INV_S05_AE_SAE_Reporting_by_Inv_v02_with_forms.pdf by JoeSouthwick

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									              Standard Operating Procedure
    for the Recording, Management and Reporting of
             Adverse Events by Investigators


SOP ID Number: JBRU/INV/S05/02                                   Effective Date: 28/10/2008


Version Number & Date of Authorisation: V2, 28/10/2008           Review Date: 28/10/2009




Revision Chronology:


                   Effective
SOP ID Number:                  Reason for Change:                                Author:
                   Date:
                                                                                  Yvanne
CRN/04/S05/00      09/09/2004 N/A
                                                                                  Enever
                                Administrative changes i.e. email address
                                update. UCL CRN to UCL Biomedicine R&D            Yvanne
BRD/04/S05/01      20/04/2005
                                Unit. Removal of UCL SAE Follow-up Form.          Enever
                                Update of UCL SAE Reporting Form.
                                Administrative changes i.e. UCL logo.
                                Additional text P2 to clarify version number,     Yvanne
BRD/04/S05/02      25/10/2005
                                plus addition of CI expectedness evaluation,      Enever
                                changes in staff titles.
                                Implementation of the Joint UCL/UCLH
                                                                                  Farhat
JBRU/07/S07/00     18/06/2007   Biomedical Research Unit and a new
                                                                                  Gilani
                                numbering system.
                                Update SOP in response to MHRA Inspection
                                to clarify procedure for management of all. In    Joanna
JBRU/07/S07/01     20/12/2007
                                particular procedure for pregnancy reporting      Galea-Lauri
                                has been updated.
                                To make SOP specific to investigator
                                responsibilities and clarify reports on deaths.
                                                                                  Joanna
JBRU/INV/S05/02    28/10/2008   To implement a new JBRU numbering system
                                                                                  Galea-Lauri
                                as     reflected      in    SOP      on    SOPs
                                JBRU/INT/S01/02




                   SOP for the Recording, Management and Reporting of AEs
                                      JBRU/INV/S05/02
                                         Page 1 of 26
                    Standard Operating Procedure
 for the Recording, Management and Reporting of Adverse Events by
                            Investigators


1. PURPOSE

This Standard Operating Procedure (SOP) describes the procedure to be used by the
investigator for the recording, management and reporting of Adverse Events (AEs), Adverse
Reactions (ARs), Serious Adverse Events (SAEs), Suspected Serious Adverse Reactions
(SSARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) that occur in
subjects participating in Clinical Trials of Investigational Medicinal Products (CTIMPs).

2. JOINT UCLH/UCL BIOMEDICAL RESEARCH UNIT (JBRU) POLICY

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

3. BACKGROUND

The European Clinical Trials Directive (EUCTD) 2001/20/EC transposed into UK Regulations by
‘The Medicines for Human Use (Clinical Trials) Regulations 2004’ (SI 2004/1031) and amended
SI 2006/1928 sets out the legal requirements for adverse event recording, management and
reporting in clinical trials i.e. pharmacovigilance responsibilities. For convenience, this document
will use the term “UK Regulations” to cover the UK legislation and the EUCTD. To comply with
the UK Regulations, organisations undertaking the role of Sponsor need to have procedures and
systems in place to support the recording, verification, reporting, analysis and management of
adverse events and serious adverse events (suspected or unexpected).


3.1 DEFINITIONS

3.1a Adverse Event (AE):

   Any untoward medical occurrence in a patient or clinical trial subject administered an
   Investigational Medicinal Product (IMP) and which does not necessarily have a causal
   relationship with this treatment.

   Therefore an AE can be any unfavourable or unintended change in the structure (signs),
   function (symptoms) or chemistry (laboratory data) in a subject to whom an IMP has been
   administered, including occurrences which are not necessarily caused by or related to that
   product.

3.1b Adverse Reaction (AR):

   Any untoward and unintended responses to an IMP related to any dose administered.

   Therefore an AR is any unfavourable or unintended change in the structure (signs), function
   (symptoms) or chemistry (laboratory data) in a subject to an IMP which is related to any dose
   administered to that subject.

3.1c Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)

Any adverse event or reaction in a trial subject that:
                      SOP for the Recording, Management and Reporting of AEs
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                                            Page 2 of 26
       (a)     results in death; or

       (b)     is life threatening;
               Note: places the subject, in the view of the investigator, at immediate risk of death
               from the experience as it occurred (this does not include an adverse experience
               that, had it occurred in a more severe form, might have caused death); or

       (c)     requires hospitalisation or prolongation of existing hospitalisation;
               Note: (hospitalisation is defined as an inpatient admission, regardless of length of
               stay), even if the hospitalisation is a precautionary measure for continued
               observation. Therefore, participants do not need to be hospitalised overnight to
               meet the hospitalisation criteria.

               Hospitalisation (including hospitalisation for an elective procedure) for a pre-
               existing condition (prior to study entry) which has not worsened does not
               constitute a serious experience.

       (d)     Results in persistent or significant disability or incapacity
               Note: substantial disruption of one’s ability to conduct normal life functions; or

       (e)     consists of a congenital anomaly or birth defect
               Note: in offspring of subjects or their partners taking the IMP regardless of time of
               diagnosis.

3.1d Other Serious Adverse Events/Reactions

Important medical events that may not be immediately life-threatening or result in death or
hospitalisation but may jeopardise the subject or may require intervention (medical or surgical)
to prevent one of the other outcomes listed in the definition above should also be considered
serious.

Such events might include:
             1. Overdoses (accidental or intentional)
             2. Pregnancy (of subject or partner)
             3. An alarming adverse experience
             4. Adverse events and/or laboratory abnormalities which are listed in the trial
                 protocol as critical to safety evaluations and requiring reporting

3.1e Suspected Serious Adverse Reaction (SSAR):

An adverse reaction that is classed in nature as serious and which is consistent with the
information about the medicinal product listed in the relevant reference documentation:
       (a) Summary of Product Characteristics (SmPC) in the case of a licensed product being
           used within its licensed dosage and indication.
       (b) An Investigator’s Brochure (IB) in the case of any other IMP or a licensed product
           being used outside its licensed dosage and indication.

3.1f Unexpected Adverse Reaction:

An adverse reaction, the nature or severity of which is not consistent with the applicable product
information (SmPC or IB).

3.1g Suspected Unexpected Serious Adverse Reaction (SUSAR)

An adverse reaction that is classed in nature as both serious and unexpected.
                      SOP for the Recording, Management and Reporting of AEs
                                         JBRU/INV/S05/02
                                            Page 3 of 26
3.2 OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN CLINICAL TRIALS

Other safety issues where they might materially alter the current benefit-risk assessment of an
IMP or that would be sufficient to consider changes in the IMP administration or in the overall
conduct of the trial also need to be considered serious, for instance:

a. an increase in the rate of occurrence or a qualitative change of an expected serious adverse
   reaction, which is judged to be clinically important,
b. post-study SUSARs that occur after the patient has completed a clinical trial and are
   reported by the investigator to the Sponsor,
c. new events related to the conduct of the trial or the development of the IMPs and likely to
   affect the safety of the subjects, such as:
       o an SAE which could be associated with the trial procedures and which could modify
           the conduct of the trial,
       o a significant hazard to the subject population such as lack of efficacy of an IMP used
           for the treatment of a life-threatening disease,
       o a major safety finding from a newly completed animal study (such as carcinogenicity),
       o any anticipated end or temporally halt of a trial for safety reasons and conducted with
           the same investigational medicinal products in another country by the same Sponsor,
d. recommendations of the Data Monitoring Committee (DMC), if any, where relevant for the
   safety of the subjects.

3.3 SEVERE ADVERSE EVENT OR REACTION

The term severe is often used to describe the intensity of an event or reaction and should not be
confused or interchanged with serious.

3.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR
This section clarifies the responsibilities for pharmacovigilance of the investigator. The
investigator can delegate the duties to other members of the team but they must be authorised
on the delegation sheet.


      The investigator should be thoroughly familiar with the appropriate use of the IMP(s), as
1     described in the protocol and other information sources such as the current IB, SPC,
      IMP dossier or other source of information. The investigator must train the other
      members of the team.
2     Follow Sponsors’ SOP for protocol writing on section that relates to Pharmacovigilance.
3     Keep detailed records of all AE/Rs that occur in trial subjects.
4     Assess each event for expectedness, causality and seriousness.
5     Report SAE/Rs and all follow-up information to the Sponsor, according to instructions
      and timelines outlined in the protocol.
6     Provide the Sponsor with details of all AEs identified in the protocol as critical to the
      evaluation of safety within the agreed timeframes specified in the protocol.
7     Supply the Sponsor with any supplementary information requested.
8     Provide the data safety committee (if there is one for the trial) will all relevant information
      required for an independent assessment.
9     Submit all pregnancy forms to the Sponsor.
10    Maintain subject confidentiality at all times.
11    The investigator may take appropriate urgent safety measures to protect clinical trial
                     SOP for the Recording, Management and Reporting of AEs
                                        JBRU/INV/S05/02
                                           Page 4 of 26
      subjects from any immediate hazard to their health and safety. This may be taken
      immediately but following the measure, the investigator must follow the SOP on
      ‘Amendments’.
12    Prepare and supply the Sponsor with an Annual Safety Report (ASR) for submission to
      the MHRA and REC. (See guide to ASR).


Where activities are often undertaken by the study nurse/trial co-ordinator it is important even in
urgent situations that every effort is made by the study nurse and/or trial co-ordinator to discuss
the SAE with the Chief Investigator or Principal Investigator (PI) at site.


4. SCOPE OF THIS SOP

What this SOP covers

This SOP covers the procedure for the recording, management and reporting of all AEs, ARs,
SAEs, SSARs and SUSARs that occur in subjects participating in CTIMPs sponsored by UCL or
UCLH/UCL jointly and that require reporting in accordance with the UK Regulations. This
document provides details of the responsibilities of the Investigator.

What this SOP doesn’t cover

Annual Safety Reporting which is also part of the pharmacovigilance responsibilities is outside
the scope of this SOP.

In circumstances where the Joint UCL/UCLH Biomedical Research Unit (JBRU) (in its role of
representative of the Sponsor) has delegated these responsibilities to a third party such as a
Clinical Research Organization (CRO) or an external Clinical Trials Unit (CTU), the procedures
to be followed for pharmacovigilance will be outlined in an agreement between the Sponsor, the
CRO and the Chief Investigator. This will be trial specific and will not be outlined here.
Description of this procedure falls outside the scope of this SOP.

Procedures used for the management of pharmacovigilance in trials that started before 2004,
might vary from the procedures described here and in such circumstances the Sponsor and the
investigator need to ensure that there is an agreement in place to meet the requirements. This is
outside the scope of this SOP.


5. RESPONSIBLE PERSONNEL

The Chief Investigator (CI) and the individual investigators within a trial team are responsible to
keeping records of all adverse events that occur in trial subjects.

The Chief investigator or one of his/her delegates can then assign who within the trial team is
responsible for reporting to the Sponsor.

Other personnel involved in SAE/R reports might be from within the Pharmacy department if
they are involved in IMP management of blinded trials.

For international trials:   responsibilities will be outlined in the contract between sites and
Sponsor.




                     SOP for the Recording, Management and Reporting of AEs
                                        JBRU/INV/S05/02
                                           Page 5 of 26
6. PROCEDURE

The following documents need to be in hand when assessing any AE in the trial, especially
since they contain the required information for the expectedness of the AE and timelines for
reporting to the sponsor:

      Protocol
      Summary of Product Characteristics (SPC; for marketed products)
      Investigator’s Brochure (IB) (if applicable)
      IMP Dossier (if applicable)
      Procedure for unblinding (in case of a SUSAR in a blinded trial)

6.1 When to start and when to stop recording AE/Rs?

All AE/Rs (non-serious, serious, expected, unexpected) need to be recorded from the point of
consent of a subject into a trial and not from the first dose of the administered IMP. This will
also include placebo run-in periods (if applicable). Serious adverse experiences for which the
onset occurs during the pre-randomisation period can be reportable if they are a result of a
protocol specified intervention or can cause the participant not to be allocated to randomisation
treatment.

All AEs and SAEs should be recorded until 14 days after last dose of the IMP or within the
established off therapy follow-up period for safety described in the protocol (if greater than 14
days). This time period needs to be defined in the protocol.


6.2 Which AE to record and which Forms to use?

As a CI/PI you need to keep detailed records of all AE/Rs that occur in the subjects taking part
in the trial. This includes non-serious, serious, expected or unexpected.
For this purpose the CI/PI needs to enter the details in:

   o   the medical records of the patients,
   o   the adverse event recording section of the CRF, and
   o   provide line listing of all AE/Rs in the Sponsor’s Form entitled: ‘Adverse Event
       Recording Form’ which is Appendix 1 to this SOP.

If the AE/R is serious the CI/PI will also need to enter the details in the Sponsor’s Form entitled:
‘Serious Adverse Event Reporting Form’ which is Appendix 2 to this SOP.

6.3 Recording ‘Other Safety Issues’

For all other safety issues listed in section 3.2, the CI/PI needs to record these in a letter headed
‘Safety Report’. There is no official form for these type of reports however the first page of the
report should reference the EudraCT number, title of the trial and the JBRU’s trial protocol code
number to which it refers and the points concerned summarised in a short section. Contact
numbers of the reporter should also be added for ease of reference.

6.4 Recording and reporting a Pregnancy

All pregnancies in clinical trial subjects need to be recorded and reported to the sponsor as soon
as the investigator is aware of the event. The Form is called Pregnancy Reporting Form which
is Appendix 3 of this SOP.

Pregnancy data provides vital data to the overall knowledge concerning the IMP. Any pregnancy
that occurs in a female trial subject during a clinical trial should be followed to termination or to
                      SOP for the Recording, Management and Reporting of AEs
                                         JBRU/INV/S05/02
                                            Page 6 of 26
term. Under special circumstances, it may be necessary to monitor the development of the
newborn for an appropriate period post delivery. There may also be special situations when it
will be necessary to monitor the pregnancy of a woman whose male partner is the trial subject.
All trial protocols should describe in detail the process for monitoring and managing pregnancy
occurrences in a trial.

6.5 What should not be reported to your Sponsor?

For well established drugs used within their licensed indication, any AE/Rs judged by the CI/PI
to be non-serious will not usually need to be reported to the Sponsor. However, the CI/PI will
need to keep a copy of the record (i.e. Form in Appendix 1) in the site file, as this is subject to
monitoring by the Sponsor. This form will need to be sent periodically to the Sponsor as outlined
in the protocol or on request from the Sponsor.

6.6 Which AE to report to your Sponsor?

All AE/Rs in subjects with novel drugs should be reported to the Sponsor.

All AE/Rs that fulfil the criteria for the definition of serious, whether expected or not, need to be
reported to the Sponsor, i.e. the JBRU, unless justified in the protocol. For drug reactions, the
sponsor will need this information to perform trend analysis and determine whether for example
there is an increased rate of occurrence in that drug reaction within the trial population. This
includes serious AE/Rs that were expected whether or not they are related to the IMP. The
protocol will list all the expected SAE/Rs that need to be reported.

6.7 When and how to report serious AE/Rs to the Sponsor?

6.7a What needs to be reported immediately or within 24 hours.

   1. All SUSARs need to be reported to the Sponsor immediately or within 24 hours.
   2. Other serious events/reactions listed in section 3.1d above also need to be reported
      immediately. This includes pregnancy.
   3. All of the safety issues listed in section 3.2 also need to be reported immediately.

6.7b When to report other SAE/Rs to the Sponsor that don’t require immediate reporting

All expected SAE/Rs also need to be reported to the Sponsor. However the timelines for which
to report these to the Sponsor are detailed in the protocol and the CI/PI will need to refer to the
timelines agreed in the protocol at all times. These timelines will vary depending on the purpose
of the trial, toxicity and efficacy endpoints, but usually it is monthly, quarterly or bi-annually.

6.8 Reporting Deaths to the sponsor

For information when and how to report deaths in the trial, you must refer to the protocol which
will state one or more of the following statements:

“All deaths will be reported to the sponsor irrespective of whether the death is related to disease
progression, the IMP, or an unrelated event”.

“Only deaths that are assessed to be caused by the IMP will be reported to the sponsor. This
report will be immediate”.

“All deaths, including deaths deemed unrelated to the IMP, if they occur earlier than expected
will be reported to the sponsor”.



                      SOP for the Recording, Management and Reporting of AEs
                                         JBRU/INV/S05/02
                                            Page 7 of 26
The timelines will be determined in the protocol, but if the outcome of a SUSAR is death, the
report must be immediate.

6.9 Where to report to AEs and SAEs?

The SAE Reporting Form (Appendix 2) and the Pregnancy Reporting Form (Appendix 3) need to
be faxed to the JBRU on 020 7380 9937 or emailed to your Lead trial co-ordinator in the JBRU.

The initial report of a SUSAR could also be done verbally to the Sponsor, but needs to be
followed promptly by the use of the SAE Reporting Form.

Subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on
all reports in relation to recording and reporting of AEs.

6.10 Other reporting arrangements for Multi-Centre Trials

If you are the PI in a multi-centre trial sponsored by UCL, the PI usually sends the report to the
lead site where the CI is and the responsible person will send the report to the Sponsor.

Such arrangements will be specified in the protocol and agreements.


6.11 Evaluation of AE/Rs during the trial

       Evaluating AEs

       As noted on the SAE Reporting Form, each AE must be evaluated for seriousness,
       causality, severity and expectedness and the responsibility for doing this can be
       shared between the CI and PIs. It maybe most appropriate for the treating PI at each
       centre to evaluate each event, before reporting it to the JBRU. Whatever the case it must
       be stated in the clinical trial protocol and the local SOP who will take responsibility for the
       assessment and reporting of such events to the JBRU and CI/PI simultaneously.

       All SAEs must be followed up until a resolution is reached (i.e. recovered, recovered with
       long term sequel, fatal, not ever going to recover).

       a. Evaluation of seriousness

       The CI/PI must assess the AE as serious as per the definition of an SAE in section 3.

       b. Evaluation of causality

       The Council for Internal Organisations of Medical Sciences (CIOMS) VI group agree that
       the Investigator's causality assessment is vital information since the Investigator is best
       placed to see how the subject has changed since baseline (before treatment is
       administered). Every effort must be made by the CI/PI to obtain all the required
       information to determine whether the AE is related to the trial intervention.

       It is important to note that if the investigator indicates an unknown causality assessment
       the adverse experience will be considered as related by the JBRU (taking the most
       conservative option) and could warrant expedited reporting.

       To help Investigators with the decision, the CIOMS VI group recommends that CI/PI be
       asked to consider the following before reaching a decision:

      Medical History

                     SOP for the Recording, Management and Reporting of AEs
                                        JBRU/INV/S05/02
                                           Page 8 of 26
      Lack of efficacy/worsening of existing condition
      Study treatment(s)
      Other treatments-concomitant or previous
      Withdrawal of study treatment-especially following study discontinuation/end of study
       treatment
      Erroneous treatment with study medication (or concomitant)
      Protocol related process
      The CI/PIs evaluation of severity

   It is common practice for events to be assessed for clinical severity (intensity defined as:
   mild, moderate or severe) of the specific event. As already explained in the definitions,
   severity must not be confused with “serious” which is a regulatory definition based on
   subject/event outcome or action criteria.

   c. Evaluation of expectedness

   The CI/PI must evaluate whether the event is expected or not. The event is considered as
   “unexpected” if it adds significant information on the specificity or severity of an expected
   event. The expectedness of an SAE/SAR should be determined according to the reference
   document as defined in the protocol (i.e. IB for non-licensed product or SmPC for a licensed
   product in the EU assuming that the product is being used in the trial exactly as stated in the
   SmPC).

6.12 How to manage reports in blinded trials

For blinded clinical trials, the Sponsor needs to make sure that there are procedures in place to
maintain the blind for the investigator and for those persons responsible for data-analysis and
interpretation of results at study’s conclusion.

However SUSARs need to be unblinded under the following conditions:

       1. Patient experiencing an adverse event and requiring treatment which cannot be given
          without knowing the trial arm the patient was randomised to,
       2. The JBRU requires unblinding of the information before a report of a SUSAR can go
          to to the MHRA and REC.

Unblinding information is usually kept by the Pharmacy department and the pharmacist will be
contacted to break the code. During working hours (9am – 5pm) the contact is the Clinical Trials
Lead within the Pharmacy. For UCLH this is ext 73020. During ‘out of hours’ contact is the on
call Pharmacist who can be bleeped via the UCLH switchboard. The unblinding procedure is
protocol specific and each trial must clearly state the procedure they are using and where the
unblinding information is to be kept.
   1. When an adverse event has occurred, the minimum information needed to unblind a
      subject should include a trial number, patient initials, contact details of person reporting
      adverse event (i.e., doctor at treating hospital), causality assessment and nature of the
      serious adverse event. This information will be provided on the SAE report form sent to
      the JBRU by the CI/PI or the research team.
   2. If the report is a SUSAR, the JBRU will request unblinding information via email from the
      Pharmacy Clinical Trials Lead and will clearly state that the patient is being unblinded for
      MHRA and REC reporting. The email will give the patient identifier details and state the
      timeframe in which the information is required.
   3. The Pharmacist identifies the patient’s trial ID number (if not known) from the patient’s
      notes and/or Trial Master File (TMF) or pharmacy records.

                     SOP for the Recording, Management and Reporting of AEs
                                        JBRU/INV/S05/02
                                           Page 9 of 26
  4. This information is stored in individual sealed envelopes which are identified by the
     patient’s trial ID number which is clearly written on the outside. Or the Pharmacy has a
     complete randomisation log kept locked in the clinical trials office, the unblinding
     information is obtained from this log, which can be assessed at any time.

  5. The Pharmacist will email back the unblinded information to the JBRU.

  6. The JBRU will then email this information and the adverse event information to the
     independent assessor to obtain causality.
  7. If the report still meets expedited reporting requirements, it will be sent to the MHRA and
     REC by the Sponsor.

  6.13 Follow-up information

  All relevant information that is missing from the initial report to the Sponsor needs to be
  written up and sent to your sponsor as soon as the information is available. This needs to be
  written up on a new SAE form.


  6.14 TRUST INCIDENT FORM FOR UCLH TRIAL SUBJECTS

  Where UCLH is jointly sponsoring the trial with UCL or hosting the trial sponsored by an
  external sponsor to UCL/UCLH, a Trust Incident Form must also be completed for all UCLH
  subjects in a trial. This is in addition to the above reporting requirements. The Incident
  Reporting Form can be downloaded from the UCLH website www.uclh.nhs.uk.

  The Trust Incident form should be filled out for all serious unexpected incidences in
  research studies. An incident may be a medical or other type of occurrence. Examples of the
  latter include the failure to obtain consent for many of the research subjects or major
  deviations from the protocol. For non medical incidents, completion of the Trust Incident form
  is all that is required.

  6.15 What to expect from Sponsor once a report has been submitted

  A representative from the sponsor (likely to be the lead trial co-ordinator or Senior
  Pharmacovigilnace Co-ordinator) will confirm receipt of all reports sent within 1 week. If you
  have not heard from your sponsor you will need to chase.

  The sponsor will most likely also email or phone the reporter to ask further or clarify any
  answers as deemed necessary.




FAILURE TO COMPLY WITH PHARMACOVIGILANCE AS SET FORTH IN THIS SOP MAY
RESULT IN REGULATORY, CRIMINAL AND/OR CIVIL ACTION AGAINST THE SPONSOR
AND RESPONSIBLE INDIVIDUALS.




                   SOP for the Recording, Management and Reporting of AEs
                                      JBRU/INV/S05/02
                                        Page 10 of 26
         Flowchart 1: Decision framework which Investigators and research personnel should
         follow to assess AEs and SAEs



                                         INVESTIGATOR RESPONSIBILITIES


                                              AE observed




                                                 Does it meet the
                                                  definition of
                            No                      serious?                          Yes




                Is the event assessed                                              Is it expected?
                      as severe*?                                            Included in the IB or SmPC.
                                                                            Check protocol if expected for
                                                                                disease or procedures
                                                                                  undertaken in trial.


                                      Yes
                                                                       No                          Yes
        No

                                                  Is it reasonably,
                                                 causally related to
                                                  the study drug?

                                                                                     If related to drug it is an expected
                                                                                                     SAR.
                                              Yes                   No
                                                                                      Assess for severity, complete SAE
       It is an AE .                                                                  report form, sign by CI and send to
Record event on trial AE                                                            Sponsor within 24 hours. (Those SAEs
 form and file in subject                                                              listed in protocol as not requiring
      notes/source                       It is a SUSAR                               immediate report must be forwarded
  documentation. Send              Complete SAE report form,                               as defined in the protocol).
  Sponsor AE form as                 sign by CI and send to
    stated in protocol              Sponsor within 24 hours.                         If not related to drug but related to
                                     Sponsor will review and                         disease or other trial intervention it is
                                   check assessment of CI/PI.                                  an expected SAE
                                                                                           Report as per protocol
                                                                                                 requirements




    *An example would be severe continuous headache whereas the reference documentation (IB or SmPC) states only
    mild headaches as an expected event for the trial

       Summary of procedures Flowchart 1
    Flowchart 1 illustrates the decision framework which Investigators and research personnel
    should follow to assess AEs and SAEs should they occur during the trial and to decide if the
    event requires further expedited reporting by the JBRU.



                                 SOP for the Recording, Management and Reporting of AEs
                                                    JBRU/INV/S05/02
                                                      Page 11 of 26
7. REFERENCES

Directive 2001/20/EC of the European Parliament and of the Council of 4th April 2001 on the
approximation of the laws, regulations and the administrative provisions of the Member States
relating to the implementation of good clinical practice in the conduct of clinical trials on
medicinal products for human use.

The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) and amended
regulations.
ICH Harmonised Tripartite Guideline for Good Clinical Practice (1996).

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

MRC/DH joint project Work stream 6: Pharmacovigilance (PV Document-final version for clinical
trials tool kit (12th Jan 2007).


8. APPENDICES

Appendix 1     Adverse Event Recording Form

Appendix 2    Serious Adverse Event Reporting Form

Appendix 3    Pregnancy Reporting Form in clinical trial subjects




Author and Job
                      Dr Joanna Galea-Lauri, Head of Clinical Trials (JBRU)
Title:

Signature:


Date:


Authorised by:
Name and Job
Title

Signature:


Date:




                     SOP for the Recording, Management and Reporting of AEs
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Appendix 1
                                                                                      Subject Initials: …………… Subject ID Number: …………….
Adverse Event Recording Form
(To be sent to sponsor on request)                                                    Trial/Study ID Number: BRD/0…...../…... and / or ..…../…..…

         Description of AE                               Date of         Outcome1             Date of             Severity         Causality               Expectedness                  Is it
                                                         Onset                               Resolution           Grade2          Assessment3                                         Serious?4




1
  Key:  1=resolved no residual effects 2=resolved residual effects 3= continuing 4=death
2
  Key:  1=mild 2= moderate 3= severe
3
  Key:  1=not related 2=possibly related 3= probably related 4= definitely related NOTE 2-4 qualifies an AE as an Adverse Reaction (AR)
4
  Key:  1=results in death 2=is life threatening 3=requires hospitalisation or prolongation of existing hospitalisation 4=results in persistent or significant disability or incapacity
        5= consists of congenital anomaly or birth defect 6= No
NOTE: If AE is SERIOUS please complete the SAE reporting form and send to the Joint UCLH/UCL Biomedical Research Unit within 24hrs Fax no.: 020 7380 9937

                                                            SOP for the Recording, Management and Reporting of AEs
                                                                               JBRU/INV/S05/02
                                                                                 Page 13 of 26
                                         Appendix 2


                                                                JOINT UCLH/UCL BIOMEDICAL
                  Serious Adverse Event                         RESEARCH UNIT (JBRU)
                     Reporting Form
                                                                Fax No 020 7380 9937
           For UCL/UCLH Sponsored CTIMPs



Sponsor Protocol No:
(please insert)                                                 Initial Report

Name of CI:                                                     Follow-up Report

Name of Site:


FOR THE ATTENTION OF:

Senior Pharmacovigilance Co-ordinator or Head of Clinical Trials at JBRU



Please complete

Name of Person sending report:

Job title of Person sending report:

Email of Person sending report:

Contact Phone number of Person sending report:



THIS IS AN URGENT REPORT THAT REQUIRES IMMEDIATE ATTENTION



DATE RECEIVED BY SENIOR PHARMACOVIGILANCE CO-ORDINATOR

OR HEAD OF CLINICAL TRIALS:




                     SOP for the Recording, Management and Reporting of AEs
                                        JBRU/INV/S05/02
                                          Page 14 of 26
                                                       Serious Adverse Event Reporting Form
Study details

Study title

                                                        Joint UCLH/UCL Biomedical                                                              EudraCT number
CTA/DDX/CTX No
                                                        Research Unit (JBRU) Project ID No
                                                                                                     Has the Chief or Principal Investigator
                                                                                                     been informed of this event prior to            Yes        No
Type of report            Initial              Follow-up                                             the completion of this form?

Patient / Treatment details

Patient initials                                                                                  Patient study number

Date of birth (DOB)                                                                              Height                     cm                 Weight                                   .       kg
                               d    d   m      m   m     y     y

Gender                                                 Female                                     Was study drug unblinded?
                                    Male

IMP(s) patient was receiving at time of SAE                                    Route of
(if applicable)                                              Dose (mg)       administration     Date of dose initiated                         Ongoing?           End date (if applicable)

                                                                                                      d     d   m   m   m   y    y               Y         N      d   d     m   m   m       y    y


                                                                                                      d     d   m   m   m   y    y               Y         N      d   d     m   m   m       y    y
                                                                                 Most recent
Date of last treatment given                                                                              Was treatment given at full
                                                                              cycle number                                                       Y         *N   *Specify:
prior to SAE                               d   d   m     m    m    y     y                                dose prior to event?
                                                                              (if applicable)

                                                                                          Did reaction reappear after
Did reaction abate after                                                                  reintroduction of study
study medication stopped?               Yes            No          N/A                    medication?                                   Yes           No        N/A




                                                       SOP for the Recording, Management and Reporting of AEs
                                                                          JBRU/INV/S05/02
                                                                            Page 15 of 26
Serious Adverse Event

COMPLETE THIS PAGE FOR EACH SERIOUS ADVERSE EVENT (photocopy as necessary for each event)
Serious Adverse event Term
                                                                    Severity     Date of onset                                                Ongoing?                                  Date resolved


                                                                                         d   d    m       m       m       y       y
                                                                                                                                                      Y        N                d   d     m    m   m     y   y


Why was the event serious? (choose most serious)                       Where did the event take place?                                                                              Outcome

      Resulted in death                                                              Home                                                                                                     Resolved

                                                                                                              Admission date                              Discharge date
      Life-threatening                                                               Hospital                                                                                                 Persisting
                                                                                                      d       d       m       m       m   y   y   d   d    m   m   m   y    y

      Required inpatient or prolonged existing hospitalisation                       Out-patient clinic                                                                                       Worsened

      Resulted in persistent or significant disability/incapacity                    Nursing Home                                                                                             Fatal

      Resulted in congenital anomaly/birth defect                                    Hospice                                                                                                  Not assessable

      Other Important Medical Event        (specify)
                                                                                     Other (specify)____________________________________________
      __________________

Expectedness

      Unexpected                  Expected             Is the event listed in the reference document, (study protocol, SmPC or Investigator’s Brochure)?

Causal relationship to event (Is the event related to the subject’s involvement in the study)?
      Trial drug              Definitely               Probably           Possibly               Unlikely                         Not related         Not assessable       Name of person making decison




Action taken

                                                       SOP for the Recording, Management and Reporting of AEs
                                                                          JBRU/INV/S05/02
                                                                            Page 16 of 26
                                                                                                    *Treatment delayed and                      Treatment                 Name of person making
      Trial drug                          *Dose reduction          *Treatment delayed
                            None                                                                           reduced                          permanently stopped                 decison




*If dose was reduced and/or delayed, please specify length of delay/how much dose was reduced by:

Treatment given for management of SAE

                                    Total daily                    Route of
Treatment                                               Units                                               Start date                      Ongoing?                        End date
                                    dose                           administration
                                                                                            d       d       m       m   m       y       y                         d   d      m   m   m   y   y

                                                                                                                                              Y      N
                                                                                                                                              Y      N
                                                                                                                                              Y      N


Any concomitant medications?                        Y              N             (If yes, please specify below and continue on separate sheet if necessary)
                                     Total daily                  Route of                              Start date                                                          End date
            Treatment                  dose             Units   administration          d       d       m       m   m       y       y       Ongoing?              d   d     m    m   m   y   y

                                                                                                                                              Y      N

                                                                                                                                              Y      N

                                                                                                                                              Y      N

                                                                                                                                              Y      N


Any relevant tests / laboratory data?               Y              N             (If yes, please specify below and continue on separate sheet if necessary or attach print outs)




                                                  SOP for the Recording, Management and Reporting of AEs
                                                                     JBRU/INV/S05/02
                                                                       Page 17 of 26
Any relevant medical history / concurrent conditions?                 Y            N           (If yes, please specify below and continue on separate sheet if necessary)




Any other relevant information?                                            (If yes, please specify below and continue on separate sheet if necessary)
                                                  Y             N




Event summary description (Give a concise medical description of the event including all relevant symptoms. Please specify the grade for all related symptoms and
complete page overleaf for all that meet the definition of serious)




For report of death: (state why the death was expected (eg disease progression, or if earlier than expected, which provide explanation)


Describe whom this SAE was discussed with for a judgement of assessment:




                                               SOP for the Recording, Management and Reporting of AEs
                                                                  JBRU/INV/S05/02
                                                                    Page 18 of 26
Describe why and how you reached the assessment of causality for expectedness and related (ie provide the reasoning for the outcome):




Signature of person
making the                                                                                                 Date of
                                                         Print name                                                                d    d   m   m   m   y   y
assessment                                                                                                 assessment
Authorised health professional
Signature of person
completing the form
if different to person                                   Print name                                        Date of report          d    d   m   m   m   y   y
abovel




                                            SOP for the Recording, Management and Reporting of AEs
                                                               JBRU/INV/S05/02
                                                                 Page 19 of 26
For Sponsor’s Office use only
 Date SAE reported to
                                                                                           Date SAE reviewed                                                          Event No
        JBRU                 d       d        m       m       m        y       y                                      d   d   m       m       m       y   y
JBRU’s Assessment of                                                                                           Is the event listed in the reference document, (study protocol, SmPC or Investigator’s
                         Expected                                                  Unexpected
    Expectedness                                                                                                                                      Brochure)?
                                                                                                                              Date reported to Main REC
                                                                  Date reported to MHRA
   Was the event a                   *Y                                                                                                                                                     Reported to             *Y
     SUSAR?                                                                                                                                                                                 all other PIs
                                     N                                                                                                                                                                              N
                                                                                                                                  d       d       m       m   m   y    y
                                                                  d        d       m   m   m   y   y


                                                                                                          Form checked by (signature)                     Print name             Date
                        Date reported to GTAC (if applicable)


                                                                                                                                                                                  d     d     m   m   m     y   y
                         d       d        m       m       m       y        y



Comments:




                                                                      SOP for the Recording, Management and Reporting of AEs
                                                                                         JBRU/INV/S05/02
                                                                                           Page 20 of 26
                                       Appendix 3


                                                               JOINT UCLH/UCL BIOMEDICAL
                     Pregnancy                                 RESEARCH UNIT (JBRU)
                   Reporting Form
                                                               Fax No 020 7380 9937
           For UCL/UCLH Sponsored CTIMPs



Sponsor Protocol No:
(please insert)                                                Initial Report

Name of CI:                                                    Follow-up Report

Name of Site:



FOR THE ATTENTION OF:

Senior Pharmacovigilance Co-ordinator or Head of Clinical Trials at JBRU



Please complete

Name of Person sending report:

Job title of Person sending report:

Email of Person sending report:

Contact Phone number of Person sending report:



THIS IS AN URGENT REPORT THAT REQUIRES IMMEDIATE ATTENTION



DATE RECEIVED BY SENIOR PHARMACOVIGILANCE CO-ORDINATOR

OR HEAD OF CLINICAL TRIALS:




                    SOP for the Recording, Management and Reporting of AEs
                                       JBRU/INV/S05/02
                                         Page 21 of 26
                                                         Pregnancy Reporting Form
Study details

Study title

                                           Joint UCLH/UCL Biomedical
CTA/DDX/CTX No                                                                                                      EudraCT number
                                           Research Unit Project ID No

1) Patient details (Any information regarding female partners of trial patients should be entered in Other Pregnancy Information section)

Patient initials                                                                           Patient study number

Gender                          Male         Female                                        Date of Birth
                                                                                                                                          d   d     m   m   m   y       y

Type of Report                  First        Follow-up                                     Height                                cm       Weight                                .       kg


                                Yes          No                                            Was study                    Yes                                     No
Has CI been informed?
                                                                                           unblinded?

2) Trial treatment
                                                                            Is this full                            Start date                                                      End date
    Drug Name               Brand         Dose     Unit    Frequency                           Route                                              Ongoing?
                                                                              dose?                         d   d   m   m   m     y   y                             d       d       m   m    m   y   y


                                                                               Y       N                                                            Y       N

                                                                               Y       N                                                            Y       N

                                                                               Y       N                                                            Y       N

                                         Date last treatment given before                                                Last treatment given before
Most recent cycle number:                       pregnancy confirmation:            d   d      m     m   m   y   y         pregnancy confirmation:                   d       d       m    m   m   y   y




                                                              SOP for the Recording,
                                                          Management and Reporting of AEs
                                                                  JBRU/S05/02
                                                                 Page 22 of 26
                                                (Only include drugs given within the last 30 days. Continue on
3) Concomitant medications?                                                                                              Continued on a separate sheet:
                               Y        N       separate sheet if necessary)                                                                                      Y       N
                                                                                                                                                          End date
                                                                                                        Start date
   Drug Name           Brand       Indication       Dose      Units   Frequency      Route                                       Ongoing?
                                                                                                                                                 d   d    m   m   m   y   y
                                                                                                d   d   m   m    m   y     y

                                                                                                                                    Y      N
                                                                                                                                    Y      N
                                                                                                                                    Y      N
                                                                                                                                    Y      N




                                                         SOP for the Recording,
                                                     Management and Reporting of AEs
                                                             JBRU/S05/02
                                                            Page 23 of 26
4) Pregnancy Information

                                                                                                                      Anticipated date of                  Mother consented for
Start date of last menses      Date pregnancy confirmed             Method of diagnosis                                                                    pregnancy monitoring
                                                                                                                      childbirth


 d    d   m   m   m   y   y      d   d    m   m   m    y    y                                                            d   d   m   m   m   y     y
                                                                                                                                                                    Y     N


Pregnancy Outcome

     Not known at this date                       Still birth                                     Induced abortion                               Spontaneous abortion

     Neonatal death                               Uneventful (normal/healthy baby)                Birth defects (provide details in Other Pregnancy Information section below)

Date of Above Outcome:
                                              d   d    m    m   m    y   y

     Date of delivery         Gestation                                                              Weight
                                              Mode of Delivery                  Gender                          Antenatal Problems                         Postnatal Problems
 d    d   m   m   m   y   y    (weeks)                                                                (kg)

                                                                             Male        Female         .


Other Pregnancy Information (concurrent conditions, medical history, complications during birth, birth defects etc)




                                                                    SOP for the Recording,
                                                                Management and Reporting of AEs
                                                                        JBRU/S05/02
                                                                       Page 24 of 26
Past Pregnancy History
     Date of delivery           Gestation                                                  Weight
                                            Mode of Delivery           Gender                       Antenatal Problems                   Postnatal Problems
 d   d   m    m   m    y    y    (weeks)                                                    (kg)

                                                                   Male         Female       .

                                                                   Male         Female       .

                                                                   Male         Female       .


Signature
PI or other participating                                          Print name                                       Date of report   d    d   m   m   m   y   y
clinicians only




                                                             SOP for the Recording,
                                                         Management and Reporting of AEs
                                                                 JBRU/S05/02
                                                                Page 25 of 26
Office use only
 Date reported to R&D
                                                                       Date SAE reviewed                                                Event No
         Unit           d   d    m     m   m       y       y                                  d   d   m   m    m        y   y                         d   d       m   m   m       y       y


                                                       Date reported to MHRA                                  Date reported to Main REC
    Was the event a         *Y                                                                                                                                    Reported to                 *Y
      SUSAR?                                                                                                                                                      all other PIs
                            N                                                                                                                                                                     N
                                                       d       d   m   m    m       y   y                       d   d       m   m   m     y   y



                                                                                                  Form checked by                   Print name
                                     Date reported to GTAC (if applicable)                           (signature)

                                                                                                                                                   Date
                                                                                                                                                          d   d       m   m   m       y       y
                                           d   d       m       m   m    y       y



Comments:




                                                                       SOP for the Recording,
                                                                   Management and Reporting of AEs
                                                                           JBRU/S05/02
                                                                          Page 26 of 26

								
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