Work Instruction Title: Serious Adverse Event Reporting
Work Instruction Number: 21
Version Number: V2
Effective Date: 19 January 2011
Author
Name: Heather Leishman
Title: PCRN-EoE Network Co-ordinator
Date: 17 February 2010
Approved by
Name: Helen Macdonald
Title: Research Delivery Manager
Date: 8 October 2014
Review date: 8 October 2016
Review History
Version No. date
V1
01.07.2013
V2
24.09.14
amendments
Minor change: Removal of PCT reference
Change from 24 hour reporting to immediate
reporting plus minor amendments HL
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1. Introduction, Background and Purpose
Pharmacovigilance is the continuous process of monitoring, evaluating and
improving the safety of medicines, which is ongoing throughout the period of drug
development, from animal testing through to post-marketing surveys.
In order to assess the safety of an investigational product, and protect trial
participants, it is important to:
 Collect baseline information on the health status of trial participants
 Be aware of and record all concomitant medications
 Ask about these, and about the subjects health status at every visit
 Record all untoward medical occurrences (Adverse Events, (AEs)) as
specified in the protocol and report within the specified timeframes
 Collect all data as accurately as possible
A Serious Adverse Event (SAE) is any untoward medical occurrence or effect that
at any dose:
 results in death
 is life threatening
 requires hospitalisation or prolongation of existing inpatients’ hospitalisation
 results in persistent or significant disability or incapacity
 is a congenital abnormality or birth defect
In this context, life threatening refers to an event in which the subject was at risk of
death at the time of the event; it does not refer to an event which hypothetically might
have caused death if it were more severe.
Medical judgement should be exercised in deciding whether an adverse
event/reaction is serious in other situations. Important adverse events/reactions that
are not immediately life threatening or do not result in death or hospitalisation but
may jeopardise the subject or may require intervention to prevent one of the other
outcomes listed in the definition above, should also be considered serious.
When a Serious Adverse Event is judged by the Principal Investigator or Sponsor as
having a reasonable causal relationship to the investigational product, at any
administered dose, it is considered to be a Serious Adverse Reaction (SAR) by the
sponsor
Should a study participant become pregnant whilst participating in an a Clinical Trial
of an investigational medicinal product (CTIMP) or aids in the conception of a child
whilst participating such a trial, the pregnancy and resulting child should be followed
up for a period of no less than 18 months to verify whether a congenital anomaly or
birth defect is present.
Severity
The term “severe” is often used to describe the intensity of a specific event. This is
not the same as “serious” which is based on patient/event outcome or action criteria.
A Serious Adverse Reaction (SAR) is any adverse event/reaction that is classed as
serious and which is consistent with the information about the investigational
medicinal product (IMP) listed in the Summary of Product Characteristics (SPC) or
Investigator’s Brochure (IB)
Suspected Unexpected Serious Adverse Reaction (SUSAR): Any adverse
reaction that is classed as serious and is suspected to be caused by the IMP that is
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NOT consistent with the information about the IMP in either the SPC or IB. The
Sponsor reports SUSARS to the MHRA and also to the research ethics committee
and drug safety committee who continually assess the safety of an IMP and the
continuation of the trial.
Each SAE should be checked for expectedness. The event should be considered a
SUSAR if:
 it is not listed as expected, or
 it has occurred in a more serious form than anticipated, or
 the outcome is not consistent with the applicable product information.
2. Abbreviations
See Reference Document: CRN Glossary of Terms and Abbreviations
3. Scope
The Work Instruction (WI) applies to all staff working on NIHR adopted interventional
studies. A clinical trial of an investigational medicinal product (CTIMP) is a legal
definition and describes those trials which fall within the scope of the Medicines for
Human Use (Clinical Trials) Regulations 2004, and subsequent amendments
Non CTIMP trials, while not governed by law, are governed by the DH Research
Governance Framework for Health and Social Care (2005), all studies therefore
require an awareness of safety reporting requirements.
This WI should be read and applied in conjunction with relevant Trust Policies and
approved study protocols.
4. Responsibilities
The Principal Investigator has responsibility to ensure that a system is in place to
ensure accurate and timely reporting of SAEs. The PI may delegate the task of initial
reporting to a delegated team member as set out in the Authorised Delegation Log
(ADL). When the study team become aware of an SAE it must be reported to the
study sponsor immediately.
Each Adverse Event must be evaluated for seriousness, causality and expectedness.
The responsibility for this evaluation can be shared between the Chief Investigator
and the Principal Investigator. The study protocol should state who has responsibility
for the assessment and reporting. The sponsor will also assess causality and
expectedness and may decide to upgrade an Investigator decision, but may not
downgrade the Investigator’s assessment of any adverse event.
5. Procedures
5.1 Planning
General Practice team/service team should consider carefully how best to capture
the SAEs in a timely manner when a study is accepted, particularly if there are
long time periods between study visits. It is important that the PI and the study
nurse/co-worker make time to examine the reporting procedures in the study
protocol carefully, ensuring they have a good supply of reporting forms, patient
emergency contact cards and study diaries (where applicable) before the study
starts recruiting. Easy access to the Investigator’ Brochure (IB), if the product is
not yet marketed, is essential for reference purposes throughout the period of the
trial when patients are seen for study visits.
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For initial reporting procedures to work well both the study participant and the
practice/service need to be organised and ready for such events.
5.2 The Investigator’s Brochure
The investigator’s brochure (if applicable) will be updated throughout a clinical trial
(at least yearly). As new information emerges about the study drug/product, this
information should be made known to the Principal Investigators - usually through
an updated Investigator’s Brochure and regular communications from the sponsor
This includes reports of SUSARs at other sites, and also SUSAR reports from
other trials in which the IMP is being administered. These notifications should be
filed in the Site File.
5.3 SAE / SUSAR reporting from the participant
One way of ensuring good and timely reporting from the participant is to explain
the reporting procedures for serious adverse events to the participant at the
informed consent visit. The participant should then understand that they need to
let the site study team know if they become very unwell. Ask the participant to
give the PI’s contact details to a family member or friend who can make contact if
anything untoward occurs so that it can be reported. The ‘Emergency contact
card’ (see Appendix 1) should also be discussed with the participant at the
informed consent visit although this may not be given to the participant until the
randomisation visit.
5.4 Note alerts
In general practice/service it is strongly recommended that the practice applies a
tag or alert to the electronic clinical records of participants who have consented to
take part in an interventional research project. In line with SOP 01 Informed
Consent, this assists locum staff at the practice/service by providing the
Participant information sheet and GP/Dr information sheet for the relevant study.
By working with administration staff to ensure all tagged/alerted study participant
incoming letters/discharge letters are passed to the PI or study nurse, adverse
event reporting is likely to occur in a timely way.
5.5 SAE/ SUSAR reporting
Serious Adverse Events should be reported in line with the study protocol. The
study nurse/co-worker or PI completes the initial SAE report form. This will be
supplied by the study team with clear guidance on where and to whom it should
be sent, See Appendix 2. Only delegated study staff can complete the SAE form.
This report should be sent immediately upon knowing about an event, including all
information that is available at the time. It is better to ‘over report’ than not to
report.
The PI must sign the SAE form, but the initial form can be sent without the PI
signature if the obtaining a signature may cause delay in reporting. In this case
the form needs to be re-sent once it has been signed by the PI.
Once the initial, signed SAE form has been sent to the study sponsor (usually the
data monitoring team), a photocopy of the form together with a cover letter giving
the full name of the study and the name of the Chief Investigator may need to be
sent to the research ethics committee that approved the study and the research
governance body that approved the study for the site. The practice/service team
will need to check local requirements for this. In many cases the sponsor will
assist with this unless this has been delegated to the site team (PI and study
nurse). The SAE form may be either paper or electronic (e-CRF). SAE forms do
not have participant identifiable data on them but are recognised by the study
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number only. If an SAE form is completed for a participant and sent to the
Sponsor and approval bodies (as described) this should be marked in the
participant’s clinical record.
5.6 Fax procedures
In order to submit the SAE form within 24 hours of the study team learning about
the event it is usual to send the form by fax. If an administrator is faxing the form
they must understand the importance of receiving confirmation that the fax has
been received by the sponsor. Faxes must be sent following the secure fax
reporting procedure as set out in the local Information Governance policy.
Otherwise the following procedure should be used.
First telephone the sponsor as set out in the site file to inform them of the report.
Send the SAE form using a fax cover sheet with the practice/service details,
number of pages, the fax number of the sponsor and the date. State the study
number of the participant and the date of the SAE.
Where possible attach the fax receipt with the fax cover sheet to the back of the
SAE form that has been sent. Ensure that the fax receipt shows that the fax was
sent. In some large trials the fax machine may often be busy and your fax may
not get through - in this case the fax receipt shows as “busy”. In this case you
must contact the team again and arrange to send the fax later. Once the fax has
been sent, contact the study team to ensure that it has been received and note
this on the SAE form.
File the SAE from and fax related paperwork in the study site file under SAEs.
5.7 Follow up SAE reports
The study protocol should stipulate when follow up SAE forms are required. The
follow up forms are usually the same as the initial reporting forms, but should be
identified as Follow Up. In the follow up period more available data will sent to the
sponsor such as X-ray reports/scans/discharge letters. It is possible that a
diagnosis may also have been made if this did not occurred initially (the initial
report may read “patient collapsed - unknown cause”). The above procedures
apply to the follow up forms except that the PI may now be asked on the form to
give an opinion about the likely causality and expectedness of the event (i.e. does
the PI think that the event was caused by the study drug?). All source data sent
with follow up SAE forms as evidence of an event must be anonymised and the
patients study number applied to the documentation.
5.8 Protocol deviation
(1) ‘The sponsor and investigator may take appropriate urgent safety measures
in order to protect the subjects of a clinical trial against immediate hazard to their
health or safety’
(2) ‘If measures are taken pursuant to paragraph (1) the sponsor shall
immediately, in any event not later than 3 days from the date the measures were
taken, give written notice to the licensing authority and the relevant ethics
committee of the measures taken and the circumstances giving rise to those
measures’
SI 2004/1031 Medicines for Human Use (Clinical trials_ regulations 2004: Part 4,
Section 30)
5.9 Incident reporting
If the PI is of the opinion that the event was caused by the study drug (even if this
has not been proven), the PI should contact the local RM&G department to
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discuss whether the event should be reported under local incident reporting
procedures.
5.11 Audit
During an audit or inspection the SAE reporting procedures will be examined
along with each adverse event report that has been reported and filed. It is good
practice therefore to ensure that the events in the site file are properly grouped by
study participant and followed up appropriately. Evidence that the SAE reports
and follow up reports were sent to the Research Ethics and Research Governance
organisations will be examined. See WI 16 Audit and Inspection.
6. Related SOPs, Work Instructions and Reference Documents
6.1 SOPs
SOP 01 Informed Consent
SOP 05 Safety Reporting
6.2 Work Instructions
WI 16 Audit and Inspection
WI 20 Adverse Event reporting
6.3 Reference Documents
ICH Good Clinical Practice (GCP)
EU Clinical Trials Directive (EUCTD)
CRN Glossary of terms and Abbreviations
7. Appendices
Appendix 1: Example of wording on Emergency Contact Card:
Appendix 2: Example of SAE Reporting Form
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Appendix 1: Example of wording on Emergency Contact Card:

Patient Name: ……………………

Patient Number:…………………..

GP Name:……………………………….

GP Number…………………………..
WARNING

This patient is taking part in a clinical trial, and may be on xxx (name of
drug)

To discuss obtaining a code-break, treating doctors should contact:

Tel no: xxx (needs to be 24/7)
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Appendix 2: Example of Serious Adverse Event Reporting Form
SERIOUS ADVERSE EVENT FORM
Date of Report
Study Name
Patient
ID
Centre
Type of Report:
1. Patient initials
(first, last)

Initial
1a Country
Date:
/
/
Final
Month
Date :
/
/
EVENT INFORMATION
2a. Age
3. Sex
4-6. Reaction Onset
Years
Day
Month Year
2. Date of Birth
Day

Year
 Patient died
 Hospitalisation or
prolonged
inpatient hospitalisation
 Involved persistence or
significant disability or
incapacity
 Life threatening
 Congenital Anomaly/Birth
defect
 Medical intervention to
prevent the above
7-13. Summary of Event (include severity level (1=mild, 2=moderate, 3=severe,4=life threatening)
Date event became serious _____/_____/_____
End date of event
8-12. Check all appropriate to
adverse reaction
_____/_____/_____ (If ongoing please complete follow form
STUDY DRUG INFORMATION
14. Study Drug(s) (include generic name)
20. Did reaction abate after stopping drug?

Yes
15. Daily Dose(s)
16. Route(s) of Administration

No
N/A
21. Did reaction reappear after
reintroduction?

Yes
17. Indication(s) for Use
18. Therapy Dates (from/to)



No
19. Therapy Duration
CAUSALITY OF OVERALL DIAGNOSIS TO STUDY DRUG
1. Almost certainly related
2. Probably related
3. Possibly related
4. Unlikely to be related
5. Unrelated
CONCOMITANT DRUG(S) AND HISTORY
22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction
23. OTHER RELEVANT HISTORY (e.g. diagnostics, allergies, pregnancy with last month of period, etc)
Batch No. of Study Drug Administered
Form completed by:
Signature of Doctor:
Reporting GP:
Contact No.
Position (PI):
PLEASE RETURN TO:
CLINICAL TRIALS UNIT
FAX NO:
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N/A