PHARMACOVIGILANCE
STANDARD OPERATING PROCEDURE NO
SOP 01
DATE RATIFIED
Sep 2014
NEXT REVIEW DATE
Sep 2016
POLICY STATEMENT/KEY OBJECTIVES:
This document outlines the procedure for defining a research incidents
severity, identifying, recording and reporting all incidents in a clinical trial.
POLICY AUTHORS:
Katie Glickman; Research Facilitator
Karen Palmer; Clinical Research Nurse Manager
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BACKGROUND
In order to meet the requirements of the European Directive (EU) on Clinical
Trials (2001/20/EC), Health care commission Core standard C12 and
Research Governance (Department of Health, 2001) all NHS Trusts are
required to have systems in place to record and report the spectrum of
research related clinical incidents for both Trust Sponsored and externally
Sponsored clinical trials. This Standard Operating Procedure (SOP) outlines
these systems and describes the classification of incidents. Where a clinical
trial is sponsored outside of the Trust, please also refer to the study protocol
for Sponsor definitions of adverse events.
Adverse Events (AEs) and Serious Adverse Events (SAEs) should be
reported in accordance with the Medicines for Human Use (Clinical Trials)
Regulations 2004 and also in compliance with the International Conference of
Harmonisation Good Clinical Practice (ICH GCP) guidance, and within any
other conditions stipulated in the trial protocol or by the host Trust. It is the
responsibility of the Sponsor to ensure that events are reported appropriately
to the competent authority; in the UK this is the Medicines and Healthcare
Regulatory Agency (MHRA) and also the Research Ethics Committee (REC)
providing the favourable opinion for the trial.
The Regulations distinguish between AEs, Adverse Reactions (ARs), SAEs,
Serious Adverse Reactions (SARs) and Suspected Unexpected Serious
Adverse Reactions (SUSARs), with differing reporting requirements for each
type of event. This clarification is also included in all study protocols that
require such reporting.
Definitions
For Lancashire Care Foundation Trust (LCFT) Sponsored studies the
following definitions apply. However, external Sponsors may apply alternative
definitions which will be defined in the study protocol:
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Adverse event (AE): Any untoward medical occurrence in a trial patient
which does not necessarily have a causal relationship with the treatment.
Serious Adverse Event (SAE): Any untoward medical occurrence that:

Results in death

Is life-threatening

Requires
inpatient
hospitalisation
or
prolongation
of
existing
hospitalisation

Results in persistent or significant disability/incapacity or

Is a congenital anomaly or birth defect

An untoward medical occurrence that is otherwise considered
medically significant to the investigator may also be reported as an
SAE.

Some Sponsors may specify other events that should be reported as
SAE although they do not fulfil any of the above criteria of SAE (this will
be specifically identified in the study protocol)
Adverse Reaction (AR): All untoward and unintended responses to an
investigational medical product related to any dose administered. Any event
that could not be determined as definitely not caused by the IMP should be
reported as an AR.
Serious Adverse Reaction (SAR): An adverse reaction resulting in serious
outcomes as listed in SAEs. Seriousness is not the same as severity, as
seriousness relates to the outcome of the event and not the intensity of the
reaction.
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse
reaction is ‘unexpected’ if its nature and severity are not consistent with the
medicinal product information (detailed in the Summary of Product
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Characteristics if a licensed product or in the Investigators Brochure if not yet
licensed).
PURPOSE
This SOP is designed to describe the process of reporting research Clinical
incidents that occur at LCFT Adherence to this will fulfil the Trusts legal
obligations under the SI1031 Medicines for human use (clinical trials)
regulations 2004.
PROCEDURE
Who?
This SOP applies to AE’s, SAE’s, AR’s, SAR’s and SUSAR’s which occur
within the LCFT or research that is being conducted by the Trust’s personnel
elsewhere.
The research team and Principal Investigators (PI) have an obligation to
report AE’s, SAE’s, AR’s, SAR’s and SUSAR’s that they become aware of to
the appropriate Sponsor. It is usual that this is Sponsor as soon as possible in
accordance with the Sponsor requirements (usually within 48 hours of
awareness of the event), by completing an incident form as stipulated in the
trial protocol and adhere to any un-blinding procedures that the protocol also
requires.
Where LCFT is acting as Sponsor the research team will report to the
Research department using the Incident reporting form (Appendix 1) within 72
hours
via
the
Research
generic
email
account;
[email protected].
The Trust Research department should also be notified of all SAE’s, SAR’s
and SUSAR’s for externally Sponsored studies.
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Additionally researchers are required to report any such incidents to the REC
and in the event of a SUSAR or a drug or device being involved and /or if the
event is deemed fatal or life threatening, the MHRA must be notified no later
than 7 days of becoming aware of the event. An event that is not fatal or life
threatening, but remains a SUSAR must be reported to the MHRA no later
than 15 days from being made aware of the reaction. Life-threatening in the
definition of a serious adverse event 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 or were left
untreated.
The Sponsor is responsible for ensuring all events are reported to the MHRA
and the REC, however in many cases, this responsibility is delegated to the
trials Chief Investigator (CI) or a Contract Research Organisation. The clinical
trial PI’s are responsible for ensuring that all events occurring at their site are
reported appropriately to the Sponsor or their delegate.
All staff and clinicians involved with managing trial patients should note
adverse events (AE’s) that are reported by the patient and make them known
to the appropriate study staff. Patients entered into clinical trials must be
encouraged as part of the consent process to contact their clinician or
research practitioner, e.g. research nurse at the time of an event occurring.
Additionally, appropriate assessments should be conducted by the study team
to identify AE’s; these must be documented in the patient records.
To aide identification of Clinical Trial participants, details of a participant’s
involvement must be clearly documented in the electronic case records. This
should include a scanned copy of the patient information leaflet and consent
form, the consent process (see SOP 06), study number, randomisation codes,
changes to patient care or treatment as a result of participation, details of trial
medications prescribed, all adverse incidents (AE’s, SAE’s, AR’s, SAR’s and
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SUSAR’s), copies of research related patient care communications (i.e. to
letters to patients General Practitioner) and end of study involvement.
Where ‘allergies’ is listed at the top of the electronic case records, a comment
should be inserted to state that ‘This patient is taking part in a clinical drug
trial, please refer to the Trust SOP (01) on Pharmacovigilance for further
guidance in the event of a patient admission, death, or other Serious Adverse
Event’.
In the event that a clinical trial participant is admitted to a LCFT ward area, the
research team must be informed by the clinical team of the hospital admission
as soon as possible. Details of an emergency research contact should be
provided in a location on the electronic case records that can be easily
accessed.
Additionally,
information
making
services
aware
of
their
responsibility to inform the study team as soon as an AE occurs (in line with
the study protocol requirements), should also be easily accessible.
All sites that are responsible for the care of participants involved in clinical
trials is also responsible for the formulation of their own site specific SOP on
the out of hour’s emergency contact processes for their staff and participants.
The processes listed in the out of hours SOP should be explained to all
clinical trial staff and participants and their potential carers at the start of a
clinical trial so that in the event of an emergency, or the need to contact the
research team out of working hours, a Physician is available to contact. A
copy of the out of hours SOP (SOP Number 12) developed by the team
should be made available to R&I.
It is the responsibility of the individual research teams to ensure that they
follow the site specific SOP requirements governed by each location in which
they work and there may be study specific requirements that impact this SOP.
It is therefore advised that each clinical trial protocol is also cross referenced
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for any requirements that may impact reporting of information during out of
hours contact.
To address the safe administration of Investigational Medicinal Products (IMP)
all administration procedures outlined in the study protocol and as adjuncts
must be followed and recorded in the participant’s medical records. A
medically qualified delegated representative of the PI (listed on the study
delegation log) must remain in attendance during first administration of IMP
and observational period, as outlined by the study protocol and agreed with
the study team. All agreements related to the observational period must be
outlined, agreed and documented in the patient’s medical notes at each visit
and a file note and should be added to the site file to describe the process of
administration and observation.
When?
At each visit or study assessment, AE’s that have occurred since the previous
patient contact should be discussed
with the patient. For source
documentation verification, these events need to be detailed in the patient’s
medical notes including the start dates, if known; of the onset of the event as
well as the date the event stopped or changed, if applicable. Adverse events
on-going on completion of the study should be followed up as required by the
protocol and as clinically indicated. For some studies, telephone contact may
be used between visits to ensure accurate and timely reporting of such
events.
How?
Adequate pharmacovigilance procedures should be clearly documented in the
study protocol. All procedures and requirements outlined in the protocol
should be followed. Awareness of procedures and documentation should form
part of initiation to the study for staff involved.
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Categorising events
This is summarised in Appendix 2. Individual adverse events should only be
categorised by a medically qualified person integrally involved in the study i.e.
the PI or delegated other and if applicable they should be reported to the
Sponsor or delegate for evaluation/clarification. Categorisation of the event
should include determination of:
1. Causality:

Is there a possible causal relationship between the
investigational medicinal product(s) (IMP) and/or concomitant
therapy and the adverse event?

The causality assessment given by the PI should not be
downgraded by the Sponsor and if the Sponsor disagrees
with the PI’s assessment, then the opinion of both the PI and
Sponsor should be provided in the report.
2. Seriousness, is it:

fatal

life-threatening

requiring inpatient hospitalisation or prolongation of existing
hospitalisation

resulting in persistent or significant disability/incapacity

a congenital anomaly or birth defect

another event specified in the protocol to be reported as an
SAE
3. Expectedness:

Is its nature and severity not consistent with the medicinal
product information- detailed in the Summary of Product
Characteristics if a licensed product or in the Investigators
Brochure if not. Information on expectedness may also be
detailed in the protocol
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An event is a SUSAR if it is unexpected, serious and is possibly related to the
trial treatment.
Reporting events
AEs are reported via a data collection tool usually provided by the Sponsor
e.g. Case Report Form or electronic case Report Form. Completed forms will
be sent to the Sponsor, or collected by them. AE reports may be submitted to
the MHRA and the REC by the Sponsor or their delegate. The Trust incident
report form, seen in appendix one, must be completed when informing Trust
Research department of incidents and submitted via the generic Research
email address [email protected] and reported within 72 hours
of site notification.
All SAEs must be reported by the site as soon as they are notified by the
participant, to the Sponsor, except where the protocol does not stipulate this.
The immediate report to the Sponsor can be brief, but must be followed up by
a more detailed report. SAE reporting forms should be provided by the
Sponsor at study set up and all staff need to be familiar with the study specific
requirements and documentation as part of their induction to the study. The
procedure for how to report to the Sponsor should be outlined in the protocol.
If a Sponsor does not provide a sample incident reporting form, sites must
utilise the Trust incident report form.
SAEs should be reported by the Sponsor in quarterly annual safety reports to
the MHRA and REC and presented regularly at the trial safety monitoring
committee if applicable. These reports should be maintained in the site file.
All SUSARs should be reported by the site to the Sponsor according in
accordance with time frames stipulated in the protocol. The Sponsor must
also report such events as per protocol and Clinical Trials Regulations to the
MHRA and the REC.
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The Sponsor must also immediately inform all PIs involved in the trial of
relevant information about SUSARs that could adversely affect the safety of
their trial patients. Any such notifications should be signed and dated by the PI
as acknowledgement of the information, the research team informed of these
and the documentation file in the safety reporting section of the site file.
The following should be documented as clearly as possible in accordance with
the protocol when reporting events:

Time and date of start and stop of event (if the patient cannot
remember, then as near as possible)

Severity of event, this may be graded by using the toxicity criteria in the
protocol. This is often mild, moderate or severe (guidance as to what
defines each of these may be in the protocol)

Action taken regarding study drug (if any) – these may include stopping
study drug temporarily or permanently.

Any treatment/medication given for the event, including the dates the
treatment/medication
was
commenced
and
the
date
it
was
stopped/changed, if applicable.

The event outcome
Complete collection of the necessary data relating to adverse events will
ensure that source data is available to ensure complete and accurate Case
Report Form completion and reporting of the adverse event adhering to the
study protocol, GCP and appropriate regulations.
Reporting SUSARs
All SAEs that are SUSARs are subject to expedited reporting to the MHRA
and the REC (by the Sponsor) and there are strict timelines set out in the
Trials Regulations. Therefore, PIs must report events to the Sponsor or
delegate immediately so as to satisfy these requirements. These are:
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1. A SUSAR which is fatal or life-threatening must be reported as soon as
possible within 7 days after the site became aware of the event. All
follow-up information must be reported within 8 days of sending the first
report.
2. A SUSAR which is not fatal or life-threatening must be reported as
soon as possible and in any event within 15 days after the site became
aware of the event.
All SUSARs associated with a comparator product in the clinical trial should
be reported, even if this product is approved. Generally treatment codes
should be broken before reporting a SUSAR to the MHRA and the REC,
although the blind could potentially be broken by the Sponsor/CI and not
made known to the PI if there is no danger in this to the patient.
For trials in high morbidity and/or high mortality disease, where efficacy endpoints could also be SUSARs or when a fatal or other "serious" outcome is the
primary endpoint in a trial, the integrity of the trial may be compromised if the
blind is broken. Under these and similar circumstances, it may be appropriate
to reach agreement with the MHRA in advance concerning serious events that
would be treated as disease-related and not subject to systematic un-blinding
and expedited reporting. This agreed procedure will be outlined in the protocol
Other expedited reporting
Other safety issues qualify for expedited reporting by the Sponsor:

Single case reports of an expected SARs with an unexpected outcome

An increase in the rate of occurrence of an expected SAR, judged to be
clinically important

Post-study SUSARs that occur after the patient has completed a trial
(the length of time after completion of the trial may be specified in the
protocol)
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
A new event, related to the conduct of the trial or the development of
the investigational medicinal product, that is likely to affect the safety of
subjects, e.g. an SAE which could be associated with the trial
procedures and which could modify the conduct of the trial or a
significant hazard to the subject population such as lack of efficacy of a
product used for the treatment of a life-threatening disease

A major safety finding from a newly completed animal study
Sending a report
The Investigator Brochure usually outlines the format for event reporting and
this should be followed. Reports of SUSARs will normally be in the CIOMS-1
format (available at www.cioms.ch) that is widely accepted as the standard
within the pharmaceutical industry.
Information on the final description and evaluation of an adverse reaction
report may not be available within the required time frames for reporting. For
regulatory purposes, initial expedited reports should be submitted within the
time limits and must contain the following minimum information:
1. A suspected investigational medicinal product
2. An identifiable subject (e.g. study subject code number)
3. An adverse event assessed as serious and unexpected, and for which
there is a reasonable suspected causal relationship
4. An identifiable reporting source
5. Where applicable, EudraCT number or in case of non EU trials the
Sponsor's trial protocol code number
6. A unique case identification, i.e. Sponsor's case identification number
Where there is incomplete information at the time of initial reporting, all the
appropriate information for an adequate analysis of causality should be
actively sought. The Sponsor or delegate should report further relevant
information after receipt as follow-up reports.
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Guidance on research adverse event forms

The research protocol number requested on the form refers to the
number used by the Trust to identify Trust research on the National
research register and will be written on your Trust approval letter. Do
not delay sending the form if this number is not available, provide the
full title and version number instead.

Document events in a clear way as far as possible. For example, the
patient may say that they ‘felt sick’. This can be interpreted in many
ways: either they felt nauseated or they may have felt unwell, or they
may even have been vomiting.

If possible ask patient the date and start and stop time of event. If the
patient cannot remember, then as near as possible.

Document the action taken regarding the intervention– if any. For
example was the treatment dose reduced, or was study drug/treatment
delayed etc.

Document any treatment/medication given for the event, including the
dates the treatment/medication was commenced and the date it was
stopped/changed, if applicable.

Document the event outcome. If all data is not available at initial
assessment send what you can to keep within the 24-hour deadline
and provide follow-up information within 5 days. This shortened
deadline is provided to enable the safety committee time to adjudicate
on the incident with 15 days.

Events on-going at study completion should be followed up as detailed
in the protocol and as clinically indicated.

Note Pregnancy in either a patient or the partner of the patient in a trial
taking trial medication should be reported as an SAE.
Verification of all these events need to be detailed in the patient’s medical
notes including the start dates (if known) of the onset of the event as well as
the date the event stopped or changed, if applicable. Adverse events should
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also be documented in the patient’s research case report form. Adverse
events on-going on completion of the study should be followed up as required
by the protocol and as clinically indicated. These guidelines have been
adapted from ICH/GCP (1996) to use in line with Sponsor incident reporting
forms to initially inform research governance personnel of an adverse event.
This has been utilized to assist with compliance and implementation within the
Trust.
The Research department are responsible for approving this standard
operating procedure for use and adherence to this procedure will be
monitored as part of research Governance audits. The Chief or Principal
Investigator of individual projects are responsible for monitoring the adverse
events that occur and have a duty to report events as appropriate to their
seriousness (see appendix 2 for definition of adverse and serious adverse
events). Managers have a responsibility to ensure staff have read and
understood the procedure. Subsequent audit results demonstrating (lack of)
adherence may require the author to develop local strategies for further
dissemination. Compliance will be measured by annual audit of completed
incident forms against source documentation for research trials held at the
Lancashire Care NHS Foundation Trust. If 100% compliance is not observed,
the staff involved will be offered further GCP training.
OTHER
RELATED
PROCEDURES,
POLICIES,
LEGISLATION
OR
GUIDANCE
International Conference on Harmonisation of Good Clinical Practice 1996
Medicines for Human Use (Clinical Trials) Regulations 2004
Medicines for Human Use (Clinical Trials) Amendment Regulations 2006
GLOSSARY
Adverse Event (AE)
Adverse Reaction (AR)
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Case Report Form (CRF)
Chief Investigator (CI)
Electronic Case Report Form (eCRF)
Medicines and Healthcare products Regulatory Agency (MHRA)
Research Ethics Committee (REC)
Principal Investigator (PI)
Serious Adverse Event (SAE)
Serious Adverse Reaction (SAR)
Standard Operating Procedure (SOP)
Suspected Unexpected Serious Adverse Reaction (SUSAR)
APPENDICES
Appendix 1: Incident Reporting Form
Appendix 2: Distinguishing event categories
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Appendix 1: Incident Reporting Form
LCFT Research Incident Report Form
Patient hospital number: _______________
DOB: _____________
Patient Initials: ______________
Study protocol Version and research number: _________________________
(as provided by the Clinical Governance department on Trust approval)
Patient study number: ______________________
Principle investigator name: _________________
Adverse event number: _____________________
(Consecutive numbers for each study)
Type of Adverse event: _____________________
(see appendix 2 for categorisation)
Is this a Serious Adverse Reaction? Yes/No
Definition of an SAE/SUSAR

Is fatal – results in death (NOTE:
death is an outcome, not an event)

Is life-threatening

Requires inpatient hospitalisation or
prolongation of existing
hospitalisation (standard length of
stay should be stated in the
protocol)

Results in persistent or significant
disability/incapacity
Or

Is a congenital anomaly/birth defect
A Suspected, Unexpected Serious Adverse
Reaction (SUSAR) Is an unexpected SAE that
is related to the intervention under
investigation.
Is this a Suspected Unexpected Serious Adverse Reaction? Yes/No
Researcher contact details:
Name: _____________________________________________
Number: ___________________________________________
Brief description of event (200 words max) including action taken
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Medication 24hours prior and after event:
(please continue on further page if necessary)
Causality
Unlikely to be due to research intervention
Possibly due to research intervention
Probably due to research intervention
Definitely due to research intervention
Outcome
Recovered
date
Recovered still under treatment
date
Recovered with sequalae
date
Permanent disability or disease
date
Death date
date
Signature: __________________________________
Date: _________________
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Assess Seriousness
Not Serious
Appendix 2: Distinguishing event categories
Serious
Adverse Event (AE)
Assess Causality
record/report
According to Protocol
Unrelated to Drug/Device
Related to Drug/Device
Definition of Serious

Is fatal – results in death
(NOTE: death is an
outcome, not an event)

Is life-threatening

Requires inpatient
hospitalisation or
prolongation of existing
hospitalisation (standard
length of stay should be
stated in the protocol)


Serious Adverse
Event (SAE)
Record/report
According to
Protocol
Expected
Serious Adverse
Results in persistent or
significant
disability/incapacity
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Is a congenital
anomaly/birth defect
Assess expectedness
Reaction (SAR)
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(Declared in Protocol)
Record/report
According to Protocol
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Unexpected
Suspected Unexpected
Serious Adverse Reaction
(SUSAR)
Record/report
According to Protocol and
Trials Legislation