Document Title: Adverse Event Reporting Document Number ... · Document Title: Adverse Event Reporting Document Number: SOP012 Staff involved in development: Job titles only RM&G

SOP012: Adverse Event Reporting

SOP012: Adverse Event Reporting Version 3.2 Review Date: April 2016 Page 1 of 16

Document Title: Adverse Event Reporting

Document Number: SOP012

Staff involved in development: Job titles only

RM&G Manager, R&D Administration Manager, Research Officers

Document author/owner: R&D Administration Manager

Directorate: Research and Development

Department: Research and Development

For use by: NHS Staff Trust-Wide

Review due: April 2016

THIS IS A CONTROLLED DOCUMENT Whilst this document may be printed, the electronic version maintained on the Trust’s Intranet is

the controlled copy. Any printed copies of this document are not controlled. ©Papworth Hospital NHS Foundation Trust. Not to be reproduced without written permission.

Key Points of this Document

This document sets out the procedures to be followed by all Papworth Staff who are

involved in the reporting of adverse events in clinical trials.

It aims to provide clear guidance on how to report adverse events and incidents that occur

in the course of research studies to ensure compliance with the Trust’s policy for the

reporting of accidents / adverse events / incidents and defects (DN70).



1 Purpose and Content

a. This document defines the Trust’s research procedures for the reporting and

investigation of any adverse event that occur involving patients in Research Studies and

Clinical Trials sponsored by Papworth Hospital’s R&D department. This includes the

completion of Adverse Event forms.

b. In accordance with the Research Governance Framework for Health and Social Care and

the Medicines for Human Use (Clinical Trials) Regulations, organisations hosting and

Sponsoring research must have systems in place that allow to give “the safety of

participants and of research and other staff priority at all times, and [ensure that] health

and safety regulations [are] strictly observed – including the provision of information,

containment, shielding and monitoring as required.”

c. The Medicines for Human Use (Clinical Trials) Regulations 2004 came into force on the

1st May 2004. These regulations apply to all clinical trials involving investigational

medicinal products (IMPs) and specify the reporting requirements for related adverse

events. To breach these requirements constitutes a breach in criminal law. These

reporting requirements have been incorporated within this policy.

d. This SOP covers the recording and reporting of Research Related Adverse Events,

including Adverse Reactions, Adverse Device Effects, Serious Adverse Events, Serious

Adverse Reactions, Serious Adverse Device Effects, Suspected Unexpected Serious

Adverse Reactions and Unanticipated Serious Adverse Device Effects. These adverse

events will be managed in line with the reporting policy of the Sponsor of a research

study.

e. The reporting requirements in this SOP are mandatory in addition to the Trust’s policy

for the reporting of accidents / adverse events / incidents and defects (DN70) and non-

compliance with may result in disciplinary procedures.

2 Roles & Responsibilities

2.1 Roles

a. All staff are responsible for ensuring that all adverse incidents, whether or not related to

research, are reported in accordance with the Papworth Hospital NHS Trust’s policy for

the reporting of accidents / adverse events / incidents and defects (DN70).

b. This Procedure applies to all personnel that are conducting research at the Trust.



c. Staff involved in the conduct of CTIMPs must comply with the requirements set out in

this SOP.

d. Flow diagrams that summarise the investigator’s and sponsor’s responsibilities for

reporting adverse events are available from the Papworth R&D department.

2.2 Investigators responsibilities

a. The investigator must ensure that the dignity, rights, safety and well being of research

participants are given priority at all times and must take appropriate action to ensure

the safety of all staff and participants in the study. The investigator will consider what

actions, if any, are required and in what timeframe following the requirements set in this

policy.

b. In the event of an adverse event / reaction (AEs) the investigator (or delegate) must

review all the documentation that is relevant to the event (e.g. patient notes, laboratory

reports). The event and relevant comments must be recorded in the subject’s medical

notes (or source data) and reported to the Sponsor as documented in the protocol.

Investigators (or delegated persons) will provide follow-up information, each time new

information is available using the study CRF provided or page 3 of the form entitled

FRM007 Papworth SAE/SUSAR Reporting Form (available from the R&D intranet pages).

This will be completed until the SAE / SADE has resolved or a decision for no further

follow-up has been taken by the PI or delegated person.

c. Unless the protocol states otherwise and has exempted certain events from being

recorded or escalated reporting, the Investigator (or delegate) is responsible for

ensuring that all adverse event / reactions are recorded in detail on case report forms or

equivalent so as to allow analysis at a later stage. A template for recording adverse

events can be found on the R&D intranet pages entitled FRM005 Adverse Event/Adverse

Reaction Reporting Form).

d. The investigator (or delegate) will make an assessment of causality for all adverse event

/ reactions. This process must be clearly documented. This must be completed by

medically qualified personnel.

Detailed guidance on making this assessment is given in the Appendix 1. A short

assessment for the internal purposes of the research team is provided in the form



entitled FRM005 Adverse Event/Adverse Reaction Reporting Form.

e. The Investigator (or delegate) must ensure that Adverse Events and / or laboratory

abnormalities identified in the protocol as critical to the evaluations of the safety of the

study shall be reported to the Sponsor in accordance with the reporting requirements

documented in the protocol.

f. The chief investigator will keep the Sponsor, the REC and MHRA (if applicable) informed

of any significant findings and recommendations by an independent Data Monitoring

Committee (DMC), or equivalent, where one has been established for the trial.

2.3 Sponsor responsibilities

a. This section applies only where Papworth R&D is the sponsor or co-sponsor of the

research study

A flow diagram summarising the R&D department’s responsibilities for adverse event

reporting is available from Papworth R&D department upon request.

b. The Senior Manager, or their delegated representative, must keep a detailed record of

all AEs relating to all clinical trial that are reported to it and ensure that system is in

place for ensuring appropriate follow-up of SAEs.

On receipt of a SAE / SUSAR report form the Senior Manager will assess whether

Papworth R&D is the sponsor. Where Papworth R&D is NOT the sponsor or cosponsor

the Senior Manager will remind the research team to inform the sponsor.

c. The Senior Manager, or their delegated representative, must ensure that cover will be

provided for the fax machine used for sending in adverse event reports to ensure events

are processed in a timely manner (which includes holiday periods).

d. The Senior Manager, or their delegated representative, is responsible for the assessment

of expectedness of adverse events. This responsibility may be delegated the chief

investigator. This delegation must be clearly documented.



2.4 For Blinded Studies:

a. Where Papworth R&D is the sponsor or cosponsor of a blinded research study, in which

the SAE / SUSAR / SADE / USADE has occurred, and a member of the research team is

unable to make a blinded assessment, the Senior Manager, or their delegated

representative, will make an unblinded assessment of the intensity, causality,

expectedness and seriousness using the criteria described in this policy.

b. In making this assessment the Senior Manager, or their delegated representative, will

consult the independent Data Monitoring Committee (DMC) for the study or, where a

DMC does not exist, a suitably qualified medical person. The unblinded assessor may be

an investigator on the same study if unblinding him / her will not affect the conduct of the

study in which the SAE has occurred.

c. A second assessment by the Sponsor is not required where the investigator making the

initial assessment is already unblinded.

d. A clear procedure must be detailed in the protocol for Papworth sponsored CTIMPs.

e. The Senior Manager, or their delegated representative, will consider whether any further

actions following an adverse event, in addition to those already taken by the Investigator,

are required and will discuss these with the Investigator.

f. The Senior Manager, on behalf of the Trust, reserves the right to suspend or withdraw

approval for a study. This may happen, but is not limited to, where public health and

safety is considered to be at risk, where the safety and well being of research subjects or

staff are considered to be at risk.

g. The sponsor is responsible for ensuring that actions that necessitate a substantial

amendment to the research protocol will be approved by ethical, R&D and MHRA (for

IMP and non CE marked devices) through the normal routes. See SOP037 “Amendments

Post Trust Approval” for further information. This duty may be delegated to the Chief

Investigator.

h. Amendments that require an immediate change to the protocol (i.e. urgent safety

measures) will be implemented and thereafter submitted for ethical, R&D and MHRA

approval. The initial notification to the REC should be by telephone. Notice in writing to

the REC, hosting R&D and MHRA should be sent within three days. The notice should set

out the reasons for the urgent safety measures and plan for further action.

i. The Sponsor is responsible for ensuring that at the conclusion of the study all adverse

events / reactions / device effects, recorded during a study are subject to statistical

analysis and that analysis and subsequent conclusions included in the final study report.



3 Definitions

AE Adverse Event - any untoward medical occurrence in a subject to whom a medicinal

product / medicinal device / intervention has been administered, including

occurrences which are not necessarily caused or related to the product.

AR Adverse Reaction - any untoward and unintended response in a subject to an

investigational medicinal product / medicinal device / intervention that is related to

any dose administered to that patient.

ADE Adverse Device Event - any malfunction or deterioration in the characteristics and /

or performance of a device, as well as any inadequacy in the labelling or the

instructions for use that might lead, or might have led to, endangering the health of a

patient or the device user.

An unexpected adverse reaction is an adverse reaction the nature and severity of

which is not consistent with the information about the medicinal product or

intervention in question set out:

in the case of a product with a marketing authorisation, in the Summary of Product

Characteristics (SmPC) for that product

in the case of any other investigational medicinal product, in the Investigators

Brochure (IB)

SAE /SADE /

SAR

An adverse event, adverse reaction, unexpected adverse reaction, adverse device

effect is defined as serious if it:

results in death

is life-threatening

requires hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity

consists of a congenital anomaly or birth defect

SAE Serious Adverse Event

SADE Serious Adverse Device Event



SAR Serious Adverse Reaction

SUSAR Suspected Unexpected Serious Adverse Reaction - is an SAR that is suspected

(possibly of probably) to be related to the investigational medicinal product /

medicinal device / intervention AND is also unexpected. This means that its nature

and severity are not consistent with the information about the medicinal product in

question set out as below:

in the case of a product with a marketing authorisation, in the Summary of Product

Characteristics (SmPC) for that product

in the case of any other investigational medicinal product, in the Investigators

Brochure (IB)

A non-IMP SUSAR is an SAE that occurs in a non-IMP trial and is:

Related – that is possibly, probably or definitely 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

USADE Unanticipated Serious Adverse Device Effect - an untoward medical occurrence that

happens in a subject or other person that is related to the investigational device,

device procedure or comparator, which is serious and was unanticipated.

If a participant is participating in a randomised clinical trial the reporting must be

carried out according to this SOP irrespective of the arm of the trial the patient is in.

4 Procedure

4.1 Reporting of Serious Adverse Events / Serious Adverse Device Effects

a. Researchers must ensure that all patient safety related incidents are reported according

to the Trust’s policy for the reporting of accidents / adverse events / incidents and

defects (DN70).

b. In addition to the Trust’s incident reporting, serious adverse events must be reported as

per Table 1. The only exception is where the protocol or Investigators Brochure identifies

an event as not requiring immediate expedited reporting.

Table 1 Report to Investigator Responsibilities

SUSAR / USADE Immediately report

to:

The investigator (or delegated person) will make an

initial report, orally or in writing, within 24 hours of



The Chief Investigator

The Sponsor

Papworth R&D

department

knowledge of the event. The initial report will include

as much information as is available at the time.

Oral reports will be followed up in writing within a

further 24 hours of the initial report.

Papworth Clinical

Governance and Risk

Management

Any other persons or

bodies specified in the

protocol

Sponsor responsible

to further expedite

the reporting of

SUSAR / USADE to the

MHRA and REC that

gave approval as soon

as possible but within

7 days of knowledge

of the event.

After the initial report the investigator is required to

actively follow up the subject. The investigator (or

delegated person) will provide information missing

from the initial report within five working days of the

initial report.

Written reports will be made by completing an SAE /

SUSAR reporting form provided by the Sponsor of the

study. In addition the REC receives a completed NRES

CTIMP Safety Report to REC

http://www.nres.npsa.nhs.uk/applications/after-

ethical-review/safetyreports/safety-reports-for-

ctimps/

Papworth R&D SAE / SAR / SUSAR report template

entitled FRM007 SAE/SAR/SUSAR Reporting Form

v1.0 is available from the Research Department

Where Papworth is the sponsor or co-sponsor or

where no form has been provided, the investigator

will use the standard Research Related SAE/SUSAR

form entitled FRM007 SAE/SAR/SUSAR Reporting

Form v1.0 that is available from R&D. Only one report

will need to be sent to Papworth R&D department.

SAE / SADE Within 24 hours

report to:


The Sponsor



protocol

As above; but no expedited reporting by the Sponsor

to the MHRA and REC.

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





For Papworth

Sponsored CTIMPs

and non-CE marked

devices also contact

the R&D department.

Urgent Safety

Measures /

Temporary Halt of

a Trial

Implement and report

immediately as a

substantial

amendment to:


The Sponsor


must inform as soon

as possible, but within

3 days:

The MHRA

The REC that gave

approval



protocol

Papworth R&D

department

The Sponsor and the Chief Investigator must be

notified of any urgent safety measures / temporary

halt of a trial that have had to be taken that are not

part of the protocol.

The report must include the reasons for the urgent

safety measure and the plan for further action. The

standard CTIMP substantial amendment form must

be used as available from MHRA / NRES websites.

http://www.nres.npsa.nhs.uk/applications/after-

ethical-review/notification-of-amendments/

Where Papworth R&D is the Sponsor (or Cosponsor)

and the host organisation only one report needs to be

sent to the R&D department.

4.2 For Papworth Sponsored Studies

a. The Chief Investigator will inform all Principal Investigators of relevant information

about SAEs / SADEs that could adversely affect the safety of subjects.

b. The Chief Investigator will provide the main REC with copies of all reports and

recommendations of any independent Data Monitoring Committee established for a

trial as part of the SUSAR / USADE expedited or periodic reporting.

http://www.nres.npsa.nhs.uk/applications/after-ethical-review/notification-of-amendments/

http://www.nres.npsa.nhs.uk/applications/after-ethical-review/notification-of-amendments/



c. For IMP / Medical Device studies, on request of the MHRA the Chief Investigator will

submit detailed records of all adverse events that have been reported.

4.3 IMP SUSARs

a. This section applies only where Papworth R&D is the sponsor or cosponsor of the

research study using an IMP in which the SAE has occurred and where the investigator

and / or sponsor has assessed the SAE to be a SUSAR.

b. The R&D Department as the Sponsor’s representative will report all SUSARs to:

The Medicines and Healthcare Regulatory Agency (MHRA)

The competent authorities (equivalent of the MHRA) of any EEA State, other than

the UK, in which the trial is being conducted

The REC that granted approval

c. Papworth R&D will report within seven days of becoming aware of the event where

these are fatal or life threatening and within fifteen days where the SUSAR was not

assessed as life threatening or fatal.

d. The R&D Department will report any additional relevant information to the bodies

described above within eight days of the last report.

e. Initial notifications of SUSARs may be made by fax, e-mail or telephone. Follow-up

reports and all other safety reports should be sent to the REC office by post.

f. Each submission of a SUSAR Sponsor report form to the main REC must be accompanied

by the NRES Safety Report form for CTIMPs available at

mailto:http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-

safety-reporting/

g. A single form may be used for the submission of several safety reports relating to the

same trial. Reports should not normally cover more than one trial. However, the REC

may permit this where two trials are very closely connected such as a main study and an

extension study with the same treatment regime.

4.4 Non-IMP SUSARs

a. Where Papworth R&D is the sponsor or cosponsor of a blinded non-IMP study, the R&D

department will report all SAEs that are assessed as non-IMP SUSARs by either the

investigator or the unblinded assessor to the research ethics committee that granted

approval within 15 days using the NRES Report of Serious Adverse Event form available

mailto:http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/




at: mailto:http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-

safety-reporting/

b. Follow-up of pregnancy within CTIMPs

c. Pregnancy does not meet the definition of an SAE, but a congenital abnormality or birth

defect is classed as an SAE.

d. For all CTIMPs, if a pregnancy occurs either in a female subject or the female partner of a

male subject the pregnancy should be followed up until at least the end of the

pregnancy.

e. The investigator is responsible for notifying the sponsor as soon as they become aware

of a pregnancy.

f. The Investigator must obtain informed consent for follow-up of the pregnancy from the

trial subject (or their partner in the case of male subjects).

g. Following the end of the pregnancy an SAE form must be completed if there is a

congenital abnormality or birth defect.

4.5 Annual Safety, Annual Progress and End of Study Reports

a. Where Papworth R&D is the sponsor or cosponsor, at the request of the Chief

Investigator, the R&D department will assist the Chief Investigator in compiling the

Annual Safety, Annual Progress and End of Study Reports. See SOP062 “Preparation of

Development Safety Update Reports”.

b. In meeting such requests the R&D Department will take all reasonable efforts to ensure

that no information that could unblind and therefore compromise the study is provided

directly to the Chief Investigator, unless the Chief Investigator is already unblinded.

5 Risk Management / Liability / Monitoring & Audit

a. The R&D SOP Committee will ensure that this SOP and any future changes to this

document are adequately disseminated.

b. The R&D Department will monitor adherence to this SOP via the routine audit and

monitoring of individual clinical trials and the Trust’s auditors will monitor this SOP as

part of their audit of Research Governance. From time to time, the SOP may also be

inspected by external regulatory agencies (e.g. Care Quality Commission, Medicines and

Healthcare Regulatory Agency).

c. In exceptional circumstances it might be necessary to deviate from this SOP for which

written approval of the Senior R&D Manager should be gained before any action is

taken. SOP deviations should be recorded including details of alternative procedures

followed and filed in the Investigator and Sponsor Master File.





d. The Research and Development Directorate is responsible for the ratification of this

procedure.



Appendix 1: Assessment of Adverse Events

Intensity The assessment of intensity will be based on the investigator’s clinical judgement using the following

definitions:

Mild: An event that is easily tolerated by the participant, 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

Causality The relationship between the drug / device / procedure and the occurrence of each adverse event

will be assessed and categorised as below. The investigator 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 be considered. The Investigator will also consult the Investigators

Brochure or other product information.

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 that 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 and the event could have been due to another, equally likely cause.

Probably related: Temporal relationship of the onset of the event, relative to 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 of the event, 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 related, probably related, definitely related the event is an

adverse reaction.



Diagram depicting how Causality determines what is an event and what is a reaction. Expectedness Adverse reactions must be considered as unexpected if they add significant information on the

specificity or severity of an expected adverse reaction. The expectedness of an adverse reaction shall

be determined according to the reference documents as defined in the study protocol (e.g.

investigator brochure or marketing information). For Papworth Sponsored studies all expected

events must be listed in the protocol.

Expected: Reaction previously identified and described in the protocol or reference documents e.g.

Investigator Brochure (IB) or Summary of Product Characteristics (SmPC).

Unexpected: Reaction not previously described in the protocol or reference documents.

NB the protocol must identify the reference documentation used.

Seriousness An event is considered serious if it meets one or more of the following criteria:

Results in death

Is life-threatening

Requires hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Consists of a congenital anomaly or birth defect

Further Document Information



Approved by: Management/Clinical Directorate Group

Research and Development Directorate

Approval date: (this version)

13th June 2013 (Chairman’s action)

Ratified by Board of Directors/ Committee of the Board of Directors:

STET

Date: N/A

This document supports: Standards and legislation

Medicines for Human Use (Clinical Trials) Regulations 2004 and all associated amendments. Research Governance Framework for Health and Social Care (2005) EN ISO 14155: 2011 Clinical Investigations of medical devices for human subjects – Good Clinical Practice ISO/TS 19218-1:2011 Medical Devices – Hierarchical coding structure for adverse events – Part 1: Event type codes EN ISO 14971: 2007 Medical Devices – Application of risk management to medical devices

Key related documents:

Trust Research Policy Research and Development Standard Operating Procedures entitled: SOP019 Research Protocol SOP037 Substantial Protocol Amendment SOP062 Preparation of Development Safety Update Reports. Trust’s policy for the reporting of accidents / adverse events / incidents and defects (DN70)

Equality Impact Assessment: Does this document impact on any of the following groups? If YES, state positive or negative, complete Equality Impact Assessment Form available in Disability Equality Scheme document DN192 and attach.

Groups Disability Race Gender Age Sexual orientation

Religious & belief

Other

Yes/No No No No No No No No

Positive/Negative

Review date: April 2016

Version Control



Version Date effective Valid to Approved by Date of approval

1.0 July 2011 RDD 5th August 2009

2.0 10th February 2012 February 2014 RDD 10th February 2012

3.0 22nd August 2013 April 2016 RDD (chairman’s action) 13th June 2013

3.1 12th February 2015 April 2016 HRA link updated

3.2 12th May 2015 April 2016 Formatting updated

4.0

Documents

Document Title: Adverse Event Reporting Document Number ... · Document Title: Adverse Event Reporting Document Number: SOP012 Staff involved in development: Job titles only RM&G