UNCONTROLLED COPY FOR PERSONAL USE, THE SIGNED ORIGINAL IS HELD BY THE ICRF QA MANAGER

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1 Title: SOP for Monitoring of Clinical Trials by ICRF Reference Number Author(s): Contact Details: Reviewer(s): ICRF-OR16.02 Jacob Bonner, Quality Assurance and Governance Manager Date written/revised: 03 Jan 2019 Approved by: Name, signature and date Ratified by: Name, signature and date Athanasia Gravani, Quality Officer ICRF Senior Management Team Q,H&S Committee Date SOP becomes Live: 18 February 2019 Due date for revision: 18 February 2022 Target Audience: Location of SOP: Related SOPs and Policies: Refer to section 7 Anyone involved in studies which are monitored by ICRF Electronic: Paper: ICRF Master File, Nurses Station, Staff Lounge This is a controlled document. Users may generate copies for training and reference purposes. Imperial CRF staff and researchers using the facility will be notified as updates become available but they are responsible for replacing local obsolete copies and ensuring staff are appropriately trained. QA Manager Use Only This section to be completed in red ink on controlled copies. All other copies are uncontrolled and the user is responsible for ensuring they use the current version. Controlled copy number Location Signature and date UNCONTROLLED COPY FOR PERSONAL USE, THE SIGNED ORIGINAL IS HELD BY THE ICRF QA MANAGER Document version numbering Version Date Updated by Reason for change 1 April 2018 Alan Sahin New SOP 2 January 2019 Jacob Bonner Changes related to drafting of monitoring plan, tracking visits and oversight of monitoring. ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 1 of 6

2 1.0 Background The NIHR Imperial CRF (ICRF) supports a broad range of clinical research studies involving both patients and healthy volunteers. A fundamental factor in conducting a clinical trial is efficient data collection and management which is then analysed to achieve the stated objectives of the study. Data management processes are required to ensure that the clinical trial report or publication contains results which are accurate and were captured in accordance with the clinical trial protocol. Only data that is relevant for the purpose of the Clinical trial should be recorded. 2.0 Purpose The EU Clinical Trials Directive 2001/20/EC, the GCP directive 2005/28/EC and the Medicines for Human Use Regulations 2004 (SI 2004/1031) set out the requirements for implementation of Good Clinical Practice (GCP) in clinical trials which involve the use of a medicinal product in humans in Europe and the UK. ICH E6 Good Clinical Practice guidance (E6 ICH-GCP; ) defines the purpose of clinical trial monitoring as verification of the following: a) Adequate protection of the rights and well-being of human subjects. b) The investigator is in compliance with applicable regulatory requirements, GCP guidelines, and the clinical study protocol. c) The reported clinical trial data are accurate, complete and verifiable from source documents. According to ICH GCP (5.18.3) the sponsor should determine the extent and nature of monitoring based on an assessment of the study including the objective, complexity, and endpoints of the clinical trial. For Imperial College London (ICL) and Imperial College Healthcare NHS Trust (ICHNT) sponsored trials, these responsibilities are delegated to the Chief Investigator. The purpose of this SOP is to provide detailed instructions for clinical trial monitoring where the ICRF has been given this responsibility and ensuring this is conducted, recorded and reported in accordance with GCP, protocol, SOPs and the applicable regulatory requirements. 3.0 Scope The SOP applies to all studies where the ICRF is responsible for carrying out monitoring activities. Any member of the ICRF core staff may carry out monitoring activities provided they are appropriately qualified and trained, and provided they have been delegated by the sponsor. For studies where the ICRF is not responsible for carrying out monitoring activities, monitoring will be conducted according to the sponsor s policies and procedures and will be facilitated by the ICRF. 4.0 Roles and Responsibilities 4.1 Sponsor Has the overall responsibility for the conduct of its studies, including ensuring the final output i.e. clinical study report or publication- contains results which are accurate and captured in accordance with the clinical trial protocol. In accordance with Good Clinical Practice (GCP) the sponsor should ensure appropriately qualified individuals are responsible for the overall conduct of the trial, handling of the data, verification of the data, conducting the statistical analysis and preparing the trial reports. 4.2 CI/PI The sponsor may delegate the task of ensuring that appropriate data management systems are in place before the study starts. The CI reviews and approves the trial s risk-based monitoring and data management plans on behalf of the sponsor. The PI is responsible for the ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 2 of 6

3 delivery of the study at their site and should work with the monitor to ensure that all findings are addressed. 4.3 Project Manager The Clinical Project Manager (CPM) is responsible for managing the trial on behalf of the sponsor / CI and will help to ensure that the study is appropriately monitored by facilitating on-site visits and helping to ensure that the Corrective and Preventative Actions (CAPAs) are appropriately implemented. The CPM will retain oversight of monitoring where this has been contracted to a 3 rd party. 4.4 Research/site staff (e.g. Doctors, Research Nurses, Clinical Trial Coordinators and Data Managers) They are responsible for collection of the source data, data entry and resolution of monitoring queries. 4.5 Monitor Appointed by the sponsor or their delegate to monitor the trial in accordance with the agreed risk-based monitoring plan. 5.0 Glossary CAPA CI CPM CRF ecrf GCP ICRF MHRA MVR PI SOP SUSAR TMF Corrective and Preventative Action Chief Investigator Clinical Project Manager Case Report Form Electronic Case Report Form Good Clinical practice NIHR Imperial Clinical Research Facility Medicines and Healthcare Products Regulatory Agency Monitoring Visit Report Principal Investigator Standard Operating Procedure Suspected Unexpected Serious Adverse Reaction Trial Master File 6.0 Procedure Clinical trial monitoring serves to provide ongoing oversight of clinical trial activities. The frequency of monitoring visits is based on the risk assessment and the requirements are specified in the clinical trial monitoring plan (ICRF-OR16 Fm1). The monitoring plan will be written by the monitor (or another qualified member of the team delegated by the CI) and approved by the Chief Investigator (CI) and the ICRF Quality Assurance and Governance Manager (QAGM). 6.1 Creating and Maintaining the Risk-based Monitoring Plan The monitoring plan should take into account risks identified in the protocol and the Clinical Risk Assessment and Management Plan (ICRF-OR09 Fm3). It will contain a monitoring-specific risk assessment, upon which the remainder of the plan will be based. It will set out in detail all aspects of the monitoring to be conducted, including the level of central and on-site monitoring, frequency of visits and areas of trial conduct to be reviewed The monitoring plan template (ICRF-OR16 Fm1) will be completed and signed off by the monitor, the CI and the ICRF QAGM prior to enrolment of the first participant in the ICRF. ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 3 of 6

4 6.1.3 The monitoring plan will specify to which participating sites it applies. Monitoring of external sites may be contracted to a 3 rd party, in which case a separate monitoring plan will be required, which will need to be reviewed and approved by the CI prior to the site commencing recruitment. Monitoring documentation generated by 3 rd parties under contract may use different templates Once finalised, the signed monitoring plan will be sent to each participating site to which it applies. Where monitoring has been contracted to a 3 rd party, they will be responsible for providing the monitoring plan to applicable sites, in accordance with their own procedures The monitoring plan will be periodically reviewed and updated whenever required. As a minimum the monitoring plan will be reviewed at the time of each substantial amendment to the trial and following identification of any serious breach of GCP in the trial. Any changes to the monitoring plan will be agreed by the monitor, the CI and the ICRF QAGM. Updated versions of the monitoring plan will be provided to all applicable participating sites. 6.2 Scheduling On-site Monitoring Visits: The trial monitor will schedule on-site visit(s) with the Principal Investigator (PI), the CPM and other relevant staff with at least 10 working days advance notice of the visit date, unless there is a serious issue requiring a more urgent visit. Internal visits confined to the ICRF may also be arranged at shorter notice where agreed by relevant staff The monitor will liaise directly with relevant staff when scheduling visits to departments outside the ICRF, such as pharmacy or radiology unless advised otherwise by the main site contact The monitor will require confirmation that the study files and all required source data will be available for the monitoring visit. At each visit, the monitor will review progress with previously agreed CAPAs The monitor will send written confirmation to the PI and CPM or equivalent, confirming the date and time of the visit, and outline the purpose of the visit Once dates are confirmed, the planned visit will be added to the monitoring tracker which is held on the ICRF shared network drive The following actions will be taken as part of the preparation for each on-site visit: Review of the monitoring plan Identification of the CRFs to be reviewed A preliminary review of the status of the CRF / ecrf should be carried out where possible to check data completeness Review of previous monitoring visit reports (MVRs), follow up letters, correspondence, and outstanding items to resolve ahead of the monitoring visit. Liaison with the site staff to identify any significant issues which have occurred since the previous visit and may require additional time during the planned monitoring visit (e.g. protocol deviations, SUSARs etc) ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 4 of 6

5 Review of recruitment rate in relation to the target/expected rate, in order to document the possible reasons for slow recruitment and plan actions to facilitate the overall study schedule. The reasons should be discussed with the ICRF CPM and a follow up plan be agreed with the site staff 6.3 Monitoring Outcomes Every monitoring activity will be documented in writing. Any observations, findings, CAPAs and responses from on-site visits will be documented using the MVR (template: ICRF-OR16 Fm2) which will be reviewed by the QAGM before sending to the site. The final MVR will be sent to the PI and other relevant staff within 10 working days of the visit. The final signed MVR and all relevant communications will be filed in the ISF, pharmacy file or TMF (as applicable) Central monitoring and other less formalised monitoring activities may be documented via correspondence CAPAs should normally be implemented by the time of the next monitoring visit unless otherwise agreed. The timeframe will be specified for major or critical findings. The monitor will review at least 20% of completed CAPAs to verify that they have been resolved as required and all CAPAs for major or critical findings A copy of the MVR and all relevant communications with participating sites should be stored in the TMF The monitor should discuss any significant findings and proposed CAPAs with the relevant site staff in person wherever possible before issuing the MVR Findings from previous visits which have not been resolved should be checked and will be followed up at subsequent monitoring visits The monitor will maintain a tracker of visits and CAPAs, and will communicate regularly with the QAGM and relevant CPMs to provide monitoring progress updates The monitor will report the following to the ICRF QAGM immediately and where required these issues will be escalated to the sponsor and/or regulatory authorities in accordance with applicable policies and procedures: Potential serious breach of GCP Suspected Fraud or Research Misconduct Persistent failure to implement agreed CAPAs Persistent failure of site staff to attend monitoring visits Obstruction of monitoring activities 6.4 Oversight of Monitoring The PI, CPM, QAGM and sponsor will maintain oversight of monitoring activities Where monitoring has been contracted to a 3 rd party, sponsor oversight will be described in the monitoring plan and may be achieved via one or more of the following means: ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 5 of 6

6 CPM receipt of monitoring reports. Where possible, these will be reviewed for obvious errors and inconsistencies. If required, documentation may be translated into English. Copies of reports will be provided to JRCO upon request. A random sample of data may be selected periodically for central review. The CI, CPM or other ICRF staff may liaise directly with the local site staff via . The sponsor may request further information or conduct audits at any time. 7.0 Related Documents and References: ICRF-OR09 Fm3 Clinical Risk Assessment and Management Plan ICRF-OR16 Fm1 Monitoring Plan Template ICRF-OR16 Fm2 Monitoring Report Template ICRF-OR16 Fm3 Monitoring Visit Checklist ICRF-OR16 Fm4 Monitoring Site Visit Log Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended) ICH Good Clinical Practice (E6): S tep_4_2016_1109.pdf 8.0 Appendices ICRF-OR16.02 Clinical Trial Monitoring v2.0, 03JAN2019 Page 6 of 6