Standard Operating Procedure For the Preparation of the Annual

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					                Standard Operating Procedure
                  For the Preparation of the
            Annual Safety Report (ASR) by the Chief
                         Investigator


SOP ID Number: JBRU/INV/S07/00                                     Effective Date: 17/11/08


Version Number & Date of Authorisation: V00, 17/11/08              Review Date: 17/11/09




Revision Chronology:


                     Effective
SOP ID Number:                      Reason for Change:                         Author:
                     Date:
                                    This is the first time an SOP has been
                                    written for the ASR. Previous to this
                                    investigators were provided with a
                                    Guide, however, the Guide was no Joanna Galea-
JBRU/INV/S07/00      17/11/08
                                    longer in line with the SOP format and Lauri
                                    there was also a need to provide one
                                    Template to be adaptable for all trial
                                    scenarios




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Standard Operating Procedure for the preparation of the
       Annual Safety Report (ASR) by the Chief Investigator


1. PURPOSE

This SOP has been written to ensure that the chief investigator or the person delegated this
responsibility has the necessary information to be able to prepare and submit an annual
safety report (ASR) as required in accordance with:

               European Union Clinical Trials Directive 2001/20/EC (EUCTD).

               Statutory Instrument (SI) - The Medicines for Human Use (Clinical Trials)
                Regulations 2004 (SI 2004 No. 1031), and as amended by SI 2006 No. 1928.

               Commission Directive 2005/28/EC of 8 April 2005 (commonly known as the
                GCP Directive).

2. JOINT UCLH/UCL BIOMEDICAL RESEARCH UNIT POLICY

All JBRU SOPS are produced, reviewed and approved in accordance with the JBRU SOP
on SOPs.

3. BACKGROUND

Under the UK Regulations for clinical trials, the sponsor has a legal obligation to furnish the
MHRA and main Research Ethics Committee with an annual safety report (ASR), in relation
to each IMP tested in clinical trials, including IMPs used as reference or placebos. The ASR
for each clinical trial covers all sites involved in the trial, including any sites from international
countries taking part.

The aim of the ASR is to describe concisely all new safety data relevant for clinical trial(s)
and to assess the safety conditions of subjects included in the concerned trial(s). During the
course of a clinical trial, the investigator needs to ensure that he/she is recording, collecting
and managing all adverse events and reactions (including serious and all suspected
unexpected serious adverse reactions).

The following terms are relevant for the ASR, and are defined in the SOP entitled: “Standard
Operating Procedure for the Recording, Management and Reporting of Adverse Events by
Investigators” and will not be redefined in this SOP.
     Adverse Event (AE),
     Adverse Reaction (AR),
     Serious Adverse Event (SAE), Serious Adverse Reaction, or Unexpected Serious
        Adverse Reaction,
     Suspected Serious Adverse Reaction (SSAR),
     Suspected Unexpected Serious Adverse Reaction (SUSAR)
     Other important medical event: Overdoses (accidental or intentional), Pregnancy (of
        subject or partner), an alarming adverse experience, non-serious adverse events
        which are listed in trial protocols as requiring reporting


The ASR of a clinical trial should have three parts:



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Part 1:
Analysis of the subjects’ safety in the concerned clinical trial(s) with an appraisal of its
ongoing risk:benefit.

Part 2:
A line listing of all suspected serious adverse reactions (including all SUSARs) that occurred
in the concerned trial(s). In a multi-site international trial, the ASR should include SUSARs
and SARs from both UK and non-UK sites, including third countries participating in the trial.
The same report should be sent to both the competent authorities and relevant ethics
committees.

Part 3:
An aggregate summary tabulation of suspected serious adverse reactions that occurred in
the concerned trial(s).


These three parts are now explained in more detail


Part 1: Analysis of the subjects’ safety of the concerned clinical trial

This section of the ASR provides a concise description and safety analysis of all relevant
findings that could have a significant impact on the clinical trial population and a benefit-risk
evaluation for the clinical trial concerned. It should describe in a concise way, all new and
relevant findings, related to the safety of the subjects in the concerned trial, including all new
findings related to the safety of IMP treatments or other treatments used in the trial and any
other findings related to clinical trial procedures.

The concept of new findings for an IMP refers to information not already present in the
reference document in force at the beginning of the period covered by the report
(investigator’s brochure or summary of product characteristics).

Conclusions and/or recommendations from the Data Monitoring Committee, if any, should be
discussed and attached to the report.

It should also analyse the safety profile of the tested IMP and its implication for subjects’
exposure, taking into account all available safety data including drop outs for safety reasons.
When relevant, the following points should be considered:
    a) relation with dose, duration, time course of the treatment;
    b) reversibility;
    c) evidence of previously unidentified toxicity in the trial subjects;
    d) increased frequency of toxicity;
    e) overdose and its treatment;
    f) interactions or other associated risks factors;
    g) any specific safety issues related to special populations, such as the elderly, children
        or any other at risk groups;
    h) positive and negative experiences during pregnancy or lactation;
    i) abuse;
    j) risks which might be associated with the investigation or diagnostic procedures of the
        clinical trial;
    k) risks which might be associated with insufficient quality of the IMP.




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The report should also consider supporting results of non-clinical studies or other experience
with the IMP that are likely to affect the subjects' safety. It should be complemented with an
analysis of the implications for the population of the clinical trial, such as:
    a) Measures previously or currently proposed to minimise the risks found, where
        appropriate;
    b) A detailed rationale for whether or not it is necessary to amend the protocol, to
        change or update the consent form, patient information leaflet and the investigator’s
        brochure. (In this instance, the ASR cannot be used to request the amendment.
        Amendments are requested according to the procedure outlined in the SOP for
        amendments).

Finally an update of the risk-benefit evaluation for the concerned clinical trial should be
provided.


Part 2: Line-listings

This section of the ASR should contain a trial-specific line-listing of all suspected serious
adverse reactions that were reported during the trial from all sites within the period covered
by the report. The line listing provides key information but not necessarily all the details
usually collected on individual cases. If in one case report, a subject has more than one
adverse reaction terms, the line listing should include each subject only once regardless of
how many adverse reaction terms are reported for the case. If there is more than one
reaction, they should all be mentioned but the case should be listed under the most serious
adverse reaction (sign, symptom or diagnosis) as judged by the chief investigator.
It is possible that the same subject may experience different adverse reactions on different
occasions. Such experiences should be treated as separate case reports. Under such
circumstances, the same subject might then be included in a line listing more than once and
the line-listings should be cross-referenced when possible.

Cases should be tabulated by body system (standard organ system classification scheme).
Usually there should be one listing for each trial, but separate listings might be provided for
active comparator or placebo, or when appropriate and relevant for other reasons, e.g. in the
same trial for different formulations, indications or routes of administration are studied.
Expectedness at the time of occurrence of the suspected serious adverse reactions will be
assessed with the reference document in force at the beginning of the period covered by the
ASR.


Part 3: Aggregate summary tabulations

In addition to individual cases line listings provided in the part 2 above, summary tabulations
of all serious adverse reactions that occurred during the trial should be provided to allow an
overview of the trial. In those tabulations, serious adverse reaction terms for signs,
symptoms and/or diagnoses across all patients should usually be presented. These
tabulations ordinarily contain more terms than subjects. When the number of cases is very
small, a narrative description would be more suitable.

The aggregate summary tabulation should specify the number of reports:
   a) for each body system
   b) for each adverse reaction term
   c) for each treatment arm, if applicable (tested IMP, comparator or placebo, blinded
      treatment).

The unexpected adverse reaction terms should be clearly identified in the tabulation.

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If you are conducting more that one clinical trial with the same tested IMP, a single ASR
referring to those trials is strongly recommended. In that case, it should be composed of:

   a) a concise global analysis on the safety profile of the tested IMP taking into account
      all relevant new safety findings related to the use of the tested IMP and an analysis
      of the implications of the findings for the population included in clinical trials,
   b) and the ASR report relating to each clinical trial concerned.


4. SCOPE OF THIS SOP

This SOP describes the procedure on how and what to include in the ASR and the timelines
on which to submit this report to the sponsor of your CTIMP. This SOP is being written for
all CI who conduct a CTIMP sponsored by UCL or UCLH.

5. RESPONSIBLE PERSONNEL

For UCL/UCLH sponsored CTIMPs, the JBRU who represent UCL/UCLH as the sponsor, is
responsible for the submission of the ASR to the MHRA and the competent authorities of
other Member States and the Ethics Committees who gave a favourable opinion for the trial.
However, the JBRU will delegate the responsibility of preparing the ASR and of submitting
this report to the sponsor, to the Chief Investigator, who might decide to delegate this
responsibility to one of the Principal Investigators in the team. Other personnel who have
responsibilities in assisting in the preparation of the ASR include the designated
appropriately qualified medical personnel or the Data Safety Monitoring Board (DSMB).



6. PROCEDURE

6.1 How often is an ASR due, and when is the first ASR due?

An ASR is due annually.

For the first ASR, the reporting timeframe starts from the date the MHRA issues an
authorisation for the CTA to the yearly anniversary of this date. So for example, if the MHRA
issued the authorisation letter on the 23rd March 2007, the reporting timeframe is till the 23rd
March 2008. This date is designated as the cut-off for data or data lock point. Your
sponsor then has up to a maximum of 60 days from this time point to receive this report,
review it, ask for clarification if necessary, and submit it to the MHRA and Ethics Committee.

6.2 When should you submit the ASR to the sponsor of your CTIMP?

As stated above, the sponsor of your CTIMP has up to a maximum of 60 days after the
anniversary date, to receive this report, review it, ask for clarification if necessary, and
submit it to the MHRA and Ethics Committee. You are therefore expected to submit your
ASR well in advance of this 60 day period, to give your sponsor enough time to finalise the
report and submit it in a timely manner to the authorities. On average, the ASR should be
received by your sponsor 30 days after the anniversary date.

6.3 When is the second and subsequent ASRs due?

The ASR will have a data lock point on the anniversary date of the day the MHRA authorised
the trial. However the reporting timeframe will only need to be for the last year and so forth.

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The timing of when you submit this to your sponsor is as for the first ASR, ie 30 days after
the anniversary date.

6.4 When is the last ASR due?

You will need to submit one last ASR to cover the reporting period between the last
anniversary date and the end of trial, if this date does not coincide with the anniversary date
of the CTA. For example, if the trial was authorised on the 30th October 2005 and will end
on 25th Feb 2010, this would mean that as you go along you will need to prepare several
ASR: an ASR with a data lock point of Oct 2006, an ASR with a data lock point of Oct 2007,
Oct 2008, Oct 2009 and then one last ASR to be submitted up to 90 days after 25th Feb
2010 when you declare the trial ended.

6.5 When is the ASR due if you are conducting a short term trial (less that one year)
such as a First-In-Man, or short term metabolism or a pharmacokinetic study?

In case of a First-In-Man trial and subsequent short term metabolism or pharmacokinetic
studies the ASR should be prepared for submission to your sponsor within 90 days of the
end of trial together with the ‘Notification of the end of the trial’ Form (see SOP on how to
declare end of trial. The ASR for these type of short trials should contain at least an analysis
of the subjects’ safety and line listings, and if appropriate aggregate summary tabulations.

6.6 When is the ASR due if you are conducting your CTIMP in more than one Member
State?

If you are conducting a CTIMP in more than one Member State, eg UK and Italy, and Italy
authorised the CTA on the 13th June 2006 and the UK authorised the CTA on the 8th Sept
2006, then the first date of authorisation will be the valid date of the ASR, and anniversaries
thereafter.

6.7 When is the ASR due if you are the Chief Investigator of more than one trial with
the same IMP?

If you are a Chief Investigator conducting more than one trial with the same IMP and same
sponsor, you are adviced to combine the data and submit one ASR. For this purpose, you
need to use the date of authorisation for the first of the trials concerned.

6.8 When is the ASR due for a clinical trial which was authorised before 1st May 2004,
on a DDX certificate?

The original date of the DDX will be used as the date of authorisation, and anniversaries
thereafter.

6.9 Do you still need to prepare an ASR if your trial has not yet recruited any subjects
within the reporting timeframe of the report?

If for some reason, the trial has not yet recruited any subjects within the reporting timeframe,
you will still need to prepare a report for the sponsor.

6.10 Preparation of the ASR

For ease of preparing the ASR, a Template has been provided as an Appendix to this SOP
with instructions as to what to include in the different sections. The sections for the ASR are
as recommended by the official guidelines issued by the European Commission following the
publication of the Clinical Trials Directive.

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The ideal person to prepare the ASR will be the Chief Investigator or a delegate. It is also
possible that for a large trial, the co-ordinating centre would have a Pharmacovigilance co-
ordinator to help with the preparation of this report. The JBRU has a dedicated
Pharmacovigilance co-ordinator who will also be able to assist with the preparation.

6.11 Other Forms necessary for submission with the ASR

In addition to the ASR, you also need to complete an NRES Form called ‘safety report to
main research ethics committee covering form’. This form will be sent to you with the
reminder letter, but it can also be downloaded from the NRES website at the following web
address:

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

Please complete the form, but do not complete the section ‘Contact details for person
making this notification’ as this will be completed for you by the sponsor who will submit
the ASR on your behalf.


6.12 Submission of the ASR and NRES Form to the sponsor

For UCL only or UCHL/UCL sponsored CTIMPs, you are requested to submit an electronic
copy of the ASR, an electronic copy of the NRES cover Form, any supporting documentation
and a paper copy of the signed signature page of the ASR to your sponsor ie the JBRU
office who represent UCL/UCLH sponsor. The person at JBRU who will deal with the ASR is
the Pharmacovigilance Co-ordinator, or in the absence of this person a delegated person.

Please note that you are not required to submit the ASR to the MHRA and main REC or
other regulatory bodies.


7. REFERENCES

The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument
2004/1031, implemented 1st May 2004, and as amended thereafter.

Detailed guidance on the collection, verification and presentation of adverse reaction reports
arising from clinical trials on medicinal products for human use’ (ENTR/CT 3, Revision 2,
April 2006).

PV Document – Work stream 6: Pharmacovigilance: Final version for Clinical Trials Tool Kit
(12th Jan 2007) MRC/DH joint project.
http://www.ct-
toolkit.ac.uk/_db/_documents/Joint_Project_Guidance_on_Pharmacovigilance.pdf


8. APPENDICES

Appendix 1     Annual Safety Report: (TEMPLATE WITH INSTRUCTIONAL TEXT)




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Author and Job
                   Joanna Galea-Lauri, Head of Clinical Trials
Title:

Signature:


Date:


Authorised by:
Name and Job
Title

Signature:


Date:




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Appendix 1

                                 Annual Safety Report
                         (TEMPLATE WITH INSTRUCTIONAL TEXT)


Title:                                    Title of the trial as per the protocol

Sponsor Protocol Number:                  Number provided by JBRU

Sponsor:                                  Name and address of the sponsor

Chief Investigator:                       Name and address of the Investigator who is named
                                          on the regulatory submission and REC documents.

EudraCT Number:                           Enter the EudraCT number.

                                          If you are still working on a DDX (pre-1st May 2004)
                                          and have never registered the trial for a EudraCT
                                          number, please insert the DDX number instead.
CTA number                                Enter latest CTA number (please refer to any
                                          updated CTA number from the MHRA which is
                                          issued following every submitted approved
                                          amendment)
Name of Investigational Medicinal         If there is more than 1 IMP in the trial please state
Product(s):                               names of all of them.

Details of latest approved protocol       Date and version number of latest approved protocol
(date and version number):
Date of MHRA approval:                    Date of original CTA authorisation letter.
                                          If you are conducting a trial on a DDX (authorised
                                          pre 1st May 2004), please insert the date of the DDX
                                          certificate, and not the date of the CTA roll-over

Date of data lock point for this          Insert date of data lock point for this ASR. This is
ASR:                                      usually the anniversary date of the MHRA original
                                          approval.
Date when the 60 day is due after         Insert the date when the ASR is due ie count 60
date for data lock point:                 calendar days from the date of data lock point.
Trial objectives:                         Objectives as per protocol.

Trial design:                             A short description of the trial as per the protocol
                                          synopsis.
Total number of subjects planned          Insert total number of planned subjects. Please
for the trial                             ensure that this matches the information in the CTA,
                                          the Ethics Application form and the protocol
Start of trial:                           Insert the date of signed consent form of first
                                          subject.
Anticipated end of trial:                 Intended last subject last visit, or an estimated date,
                                          or state if still ongoing.


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Total number of subjects                 Insert total number of subjects consented from the
consented from the start of the          start to the latest date of data lock point
trial to the latest date of data lock
point:

Total number of subjects for which Insert total number of subjects for which this report is
this ASR is being prepared:        being prepared. This could include subjects from
                                   the previous reporting times, if the subjects had
                                   serious adverse events thereafter



Trial Status

Please use one of the following statements:

The trial has had approvals from all relevant authorities (ie MHRA) and MREC but is not yet
open to recruitment, due to XXXXXXXX.

The trial has been open to recuitment since XXXXXX, but to date no patients have been
recruited. Thus, There are no safety data to report. The reason for the delay of recruitment
is XXXXXXXX. It is anticipated that the trial will start to recruit from XXXXXXX.

The trial is open to recruitment.



PART 1.        REPORT ON THE SAFETY OF SUBJECTS

The report must provide for a concise safety analysis and risk-benefit evaluation for the trial,
describing all new findings related to the safety of the IMP and providing a critical analysis of
them with respect to their impact for the subjects. The following sections should be
completed:

1.1    Overview of Data

If the trial is still ongoing, it is necessary to state this and to say that the database has not
been locked; the data is preliminary and has not been cleaned (if appropriate).

If the trial has ended and database lock has occurred, the details of this should be given.

1.2    Non-serious Adverse Events

Please describe any significant implications (if any) that any non-serious adverse events
have on the trial or trial subjects..

1.3    New Findings Related to the Safety of the IMP

Give details of any new data emerging on the safety of any of the IMPs as a result of the
trial. ‘New’ refers to findings not already present in the reference document such as the
Investigator Brochure.

If there are none, use the following statement:

There have been no new findings related to the safety of the IMP(s) in this trial.

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1.4    Analysis of the safety of the tested IMP

Describe what these new findings might mean to the trial subjects bearing in mind the
following:

              Relationship with dose, duration, time course of the treatment
              Reversibility
              Evidence of previously unidentified toxicity in trial subjects
              Increased frequency of toxicity
              Overdose and its treatment
              Interactions or other associated risks
              Abuse of the IMP
              Risks which may be associated with the investigation or diagnostic
               procedures of the trial


If there have been no findings of note, include the following statement:

There have been no new findings related to the safety of the IMP(s) in this trial.

1.5    Implications for the Population of the Trial

Describe any safety findings that have implications for any specific populations such as
children elderly, renally impaired, diabetic, pregnant women etc.

1.6    Summary of any published literature relevant to the safety of the subjects in
       the trial

Please provide brief summary

1.7    Conclusions and/or recommendations from the DMC

Describe any significant recommendations from the DMC and summary of any concerns
from the DMC on safety of subjects in the trial.


1.8    Analysis of the Safety Profile of the Tested IMP

This is a subjective analysis and is really a risk benefit analysis on the pros and cons of the
treatment and its risks.

1.9    Supporting results of non-clinical studies or other experience with the IMP that
       are likely to affect the subjects’ safety

Please desribe briefly and include aggregated reports of any relevant unpublished data
known by the Chief Investigator.

1.10   Measures Proposed to Minimise Risks Found

Where appropriate, give details of any measures previously taken or now proposed to
minimise the risks identified.

Explain why you feel it is necessary, or not, to amend the protocol, consent form or
participant information leaflet as a result of the risks identified.

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If none have been identified, use the following statement:

There have been no risks identified related to the safety of the IMP(s) in this trial.

1.11   Update of the risk-benefit evaluation for the concerned clinical trial

Please update information on risk-benefit evaluation



PART 2.        LINE LISTINGS

The line listing should give details of all suspected SARs reported during the trial (including
SUSARs). It should include each subject only once regardless of how many AR terms are
reported for an event (ie case). In other words, if one subject has one event for which 3 AR
terms have been reported (this does sometimes happen), the event will only appear once in
the listing for that event and will be listed under the most serious AR term as judged by the
Medical Advisor. The other AR terms should be mentioned within the listing.

If a subject has more than one reaction on separate occasions, then they should be listed as
separate events, should be cross-referenced within the listings.

Cases should be tabulated by body system (standard organ system classification scheme).

Usually there should be one listing per trial, but separate listings should be provided for
active comparator or placebo or when appropriate and relevant for other reasons e.g.
different formulations, indications or routes of administration studied in the same trial.

2.1 A line listing is a table, and it should have the following headings:

              Unique reference number as per the database (UCL Biomedicine R&D will be
               able to assist with this)
              Country in which the event occurred
              Subject’s trial identification number
              Age and sex of the subject
              Daily dose of IMP
              Dosage form
              Route of administration
              Date of onset of the event (or best estimate of time from start of trial
               medication. If started after cessation of trial medication, estimate of time
               afterwards)
              Dates of treatment with the IMP
              Description of the reaction as reported (where medically appropriate signs
               and symptoms can be lumped into diagnoses as per the MedDRA dictionary.)
               See below for the main categories.
              Outcome of the event (use the terms resolved, fatal, improved, improved with
               sequelae or unknown. Use the worst of the different outcomes for multiple
               reactions)
              Causality
              Unblinding of IMP (in the case of SUSARs only, plus expectedness assessed
               with the reference document (e.g. IB) in force at the beginning of the period
               covered by the report.



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2.2 The Medical Dictionary for Regulatory Activities Terminology (MedDRA) Soc List

Internationally agreed order:

                 Infections and infestations
                 Neoplasms benign and malignant (including cysts and polyps)
                 Blood and the lymphatic system disorders
                 Immune system disorders
                 Endocrine disorders
                 Metabolism and nutrition disorders
                 Psychiatric disorders
                 Nervous system disorders
                 Eye disorders
                 Ear and labyrinth disorders
                 Cardiac disorders
                 Vascular disorders
                 Respiratory, thoracic and mediastinal disorders
                 Gastrointestinal disorders
                 Hepato-biliary disorders
                 Skin and subcutaneous tissue disorders
                 Musculoskeletal, connective tissue and bone disorders
                 Renal and urinary disorders
                 Pregnancy, puerperium and perinatal conditions
                 Reproductive system and breast disorders
                 Congenital and familial/genetic disorders
                 General disorders and administration site conditions
                 Investigations
                 Injury and poisoning
                 Surgical and medical procedures
                 Social circumstances


PART 3.           SUMMARY TABULATIONS

In addition to individual cases line listings, summary tabulations of SSAR terms for signs,
symptoms and diagnoses across all subjects should be presented to provide an overview of
the trial. These tabulations will usually contain more terms than subjects (this is because one
subject may have several reported terms for one event)

When the number of cases is very small a narrative description may be more suitable.

The summary tabulation should specify the number of reports:

              for each body system
              for each AR term
              for each treatment arm (IMP, comparator or placebo, blinded treatment)

The SUSARS should be clearly identified. The following table is an example:

Table xx - Number of Reports by terms (signs, symptoms and diagnoses) for Trial Number
xx




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Body system/AR         Active
term                                    Placebo
CNS
Term 1                2                 0
Term 2*               1                 0

Sub total             3                 0

CV
Term 1*               1                 0
Term 2                0                 1
Term 3*               1                 0

Sub total                2             1
*use an asterisk to indicate any SUSARs




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                             SIGNATURE PAGE OF ASR

For use by the Chief Investigator (or delegate)

Name and Title of
person preparing and
writing the report:

Department and
Address:

Email address:

Telephone number:

Other relevant
personnel involved in
the preparation/approval
of the ASR assigned by
the CI:

Date report finalised
before submission to
sponsor:

Signature of person
preparing and writing
the report:



For use by the Sponsor

Name of person
approving the ASR on
behalf of the sponsor:

Address:

Insert any significant     Comment on whether the safety committee or an independent
input from independent     expert was asked to provide advice or input in the report
experts

Date ASR approved for
submission to MHRA
and main REC:

Signature of person
approving the ASR on
behalf of sponsor:




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