RESEARCH RELATED ADVERSE EVENT REPORTING POLICY adverse reaction by benbenzhou

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									    RESEARCH RELATED ADVERSE EVENT REPORTING POLICY

     Policy Number:
     Version:                                  2.0
     Authorisation Committee:                  R&D Steering Group
     Date of Authorisation:                    Chair’s Action (Cliff Shearman), 28 May 2010
     Ratification Committee:                   Healthcare Governance Steering Group
                                               (for V1.0 on 14 Jul 2006)
     Date of Ratification                      14 Jul 2006
     Signature of ratifying
     Committee Chair
     Lead Job Title of author:                 Research Governance & Quality Assurance
                                               Manager (R&D)
     Name of responsible                       Claudia Fellmer
     individual
     Date issued:                              First issued as V1.0 14 July 2006
     Review date:                              28 May 2013
     Target audience:                          Clinical/Non-clinical Researchers, Research
                                               Nurses/Health Care Professionals, Research
                                               Administrators, Care Group R&D Leads
     Key words                                 AE, SAE, SUSAR, ADE, SADE, USADE,
                                               Serious    Adverse     Event,    Suspected
                                               Unexpected Serious Adverse Reaction,
                                               Serious Adverse Device Effect. Unanticipated
                                               Serious Adverse Device Effect
     Main areas affected                       Trustwide,     all   staff/research visitors
                                               contributing to research; WTCRF, BRU
     Consultation:                             R&D Steering Group
     Equality Impact                           19 May 2010
     Assessments completed
     and policy promotes Equity
     Number of pages:                          17 and Appendices

The Trust strives to ensure equality of opportunity for all, both as a major employer and as a
provider of health care. This Research Related Adverse Event Policy has therefore been
equality impact assessed by the R&D Steering Group to ensure fairness and consistency for
all those covered by it, regardless of their individual differences, and the results are shown in
Appendix A.


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Contents

Paragraph                                                                                                 Page

                  Executive Summary                                                                         3
         1        Introduction                                                                              4
      1.2         Scope                                                                                     4
      1.3         Purpose (objectives and intended outcomes)                                                4
      1.4         Definitions                                                                               5
      1.5         Assessment of Adverse Events                                                              8
         2        Related Trust Policies                                                                    9
         3        Roles and Responsibilities                                                                9
      3.1         All Staff                                                                                 9
      3.2         Investigator Responsibilities                                                             9
      3.3         R&D Department Responsibilities                                                           14
         4        Implementation                                                                            16
         5        Process for Monitoring Compliance/Effectiveness                                           16
         6        Arrangements for review of the policy                                                     16
         7        References                                                                                16

Appendices

 Appendix A       Equality Impact Assessment
 Appendix B       Guidance on content of annual safety reports
Appendix C        SUHT Weblink to relevant Adverse Event procedures and forms




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Executive Summary
This policy sets out the definitions of adverse events related to research, the responsibilities
of investigators and the R&D Department with regard to managing, documenting, and
reporting these in an effective and timely manner. The Policy aims to ensure the safety and
well-being of research participants, research staff and those visiting the research premises.




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1.       Introduction

         The Trust Board is committed to supporting the effective and timely reporting and
         investigation of any adverse incident/accident that occurs involving patients,
         employees or other persons on the Trust premises or business, including visitors and
         contractors. To this end the Trust Board has put the ‘Incident Reporting and
         Management Policy’ in place.

1.1      Overview

         In 2001 the Government published the Research Governance Framework for Health
         and Social Care (as amended). Enquiries into adverse incidents relating to research
         have criticised the lack of clarity in relation to responsibilities and accountabilities for
         research in health and social care. This is of particular importance given the very
         wide range of individuals and organisations that can be involved in research. The
         Framework pays particular attention to clarifying responsibilities and accountabilities
         with the aim of forestalling research related adverse incidents.

         The Medicines for Human Use (Clinical Trials) Regulations 2004 came into force on
         the 1st May 2004. These regulations apply to all clinical trials involving investigational
         medicinal products (IMPs) and specify the reporting requirements for research
         related adverse events. To breach these requirements constitutes a breach in
         criminal law. These requirements have been incorporated within this policy.

1.2      Scope

         Recording and reporting of Research Related Adverse Events, including Adverse
         Reactions, Adverse Device Effects, Serious Adverse Events, Serious Adverse
         Reactions, Serious Adverse Device Effects, Suspected Unexpected Serious Adverse
         Reactions and Unanticipated Serious Adverse Device Effects will be managed in line
         with the reporting policy of the Sponsor of a research study.

         Where SUHT is the Sponsor or Co-Sponsor, where no Sponsor policy exists, or
         where the minimum reporting requirements laid out within the SUHT Research
         Related Adverse Event Reporting Policy are not met, the SUHT policy must be
         followed as a minimum.

1.3      Purpose (objectives and intended outcomes)

         In accordance with the Research Governance Framework for Health and Social Care
         and the Medicines for Human Use (Clinical Trial) Regulations, organisations hosting
         and Sponsoring research must have systems in place that allow to give “the safety of
         participants and of research and other staff […] priority at all times, and [ensure that]
         health and safety regulations [are] strictly observed – including the provision of
         information, containment, shielding and monitoring as required.”

         For these reasons SUHT has implemented this policy in addition to the Incident
         Reporting and Management Policy to record, investigate and report adverse
         incidents arising specifically from any research undertaken within the Trust.



         This policy seeks to:

         define adverse events and levels of severity (AE, SAE, SUSAR, SSAR, SADE,
         USADE)

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         define research investigator responsibilities in managing an adverse event
         set time frames for immediate and periodical reporting of adverse events
         define the assessment criteria for adverse events (intensity, causality, expectedness,
         seriousness)
         define the responsibilities of SUHT R&D


1.4      Definitions


         AI                  Adverse Incident

         AE                  Adverse Event

         AR                  Adverse Reaction

         ADE                 Adverse Device Effect

         CTIMP               Clinical Trial of an Investigational Medicinal Product

         IMP                 Investigational Medicinal Product

         MDI                 Medical Device Investigation (acronyms not commonly used)

         MHRA                Medicines and Healthcare products Regulatory Agency

         R&D                 Research and Development Department

         REC                 Research Ethics Committee

         SAE                 Serious Adverse Event

         SADE                Serious Adverse Device Effect

         SAR                 Serious Adverse Reaction

         SSAR                Suspected Serious Adverse Reaction

         SUSAR               Suspected Unexpected Serious Adverse Reaction

         USADE               Unanticipated Serious Adverse Device Effect

         An Investigational Medicinal Product is a pharmaceutical form of an active
         substance or placebo being tested or used as a reference in a clinical trial including a
         medicinal product which has a marketing authorisation but is, for the purposes of the
         trial, being used or assembled (formulated or packaged) in a way different from the
         approved form or being used for an unapproved indication or when used to gain
         further information about an approved use.

         A Medical Device means any instrument, apparatus, appliance, material or other
         article, whether used alone or in combination, including the software necessary for its
         proper application intended by the manufacturer to be used for human beings for the
         purpose of:
             a) diagnosis, prevention, monitoring, treatment or alleviation of disease,
             b) diagnosis, monitoring, treatment, alleviation of or compensation for an injury

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                or handicap,
             c) investigation, replacement or modification of the anatomy or of a physiological
                process,
             d) control of conception,

         and which does not achieve its principal intended action in or on the human body by
         pharmacological, immunological or metabolic means, but which may be assisted in
         its function by such means.

         A Research Ethics Committee (REC) must be authorised under the Governance
         Arrangement for Research Ethics Committees (GAfREC). RECs conducting ethical
         reviews of clinical trials of investigational medicinal products (CTIMPs) must in
         addition be recognised by the United Kingdom Ethics Committee Authority (UKECA).

         An adverse incident (AI) is any incident/accident, near miss or untoward event
         which had or may have had, the potential to cause harm, dissatisfaction or injury to
         persons, loss or damage to property. In clinical terms, an adverse event is any
         occurrence, which did or could have resulted in unintended or unexpected harm to
         one or more participants(s). This definition includes hazards, accident, ill health,
         dangerous occurrences and near misses.

         An adverse event (AE) is any untoward medical occurrence in a subject to whom a
         medicinal product/medical device/intervention has been administered, including
         occurrences which are not necessarily caused by or related to that product.

         Comment: An adverse event can therefore be any unfavourable and unintended sign
         (including abnormal lab results, traffic accident, pregnancy), symptom or disease
         temporally associated with the use of the medicinal product/medical
         device/intervention, whether or not considered to be related to the medicinal
         product/medical device/intervention.

         An adverse reaction (AR) is any untoward and unintended response in a subject to
         an investigational medicinal product/medical device/intervention which is related to
         any dose administered to that subject.

         Comment: Any adverse event judged by either the reporting investigator or the
         Sponsor as having reasonable causal relationship to a medicinal product/medical
         device/intervention qualifies as an adverse reaction; there is evidence or argument to
         suggest a causal relationship. All adverse reactions are adverse events.

         An adverse device effect/incident (ADE) is any malfunction or deterioration in the
         characteristics and/or performance of a device, as well as any inadequacy in the
         labelling or the instructions for use which might lead to or might have led to
         endangering the health of a patient or the device user.

         Comment: The EU Medical Device Directive 93/42 and UK’s Medical Device
         Regulations 2002:618 (as amended) currently do not provide a common terminology
         and definition, both “effect” and “incident” are used. The ISO 14155-2:2003 Clinical
         investigation of medical devices for human subjects -- Part 2: Clinical investigation
         plans uses the term “effect”. Unless the study Sponsor requests otherwise, for SUHT
         recording and reporting purposes the term “effect” should be used.

         An unexpected adverse reaction is an adverse reaction the nature and severity of
         which is not consistent with the information about the medicinal product or
         intervention in question set out:



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         (a) in the case of a product with a marketing authorisation, in the Summary of
         Product Characteristics (SmPC) for that product,
         (b) in the case of any other investigational medicinal product, in the Investigator's
         Brochure (IB).

         Comment: When the outcome of the adverse reaction is not consistent with the
         applicable product information this adverse reaction should be considered as
         unexpected. All unexpected adverse reactions are adverse events.

         An adverse event, adverse reaction, unexpected adverse reaction, adverse
         device effect is defined as serious if it:

              a)   results in death,
              b)   is life-threatening,
              c)   requires hospitalisation or prolongation of existing hospitalisation,
              d)   results in persistent or significant disability or incapacity,
              e)   consists of a congenital anomaly or birth defect.

         Comment: Life threatening in the definition of an SAE/SAR/SADE refers to an event
         in which the subject was at risk of death at the time of the event; it does not refer to
         an event that hypothetically might have caused death if it were more severe. Medical
         judgement should be exercised in deciding whether an SAE/SAR/SADE is serious in
         other situations. Important SAE/SAR/SADEs that are not immediately life-threatening
         or do not result in death or hospitalisation but may jeopardise the subject or may
         require intervention to prevent one or the other outcomes listed in the definition
         above, should also be considered serious.

         A suspected serious adverse reaction (SSAR), is any serious adverse reaction
         that is suspected (possibly or probably) to be related to the investigational medicinal
         product/medical device/intervention.

         A suspected unexpected serious adverse reaction (SUSAR) is an SSAR which is
         also “unexpected”, meaning that its nature and severity are not consistent with the
         information about the medicinal product in question set out:

         a)        in the case of a product with a marketing authorisation, in the summary of
                   product characteristics for that product
         b)        in the case of any other investigational medicinal product, in the investigator’s
                   brochure relating to the trial in question.

         A non-IMP SUSAR is an SAE that occurs in a non-IMP trial and is:
         a)     “Related” – that is, possibly, probably or definitely resulted from administration
                of any of the research procedures, and
         b)     “Unexpected” – that is, the type of event is not listed in the protocol as an
                expected occurrence.

         An Unanticipated Serious Adverse Device Effect (USADE) is an untoward
         medical occurrence that happens in a subject or other person; which is related to the
         investigational device, device procedure, or comparator; which is serious and was
         unanticipated.




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1.5      Assessment of Adverse Events

         Intensity
         The assessment of intensity will be based on the investigator’s clinical judgement
         using the following definitions:
         • Mild: An event that is easily tolerated by the participant, causing minimal
                 discomfort and not interfering with everyday activities.
         • Moderate: An event that is sufficiently discomforting to interfere with normal
                 everyday activities.
         • Severe: An event that prevents normal everyday activities.

         Comment: The term severity is often used to describe the intensity (severity) of a
         specific event. This is not the same as ‘seriousness’, which is based on
         participant/event outcome or action criteria.

         Causality
         The relationship between the drug/device/procedure and the occurrence of each
         adverse event will be assessed and categorised as below. The investigator will use
         clinical judgement to determine the relationship. Alternative causes, such as natural
         history of the underlying diseases, concomitant therapy, other risk factors etc. will be
         considered. The Investigator will also consult the Investigator Brochure or other
         product information.
         • Not related: Temporal relationship of the onset of the event, relative to
                    administration of the product, is not reasonable or another cause can by
                    itself explain the occurrence of the event.
         • Unlikely: Temporal relationship of the onset of the event, relative to
                    administration of the product, is likely to have another cause which can by
                    itself explain the occurrence of the event.
         • *Possibly related: Temporal relationship of the onset of the event, relative to
                    administration of the product, is reasonable but the event could have been
                    due to another, equally likely cause.
         • *Probably related: Temporal relationship of the onset of the event, relative to
                    administration of the product, is reasonable and the event is more likely
                    explained by the product than any other cause.
         • *Definitely related: Temporal relationship of the onset of the event, relative to
                    administration of the product, is reasonable and there is no other cause to
                    explain the event, or a re-challenge (if feasible) is positive.

         *Where an event is assessed as possibly related, probably related, definitely
         related the event is an adverse reaction.

         Expectedness
         Adverse reactions must be considered as unexpected if they add significant
         information on the specificity or severity of an expected adverse reaction. The
         expectedness of an adverse reaction shall be determined according to the reference
         documents as defined in the study protocol (e.g. investigator brochure or marketing
         information).
         • Expected: Reaction previously identified and described in protocol and/or
                  reference documents e.g. Investigator Brochure, Summary of Product
                  Characteristics (SmPC).
         • Unexpected: Reaction not previously described in the protocol or reference
                  documents.

         NB The protocol must identify the reference documentation used.



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         Seriousness
         An event is considered serious if it meets one or more of the following criteria:
         • Results in death.
         • Is life-threatening.
         • Requires hospitalisation or prolongation of existing hospitalisation.
         • Results in persistent or significant disability or incapacity.
         • Consists of a congenital anomaly or birth defect.


2        Related Trust Policies


         Incident Reporting and Management Policy
         Research and Development General Policy



3        Roles and Responsibilities

3.1      All Staff

         All staff are responsible for ensuring that all adverse incidents, whether or not related
         to research, are reported in accordance with the SUHT Incident Reporting &
         Management Policy..


3.2      Investigator Responsibilities
         A flow diagram summarising the Investigator’s responsibilities is available on the
         SUHT R&D web site. R&D Information Sheet – Adverse Events: Investigator
         responsibilities.

         The Investigator must ensure that the dignity, rights, safety and well being of subjects
         are given priority at all times and must take appropriate action to ensure the safety of
         all staff and participants in the study. The Investigator will consider what actions, if
         any, are required and in what timeframe following the requirements set in this policy.

         Action necessitating substantial amendments to the research protocol will require
         ethical, R&D and MHRA (IMP trials and non-CE marked devices investigations)
         approval through the usual routes. Amendments requiring immediate changes to the
         protocol (e.g. urgent safety measures) will be implemented and thereafter submitted
         for ethical, R&D and MHRA approval. The initial notification to the REC should be by
         telephone. Notice in writing to REC, hosting R&D and MHRA should be sent within
         three days. The notice should set out the reasons for the urgent safety measures and
         plan for further action.

         In the event of an adverse event/reaction, the investigator (or delegated member of
         research team) must review all documentation (e.g. hospital notes, laboratory and
         diagnostic reports) relevant to the event. The event and relevant comments must
         then be recorded in the subject’s medical notes (or source data where this is not
         the medical notes).

         Except where the protocol states otherwise and has exempted certain events from
         recording or escalated reporting, all adverse event/reactions must be recorded in
         detail on a case report form or equivalent to allow analysis at a later stage. A
         template for recording adverse events is provided in the forms that accompany this


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         policy which are available on the SUHTranet (Form 1 - SUHT Investigator’s Template
         for recording Research Adverse Events).

         For all adverse event/reactions the investigator will make an assessment of
         intensity, causality, expectedness and seriousness. Detailed guidance on making
         this assessment is given in section 1.4. A short assessment for the internal purposes
         of the research team is provided in the forms that accompany this policy which are
         available on the SUHTranet (Form 1 - SUHT Investigator’s Template for recording
         Research Adverse Events).

         Adverse events and/or laboratory abnormalities identified in the protocol as
         critical to the evaluations of the safety of the study shall be reported to the Sponsor
         in accordance with the reporting requirements documented in the protocol.

         The Chief Investigator will keep the Sponsor, the REC and MHRA (where applicable)
         informed of any significant findings and recommendations by an independent Data
         Monitoring Committee or equivalent body where one has been established for the
         trial.

         At the conclusion of the study all adverse events/reactions/device effects,
         recorded during a study must be subject to statistical analysis and that analysis and
         subsequent conclusions included in the final study report.




         Expedited Reporting of Serious Adverse Events/Serious Adverse Device
         Effects

         Researchers must ensure that all patient safety related incidents must always be
         reported according to the Trust’s Incident Reporting and Management Policy.

         In addition to the trust Incident reporting, serious adverse events are expedited to the
         people and departments identified below. The only exception is where the protocol or
         Investigator’s Brochure identifies an event as not requiring immediate expedited
         reporting.

          SUSAR/               Immediately report to:           The investigator (or delegated person) will
          USADE                                                 make an initial report, orally or in writing. The
                                    the Chief
                                                                initial report will include as much information
                                    Investigator
                                                                as is available at the time.
                                    the Sponsor                 Oral reports will be followed up in writing
                                    the hosting R&D             within a further 24 hours of the initial report.
                                    Department




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                                    SUHT Patient
                                                                After the initial report the investigator is
                                    Safety team (using
                                                                required actively to follow up the subject. The
                                    Trust incident
                                                                investigator (or delegated person) will provide
                                    reporting form)
                                                                information missing from the initial report
                                    any other persons           within five working days of the initial report.
                                    or bodies specified
                                    in the protocol (e.g.       Written reports will be made by completing an
                                    Data Safety                 SAE/SUSAR reporting form provided by the
                                    Monitoring Board)           Sponsor of the research study. In addition,
                                    the University of           the REC receives a completed NRES CTIMP
                                    Southampton (if             Safety Report to REC
                                    involved)
                                                                http://www.nres.npsa.nhs.uk/applications/afte
                                                                r-ethical-review/safetyreports/safety-reports-
                                                                for-ctimps/#safetyCTIMPsSubmission
                               Sponsor responsible to
                               further expedite the             SUHT Incident report template available from
                               reporting of                     SUHTranet or Departmental log books
                               SUSAR/USADE to the
                               MHRA and REC that
                               gave approval as soon            Where SUHT is the Sponsor or Co-Sponsor
                               as possible but within           or where no form has been provided, the
                               7 days                           investigator will use Form 2 - Research
                                                                Related SAE/SUSAR Initial Report Form
                                                                provided in the forms that accompany this
                                                                policy and available on the SUHTranet.
                                                                (Where SUHT is both the Sponsor or Co-
                                                                Sponsor and the host organisation, only one
                                                                report needs be sent to the SUHT R&D
                                                                Department).
          SAE/                 Within 24 hours report As above; but no expedited reporting by the
          SADE                 to:                    Sponsor to the MHRA and REC.

                                    the Chief
                                    Investigator
                                    the Sponsor
                                    the hosting R&D
                                    Department
                                    SUHT Patient
                                    Safety team (using
                                    Trust incident
                                    reporting form)


                                    any other persons
                                    or bodies specified
                                    in the protocol (e.g.
                                    Data Safety
                                    Monitoring Board)
          Urgent Safety        Implement and report             The Sponsor and the Chief Investigator must
          Measures/            immediately as a                 be notified of any urgent safety
          Temporary            substantial                      measures/temporary halt of a trial that have
          Halt of a Trial      amendment to:                    had to be taken that are not part of the
                                                                protocol.

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                                    the Chief                   The report must include the reasons for the
                                    Investigator                urgent safety measure and the plan for
                                    the Sponsor                 further action. The standard CTIMP
                                                                substantial amendment form must be used,
                                                                as available from MHRA/NRES websites.
                               The Chief Investigator           http://www.nres.npsa.nhs.uk/applications/afte
                               must inform as soon              r-ethical-review/amendments/
                               as possible but within
                               3 days:                          Where SUHT is both the Sponsor or Co-
                                  the MHRA                      Sponsor and the host organisation only one
                                  the REC that                  report need be sent to the SUHT R&D
                                  granted approval              Department.
                                  any other persons
                                  or bodies specified
                                  in the protocol (e.g.
                                  Data Safety
                                  Monitoring Board)
                                  the hosting R&D
                                  Department
                                  the University of
                                  Southampton (if
                                  involved)



         Investigators (or delegated persons) will provide follow-up information, each time new
         information is available, using Form 3 - Research Related SAE/SUSAR Follow Up
         Report Form provided in the forms that accompany this policy and available on the
         SUHTranet, until the SAE/SADE has resolved or a decision for no further follow-up
         has been taken by the PI or delegated person.

         For all studies the Chief Investigator will inform all Principal Investigators of relevant
         information about SAEs/SADEs that could adversely affect the safety of subjects.

         The Chief Investigator will provide the main REC with copies of all reports and
         recommendations of any independent Data Safety Monitoring Board established for a
         trial as part of the SUSAR/USADE expedited or periodic reporting.

         For IMP/Medical Device studies, on request of the MHRA the Chief Investigator will
         submit detailed records of all adverse events that have been reported.



         Periodic Safety Reporting

         Copies of all annual and end of study reports must be provided to the SUHT R&D
         Office at the time of submission to the REC and the MHRA as applicable.

          Six-monthly           Report to:                       The Chief Investigator prepares the Six-
          Safety                  REC that granted               monthly Report to the commercial Sponsor
          Reports for             approval                       on the safety of subjects in all CTIMPs for
          CTIMPs                                                 which the Sponsor is responsible worldwide,
                                                                 summarising any issues affecting safety or
                                Six-monthly safety
                                                                 participants, including a global line listing of
                                reports are only
                                                                 SUSARs occurring in these trials in the
                                required for CTIMPs

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                                where a commercial               reporting period.
                                Sponsor is responsible
                                for trials on the IMP at
                                non-UK sites.
                                CTIMPs falling outside
                                these two criteria only
                                need to report annually.
          Annual               Annual Safety Reports             Each submission of an ASR to the main
          Safety               (ASR) must be provided            REC must be accompanied by the Safety
          Reports for          to:                               Report Form for CTIMPs available at:
          CTIMPs                                                 http://www.nres.npsa.nhs.uk/applications/aft
                                   the MHRA
                                                                 er-ethical-review/safetyreports/safety-
                                   the REC that granted          reports-for-
                                   approval                      ctimps/#safetyCTIMPsSubmission
                                   the hosting R&D
                                   Department                    Annual Safety Reports should contain:
                                   the University of             Analysis of the subjects’ safety in the
                                   Southampton (if               concerned clinical trial(s) with an appraisal
                                   involved)                     of its ongoing risk : benefit.
                               at yearly intervals from          A line listing of all suspected serious
                               the date of the original          adverse reactions (SSAR) (including all
                               CTX/DDX exemption                 SUSARs) that occurred in the concerned
                               (for trials ongoing               trial(s), including all serious adverse
                               on/before 1 May 2004),            reactions from third countries.
                               or the date of the CTA            An aggregate summary tabulation of
                               approval (for trials              suspected serious adverse reactions that
                               starting after 1 May              occurred in the concerned trial(s).
                               2004). For trials with
                               marketed products, the            Where SUHT is the Sponsor or Co-Sponsor
                               date is the first                 or where no form has been provided, the
                               marketing authorisation           investigator will use Form 5- Six-Monthly /
                               granted in the EU.                Annual Safety Report Form - IMP Studies –
                                                                 SUHT Sponsor/Co-Sponsor provided in the
                                                                 forms that accompany this policy and
                                                                 available on the SUHTranet.

          Annual               All studies submit an             For CTIMPs, Chief Investigators submit the
          Progress             annual progress report            Annual Progress Report in addition to the
          Reports for          to:                               Annual Safety Report, using the specific
          all research                                           “CTIMP Annual Progress Report Form”
                                   the REC that granted
          studies                                                http://www.nres.npsa.nhs.uk/applications/aft
                                   approval
                                                                 er-ethical-review/annual-progress-reports/
                                   the Sponsor
                                                            Non-CTIMPs include any safety information,
                                   the hosting R&D
                                                            and SAE line listing within the Annual
                                   Department
                                                            Progress Report using the specific “Annual
                                                            Progress Report form for all other research”
                                                            http://www.nres.npsa.nhs.uk/applications/aft
                                                            er-ethical-review/annual-progress-
                                                            reports/#progressForms
                               For blinded studies where SUHT is Sponsor or Co-Sponsor, in
                               compiling these reports, at the request of the Chief Investigator the
                               R&D Department will provide any additional information required
                               relating to the Sponsor’s assessment of SAEs. The R&D Department
                               will take all reasonable efforts to ensure that no information that could

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                       unblind and therefore compromise the study is provided directly to the
                       Chief Investigator.
          End of Study Chief Investigator will  The report should include information on
          Report non-  submit an end of study   whether the study achieved its objectives,
          CTIMP/other  report to:               the main findings and arrangements for
          research                              publication or dissemination, including
                           Sponsor (where
                                                feedback to participants.
                           SUHT is the Sponsor
                           or Co-Sponsor this   http://www.nres.npsa.nhs.uk/applications/aft
                           will be the R&D      er-ethical-
                           Department).         review/endofstudy/#endofstudyDeclaring
                           REC that granted
                           approval
          End of Study Within 90 days from      Chief Investigator submits End of Trial
          Report CTIMP conclusion (or 15 days   Declaration from EudraCT website
                       in case of early         https://eudract.emea.europa.eu/eudract/ind
                       termination) the Chief   ex.do
                       Investigator will submit
                       an end of study report
                       to:
                           the Sponsor (where
                           SUHT is the Sponsor
                           or Co-Sponsor this
                           will be the R&D
                           Department)
                           the MHRA
                           the REC that granted
                           approval
                           the hosting R&D
                           Department



3.3       R&D Department Responsibilities

         A flow diagram summarising the R&D Department’s responsibilities is available on
         the SUHT R&D web site. R&D Information Sheet – Adverse Events: R&D
         responsibilities

         On receipt of a SAE/SUSAR Report Form the R&D Department will assess whether
         SUHT is the Sponsor or Co-Sponsor and whether there is University of Southampton
         staff/student involvement.

         Where SUHT is NOT the Sponsor or Co-Sponsor the R&D Department will remind
         the research team to inform the Sponsor.



         Where there is university involvement the R&D Department will inform the University
         of Southampton Research Governance Office.



         Where SUHT is the Sponsor or Co-Sponsor of a blinded research study, in which the
         SAE/SUSAR/SADE/USADE has occurred, where a member of the research team is
         unable to make a blinded assessment, the R&D Department will make an unblinded
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         assessment of intensity, causality, expectedness and seriousness using the criteria
         described in this policy. In making this assessment the R&D Department will consult
         the independent Data Safety Monitoring Board (DSMB) for the study or, where a
         DSMB does not exist, a suitably medically qualified person (refer to R&D Department
         internal SOP Recording and Reporting SAEs/SUSARs). This unblinded assessor
         may be an investigator on the same study if unblinding him/her will not affect the
         conduct of the study in which the SAE has occurred; this will not be the person who
         made the initial assessment.

         NB A second assessment by the Sponsor is not required where the investigator
         making the initial assessment is already unblinded.

         The R&D Department will consider whether any further actions, in addition to those
         already taken by the investigator, are required and will discuss these with the
         Investigator.

         The R&D Department reserves the right to suspend or withdraw approval for a study.
         This may happen, but is not limited to, where public health and safety is considered
         to be at risk, where the safety and well being of research subjects or staff are
         considered to be at risk.


         Non-IMP SUSARs

         Where SUHT is the Sponsor or Co-Sponsor of a blinded non-IMP study, the R&D
         Department will report all SAEs that are assessed as non-IMP SUSARs by either the
         investigator or the un-blinded assessor to the research ethics committee that granted
         approval within 15 days using the NRES Report of Serious Adverse Event form
         available at: http://www.nres.npsa.nhs.uk/applications/after-ethical-
         review/safetyreports/safety-reports-for-all-other-research/#safetynonCTIMPSAEs


         IMP SUSARs

         This section applies only where SUHT is the Sponsor or Co-Sponsor of the research
         study using an IMP in which the SAE has occurred and where the investigator and/or
         Sponsor has assessed the SAE to be a SUSAR.

         The R&D Department as the Sponsor’s representative will report all SUSARs to:
         • The Medicines and Healthcare products Regulatory Agency (MHRA)
         • The competent authorities (equivalent of MHRA) of any EEA State, other than the
            United Kingdom, in which the trial is being conducted
         • The REC that granted approval.1

         SUHT will report within seven days of becoming aware of the event where these are
         fatal or life-threatening and within 15 days where the SUSAR was not assessed
         as life threatening or fatal.




         1
           In the case of the main REC, SUHT is only required to report in an expedited fashion SUSARs
         occurring in the UK.



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         The R&D Department will report any additional relevant information to the bodies
         described above within eight days of the last report.

         Initial notifications of SUSARs may be made by fax, e-mail or telephone. Follow-up
         reports and all other safety reports should be sent to the REC office by post.

         Each submission of a SUSAR Sponsor report form to the main REC must be
         accompanied by the NRES Safety Report form for CTIMPs available at:
         http://www.nres.npsa.nhs.uk/applications/after-ethical-review/safetyreports/safety-
         reports-for-ctimps/#safetyCTIMPsSubmission

         A Single form may be used for the submission of several safety reports relating to the
         same trial. Reports should not normally cover more than one trial. However, the
         REC may permit this where two trials are very closely connected, for example a main
         study and an extension study with the same treatment regime.



         Annual Safety, Annual Progress and End of Study Reports

         Where SUHT is Sponsor or Co-Sponsor, at the request of the Chief Investigator the
         R&D Department will assist the Chief Investigator in compiling the Annual Safety,
         Annual Progress and End of Study Reports. In meeting such requests the R&D
         Department will take all reasonable efforts to ensure that no information that could
         unblind and therefore compromise the study is provided directly to the Chief
         Investigator, unless the Chief Investigator is already unblinded.




4.       Implementation

This was originally implemented in July 2006. The most up-to-date version is available on
the Trust’s internal and external websites and upon request directly from the R&D
Department. The core aspects of this policy form part of the Trust’s Research Governance
and Good Clinical Practice training for researchers.



5.       Process for Monitoring Compliance/Effectiveness

The compliance and effectiveness of this policy will be monitored by the R&D department
through the routine monitoring programme detailed as required in the relevant sections of
the SUHT R&D General Policy and in accordance with the R&D monitoring standard
operating procedure available upon request from the R&D Department.

Non-compliance with a Trust Policy, Procedure, PGD, protocol or participant information
standard may result in disciplinary action.



6.       Arrangements for review of the policy

This policy is to be reviewed every two years, or sooner if applicable in line with SUHT policy
review schedules. The review is conducted by the R&D Department.




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7.       References

COUNCIL DIRECTIVE 93/42/EEC of 14 June 1993 concerning medical devices; http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31993L0042:en:HTML and
http://ec.europa.eu/enterprise/sectors/medical-devices/regulatory-framework/legislation/

Department of Health: Research governance framework for health and social care: Second
edition, 24 April 2005,
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidan
ce/DH_4108962

EudraLex - Volume 10 Clinical trials guidelines, Chapter II: Monitoring and
Pharmacovigilance;
http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-
10/index_en.htm#h2-chapter-ii:-monitoring-and-pharmacovigilance

         •   Detailed guidance on the collection, verification and presentation of adverse reaction
             reports arising from clinical trials on medicinal products for human use [87 KB]
             (revision 2 of April 2006)
         •   Detailed guidance on the European database of Suspected Unexpected Serious Adverse
             Reactions (Eudravigilance - Clinical Trial Module)      [114 KB] (revision 1 of April 2004)
         •   Questions & Answers specific to adverse reaction reporting in clinical trials           [102 KB]
             (December 2009)

ISO 14155-2:2003 Clinical investigation of medical devices for human subjects -- Part 2:
Clinical investigation plans; http://www.iso.org/iso/catalogue_detail?csnumber=32217

Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No.
1031; http://www.opsi.gov.uk/si/si2004/20041031.htm#33

Medical Devices Regulations 2002, Statutory Instrument 2002:0618;
http://www.opsi.gov.uk/si/si2002/20020618.htm

National Research Ethics Service: (website) Safety Reports
http://www.nres.npsa.nhs.uk/applications/after-ethical-review/safetyreports/ (accessed 16
May 2010)

Stark, Nancy J.: “Can you handle the truth?” A New Standard for Medical Device Adverse
Event Classification, Journal of Clinical Research Best Practices, vol. 5, no. 12, December
2009; http://firstclinical.com/journal/2009/0912_ISO_14155.pdf


Acknowledgements:

R&E Department
United Bristol Healthcare Trust

Ms Tanya Symons
T Symons Associates Ltd. 154 Tivoli Crescent North, Brighton, East Sussex.




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Appendix A: Equality Impact Assessment



Provided as a separate document




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Appendix B: Guidance on content of annual safety reports



Where SUHT is the Sponsor or Co-Sponsor or where no form has been provided by the
Sponsor organisation, the investigator will use Form 3 - Research Related SAE/SUSAR
Initial Report Form provided in the forms that accompany this policy and available on the
SUHTranet.



The annual safety report of a clinical trial should include:

             •    A report on the subjects’ safety in the concerned clinical trial.
             •    A line listing of all suspected SSARs (including all SUSARs) occurred in the
                  concerned trial.



1. Report on the subjects’ safety of a clinical trial

    Based on the information provided by investigators and the Sponsor’s own assessments,
    the Sponsor will report all new findings related to the safety of the IMP treatments in the
    concerned trial. The concept of new findings refers to information not already present in
    the investigator’s brochure or, for licensed drugs, the summary of product characteristics.
    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, the
        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

    The report should also consider other experiences with the investigational medicinal
    product that are likely to affect the subjects' safety. It should detail the measures
    previously or currently proposed to minimise the risks found where appropriate. Finally, a
    rationale must be given on 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. This report will not replace the request for protocol amendments, which will
    follow its own specific procedure.


2. Line-listings

    The annual report should contain a trial-specific line-listing of all reports of Suspected
    SARs that were reported during this trial. The line listing provides key information but not
    necessarily all the details usually collected on individual cases. It 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

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    should be listed under the most serious adverse reaction (sign, symptom or diagnosis)
    as judged by the Sponsor. It is possible that the same subject may experience different
    adverse reactions on different occasions. Such experiences should be treated as
    separate reports. In 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 system organ
    classification scheme). The line listing identifiable by the Sponsor listing reference
    number or date and time of printing should include the information per case as described
    in 2.1. 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 case that in the same trial for different formulations, indications or
    routes of administration are studied.



    2.1 Content of line listing

    The line listing identifiable by the Sponsor listing reference number or date and time of
    printing should include the following information per case:

    (a) clinical trial identification
    (b) Study subjects identification number in the trial
    (c) case reference number (Case-ID-Number) in the Sponsor’s safety database for
        medicinal products
    (d) country in which case occurred
    (e) age and sex of trial subject
    (f) daily dose of Investigational Medicinal Product, (and, when relevant, dosage form
        and route of administration)
    (g) date of onset of the adverse reaction. If not available, best estimate of time to onset
        from therapy initiation. For an ADR known to occur after cessation of therapy,
        estimate of time lag if possible.
    (h) dates of treatment (if not available, best estimate of treatment duration.)
    (i) adverse reaction: description of reaction as reported, and when necessary as
        interpreted by the Sponsor, where medically appropriate, signs and symptoms can
        be lumped into diagnoses. MedDRA (Medical Dictionary for Regulatory Activities
        http://www.meddramsso.com/ ) should be used.
    (j) patient’s outcome (e.g. resolved, fatal, improved, sequelae, unknown). This field
        should indicate the consequences of the reaction(s) for the patient, using the worst of
        the different outcomes for multiple reactions
    (k) comments, if relevant (e.g. causality assessment if the Sponsor disagrees with the
        reporter; concomitant medications suspected to play a role in the reactions directly or
        by interaction; indication treated with suspect drug(s); dechallenge/rechallenge
        results if available)
    (l) unblinding results in the case of unblinded SUSARs expectedness at the time of the
        occurrence of the Suspected SARs, assessed with the reference document (i.e.
        investigator’s brochure) in force at the beginning of the period covered by the report.




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Appendix C: SUHT Weblink to relevant Adverse Event procedures and forms




http://www.suht.nhs.uk/Research/Researchers/ResearchGovernance/SafetyReportingRequir
ements.aspx




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