Adverse Event reporting
UoB QMS reference number: UoB-CLN-AES-SOP-001
Purpose:
This Standard Operating Procedure (SOP) describes the processes involved in Adverse Event
reporting from trial set up to trial closure.
Scope:
The SOP must be adhered to in all clinical trials where the University of Birmingham (UoB) takes on
the Sponsor responsibility for pharmacovigilance. This SOP may be used as a guidance document in
all other cases.
Implementation plan:
This SOP will be implemented directly after the implementation date for any trials that have not been
set up. For any trials that have already been set up, the reporting requirements to the Research
Ethics Committee (REC), Competent Authority (CA) and the UoB Research Governance Team (RGT)
will be implemented directly after the implementation date. All other processes should be adhered to
as far as possible.
Date of implementation:
16-Dec-2013
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Adverse Event Reporting
Abbreviations and Definitions:
Term
Description
Adverse Event
Any untoward medical occurrence in a patient or clinical trial subject
administered a medicinal product and which does not necessarily have a
causal relationship with this treatment.
Comment:
An Adverse Event can therefore be any unfavourable and unintended sign
(including abnormal laboratory findings), symptom or disease temporally
associated with the use of a medicinal product, whether or not related to the
medicinal product.
Adverse Reaction
For CTIMPs, all untoward and unintended responses to an investigational
medicinal product related to any dose administered.
AE
See ‘Adverse Event’.
AR
See ‘Adverse Reaction’
Reference Safety
Information
Term used within EC Detailed Guidance (CT3) June 2011, meaning the
applicable product information which is used to determine the expectedness of
an Adverse Reaction. This information is normally obtained from within the
Summary of Product Characteristics or Investigator Brochure; when referring to
the Investigator Brochure the relevant section must be defined. It may be a
separate document in its own right. It must be defined at the start of a trial.
RSI
See ‘Reference Safety Information’
SAE
See ‘Serious Adverse Event’.
SAR
See ‘Serious Adverse Reaction’
Serious Adverse
Event
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 anomaly/birth defect

Or is otherwise considered medically significant by the Investigator**
Comments:
The term severe is often used to describe the intensity (severity) of a specific
event. This is not the same as serious, which is based on participants/event
outcome or action criteria.
* Life threatening in the definition of an SAE refers to an event in which the
participant was at risk of death at the time of the event; it does not refer to an
event that hypothetically might have caused death if it were more severe.
** Medical judgment should be exercised in deciding whether an AE is serious
in other situations. Important AEs 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 be considered serious.
Serious Adverse
Reaction
For CTIMPs, an adverse reaction which also meets the definition of a Serious
Adverse Event.
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SUSAR
See ‘Suspected Unexpected Serious Adverse Reaction’
Suspected
Unexpected
Serious Adverse
Reaction
For CTIMPs, A Serious Adverse Reaction that is unexpected i.e. the nature, or
severity of the event is not consistent with the applicable product information.
A SUSAR should meet the definition of an Adverse Reaction, an Unexpected
Adverse Reaction and a Serious Adverse Reaction
UAR
See ‘Unexpected Adverse Reaction’
Unexpected
Adverse Reaction
For CTIMPs, an Adverse Reaction, the nature or severity of which is not
consistent with the applicable product information (e.g. investigator's brochure
for an unauthorised investigational product or summary of product
characteristics for an authorised product).
Unexpected and
Related Event
For non-CTIMPs, an event which meets the definition of both an Unexpected
Event and a Related Event.
Unexpected Event For non-CTIMPs, the type of event that is not listed in the protocol as an
expected occurrence.
Background:
The process of Adverse Event reporting is key to any clinical trial, be it a Medical Devices trial, a
Clinical Trial using an Investigational Medicinal Product (CTIMP) or any other trial. The needs for and
responsibilities relating to Adverse Event reporting are described in the NHS Research Governance
Framework; see link:
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/139565/dh_4122427.pd
f.
This SOP covers adverse event reporting for all trials, detailing specifics for specific groups of trials
where applicable.

For Clinical Trials using Investigational Medicinal Products (CTIMPs), The Medicines for
Human Use (Clinical Trials) Regulations 2004 and amendments detail the pharmacovigilance
reporting requirements of the Sponsor or the Sponsor’s delegate.

Part 5 of this act lists the legal responsibilities of Investigators and the Sponsor with regard to
pharmacovigilance reporting. Additional guidance has been published by the EU 2011/C
172/01: ‘CT-3’, June 2011: Detailed guidance on the collection, verification and presentation
of adverse event/reaction reports arising from clinical trials on medicinal products for human
use’ (subsequently referred to as the detailed guidance:
http://ec.europa.eu/health/files/eudralex/vol-10/21_susar_rev2_2006_04_11_en.pdf ).

Advanced Therapies Medicinal Products are further regulated via the ‘Regulation (EC) No
1394/2007 of the European Parliament and of the council of 13 November 2007 on advanced
therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No
726/2004’; this regulation and further guidance can be found on the MHRA website, link:
http://www.mhra.gov.uk/Howweregulate/Advancedtherapymedicinalproducts/Aboutadvancedt
herapymedicinalproducts/index.htm .

Each competent authority within the EU also publishes its own set of guidelines. The MHRA
provides additional guidance and requirements for safety reporting within clinical trials in the
UK. This detail is available on their website: the current link
ishttp://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safet
yreporting-SUSARSandASRs/index.htm

Feedback from MHRA Good Clinical Practice inspections may also be taken as guidance
(See MHRA (2012) Good Clinical Practice Guide, UK: The Stationery Office).

The MRC/DH/MHRA have also published a paper called “Joint Project Risk-adapted
Approaches to the Management of Clinical Trials of Investigational Medicinal Products”
(http://www.mhra.gov.uk/home/groups/l-ctu/documents/websiteresources/con111784.pdf)
which defines a simple risk categorisation for clinical trials based on the marketing information
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of the IMP and standard of care. This document specifies that a risk based strategy can be
applied to safety monitoring of clinical trials.

The International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) Guidelines have also been issued to describe the
scope and content of a Development Safety Update Report (DSUR) which replaces the
requirement to submit an Annual Safety Report in the EU as of the 1st September 2011. See
link:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2F/Present
ation/ICH_E2F_step_4_October_2010.pdf.
For medical devices there are a number of directives and guidelines – details can be found
on: http://www.mhra.gov.uk/Howweregulate/Devices/ and http://ec.europa.eu/health/medicaldevices/files/meddev/2_7_3_en.pdf
All links are correct at the time of writing.

Responsibilities:
Sponsor (for UoB via the Research Governance Team):

Ensure safety information is reported annually to the relevant CA(s) and REC(s)

Upon request provide contact details of any trials using the same IMPs sponsored by the
same Sponsor.

When informed of any potential significant safety issues that may have to be reported to the
Chief Investigators (CIs) of any other trials in the Sponsor’s portfolio using the same IMP,
ensure further reporting is undertaken
Sponsor duties delegated to Chief Investigator or delegate:
Where the UoB takes on the Sponsor responsibility for pharmacovigilance, the UoB will delegate the
majority of pharmacovigilance duties to the CI, who may delegate these duties further to their trials
team. These include the following:

Decide on the level of Adverse Event reporting and ensure this is documented in the protocol

Decide on the applicable product information; for CTIMPS the Reference Safety Information
(RSI)

Continuously weigh anticipated benefits and risks of the clinical trial which includes ongoing
safety evaluation of IMPs

Where producing an Investigator Brochure (IB) for a trial, ensure that the IB is validated at
least once a year

Where using an existing IB or Summary of Product Characteristics (SmPC), ensure its
contents is reviewed on a regular basis; e.g. once a year

Set up systems for Adverse Event reporting according to the applicable regulations and/or
guidance

Ensure site staff are appropriately trained on the trial specific Adverse Event reporting
requirements including the need for the PI or their delegate to perform the causality
assessment and ensure training is documented

Keep detailed records of all adverse events relating to a clinical trial reported to the Sponsor
by the investigators of that trial

Review causality assessments and perform expectedness assessments

Categorise SAEs

Notification of:

For CTIMPs: Suspected Unexpected Serious Adverse Reactions (SUSARs) to CA(s) and
REC within the required timelines.

For Medical Devices: SAEs to CA/REC
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
For other trials: Unexpected and Related Serious Adverse Events (SAEs) to the REC
within the required timelines.

Where conducting a trial in a site based in a third country (i.e. a non-EU member state),
ensure the local regulations are adhered to and ensure all SUSARs occurring at that site are
entered in the European database

Inform Principal Investigators of any safety issues in a timely fashion; for CTIMPs this includes
forwarding information about SUSARs

For CTIMPs: generate a DSUR annually and send to the CA(s) and REC

For non-CTIMPs generate Annual Progress Report and submit to REC
Site Principal Investigator or delegate
As per the trial specific procedures and any local procedures

Ensure the Sponsor is immediately informed of any Serious Adverse Events (SAEs) (except
for those identified in the protocol as not requiring immediate reporting)

Perform causality assessments

When requested, provide any further information
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Procedure:
During trial set up:
o Decide on the level of Adverse Event reporting
o Decide on the applicable product information; for CTIMPS the RSI
o Include a section in the protocol regarding adverse event reporting requirements; see section 9 of UoB-CLN-ESDo
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
QCD-001 Protocol template
Develop a SAE form:
· For Medical Devices, consider using the MEDDEV SAE template form; see references below
· See for an optional template UoB-CLN-AES-QCD-002: SAE Form template
· Develop an internal process for SAE handling; see for an example UoB-CLN-AES-QCD-003: Internal process for
SAE handling example. Ensure any Sponsor specific requirements are embedded in the process. Note this
process may be embedded in local SOPs
Ensure site staff are appropriately trained on the trial specific Adverse Event reporting requirements, including the
need for the PI or their delegate to perform the causality assessment and that training is documented
Remind sites of possible need of reporting any SAEs to their R&D departments as per their local practices
Consider developing pregnancy notification form
Consider setting up as SAE tracking log
Consider registering the trial at the eSUSAR website; see references below
During trial – monitor Adverse Event reporting
Continuously weigh anticipated benefits and risks of the clinical trial which includes ongoing safety evaluation of
IMPs
Keep detailed records of all adverse event relating to a clinical trial reported to the Sponsor by the investigators of
that trial
Process any SAEs as per pre-defined process:
· Review causality assessments, perform expectedness assessments and categorise SAEs
· For CTIMPs report SUSARs to the REC and the CA, for MHRA using the MHRA eSUSAR form; see reference
below
· For non-CTIMPs report Unexpected and Related SAEs to the REC; see NRES website referenced below
· For Medical Devices, report any SAEs to the CA and REC following their guidelines; for the UK see the MHRA
website referenced below for further guidance
Inform Principal Investigators of any safety issues in a timely fashion; for CTIMPs this includes forwarding
information about SUSARs
Ensure annual reporting is undertaken as required:
· For CTIMPs ensure a DSUR is completed and sent to the CA and REC on an annual basis; see for an optional
template UoB-CLN-AES-QCD-004 DSUR template
· For non-CTIMPs, ensure safety information is including in the Annual Progress Report and sent to the REC on
an annual basis; see the NRES website referenced below for further guidance
Where producing an IB for a trial, ensure that the IB is validated at least once a year
Where using an existing IB or Summary of Product Characteristics (SmPC), ensure its contents is reviewed on a
regular basis; e.g. once a year
Where a Data Monitoring Committee is in place, ensure safety information is made available for their review at the
scheduled time points
Supply information to Sponsor as requested. For UoB (co-)sponsored trials send a copy of the reports to the RGT at
the time of reports being sent to the REC and CA (if applicable); the RGT will review their trials database and ensure
CIs of trials (co)sponsored by the UoB involving the same IMP are informed of any major safety issues within 5
working days of them having received the report. RGT will also assess the impact upon Sponsorship/Insurance or
contractual obligations and respond as necessary. Reports include:
· Reports of any major safety issues, e.g. urgent safety measures
· Any SUSARs (for CTIMP) or Unexpected and Related Serious Adverse Events (non-CTIMPs); include a note
from the CI explaining how this case impacts the safety profile of the study
· DSURs (for CTIMPs) or ASRs (Annual Safety Reports)
Ensure sites follow up on any AEs/SAEs until resolution or stabilisation
o
o
At the end of the trial
If SAE information is kept in a separate system, ensure information is reconciled with the main trial database
Ensure SAE forms and related information are archived as part of the TMF
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Reporting timelines:
For CTIMPs the following timelines apply –

Fatal/life threatening SUSAR: initial report to competent authority and REC within 7 days of
the Sponsor being notified of the event, and any additional information within 8 days of
sending the first report.

Non-fatal/non-life threatening SUSAR: report to competent authority and REC within 15 days
of the Sponsor being notified of the event.
For all other non-CTIMPs only related and unexpected SAEs must be reported to the REC within 15
days of the Sponsor being notified of the event.
For Medical Devices, all SAEs need to be reported to the competent authority; in the UK this should
be done as soon as possible.
Causality assessments in CTIMPs:
Causality assessment decisions must be made by a qualified doctor or, when appropriate, a qualified
dentist. If the investigator is not a qualified doctor (or dentist), this task must be formally delegated to
a qualified doctor (or dentist) who is a member of the research team. The trial delegation log should
reflect this.
In addition, the EU detailed guidelines clearly state that the causality assessment given by the
Principal Investigator should not be downgraded by the Sponsor. If the Sponsor (or CI where this duty
is delegated to the CI) disagrees with the Principal Investigator’s causality assessment, the opinion of
both parties should be documented, and where the event requires further reporting, the opinion
should be provided with the report.
Related documents:

UoB-CLN-ESD-QCD-001: Protocol template

UoB-CLN-AES-QCD-002: SAE form template

UoB-CLN-AES-QCD-003: Internal process for SAE handling example

UoB-CLN-AES-QCD-004: DSUR template
See UoB-CLN-CTM-SOP-001 Clinical Trial Management for further inter-relations
References:

HRA. (n.d.). During your research project - Safety Information. Retrieved October 17, 2013,
from HRA: http://www.hra.nhs.uk/research-community/during-your-research-project/safetyreporting/

Department of Health. (2005, April 24). Research governance framework for health and social
care: Second edition. Retrieved February 20, 2012, from Publications policy and guidance:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidanc
e/DH_4108962

European Commission. (2010, December). Clinical Investigations: Serious Adverse Event
Reporting (including SAE template). Retrieved October 14, 2013, from Guidelines on Medical
Devices: http://ec.europa.eu/health/medical-devices/files/meddev/2_7_3_en.pdf

European Commission. (2013, October 14). Medical Devices - Regulatory Framework.
Retrieved October 14, 2013, from EC Public Health: http://ec.europa.eu/health/medicaldevices/regulatory-framework/index_en.htm

European Committee. (2011). ‘Detailed guidance on the collection, verification and
presentation of adverse event/reaction reports arising from clinical trials on medicinal products
for human use. Retrieved April 15, 2013, from Eudralex Volume 10:
http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf
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
MHRA. (2012). eSUSAR. Retrieved October 15, 2013, from MHRA electronic reporting site for
SUSARs: https://esusar.mhra.gov.uk/

MHRA. (2013, July). Guidance for manufacturers on clinical investigations to be carried out in
the UK (including SAE reporting requirements for Medical Devices). Retrieved October 17,
2013, from MHRA: http://www.mhra.gov.uk/home/groups/esera/documents/publication/con007504.pdf

MHRA. (2011, July 11). How we regulate devices. Retrieved May 13, 2013 , from MHRA:
http://www.mhra.gov.uk/Howweregulate/Devices/
Acknowledgements:
The first version of this document and the SAE form template has been developed using examples of
and with input from the Birmingham Clinical Trials Unit, Cancer Research UK Clinical Trials Unit and
Primary Care Clinical Research and Trials Unit. We would like to thank all staff members within the
CTUs and UHB R&D who have been involved in developing these documents for their time and
efforts.
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Development summary:
Author:
Name:
Wilma van Riel
Signature:
Function:
Clinical Trials Quality Assurance Manager
Date:
See original copy
Reviewed by:
Anna Grier, CRCTU Senior Trial Coordinator, Clinical Trials Oversight Committee,
LES Research Support Partner
See original copy
Authorised by:
Name:
Prof. Pam Kearns
Signature:
See original copy
Function:
Chair of Clinical Trials Oversight Committee
Date:
See original copy
Name:
Prof. Chris Miall
Signature:
See original copy
Function:
Director of Research and Knowledge Transfer, LES
Date:
See original copy
Issue date:
02-Dec-2013
Supersedes:
N/A
Reason for update:
N/A
Review of final version:
Date:
Reviewed by:
Signature:
Outcome:
N/A
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Editorial Amendments
Tick box if not applicable
Reason for update:
Administrative update: inclusion of immediate reporting of SAE to Sponsor in process map and
coding, links and style updated
Date of amendment:
27-Jan-15
Supersedes:
UoB-CLN-SOP-002 v1.0 16-Dec-13 – Adverse Event Reporting SOP
Editor:
Name:
Conor McGoldrick
Function:
Clinical Trials Compliance Officer
Date:
27-Jan-15
Signature:
See original copy
Signature:
See original copy
Authoriser:
Name:
Wilma van Riel
Function:
Clinical Trials Quality Assurance Manager
Date:
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