STANDARD OPERATING PROCEDURE R&D SOP 330. Monitoring Clinical Trials. NNUH UEA Joint Research Office

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1 STANDARD OPERATING PROCEDURE R&D SOP 330 Monitoring Clinical Trials Version 1.4 Version date Effective date Number of pages 15 Review date November 2018 Author NNUH UEA Joint Research Office Approved by Lisa Chalkley Role Research Services Manager Signature Lisa Chalkley Date Authorised for NNUH Prof Alastair Forbes and UEA by Role Chief of Research and Innovation Signature Prof Alastair Forbes Date COPIES PRINTED FROM THE WEBSITE ARE VALID ONLY ON THE DAY OF PRINTING SOP 330 v 1.4 Effective date: Page 1 of 15

2 It is the responsibility of all users of this SOP to ensure that the correct version is being used. All staff should regularly check the NNUH R&D website for information relating to the implementation of new or revised versions of SOPs. Staff must ensure that they are adequately trained in the new procedure and must make sure that all copies of superseded versions are promptly withdrawn from use. The definitive versions of all Joint NNUH/UEA health care research SOPs appear online. If you are reading this in printed form please check that the version number and effective date is the most recent one as shown on the NNUH R&D website: TABLE OF CONTENTS 1 ABBREVIATIONS 3 2 INTRODUCTION 3 3 SCOPE 4 4 DEFINITIONS 4 5 RESPONSIBILITIES 5 6 PROCEDURES Risk Assessment Developing the Monitoring Strategy Monitoring Plan Preparing for monitoring visits During the visit Interim Monitoring Visits Following the visit Closure of the study UEA Monitored Studies Norwich Clinical Trials Unit Monitored Studies 9 7 REFERENCES 9 8 RELATED DOCUMENTS 9 9 LIST OF APPENDICES 9 Appendix 1: Focus of Monitoring Visits for NNUH Sponsored CTIMPs 10/11 and Device Studies Appendix 2: Frequency of Monitoring Visits - Guidance for NNUH 12/13 Sponsored Studies Appendix 3: Change control form and Revision sheet 14/15 SOP 330 v 1.4 Effective date: Page 2 of 15

3 1 ABBREVIATIONS CI Chief Investigator CTU Clinical Trials Unit CTIMP Clinical Trial of an investigational Medicinal Product GCP Good Clinical Practice ICH International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use IMP Investigational Medicinal Product NNUH Norfolk and Norwich University Hospitals NHS Foundation Trust PI Principal Investigator REN Research and Enterprise Services at University of East Anglia RF Research Facilitator SOP Standard Operating Procedure UEA University of East Anglia CRF Case Report Form SDV Source Data Verification SIV Site Initiation Visit SOV Sponsor Overview Visit TMF Trial Master File 2 INTRODUCTION The aim of this SOP is to describe the process for Monitoring of Clinical Trials sponsored by the Norfolk and Norwich University Hospitals NHS Foundation Trust. This SOP outlines the responsibilities of the Sponsor and Investigators with regard to monitoring clinical trials sponsored by the NNUH and describes the processes to be undertaken by the monitor or delegated staff to prepare, conduct, report and follow-up monitoring visits from study set-up until close down. Monitoring is an integral process in the Quality Control (QC) of a clinical trial. Monitoring is the act of overseeing the progress of the clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, applicable SOPs & policies, GCP, and the applicable regulatory requirement(s) (section 1.38 ICH Guideline for Good Clinical Practice E6 (R1), dated 10 June 1996) According to the principles of ICH GCP (section , ICH Guideline for Good Clinical Practice E6 (R1), dated 10 June 1996) the purposes of trial monitoring is to verify that: The rights and well being of human subjects are protected. The reported trial data are accurate, complete and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s). SOP 330 v 1.4 Effective date: Page 3 of 15

4 Monitoring is part of a multi-factor approach to ensure the quality of research for all NNUH sponsored clinical trials. Monitoring may take place by on-site visits or by centralized monitoring, or a combination of the two. 3 SCOPE This SOP applies to all clinical trials sponsored by NNUH which fall within the scope of the Research Governance Framework (2nd edition 2005) or its successor. Where additional legislation applies for example the Medicines for Human Use (Clinical Trials) Regulations 2004 (and amendments) or the Medical Devices Regulations 2002, required procedures will be indicated. External collaborators may require use of their own SOPs and this will be agreed during study set-up. It is the responsibility of the local PI to ensure that study specific SOPs can be operated without conflict to this SOP and in accordance with all organisational polices related to research. 4 DEFINITIONS Source Data Verification (SDV): An important part of monitoring is to compare the entries in case report forms (CRFs) with the original source documents (e.g. patient notes, test results). This procedure is known as Source Data Verification (SDV). On-site monitoring: Monitoring activities primarily undertaken during a physical visit to the investigator site by one or more monitoring personnel. Central or remote monitoring: Monitoring activities undertaken by the monitoring personnel in a location remote from the investigator site (for example, a data centre). Monitoring Plan: A description of the methods, responsibilities and requirements for monitoring the trial, according to the Integrated Addendum in GCP E6 (R2) Monitoring Report: A written report from the monitor to the sponsor after each site visit. Likelihood: the state or fact of something being likely. Probability Low Risk: Likely to be safe or without problem. Documentation and relevant experience/training in place. Medium Risk: Concern of a possible effect on safety and/or possible problem arising, but evidence presented to address possible safety issues/problems. The majority of essential documentation and training in place with evidence of a plan to acquire missing documentation/training in place. High Risk: Issues identified regarding safety and/or problems arising, with no evidence presented to address safety issues/problems. Essential documentation missing with no plan in place for acquiring documents. Evidence of relevant experience and or training not documented, or documented as deficient but with no plan in place to acquire necessary training/experience. 5 RESPONSIBILITIES SOP 330 v 1.4 Effective date: Page 4 of 15

5 Sponsor The Sponsor is responsible for overall management of trial. The Sponsor is responsible for the selection of monitoring personnel. The Sponsor should ensure that the monitor is appropriately qualified and trained to monitor the trial adequately. The Sponsor will determine the extent and nature of monitoring required for each sponsored clinical trial based on review of the risk assessment for the study. This will be documented in the trial specific risk adapted monitoring plan for which the Sponsor will provide approval. Monitor The main responsibility is for the monitor to act as the main line of communication between the sponsor and the investigator (ICH GCP E6 (R1) a) For NNUH sponsored CTIMPs the monitor should ensure that a trial specific monitoring plan is developed proportionate to the requirements of the study and its level of risk. This must be approved by the Sponsor prior to the study starting at site. The monitor is expected to comply with the monitoring plan and any deviations should have prior approval of the Sponsor. The monitor should be present at the site initiation visit (SIV). Interim monitoring visits are to be conducted at a frequency and intensity specified in the trial monitoring plan. At the end of study a close-out monitoring visit will be performed. Research Facilitator For non-ctimps sponsored by the NNUH, the Research Facilitator (RF) should ensure that a trial specific sponsor visit plan is developed proportionate to the requirements of the study and its level of risk. This must be approved by the Sponsor prior to the study starting at site. The RF is expected to conduct sponsor visit(s) in accordance with the sponsor visit plan and any deviations should have prior approval of the Sponsor. Chief Investigator/Principal Investigator The Chief Investigator (CI) should review and agree the monitoring plan and facilitate monitoring access for the study. The CI is to ensure that all essential documents/source data are available for inspection at monitoring visits, receive monitoring reports, act on any issues identified in the monitoring reports, as appropriate; respond to monitor requests for completion/correction of data, and coordinate trial management to facilitate central and/or site monitoring. The CI who will be based at the NNUH or the Principal Investigator (PI) based at additional study sites should liaise with the designated Pharmacist (Clinical Trial Pharmacist) to make sure that the records of IMP delivery, storage, accountability are maintained. SOP 330 v 1.4 Effective date: Page 5 of 15

6 6 PROCEDURES 6.1 Risk Assessment A risk assessment for a clinical trial should be agreed between the Sponsor and the Chief Investigator. In reviewing the study for approval, the Sponsor shall take a proportionate approach to risk assessment in determining approvals and informing the method of monitoring and the monitoring plan. Studies deemed to be medium risk may require extensive on-site monitoring while low-risk studies may appropriately employ more or exclusively, central monitoring. Refer to SOP 720 Risk Assessment for Trials Sponsored by the NNUH and UEA for further information. 6.2 Developing the Monitoring Strategy The monitoring strategy should be developed based on the outcome of the risk assessment and the nature of the study. The monitoring strategy should consider: i. The intensity (frequency and level of SDV) of monitoring; ii. The focus of the monitoring; and iii. The methods (on-site or central, or a combination thereof) for monitoring. The Monitoring strategy will be documented, and include the rational for the strategy chosen. (e.g. in the monitoring plan), according to the Integrated Addendum in GCP E6 (R2). For NNUH Sponsored CTIMPs and Medical Device Studies For CTIMP and Medical Device Studies, developing a monitoring strategy is based on a two part process; refer to Appendix 1 for the focus of the monitoring plan. The focus is based on the type of the CTIMP and/or Medical Device and the level of risk associated with the design methods or conduct of the trial (other than the intervention) which remain after mitigations are in place. Once the focus of the monitoring plan has been established, refer to Appendix 2 for a guide to the frequency of the monitoring visits. This is based on the overall level of risk after mitigations are in place. For other Studies Sponsored by the NNUH For non CTIMP/Medical Device Studies, refer to Appendix 2 only for the guide to the frequency of the sponsor visits. This is based on the overall level of risk after mitigations are in place. 6.3 Monitoring Plan For NNUH Sponsored CTIMPs and Medical Device Studies A trial specific monitoring plan will be developed by the monitor adopting a risk adapted strategy for monitoring. The monitoring plan should be agreed between the Sponsor and the Chief Investigator and approved by the Sponsor prior to Sponsor SOP 330 v 1.4 Effective date: Page 6 of 15

7 approval to start the study at site. The monitoring plan should detail the frequency and nature of the visits or activities relating to the trial. If the level of risk is low for particular aspects of a trial it may be appropriate to monitor centrally rather than by a site visit. Source data for the study will be defined and source data verification with the CRF will be planned. Monitoring should be proportionate to the objective, design, complexity, blinding and endpoints associated with the study. The monitoring plan will be presented at the site initiation visit and a copy retained in the TMF. Monitoring visits will be performed at the therapeutic department in which the clinical trial is being run and at the pharmacy department in which the study medication is stored and dispensed. The monitoring plan should be reviewed during the course of the study in terms of relevance and effectiveness. If during the course of the study, concerns are raised either by the Investigator or by the Sponsor, the monitoring plan shall be reviewed. Any deviations from the previously approved monitoring plan should be approved by the Sponsor and reported to the Joint Research Governance Committee. A copy of the agreed monitoring plan and any subsequent revisions and relevant correspondence should be saved in the shared drive study projects folder under monitoring and in ReDA under the project folder documents. A study initiation visit/meeting should take place before recruitment begins at the site. The study monitor will work with the CI/PI and the trial manager/trial coordinator to ensure that all essential documents are in place, that trial processes are discussed with the study team and research staff have been trained in study procedures before the study starts. This will involve, but will not be limited to, checking that staffs are trained in SOPs and GCP. Refer to SOP 325 Study Start Up Activities for Clinical Research Trials. For other Studies Sponsored by the NNUH Refer to the Guidance Document for Sponsor oversight of non-ctimps sponsored by Norfolk and Norwich University Hospitals NHS Foundation Trust for the monitoring of non-ctimps sponsored by the NNUH. The document is filed on ReDA - Work Area SOP Store NNUH Office Procedures. 6.4 Preparing for monitoring visits The monitor should inform the research team where, when and for how long the visit will take place. The site file, all case report forms and source documents should be available for monitoring visits. If large numbers of patients have been recruited the monitor should agree with the research team which patient files will be reviewed prior to the visit. The monitor will inform the CI and PI of the schedule of monitoring visits The monitor will arrange with the research team for a room/desk to be available for the visit. SOP 330 v 1.4 Effective date: Page 7 of 15

8 If other departments (e.g. pharmacy) are to be visited they should be informed and arrangements made to review the files. 6.5 During the visit A member of the research team should be available during the visit to ensure that all case report forms and source data is available. If required, the CI or PI should be available for part of the visit. The monitor will usually require a review of the case report forms and source data alone and then arrange to meet with CI/PI or a delegated member of the research team to discuss the summary of findings (when applicable). The monitor will complete the monitoring report. Specific monitor activities are listed in ICH GCP E6 (R1) 1996 section and the Integrated Addendum in GCP E6(R2). 6.6 Following the visit All source documents should be returned to the respective departments. The monitor will submit the Monitoring Report to the CI/PI and the Sponsor within 2 weeks of the visit (or as per Monitoring Plan), summarising what has been reviewed and stating significant findings and discrepancies. They should also include any recommendations for corrective and preventative action. The Monitoring Report should be filed in the study file. The monitor will also file an electronic copy of the report on the R&D office database. The CI/PI should ensure that all outstanding actions are addressed promptly, and prior to the next visit, unless a specific time for implementation is required. 6.7 Interim Monitoring Visits Interim monitoring visits will be carried out at a frequency and extent defined in the monitoring plan. If interim monitoring visits identify any individual events or a series of events which may be considered as potential serious breach of GCP and/or protocol, the monitor should ensure that the findings are escalated to the Sponsor as soon as possible after they are identified. Reporting and escalation processes detailed in SOP 210 on Breaches of GCP or Trial Protocol should be followed. 6.8 Closure of the study Following notification to the Sponsor of last patient last visit, the monitor should arrange a final close-down visit. This is to ensure that all essential documents at site are complete/reconciled, any outstanding follow-up or corrective actions are completed by the study team, that drug accountability is complete and to ensure that data is prepared for archiving. Site close-down visits are mandatory and it is the responsibility of the CI to ensure that these occur for sites that have been activated (i.e. site initiation took place). A close-down report will be completed by monitor after the visit and a copy of this will be filed in the TMF and investigator site file. SOP 330 v 1.4 Effective date: Page 8 of 15

9 6.9 UEA Monitored Studies Please refer to SOP 705 Quality Control and Quality Assurance for further guidance Norwich Clinical Trials Unit Monitored Studies For either NNUH or UEA sponsored studies that the Norwich Clinical Trials Unit (NCTU) has been delegated to monitor, their monitoring processes and documentation will apply. 7 REFERENCES ICH Harmonised Tripartite Guideline for Good Clinical Practice E6 (R1), dated 10 June 1996 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, E6 (R2), Step 2, Dated 11 June 2015 NIHR Clinical Trials Toolkit: Trial Management and Monitoring. MHRA risk-adapted approaches to the Management of Clinical Trials of Investigational Medicinal Products 8 RELATED DOCUMENTS SOP 210 Breaches of Good Clinical Practice or the Trial Protocol SOP 325 Study Start-up Activities for Clinical Research Trials SOP 400 Joint Arrangements for Research Authorisation of Research Sponsorship SOP 705 Quality Control and Quality Assurance SOP 720 Risk Assessment for Trials Sponsored by the NNUH and UEA Guidance Document for Sponsor oversight of non-ctimps sponsored by Norfolk and Norwich University Hospitals NHS Foundation Trust. 9 LIST OF APPENDICES Appendix 1 Focus of Monitoring Visits for NNUH Sponsored CTIMPs and Device Studies Appendix 2 Frequency of Monitoring Visits - Guidance for NNUH Sponsored Studies Appendix 3 Change control, Revision and Revision sheet Appendix 1: Focus of Monitoring Visits for NNUH Sponsored CTIMPs and Medical Device Studies SOP 330 v 1.4 Effective date: Page 9 of 15

10 Risk associated with the IMP and or Device. Concerns identified in the assessment of risk associated with the design Methods or conduct of the trial (other than the intervention) which remain after migrations are in place. No Yes Where a study is both a IMP and device Trial the higher level of intensity of the two will be followed for monitoring purposes. Low Risk Likely to be safe or without problem. Documentation and relevant experience / training in place. Medium Risk Concern of a possible effect on safety and / or possible problem arising, but evidence presented to address possible safety issues / problems. Majority of essential documentation and training in place with High Risk Issues identified regarding safety and or problems arising, with no evidence presented to address safety issues / problems. Essential Documentation missing with no plan in place for acquiring documents. Evidence of relevant experience and or evidence of a plan to training not demented / acquire missing documented, with no plan documentation / training in place to acquire in place. necessary training / experience Low intensity Central Monitoring of As per Low Intensity, A mitigating action plan Type A risk comparable to that of standard medical care protocol adherence and data quality. No requirement for site visiting unless there are concerns identified from central monitoring that plus appropriate monitoring to address the specific Vulnerabilities identified in the risk assessment will need to be in place and documented prior to the acceptance of the study. If risks are identified which are not appropriately CE marked device used within its intended purpose(s) cannot be addressed by other means. managed/mitigated by the study team the RSM/RGC will decide appropriate action including halting study set up activities. Moderate intensity Central monitoring of As per moderate A mitigating action plan Type B risk somewhat higher than that of standard medical care safety data quality and timeliness as well as protocol adherence and quality of other trial data. Triggered visits for poor data return or protocol intensity plus appropriate monitoring to address the specific Vulnerabilities identified in the risk assessment. will need to be in place and documented prior to the acceptance of the study. If risks are identified which are not appropriately managed/mitigated by the adherence concerns as study team the RSM/RGC SOP 330 v 1.4 Effective date: Page 10 of 15

11 CE marked device which has been modified or will be used outside its intended purpose(s) well as unusually low or high frequency of SAE reports (for studies where between sites comparisons are possible.) will decide appropriate action including halting study set up activities. High intensity More intense monitoring As per higher intensity If risks are identified which Type C risk markedly higher than that of standard medical care than above to have confidence in the completeness and reliability of safety data For High level monitoring liaise with Research plus appropriate monitoring to address the specific Vulnerabilities identified in the risk assessment are not appropriately managed/mitigated by the study team the RSM/RGC will decide appropriate action including halting study set up activities. Non-CE marked device Governance Coordinator and Research Services Manager to ensure appropriate monitoring plan is devised. SOP 330 v 1.4 Effective date: Page 11 of 15

12 Appendix 2: Frequency of Monitoring Visits - Guidance for NNUH Sponsored Studies Likelihood Definition Monitoring Visit Plan Guidance CTIMPs Non CTIMPS Low Likely to be safe or without 1 st MV = SIV Research Facilitator to discuss with the Research Governance Co- problem. Documentation and relevant experience / training in place. 2 nd MV = after FPFV (No later than 14 days after) include labs and pharmacy items. ordinator and/or Research Services Manager to decide whether a study sponsor oversight visit (SOV) is required, the decision will be made by the Research Services Manager and clearly documented. 3 rd MV = first patient has completed. Include labs and pharmacy items if previous visit finding indicate it would be appropriate A sponsor review visit after recruitment of first participant should be conducted, If there are significant issues identified during the sponsor Close Down MV. review visit, a full audit of the study will be scheduled after discussion with the Research Services Manager Centralised monitoring can commence after 2nd MV if recent MV Report Indicate it to be appropriate. If centralised monitoring is not deemed appropriate a revised monitoring plan will be implemented. Medium Concern of a possible effect 1 st and 2 nd MV = as above Research Facilitator to conduct SOV and any concerns raised from on safety and / or possible problem arising, but evidence presented to address possible safety issues / problems. Majority of essential 3 rd MV = after 3 rd patient has been consented for studies recruiting 3+ participants. OR first patient is half way through if recruitment target is less than 3. Whichever comes first. Include labs and pharmacy items if previous visit finding indicate it would be appropriate. the SOV to be addressed with the Research Governance Coordinator and/or Research Services Manager. A sponsor review visit after recruitment of first participant should be conducted, If there are significant issues identified during the sponsor review visit, a full audit of the study will be scheduled after documentation and training in 4 th MV = first patient has completed. Include Labs and pharmacy items discussion with the Research Services Manager place with evidence of a plan SOP 330 v 1.4 Effective date: Page 12 of 15

13 to acquire missing documentation / training in place. Joint Arrangements for Research Close Down MV. Centralised monitoring can commence after 3rd MV if recent MV Report Indicate it to be appropriate If centralised monitoring is not deemed appropriate a revised monitoring plan will be implemented. High Issues identified regarding safety and or problems arising, with no evidence presented to address safety issues / problems. Essential Documentation missing with no plan in place for acquiring documents. Evidence of relevant experience and or training not demented / documented, with no plan in place to acquire necessary training / experience. For new studies any aspect rated high risk after mitigating factors have been taken into account will not be accepted for sponsorship. Sponsorship will be reviewed once it has been demonstrated that appropriate mitigating factors has been implemented to reduce the likelihood of risk to at least a medium risk level. In the case of existing studies every effort will be made to implement appropriate mitigating factors and monitoring plan, however if this is not possible the study will be halted until appropriate mitigating factors and monitoring plan are in place. SOP 330 v 1.4 Effective date: Page 13 of 15

14 Appendix 3: Change Control, Revision and Review Sheet CHANGE CONTROL, REVISION and REVIEW SHEET: SOP 330 Version No Change Reason for Change Date 1.2 Updated to include paragraph on risk assessment and associated references. Updated Monitoring report form added as Appendix 1 Reviewer : R Mold Designation: Head of Joint Research Office Signature and date /08/2015 Updates to all sections to reflect working arrangements. Monitoring report form removed from appendices. Reviewer: S Gopinath Designation: Research Governance Co-ordinator Signature and date: /11/2016 Updated web link to SOPs Research Facilitator responsibilities added Updates made to definitions Guidance for developing the monitoring strategy added. Guidance for monitoring Sponsored Non-CTIMPs added. Reference to SOP 720 Risk Assessment for Trials Sponsored by the NNUH Reference to Guidance Document for Sponsor oversight of non-ctimps sponsored by Norfolk and Norwich University Hospitals NHS Foundation Trust added. SOP 330 v 1.4 Effective date: Page 14 of 15

15 Addition of 6.9 UEA Monitored Studies Addition of 6.10 Norwich Clinical Trials Unit Involvement Update with references to GCP E6R2 Appendix 1: Focus of Monitoring Visits for NNUH Sponsored CTIMPs and Device Studies added Appendix 2: Frequency of Monitoring Visits - Guidance for NNUH Sponsored Studies added. Reviewer: Designation Signature and date: Francesca Dockerty Clinical Trial Monitor Francesca Dockerty 10Nov2016 SOP 330 v 1.4 Effective date: Page 15 of 15