Date: 21 st May 2014 Version: 5 Page 1 of 11. Principal Author Name D. Skelhorn Signature: D. Skelhorn Date: 22 nd May 2014

Transcription

1 Date: 21 st May 2014 Version: 5 Page 1 of 11 STANDARD OPERATING PROCEDURE FOR MONITORING CLINICAL TRIALS (NWORTH 3.07) Approvals Principal Author Name D. Skelhorn Signature: D. Skelhorn Date: 22 nd May 2014 Quality Assurance Officer Name: p.p. J. Ryan Signature: J. Ryan Date: 22 nd May 2014 NWORTH Director Name: R.T. Woods Signature: R.T. Woods Date: 27 th May 2014 Disclaimer: Printed SOP's are considered uncontrolled. To ensure you are working with current version always refer to the pdf version on the NWORTH website North Wales Organisation for Randomised Trials in Health (& Social Care) (NWORTH) Institute of Medical & Social Care Research (IMSCaR) Y Wern, Holyhead Road, Bangor University, Bangor, Gwynedd, LL57 2PZ Telephone: nworth@bangor.ac.uk

2 SOP number: NWORTH 3.07 Page 2 of 11 DOCUMENT HISTORY Version number Effective date Authorship (compiled) S.H. Roberts S.H. Roberts E. Bedson S.H. Roberts E. Bedson 4 29/03/12 S.H. Roberts E. Bedson D. Skelhorn Summary of changes New Updates SOP numbering and layout, safety monitoring reported in SOP 4.03 Responsibilities updated and minor text changes to section5 5 02/06/14 D. Skelhorn Minor changes. Layout and SOP references standardised, links updated, reference to monitoring plan development added to flowchart and section 5.3, duplication removed from section Table of Contents 1. Table of Contents Purpose Scope Responsibilities Procedure Process Flow chart Overview of monitoring requirements Setting up a trial monitoring structure Safety monitoring and reporting Inspections and site visits Training plan for SOP implementation Glossary of Terms References Referenced SOPs Appendices... 11

3 SOP number: NWORTH 3.07 Page 3 of Purpose To describe the way trial monitoring will be planned and carried out by NWORTH. 3. Scope This SOP applies only to trials where all monitoring responsibilities have been delegated to NWORTH. For the purposes of this SOP, the term monitor will be used to refer to any member or committee designated by NWORTH to undertake specific monitoring task. 4. Responsibilities All staff associated with NWORTH who have been delegated monitoring activities should ensure that they are familiar with this SOP, particularly staff working in clinical trials with Investigational Medicinal Products (IMPs). The sponsor has overall responsibility for ensuring a trial is monitored (see SOP 4.04 arranging sponsorship, contracts/agreements and indemnity). However, the sponsor can delegate trial monitoring activities to NWORTH. Where the University is the sponsor, monitoring activities may be delegated to NWORTH through the CoHaBS board. NWORTH Trials Unit Manager is responsible for ensuring: that the requirements of this SOP are adhered to, the tasks that are delegated to the trial manager are clearly documented in the delegation log. Trial Manager (TM) - when delegated monitoring duties is responsible for ensuring they have: a thorough understanding of trial monitoring requirement as documented in the Research Governance Framework for Health and Social Care and for good clinical practice guidelines (where applicable ICH topic E6(R1)), a thorough understanding of the relevant clinical trials (CT) regulations, adequate documented training to carry out the monitoring activities, when tasks specified within this SOP are delegated to the TM.

4 SOP number: NWORTH 3.07 Page 4 of Procedure 5.1 Process Flow chart Sponsor in discussion with NWORTH determines level of monitoring required Develop monitoring plan during protocol development, based on risk assessment Trial Manager or other person/committee appointed to carry out monitoring duties Is a monitoring committee required? Yes Monitoring structure established (Sponsor may delegate the task of setting up TMG, TSC, and DMEC to NWORTH, CI / PI, or TM). No Verification that conduct of trial is in accordance with the protocol and principles of GCP Report findings to CI/PI and Sponsor Note: Safety monitoring and reporting is NWORTH 4.03 Safety monitoring including pharmacovigilance.

5 SOP number: NWORTH 3.07 Page 5 of Overview of monitoring requirements Monitoring is defined in section 1.38 of the ICH guideline GCP as: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirement(s) According to section of the ICH guideline GCP, the purposes of trial monitoring are to verify that the: Rights and well-being of the human participants are protected Reported trial data are accurate, complete and verifiable from source documents; Conduct of the trial is in compliance with the currently approved protocol / amendment(s), with GCP and with the applicable regulatory requirements. Note: Adherence to GCP is required for all clinical trials. However, adherence to ICH guideline (E6(R1)) is required only for commercial CTIMP studies but provides a good example how monitoring activities should be set up and implemented for other trials. Setting up a trial monitoring structure and reporting Adverse Events (AEs) are key monitoring activities. This SOP will provide guidance on setting up the monitoring structure only. For AE reporting see SOP 4.03 Safety monitoring including Pharmacovigilance. For CTIMPs a formal monitoring structure must be established where the role and responsibilities of the monitor(s) are delegated to the Trial Steering Committee (TSC). This is also true for CTs of non-pharmacological interventions. The duties associated with monitoring can then be delegated to NWORTH by the TSC. Central monitoring of data using statistical techniques is also useful for identifying unusual patterns in the data and can be used to identify sites or contributors that may be deviating from the protocol. In line with GCP, individuals monitoring trials should be appropriately trained and have the scientific/clinical knowledge needed to monitor the trial adequately. A formal record of the qualifications and training of monitoring individuals should be kept. They should be thoroughly familiar with the intervention, the protocol, consent form and any other written information to be provided to human participants, the sponsor s SOPs relating to clinical trials, relevant NWORTH SOPs, GCP and the applicable regulatory requirement(s). The monitor(s) should act as the main line of communication between the sponsor and the investigator(s), and their responsibilities include: verifying that the investigator has adequate qualifications and resources, and will remain adequate throughout the trial period; and that facilities including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial verifying that storage conditions, supplies, instructions, dispensing recording and disposal of the investigational product(s) are acceptable

6 SOP number: NWORTH 3.07 Page 6 of 11 Verifying, for investigational product(s): a) that the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s) b) subjects are provided with necessary instruction on properly using, handling, storing and returning the investigational product(s). c) the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately d) the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor. verifying that investigator(s) comply with the protocol verifying that written consent is obtained for each participant verifying that investigator(s) have all the up-to-date required documents to conduct the trial properly and to comply with the regulatory bodies ensuring that all investigator(s) and trial staff are adequately informed of the trial verifying that all investigator(s) and trial staff are adequately performing the trial functions in accordance with the protocol and any agreement with the sponsor, and have not delegated these functions to unauthorised individuals verifying that investigator(s) are enrolling only eligible subjects reporting subject recruitment rates verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained checking completeness of CRFs by specifically verifying that: a. the data required by the protocol are reported accurately on the CRF b. treatment modifications are well documented for each trial subject c. AEs are reported in accordance to the protocol d. visits or tests/examinations which were not conducted are clearly reported as such on the CRF e. all withdrawals and dropouts are reported and explained on the CRF and investigator(s) informed of any error on the CRF determining whether all AEs are reported adequately in the time frames specified by the protocol, sponsor, and regulatory authorities determining whether essential documents in the Trial Master File (TMF) are maintained communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations Monitoring is designed to demonstrate a trial s quality by continuously verifying that trial related activities are performed appropriately and to quality standards, i.e. in line with current protocol, GCP and regulatory requirements (Quality Control (QC)). Assessing and assuring the reliability and integrity of the quality control systems is undertaken through audit rather than by monitoring as this type of Quality Assurance (QA) is about measuring performance against a set of standards. Implementing QA is also the responsibility of the sponsor but is not covered by this SOP. This SOP is concerned only with monitoring (i.e. QC).

7 SOP number: NWORTH 3.07 Page 7 of 11 Prior to a trial starting, the sponsor in discussion with the CI/PI (and where applicable NWORTH) will decide the extent and nature of monitoring required. The type of monitoring should reflect the size, complexity and risks (both to the human participants and to the results) associated with the trial. Specific trial monitoring procedures and processes should be detailed in the trial protocol (see SOP 3.02 Protocol Development). 5.3 Setting up a trial monitoring structure An appropriate trial monitoring structure must be in place for all trials. For some trials (e.g. pilot studies or non-drug trials) the sponsor may deem it acceptable to identify an appropriately trained person to serve as monitor. Where possible the monitoring plan should be developed during protocol development and should be based on a risk assessment of the study.the Sponsor and the CI need to agree the monitoring plan and determine the extent and nature of monitoring required as stated above. For large, multi-centre trials and/or CTIMPs, an independent monitoring structure is required. This structure should be as follows: Trial Management Group (TMG) Individuals responsible for the day-to-day running of the trial should be included in this group. These include CI, PIs, TM, statistician, research staff, data manager, and collaborating clinicians, as necessary. The TMG s role is to monitor all aspects of the trial s conduct and progress. The group should ensure the protocol is adhered to, take appropriate action to safeguard participants, and ensure the quality of the trial itself. Trial Steering Committee (TSC) A TSC is set up to oversee the running of the trial on behalf of the sponsor/funder and has the overall responsibility for the continuation or termination of the trial. Committee membership should include individuals who are independent of the trial and investigators (in particular an independent chairperson), a public involvement representative as well as the CI and TM. The role of the TSC is to ensure that the trial is being conducted in accordance with the principles of GCP and the relevant regulations, and provide advice on all aspects of the trial. A trial protocol and any subsequent amendments must be agreed by the TSC. Data Monitoring and Ethics Committee (DMEC) It is NWORTH policy that an independent DMEC should be set up for all full trials and must be set up for any trial of an investigational medicinal product (IMP) or medical device (MD). The DMEC may be a subcommittee of the TSC providing all members are independent from the trial investigators and sponsor/funder, and that a sufficient quorum of the remaining independent TSC members (no less than 2 members) is available for decision making. The role of the DMEC is to review the accruing trial data and to assess whether there are any concerns about the safety of the intervention. DMECs are responsible for considering any newly published research data which might affect the trial, any additional information that should be passed on to participants, and any reasons that affect the continuation of the trial. The trial

8 SOP number: NWORTH 3.07 Page 8 of 11 statistician must be available to answer any questions and to provide blinded and, if requested, unblinded trial data for interim analysis. The TMG will provide regular safety reports to the DMEC. The DMEC reports to and makes recommendations to the TSC. Day to day monitoring of the trial must take place to ensure that: collected data are consistent with protocol adherence; only authorised persons complete Case Report Forms (CRFs); there are no missing data; data are valid through validation checks (e.g. range and consistency checks); and, recruitment rates, withdrawals and losses to follow-up are reviewed overall and by site. Communication is key to the effective monitoring of a trial. The CI/PI will communicate regularly with: staff involved with conducting the trial; all PIs at participating sites; and the clinical trials unit NWORTH. It is considered good practice for the Sponsor to provide an annual progress report to the REC, The HRA web site contains a standard template for reporting. 5.4 Safety monitoring and reporting For monitoring and reporting the safety of an intervention see NWORTH SOP 4.03 Safety monitoring including Pharmacovigilance which covers the requirements for MHRA Development update safety reports (DSURs). 5.5 Inspections and site visits As part of the monitoring process, on-site visits may be necessary to verify the appropriate conduct of the trial, particularly for multi-centre trials. In general there is a need for on-site monitoring, before, during, and after the trial. Arrangements for site visiting may vary from routine visits to all sites, visits to a random selection of sites or visits targeted at less experienced sites or those for which the trial s central monitoring procedures suggested possible problems. For trials involving an investigational medical product or a medical device, the MHRA may make additional site visits to ensure compliance with the regulations (see NWORTH SOP 4.02 for MHRA approval). Following each site visit the monitor or monitoring committee should submit a written report to the CI with a copy to the PI and site staff. The report should include: the date, site, name of the monitor(s) and name of the investigator or other individual(s) contacted a summary of what the monitor(s) reviewed and the monitors statements concerning the significant findings, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance

9 SOP number: NWORTH 3.07 Page 9 of 11 The review and follow-up of the monitoring reports on the site visits should be documented by the CI (or person to whom the CI has delegated this duty). 6. Training plan for SOP implementation Training will be carried out in accordance with NWORTH training SOP Glossary of Terms AE Adverse Event Any adverse occurrence happening to a patient in a clinical trial, whether or not that occurrence is thought to be a reaction to the trial intervention. An AE can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the trial intervention. CI Chief Investigator The investigator with overall responsibility for the research. In a multi-site study, the CI has co-ordinating responsibility for research at all sites. All applications for ethical review should be submitted by the CI. CRF Case Report Form A printed, optical or electronic document designed to record all of the protocolrequired information to be reported to the sponsor on each trial subject. CTIMP Clinical Trial of an Investigational Medicinal Product Any investigation in human subjects, other than a non-interventional trial, intended: a. To discover or verify the clinical, pharmacodynamic effects of one or more medicinal products; b. To identify any adverse reactions to one or more such products; c. To study absorption, distribution, metabolism and excretion of one or more such products with object of ascertaining the safety or efficacy of those products. DMEC GCP Data Monitoring and Ethics Committee Good Clinical Practice, as defined by the ICH ICH International Conference on Harmonisation of Technical Requirementsof registration of pharmaceuticals for human use. IMP Investigational Medicinal Product A pharmaceutical form of an active substance or placebo being tested, or used, or to be used, as a reference in a clinical trial, and includes a medicinal product which has a marketing authorisation but is, for the purposes of the trial: a. Used or assembled (formulated or packaged) in a way different from the form of the product authorised under the authorisation; b. Used for an indication not included in the summary of product characteristics under the authorisation for that product;

10 SOP number: NWORTH 3.07 Page 10 of 11 c. Use to gain further information about the form of that product which are relevant to the study of the product in human subjects. MD Medical Device Any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of: - diagnosis, prevention, monitoring, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, - investigation, replacement or modification of the anatomy or of a physiological process, - control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. MHRA Medicines and Healthcare products Regulatory Agency MHRA (medicines) is the competent authority for the UK in relation to the EU Directive and the Clinical Trials Regulations. MHRA (Devices) is the competent authority for the UK in relation to the medical Devices Regulations NWORTH care) North Wales Organisation for Randomised Trials in Health (and social PI Principal Investigator The investigator responsible for the research site where the study involves specific procedures requiring site-specific assessment. There should be one PI for each research site. In the case of a single-site study, the CI and PI will normally be the same person. QA Quality Assurance All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s). QC Quality Control The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. Sponsor The person who takes on ultimate responsibility for the initiation, management, financing (or arranging the financing) of a clinical trial. SOP Standard Operating Procedure. Written instructions and records of procedures agreed and adopted as standard practice. TM TMF Trial Manager Trial Master File

11 SOP number: NWORTH 3.07 Page 11 of 11 File kept at NWORTH for each trial containing essential documents for that trial, as defined for CTIMP in section 8 of ICH GCP) TMG TSC Trial Management Group Trial Steering Committee 8. References 1. Fellows, T., ICH Harminised Tripartite Guideline for Good Clinical Practice. GCP Training. 2004, Marlow, Bucks: Institute of Clinical Reserach. 2. University of Sheffield, Standard Operating Procedure ( SOP ) for Universitysponsored Clinical Trials of Investigational Medicinal Products ( IMP-Trials ): Monitoring of University-Sponsored Clinical Trials of Investigational Medicinal Products (IMP-Trials). 2006, University of Sheffield: Sheffield. 3. National Institute of Allergy and Infectious Diseases, Clinical Trial Monitoring SOP. 2007, National Institute of Allergy and Infectious Diseases. 4. The European Parliament and the Council of the European Union, Directive 2001/20/EC of the European Parliament and of the Council of 4 April Official Journal of European Union, Article 2(Definitions): p. L121/36- L121/ ICH E6 (R1) Guideline to good clinical practice Referenced SOPs NWORTH Training SOP 2.01 NWORTH Protocol development SOP 3.02 NWORTH Trial initiation and Site set up SOP 3.03 NWORTH Trial supplies/labelling SOP 3.08 NWORTH NHS Ethical and Research & Development Approval SOP 4.01 NWORTH MHRA approval SOP 4.02 NWORTH Safety monitoring including Pharmacovigilance SOP 4.03 NWORTH Arranging sponsorship, contracts/agreements and indemnity SOP Appendices None