Keele Clinical Trials Unit

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1 Keele Clinical Trials Unit Standard Operating Procedure (SOP) Summary Box Title Safety Reporting and Pharmacovigilance SOP Index Number SOP 20 Version 4.0 Approval Date 31-Jan-2017 Effective Date 14-Feb-2017 Review Date January 2019 Lead Author Tracy Nevatte Reference KCTU/SOP20/v4.0/14-Feb-2017 DISCLAIMER This SOP is the property of Keele Clinical Trials Unit (Keele CTU), Faculty of Health, Keele University and the content cannot be reproduced without specific permission from the owner. All SOPs and associated documents must be accessed through the dedicated SOP area of the RI for Primary Care and Health Sciences (ipchs) Intranet to ensure the correct version is being used. If this document is being accessed through any other method, such as electronic copies saved onto a network drive or in printed form, it is only valid for use if the version number and effective date shown above is the same as that shown on the ipchs Intranet. Any superseded versions of this document need to be promptly withdrawn from use. All individuals undertaking functions outlined in this document are responsible for ensuring that they are trained in the procedures outlined in the correct version of this document. SOP Template v6.0 date 18 Aug 2016 Signature Box Role Print Name Signature Date CTU Deputy Director: Operations Kris Clarkson Signed hard copy stored in approved SOP file with QA office 31-Jan-2017 Head of Research Clark Crawford Signed hard copy stored in 31-Jan-2017 Integrity approved SOP file with QA office Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 1 of 16

2 Version History Log Version Date Reason(s) for Change Approved Approval of version Nov-2015 Move to SOP template V5.0. Change terminology from Centre to CTU. Addition of USM section. Added references to QA Office. Added out of hours cover section Jul-2016 Added details of DSUR checklist and changes to RSI/SPC Jan-2017 Addition of details for blinded CTIMP trials. Implementation Plan All RI staff will be notified of the revised SOP. Staff are expected to read the updated version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date. All RI staff will be notified of the revised SOP. Staff are expected to read the updated version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date. All Keele Health and Social Care Research QMS users will be notified of the new SOP. Staff are expected to read the new version of the SOP when it is released, as applicable to their role. The updated procedures are to be implemented from the SOP effective date Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 2 of 16

3 Table of Contents 1. Purpose Scope and Applicability Procedures Safety Reporting in non-ctimps Definitions Operational Definitions Notification and Reporting of SAEs CTU Review of SAEs Expedited reporting to REC Reporting to Independent Steering Committees Reporting to Sponsor Periodic Safety Reports Pharmacovigilance in CTIMPs Definitions Reference Safety Information (RSI) Blinded Trials Out of Hours Medical Cover Notification and Reporting of AEs and ARs Notification and Reporting of SAEs and SUSARS CTU Review of SAEs and SUSARs Expedited reporting of SUSARs and Other Safety Issues to Competent Authorities and Ethics Committees Requirements for reporting SAEs and SUSARs to the Sponsor Requirements for notifying Investigators of SUSARs Reporting to the TSC and DMC Periodic Safety Reports to the MHRA and Main REC Urgent Safety Measures For non-ctimps: For CTIMPs: Key Personnel to whom this SOP Applies Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 3 of 16

4 1. Purpose This Standard Operating Procedure (SOP) defines the processes for the collection, data management and reporting of Adverse Events (AEs) and Adverse Reactions (ARs) in clinical studies. It also describes the process for notification of Urgent Safety Measures (USM) to the appropriate regulatory agencies, which may be taken to protect study participants. Safety reporting is fundamental to all clinical studies undertaken by the CTU which must follow and adhere to Good Clinical Practice (GCP). For Clinical Trials of Investigational Medicinal Products (CTIMPs), the Medicines for Human Use (Clinical Trials) Regulations SI 2004 No (as amended by Statutory Instruments SI 2006 No. 1928, SI 2006 No and SI 2008 No. 941) define the responsibilities of the Sponsor, delegate(s) and Investigators in relation to safety reporting. Further detailed operational guidance is provided in the European Commission Communication Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (CT-3). Members of staff involved in pharmacovigilance are required to be familiar with relevant regulatory requirements as detailed in the aforementioned documents. The requirements for the collection and reporting of safety data must be agreed during the development of, and detailed in, the trial protocol. 2. Scope and Applicability This SOP applies to all individuals undertaking functions outlined herein. This includes all core Keele CTU staff and all other academic, research, management or admin staff, or students working on Keele University sponsored/ Keele CTU managed clinical research projects through site agreements, service or other contractual arrangements. This SOP must be followed in line with the NHS Research Governance Framework, and the University, Research Institute and CTU policies. Where applicable to Clinical Trials of Investigational Medicinal Products (CTIMPs) this SOP must be followed in line with the UK Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments, and the EU Clinical Trials Directive. Where applicable to non-ctimp studies this SOP must be followed in line with the appropriate Good Clinical Practice guidance. The procedures covered in this SOP are divided into those which apply only to CTIMPs as described within section 3.2, and those which apply to all other (non-ctimp) studies as described within section 3.1. For Keele University Sponsored CTIMPs, operational responsibility for identification, classification and reporting of safety events is delegated to the Chief Investigator with the support of the CTU. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 4 of 16

5 Where the Sponsor of the CTIMP is NOT Keele University, the responsibilities and processes for the management of safety reporting events must be in accordance with the protocol and relevant Sponsor Delegation of Functions agreement. Where the function of reporting notifiable events to the main REC and MHRA is delegated by the Sponsor to Keele CTU, the arrangement does not affect the legal responsibility of the Sponsor. 3. Procedures 3.1 Safety Reporting in non-ctimps The following section (3.1) is applicable to non-ctimp studies only. For pharmacovigilance procedures applicable to CTIMPs, see section Definitions In research other than CTIMPs, a Serious Adverse Event (SAE) is defined by the Health Research Authority (HRA) as an untoward occurrence that: (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; or (f) is otherwise considered medically significant by the investigator. An SAE occurring to a research participant must be reported to the main Research Ethics Committee (REC) where in the opinion of the Chief Investigator the event was: Related that is, it resulted from administration of any of the research procedures, and Unexpected that is, the type of event is not listed in the protocol as an expected occurrence. Where applicable (in accordance with the study risk assessment), the definition of Seriousness must be specified in protocols written by the CTU Operational Definitions Where relevant, the protocol must describe which SAEs will be reportable to the CTU, and how (e.g. using a Case Report Form). Where applicable, expected AEs and SAEs should also be defined and it made clear that expected events would not be considered to be Related Unexpected SAEs Notification and Reporting of SAEs The local Principal Investigator (PI), or their delegate, at each site involved in the study is required to immediately report to the CTU any serious adverse event (SAE) that is considered to be potentially related to the research procedures given as part of the study. Likewise, the participants GP should be asked to report to the CTU any SAE that they consider may possibly be related to the research procedures as soon as possible. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 5 of 16

6 In accordance with the relevant site agreement, the local PI retains responsibility for following safety reporting procedures required by local policies and for following local Clinical Governance procedures. Where the CTU is notified of an SAE, initially by telephone or , the study Chief Investigator (CI) must be informed immediately and timelines start from this initial notification to the CI. There must be a study-specific working procedure on safety reporting, which includes details of the internal lines of communication with timescales, cover and out of hours arrangements. See TEM39 Template to Record a Serious Adverse Event. Where the SAE is categorised as a Related and Unexpected SAE, expedited reporting is carried out by the SC in accordance with section CTU Review of SAEs The CI is responsible for assessing whether the event is related to, or results from, any research procedure, according to the process laid out in the protocol Assessment of SAE relatedness to the study The PI at the participating site (or their delegate) is responsible for making an initial evaluation of seriousness and relatedness in accordance with the study protocol. This evaluation must also be carried out in accordance with the local site s Clinical Governance procedures. Where it is not possible for the local PI or other authorised individual at site to make this evaluation, the CI assumes the responsibility for providing the assessment in order to meet any ethical reporting timelines. In order to ascertain whether the SAE is related to the study, the TEM40 Template to assess if the SAE is related to the study needs to be completed Expedited reporting to REC What to report Any SAE considered to be related to the research procedure that is unexpected must be reported by the CI to the main REC within 15 days of becoming aware of the event using the SAE report form for non-ctimps published on the HRA website. All related unexpected SAEs occurring whilst the subject is participating in the study are subject to expedited reporting to the main REC. Other safety issues which could adversely affect the safety of study subjects require expedited reporting to the main research ethics committee. These include: Single case reports of an expected serious adverse event with an unexpected (e.g., fatal) outcome. An increase in the rate of occurrence of an expected serious adverse event which is judged to be clinically important. Post-study related unexpected SAEs that occur after the patient has completed a clinical study and are reported by the investigator to the CTU. A new event, related to the conduct of the study or the development of the device or procedure that is likely to affect the safety of the subjects, such as: An SAE associated with the study and which could modify the conduct of the study. A significant hazard to the subject population such as lack of efficacy of a device used for the treatment of a life-threatening disease. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 6 of 16

7 When to report The CI (or delegate) must inform the main REC of a related unexpected SAE as soon as possible and in any event within 15 days from becoming aware of the event. Further relevant follow-up information may be requested from site by the CTU and reported as soon as possible and in any event within 15 days of receipt, where required How to submit related unexpected SAE reports to the main REC The expedited report template for reporting related unexpected SAEs to the main REC is available on the HRA website Reporting to Independent Steering Committees For trials, all related unexpected SAEs are reported to the Chair of the Trial Steering Committee (TSC) and the Chair of the Data Monitoring Committee (DMC) at the same time (and within the same timescales) as reporting to the main REC (section 3.1.5). All other SAEs are reported to the TSC and DMC in the Interim Progress Report for the trial in accordance with their requirements. The DMC/TSC will review all safety data and make any decisions regarding early termination of the study in line with their respective Terms of Reference (TOR05 DMC Terms of Reference;;TOR06 TSC Terms of Reference). For other clinical studies all related unexpected SAEs are to be reported to the Independent Steering Committee for the study Reporting to Sponsor Copies of all safety reports are submitted to the relevant Sponsor, in accordance with their requirements Periodic Safety Reports Main REC The CI (or their delegate) is responsible for including a report on the safety of participants in the annual progress report. This must be completed every 12 months after the date of the favourable opinion and submitted to ethics within 30 days. All new available safety information received since the start of the study is collated and a cumulative set of events reported. The content of the annual safety report must be as per the HRA guidance available on their website Other The CI is responsible for ensuring that the CTU Director is kept informed of the frequency of related unexpected SAEs. 3.2 Pharmacovigilance in CTIMPs For a summary of these procedures please refer to FLO03 Safety Reporting Summary for CTIMPs flow diagram. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 7 of 16

8 3.2.1 Definitions The following definitions are applicable to CTIMPs in accordance with the EU Clinical Trials Directive 2001/EC and must be included in all protocols of CTIMPs. Further details and guidance can be found in the Detailed guidance on the collection, verification and presentation of adverse event / reaction reports arising from clinical trials on medicinal products for human use ( CT-3 ). Adverse Event (AE) any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Adverse Reaction (AR) all untoward and unintended responses to an investigational medicinal product (IMP) related to any dose administered. - All AEs judged by either the Investigator or the Sponsor as having a reasonable suspected causal relationship to an IMP qualify as adverse reactions. The expression reasonable causal relationship should convey that there are facts (evidence) or arguments to suggest a causal relationship. Unexpected Adverse Reaction an adverse reaction, the nature, or severity of which is not consistent with the applicable product information (for example, the Investigator s Brochure, or Summary of Product Characteristics). Suspected Serious Adverse Reaction (SSAR) or Serious Adverse Event (SAE) any untoward medical occurrence or effect that at any dose - 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. - jeopardised the patient and/or required intervention to prevent one of the outcomes listed above *The term life-threatening refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it was more severe. Suspected Unexpected Serious Adverse Reaction (SUSAR) any SAR that is suspected to have a causal relationship to the IMP, comparator or placebo but whose nature or severity is not consistent with the applicable product information. The definition of Seriousness must be specified in all CTIMP protocols written by the CTU Operational Definitions The protocol must describe the following for (S)AEs and (S)ARs: a) What will be reported to the CTU and how (e.g. by telephone and using which Case Report Form) b) Whether (S)AEs and (S)ARs will be evaluated for duration and intensity according to standard reference tools (e.g. a mild, moderate, severe rating scale) The identification of (S)AEs and (S)ARs that require reporting to the CTU will differ for individual trials and will be influenced by: Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 8 of 16

9 the nature of the intervention, for example: IMP with well-known safety profile; using licensed drug in licensed indication: in such trials it may be considered appropriate that certain AEs and ARs are not required to be reported if they will not improve the knowledge regarding the safety profile of the drug and are not required for the trial analysis or descriptive statistics. IMP trial with less well known safety profile; using licensed drug outside of the licensed indication. In such trials it may be considered appropriate that all ARs are required to be reported with consideration given to whether all or certain AEs will be reported. the endpoints or design of the trial, for example: Where efficacy endpoints could also be (S)AEs or (S)ARs the integrity of the trial may be compromised by having such events reported through the safety monitoring / pharmacovigilance process. In such cases, the protocol can specify that deterioration of the existing condition or known side-effects recorded as primary or secondary endpoints are not reported as (S)AEs or (S)ARs but are recorded separately. other exceptions may include hospitalisation for: Routine treatment or monitoring of the studied indication not associated with any deterioration in condition. Treatment which was elective or pre-planned, for a pre-existing condition not associated with any deterioration in condition, e.g. pre-planned hip replacement operation which does not lead to further complications. Any admission to hospital or other institution for general care where there was no deterioration in condition. Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of serious as given above and not resulting in hospital admission. Adverse reactions considered expected as part of the trial treatment (as per the SPC), such as standard side effects or anticipated adverse events related to trial procedures (unless the frequency or severity of such events is unusual) Anticipated events from disease progression End-points In all cases AEs and / or laboratory abnormalities that are critical to the safety evaluation of the participant must be reported to the CTU; these may be volunteered by the participant, discovered by the investigator or detected through physical examination, laboratory test or other investigation. Where certain AEs are not required to be reported to the CTU, these should still be recorded in the participant s healthcare records in accordance with routine clinical practice. Clear guidance in the protocol must state where this is the case. Expected SAEs for the disease and trial drug / intervention must be listed in the protocol and it should be stated that these would not be considered to be SUSARs unless the severity of the event was considered to be unexpected. Where SAEs are listed but happen rarely then an explanation of the likely risk of an event may be considered of value Reference Safety Information (RSI) The RSI must be used to determine the causality and expectedness of an event. For studies run by the CTU, the RSI is usually the relevant section of the Summary of Product Characteristics (SPC) that has been approved by the MHRA for use in the trial through the Clinical Trial Authorisation (SOP 11: Regulatory Submission). Where any brand (generic) of IMP may be used, one comprehensive SPC should be chosen at the time of request for a CTA for use in the trial for the purposes of pharmacovigilance monitoring only. For any other information regarding a generic IMP, the site should be instructed to refer to the Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 9 of 16

10 relevant manufacturer s SPC and ensure that a copy of this is saved in the Investigator Site File. The CI (or their delegate) must check for amendments to the relevant RSI at least yearly, on the anniversary of the CTA. This should be documented using the CHL11 DSUR Report Checklist/SPC Update Review. The CI (or their delegate) must be registered to receive MHRA drug alerts and ensure that these are reviewed in relation to any study IMP. Any changes to the RSI that are identified should be reviewed by the CI and relevant members of the Trial Management Group, and verified with the Sponsor whether the change requires a substantial amendment to the trial. This review takes place within 1 month of identification of the updated RSI. The current version of the SPC/RSI is the version that has been most recently approved by the MHRA whether either in the original Clinical Trial Authorisation or subsequent amendment. If the CI is made aware of changes to the current version of the SPC outside of the normal annual review cycle for the DSUR, the CHL11 DSUR Report Checklist/SPC Update Review form must be completed. There needs to be a clear justification if there is an impact on the SPC/RSI but it has been decided not to update the SPC/RSI in use. An example of this would be if recruitment had finished and all IMP ceased or if the trial is about to end in a couple of weeks. When the SPC/RSI has been changed through an approved amendment, all sites must be notified of, and acknowledge, the changes Blinded Trials For blinded trials, it should be outlined in the study protocol when un-blinding / code breaking will be performed. If un-blinding is unable to take place immediately, the treating clinician should treat the participant as if they had received the active IMP. All un-blinding / code breaking notification requests on a daily basis (working days) must be printed and reviewed, and the need for SAE/SUSAR reporting considered and initiated accordingly. If further information is required, this should be followed up with the site PI and again initiated accordingly. All communications must be stored in the Study Master File (SMF) according to SOP 6. PLEASE NOTE: Care MUST be given to ensure blinding is maintained as outlined in the trial protocol at all times. For blinded trials, the CI must ensure that there are appropriate delegates (other medics / pharmacists with the clinical expertise in the area who has received trial specific training who is listed on the authorised personnel log) to review potential SAE s and SUSARs Out of Hours Medical Cover The requirement for out-of-hours medical cover for participating sites must be determined using a risk-based approach depending on the IMP and the study population under investigation. Justification for the level of out-of-hours cover is provided in the Risk Assessment and details of any cover are described in the protocol or study-specific working instruction. Any medics involved in providing out of hours cover must have a knowledge of or access to the trial protocol and SPC / IB. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 10 of 16

11 3.2.5 Notification and Reporting of AEs and ARs Where the protocol requires reporting of AEs and ARs, they are reported to the CTU by the local PI, or authorised member of the research team, within the time periods specified within the trial protocol. There must be a study-specific working procedure on safety reporting, which includes details of the internal lines of communication with timescales, cover and out of hours arrangements where applicable. The local PI or authorised clinician within the research team at the site is responsible for making an evaluation of seriousness and assigning causality, in accordance with the trial protocol. The CI (or their delegate) is responsible for assigning expectedness Notification and Reporting of SAEs and SUSARS All SAEs, as defined in the protocol, are required to be reported to the CTU by the participating site either by telephone, or through completion and submission of the relevant Case Report Form (CRF), within 24 hours of the site trial team becoming aware of the event becoming serious. It is the responsibility of the local PI, or other authorised medic to make an evaluation of seriousness and assign causality. Where this is not possible, the Chief Investigator for the trial assumes the responsibility for providing the assessment of seriousness and assigning causality in order to meet regulatory reporting timelines. The local PI is informed of the Chief Investigator s opinion as soon as possible and is requested to also provide their opinion. The CTU s SAE Case Report Form (CRF) must be used to report SAE information to the CTU. The SAE CRF meets the complete requirements for information that must be reported to the ethics committees and competent authorities. When using any other form it is the responsibility of the CTU PI to ensure that reporting requirements are met according to current European Commission Guidance. Where the CTU are notified of an SAE initially by telephone or , a contact report must be prepared and timelines start from this initial notification. The participating site is requested to complete the SAE CRF immediately even where information is incomplete. Within 1 working day of receipt of the CRF, and in accordance with the trial protocol and/or working instruction, the Study Co-ordinator (SC, or their delegate) performs the following: Checks that the assessments of seriousness and causality have been provided by the Local PI (or authorised medic) If seriousness, causality, SAE description and/or signature are missing from the safety report then these are followed-up immediately If the event cannot be assessed by an authorised medic at the participating site within a reasonable timeframe (i.e. if site cannot say when the review will be performed or will not meet the regulatory reporting timeframes for a SUSAR), the event must be sent to the CI (or delegate) for assessment Until expectedness is assigned by the CI (or their delegate), events must be treated as SUSARs until confirmed otherwise (i.e. actions performed in timeframes to allow for expedited reporting) Checks the number of SAEs and SUSARs previously experienced by this participant and assigns each case with a unique code number in the format of Nxxxxx (Site Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 11 of 16

12 number) / xxxxx (Trial number) / xxx, where xxx is the sequential number of SAEs for that participant Confirms receipt of the SAE report (initial or follow-up) to the site Investigator within 2 working days (which does not include CTU closure days, weekends or bank holidays). SAEs can be confirmed by fax, or letter using gender, trial number, date of birth and SAE ID Notifies the QA Office Enters the CRF data onto the relevant study database within 2 working days If the causality assessment is assigned as related to the IMP or is missing: The SC forwards the information to the CI (or their delegate) for assessment of expectedness Upon receipt of the SAE, the CI (or delegate) (within 1 working day), reviews the SAE, requesting additional information if necessary and provides an assessment of expectedness of the event If the SAE is assigned as unexpected, this is a SUSAR and the additional information required by part B of the SAE CRF must be requested from the participating site If the causality assessment is assigned as not related to the IMP, immediate CI review is not required and the event will not be considered a SUSAR. Such events should be reviewed by the CI (or delegate) in accordance with section Any SAE/ SUSAR must be followed up until it is resolved, or a final outcome is reached. Once it has been confirmed that the SAE/ SUSAR has reached its final outcome, the site should be instructed to return the original CRF to the CTU and retain a copy for their records. Where the SAE is categorised as a SUSAR, procedures must be followed to ensure expedited reporting in accordance with regulatory requirements (section 3.2.7). All SAEs suspected to be related to the trial treatment (SSARs and SUSARs) must be coded by body system. The CI, or any suitably qualified person delegated by the CI and CTU, is permitted to undertake the task. Timelines vary for each trial, but codes are assigned prior to each Development Safety Update Report (DSUR). In accordance with the relevant Sponsor-site agreement, the local PI retains responsibility for following safety reporting procedures required by local policies and for following local Clinical Governance procedures CTU Review of SAEs and SUSARs SAEs and SUSARs must be reviewed in accordance with the trial protocol and/or Working Instruction, as agreed with the Chief Investigator, Sponsor and any other relevant 3rd Party Organisation. It is expected that as a minimum, cumulative line-listings of all SAEs are presented at the relevant internal meeting groups to allow a review of the overall safety profile of the study All related SAEs are sent to the CI (or their delegate) for assessment of expectedness within one working day of the CTU becoming aware. The CI (or delegate) must respond within sufficient time to ensure the timelines are met for expedited reporting. The causality assessment given by the local PI or authorised medic at the site is not permitted to be downgraded by the Sponsor, CI or any other 3rd party organisation. If there is disagreement about causality, all opinions should be provided with the report. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 12 of 16

13 Unrelated SAEs should be reviewed by the CI (or their delegate) in accordance with the trial protocol and / or safety monitoring plan. Minimally, this should be through the cumulative line listings described above Expedited reporting of SUSARs and Other Safety Issues to Competent Authorities and Ethics Committees What to Report: Expected SARs and unrelated SAEs are not subject to expedited reporting to the MHRA or ethics committee (FLO03 Safety Reporting Flow Diagram for CTIMPs). All SUSARS are subject to expedited reporting to the MHRA and ethics committee and these include (but are not limited to): Single case reports of an expected serious adverse reaction with an unexpected (e.g. fatal) outcome Post-study SUSARS that occur after the participant has completed a clinical trial and are reported by the investigator to the CTU When to Report Fatal or life-threatening SUSARs must be reported to the MHRA and ethics committee within 7 calendar days after CTU became aware of the SUSAR. Any additional relevant information, including missing information or a change in condition, must be reported within 8 calendar days of sending the first report. All other SUSARs and other safety issues requiring expedited reporting must be reported to the MHRA and ethics committee as soon as possible and in any event within 15 calendar days after the CTU became aware of the SUSAR / issue. Further relevant follow-up information will be requested from the site by the CTU and reported as soon as possible and in any event within 15 days of receipt of this information. Initial expedited reports should be submitted within the timelines above as soon as the minimum following criteria are met / information is available: a suspected causal relationship to an IMP an identifiable subject (e.g. patient ID) an adverse event assessed as serious and unexpected and for which there is reasonable suspected causal relationship EudraCT number or sponsor s trial protocol code number unique case identification an identifiable reporting source i.e. the signature of the investigator or other medic authorised by the investigator How to submit SUSAR reports to the Competent Authority All SUSARs occurring in a trial being run in the UK must be reported to the MHRA via the MHRA s electronic SUSAR (esusar) website. Once a SUSAR has been confirmed or relevant follow-up information on a SUSAR becomes available, the QA Manager (or delegate) submits the information onto the esusar website in accordance with regulatory reporting timeframes (section ). Following submission/update, a PDF version of the esusar report is downloaded and a copy sent to the SC to be filed within the relevant section of the Study Master File. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 13 of 16

14 How to submit SUSAR reports to an Ethics Committee All SUSARs originating in the UK are reported to the main REC by the SC (or delegate) When a confirmed SUSAR has been received or relevant follow-up information on a SUSAR becomes available, a copy of the latest esusar report submitted to the MHRA is ed along with a completed copy of the applicable cover form as available on the HRA website Requirements for reporting SAEs and SUSARs to the Sponsor SAEs and SUSARs are reported by the SC (or delegate) to the Sponsor in accordance with the Sponsor s processes. For Keele University sponsored CTIMPs, all SAEs and SUSARs must be notified to the QA Office within 1 working day of receipt Requirements for notifying Investigators of SUSARs Reports of individual cases of SUSARs for circulation to investigators in clinical trials are known as Investigator Notifications (INs). The frequency at which INs are generally circulated to local PIs must be based on the Trial Risk Assessment and is agreed by the Trial Management Group (TMG). Within 5 working days of reporting a SUSAR in the trial in question to the MHRA and ethics committee, the CI (or delegate) must make an assessment as to the urgency for notifying participating investigators Reporting to the TSC and DMC All SUSARs are reported to the TSC and DMC at the same time (and within the same timescales) as reporting to the main REC (section 3.2.8). All other SAEs are reported to the TSC and DMC in accordance with their requirements, or minimally at the time of the next report. The DMC/TSC will review all safety data and make any decisions regarding early termination of the study in line with their respective Terms of Reference (DMC3 Terms of Reference; see example TSC Terms of Reference from INSTINCTS). The DMC can request, in writing from the CI un-blinded analysis to be undertaken at any point during the study if there are specific safety concerns Periodic Safety Reports to the MHRA and Main REC The DSUR The DSUR must be written in line with The Development Safety Update Report (DSUR) Guidance (ICH E2F) available on the ICH website using TEM41 DSUR Template and the GDC06 DSUR Guidance. The CI and SC are responsible for ensuring completion of the report and its content, but may delegate the completion to a member of the study team. A date for completion of data entry onto the relevant study database should be agreed by the trial team. It should be ensured that appropriate data management procedures are undertaken to provide as complete a data set as possible. This includes ensuring that an updated outcome of all SAEs has been provided wherever possible prior to the download of data and that all events have been assigned a Body System Code (section 3.2.6). Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 14 of 16

15 The report must be authorised and signed by the CI prior to submission. In sufficient time to meet the DSUR reporting deadline, the DSUR is sent to the MHRA in accordance with their reporting requirements (refer to MHRA website for current guidance). In sufficient time to meet the DSUR reporting deadline, the DSUR is ed with a completed copy of the applicable cover form (available from the HRA website) to the main REC. The completed DSUR is sent to the QA Office in all cases and also the Sponsor. The DSUR may also be provided to the TSC and DMC at their request Timelines for Reporting The QA Office issues a reminder when DSURs become due. The DSUR must be reported to the MHRA and main REC within 60 days of the anniversary of the CTA approval date or upon request. Data must be locked on the anniversary of the CTA approval date and the DSUR should be submitted as soon as possible thereafter, within a maximum of 60 days of this date. 3.3 Urgent Safety Measures For all research, urgent safety measures may be identified through any trial activity, but in particular; self-reporting from trial sites, pharmacovigilance procedures, data management procedures and review of the protocol and trial procedures. Urgent Safety measures can be undertaken without prior authorisation from the MHRA and / or main REC. The CI (or delegate) reports the urgent safety measure(s) to the QA Office, CTU Director and Sponsor (in accordance with the Sponsor s requirements). All correspondence relating to the Urgent Safety Measure must be collated and supplied to the Sponsor, regardless of the Sponsor s requirements For non-ctimps: Where the Sponsor has delegated reporting responsibilities to the CTU, the CTU: Notify the main REC of an urgent safety measure within 3 calendar days that such measures have been taken, the reasons why and the plan for further action For CTIMPs: For CTIMPs, the UK Clinical Trial Regulations state: 1) The Sponsor and investigator may take appropriate urgent safety measures in order to protect the participants of a clinical trial against any immediate hazard to their health or safety. 2) If measures are taken pursuant to paragraph (1), the Sponsor shall immediately and in any event no later than 3 calendar days from the date the measures are taken, give written notice to the licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures. Any new event, related to the conduct of the trial or the development of the IMP that is likely to have an immediate affect the safety of the participants, must also be reported, such as: o An SAE associated with 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 Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 15 of 16

16 o o A major safety finding from a newly completed animal study (such as carcinogenicity) Recommendations of the Data Monitoring Committee where relevant for the safety of the subjects in the trial. Where the Sponsor has delegated reporting responsibilities to the CTU, the CI (or delegate): Discusses the urgent safety measure with a medical assessor at the Clinical Trial Unit at the MHRA, immediately when the CTU becomes aware of the urgent safety measure. Notifies the main REC via telephone. Confirms the urgent safety measure in writing to the MHRA and the main REC within 3 calendar days of the CTU becoming aware. Current contact details for the reporting of urgent safety measures to the MHRA can be found on the MHRA website. Maintains, constant ongoing communication with the MHRA, CI, QA Office as to the progress of the measure being undertaken and agrees appropriate action to be taken (e.g. temporary/permanent halt to the trial, substantial amendment to the protocol, etc.) 4. Key Personnel to whom this SOP Applies The CI and local PIs are responsible for ensuring safety reporting and pharmacovigilance (in the case of CTIMPs) procedures are compliant with the applicable standards and regulations, and are in accordance with the study protocol and Sponsor s requirements. Ref: KCTU/SOP20/v4.0/14-Feb-2017 Page 16 of 16