 20/12/2007
accordingly. In particular procedure for Gilani
pregnancy reporting has been updated.
To make SOP specific to investigator
Joanna
responsibilities and clarify reports on deaths. To
28/10/2008 Galea-
JBRU/INV/S05/02 implement a new JBRU numbering system as
Lauri
reflected in SOP on SOPs JBRU/INT/S01/02
To amend the SAE form and provide alternatives Anne
JBRU/INV/S05/03
10/01/2010 in the absence of the Senior Pharmacovigilance Marie
Co. format amended in line with revised SOP on Downey
SOP for the Recording, Management and Reporting of AEs by Investigators

JRO/INV/S05/06
Page 1 of 19
SOPs to incorporate a UCL logo only, an

Acronyms table, eDocument file path, associated
templates/log table, SOP dissemination and
training and a signature page.
Update SOP to reflect current system including e-

SUSAR reporting, SPC review, DSUR, Drug Farhat
JRO/INV/S05/04 11/01/2012
Alerts and Safety Warnings, Safety Management Gilani
Plan, Overdose and Sponsor Oversight.
Administration update and removal of forms from Farhat

JRO/INV/SO5/05 16/06/2012
SOP. Gilani
Farhat
JRO/INV/SO5/06 12/12/13 Formatting and administration changes
Gilani

JRO/INV/S05/06
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ACRONYMS:
AE Adverse Event
AR Adverse Reaction
CI Chief Investigator
CRF Case Report Form
CTIMP Clinical Trial Investigational Medicinal Product
DSMC Data Safety Monitoring Committee
DSUR Development Safety Update Report
e-SUSAR MHRA Electronic SUSAR
GCP Good Clinical Practice
IB Investigator’s Brochure
IDMC Independent Data Monitoring Committee
IMP Investigational Medicinal Product
IMPD Investigational Medicinal Product Dossier
ISF Investigator Site File
JRO Joint Research Office www.ucl.ac.uk/jro
NRES National Research Ethics Service
PI Principal Investigator
PV Pharmacovigilance
SAE Serious Adverse Event
SAR Serious Adverse Reaction
SI Statutory Instrument
SPC Summary of Product Characteristics
SOP Standard Operating Procedure
SRA Sponsor Regulatory Advisor
SUSAR Suspected Unexpected Serious Adverse Reaction
TMF Trial Master File

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Standard Operating Procedure for the Recording, Management and Reporting of

Adverse Events by Investigators
1. PURPOSE
This Standard Operating Procedure (SOP) has been written to describe the procedure to be
used by the investigator for the recording, management and reporting of Adverse Events (AEs),
Adverse Reactions (ARs), Serious Adverse Events (SAEs), Suspected Serious Adverse
Reactions (SSARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) which
occur in subjects participating in Clinical Trials of Investigational Medicinal Products (CTIMPs).
It will further describe the procedure for safety reference document updates, safety alerts; drug
recall, management of pregnancy and overdose reports.
2. JOINT RESEARCH OFFICE POLICY
All JRO SOPs will be produced, reviewed and approved in accordance with the JRO SOP on
SOPs.
3. BACKGROUND
All SOPs are written in accordance with applicable GCP requirements as outlined in Directives
2001/20/EC and 2005/28/EC (in the UK, these Directives were transposed into UK law by SI
2004/1031, SI 2006/1928) and subsequent amendments and where applicable incorporates
elements of ICH GCP tripartite guidelines (E6).
To comply with the UK Regulations which set out the responsibilities of the sponsor, this SOP
will focus on the trial site team procedures for the adequate recording, evaluation and reporting
of AEs, ARs, SAEs, SARs and SUSARs in trials involving IMPs. It will further outline the
Investigator’s responsibilities to ensure oversight and management of pharmacovigilance
systems in UCL sponsored trials.
For convenience, this document will use the term “UK Regulations” to cover the UK legislation
and the EU Clinical Trials Directive (CT3).
3.1. DEFINITIONS
The following definitions have been adapted from the UK regulations:
Adverse Event
Any untoward medical occurrence in a patient or clinical trial subject administered an
Investigational Medicinal Product (IMP) and which does not necessarily have a causal
relationship with this treatment.
Therefore an AE can be any unfavourable or unintended change in the structure (signs),

function (symptoms) or chemistry (laboratory data) in a subject to whom an IMP has been
administered, including occurrences which are not necessarily caused by or related to that
product.
Adverse Reaction (AR)

All untoward and unintended responses to an IMP related to any dose administered
This definition also covers medication errors and uses outside what is foreseen in the
protocol, including misuse and abuse of the product.
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The definition implies a reasonable possibility of a causal relationship between the event and
the IMP. This means that there are facts (evidence) or arguments to suggest a causal
relationship.
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)

Any adverse event or reaction in a trial subject that:
(a) results in death; or

(b) is life threatening;
Note: places the subject, in the view of the investigator, at immediate risk of death from
the experience as it occurred (this does not include an adverse experience that, had it
occurred in a more severe form, might have caused death); or
(c) requires hospitalisation or prolongation of existing hospitalisation;
Note: (hospitalisation is defined as an inpatient admission, regardless of length of stay), even

if the hospitalisation is a precautionary measure for continued observation. Therefore,
participants do not need to be hospitalised overnight to meet the hospitalisation
criteria.
Hospitalisation (including hospitalisation for an elective procedure) for a pre-existing condition

(prior to study entry) which has not worsened does not constitute a serious event.
(d) Results in persistent or significant disability or incapacity
Note: substantial disruption of one’s ability to conduct normal life functions; or
(e) consists of a congenital anomaly or birth defect
Note: in offspring of subjects or their partners taking the IMP regardless of time of diagnosis.
Important Safety Issues

Important medical events that may not be immediately life-threatening or result in death or
hospitalisation but may jeopardise the subject or may require intervention (medical or
surgical) to prevent one of the other outcomes listed in the definition above should also be
considered serious. Such events might include:
1. Overdoses (accidental or intentional)
2. Pregnancy (of subject or partner)
3. An alarming adverse experience
4. Specific Adverse events and/or laboratory abnormalities which are listed in the trial
protocol as critical to safety evaluations and requiring reporting
Suspected Serious Adverse Reaction (SSAR)

An adverse reaction that is classed in nature as serious and which is consistent with the
information about the medicinal product listed in the relevant reference documentation:
(a) Summary of Product Characteristics (SPC) in the case of a licensed product being used
within its licensed dosage and indication.
(b) An Investigator’s Brochure (IB) or a simplified IMPD in the case of any other IMP or a
licensed product being used outside its licensed dosage and indication.
Unexpected Adverse Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable
product information (SPC or IB).
Suspected Unexpected Serious Adverse Reaction (SUSAR)

An adverse reaction that is classified in nature as both serious and unexpected.
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3.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN CLINICAL TRIALS
Events which may materially alter the current benefit-risk assessment of an IMP or which could
be sufficient to consider changes in the IMP administration or in the overall conduct of the trial
may fall into the category of ‘Other Safety Issues’ and be considered as serious events which
will require reporting to the sponsor in a letter headed Safety Report:
a. An increase in the rate of occurrence or a qualitative change of an expected serious adverse

reaction, which is judged to be clinically important,
b. Post-study SUSARs that occur after the patient has completed a clinical trial and are
reported by the investigator to the Sponsor,
c. New events related to the conduct of the trial or the development of the IMPs and likely to
affect the safety of the subjects, such as:
 an SAE which could be associated with the trial procedures and which could modify the
conduct of the trial,
 a significant hazard to the subject population such as lack of efficacy of an IMP used for the
treatment of a life-threatening disease,
 a major safety finding from a newly completed animal study (such as carcinogenicity),
 any anticipated end or temporally halt of a trial for safety reasons and conducted with the
same investigational medicinal products in another country by the same Sponsor,
d. Recommendations of the Data Monitoring Committee (DMC), if any, where relevant to the
safety of the subjects.
An ‘Other Safety Issue’ can also fall into the category of Urgent Safety Measures. Please refer
to Standard Operating Procedure for the Recording and Reporting of Deviations, Violations,
Potential Serious breaches, Serious breaches and Urgent Safety Measures. Details pertaining
to an ‘Other Safety Issue’ will be documented in the DSUR.
3.3 SEVERE ADVERSE EVENT OR REACTION
The term “severe” is often used to describe the intensity of an event or reaction (e.g. mild,
moderate or severe) and should not be confused or interchanged with the term “serious”.
3.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR
This section describes the key pharmacovigilance responsibilities of the investigator, further
delegation of these responsibilities to other team members must be documented on the trial
delegation log.
Safety Reference Documents: The CI must ensure that the trial team are using the
most up to date version of safety reference document described in the CTA application
and protocol. The CI must also ensure that the team have all reviewed and are familiar
with the updated information.
The CI must request the updated IB/IMPD from the manufacturer annually for IMP
sourced from a manufacturer directly. Please refer to SOP JRO/SPON/S03/ Standard
1
Operating Procedure for creating and maintaining an Investigator’s Brochure (IB) for UCL
Developed Products for procedures relating to UCL developed products.
For trials using SPCs, the CI must ensure they perform a check for updates regularly
either by contacting the manufacturer or searching on the following website:
http://www.medicines.org.uk/emc. The CI must ensure a copy is filed in the TMF/ ISF/
PSF and a copy is forwarded to all sites to PIs and Pharmacies.

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The investigator must further ensure that the team are all familiar with the appropriate
use of the IMP(s), as described in the protocol, safety reference document and/or IMPD.
Protocol: The protocol must be written using the JRO UCL protocol template in order
2 that the appropriate pharmacovigilance information is included JRO/INV/S07
AE Recording: All AEs must be recorded in the medical records (if source data) and/or
3 the CRF, SAE forms and AE logs as described in the protocol.
AE Assessment: The investigator must assess each event for seriousness,

4 expectedness and causality using the appropriate documentation (protocol and safety
reference document).
Trend/signal analysis: The CI must ensure the AE log is reviewed regularly. This can
be performed by the CI alone or reviewed collectively at trial meetings. These reviews
need to be documented.
5
For some Phase I and high risk trials (and if deemed necessary by the Safety Committee
for Phase I/II trials), an Independent Data Monitoring Committee may be requested to
perform this duty.
SAE Reports: The CI must ensure that initial and follow-up SAE reports are sent to the
6 JRO, according to the protocol.
AEs of interest: The CI must provide the JRO with details of all AEs identified in the
7 protocol as critical to the evaluation of safety within the agreed timeframes specified in
the protocol.
Follow-up reports: The CI must supply the JRO with any supplementary information
8 requested as soon as possible in order for the JRO to meet their regulatory timelines.
IDMC: For some phase I and high risk trials, an Independent Data Monitoring Committee
or Data Safety Committee must be established. In cases of phase I/II trials, advice from
9 the sponsor’s Safety Committee may be sought to establish the need of the committee.
Members of the IDMC must have signed the UCL IDMC charter.
Data Safety Monitoring Committee: Provide the DSMC (if there is one for the trial) with
10 all relevant information required for an independent assessment.
11 Pregnancies: The CI must submit all initial and follow-up pregnancy forms to the JRO.
Confidentiality: The CI must maintain subject confidentiality at all times. No patient

12 identifiable data is to be sent to the JRO or other external organisations by the PIs.
Urgent Safety Measure: The investigator may take appropriate urgent safety measures
to protect clinical trial subjects from any immediate hazard to their health and safety. This
13 may be taken immediately. However, following the measure the investigator must follow
the SOP on “Deviations, serious breaches and urgent safety measures” JRO/SPON/S15
DSUR: In conjunction with the JRO, the CI must aid in the production of the DSUR as per
14 SOP on DSURs JRO/SPON/S31

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4. SCOPE OF THIS SOP

What this SOP covers
This SOP covers the procedures for the recording, management and reporting of all AEs, ARs,
SAEs, SSARs and SUSARs that occur in subjects participating in CTIMPs sponsored by UCL.
This document further details pregnancy and overdose reports, safety alerts, safety reference
document updates, DSURs and highlights the key PVG responsibilities of the CI.
What this SOP doesn’t cover
In circumstances where the JRO (in its role as a representative or a legal representative of the
Sponsor) has delegated the responsibilities to a third party such as a Clinical Research
Organisation (CRO) or an external Clinical Trials Unit (CTU), the pharmacovigilance procedures
will be outlined in a trial specific agreement between the Sponsor, the CRO and the Chief
Investigator. Therefore description of this procedure falls outside the scope of this SOP.
5. RESPONSIBLE PERSONNEL
The CI and the individual investigators within a trial team are responsible for keeping records of
all adverse events that occur in trial subjects as per protocol.
The CI may further delegate who within the trial team is responsible for reporting to the
Sponsor. This delegation must be performed on whether trial members are qualified to perform
the delegated task. This must be authorised in the delegation log.
For international trials: responsibilities will be outlined in the contract between sites, CTU (if
appropriate) and Sponsor.
6.PROCEDURE
Please ensure that you are using the most recent SOP version by looking up
www.ucl.ac.uk/jro
6.1 Duration of AE Recording

The protocol must clearly define the duration of AE recording.
All S/AEs should be recorded and reported within the established off therapy follow-up period
for safety described in the protocol. This time period will be defined in the protocol as per the
UCL protocol template.
6.2 Which AE to record and which Forms to use?
The table below provides guidelines for where to record AE information:
Type of Adverse Events Format of Recording Information

All Adverse events Medical Records
All AEs and SAEs (as per protocol) AE section of CRF
All SAEs (as per protocol) AE log
All SAEs (as per protocol) SAE report form

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6.3 Which AE to report to the JRO?
All AE/Rs that fulfil the criteria for the definition of serious, whether expected or not, need to be
reported to the JRO, unless specified in the protocol. The protocol will list all the expected
SAE/Rs that do not need to be reported to the JRO.
6.4 When and how to report Serious AE/Rs to the Sponsor?

6.4.1 What needs to be reported within 24 hours?
5. SUSARs
6. Serious adverse events/reactions as defined in section 3.1
7. Other Safety Issues.
6.5 When to report other SAE/Rs to the JRO which do not require expedited reporting?
Some expected SAE/Rs should be reported to the JRO on the AE log only as per protocol. The
timeline for submission will vary depending on the purpose of the trial, toxicity and efficacy
endpoints.
6.6 Where to report AEs and SAEs?

The SAE Reporting Form, line listings and the Pregnancy Reporting Form must be emailed to
sae@ucl.ac.uk. The report can alternatively be faxed to the JRO on 020 3108 2312.
The trial team must request an acknowledgment of receipt of the report which should be kept
with the original form in the TMF.
In the event that the form is not acknowledged by the Sponsor’s office within 3 days, site must
contact relevant members of the sponsor’s office to confirm receipt of the report.
Most Trusts’ R&D Departments request the PIs to notify them of the SUSARs occurring within
their Trust by sending a copy of the SAE form to the R&D Department. In addition, a number of
Trusts will expect SUSARs to be reported to them as ‘incidents’ via the DATIX system.
Subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on
all reports in relation to recording and reporting of AEs. No personal identifiable data must be
forwarded to the JRO or other external organisations.
6.7 Other reporting arrangements for Multi-Centre Trials
For multi-centre trial sponsored by UCL, PIs will report directly to a trial management team at a
lead site and the trial Pharmacovigilance responsible person will be responsible for forwarding
the report to the JRO within 24 hours of receipt. Trial specific arrangements for SAE
management must be documented in the protocol and contractual agreements.
6.8 Evaluation of AE/Rs during the trial
The following documents need to be referred to when assessing any AE in the trial:
 Protocol
 Safety Reference Document (SPC, IB)
 Trial specific Procedure for unblinding (if applicable)
Each AE must be evaluated for seriousness, causality, severity and expectedness. The treating
physician should make these assessments which are documented on the SAE Reporting Form.
For multi-sites trials a CI cannot downgrade a PI’s assessment of an event but the CI may
upgrade an event.
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6.8.1. Evaluation of seriousness
The PI must assess the AE as serious as per the definition of an SAE in section 3.
6.8.2. Evaluation of causality
The Council for Internal Organisations of Medical Sciences (CIOMS) VI group agree that the
Investigator's causality assessment is vital information since the Investigator is best placed to
review how the subject has changed since baseline (before treatment is administered). Every
effort must be made by the PI to obtain all the required information to determine whether the AE
is related to the trial intervention.
It is important to note that if the investigator indicates an unknown causality assessment,

the adverse experience will be considered as related by the JRO (taking the most
conservative option) and could warrant expedited reporting.
To help Investigators with the decision, the CIOMS VI group recommends that PI be asked to
consider the following before reaching a decision:
 Medical History
 Lack of efficacy/worsening of existing condition
 Study treatment(s)
 Other treatments-concomitant or previous
 Withdrawal of study treatment-especially following study discontinuation/end of study
 Erroneous treatment with study medication (or concomitant)
 Protocol related process
 The CI/PIs evaluation of severity
It is common practice for events to be assessed for clinical severity (intensity defined as: mild,
moderate or severe) of the specific event. As already explained in the definitions, severity must
not be confused with “serious” which is a regulatory definition based on subject/event outcome
or action criteria.
6.8.3. Evaluation of expectedness
The PI must evaluate whether the event is expected or unexpected against the protocol
and the safety reference documents for the trial (i.e. IB for non-licensed product or SPC for a
licensed product in the EU assuming that the product is being used in the trial exactly as stated
in the SPC). An event can be considered as “unexpected” if it adds significant information on
the specificity or severity of an expected event.
6.9 How to manage reports in blinded trials
The blind for the investigator and if applicable, for those persons responsible for data-analysis
and interpretation of results should be maintained until the trial data is locked.
However a patient’s allocation may need to be unblinded under the following conditions:
1. Emergency unblinding: Patient experiencing an adverse event and requiring treatment which
cannot be given without knowledge of the trial arm the patient was randomised to.
2. SUSAR Unblinding: The JRO requires unblinding for the submission of a SUSAR report to
the MHRA and REC.
The unblinding procedure is protocol specific and each trial must clearly document their
procedure and the location of the unblinding information. The Investigator must forward the Trial
specific unblinding SOP to the JRO. This SOP must be written using the JRO “Standard

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Operating Procedure for the Preparation of a Study Specific Randomisation, Blinding and Code
Break Standard Operating Procedure”.
6.10 Follow-up information
On receipt of relevant or missing information, site staff must complete a new SAE report form
and tick the follow-up box. The form must be forwarded to the JRO as per section 6.9.
All SAEs must be followed up until a resolution is reached (i.e. recovered, recovering, recovered
with sequelae, fatal, not recovered or unknown).
6.11 Recording and Reporting a Pregnancy
Pregnancy data provides vital information to the overall knowledge concerning the IMP and is
therefore reportable to the sponsor but not reportable to the regulatory agencies as expedited
reports and will be incorporated into the DSUR report.
On the notification of a pregnancy in a trial participant or their partner, a member of the trial
team must inform the PI. The pregnancy needs to be recorded in the medical notes, AE log and
CRF. The JRO Pregnancy Reporting Form must also be completed and forwarded to the
sponsor within 24 hours of being made aware of the event by email to sae@ucl.ac.uk . The
report can alternatively be faxed to the JRO on 020 3108 2312.The completed pregnancy report
form should be kept in the TMF/ISF with any relevant correspondence. The Sponsor must be
kept informed of any new developments involving the pregnancy.
Any pregnancy that occurs in a female trial subject during a clinical trial should be followed to
termination or to term. Under special circumstances, it may be necessary to monitor the
development of the new-born for an appropriate period post-delivery. There may also be special
situations when it will be necessary to monitor the pregnancy of a woman whose male partner is
the trial subject.
In the event that the pregnancy report form is not acknowledged by the Sponsor’s office within 3
days, site must contact relevant members of the sponsor’s office to confirm receipt.
6.11.1 Escalation of report to the Safety Committee
The JRO will forward the pregnancy report form, safety reference document and protocol to the
chair of the safety committee and a second clinician on the committee for review and comment
on recommended follow-up (as appropriate) and tests/procedures to be performed above the
protocol to protect the patient and the foetus.
6.11.2 Update to PIS/Consent Form
Recommendations from the safety committee will be forwarded to the CI by the JRO. A new PIS
and consent form will be supplied to the trial team to re-consent the patient or partner for follow-
up of pregnancy until term or termination. These must be kept in the TMF.
6.11.3 Follow-up of pregnancy
Once site are made aware of the pregnancy outcome, (birth or termination) the outcome section
must be completed and forwarded to the JRO within 24 hours.
If the event that the pregnancy meets the following definition; a SAE report form must also be
completed and forwarded to the JRO with the pregnancy follow-up form within 24 hours:

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 Congenital anomaly(ies) in the foetus/child

 Foetal death or spontaneous abortion
 Any SAE occurring in the neonate or mother
6.12 Overdose Reports
In the event of an accidental or intentional overdose by a trial participant, the site staff must
immediately inform the PI and the Sponsor’s office. The deviation log must be completed and
the medical notes, CRF, AE log updated to reflect this information. In the event that the
overdose is associated with an S/AE, the two events should be linked.
In the event of an AE associated with an overdose, a SAE report form must be completed
detailing the AE and the overdose details.
6.13 Review of new safety reference document
It is the CI’s responsibility to check which document (IB or SPC) is referred to in the CTA
application and request the relevant updated document as explained below
6.13.1 IBs
IBs are required to be updated annually. For trials where the IB is supplied by a drug supplier,
the update will normally be requested by the site team from the supplier directly. Please refer to
SOP JRO/SPON/S03 for procedures relating to UCL developed products. The CI must provide
the JRO with a copy of the updated IB and confirm if the new information impacts on the trial
and patient safety and if any amendments are required to the protocol, PIS and consent forms.
An updated IB must be submitted to the regulatory authorities as a substantial amendment if the
update affects patient safety or trial documentation. The previous version must be superseded
in the TMF and a copy of the updated document placed in the file.
6.13.2 SPCs
The investigator must regularly check for SPC updates. When the Investigator is made aware of
an update to a SPC, the CI must review the document and assess if the updated information
affects the study protocol, safety of the study patients or the Patient Information Sheets and
consent forms. The trial team must be forwarded a copy of the updated SPC as well as a copy
sent to the relevant members of the sponsor’s office. The CI must confirm they have read the
document and detail any actions required (if appropriate). The previous version must be
superseded in the TMF and a copy of the updated document placed in the file.
6.13.3 Safety warning and drug alerts
Safety Alerts (from the MHRA and drug suppliers) may be forwarded by the JRO or be sent
directly by another organisation to the CI.
The received information must be reviewed immediately by the CI or delegated member of the
trial team to assess whether action is required to protect patient safety. The information must
be forwarded to the JRO with any recommendations and an acknowledgement receipt
requested. The CI(s) must confirm what actions (if any) are required.
6.13.4 Provisions in Multicentre trials
The CI or delegated member of the trial must ensure all updates are forwarded to PIs in an
appropriate timeframe and confirm that any relevant training on the new document is performed.
This must be documented in the TMF/ISF.

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6.14 What to expect from the JRO once a report has been submitted
A member of the JRO will confirm receipt of all reports within 3 days. In the event that the report
is not acknowledged by the Sponsor’s office within 3 days, site must contact the JRO.
6.15 Development Safety Update Report
The Investigator and relevant trial staff will be made aware when the data lock point for the
DSUR has been reached. The trial staff will work in conjunction with the JRO to facilitate in the
production of the report. Please review SOP on DSURs.

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Flowchart 1: Decision framework for assessment of adverse events by Investigators and research personnel
Adverse events noted
Seriousness
Adverse Events (AE) Serious Adverse Event (SAE)

Causality
Unrelated Related to IMP Unrelated to Related to IMP
to IMP IMP
Adverse Event (AE) Adverse Serious Adverse Serious Adverse

Reaction (AR) Event (SAE) Reaction (SAR)
Expectedness
Unexpected Expected Unexpected Expected Unexpected Expected Unexpected Expected

AE AE AR AR SAE SAE SAR SAR
SUSAR
Summary of procedures Flowchart 1
Flowchart 1 illustrates the decision framework which Investigators and research personnel should follow to assess S/AEs and to determine
if the event requires further expedited reporting.
Please note: The CI cannot downgrade the PI’s assessment

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7. REFERENCES
www.ucl.ac.uk/jro
Directive 2001/20/EC of the European Parliament and of the Council of 4th April 2001 on the
approximation of the laws, regulations and the administrative provisions of the Member States
relating to the implementation of good clinical practice in the conduct of clinical trials on
medicinal products for human use.
The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) and amended
regulations.
European Commission Document “Detailed guidance on the collection, verification and

presentation of adverse reaction reports arising from clinical trials on medicinal products for
human use” April 2006 (Revision 2) Brussels, ENTR/CT 3.
MRC/DH joint project Work stream 6: Pharmacovigilance (PV Document-final version for clinical
trials tool kit (12th Jan 2007).
Sponsor’s SOP for the Preparation of a Study Specific Randomisation, Blinding and Code Break
Standard Operating Procedure
Sponsor’s SOP for the Recording and Reporting of Deviations, Serious Breaches and Urgent
Safety Measures
8. APPENDICES NA
9. TEMPLATES/LOGS ASSOCIATED TO THIS SOP
1 Adverse Event Recording & Reporting log
2 Serious Adverse Event Reporting Form
3 Pregnancy Reporting Form in clinical trial subjects
10. SOP DISSEMINATION & TRAINING
This SOP will be provided to the PIs prior to, or at initiation at the latest. All staff trial team
concerned by this SOP will sign the SOP training log (12. SOP TRAINING LOG) part of this
SOP. This SOP should be filed in the ISF.
Existing trials “in progress”: This SOP will be emailed to the PIs and their teams. These
investigators will be requested to read the new SOP and email back to acknowledge receipt
and understanding of this new SOP. These PIs should ensure that relevant team members have
read and understood this SOP. They should ensure that section 12 has been signed by all
the trial team members. The email sent to the PIs and their email acknowledging receipt and
understanding of the SOP should be printed out and filed in the JRO SOP folder.

JRO/INV/S05/06
Page 15 of 19
11. SIGNATURE PAGE
Author and Job Title: Farhat Gilani, Pharmacovigilance Manager
Signature:
11/11/13
Date:
Authorised by:
Helen Cadiou, Quality Assurance Manager
Name and Job Title:
Signature:
Date: 11/11/13

JRO/INV/S05/06
Page 16 of 19
12. SOP TRAINING LOG:
Name of Staff Job Title: I confirm that I
(Capital letters): understand & agree
Department:
Training to work to this SOP Name of Trainer
Date SIGNATURE (if applicable) Signature Date
1
SOP for the Recording, Management and Reporting of AEs by investigators

JRO/S05/06
Page 17 of 19
Department:
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10
11
12
13
14

JRO/S05/06
Page 18 of 19
Department:
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JRO/S05/06
Page 19 of 19

Standard Operating Procedure For The Recording, Management and Reporting of Adverse Events by Investigators

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Standard Operating Procedure for the Recording,

SOP Number: JRO/INV/S05/06 Effective Date: 12/12/13

Review Date: 12/12/16

SOP eDocument Kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Investigator

SOP for the Recording, Management and Reporting of AEs by Investigators

SOPs to incorporate a UCL logo only, an

Update SOP to reflect current system including e-

Administration update and removal of forms from Farhat

SOP for the Recording, Management and Reporting of AEs by Investigators

SOP for the Recording, Management and Reporting of AEs by Investigators

Standard Operating Procedure for the Recording, Management and Reporting of

2. JOINT RESEARCH OFFICE POLICY

The following definitions have been adapted from the UK regulations:

Therefore an AE can be any unfavourable or unintended change in the structure (signs),

Adverse Reaction (AR)

Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)

(a) results in death; or

Note: (hospitalisation is defined as an inpatient admission, regardless of length of stay), even

Hospitalisation (including hospitalisation for an elective procedure) for a pre-existing condition

Important Safety Issues

Suspected Serious Adverse Reaction (SSAR)

Unexpected Adverse Reaction

Suspected Unexpected Serious Adverse Reaction (SUSAR)

3.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN CLINICAL TRIALS

a. An increase in the rate of occurrence or a qualitative change of an expected serious adverse

3.3 SEVERE ADVERSE EVENT OR REACTION

3.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR

SOP for the Recording, Management and Reporting of AEs by Investigators

AE Assessment: The investigator must assess each event for seriousness,

Confidentiality: The CI must maintain subject confidentiality at all times. No patient

SOP for the Recording, Management and Reporting of AEs by Investigators

4. SCOPE OF THIS SOP

6.1 Duration of AE Recording

Type of Adverse Events Format of Recording Information

SOP for the Recording, Management and Reporting of AEs by Investigators

6.3 Which AE to report to the JRO?

6.4 When and how to report Serious AE/Rs to the Sponsor?

6.6 Where to report AEs and SAEs?

6.8.1. Evaluation of seriousness

6.8.2. Evaluation of causality

It is important to note that if the investigator indicates an unknown causality assessment,

SOP for the Recording, Management and Reporting of AEs by Investigators

6.11 Recording and Reporting a Pregnancy

6.11.1 Escalation of report to the Safety Committee

6.11.2 Update to PIS/Consent Form

6.11.3 Follow-up of pregnancy

SOP for the Recording, Management and Reporting of AEs by Investigators

 Congenital anomaly(ies) in the foetus/child

6.12 Overdose Reports

6.13 Review of new safety reference document

6.13.3 Safety warning and drug alerts

6.13.4 Provisions in Multicentre trials

SOP for the Recording, Management and Reporting of AEs by Investigators

6.15 Development Safety Update Report

SOP for the Recording, Management and Reporting of AEs by Investigators

Adverse events noted

Adverse Events (AE) Serious Adverse Event (SAE)

Adverse Event (AE) Adverse Serious Adverse Serious Adverse

Unexpected Expected Unexpected Expected Unexpected Expected Unexpected Expected

Summary of procedures Flowchart 1