SOP19a & 19b: Standard Operating Procedure for (a) Safety Monitoring (especially Pharmacovigilance) & (b) Urgent Safety Measures

SOP19a & 19b: Standard Operating Procedure for (a) Safety Monitoring (especially Pharmacovigilance) & (b) Urgent Safety Measures Authorship Team: Anne Seagrove, Melanie Storey, Ian Russell for Joint SOP Group on Trial Processes (viz Yvette Ellis, Jemma Hughes, Leanne Quinn) Approved Signature Date 07 May 2014 0 Version Record Version number Effective Date Reason for Change 0 01 Dec 2008 Derived from SOP approved by NWORTH 0.1 30 Jan 2009 Reviewed by TAF on 30 January 2009 0.2 30 Mar 2009 Further edits based on changes to Monitoring SOP17 27 Mar 2009 0.3 22 Apr 2009 Further edits based on comments from JGW & JH and further reading by KT 0.4 30 Apr 2009 Further edits and splitting of document to create new SOP Urgent Safety Measures v0.1 0.5 27 May 2009 Merging of 19a and 19b and further amendment of both SOPs following review meeting 220509 0.6 22 Jul 2009 Further amendments to SOP for WDG review by Steve Allen for final sign off 1 27 Aug 2009 SOP signed off by Prof Ian Russell as approved in principle 1.1 05 May 2010 Replacement of SUSAR Initial Report Form and SUSAR Follow up Report Form with SUSAR Report Form 1.2 15 May 2010 Minor formatting amendments 1.3 24 May 2010 Amendment of SUSAR Report Form in Appendix 1.4 16 Jul 2010 Update of SOP to describe WWORTH s role in the new esusar reporting process to the MHRA 1.5 21 Jul 2010 Review by ITR. Tracked changes accepted. Send for TAF & SOP review group comments 1.6 06 Aug 2010 Amendments to SOP following ABM UHB inspection report, TAF comments. V1.6 to be sent to ITR, then Joint SOP WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 1 of 37

Group 1.7 31 Aug 2010 Review by Joint SOP Group. Edits by KT. Approved for use. 1.8 04 Nov 2011 Updated by KT for JSOPG 1.9 16 Jun 2012 JSOPG sign off 2.0 23 Aug 2012 JMG final approval 2.1 31 May 2013 Updated agreed header & formatting 2.2 13 Jan 2014 Edits by MS/ACS. Inclusion of MACRO 4 software, clarified reporting responsibilities, 2.3 13 Mar 2014 Review and amendments by MS/ACS. 2.4 25 Mar 2014 Review and amendments by MS/ACS. 2.5 07 May 2014 Remove training log post JSOPG discussion - MS & CS WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 2 of 37

1 Table of Contents 0 Version Record... 1 1 Table of Contents... 3 2 Glossary... 4 3 Introduction... 4 4 Purpose... 5 5 Roles and Responsibilities... 5 6 Procedures... 7 6a Safety monitoring, especially pharmacovigilance... 7 6a.1 Deciding what type of events require reporting... 7 6a.2 Notification of a potential AE occurring in a trial participant... 9 6a.3 Classification of adverse events... 10 6a.4 Recording reportable adverse events... 11 6a.5 Reporting events to the CI... 11 6a.6 Maintenance of blinding... 12 6b Reporting SAEs, SARs or SUSARs to external bodies...12 6b.1 Urgent Safety Measures (USM) (for CTIMPS only)... 13 6b.2 Expedited reporting... 17 6b.3 Interval-based reporting... 21 7 Training Plan...22 8 References...23 9 Related SOPs...23 10 Appendices...24 Appendix 1: Example flowchart depicting the classification of adverse events where expectedness is assessed first...25 Appendix 2: Analysis of causality, seriousness & expectedness of adverse events...26 Appendix 3: Exemplar of AE Screening Form (CONSTRUCT Trial)...28 Appendix 4: Exemplar of SAE-SUSAR Report Form for CTIMPs...31 Appendix 5: esusar questions...37 WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 3 of 37

2 Glossary The full Glossary is in Swansea University H drive/documents/526- WWORTH/Development Group/Glossary. 3 Introduction Standard Operating Procedures (SOPs) are succinct formal documents designed to achieve consistency in specified trial functions by specifying standard practice in performing those functions (GCP 1.55 & 5.1.1 EMeA, 2002) [1]. While SOPs should cite relevant legislation & regulations, and key references & evidence, they need not expound theory. WWORTH SOPs should accord with all relevant regulations, including the European Union Clinical Trial Directive, ICH Good Clinical Practice (GCP) and the current NHS Research Governance Framework. They will seek to distinguish between regulations for CTIMPs and for other research. This document forms part of the set of standard operating procedures of the West Wales Organisation for Rigorous Trials in Health - WWORTH. It describes the roles, responsibilities and actions of the individuals responsible for safety reporting, especially Pharmacovigilance and urgent safety measures in clinical trials of investigational medicinal products (CTIMPs). If there is any uncertainty about whether or not the research is a CTIMP, the MHRA provide a useful algorithm to help decide (see WWORTH SOP15 MHRA approval). It is a legal requirement for CTIMPs to adhere to the Medicines for Human Use (Clinical Trials) Regulations 2004, which implement the EU Clinical Trials Directive 20011 into UK law. The Clinical Trials Regulations incorporate the Commission Directive 2005/28/EC on GCP. WWORTH SOPs are written in compliance with the EU Clinical Trial Directive and other regulatory requirements, including ICH-GCP2 & the NHS Research Governance Framework3. In this SOP, the term adverse event is used to describe an untoward medical event which may or may not be serious, expected or causally related to the intervention under investigation. The term is used as a global phrase to include all adverse events (AEs), adverse reactions (ARs), Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). Under the Clinical Trial Regulations, AEs must be appropriately recorded and reported by the Chief Investigator (CI) to the relevant external regulatory bodies, namely Medicines and Healthcare products Regulatory Agency (MHRA), Research Ethics Committee (REC), Sponsor, Trial Steering Committee (TSC), and Data Monitoring and Ethics Committee (DMEC) and to WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 4 of 37

all Principal Investigators (PIs) in a multi-centre study. Where the sponsor has delegated responsibility for phamacovigilance to WWORTH, It is important for WWORTH to manage all SAEs following notification until resolution. This facilitates effective QA and adherence to the trial protocol by trial centres. 4 Purpose To describe the process of Safety Monitoring (especially Pharmacovigilance) and Urgent Safety Measures to be carried out by WWORTH-adopted trials. Pharmacovigilance comprises monitoring of investigational medicinal products (IMPs), assessing their harms and benefits, reporting adverse events (AEs) or adverse reactions (ARs), and responding to the classification of an SAE, SAR or SUSAR. These actions are fundamental to improving the efficacy and safety of IMPs. The defined criteria for identifying, recording and reporting all forms of AEs to the Sponsor (or WWORTH or CI where responsibility is delegated) by the PI of a study site (or the CI if a single-centre study) are described in Section A of this SOP. The CI, PIs or other designated co-investigators, acting in consultation with WWORTH on behalf of the Sponsor, may take appropriate urgent safety measures (USMs) based on new knowledge that necessitates an immediate change in the study procedures or a temporary halt to protect trial subjects from any immediate hazard to their health and safety. The appropriate actions are described in Section B of this SOP. The expedited and routine reporting of safety issues to relevant external bodies such as MHRA, REC, Sponsor, DMEC and TSC by the CI are also described in Section B of this SOP. The legal requirement to report safety issues applies specifically to CTIMPs unless otherwise stated. Nevertheless it is good practice to monitor safety in non-ctimps. 5 Roles and Responsibilities The Sponsor, in collaboration with WWORTH, will conduct a risk assessment of the trial and recommend: 1) which AEs should be recorded, where and how WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 5 of 37

2) which AEs should be notified to the Sponsor, when and how. The PIs (in multi-centre CTIMPs) are responsible for monitoring the safety of the IMP in their sites and reporting all safety issues in good time in accordance with the study protocol to the CI using standard reporting proformas (e.g. Appendix 4). In a single-centre CTIMP, the PI acts as the CI and should also follow the guidance below. The CI (when the Sponsor has delegated responsibility and no research partner has taken on the duty of reporting SUSARs) must promptly notify the following of findings that could adversely affect the safety of CTIMP participants or the conduct of the CTIMP, or alter the REC s favourable opinion to conduct the CTIMP: MHRA, REC, Sponsor, DMEC, all PIs in the CTIMP and partner institutions. The CI must also report all SUSARs in the trial to the WWORTH QA Manager, with a copy to the Unit Manager, immediately to facilitate expedited reporting to the MHRA using the esusar website. When WWORTH allocates passwords to CIs, they will register SUSARs themselves and inform the WWORTH QA Manager, with a copy to the Unit Manager immediately. The CI or delegate must also report to the DMEC all SARs, ARs, SAEs and AEs listed in the protocol as not requiring expedited reporting. The Trial Manager (TM) (when the CI has delegated responsibility for reporting SUSARs to the TM) must act promptly upon all reportable SAEs, SARs and SUSARs that occur during a CTIMP. When PIs or other authorised persons send the TM a completed SAE reporting form, the TM will forward the information to the CI (and WWORTH where relevant) within the prescribed timescales. TMs will maintain a record of all reports that they receive. TMs will arrange for suitable, appropriately trained persons to cover their roles in safety reporting in their absence. In the absence of any personnel within a trial to do this, the WWORTH QA Manager or Unit Manager may cover the role if given appropriate training (see WWORTH SOP02 Training). The Trial Data Manager (TDM) (where delegated by the CI) should report to the DMEC those ARs and SAEs listed in the protocol as not requiring immediate reporting within the prescribed timescales. The WWORTH QA Manager or if unavailable, the Unit Manager will manage all SUSARs from WWORTH-adopted trials to MHRA via the esusar system, by either reporting them personally or by designating other responsible people to report them. When authorised by the CI, WWORTH will also be responsible for reporting to other external bodies (e.g. REC and DMEC). WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 6 of 37

All co-investigators and local collaborators caring for participants are responsible for identifying, recording and notifying the PI (or CI in a singlecentre trial) of all AEs not stated in the protocol as being exempt from the recording process. They should also report the event to the CI if they are authorised to do so by the delegation log in a multi-centre trial. All WWORTH members and core staff should ensure that they are familiar with this SOP, particularly staff working in CTIMPs. 6 Procedures 6a Safety monitoring, especially pharmacovigilance This section details requirements for the recording and reporting of all types of AEs and ARs in CTIMPs or non-ctimps from study sites or centres to WWORTH acting for the Sponsor. The Sponsor will usually delegate to the CI (who may in turn delegate to WWORTH) decisions about how to record and report any types of AEs or ARs (see WWORTH SOP31 Sponsorship and Adoption). Hence the text of this SOP assumes that the CI is responsible for safety monitoring for the trial. Where the process is different for CI and Sponsor or WWORTH, the text draws a distinction. 6a.1 Deciding what type of events require reporting For all trials, CTIMPs and non-ctimps, the following must be decided during protocol development (see WWORTH SOP13 Protocol Development): 1. the level of recording of AEs appropriate to the trial; 2. which ARs are to be expected from participants in the trial; and 3. procedures for reporting AEs, ARs, SAEs, SARS, and SUSARs, which should follow the general principles set out in this SOP. For CTIMPs specifically, regulations stipulated by the MHRA should also be adhered to. The MHRA has a website on Good Pharmacovigilance Practice which can be found at http://www.mhra.gov.uk/howweregulate/medicines/inspectionandstandard s/goodpharmacovigilancepractice/index.htm. Depending on the risks associated with the IMP or intervention under study, and on the characteristics of the participants, the protocol should require the collection of one of the following: WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 7 of 37

All AEs (serious and non-serious) All ARs (serious and non-serious) All AEs or ARs of a defined minimal severity on standard toxicity grading scales Only SAEs (or, in certain circumstances, only specific types of SAE) Only SARs (SSARs and SUSARs) Only SUSARs The following inclusion and exclusion criteria for identifying, recording and reporting AEs and ARs apply to all trials unless the protocol states otherwise: Include: Exclude: Exacerbation of a pre-existing illness; increase in frequency or intensity of a pre-existing episodic event or condition; deterioration in persistent disease or symptoms present at baseline following the administration of the IMP or intervention under study. a condition detected after administration of IMP or intervention under study, even though it may have been present before the start of the trial. medical or surgical procedures unless they are in response to the AE or AR. In this situation, the causal AE should be reported. pre-existing disease or conditions detected before treatment that do not worsen; unrelated medical occurrence e.g. cosmetic elective surgery; overdose of medication without signs or symptoms; WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 8 of 37

the disease being treated, or associated symptoms or signs, unless it is more severe than expected for the participant in question. Although pregnant women are usually excluded, unless part of the CTIMP design, if a pregnancy occurs in a participant in a CTIMP during the study period, it is reportable to the CI by the PI, although not as an AE or SAE. The pregnancy and the delivery require monitoring and follow up. It may be necessary to monitor the development of the newborn for an appropriate period post delivery. Any occurrences that result in an SAE should be reported as per protocol. Where the risk-benefit profile of the IMP or intervention under study is already well established, it may not be necessary to collect information on non-serious AEs for regulatory reasons. The option chosen should be consistent with the purpose of the trial and the choice of toxicity and efficacy or effectiveness end points. 6a.2 Notification of a potential AE occurring in a trial participant to the PI or other authorised person Before participants consent to the trial, they must be aware of any potential effect on their health from participating in the trial (see WWORTH SOP05 Participant Info and Consent). They should be given guidance on reporting any health-related AE, not just those thought to be related to the IMP or intervention. From the outset of the trial they should be encouraged to contact their GP, PI or other authorised person immediately about any AE. It is especially important that trial staff learn of participants admission to hospital following AEs as soon as possible (Appendix 1). Participants should receive a trial membership card and advice to carry it at all times and present it whenever they are in hospital. The card should instruct clinical staff to alert the PI, or TM if the hospital is not a designated trial site. In addition, the PI should check for any hospital admissions at each scheduled follow up. Though this may identify only SAEs, SARs and SUSARs occurring locally, to seek more may prove counter-productive. The delegation log should list co-investigators and local collaborators in contact with participants who are responsible for identifying, recording and reporting AEs with the PI. WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 9 of 37

6a.3 Classification of adverse events Usually the AE is first assessed for causality by a qualified person listed on the delegation log who uses the information in Table A1.1 of Appendix 2 to assess whether it is an AE (not causally related to the IMP) or an AR (causally related to the IMP). Usually the AE or AR is next assessed for seriousness using Table A1.2 of Appendix 2. If serious, an AE is upgraded to an SAE and an AR to an SAR. If not serious, the original classification as AE or AR stands. Any SAR must be further assessed for expectedness to classify it as an expected Suspected SAR or a Suspected Unexpected SAR (SUSAR) seea1.3 in Appendix 2. The flowchart below illustrates the classification process when causality precedes seriousness, which precedes expectedness. However individual trials should assess causality, seriousness, and expectedness in the order most likely to identify SUSARs accurately while minimising resource use. Appendix 1 displays an AE classification flowchart where expectedness is assessed first because the Summary of Product Characteristics for both drugs under study list very many expected AEs. Appendix 3 shows an example of an AE Screening Tool that may be used. Adverse event to be assessed Unrelated Possibly / probably / almost certainly related Serious Not serious Serious Not serious SAE AE Expected Unexpected AR SAR SUSAR WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 10 of 37

6a.4 Recording reportable adverse events PIs and others authorised on the delegation log will record all reportable AEs, typically SAEs and SARs (Section 6a.1) in accordance with the study protocol and initiate and file an SAE-SUSAR Report Form (see Appendix 4) in both the participant s notes and Case Report Form (CRF). The PI or other authorised person capable of assessing the causality, seriousness and expectedness of the event in good time will complete the SAE-SUSAR Report Form. Appendix 4 displays a SAE-SUSAR Report Form approved by the MHRA for a CTIMP adopted by WWORTH, which contains all the necessary fields. The format may be amended but the data items should always be present. 6a.5 Reporting events to the CI Unless otherwise stated in the study protocol, all SAEs and SARs must be reported to the Trial Office on a SAE-SUSAR Report Form such as the one in Appendix 4 (Sections 1-6 at initial reporting stage) in accordance with timeframes stated in the protocol. All SUSARs must be reported to the Trial Office within 24 hours of knowledge of the event. To meet this deadline for reporting expedited SAEs and SUSARs to the CI, it may not always be possible for the PI to sign the SAE-SUSAR Report Form. The form should then be sent without signature, and signed and resent as soon as possible. Once sent to the Trial Office, the completed form will also be kept in the Trial Site File (TSF) for monitoring and audit (see WWORTH SOP03 Master and Site File, WWORTH SOP17 Monitoring and WWORTH SOP18b External Audit And Inspection). The CI will usually authorise the TM to receive these faxes, inform the CI, contact the PI to ask for supplementary information for external bodies and ensure the appropriate process is in place for entering the data on MACRO 4. MACRO 4 is the single data management system that will centralise, automate, streamline and enhance the process of reporting AEs whenever possible. The PI must send follow up information to the CI within five days by completing Sections 7-9 on the semi-complete SAE-SUSAR Form sent as the original report. Alternatively, a separate SAE-SUSAR Follow Up Form may be preferred by the trial. Where possible reported SAEs, SARs and SUSARs will be followed until resolved, even if the participant withdraws from the trial. The SAE-SUSAR Form in Appendix 4 is only an example. The form can be adapted for trial-specific use (e.g. collecting secondary outcome measures) so long as the key elements (see Appendix 4) remain as they WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 11 of 37

are essential for esusar reporting to the MHRA. The PI decision on causality cannot be downgraded by the CI or Sponsor. If there is a difference in opinion both should be recorded and reported. Lists of AEs that do not require expedited reporting according to the protocol will be signed off and sent to the CI at agreed intervals (e.g. annually) using an agreed method. 6a.6 Maintenance of blinding Some trials are conducted in a blinded manner to reduce bias when analysing the results. Whenever possible procedures for SAE-SUSAR reporting will maintain blinding of trial staff and clinicians running the trial in accordance with the trial protocol. However, unblinding PIs is unavoidable when the identity of the allocated IMP (or intervention) is essential for the medical management of a trial participant. The safety of participants in the trial always takes priority. Whenever possible trial staff, especially the statistician, will remain blind. When the PI and co-investigators can remain blind without detriment to the participant s care, they should assess seriousness, causality and expectedness as though the participant had received the active intervention. In these circumstances SUSARs should be unblinded by the Trial Office, WWORTH or the DMEC. Only SUSARs occurring to participants in an active intervention group should be labelled as such and reported to MHRA and REC (unless thought to be due to a component of the placebo). Each trial will specify their unblinding procedure and where they will keep the unblinded information (WWORTH SOP13 Protocol Development and WWORTH SOP24 Randomisation). SUSARS should be unblinded prior to reporting to the MHRA and REC. This is in order to provide meaningful information that can enable a full evaluation of the data in the context of the sfaety profile of the IMP. Blinded information is not useful to the MHRA; SUSAR reports where a suspected drug is not unblinded, will not be accepted. At WWORTH, unblinding for SUSAR reporting is performed by the WWORTH QA Manager or Unit Manager). 6b Reporting SAEs, SARs or SUSARs to external bodies This section covers reporting to external bodies in descending urgency of reporting: WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 12 of 37

6b.1 urgent safety measures (including temporary halt to a trial) 6b.2 expedited reporting 6b.3 interval-based reporting Details of MHRA reporting procedures summarised in this SOP are in http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedi cines Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htm and http://ec.europa.eu/health/files/eudralex/vol- 10/21_susar_rev2_2006_04_11_en.pdf External bodies that need to be notified of SARs and SUSARs & SAEs as documented in the Protocol: MHRA (or other Competent Authority) The REC The Sponsor or WWORTH on their behalf Research partners The DMEC and hence the TSC The Sponsor usually delegates the CI to report to these bodies at a time consistent with the assessed seriousness, causality and expectedness of the event. CIs should use the completed SAE-SUSAR Report Form from the PI to complete the necessary reports for these bodies. Where possible they should use these bodies own proformas in accordance with accompanying guidelines. The MHRA have a web-based reporting system which includes a facility to download a full report in PDF or XML format for submission to RECs. Where no proforma is available, the CI should agree a reporting method with bodies including DMEC and TSC. 6b.1 Urgent Safety Measures (USM) (for CTIMPS only) Clinical Trials Regulations (SI2004/131) and amendment (SI2009/1164) states: (1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the subjects 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 WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 13 of 37

(a) (b) where paragraph (3) applies, as soon as possible; and in any other case, immediately, and in any event no later than 3 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. (3) This paragraph applies for any period during which a disease - (a) (b) is pandemic; and is a serious risk to human health or potentially a serious risk to human health. A USM may be any measure taken in order to protect clinical trial subjects from any immediate hazard to their health and safety. A notification of an urgent USM may be received at any point during the conduct of a clinical trial. The decision to undertake appropriate safety measures may be taken by: the CI, PI, DMEC, TSC, TMG, Sponsor or WWORTH, the MHRA or the relevant drug/medical device manufacturer of the trial. Sponsors must (delegate WWORTH to) contact the Clinical Trials Unit at the MHRA on clintrialhelpline@mhra.gsi.gov.uk or 020 308 6456 and discuss the issue with a safety scientist immediately. This telephone conversation should be fully documented. WWORTH will take any necessary actions to protect patients immediately without waiting for approval, but inform the MHRA and REC of these actions and the reasons for them within three days by submitting a substantial amendment. When investigators act independently of the Sponsor, they must also inform the Sponsor immediately of any USM they take. Actions to be taken: Step 1: Trial Manager receives a notification which may constitute a USM and may impact on the study concerned a. acknowledge USM notification with the sender b. arrange an immediate meeting/teleconference with the CI, Sponsor (or their respresentative) and the WWORTH QA Manager to decide whether the notification affects the running of the trial/study concerned. If necessary/practicable the MHRA Safety Scientists (020 308 806456) may also be contacted to discuss the matter and determine whether the WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 14 of 37

notification may affect the running of the trial. This telephone conversation should be fully documented. Step 2: Where the USM does not affect the running of the trial a. if there are to be no actions which will affect the running of the trial, the MHRA Clinical Trial Unit should be telephoned (020 308 806456) and the main REC within 24 hours of receipt of the USM notification. This telephone conversation should be fully doucmented. b. a report should be written detailing the USM notification and the reasons for no further action affecting the running of the trial. This report should be sent to the MHRA, REC, and Sponsor, plus a copy to the pharmaceutical company (if required) within 3 days of receipt of the USM notification. c. file all documentation relating to the USM notification appropriately in the TMF and ensure the Sponsor and WWORTH QA Manager receive copies of all correspondence. Step 3: Where the USM does affect the running of the trial the study coordinates the production of an action plan a. develop a USM action plan; this may include immediately halting the study. The action plan should be discussed with a medical assessor at the MHRA via telephone (020 308 806456) and REC with 24 hours of receipt of the USM notification. If there are recommendations made by the medical assessor, these should be incorporated into the action plan (as appropriate). This telephone conversation should be fully documented. Please omit telephone call for non-ctimps. b. the revised action plan should be endorsed by the study/trial lead, the CI and Sponsor. c. the USM should be implemented appropriately and personnel (including Investigators) and pharmaceutical companies/medical devices companies informed accordingly. Step 4: The study notifies all concerned bodies of the USM and action plan by way of a substantial amendment WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 15 of 37

a. although approval from the MHRA and REC is not required for the implementation of the USM, these bodies must be notified in writing with 3 calendar days. This report to the MHRA and REC should be in the form of a Notification of Amendment form (proforma available on the EudraCT website at http://ec.europa.eu/health/files/eudralex/vol- 10/substantial_amendment_notification_form_.doc and include the following: details of the USM notification measures taken reasons for these measures details of the MHRA medical assessor contacted any relevant and supporting documentation The substantial amendment plus the cover letter must be sent as PDF documents on disk to the MHRA at: Information Processing Unit Area 6 Medicines and Healthcare products Regulatory Agency 151 Buckingham Palace Road Victoria London SW1W 9SZ Please omit report to the MHRA for non-ctimps The substantial amendment and the cover letter must be sent in the same format to the REC via the preferred means for that REC. The Sponsor should be copied into all correspondence. Step 5: If the trial is temporarily halted as a result of the USM, the study notifies the MHRA and REC a. the MHRA and and REC should be notified immediately, and at least within 15 calendar days from when the trial is temporarily halted b. this notification is made as a substantial amendment using the Notification of Amendment form. It should clearly describe what has been halted and the reason why c. this should be performed in accordance with WWORTH SOP XXX WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 16 of 37

To restart a temporarily halted trial, the Sponsor (or CI if delegated) should submit another Notification of Amendment form. This will provide evidence that it is safe to restart the trial. If Sponsor or CI decides not to restart such a trial, they should notify MHRA and REC within 15 days using the End of Trial Declaration and explain why (https://eudract.ema.europa.eu/). WWORTH SOP07 Site Closure defines procedures to follow when a trial ends prematurely. Step 6: Trial Manager files all documentation relating to a USM in the TMF a. all documentation relating to a USM notification (including all copies of correspondence) must be filed appropriately in the TMF) b. ensure the sponsor and WWORTH QA Manager receive copies of correspondence. 6b.2 Expedited reporting Expedited reporting is essential for all SUSARs and those AEs, ARs, SAEs and SARs (described as SAEs in this section) identified as needing expedited reporting in the protocol. European Commission Detailed Guidance CT-3 states: 93. The clock for expedited initial reporting (day 0 = Di 0) starts as soon as the information containing the minimum reporting criteria has been received by the sponsor. Reference to received by sponsor means the date the SAE Report was transmitted from a site to WWORTH, i.e. the date on the fax header (rather than the date that a WWORTH staff member picks up and processes this information). It is important to have appropriate cover between Christmas and New Year and around the Easter weekend. Please note that the timeframes stipulated within clinical trials regulations, guidelines etc. pertain to calendar days; these documents do not allow for working hours, which is something that needs to be managed within organisations conducting trials. a. To the MHRA for CTIMPs WWORTH is registered to report SUSARs using the MHRA s esusar system at https://esusar.mhra.gov.uk/, a password-protected electronic reporting system. Registration can be done by completing the online form at WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 17 of 37

http://www.mhra.gov.uk/home/groups/lctu/documents/websiteresources/co n082186.doc and emailing it to esusar@mhra.gsi.gov.uk with the subject line esusar Registration. Sponsors or CIs wishing to use this service should arrange to send all SUSAR Report Forms to the WWORTH Manager, copy to the Unit Manager (or other designated person) as soon as possible after receiving them and checking that they have answered all questions that will need to be completed on the esusars website (see Appendix 5). This will enable them to meet the following legal requirements: SUSARs that are fatal or life-threatening initial report containing at least the miminum information to the MHRA as soon as possible and no later than seven days after being made aware of the SUSAR SUSARs that are NOT fatal or life-threatening - initial report to the MHRA not later than 15 days after being made aware of the SUSAR. When the information in the initial report is incomplete, all the information needed to assess causality should be provided in follow-up reports as it becomes available and within an additional eight days of the initial report (see detailed guidance at http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedi cines/clinicaltrials/safetyreporting-susarsandasrs/index.htm and http://ec.europa.eu/health/files/eudralex/vol- 10/21_susar_rev2_2006_04_11_en.pdf). WWORTH is therefore required to obtain the minimum information for esusar submission from the site and clinical reviewer within 7 days for fatal/life threatening events and 15 days for non-fatal/non-life-threatening events from the date the SAE form is received at WWORTH, i.e. date on fax header. The MHRA esusar database will not allow transmission unless the required fields have been completed. The required fields include all of the following: valid EudraCT number (where applicable) sponsor study number one identifiable coded subject WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 18 of 37

one identifiable reporter one SUSAR one suspect IMP (including active substance name- code) a causality assessment If a causality assessment has not been provided or the investigator assigns the causality as not assessable (so no suspect IMP has been indicated), the case should be treated as causally related and therefore a SAR, and if unexpected, qualifies as a SUSAR which must be reported within the 7 or 15 day timeframe from receiving the SAE Report. This may be downgraded if further information from the site indicates otherwise. If the initial 7 day SUSAR Report is incomplete, a further follow-up report regarding any additional information relevant to the SUSAR is required within 8 calendar days of submitting the initial report. As the reporting and downgrading of SUSARs can be time-consuming, it is important to case outstanding data on SAEs from sites immediately. The following strict timelines should be provided for the return of information from sites and return of the clinical review by the CI (or appropriately medically qualified delegated clinical reviewer): Fatal or life threatening events: 24 hours Non-fatal or non-life-threatening events: 4 calendar days The esusar website generates a downloadable form in PDF or XML format, which can be used for reporting to other bodies with their agreement. The WWORTH QA Manager or if unavailable, the Unit Manager will save copies of these forms for the trial to file and copy to external bodies as appropriate. If significant new information on an already reported 7 or 15 days SUSAR is received at WWORTH, the clock starts again at day 0 (ie the date received at WWORTH - date on the SAE report fax header). This followup information should be reported to the MHRA and REC as a follow-up report within 15 days. There may be cases where a SUSAR turns out fatal of life-threatening, whereas initially it was considered as non-fatal or non-life-threatening. The non-fatal or non-life-threatening SUSAR should be reported to the MHRA and REC within 15 days. The fatal or lifethreatening SUSAR follow-up report should be reported to the MHRA and REC within 7 days after first knowledge of the reaction being fatal or lifethreatening. b. To the REC about CTIMPs Sponsors (or CIs or WWORTH if delegated) must report all SUSARs (and SARs/SAEs where relevant) that occur in CTIMPs within the UK to the main REC using the form and timescales above for the MHRA. WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 19 of 37

c. To the Sponsor of CTIMPs The Sponsor can delegate responsibility for expedited reporting to the CI or an external body like WWORTH. The responsible person or organisation must receive initial reports on SUSARs (and SARs/SAEs where relevant) within 24 hours; and on findings that could adversely affect participants safety in an expedited manner. Though the format of these reports should meet the Sponsor s requirements, the MHRA s downloadable form is likely to be acceptable. d. To WWORTH about CTIMPs When responsibility has been delegated to WWORTH, the CI (or TM if delegated) must inform the WWORTH Unit Manager immediately about all SUSARs (and SARs/SAEs where relevant) to the MHRA. The WWORTH Unit Manager will take responsibility for onwards reporting to the MHRA via the esusars website on behalf of WWORTH as registered reporting organisation. In particular the WWORTH QA Manager or if unavailable the Unit Manager will report the details provided on behalf of the trial within the timeframes specified by the MHRA for fatal and non-fatal SUSARs; and will provide the CI (or TM if delegated) with copies of the printable form generated by the esusar website to summarise the data submitted. e. To the trial DMEC & TSC The CI (or WWORTH if delegated) must report all SUSARs (and SARs/SAEs where relevant) in CTIMPs to the Chair of DMEC at same time as the MHRA. The CI should therefore agree a reporting format at the start of the trial, where possible by getting agreement to use the MHRA downloadable form. More generally the DMEC should agree a charter describing their roles and responsibilities. This or the minutes of the first meeting should record one of the following as the trigger for the CI to submit an expedited report to the DMEC: 1. the total number of SAEs or SARs in a blinded trial; or 2. the number of SAEs or SARs in each intervention group in an open trial. The DMEC will examine such expedited reports swiftly. If there is evidence of imbalance in SAEs between groups that requires further action, they will immediately report this to the TSC. To facilitate communication between DMEC and TSC, it is advisable for the CI to copy the DMEC report on SAEs to the TSC. WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 20 of 37

6b.3 Interval-based reporting a. To the MHRA about CTIMPs In addition to the expedited reporting required for SUSARs, the Sponsor (or CI if delegated) must submit a safety report called the Development Safety Update Report (DSUR) (previously known as the Annual Safety Report or ASR) on an annual basis from the date of the first clinical trials approval throughout the clinical trial or on request (see http://www.ich.org/products/guidelines/efficacy/efficacysingle/article/development-safety-update-report.html) The DSUR should describe concisely all new safety information relevant for one or several clinical trial(s) and to assess the safety of subjects included in these studies and should include the following: Part 1: Part 2: Part 3: Analysis of the subjects safety in the concerned clinical trial(s) with an appraisal of its ongoing risk:benefit A line listing of all suspected SARs (including all SUSARs) that occurred in the concerned trial(s), including all serious adverse reactions from third countries An aggregate summary tabulation of suspected SARs that occurred in the concerned trial(s) Full details of what to include in the DSUR can be found in http://ec.europa.eu/health/files/eudralex/vol- 10/21_susar_rev2_2006_04_11_en.pdf5 DSURs should be provided as electronic documents on disk and be sent to: Information Processing Unit, Area 6, Medicines & Healthcare products Regulatory Agency, 151 Buckingham Palace Road, Victoria, London SW1W 9SZ b. To the REC The DSUR sent to the MHRA (see Section 6b.4a) should also be submitted to the main REC at the same time. Guidance is available from the NHS Health Research Authority website: http://www.hra.nhs.uk/research-community/.6 The main REC notification must be accompanied by the standard ethics covering letter. c. To the Sponsor The CI will report to the Sponsor using written reports, as agreed and within the prescribed timescales, regarding AEs identified in the protocol as being critical to safety evaluations. WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 21 of 37

d. To the DMEC and TSC Reportable but non-urgent AEs / ARs will be reported in scheduled reports by the CI. 7 Training Plan All WWORTH staff involved with trials must undertake the appropriate generic and trial-specific training to ensure that they meet with the specific employers mandatory training requirements and the specific requirements of the trial. For example, for SU staff, all new employees must attend induction, fire and safety training (as well as role-specific training courses, e.g. laboratory safety). For new staff, additional training requirements should be identified alongside the specific role requirements and the WWORTH Unit Manager should make provision for the new staff member to attend the necessary courses as soon after appointment as is practicably possible. It is the responsibility of the WWORTH Unit Manager (alongside the CI or TM) to identify all the SOPs that are relevant to a specific trial and in which the new member of staff should be trained. The WWORTH UM or the SOP author will provide group training for trial staff and/or one-to-one training, as required for new staff in relation to the specific SOPs identified. Training records should be filed both by the main employer and the staff member, in accordance with the specific employer requirements. Trial specific training should be filed in TMF or TSF as appropriate and every individual involved in a trial should have an individual training record (see WWORTH SOP02 Training). Where the tasks specified in the individual SOPs are delegated to WWORTH staff, CIs/PIs or TMs, these delegated staff must ensure that they have attended a training course on GCP and keep up-to-date through attending refresher courses. It is the responsibility of the CI/PI to ensure that all staff allocated duties on the study delegation log template of responsibilities are suitably trained in the activities linked to those duties (see WWORTH SOP16 Site Setup, Appendix 9 and Appendix 10). Each trial should maintain a central training log and ensure that WWORTH has access to that log, not least to integrate the logs of staff who work on more than one trial. Similarly trials should ensure that each site maintains a local training log, not least to integrate the logs of staff who work for more than one sponsor. All WWORTH staff involved with trials, especially CTIMPS, must ensure that they are familiar with this SOP. Depending on the requirements of the sponsor, some of the tasks specified in this SOP may be carried out by WWORTH, CIs / PIs or TMs depending on the trial design and level of WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 22 of 37

delegation. Appropriate WWORTH members will attend MHRA Conferences on Pharmacovigilance in Clinical Trials. These events cover varying topics including applications to RECs and GCP audits and inspections and is specifically designed for non-commercial participants. They should obtain certificates of attendance to be files in their training log (see WWORTH SOP02 Training). Forthcoming MHRA conferences can be viewed at http://www.mhra.gov.uk/conferenceslearningcentre/conferences/index.htm. 8 References 1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. Official Journal of the European Communities 2. http://www.eortc.be/services/doc/clinical-eu-directive-04-april-01.pdf 3. The European Agency for the Evaluation of Medicinal Products (EMEA). ICH Topic E 6 (R1) Guideline for Good Clinical Practice 2002. http://www.ema.europa.eu/docs/en_gb/document_library/scientific_gui deline/2009/09/wc500002874.pdf 4. Department of Health. Research Governance Framework for Health and Social Care (2nd Edition) 2005 5. Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial http://ec.europa.eu/health/files/eudralex/vol- 10/2010_c82_01/2010_c82_01_en.pdf 6. European Commission 2006 Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use (located at http://ec.europa.eu/health/files/eudralex/vol- 10/21_susar_rev2_2006_04_11_en.pdf 7. http://www.hra.nhs.uk/research-community 9 Related SOPs WWORTH SOP02 Training WWORTH SOP03 Master Site Files WWORTH SOP05 Participant Info Consent WWORTH SOP07 Site Closure WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 23 of 37

WWORTH SOP13 Protocol Development WWORTH SOP15 MHRA Approval WWORTH SOP18b External Audit Inspection WWORTH SOP24 Randomisation WWORTH SOP31 Sponsorship and Adoption WWORTH SOP32 Detecting and Managing Misconduct, Serious Breaches and Deviations from GCP/protocol 10 Appendices Appendix 1 Appendix 2 Appendix 3 Appendix 4 Appendix 5 Example flowchart depicting the classification of adverse events where expectedness is assessed first Analysis of seriousness, expectedness, causality and severity of adverse events Exemplar of AE Screening Form Exemplar of SAE/SUSAR Report Form esusar questions WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 24 of 37

Appendix 1: Example flowchart depicting the classification of adverse events where expectedness is assessed first PI or other authorised person is made aware of a trial participant with a symptom(s) or problem(s) that may be a potential adverse event No Is the symptom a recognised (i.e. expected) undesirable effect Yes Is it a symptom of a pre-existing condition? Yes No Is it a symptom of disease exacerbation? Yes No Is it a medical / surgical procedure? Yes It is not an adverse event. It is the outcome of an adverse event No The symptom is an UNEXPECTED EVENT AND POTENTIALLY A SUSAR. Record seriousness & causality Is the unexpected event serious & causally related to the IMP administered? No Potential adverse event is not a SUSAR. Yes SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR). Yes Is it causally related to the IMP administered? Yes Is it serious? No No Serious Adverse Reaction (SAR) Adverse Reaction (AR) Is it serious? Yes No Serious Adverse Event (SAE) Adverse Event (AE) WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 25 of 37

Appendix 2: Analysis of causality, seriousness & expectedness of adverse events A1.1 Assessment of causality The PI will assess whether each AE is related to the use of the IMP informed by the following criteria as appropriate Criteria Strength Consistency Specificity Temporality Biological gradient Plausibility Coherence Experimental evidence Consideration of alternate explanations Description Defined by the size of the association as measured by appropriate statistical tests The association is consistent when results are replicated in studies in different settings using different methods This is established when a single putative cause produces a specific effect Does the exposure always precede the outcome? An increasing amount of exposure increases the risk. If a dose-response relationship is present, it is strong evidence for a causal relationship. However, as with specificity, the absence of a dose-response relationship does not rule out a causal relationship The association agrees with currently accepted understanding of pathological processes The association should be compatible with existing theory and knowledge The AR can be altered (prevented or ameliorated) by an appropriate experimental regimen In judging whether a reported association is causal, it is necessary to determine the extent to which researchers have taken other possible explanations into account and have effectively ruled out such alternate explanations A causal association is suspected between the trial drug and the AE if the relatedness is classified from the list below as possibly, probably or definitely. Decision Description Classification Not related Unlikely to be related Possibly related Probably related Definitely related Temporal relationship of the onset of the event, relative to the administration of the product, is not reasonable or another cause can itself explain the occurrence of the event. Temporal relationship of the onset of the event, relative to the administration of the product is unlikely but cannot be ruled out. Temporal relationship of the onset of the event, relative to the administration of the product, is reasonable and the event could have been due to another, equally likely cause. Temporal relationship of the onset of the event, relative to the administration of the product, is reasonable and the event is more likely explained by the drug than by any other cause. Temporal relationship of the onset of the event, relative to the administration of the product, is reasonable and there is no other cause to explain the event or a re-challenge is positive. AE AE AR AR AR WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 26 of 37

A1.2 Assessment of seriousness The PI must assess the AE as serious if the AE: a. Results in death; b. Is life-threatening 1 c. Requires hospitalisation 2 or prolongation of existing inpatients hospitalisation; d. Results in persistent or significant disability or incapacity; e. Is a congenital anomaly or birth defect; f. Is defined as such by an individual trial Note: Other important medical events that may not result in death, be lifethreatening, or require hospitalisation may be considered a serious adverse event/experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. A1.3 Assessment of expectedness (SARs only) An SAR is classified as unexpected (a SUSAR) if it is not included or is more severe than the reactions listed in the Summary of Product Characteristics (SmPC) (for a product with marketing authorisation) or in the investigator s brochure or protocol. 1 Life-threatening in the definition of serious 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 were more severe. 2 Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a preexisting condition do not constitute an SAE. WWORTH-SOP19PharmacovigilanceUrgentSafetyMeasuresV2.5-140507 Page 27 of 37