Standard Operating Procedure

(SOP)
Research and Development Office

Title of SOP: Recording, Managing and Reporting

Adverse Events
SOP Number: 2
Version Number: 3.0
Supersedes: 2.1
Effective date: May 2013
Review date: May 2015

Author: Alison Murphy, Research Manager

Endorsed by Paul Carlin
Approved by: Dr Hill

Signed:

Date: 01 August 2013

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Version History:

Version No. Date Author Reason for Change

1.0 Sept 2007 Katrina Hughes N/A
2.0 Dec 2007 Katrina Hughes add annual reporting
requirements and other
expedited reports
2.1 May 2009 Katrina Hughes Addition of reference to adverse
event reporting for tissue
samples
Addition of information
surrounding definition of SAE
3.0 May 2011 Alison Murphy Title revised, included guidance
on study planning, eSUSAR
reporting requirements,
recording and reporting a
pregnancy and expanded
guidance in other sections.
Additional appendices added.

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Table of contents

1. Introduction
2. Objective
3. Scope
4. Study Planning
4.1 Which AE to record
4.2 Which SAE to report
4.3 When to start and stop recording AE/Rs
5. Adverse Event (AE) / Adverse Reaction (AR)
5.1 Definition
5.2 Reporting adverse events
6. Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR)
6.1 Definition
6.2 Reporting serious adverse events / serious adverse reaction
7. Suspected Serious Adverse Reaction (SSAR)
7.1 Definition
7.2 Reporting Suspected Serious Adverse Reaction
8. Suspected Unexpected Serious Adverse Reaction (SUSAR)
8.1 Definition
8.2 Reporting Suspected Unexpected Serious Adverse Reaction
8.3 Reporting to PIs involved in Study
9. Evaluating Adverse Events
9.1 Seriousness
9.2 Causality
9.3 Severity
9.4 Expectedness
10. Other Safety Issues Considered to be Serious in Clinical Trials
11. Recording and Reporting a Pregnancy
12. Annual Safety Reports (ASR)
12.1 Submitting Annual Safety Reports
13. Developmental Safety Update Reports (DSUR)
14. Contact details for CI reporting SUSARs to the Trust Research Office
15. Regulations, Guidelines, references, SOP Links etc
16. Appendices
16.1 Serious Adverse Event Form
16.2 NRES Report of Serious Adverse Event (SAE) (For all studies
except clinical trials of investigational medicinal products)
16.3 eSUSAR Reporting Form
16.4 NRES Clinical Trials of Investigational Medicinal Products Safety
Report to Main Research Ethics Committee
16.5 Pregnancy Reporting Form
16.6 Template Annual Safety Report

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1. Introduction

There are different reporting requirements for NHS/HSC research involving clinical
trials and medicines (where legal requirements for reporting have been introduced)
and non-clinical trials.

The European Clinical Trials Directive 2001/20/EC transposed into UK Regulations

by ‘The Medicines for Human Use (Clinical Trials) Regulations 2004’ (SI2004/1031)
and subsequent amendments, set out the legal requirements for adverse event
recording, management and reporting in clinical trials. The pharmacovigilance
strategy in the EU Clinical Trials Directive is designed to ensure:
- The prompt reporting of serious adverse events (SAE’s) and the ongoing
review of safety in CTIMPs
- The identification of AEs where an association with a study drug is suspected
- The effective dissemination of information on SUSARs across the EU and the
research community

Adverse event reporting for clinical and non-clinical trials should be undertaken in
accordance with the Trust Policy on reporting and managing adverse events and it is
the researcher’s responsibility to familiarise themselves with Trust incident policies.
Adverse events and near misses should be reported, as appropriate, to the Clinical
Risk Department using the Accident/Incident form reporting system. However,
researchers are also responsible for ensuring that legal requirements relating to the
use of a medicinal product or a medical device are fulfilled.

2. Objective

The objective of the Standard Operating Procedure (SOP) is to set out the procedure
to be followed when reporting an adverse or serious adverse event. Adherence to
the guidance included in this SOP and any associated notes should ensure
compliance with the protocol and legislative requirements.

3. Scope

All clinical trials involving medicinal products requiring registration with the MHRA
and all other research projects, sponsored by South Eastern Health & Social Care
Trust. All staff with responsibility for recording or reporting adverse events.

Research studies sponsored by an external organisation are exempt from this SOP,
but researchers must follow sponsor or study specific SOPs.

4. Study Planning

All protocols should list known side effects and adverse reactions contained within
the manufacturer’s product information. This should be written in agreement with the
relevant drug company where applicable. Rare/very rare events may or may not be
included depending on individual study requirements.

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A detailed explanation of SAE reporting procedures should also be included in the

protocol

A generic SAE reporting Form is available in Appendix 1. This form can be amended
to create a study specific form.

4.1 Which AE to record

The Chief Investigator (CI) can decide how to record and report adverse events,
whether expected or not. Adverse events are usually described on case report forms
(CRFs), unless they are classified as serious, in which case they should be reported
on a specific SAE Form (see appendix 1). It should be clearly stated in the study
protocol and the trial specific SOP (if applicable) what will be recorded and how the
reporting is to be managed.

It may be decided that all, or only some, non-serious AEs are to be recorded.
Whatever option is chosen, it must be consistent with the purpose of the trial and any
toxicity and efficacy end points.

4.2 Which SAE to Report

The management and reporting arrangements for SAEs should be clear for all trials.
Agreements at the beginning of the trial should be made for such SAEs that can be
defined as disease-related and therefore not subject to expedited reporting. The
procedures for managing and reporting SAEs must be clearly defined in the protocol.

It is recommended that an Independent Data Monitoring Committee (IDMC) is

appointed in order to review safety data regularly throughout the trial and when
necessary, recommend to the sponsor whether to continue, modify or terminate the
trial. Again this procedure must be defined in the protocol.

As with all recording and reporting, subject confidentiality and adherence to the Data
Protection Act (1998) must be maintained on all reports.

4.3 When to start and stop recording AE/Rs

All AE/Rs (non-serious, serious, expected, unexpected) need to be recorded from the
point of consent of a subject into a trial and not from the first dose of the administered
IMP. This will also include placebo run-in periods (if applicable). Serious adverse
events for which the onset occurs during the pre-randomisation period should be
reportable if they are a result of a protocol specified intervention or can cause the
participant not to be allocated to randomisation treatment.

All AEs and SAEs should be recorded within the established off therapy follow-up
period for safety described in the protocol, normally through to 3 months after study
compound has finished. This time period needs to be defined in the protocol.

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5. Adverse Event (AE) / Adverse Reaction (AR)

5.1 Definition

An adverse event is any untoward medical occurrence in a patient or clinical trial

subject administered an investigational medicinal product and which does not
necessarily have a causal relationship with this treatment.

An adverse reaction is any untoward and unintended responses to an investigational

medical product related to the investigational medicinal product.

5.2 Reporting Adverse Events

Adverse events that are not considered to be serious should be recorded on the
relevant case report forms and reported in the medical notes of the patient in
accordance with Good Clinical Practice guidelines. This will include adverse events
concerning tissue samples that come under the remit of the Human Tissue Act (SOP
28)

Adverse events must be monitored and followed throughout the study period. For
instance, in studies involving investigative medicinal products, the study period runs
from enrolment and commencement of study compound through to 3 months after
study compound has finished.

Should an adverse event be upgraded to a serious adverse event then the procedure
for dealing with a serious adverse event should be followed.

6. Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR)

6.1 Definition

This is an adverse event or adverse reaction that

 Results in death.
Death may occur as a result of the basic disease process. Nevertheless, all
deaths occurring within 30 days of the last administration of the study agent must
be treated as an SAE and reported as such. All deaths which may be considered
as related to the trial agent, regardless of the interval, must be treated as a SAE
and reported as such.

 Is life-threatening
It 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

 Requires hospitalisation or prolongation of existing hospitalisation (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

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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 experience; or

 Results in persistent or significant disability or incapacity (substantial disruption of

one’s ability to conduct normal life functions)

 Consists of a congenital anomaly or birth defect (in offspring of subjects or their

partners) taking the IMP regardless of time of diagnosis; Or

 Other Important Medical Event,

(these can include events that do not meet the standard criteria for seriousness
but based on appropriate medical judgement are considered serious as they may
jeopardise the participant and may require medical or surgical intervention to
prevent the above outcomes from occurring. They also include:

o Overdoses (accidental or intentional)

o Pregnancy (of subject or partner)
o An alarming adverse experience
o Non-serious adverse events and/or laboratory abnormalities which are
listed in the trial protocol as critical to safety evaluations and requiring
reporting

6.2 Reporting Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR)

If the AE/AR is assessed as serious, the PI must report the event to the CI
immediately or within 24 hours of being made aware of the event (other than those
SAEs identified in the protocol as not requiring immediate reporting). The initial
report can be made verbally but must be promptly followed with a detailed written
report. The PI must record the event with their assessment of seriousness, (along
with causality, expectedness and severity) on a trial SAE form, provided by the CI
(see appendix 1). The PI should ensure that follow up information is provided when
available.

Serious Adverse events should be documented in the patient’s medical notes. This
should include times, dates, nature of event, actions, plan of action and should
include legible signatures.

Serious adverse events and near misses should also be reported through local Trust
procedures, as appropriate.

6.2.1 Trust Sponsored CTIMPs

The CI must send all SAE/SAR reports to the Trust Research Office as soon as
possible after becoming aware of the event.

There is no requirement to routinely report SAE/SARs to the REC, other than through
the Annual Safety Report (ASR).

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6.2.2 Trust sponsored Other Research

There is no requirement to routinely report SAE/SARs to the Trust Research Office,

other than through the Annual Progress Report.

The CI must report all SAE/SAR to the Research Ethics Committee that gave a
favourable opinion of the study (the ‘main REC’) where in the opinion of the chief
investigator the event was:

 ‘related’: that is, it resulted from administration of any of the research procedures;
and
 ‘unexpected’: that is, the type of event is not listed in the protocol as an expected
occurrence.

Reports of related and unexpected SAEs should be submitted within 15 days of the
chief investigator becoming aware of the event, using the form in appendix 2. The
form should be completed in typescript and signed by the chief investigator.

7.0 Suspected Serious Adverse Reaction (SSAR)

7.1 Definition

This is an adverse reaction that is classed in nature as serious and which is

consistent with the information about the medicinal product in question set out in
the,

 Summary of Product Characteristics (SmPC) in the case of a licensed product

being used within its licensed dosage and indication

 Investigator’s Brochure (IB) in the case of any other investigational medicinal

product or a licensed product being used outside its licensed dosage and
indication

7.2 Reporting Suspected Serious Adverse Reaction (SSAR)

If the AR is assessed as serious, the PI must report the event to the CI immediately
or within 24 hours of being made aware of the event (other than those SARs
identified in the protocol as not requiring immediate reporting). The initial report can
be made verbally but must be promptly followed with a detailed written report. The PI
must record the event with their assessment of seriousness, (along with causality,
expectedness and severity) on a trial SAE/AR form, provided by the CI (see appendix
1). The PI should ensure that follow up information is provided when available.

SSARs should be documented in the patient’s medical notes. This should include
times, dates, nature of event, actions, plan of action and should include legible
signatures.

Serious adverse events and near misses should also be reported through local Trust
procedures, as appropriate.

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The CI should include all SSARs in the Annual Safety Report (ASR).

7.2.1 Trust Sponsored CTIMPs

The CI must send all SSAR reports to the Trust Research Office as soon as possible
after becoming aware of the event.

There is no requirement to routinely report SSARs to the REC, other than through the
Annual Safety Report (ASR).

8.0 Suspected Unexpected Serious Adverse Reaction (SUSAR)

8.1 Definition

This is an adverse reaction that is classed in nature as serious and which is not
consistent with the information about the medicinal product in question set out in the
Summary of Product Characteristics (SmPC) or Investigator’s Brochure (IB)

An event that is assessed as being

 Serious
 Possibly, probably or definitely related to the administration of the IMP and is
 Unexpected

Is defined as a SUSAR.

8.2 Reporting Suspected Unexpected Serious Adverse Reaction (SUSAR)

The CI should contact the Research Office immediately the decision is taken that an
SAR is a SUSAR, using the dedicated email address (see section 14.0). The
Research Manager/Associate Medical Director (Research) and CI will undertake a
further assessment to determine whether it is a fatal or life-threatening SUSAR, or a
non-fatal or life-threatening SUSAR.

For fatal or life-threatening SUSARs (7 day reporting), the Research Office in

collaboration with the CI will submit the SUSAR report as soon as possible but, within
seven days of the becoming aware of the event.

For non-fatal or life-threatening SUSARs (15 day reporting), the Research Office in
collaboration with the CI will submit the SUSAR as soon as possible but within fifteen
days of becoming aware of the event.

All SUSAR reports are to be reported electronically through the MHRAs e SUSAR
website (www.esusar.mhra.gov.uk). The CI will provide the required information for
the eSUSAR Report, see appendix 3, to enable the Research Office to submit the
eSUSAR report.

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The eSUSAR website will provide a pdf output to report to the Research Ethics
Committee. However, there is a standard covering form for sending reports to RECs
in the UK, see appendix 4.

Where incomplete information is available at the time of initial reporting, all the
appropriate information for an adequate analysis of causality should be provided as
follow up reports as it becomes available.

The CI will retain a copy of the expedited report and associated documentation in the
TMF. SUSARs should be documented in the patient’s medical notes. This should
include times, dates, nature of event, actions, plan of action and should include
legible signatures.

8.3 Reporting to PIs involved in Study

All PIs within the trial concerned must also be informed of the SUSAR, although this
does not have to be within the 7/15 day deadline. The CI should send all PIs a
summary of SUSARs approximately every 3 months. This timeframe may vary
between trials depending on the rates of recruitment and/or SUSARs.

If the CI is informed of SUSARs from other trials by a pharmaceutical company, the

CI should inform PIs as above.

9.0 Evaluating Adverse Events

The following documents need to be at hand when assessing any AE in the trial,
especially since they contain the required information for the expectedness of the AE
and timelines for reporting to the sponsor.

 Protocol
 Summary of Product Characteristics (for marketed products only)
 Investigator’s Brochure (if applicable)
 IMP Dossier (if applicable)
 Trial specific procedure for unblinding (in the case of a SUSAR in a blinded
trial)

Each AE must be evaluated for seriousness, causality, severity and expectedness.

The responsibility for this evaluation can be shared between the CI and PIs. It may
be most appropriate for the treating PI at each local site to evaluate each event,
before reporting it to the CI. It should be stated in the clinical trial protocol and trial
specific SOP (if applicable) who will take responsibility for the assessment and
reporting of such events to the Sponsor and CI simultaneously. This SOP assumes
that responsibility of initial assessment and reporting to the CI lies with the PI. The
CI cannot downgrade the PI’s assessment.

9.1 Seriousness

Seriousness should be assessed as per the definition of a SAE in section 6.0

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9.2 Causality

The relationship between the drug and the occurrence of each adverse event will be
assessed and categorised (as detailed below). The CI/PI will use clinical judgement
to determine the relationship. Alternative causes, such as natural history of the
underlying diseases, concomitant therapy, other risk factors etc. will also be
considered. The CI/PI will also consult the IB or SmPC.

 Not Related: Temporal relationship of the onset of the event, relative to

administration of the product, is not reasonable or another cause can by itself
explain the occurrence of the event.

 Unlikely: Temporal relationship of the onset of the event, relative to

administration of the product, is likely to have another cause which can by
itself explain the occurrence of the event.

 *Possibly related: Temporal relationship of the onset of the event, relative to

administration of the product, is reasonable but the event could have been due
to another, equally likely cause.

 *Probably related: Temporal relationship of the onset of the event, relative to

the administration of the product, is reasonable and the event is more likely
explained by the product than any other cause.

 *Definitely related: temporal relationship of the onset, relative to

administration of the product, is reasonable and there is no other cause to
explain the event, or a re-challenge (if feasible) is positive.

* Where an event is assessed as possibly, probably or definitely related, the event is

an AR.

9.3 Severity

The assessment of severity will be based on the CI/PIs clinical judgement using the
following definitions:

 MILD: An event that is easily tolerated by the patient, causing minimal

discomfort and not interfering with everyday activities.
 MODERATE: An event that is sufficiently discomforting to interfere with
normal everyday activities.
 SEVERE: An event that prevents normal everyday activities.

Note: severity is often used to describe the intensity of a specific event. This is not
the same as ‘seriousness’, which is based on patient/event outcome or action
criteria.

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9.4 Expectedness

This will be determined according to the reference documents as defined in the study
protocol (e.g. Investigator Brochure or Summary of Product Characteristics).

 Expected reactions are previously identified and described in protocol and/or

reference documents.

 Unexpected reactions are not previously described in the protocol or reference

documents.

Note: ARs must also be considered as unexpected if they add significant information
on the specificity or severity of an expected AR.

10. Other Safety Issues Considered to be Serious in Clinical Trials

Other safety issues where they might materially alter the current benefit-risk
assessment of an IMP or that would be sufficient to consider changes in the IMP
administration or in the overall conduct of the trial also need to be considered
serious, for example,

 An increase in the rate of occurrence or a qualitative change of an expected

serious adverse reaction, which is judged to be clinically important
 Post-study SUSARs that occur after the patient has completed clinical trial and
are reported by the investigator to the sponsor,
 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 temporary halt of a trial for safety reasons and
conducted with the same investigational medicinal products in another country
by the same sponsor.
 Recommendations of the Data Monitoring Committee (DMC), if any, where
relevant for the safety of the subjects.

11.0 Recording and Reporting a Pregnancy

All pregnancies in clinical trial subjects need to be recorded and reported to the
sponsor as soon as the investigator is aware of the event. See appendix 5 for
Pregnancy Reporting Form.

Pregnancy data provides vital data to the overall knowledge concerning the IMP.
Any pregnancy that occurs in a female trial subject during a clinical trial should be

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followed to termination or to term. Under special circumstances, it may be necessary

to monitor the development of the newborn for an appropriate period post delivery.
There may be special situations when it will be necessary to monitor the pregnancy
of a woman whose male partner is the trial subject. All trial protocols should describe
in detail the process for monitoring and managing pregnancy occurrences in a trial.

12.0 Annual Safety Reports (ASR)

Annual Safety Reports are required to be produced by the CI and submitted to the
MHRA and the REC that granted the favourable opinion, 12 months after the date of
the granting of a CTA Certificate and annually thereafter.

See appendix 6 for a template Annual Safety Report, which should include,

(1) A report on the subjects' safety in the clinical trial

 Concise safety analysis and benefit-risk evaluation describing all new findings
related to the safety of the IMP treatments and critical analysis of them with
respect to their impact for the subjects
 An analysis of the implications for the population of the clinical trial, analysis of
the safety profile of the tested IMP and its implications for subjects’ exposure ,
taking into account all available safety data
 When relevant the following points should be considered;
o Relation with dose, duration, time course of the treatment
o Reversibility
o Evidence of previously unidentified toxicity in the trial subjects
o Increased frequency of toxicity
o Overdose and its treatment
o Interactions or other associated risk factors
o Any specific safety issues related to special populations
o Positive and negative experiences during pregnancy or lactation
o Abuse or misuse of IMP
o Risks which might be associated with the investigation or diagnostic
procedures of the clinical trial
o Supporting results of non-clinical studies or other experience with the
IMP likely to affect subject’s safety
o Detailed rationale on whether necessary to amend the protocol/consent
form/patient information leaflet and Investigator Brochure.

(2) A line listing of all suspected SSARs (including all SUSARs) that occurred in the
trial
 Trial-specific line listing of all suspected SARs reported during the trial
 Key information but not necessarily all the details usually collected on
individual cases
 Should include each subject only once regardless of how many adverse
reaction terms are reported for the case
 Different adverse reactions on different occasions should be treated as
separate reports tabulated by body system
 One listing for each trial, but separate listings for active comparator or placebo

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(3) An aggregate summary tabulation of suspected SARs that occurred in the trial
 Summary tabulations of SAR terms for signs, symptoms and/or diagnoses
across all patients to provide an overview for the trial
 These tabulations should contain more terms than subjects
 If the number of cases is very small, a narrative description may be more
suitable
 The summary tabulation should specify the number of reports; for each body
system; for each ADR term; for each treatment arm (if applicable)
 The unexpected ADR terms should be clearly identified in the tabulation

12.1 Submitting Annual Safety Reports

12.1.1 Submission to MHRA

Annual safety reports should be provided as electronic documents on disk and be

sent to:
Information Processing Unit
Area 6
Medicines & Healthcare products Regulatory Agency
151 Buckingham Palace Road
Victoria
London
SW1W 9SZ

12.1.2 Submission to REC

There is a standard covering form for sending reports to RECs in the UK, see
appendix 4, which should be used when submitting the ASR to the REC.

12.1.3 Submission to the Trust Research Office

A reminder will be sent by the Research Office to the CI one month prior to the due
date of the ASR requesting an electronic copy of the ASR and covering REC form
and a paper SIGNED copy of the two reports. Confirmation that the reports have
been submitted to the REC and MHRA will also be required.

13.0 Development Safety Update Reports (DSUR)

As of 1 September 2011 Development Safety Update Reports (DSUR), will replace

the Annual Safety Reports (ASR).

Guidance on the DSUR can be found on the ICH DSUR guidance page
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/development-
safety-update-report.html

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14.0 Contact details for CI Reporting SUSARs to the Trust Research Office

A dedicated email account has been set up for the reporting of SUSARS to the
Research Office for Trust Sponsored CTIMPs,

Clinical.Trials@South Easterntrust.hscni.net

This email address should only be used for the reporting of SUSARs, all other
reports should be submitted directly to the Post Approval Team within the Research
Office.

15.0 Regulations, Guidelines, references, SOP Links etc

The Medicines for Human Use (Clinical Trials) Regulations 2004

http://www.uk-legislation.hmso.gov.uk/si/si2004/20041031.htm

The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006
http://www.opsi.gov.uk/si/si2006/20061928.htm

Detailed guidance on the collection, verification and presentation of adverse reaction

reports arising from clinical trials on medicinal products for human use. April 2006
http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2006/04_2006/susar_rev2_2006
_04_11.pdf

16.0 Appendices

16.1 Serious Adverse Event Form

16.2 NRES Report of Serious Adverse Event (SAE) (For all studies except clinical
trials of investigational medicinal products)

16.3 eSUSAR Reporting Form

16.4 NRES Clinical Trials of Investigational Medicinal Products Safety Report to Main
Research Ethics Committee

16.5 Pregnancy Reporting Form

16.6 Template Annual Safety Report

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Appendix 16.1

Serious Adverse Event Form

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 Serious Adverse Event Reporting Form

Study title

SEHSCT Research Office EudraCT number

CTA/DDX/CTX No
Project ID No
Has the Chief or Principal Investigator
been informed of this event prior to Yes No
Type of report Initial Follow-up the completion of this form?
Patient / Treatment details

Patient initials Patient study number

Date of birth (DOB) Height cm Weight . kg

d d m m m y y

Gender Female Was study drug unblinded?

Male

IMP(s) patient was receiving at time of SAE Route of

(if applicable) Dose (mg) administration Date of dose initiated Ongoing? End date (if applicable)

d d m m m y y Y N d d m m m y y

d d m m m y y Y N d d m m m y y
Most recent Was treatment given
Date of last treatment given
cycle number at full dose prior to Y *N *Specify:
prior to SAE d d m m m y y
(if applicable) event?
Did reaction reappear after
Did reaction abate after reintroduction of study
study medication stopped? Yes No N/A medication? Yes No N/A
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Serious Adverse Event

COMPLETE THIS PAGE FOR EACH SERIOUS ADVERSE EVENT (photocopy as necessary for each event)
Serious Adverse event Term Severity Date of onset Ongoing?
(Mild, Moderate, Date resolved
Severe)

d d m m m y y
Y N d d m m m y y

Why was the event serious? (choose most serious) Where did the event take place? Outcome

Resulted in death Home Resolved

Admission date Discharge date

Resolved with
Life-threatening Hospital
sequelae
d d m m m y y d d m m m y y

Required inpatient or prolonged existing hospitalisation Out-patient clinic Unresolved

Resulted in persistent or significant disability/incapacity Nursing Home Worsened

Resulted in congenital anomaly/birth defect Hospice Fatal

Other Important Medical Event (specify) Not

Other (specify)________________________________________
__________________ assessable
Expectedness

Unexpected Expected Is the event listed in the reference document, (study protocol, SmPC or Investigator’s Brochure)?
Causal relationship to event (Is the event related to the subject’s involvement in the study)?
Trial drug Definitely Probably Possibly Unlikely Not related Not assessable Name of person making decision
making decison

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Action taken
None *Treatment delayed and Treatment permanently Name of person making
Trial drug *Dose reduction *Treatment delayed decision
reduced stopped

*If dose was reduced and/or delayed, please specify length of delay/how much dose was reduced by:

Treatment given for management of SAE

Total daily Route of Start date End date
Treatment Units Ongoing?
dose administration d d m m m y y d d m m m y y

Y N
Y N
Y N

Any concomitant medications? Y N (If yes, please specify below and continue on separate sheet if necessary)
Total daily Route of Start date End date
Treatment dose Units administration d d m m m y y Ongoing? d d m m m y y

Y N

Y N

Y N

Y N

(If yes, please specify below and continue on separate sheet if necessary or
Any relevant tests / laboratory data? Y N attach print outs)

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(If yes, please specify below and continue on separate sheet

Any relevant medical history / concurrent conditions? Y N if necessary)

Any other relevant information?

Y N (If yes, please specify below and continue on separate sheet if necessary)

Event summary description (Give a concise medical description of the event including all relevant symptoms. Please specify the grade for all related
symptoms and complete page overleaf for all that meet the definition of serious)

For report of death: (state why the death was expected (eg disease progression, or if earlier than expected, provide explanation)

Describe whom this SAE was discussed with for a judgement of assessment:

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Describe why and how you reached the assessment of causality for expectedness and related (ie provide the reasoning for the outcome):

Signature of person
making the Date of
Print name d d m m m y y
assessment assessment
Authorised health professional
Signature of person
completing the form
if different to person Print name Date of report d d m m m y y
abovel

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For Sponsor’s Office use only

Date SAE reported to
Date SAE reviewed Event No
Research Office d d m m m y y d d m m m y y
Office Assessment of Is the event listed in the reference document, (study protocol, SmPC or
Expected Unexpected
Expectedness Investigator’s Brochure)?
Was the event a
SUSAR? ( ie unexpected Date reported to Main REC
Date reported to MHRA
and either of the *Y Reported to all
following: Definitely, other PIs *Y N
Probably or Possibly N
d d m m m y y
d d m m m y y
related to the IMP)

Form checked by (signature) Print name Date

Date reported to GTAC (if applicable)

d d m m m y y
d d m m m y y

Comments:

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Appendix 16.2

NRES Report of Serious Adverse Event (SAE) (For all studies except clinical trials of
investigational medicinal products)

Original Copy of Form can be found at:

http://www.nres.npsa.nhs.uk/applications/after-ethical-review/safetyreports/safety-reports-for-all-
other-research/#safetynonCTIMPrepotingSAEs
South Eastern Health and Social Care Trust

REPORT OF SERIOUS ADVERSE EVENT (SAE)

(For all studies except clinical trials of investigational medicinal products)

The Chief Investigator should report any SAE that is both related to the research procedures
and is unexpected. Send the report to the Research Ethics Committee that gave a favourable
opinion of the research within 15 days of the CI becoming aware of the event.

1. Details of Chief Investigator

Name:
Address:

Telephone:
Email:
Fax:

2. Details of study

Full title of study:

Name of main REC:

Main REC reference number:

Research sponsor:
Sponsor’s reference for this report:
(if applicable)

3. Type of event
Please categorise this event, ticking all appropriate options:

Death Life threatening Hospitalisation or

prolongation of existing
hospitalization

Persistent or significant Congenital anomaly Other

disability or incapacity or birth defect

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4. Circumstances of event

Date of SAE:

Location:

Describe the circumstances of

the event:

(Attach copy of detailed report if

necessary)

What is your assessment of the

implications, if any, for the
safety of study participants and
how will these be addressed?

5. Declaration

Signature of Chief Investigator:

Print name:

Date of submission:

6. Acknowledgement of receipt by main REC (please insert name):

The [ ] Research Ethics Committee acknowledges receipt of the above.

Signed:

Name:

Position on REC:

Date:

Signed original to be sent back to Chief Investigator (or other person submitting report)
Copy to be kept for information by main REC.

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Appendix 16.3

eSUSAR Reporting Form

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MHRA eSUSAR Reporting Form

Patient Information

Initials
Sex Male / Female / Unknown
Age at time of Reaction Years or Months or Days
Subject ID Number
Weight kg stones pounds
Height cm feet inches
Disease History
(MedDRA term)
Start Date dd/mm/yyyy
End Date dd/mm/yyyy
Continuing Yes / No / Unknown
Please enter details of any non-study medication that the patient has taken
outside of the last 3 months. Any medication taken within the last 3 months should be
entered as Concomitant in Step 4 - IMP Details
Drug History
(MHRA Drug dictionary)
Start Date dd/mm/yyyy
End Date dd/mm/yyyy

Reaction Details

Please enter details of the reactions suffered by the patient

Country of origin
(Country SUSAR occurred
in)
Reaction
(MedDRA term)
Reaction Outcome Recovered
Recovering
Not Recovered
Recovered with sequelae
Fatal
Unknown
Start Date dd/mm/yyyy
End Date dd/mm/yyyy
Narrative (Please provide a narrative of the reactions, together with any other information relevant to the
SUSAR report, in no more than 20,000 characters)

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Seriousness Death
Life threatening
Hospitalisation
Disabling
Congenital anomali
Other
Please enter details of any medical tests undertaken on the patient that are relevant to
the SUSAR report.
Test
(MedDRA term)
Result
Unit
Test Date dd/mm/yyyy

IMP Details

Please enter details of all study medication the patient has taken in the last 3 months.

Note regarding Drug Name entry: A dictionary of drug terms and codes is associated
with the eSUSAR reporting form. This is regularly updated with new terms that have
been submitted to the MHRA in CTA applications. The term entered into the Drug Name
field will be matched against the drug dictionary in real time. When no match is found,
the user will be prompted to check and re-enter the term. When no match is found for a
second time, the user will be permitted to continue and submit the report with an
unmatched name.

Drug Name
Drug Characterisation Suspect/Concomitant
(Select Suspect if the drug is the
suspected cause of the SUSAR)
If the patient is taking 200mg four times a day, this should be entered as '800' for the drug dose, 'mg' as the drug dosage
unit, '1' as the drug dosage interval, and 'day' as the drug dosage interval unit.
Drug Dosage Unit
Drug Dosage Interval Unit
Form
Route of Administration
Indication
(MedDRA term)
Start Date dd/mm/yyyy
End Date dd/mm/yyyy
Action Taken Drug withdrawn /
Dose reduced /
Dose increased /
Dose not changed /
Unknown /
Not applicable

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Appendix 16.4

NRES Clinical Trials of Investigational Medicinal Products Safety Report to Main Research
Ethics Committee

Original Copy of Form can be found at:

http://www.nres.npsa.nhs.uk/applications/after-ethical-review/safetyreports/safety-reports-for-
ctimps/submitting-safety-reports-to-the-rec/

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CLINICAL TRIALS OF INVESTIGATIONAL MEDICINAL PRODUCTS

SAFETY REPORT TO MAIN RESEARCH ETHICS COMMITTEE

Please indicate which type(s) of safety report you wish to notify with this cover sheet (tick all that
apply). Use a separate sheet for notifications relating to different trials. Please only send this to
the main REC. For further guidance see:
http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-
ctimps/

1. Expedited report(s) of SUSAR in the UK

Notify only Suspected Unexpected Serious Adverse Reactions occurring in
the concerned trial at a UK site.

2. 6-monthly safety report

Include a global list of all SUSARs related to the investigational medicinal product
(IMP) and occurring in the reporting period.

3. Annual safety report

Include a global list of all SSARs (Suspected Serious Adverse Reactions) related
to the IMP and occurring in the reporting period.

4. Other
For example, report of Data Monitoring Committee or other safety review.

Full title of study:

EudraCT number:

Research sponsor:

Name of Chief Investigator:

Name of main REC:

Main REC reference number:

Contact details for person making this notification

Name:

Address:

Telephone:

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Fax:
Email:

Date of this notification:

Signature:

List of enclosed documents

Please list each report submitted with this notification (insert extra rows in table as required).

1. Expedited SUSARs (UK only)

Sponsor’s report Date SUSAR first Is this a 7 or 15

Trial site day report?
no./reference reported to sponsor

2. Other reports

Type of report Date of report

Acknowledgement of receipt by main REC (please insert name):

The [ ] Research Ethics Committee acknowledges receipt of the above.

Signed:

Name:

Position on REC:

Date:

Signed original to be sent back only to the sponsor (or other person submitting the report)
Copy to be kept for information by main REC.

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Appendix 16.5

Pregnancy Reporting Form

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 Pregnancy Reporting Form
Study details

Study title

SEHSCT Research Office EudraCT

CTA/DDX/CTX No Project ID No number

1) Patient details (Any information regarding female partners of trial patients should be entered in Other Pregnancy Information section)

Patient initials Patient study number

Gender Male Female Date of Birth

d d m m m y y

Type of Report First Follow-up Height Weight . kg

cm

Yes No Was study Yes No

Has CI been informed?
unblinded?

2) Trial treatment

Is this full Start date End date

Drug Name Manufacturer Dose Unit Frequency Route Ongoing?
dose? d d m m m y y d d m m m y y

Y N Y N

Y N Y N

Y N Y N

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 Last treatment

Most recent cycle number: given before

Date last treatment given before
pregnancy confirmation: d d m m m y y pregnancy d d m m m y y

confirmation:

(Only include drugs given within the last 30 days. Continue Continued on a
3) Concomitant medications? Y N on separate sheet if necessary) separate sheet: Y N
Start date End date
Drug Manufa
Indication Dose Units Frequency Route Ongoing?
Name cturer d d m m m y y
d d m m m y y

Y N
Y N
Y N
Y N

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4) Pregnancy Information
Mother consented for
Start date of last menses Date pregnancy confirmed Method of diagnosis Anticipated date of childbirth
pregnancy monitoring

d d m m m y y d d m m m y y d d m m m y y
Y N

Pregnancy Outcome

Not known at this date Still birth Induced abortion Spontaneous abortion

Birth defects (provide details in Other Pregnancy Information section

Neonatal death Uneventful (normal/healthy baby)
below)

Date of Above Outcome:

d d m m m y y

Date of delivery Gestation Weight

Mode of Delivery Gender Antenatal Problems Postnatal Problems
d d m m m y y (weeks) (kg)

Male Female .

Other Pregnancy Information (concurrent conditions, medical history, complications during birth, birth defects etc)

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Past Pregnancy History
Date of delivery Gestation Weight
Mode of Delivery Gender Antenatal Problems Postnatal Problems
d d m m m y y (weeks) (kg)

Male Female .

Male Female .

Male Female .

Signature
Print name Date of report d d m m m y y
PI or other participating clinicians only

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Sponsor Office use only
Date reported to
Date SAE reviewed Event No
Research Office d d m m m y y d d m m m y y d d m m m y y

Was the event a SUSAR?

Date reported to MHRA Date reported to Main REC
( ie unexpected and either
Reported to all other
of the following: Definitely, *Y N *Y N
PIs
Probably or Possibly
d d m m m y y d d m m m y y
related to the IMP)

Form checked by Print name

Date reported to GTAC (if applicable) (signature)

Date
d d m m m y y
d d m m m y y

Comments:

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Appendix 16.6

Template Annual Safety Report

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 Clinical Trials of Investigational Medicinal Products

Annual Safety Report to MHRA

Report Covering Period xxx to xxx

Full title of trial

Short title
IMP(s) under investigation
Sponsor
EudraCT number
MREC that approved the Trial
Chief Investigator
CTA number
Trial start date
Trial end date
Target number of subjects for whole
trial

Contact details for person making this notification

Name
Address
Telephone
Fax
Email
Date of this notification

Safety information in reporting period

Number of subjects enrolled during

the review period
How many subjects have been
enrolled since the trial started
Number of SAEs observed

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1
1. Are there any new and relevant findings related to the safety of the subjects, Yes
including all new findings related to the safety of the investigational medicinal product
(IMP) (s) or other treatments used in the trial and any other findings related to the No
clinical trial procedures?
2
If yes, provide a concise description :

2. Have there been any non-clinical studies or other experiences with this IMP (s) that Yes
are likely to affect the subjects’ safety?
No

If yes, provide details:

3. Are there any implications for the population of the clinical trial such as new Yes
measures to minimise any risks found or any need to amend the protocol, patient
information sheet, consent form and investigator’s brochure? No

If yes, provide details:

4. Is there an update of the risk-benefit evaluation for the clinical trial? Yes

No

If yes, provide details:

1
New findings refers to information not already present in the investigator’s brochure or for licensed drugs the summary of product
characteristics.
2
When relevant, the following points should be considered: relation with dose, duration, time course of the treatment; reversibility;
evidence of previously unidentified toxicity in the trial subjects; increased frequency of toxicity; overdose and its treatment; interactions or
other associated risks factors; any specific safety issues related to special populations, such as the elderly, the children or any other at risk
groups; positive and negative experiences during pregnancy or lactation; abuse; risks which might be associated with the investigation or
diagnostic procedures of the clinical trial.
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 Trial Safety Report Line Listing

Body system Unblinding

CTC Version Case Date of Results
3 Reference Dates of Onset of (where
Subject ID
See appendix Number Country DOB Sex Dose of IMP Treatment AE Adverse Reaction Outcome Comments applicable)

Trial Aggregate Summary Tabulation

Body System / ADR term Arm A Arm B Total

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 APPENDIX 1
Guidance Notes for Annual Safety Reports Line Listing and Summary Tabulation

Field Comment
Subject ID Patient trial number
Body System Body system is classified according to the Common Toxicity Criteria (Version 3.0)
1. Allergy/Immunology
2. Auditory/Ear
3. Blood/Bone Marrow
4. Cardiac Arrhythmia
5. Cardiac General
6. Coagulation
7. Constitutional Symptoms
8. Death
9. Dermatology/Skin
10. Endocrine
11. Gastrointestinal
12. Growth & Development
13. Hemorrhage/Bleeding
14. Hepatobiliary/Pancreas
15. Infection
16. Lymphatics
17. Metabolic/Laboratory
18. Musculoskeletal/Soft Tissue
19. Neurology
20. Ocular/Visual
21. Pain
22. Pulmonary/Upper respiratory
23. Renal/Genitourinary
24. Secondary Malignancy
25. Sexual/Reproductive Function
26. Surgery/Intra-operative Injury
27.Syndromes
28. Vascular
29. Other
Case Reference Number This is a number to uniquely identify the SAE event
Country This refers to the country in which the case occurred
DOB Date of Birth (dd/mm/yyyy)
Sex F=female M=male
Dose of IMP This is given in mg.
Dates of Treatment Date patient started cycle related to event (dd/mm/yyyy)
Date of onset of AE Date the symptoms started (dd/mm/yyyy)
Adverse Reaction Describes the symptoms patient experienced during the manifestation of the event,
progression of event, test etc
Outcome Refers to treatment given (trial or otherwise)
Other Comments This section is optional, only complete if relevant eg causality disagreement,
concomitant medications also suspected
Unbinding Results (where Provide details if unblinding took place
applicable)

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