Adverse Event Reporting - A Guide for Researchers

Background
The EU Clinical Directive was transposed into English Law on 1st May 2004. It places
a number of legal responsibilities on personnel involved in interventional clinical trials
using medicinal products. One of these responsibilities is the collection, verification
and presentation of adverse reaction reports arising from such trials. This document
aims to provide a brief overview of those responsibilities and of local arrangements
within the Trust.

Definitions
Directive 2002/20/EC gives the following definitions:

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”

Adverse reactions
“All untoward and unintended responses to an investigational product related to any
dose administered”

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 hospitalisation, results
in persistent or significant disability or incapacity or is a congenital anomaly or birth
defect.”

Unexpected adverse reaction

“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
medicinal product or summary of product characteristics for an authorised product)”

Assessment of causality

The Directive gives a classification for the relationship of the product being studied to
the adverse event. It is not mandatory to use these categories.

1. Not related – temporal relationship of the onset of the event, relative to the
administration of the product, is not reasonable or another cause can by itself
explain the occurrence of the event.

2. Unlikely

3. 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.

4. 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 by another cause.

5. Definitely related – temporal relationship of the onset of the event, relative to

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

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 Of the above definitions,
“possibly”, “probably” and “definitely” related to an investigational medical product are
considered adverse reactions
“unlikely” and “not related” do not qualify as a causal relationship.

The severity and causality of a serious adverse event, adverse event or SUSAR
(Suspected Unexpected Serious Adverse Reaction) should be assessed by a
qualified medical practitioner, usually (but not always) the Principal Investigator (PI).

Adverse events or reactions that are not life threatening and do not result in death or
hospitalisation may also be considered serious if they jeopardise the subject or
require intervention.

All adverse events must be reported to the sponsor immediately, unless they are
identified as not requiring this in the trial protocol.
It is then the responsibility of the sponsor to report the incident to the MHRA and
eudravigilance http://www.eudravigilance.org/newindex.htm

Eudravigilance is the name for the European data processing network and
management system, which was launched in 2001. This means that post-
authorisation pharmacovigilance data can be processed more efficiently between the
European Medicines Agency (EMEA), Competent Authorities (such as the MHRA)
and Pharmaceutical Companies that hold Marketing Authorisations in the European
Economic Area. As from 1st May 2004, the sponsors of all clinical trials need to obtain
a EudraCT number by registering the trial with the EudraCT Database. In addition,
sponsors of clinical trials conducted within the EEA must ensure that all SUSARs are
recorded and reported to the Competent Authorities in the member states concerned
and to the appropriate Ethics Committees.

The time period allowed for reporting such events to the MHRA/ Eudravigilance
are as follows:
Reaction which is fatal or life threatening – 7 days
Reaction which results in hospitalisation /disability/congenital anomaly – 15
days

THE SPONSOR SHOULD BE INFORMED OF ALL SUCH EVENTS AS SOON AS

POSSIBLE AFTER OCCURRENCE- PLEASE CALL
0161 – 291 – 5773
OR FAX COMPLETED FORMS TO
0161 291 5771
SO THAT INCIDENTS CAN BE REPORTED PROMPTLY

For trials that commenced before May 2004 (and therefore do not have a CTA) there
is no need to apply for a EudraCT number retrospectively.
Please note that in accordance with Article 24 of Regulation (EC) No 726/2004,
adverse drug reactions have to be transmitted electronically as from 20th
November 2005

If the reaction/illness is listed in the trial protocol as an expected reaction, then the
CRF should be completed as per the protocol. There is no need for expedited
reporting to the MHRA of such events.

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Reporting to the Ethics Committee
The Ethics Committee that gave a favourable opinion for the trial should routinely
receive the following reports:
• Expedited reports of all SUSARs occurring in a clinical trial of an
investigational medicinal product for which the sponsor is responsible. This
includes SUSARs associated with active comparator drugs. Expedited reports
should be sent to the relevant Ethics Committee within the timelines as stated
below.

• A sponsor shall ensure that all relevant information about a suspected

unexpected serious adverse reaction (SUSAR) which occurs during the
course of a clinical trial in the United Kingdom and is fatal or life-threatening is
reported as soon as possible to the MHRA, the competent authorities of any
EEA State, other than the United Kingdom, in which the trial is being
conducted, and the relevant Ethics Committee. This needs to be done not
later than seven days after the sponsor was first aware of the reaction. Any
additional relevant information should be sent within eight days of the report.

• A sponsor shall ensure that a suspected unexpected serious adverse reaction

(SUSAR) which is not fatal or life-threatening is reported as soon as possible,
and in any event not later that 15 days after the sponsor is first aware of the
reaction.

• Quarterly safety reports on all clinical trials for which the sponsor is
responsible for worldwide, with a global line listing of SUSARs occurring in
these trials in the reporting period.

• Annual safety reports on the safety of subjects in all clinical trials for which the
sponsor is responsible worldwide, with an aggregated global line listing of all
suspected serious adverse reactions (SSARs) occurring in these trials to
date.

• Reports and recommendations of any independent data monitoring

committee established for the trial.

Whilst COREC do not prescribe a format for quarterly/annual safety reports, there is
a standard covering form to be used when sending these reports to RECs in the UK.
It can be obtained from the COREC website www.corec.org.uk/ .

Safety reports may be submitted by the sponsor, or by the sponsor’s representative,

or by the chief investigator.

Blinding
Treatment codes should be broken by the sponsor before reporting a SUSAR to the
MHRA and appropriate ethics committee. It is recommended that the blind be broken
for that specific patient by the sponsor even if the investigator has not broken the
blind. It is also recommended that the blind should be maintained (where possible
and appropriate) for personnel responsible for data analysis and interpretation. The
unblinding of single cases by investigators in the course of a clinical trial should only
be performed if necessary for the safety of the trial subject.
It is recommended that in the case of a blinded study, the case is assessed for
seriousness, expectedness and causal relationship as if it was the tested IMP that

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caused the reaction. If the case appears to be a SUSAR then it should be unblinded
and the following considered:
a) If the administered product is the tested IMP, the case would be reported as a
SUSAR to the MHRA and appropriate Ethics Committee
b) If the administered product is a comparator with a marketing authorisation,
the adverse reaction should be reassessed for expectedness according to the
study protocol. If the adverse reaction is unexpected then the SUSAR should
be reported; otherwise it is an expected serious adverse reaction and not
reportable on an expedited basis.

Local Arrangements for the reporting of SUSARs

Please see also Figure 1 -flow chart of adverse event reporting procedure
All adverse events/ SUSARs occurring within UHSM should be reported in the
following manner:

Upon enrolment into a clinical trial, the subject should be given contact details for a
member of the research team. The subject should be instructed to inform the
member of the trial team of any hospitalisation or illness occurring whilst in the trial. It
is important that each subject is given this information when enrolling in a trial.

A member of the research team will thus be informed about each episode of
illness/hospitalisation and will inform the PI.

The PI will assess the event and make a decision based on the severity of the illness
and assess the causality.

All adverse events and SUSARs need to be reported to the Sponsor as soon as
possible after their occurrence. The sponsor must then inform the MHRA within 24
hours of such notification. For fatal SUSARs, the MHRA must be informed within 7
days of their occurrence. For SUSARs resulting in prolonged illness/hospitalisation,
disability, or where there is a congenital anomaly, where the Trust is sole sponsor,
SUSARs should be reported to the R&D Directorate on 291 5770. They will then
inform the MHRA and appropriate Ethics Committee.
Where there is a co-sponsorship arrangement with The University of Manchester, the
Trust Research Governance Manager will still inform the appropriate authorities and
also liaise with the University.
Where there is a commercial sponsor for a trial, then the commercial sponsor is
responsible for notifying the MHRA, appropriate ethics committee and the Research
Governance Manager within the allotted time limits as set out above.

The Principal Investigator is responsible for monitoring the adverse event/SUSAR

through to its conclusion, and informing the Research Governance Manager of the
outcome of each event.

Where a trial is conducted over more than one site, it will be the responsibility of the
sponsor to report SUSARs and adverse events. Where UHSM is the sponsor for the
trial, it is the responsibility of the Chief Investigator for the trial to ensure that details
of SUSARs and adverse events are passed to the Research Governance Manager at
UHSM for reporting to the appropriate authorities within the time limits set out above.
The other Principal Investigators involved in the trial must report all SUSARs and
adverse events to the Chief Investigator as soon as possible. The Chief Investigator
is then responsible for reporting events to the Research Governance Manager, as
detailed above.

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Where a trial is conducted over more than one site and UHSM is not the sponsor for
the trial, the Principal Investigator at UHSM should report the SUSAR/adverse event
to the Sponsor and Chief Investigator directly. The Principal Investigator should also
inform the Research Governance Manager of the event.

THE SPONSOR SHOULD BE INFORMED OF ALL SUCH EVENTS AS SOON AS

POSSIBLE AFTER OCCURRENCE- PLEASE CALL
0161 – 291 – 5770
OR FAX COMPLETED FORMS TO
0161 291 5771
SO THAT INCIDENTS CAN BE REPORTED PROMPTLY

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Figure 1 - flow chart of adverse event reporting
procedure
Adverse
Event

Report to
PI

Assessme
nt of
causality

Listed in Y Complete
Protocol? CRF as per
protocol

Report to
Sponsor
ASAP. Fatal/life-
Y
Sponsor threatening
informs ?
MHRA within
7 days
N

Report to Sponsor
ASAP. Sponsor
informs MHRA
within 15 days

Complete Trust
SUSAR form

Follow up

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