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

Transcription

1 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 1 of 19 Standard Operating Procedure for the Recording, Management and Reporting of Adverse Events by Investigators SOP Number: Effective Date: 12/12/13 Version Number & Date of Authorisation: V06, 11/11/13 Review Date: 12/12/16 SOP edocument Kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Investigator SOP\INV_S05_SOP for AE_SAE Reporting by Inv & ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Revision Chronology: SOP ID Number Effective Date Reason for Change CRN/04/S05/00 09/09/2004 N/A BRD/04/S05/01 20/04/2005 BRD/04/S05/02 25/10/2005 JBRU/07/S07/00 18/06/2007 JBRU/07/S07/01 20/12/2007 JBRU/INV/S05/02 JBRU/INV/S05/03 28/10/ /01/2010 Administrative changes i.e. address update. UCL CRN to UCL Biomedicine R&D Unit. Removal of UCL SAE Follow-up Form. Update of UCL SAE Reporting Form. Administrative changes i.e. UCL logo. Additional text P2 to clarify version number, plus addition of CI expectedness evaluation, changes in staff titles. Implementation of the Joint UCL/UCLH Biomedical Research Unit, clarification of definitions, inclusion of pregnancy, unblinding, update SAE report form, overdose reporting and a new numbering system. Update SOP in response to MHRA Inspection to ensure all AE/Rs are recorded and reported accordingly. In particular procedure for pregnancy reporting has been updated. To make SOP specific to investigator responsibilities and clarify reports on deaths. To implement a new JBRU numbering system as reflected in SOP on SOPs JBRU/INT/S01/02 To amend the SAE form and provide alternatives in the absence of the Senior Pharmacovigilance Co. format amended in line with revised SOP on Author Yvanne Enever Yvanne Enever Yvanne Enever Farhat Gilani Farhat Gilani Joanna Galea- Lauri Anne Marie Downey Page 1 of 19

2 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 2 of 19 SOPs to incorporate a UCL logo only, an Acronyms table, edocument file path, associated templates/log table, SOP dissemination and training and a signature page. JRO/INV/S05/04 11/01/2012 Update SOP to reflect current system including e- SUSAR reporting, SPC review, DSUR, Drug Alerts and Safety Warnings, Safety Management Plan, Overdose and Sponsor Oversight. Farhat Gilani JRO/INV/SO5/05 16/06/2012 Administration update and removal of forms from SOP. Farhat Gilani JRO/INV/SO5/06 12/12/13 Formatting and administration changes Farhat Gilani Page 2 of 19

3 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 3 of 19 ACRONYMS: AE AR CI CRF CTIMP DSMC DSUR e-susar GCP IB IDMC IMP IMPD ISF JRO NRES PI PV SAE SAR SI SPC SOP SRA SUSAR TMF Adverse Event Adverse Reaction Chief Investigator Case Report Form Clinical Trial Investigational Medicinal Product Data Safety Monitoring Committee Development Safety Update Report MHRA Electronic SUSAR Good Clinical Practice Investigator s Brochure Independent Data Monitoring Committee Investigational Medicinal Product Investigational Medicinal Product Dossier Investigator Site File Joint Research Office National Research Ethics Service Principal Investigator Pharmacovigilance Serious Adverse Event Serious Adverse Reaction Statutory Instrument Summary of Product Characteristics Standard Operating Procedure Sponsor Regulatory Advisor Suspected Unexpected Serious Adverse Reaction Trial Master File Page 3 of 19

4 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 4 of 19 Standard Operating Procedure for the Recording, Management and Reporting of Adverse Events by Investigators 1. PURPOSE This Standard Operating Procedure (SOP) has been written to describe 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) which occur in subjects participating in Clinical Trials of Investigational Medicinal Products (CTIMPs). It will further describe the procedure for safety reference document updates, safety alerts; drug recall, management of pregnancy and overdose reports. 2. JOINT RESEARCH OFFICE POLICY All JRO SOPs will be produced, reviewed and approved in accordance with the JRO SOP on SOPs. 3. BACKGROUND All SOPs are written in accordance with applicable GCP requirements as outlined in Directives 2001/20/EC and 2005/28/EC (in the UK, these Directives were transposed into UK law by SI 2004/1031, SI 2006/1928) and subsequent amendments and where applicable incorporates elements of ICH GCP tripartite guidelines (E6). To comply with the UK Regulations which set out the responsibilities of the sponsor, this SOP will focus on the trial site team procedures for the adequate recording, evaluation and reporting of AEs, ARs, SAEs, SARs and SUSARs in trials involving IMPs. It will further outline the Investigator s responsibilities to ensure oversight and management of pharmacovigilance systems in UCL sponsored trials. For convenience, this document will use the term UK Regulations to cover the UK legislation and the EU Clinical Trials Directive (CT3) DEFINITIONS The following definitions have been adapted from the UK regulations: Adverse Event 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. Adverse Reaction (AR) All untoward and unintended responses to an IMP related to any dose administered This definition also covers medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of the product. Page 4 of 19

5 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 5 of 19 The definition implies a reasonable possibility of a causal relationship between the event and the IMP. This means that there are facts (evidence) or arguments to suggest a causal relationship. Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) Any adverse event or reaction in a trial subject that: (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 event. (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. Important Safety Issues 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. Specific Adverse events and/or laboratory abnormalities which are listed in the trial protocol as critical to safety evaluations and requiring reporting 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 (SPC) in the case of a licensed product being used within its licensed dosage and indication. (b) An Investigator s Brochure (IB) or a simplified IMPD in the case of any other IMP or a licensed product being used outside its licensed dosage and indication. Unexpected Adverse Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (SPC or IB). Suspected Unexpected Serious Adverse Reaction (SUSAR) An adverse reaction that is classified in nature as both serious and unexpected. Page 5 of 19

6 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 6 of OTHER SAFETY ISSUES CONSIDERED TO BE SERIOUS IN CLINICAL TRIALS Events which may materially alter the current benefit-risk assessment of an IMP or which could be sufficient to consider changes in the IMP administration or in the overall conduct of the trial may fall into the category of Other Safety Issues and be considered as serious events which will require reporting to the sponsor in a letter headed Safety Report: 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: an SAE which could be associated with the trial procedures and which could modify the conduct of the trial, a significant hazard to the subject population such as lack of efficacy of an IMP used for the treatment of a life-threatening disease, a major safety finding from a newly completed animal study (such as carcinogenicity), 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 to the safety of the subjects. An Other Safety Issue can also fall into the category of Urgent Safety Measures. Please refer to Standard Operating Procedure for the Recording and Reporting of Deviations, Violations, Potential Serious breaches, Serious breaches and Urgent Safety Measures. Details pertaining to an Other Safety Issue will be documented in the DSUR. 3.3 SEVERE ADVERSE EVENT OR REACTION The term severe is often used to describe the intensity of an event or reaction (e.g. mild, moderate or severe) and should not be confused or interchanged with the term serious. 3.4 KEY RESPONSIBILITIES FOR THE INVESTIGATOR This section describes the key pharmacovigilance responsibilities of the investigator, further delegation of these responsibilities to other team members must be documented on the trial delegation log. Safety Reference Documents: The CI must ensure that the trial team are using the most up to date version of safety reference document described in the CTA application and protocol. The CI must also ensure that the team have all reviewed and are familiar with the updated information. 1 The CI must request the updated IB/IMPD from the manufacturer annually for IMP sourced from a manufacturer directly. Please refer to SOP JRO/SPON/S03/ Standard Operating Procedure for creating and maintaining an Investigator s Brochure (IB) for UCL Developed Products for procedures relating to UCL developed products. For trials using SPCs, the CI must ensure they perform a check for updates regularly either by contacting the manufacturer or searching on the following website: The CI must ensure a copy is filed in the TMF/ ISF/ PSF and a copy is forwarded to all sites to PIs and Pharmacies. Page 6 of 19

7 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 7 of 19 The investigator must further ensure that the team are all familiar with the appropriate use of the IMP(s), as described in the protocol, safety reference document and/or IMPD Protocol: The protocol must be written using the JRO UCL protocol template in order that the appropriate pharmacovigilance information is included JRO/INV/S07 AE Recording: All AEs must be recorded in the medical records (if source data) and/or the CRF, SAE forms and AE logs as described in the protocol. AE Assessment: The investigator must assess each event for seriousness, expectedness and causality using the appropriate documentation (protocol and safety reference document). Trend/signal analysis: The CI must ensure the AE log is reviewed regularly. This can be performed by the CI alone or reviewed collectively at trial meetings. These reviews need to be documented. For some Phase I and high risk trials (and if deemed necessary by the Safety Committee for Phase I/II trials), an Independent Data Monitoring Committee may be requested to perform this duty. SAE Reports: The CI must ensure that initial and follow-up SAE reports are sent to the JRO, according to the protocol. AEs of interest: The CI must provide the JRO with details of all AEs identified in the protocol as critical to the evaluation of safety within the agreed timeframes specified in the protocol. Follow-up reports: The CI must supply the JRO with any supplementary information requested as soon as possible in order for the JRO to meet their regulatory timelines. IDMC: For some phase I and high risk trials, an Independent Data Monitoring Committee or Data Safety Committee must be established. In cases of phase I/II trials, advice from the sponsor s Safety Committee may be sought to establish the need of the committee. Members of the IDMC must have signed the UCL IDMC charter. Data Safety Monitoring Committee: Provide the DSMC (if there is one for the trial) with all relevant information required for an independent assessment. 11 Pregnancies: The CI must submit all initial and follow-up pregnancy forms to the JRO Confidentiality: The CI must maintain subject confidentiality at all times. No patient identifiable data is to be sent to the JRO or other external organisations by the PIs. Urgent Safety Measure: The investigator may take appropriate urgent safety measures to protect clinical trial subjects from any immediate hazard to their health and safety. This may be taken immediately. However, following the measure the investigator must follow the SOP on Deviations, serious breaches and urgent safety measures JRO/SPON/S15 DSUR: In conjunction with the JRO, the CI must aid in the production of the DSUR as per SOP on DSURs JRO/SPON/S31 Page 7 of 19

8 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 8 of SCOPE OF THIS SOP What this SOP covers This SOP covers the procedures for the recording, management and reporting of all AEs, ARs, SAEs, SSARs and SUSARs that occur in subjects participating in CTIMPs sponsored by UCL. This document further details pregnancy and overdose reports, safety alerts, safety reference document updates, DSURs and highlights the key PVG responsibilities of the CI. What this SOP doesn t cover In circumstances where the JRO (in its role as a representative or a legal representative of the Sponsor) has delegated the responsibilities to a third party such as a Clinical Research Organisation (CRO) or an external Clinical Trials Unit (CTU), the pharmacovigilance procedures will be outlined in a trial specific agreement between the Sponsor, the CRO and the Chief Investigator. Therefore description of this procedure falls outside the scope of this SOP. 5. RESPONSIBLE PERSONNEL The CI and the individual investigators within a trial team are responsible for keeping records of all adverse events that occur in trial subjects as per protocol. The CI may further delegate who within the trial team is responsible for reporting to the Sponsor. This delegation must be performed on whether trial members are qualified to perform the delegated task. This must be authorised in the delegation log. For international trials: responsibilities will be outlined in the contract between sites, CTU (if appropriate) and Sponsor. 6.PROCEDURE Please ensure that you are using the most recent SOP version by looking up Duration of AE Recording The protocol must clearly define the duration of AE recording. All S/AEs should be recorded and reported within the established off therapy follow-up period for safety described in the protocol. This time period will be defined in the protocol as per the UCL protocol template. 6.2 Which AE to record and which Forms to use? The table below provides guidelines for where to record AE information: Type of Adverse Events All Adverse events All AEs and SAEs (as per protocol) All SAEs (as per protocol) All SAEs (as per protocol) Format of Recording Information Medical Records AE section of CRF AE log SAE report form Page 8 of 19

9 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 9 of Which AE to report to the JRO? All AE/Rs that fulfil the criteria for the definition of serious, whether expected or not, need to be reported to the JRO, unless specified in the protocol. The protocol will list all the expected SAE/Rs that do not need to be reported to the JRO. 6.4 When and how to report Serious AE/Rs to the Sponsor? What needs to be reported within 24 hours? 5. SUSARs 6. Serious adverse events/reactions as defined in section Other Safety Issues. 6.5 When to report other SAE/Rs to the JRO which do not require expedited reporting? Some expected SAE/Rs should be reported to the JRO on the AE log only as per protocol. The timeline for submission will vary depending on the purpose of the trial, toxicity and efficacy endpoints. 6.6 Where to report AEs and SAEs? The SAE Reporting Form, line listings and the Pregnancy Reporting Form must be ed to sae@ucl.ac.uk. The report can alternatively be faxed to the JRO on The trial team must request an acknowledgment of receipt of the report which should be kept with the original form in the TMF. In the event that the form is not acknowledged by the Sponsor s office within 3 days, site must contact relevant members of the sponsor s office to confirm receipt of the report. Most Trusts R&D Departments request the PIs to notify them of the SUSARs occurring within their Trust by sending a copy of the SAE form to the R&D Department. In addition, a number of Trusts will expect SUSARs to be reported to them as incidents via the DATIX system. Subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on all reports in relation to recording and reporting of AEs. No personal identifiable data must be forwarded to the JRO or other external organisations. 6.7 Other reporting arrangements for Multi-Centre Trials For multi-centre trial sponsored by UCL, PIs will report directly to a trial management team at a lead site and the trial Pharmacovigilance responsible person will be responsible for forwarding the report to the JRO within 24 hours of receipt. Trial specific arrangements for SAE management must be documented in the protocol and contractual agreements. 6.8 Evaluation of AE/Rs during the trial The following documents need to be referred to when assessing any AE in the trial: Protocol Safety Reference Document (SPC, IB) Trial specific Procedure for unblinding (if applicable) Each AE must be evaluated for seriousness, causality, severity and expectedness. The treating physician should make these assessments which are documented on the SAE Reporting Form. For multi-sites trials a CI cannot downgrade a PI s assessment of an event but the CI may upgrade an event. Page 9 of 19

10 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 10 of Evaluation of seriousness The PI must assess the AE as serious as per the definition of an SAE in section 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 review how the subject has changed since baseline (before treatment is administered). Every effort must be made by the 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 JRO (taking the most conservative option) and could warrant expedited reporting. To help Investigators with the decision, the CIOMS VI group recommends that PI be asked to consider the following before reaching a decision: Medical History 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 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 Evaluation of expectedness The PI must evaluate whether the event is expected or unexpected against the protocol and the safety reference documents for the trial (i.e. IB for non-licensed product or SPC for a licensed product in the EU assuming that the product is being used in the trial exactly as stated in the SPC). An event can be considered as unexpected if it adds significant information on the specificity or severity of an expected event. 6.9 How to manage reports in blinded trials The blind for the investigator and if applicable, for those persons responsible for data-analysis and interpretation of results should be maintained until the trial data is locked. However a patient s allocation may need to be unblinded under the following conditions: 1. Emergency unblinding: Patient experiencing an adverse event and requiring treatment which cannot be given without knowledge of the trial arm the patient was randomised to. 2. SUSAR Unblinding: The JRO requires unblinding for the submission of a SUSAR report to the MHRA and REC. The unblinding procedure is protocol specific and each trial must clearly document their procedure and the location of the unblinding information. The Investigator must forward the Trial specific unblinding SOP to the JRO. This SOP must be written using the JRO Standard Page 10 of 19

11 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 11 of 19 Operating Procedure for the Preparation of a Study Specific Randomisation, Blinding and Code Break Standard Operating Procedure Follow-up information On receipt of relevant or missing information, site staff must complete a new SAE report form and tick the follow-up box. The form must be forwarded to the JRO as per section 6.9. All SAEs must be followed up until a resolution is reached (i.e. recovered, recovering, recovered with sequelae, fatal, not recovered or unknown) Recording and Reporting a Pregnancy Pregnancy data provides vital information to the overall knowledge concerning the IMP and is therefore reportable to the sponsor but not reportable to the regulatory agencies as expedited reports and will be incorporated into the DSUR report. On the notification of a pregnancy in a trial participant or their partner, a member of the trial team must inform the PI. The pregnancy needs to be recorded in the medical notes, AE log and CRF. The JRO Pregnancy Reporting Form must also be completed and forwarded to the sponsor within 24 hours of being made aware of the event by to sae@ucl.ac.uk. The report can alternatively be faxed to the JRO on The completed pregnancy report form should be kept in the TMF/ISF with any relevant correspondence. The Sponsor must be kept informed of any new developments involving the pregnancy. Any pregnancy that occurs in a female trial subject during a clinical trial should be followed to termination or to term. Under special circumstances, it may be necessary to monitor the development of the new-born 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. In the event that the pregnancy report form is not acknowledged by the Sponsor s office within 3 days, site must contact relevant members of the sponsor s office to confirm receipt Escalation of report to the Safety Committee The JRO will forward the pregnancy report form, safety reference document and protocol to the chair of the safety committee and a second clinician on the committee for review and comment on recommended follow-up (as appropriate) and tests/procedures to be performed above the protocol to protect the patient and the foetus Update to PIS/Consent Form Recommendations from the safety committee will be forwarded to the CI by the JRO. A new PIS and consent form will be supplied to the trial team to re-consent the patient or partner for followup of pregnancy until term or termination. These must be kept in the TMF Follow-up of pregnancy Once site are made aware of the pregnancy outcome, (birth or termination) the outcome section must be completed and forwarded to the JRO within 24 hours. If the event that the pregnancy meets the following definition; a SAE report form must also be completed and forwarded to the JRO with the pregnancy follow-up form within 24 hours: Page 11 of 19

12 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 12 of 19 Congenital anomaly(ies) in the foetus/child Foetal death or spontaneous abortion Any SAE occurring in the neonate or mother 6.12 Overdose Reports In the event of an accidental or intentional overdose by a trial participant, the site staff must immediately inform the PI and the Sponsor s office. The deviation log must be completed and the medical notes, CRF, AE log updated to reflect this information. In the event that the overdose is associated with an S/AE, the two events should be linked. In the event of an AE associated with an overdose, a SAE report form must be completed detailing the AE and the overdose details Review of new safety reference document It is the CI s responsibility to check which document (IB or SPC) is referred to in the CTA application and request the relevant updated document as explained below IBs IBs are required to be updated annually. For trials where the IB is supplied by a drug supplier, the update will normally be requested by the site team from the supplier directly. Please refer to SOP JRO/SPON/S03 for procedures relating to UCL developed products. The CI must provide the JRO with a copy of the updated IB and confirm if the new information impacts on the trial and patient safety and if any amendments are required to the protocol, PIS and consent forms. An updated IB must be submitted to the regulatory authorities as a substantial amendment if the update affects patient safety or trial documentation. The previous version must be superseded in the TMF and a copy of the updated document placed in the file SPCs The investigator must regularly check for SPC updates. When the Investigator is made aware of an update to a SPC, the CI must review the document and assess if the updated information affects the study protocol, safety of the study patients or the Patient Information Sheets and consent forms. The trial team must be forwarded a copy of the updated SPC as well as a copy sent to the relevant members of the sponsor s office. The CI must confirm they have read the document and detail any actions required (if appropriate). The previous version must be superseded in the TMF and a copy of the updated document placed in the file Safety warning and drug alerts Safety Alerts (from the MHRA and drug suppliers) may be forwarded by the JRO or be sent directly by another organisation to the CI. The received information must be reviewed immediately by the CI or delegated member of the trial team to assess whether action is required to protect patient safety. The information must be forwarded to the JRO with any recommendations and an acknowledgement receipt requested. The CI(s) must confirm what actions (if any) are required Provisions in Multicentre trials The CI or delegated member of the trial must ensure all updates are forwarded to PIs in an appropriate timeframe and confirm that any relevant training on the new document is performed. This must be documented in the TMF/ISF. Page 12 of 19

13 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 13 of What to expect from the JRO once a report has been submitted A member of the JRO will confirm receipt of all reports within 3 days. In the event that the report is not acknowledged by the Sponsor s office within 3 days, site must contact the JRO Development Safety Update Report The Investigator and relevant trial staff will be made aware when the data lock point for the DSUR has been reached. The trial staff will work in conjunction with the JRO to facilitate in the production of the report. Please review SOP on DSURs. Page 13 of 19

14 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 14 of 19 Flowchart 1: Decision framework for assessment of adverse events by Investigators and research personnel Adverse events noted Seriousness Adverse Events (AE) Serious Adverse Event (SAE) Causality Unrelated to IMP Related to IMP Unrelated to IMP Related to IMP Adverse Event (AE) Adverse Reaction (AR) Serious Adverse Event (SAE) Serious Adverse Reaction (SAR) Expectedness Unexpected AE Expected AE Unexpected AR Expected AR Unexpected SAE Expected SAE Unexpected SAR Expected SAR SUSAR Summary of procedures Flowchart 1 Flowchart 1 illustrates the decision framework which Investigators and research personnel should follow to assess S/AEs and to determine if the event requires further expedited reporting. Please note: The CI cannot downgrade the PI s assessment Page 14 of 19

15 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 15 of REFERENCES Directive 2001/20/EC of the European Parliament and of the Council of 4 th 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. 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 (12 th Jan 2007). Sponsor s SOP for the Preparation of a Study Specific Randomisation, Blinding and Code Break Standard Operating Procedure Sponsor s SOP for the Recording and Reporting of Deviations, Serious Breaches and Urgent Safety Measures 8. APPENDICES NA 9. TEMPLATES/LOGS ASSOCIATED TO THIS SOP 1 Adverse Event Recording & Reporting log 2 Serious Adverse Event Reporting Form 3 Pregnancy Reporting Form in clinical trial subjects 10. SOP DISSEMINATION & TRAINING This SOP will be provided to the PIs prior to, or at initiation at the latest. All staff trial team concerned by this SOP will sign the SOP training log (12. SOP TRAINING LOG) part of this SOP. This SOP should be filed in the ISF. Existing trials in progress : This SOP will be ed to the PIs and their teams. These investigators will be requested to read the new SOP and back to acknowledge receipt and understanding of this new SOP. These PIs should ensure that relevant team members have read and understood this SOP. They should ensure that section 12 has been signed by all the trial team members. The sent to the PIs and their acknowledging receipt and understanding of the SOP should be printed out and filed in the JRO SOP folder. Page 15 of 19

16 ASR\INV_S05_SOP for AE_SAE_Reporting by Inv_V06.doc Page 16 of SIGNATURE PAGE Author and Job Title: Farhat Gilani, Pharmacovigilance Manager Signature: Date: 11/11/13 Authorised by: Name and Job Title: Helen Cadiou, Quality Assurance Manager Signature: Date: 11/11/13 Page 16 of 19

17 1 Name of Staff (Capital letters): Job Title: Department: 12. SOP TRAINING LOG: Training Date I confirm that I understand & agree to work to this SOP SIGNATURE Name of Trainer (if applicable) Signature Date SOP for the Recording, Management and Reporting of AEs by investigators JRO/S05/06 Page 17 of 19

18 8 Name of Staff (Capital letters): Job Title: Department: Training Date I confirm that I understand & agree to work to this SOP SIGNATURE Name of Trainer (if applicable) Signature Date SOP for the Recording, Management and Reporting of AEs by investigators JRO/S05/06 Page 18 of 19

19 15 Name of Staff (Capital letters): Job Title: Department: Training Date I confirm that I understand & agree to work to this SOP SIGNATURE Name of Trainer (if applicable) Signature Date SOP for the Recording, Management and Reporting of AEs by investigators JRO/S05/06 Page 19 of 19