SOP17: Standard Operating Procedure for Monitoring · 6 Procedure As detailed in SOP31 Sponsorship and Adoption for in-house trials, there may be flexibility in the central monitoring

Canolfan Hap-dreialon Iechyd Gorllewin Cymru – yn Abertawe

West Wales Organisation for Rigorous Trials in Health (WWORTH) – the Clinical Trials Unit in Swansea Prifysgol Abertawe Coleg Meddygaeth Swansea University College of Medicine Athrofa Gwyddor Bywyd 2, Parc Singleton Institute of Life Science 2, Singleton Park Abertawe SA2 8PP Swansea SA2 8PP Ffon (01792) 606545 Ebost [email protected] Phone (01792) 606545 Email [email protected]

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WWORTH-SOP17_Monitoring_V2.6 MS edits 140506 Page 1 of 82 Not guaranteed if printed

SOP17: Standard Operating Procedure for Monitoring

Authorship Team: Jemma Hughes, Tina Morgan, Kirsty Price, Mel Storey, Lisa Seale for Joint SOP Group on Trial Processes (viz Alex Nicholson, Leanne Quinn, Ian Russell, Anne Seagrove, John Williams, Bridget Wells, Yvette Ellis) Approved by WWORTH JMG (Ian Russell in chair)

Signature: __________________________ Date: ____________________

0 Version Record

Version Number Effective Date Reason for Change 0 01 Dec 2008 Derived from SOP approved by NWORTH

0.1 27 Mar 2009 Reviewed by JSOPG on 27th March 2009

0.2 14 Apr 2009 Further edits based on discussions at JSOPG on 27th

March 2009

0.3 23 Apr 2009 Reviewers tracked changes added

0.4 02 Jun 2009 Further edits based on JSOPG 22nd

May 09

0.5 12 Jun 2009 Further edits by KT

1.0 31 Jul 2009 Approved in principle at JMG

1.1 16 May 2010 Minor formatting amendments

1.2 13 Oct 2011 Revise SOP for JSOPG by MS. Egs in use, CONSTRUCT, CRU any trial, PROBAT.

1.3 18 Oct 2011 Further edits made by JH

1.4 18 Oct 2011 Further edits made by CD

1.5 08 Dec 2011 Further edits made by JH

1.6 06 Feb 2012 Further edits made by JH

1.7 14 Mar 2012 Agreed minor amendments

1.8 27 Mar 2012 Formatting amendments

2.0 02 Apr 2012 Authorised for use by JEG

2.1 11 Jan 2013 Revisions to reflect new process

2.2

02 Jul 2013 Formatting amendments/Further edits to describe new processes

2.3 30 Aug 2013 Edits for further clarification

2.4 11 Dec 2013 Further edits following JSOPG discussion on October 25

th 2013

2.5 26 Mar 2014 Edits by LS following JSOPG discussion

2.6 06 May 2014 MS amendments post JSOPG discussion

mailto:[email protected]


Canolfan Hap-dreialon Iechyd Gorllewin Cymru – yn Abertawe West Wales Organisation for Rigorous Trials in Health (WWORTH) – the Clinical Trials Unit in Swansea

Prifysgol Abertawe Coleg Meddygaeth Swansea University College of Medicine Athrofa Gwyddor Bywyd 2, Parc Singleton Institute of Life Science 2, Singleton Park Abertawe SA2 8PP Swansea SA2 8PP Ffon (01792) 606545 Ebost [email protected] Phone (01792) 606545 Email [email protected]

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1 Table of Contents

0 Version Record ............................................................................................................ 1

1 Table of Contents ........................................................................................................ 2

2 Glossary ....................................................................................................................... 4

3 Introduction.................................................................................................................. 4

4 Purpose ........................................................................................................................ 5

5 Roles & Responsibilities ............................................................................................. 5

6 Procedure ..................................................................................................................... 6

6.1 Centralised Monitoring of CTIMPS ............................................................................. 6 6.1.1 Trial Management Group (TMG) ....................................................................................... 7 6.1.2 Trial Steering Committee (TSC) ........................................................................................ 7 6.1.3 Data Monitoring and Ethics Committee (DMEC) ............................................................... 7 6.1.4 Communication .................................................................................................................. 8

6.2 Site Specific Monitoring Plans .................................................................................... 8 6.2.1 ABMU Health Board Sponsored studies ........................................................................... 8 6.2.2 Site Initiation Visit .............................................................................................................. 9

6.3 Qualifications and Duties of Monitors ......................................................................... 9 6.4 Study Close Out ........................................................................................................11

6.4.1 Sponsor Responsibilities – Health Board Sponsored Studies ......................................... 12 6.4.2 Chief Investigator (CI) Responsibilities – Health Board Sponsored Studies ................... 13 6.4.3 Pharmacy ......................................................................................................................... 14 6.4.4 Clinical Laboratories ........................................................................................................ 14 6.4.5 Close-Out Monitoring Visit ............................................................................................... 14 6.4.6 Health Board R&D Department Responsibilities ............................................................. 15

6.5 Flowchart of monitoring process ...............................................................................17

7 Training Plan ...............................................................................................................17

8 References ..................................................................................................................18

9 Related SOPs ..............................................................................................................19

10 Appendices .................................................................................................................19

Appendix 1: Prioritisation Tool for Monitoring .......................................................................21 Appendix 2: Monitoring Plan Template .................................................................................23 Appendix 3: Initiation Tool ....................................................................................................26 Appendix 4: Monitoring Tool .................................................................................................43 Appendix 5: Pharmacy Monitoring Log .................................................................................60 Appendix 6: Laboratory Checklist .........................................................................................62





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Appendix 7: Monitoring Visit Log .........................................................................................65 Appendix 8: Monitoring / Audit Visit Report Template ...........................................................66 Appendix 9: Trial Close Out Report Template ......................................................................68





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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). 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 Medicines for Human Use (Clinical Trials) Regulations (2004), 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 identifies the roles, responsibilities and actions of the individuals involved in the preparation, issue, control, review and approval of standard operating procedures.

Monitoring is defined in section 1.38 of the ICH-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)”[1].

According to section 5.18.1 of the ICH-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 (1)

The sponsor has overall responsibility for ensuring that a trial is adequately monitored and should determine the extent and nature of monitoring. A trial monitor(s) should be appointed by the sponsor [1] (see WWORTH SOP31





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Sponsorship and Adoption). Sponsor can modify WWORTH SOPs to fit in with local practices and the appendices may be used as exemplars.

Monitoring is designed to demonstrate a trial’s quality by continuously verifying the quality of any data collected and of the trial’s processes as a whole (Quality Control (QC)).

Assessing and assuring the reliability and integrity of the QC 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 [1, 2]. Implementing QA is also the responsibility of the sponsor but is not covered by this SOP. More detail on this can be found in WWORTH SOP18a Quality Management. This SOP is concerned only with monitoring (i.e. QC).

4 Purpose

To describe trial monitoring procedures for in-house sponsored studies to be conducted by WWORTH or Abertawe Bro Morgannwg University Health Board (ABMU) R&D Department and to describe the approach adopted for oversight of externally sponsored studies. For the purposes of this SOP, the term monitor will be used to refer to any member or committee designated by a Sponsor to undertake a specific monitoring task.

5 Roles & Responsibilities

All staff associated with WWORTH and ABMU R&D Department should ensure that they are familiar with this SOP.

The sponsor has overall responsibility for ensuring a trial is monitored (see WWORTH SOP31 Sponsorship and Adoption). Where Swansea University or ABMU is the sponsor, this responsibility may be delegated to WWORTH. WWORTH or ABMU R&D (for non-adopted studies) is responsible for ensuring that this SOP is carried out but can delegate the tasks specified within it to the Chief Investigator (CI) of the trial.

When tasks specified within this SOP are delegated to the CI or the Trial Manager (TM), he or she should ensure that they have a thorough understanding of, and training in, the monitoring process, GCP, and all clinical trials regulations.

Where WWORTH/ABMU R&D delegates specific monitoring tasks to an individual QA officer or independent monitoring committee, they must be familiar with this SOP.





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6 Procedure

As detailed in SOP31 Sponsorship and Adoption for in-house trials, there may be flexibility in the central monitoring structures to ensure monitoring oversight is commensurate with the risk of the trial, as determined by ABMU in its capacity as Sponsor. Once agreed, the central trial monitoring procedures and processes should be detailed in the trial protocol. Joint Scientific Review Committee (JSRC) approved Protocol templates for CTIMP and Non-CTIMP trials will be used for all ABMU Sponsored studies. Individual site monitoring plans will be kept in the Trial Site File (TSF) following a site specific risk assessment undertaken by the site in collaboration with WWORTH (for adopted studies only), ABMU R&D and the CI.

Monitoring of the trial must take place to ensure that:

1. Collected data are consistent with protocol adherence;

2. Only authorised persons complete Case Report Forms (CRFs);

3. Data queries are resolved (including missing data);

4. Data are valid through validation checks (e.g. range and consistency checks);

5. Recruitment rates, withdrawals and losses to follow-up are reviewed overall and by site to enable early identification and rectification of issues, which may be adversely affecting achievement of planned target recruitment. Trialists are asked to check for volunteer bias by comparing recruited and retained samples with the relevant population, for example all patients attending clinics where recruitment took place or the SAIL population, matched for demographic indicators (e.g. age, location) (cf Jordan et al 2013). Results of this quality check should be passed to WWORTH.

For All ABMU or Swansea University Sponsored studies, data will be managed via MACRO4, with an assigned Data Administrator. See WWORTH SOP21 IT & Databases.

6.1 Centralised Monitoring of CTIMPS

For a CTIMP a formal monitoring structure should be established where the role and responsibilities of the monitor(s) are delegated by the Trial Steering Committee (TSC) or Sponsor directly. Therefore, the formal central structure for monitoring CTIMPS in multi centre studies will usually be as follows:





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6.1.1 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, trial data manager (TDM), and collaborating clinicians, as necessary. The TMG’s role is to monitor all aspects of the trial’s conduct and progress on a regular (e.g. monthly) basis. The group should ensure the protocol is adhered to, take appropriate action to safeguard participants, and ensure the quality of the trial itself.

6.1.2 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. The TSC should meet either annually or biannually depending upon the trial and should be attended by the CI and TM.

6.1.3 Data Monitoring and Ethics Committee (DMEC)

It is ABMU & WWORTH policy that an independent DMEC is set up for all full (excluding pilot) trials and must be set up for any trial of an investigational medicinal product (IMP) or medical device (MD). The DMEC can either be a completely different group of individuals from the TMG/TSC or they may be a subcommittee of the TMG/TSC providing all members are independent from the trial investigators and sponsor/funder, and that a sufficient quorum of the remaining independent TMG/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(s). 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. DMECs should meet as appropriate depending on the risk assessment outcome, usually before the TSC meet.

For ABMU sponsored trials, the JSRC is acting in the capacity of Sponsor TSC, therefore the quarterly DMEC will make recommendations to the JSRC, who in turn will make recommendations to ABMU R&D Department as Sponsor Representative. The trial statistician must be available to the DMEC to answer any questions. The ABMU QA Officer and TDM (or TM if no TDM is in place) will act on behalf of the TMG to provide regular safety





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reports to the DMEC and to provide blinded and, if requested, unblinded trial data for interim analysis to ensure that the blinding of the trial is not compromised. The DMEC reports to and makes recommendations to the TSC.

Additionally, alongside the formalised structures for central monitoring, central monitoring of data may also use statistical techniques for identifying unusual patterns of data and can be used to identify sites or contributors that may be deviating from the protocol [2]. This process can be employed for all studies as well as CTIMPs.

For single centre trials, a DMEC & TMG may be sufficient omitting a TSC, however the TMG would also perform the role of a TSC in that case.

6.1.4 Communication

Communication is key to the effective monitoring of a trial. First, the CI will communicate regularly with (1) staff involved with conducting the trial, (2) all PIs at the participating sites; (3) the clinical trials unit WWORTH (4) ABMU R&D QA Officer. Second, the TMG will report to the DMEC and TSC (JSRC in ABMU Sponsored studies). The DMEC will report to the TSC/JSRC and the TSC reports to the Sponsor/funder. Regular safety reports (usually annually) will be submitted to the REC and the trial sponsor/funder. For trials involving an IMP, additional safety monitoring procedures are required and annual safety reports must be submitted to the MHRA (see WWORTH SOP15 MHRA Approval). For further details on safety reporting in CTIMPS, please refer to WWORTH SOP19a Pharmacovigilance and WWORTH SOP19b Urgent Safety Measures.

6.2 Site Specific Monitoring Plans

6.2.1 ABMU Health Board Sponsored studies

The frequency of monitoring is determined through the risk assessment process and is logged on the QA risk register, which is maintained by the local QA team. Studies deemed high risk are monitored 1-2 monthly, medium risk are monitored every 3-6 months and low risk monitored annually, unless more frequent visits are necessitated due to findings. Studies which have non-commercial Sponsors are monitored by default every 6 months unless the QA team have determined more frequent visits are required due to the risk associated with the study. Commercial Studies have regular on-site visits by the Sponsor company or their contracted Clinical Research Organisation (CRO). However, some commercial Sponsors are seeking to adopt remote monitoring and limiting the amount of on-site visits. For such studies, the Health Board R&D QA team will adopt the same approach as applied to non-commercial Sponsored studies (Please refer to Appendix 1 for Prioritisation Tool and Appendix 2





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for Monitoring Plan Template).

6.2.2 Site Initiation Visit

Following local approval of a study, the Sponsor usually undertakes a Site Initiation Visit (SIV).

For all ABMU Sponsored studies, the SIV will be conducted by the R&D team.

Following a successful SIV, the Sponsor issues a ‘greenlight’ for the study to commence at the site, scheduling the 1st monitoring visit to take place after the 1st patient has been recruited and such recruitment notified to the Sponsor. (Please refer to Appendix 3 for Initiation Tool).

During each site visit the monitor should complete a Monitoring Tool (Appendix 4) to be submitted to the CI with a copy to the PI and site staff once complete. 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

Reports will be fed back to the Sponsor (using Appendix 8), through the centralised structures in place for the individual study, as described in section 6.1 above. Annual Safety Reports & Progress reports must be submitted by the CI to the appropriate Research Ethics Committee (C.f. SOP14a Ethical Approval) and MHRA(c.f.SOP15) (if applicable) until study closure.

6.3 Qualifications and Duties of Monitors

In line with Section 5.18.4 of ICH-GCP [1] individuals monitoring trials should be appropriately trained and have the scientific/clinical knowledge needed to monitor the trial adequately. A record of the qualifications of monitoring individuals should be kept [1, 2].

The appointed monitoring officer may be employed by the Sponsor or WWORTH’s own Quality Assurance Officer or may be outsourced to an external research network, such as the Research Professional Network employed by NISCHR CRC or equivalent CLRNs.





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As a minimum, 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, 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:

1. The investigator has adequate qualifications and resources to run the trial, that these resources remain adequate throughout the trial period, and that facilities including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial.

2. Storage conditions, supplies, instructions, dispensing recording and disposal of the investigational medicinal product(s) are acceptable (Please refer to Appendix 5).

3. Investigator(s) comply with the protocol.

4. Appropriate informed consent processes are followed.

5. Investigator(s) have all the up-to-date required documents to conduct the trial properly and to comply with the regulatory bodies.

6. All investigator(s) and trial staff are adequately trained to deliver their role in the trial.

7. All investigator(s) and trial staff are adequately trained in performing the trial functions in accordance with the protocol and any agreement with the Sponsor, and have not delegated these functions to unauthorised individuals.

8. Investigator(s) are enrolling only eligible subjects.

9. Recruitment rates are meeting targets through regular reports.

10. Source documents and other trial records are accurate and complete, kept up-to-date and maintained.

11. Checking completeness of CRFs by specifically verifying:

a. the data required by the protocol are reported accurately on the CRF;





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b. treatment modifications are well documented for each trial subject;

c. Adverse Events are reported in accordance with the protocol;

d. Visits or tests/examinations not conducted are clearly reported as such on the CRF;

e. All withdrawals and dropouts are reported and explained on the CRF.

12. Informing investigator(s) of any error on the CRF.

13. Adverse Events are reported adequately in the time frames specified by the protocol, Sponsor, and regulatory authorities. See WWORTH SOP19a Pharmacovigilance and WWORTH SOP19b Urgent Safety Measures.

14. Checking that essential documents in the Trial Master File (TMF) or Trial Site File (TSF) are maintained.

15. Communicating any deviations from Protocol, SOP or GCP, and regulatory requirements to the investigator and taking appropriate action to prevent recurrence of the detected deviation.

16. Calibration and study equipment checks.

17. Laboratory checks, where resource permits (Appendix 6).

18. 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) (2)

A Monitoring Visit Log will need to be completed by a member of the Sponsor team after each visit (Appendix 7).

6.4 Study Close Out

To complete the monitoring process, a close out visit is conducted by the Sponsor after the last patient has been recruited and all patient follow up visits have been completed.

An End of Study notification form must then be completed and sent to the REC and/MHRA within 90 days of the end of the trial as it is defined in the trial protocol or within 15 days if the study has been terminated early (see





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WWORTH SOP07 Trial Closure at Sites). The end of study notification form will need to be followed by the Final Study Report at the annual anniversary of the end of study date, as detailed in the End of Study Notification form. The Final Study Report must be submitted to the relevant Sponsor Committee, REC and MHRA (if applicable) WWORTH SOP07 Trial Closure at Sites.

For all ABMU Sponsored CTIMPs a close out visit will be undertaken by the R&D QA team (Appendix 9 Trial Close Out Report template). The relevant team may also ensure and support the local research teams to have conducted close out checks for the hosted externally Sponsored studies they have been supporting, if this has been delegated to the site by the Sponsor.

A site must be closed as soon as is practicable to do so.

6.4.1 Sponsor Responsibilities – Health Board Sponsored Studies

This includes ensuring:

Relevant Sponsor Scientific Panel receive copy of End of Study Report.

Investigator/institution and sponsor files are reviewed and all essential documentation for a particular site are confirmed in the appropriate files, providing a clear audit trail of study conduct at the site.

All site data are collected, entered, validated and all data queries resolved where feasible. This includes queries resulting from reconciliation of the clinical and safety database.

All issues from previous study monitoring procedures are resolved and documented.

All financial matters are resolved and all site payments are complete as agreed and documented in study contracts/agreements/approvals.

All unused trial supplies are returned or destroyed according to study and/or sponsor requirements.

Final drug accountability is complete and return (if returned) or destruction of unused study drug is documented in the site file (if destroyed locally at site).





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Investigator(s) are aware of the study publication policy, as documented in the study protocol and/or study contracts/agreements.

Investigator(s) are aware of and have implemented relevant ongoing requirements such as site archiving, subsequent audit/inspection procedures and any ongoing reporting requirements.

The Chief Investigator (CI) site should not be closed until all the participating sites have been closed-out.

Consideration must also be given to those trials that can be ‘closed’ but where the patients are placed into long term follow-up (e.g. Oncology trials).

6.4.2 Chief Investigator (CI) Responsibilities – Health Board Sponsored Studies

It is the responsibility of the CI, acting on behalf of the Sponsor, to notify the main REC, the MHRA and the Sponsor Scientific Panel (via R&D Department) of the end of the trial for every participating site and CI site using the Declaration of End of Trial Form.

The CI must notify the end of the trial within 90 days of the trial ending (trial end as defined in the protocol) or within 15 days if terminated early.

Once notified of the end of trial, the CI will contact the Monitor in order to arrange a Close-Out monitoring visit for each site. Support departments (e.g. pharmacy) should also be notified in order that they can prepare for Close-Out.

Organise Trial Master File (TMF) ensuring all necessary documents are present. The CI must acknowledge the requirement to submit a Clinical Study Report (Final Report) to the Sponsor, REC and MHRA within 1 year (by the anniversary of the notified end of the trial date).

Instigate archiving procedures in line with WWORTH SOP08 Archiving ensuring that files are retrieved from support departments (e.g. pharmacy) so that all essential documents relating to a particular trial are archived together.





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6.4.3 Pharmacy

All Investigational Medicinal Product (IMP) must be accounted for, including a check that all IMP has been returned by trial subjects and that all IMP not used for the study is present and unopened. All IMP logs must be checked for accuracy and any discrepancies must be accounted for. Serious breaches in IMP accountability must be brought to the attention of the CI and Sponsor. Return and destruction of IMPs must be carried out according to protocol and legal requirements. IMPs must not be destroyed until permission to do so is given by the Sponsor. A Certificate of Destruction should be obtained when the IMP is destroyed, this should be filed in the Trial Pharmacy File. Any local site Pharmacy procedures may also need to be considered.

6.4.4 Clinical Laboratories

Storage and destruction of clinical samples must be carried out according to Protocol and Sponsor requirements, including local site laboratory procedures.

6.4.5 Close-Out Monitoring Visit

Monitor’s Close-Out procedures.

Before the visit:

Ensure that all routine monitoring issues have been addressed.

Arrange a mutually convenient date, time, duration and agenda for the site monitor to conduct the closeout visit for the final review of regulatory files, source data verification, drug accountability reconciliation, and review of the record storage plan, as soon as practical after the last subject has completed all scheduled visits

Ensure that all regulatory documentation, source documents, and case report forms are complete and available for review.

Ensure that all data queries have been resolved to the extent possible.

Ensure that participants’ medical records will be available for review.

Meet with the study pharmacist.

During the visit:





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Ensure that all study personnel are available to resolve any open issues.

Ensure that the site monitor signs the Monitoring Visit Log (Appendix 7).

Give the site monitor access to all documents required to complete the closeout visit.

Discuss any study-related issues.

Discuss the possibility of a sponsor audit or MHRA inspection.

Review drug accountability records.

Agree and action correct Sponsor process for disposal or return of unused CRFs and clinical supplies etc.

The local trial team should inform site monitor of storage location of study records.

If data were entered on computers, determine when hard copies of CRFs will be provided to the site and review the Sponsor’s plan for protecting the integrity of the electronic data.

Discuss with the site monitor the Sponsor’s requirements for participant follow-up for SAEs after closeout.

Discuss the possibility of publication of the data and participation in future studies.

If appropriate, provide the final closeout report. If there are any open issues, discuss them and arrange for follow-up.

Identify points of contact for new issues that may arise, such as data queries and inspections.

6.4.6 Health Board R&D Department Responsibilities

Receive End of Study notification from CI and copy of Clinical Study Report (when available).

Update end date on ReDA database and change study status tocompleted / closed.





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Notify the CI that R&D Study records have been closed.

Oversee the CI’s production and submission of the Clinical Study Report (Final Report).

Prepare R&D files (and Sponsor files where applicable) for archiving.

At the time when trial documentation is ready for archive, the Named Archivist will prepare archive boxes in line with WWORTH SOP 08 Archiving.





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6.5 Flowchart of monitoring process

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

6. Monitoring structure determined as per SOP

31sponsorshipandadoption -

6.2 Monitoring will take place following 1st patient recruited

6.2 Monitoring visits to continue as per agreed frequency subject to

adjustment depending on monitoring findings.

6.2 In line with Sponsor agreed frequency, monitoring findings will be reported by or on behalf of the TMG to the DMEC,TSC &

Sponsor.

6.2 Annual Safety & Progress reports submitted to appropriate

REC/MHRA (if applicable) until Study Closure

6.4 Study Close Out Visit

6.2 Study

Initiation31sponsorshipandadoption -structures

established.





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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 must ensure that they are familiar with this SOP. In principle the trainer should be one of the authors. Training will be in two stages. First training in the principles of that SOP will take place during monthly meetings of SOP JSOPGs. Second training in using that SOP in practice will take the form of regular supervision by an experienced trialist, culminating in approval of that SOP. Both trainer and trainee will sign the log (Appendix 8) to confirm that training is complete. To help individual staff record training for the purpose of their Continuing Professional Development, and help individual trials and WWORTH record training for quality assurance, WWORTH will aggregate training logs by individual within trial.

8 References

1. Fellows, T., ICH Harmonised Tripartite Guideline for Good Clinical Practice. GCP Training. 2004, Marlow, Bucks: Institute of Clinical Research





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2. Research Governance Framework for Health & Social Care in Wales, 2nd Edition November 2009, Welsh Government.

3. University of Sheffield, Standard Operating Procedure (‘SOP’) for University-sponsored 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.

4. National Institute of Allergy and Infectious Diseases, Clinical Trial Monitoring SOP. 2007, National Institute of Allergy and Infectious Diseases.

5. 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 2001. Official Journal of European Union, 2001. Article 2(Definitions): p. L121/36-L121/37.

6. Jordan S, Watkins A, Storey M, Allen SJ, Brooks CJ, et al. (2013) Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis. PLoS ONE 8(7): e67912. doi:10.1371/journal.pone.0067912 DOI: is: 10.1371/journal.pone.0067912 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067912

9 Related SOPs

WWORTH SOP 02 Training WWORTH SOP 07 Trial Closure at Sites WWORTH SOP 08 Archiving WWORTH SOP 14a Ethical Approval WWORTH SOP14b Applying for NHS R&D Permission WWORTH SOP15 MHRA Approval WWORTH SOP16 Site Setup WWORTH SOP18 Quality Management WWORTH SOP18b Preparing for Audit and Inspection WWORTH SOP19a Pharmacovigilance WWORTH SOP19b Urgent Safety Measures WWORTH SOP31 Sponsorship and Adoption

10 Appendices

Appendix 1: Prioritisation Tool for Monitoring



http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067912

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067912



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Appendix 2: Monitoring Plan Template Appendix 3: Initiation Tool Appendix 4: Monitoring Tool Appendix 5: Pharmacy Monitoring Log Appendix 6: Laboratory Checklist Appendix 7: Monitoring Visit Log Appendix 8: Monitoring / Audit Report Template Appendix 9: Trial Close Out Report Template





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Appendix 1: Prioritisation Tool for Monitoring

Prioritisation Tool for Monitoring R&D Sponsored Research

by the Quality Assurance Officer Study Title:

ReDA reference:

Chief Investigator:

Please tick boxes

Prioritisation Criteria*

Y N N/A Comment

1. Is the research sponsored by ABMU LHB Trust?

2. Is the study a CTIMP?

3. Scale of Research: Large patient population and limited trial/study team resource.

4. Patient Population: Research involving children or other vulnerable patient group?

5. Intervention: Study is interventional (involves procedures, tests, treatments administered for purposes of the research) as opposed to observational

6. Investigator/Research Team: Inexperienced or under-resourced (e.g. sole investigator / multiple studies ongoing) or previous history of serious breach / non-compliance with applicable standards / SOPs? Inexperienced clinical team (clinically and GCP)

7. Information/Personal Data: Doubt about adequacy of data storage or data to be sent outside of EU or previous breaches of data protection / confidentiality?

8. Consent: Process complex or involve unusual timing / staff in taking consent? Patient entering trial without fully informed consent.

9. Randomised and / or blinded trial?





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10. IMP issues? IMP used in novel setting / indication not listed in the Summary of Product Characteristics / to be used within strict settings? (e.g. storage temperatures, short shelf life etc).

11. Additional Invasive Tests, i.e. radiological exposure, blood samples.

12. Protocol Deviations (Violation of inclusion and exclusion criteria).

13. Risk to completion of the trial Recruitment and follow up

*Add up the total number of ticks in the yes section, which will determine the risk

criteria e.g. 5 ticks in Y category is MEDIUM RISK

Prioritisation Categories Prioritisation Category for Study (result of process below – circle applicable category)

C1 C2 C3 C4

These will be monitored by the R&D Quality Assurance Officer as follows:

FREQUENCY OF MONITORING – Sponsored CTIMPs/Non-CTIMPs

Monitoring Category C1

NO/MINIMAL RISK


LOW RISK


MEDIUM RISK


SUBSTANTIAL / HIGH RISK

*Meets 0-1 ticks of Y criteria




Initiation No Monitoring

Closeout

Initiation Once per year

Closeout

Initiation Twice per year

Closeout

Initiation six per year

Closeout

Completed by: Quality Assurance Officer Signature:

Date:





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Appendix 2: Monitoring Plan Template Drafting Note: If any item not applicable (e.g. no trial co-ordinator) state ‘none’ or N/A.

Study Title (short): ReDA Reference:

EUDRACT Number:

C.I. / P.I.:

Trial Co-ordinator/Research Nurse: Primary objective of trial: Trial timelines: Planned total number of participants in trial:

Number of sites:

Number of participants per site:

Participant ID numbering system:

External partners involved:

Randomisation: drafting note – who / where is this being done CRF – paper / electronic / components:

Data entry responsibilities: Pharmacovigilance responsibilities: drafting note: who is responsible for all elements of this – e.g. any involvement of external CROs Data Monitoring Committee: drafting note: chair / contact details / meeting frequency and timing (to co-ordinate provision of monitoring reports)





____________________________________________________________________________


Sponsor/TMG: Sponsor representative contact details: drafting note: the person (usually in the R&D Department) who will be the Monitor’s link with the Sponsor

Monitor:

Reference documentation to be used for this trial Drafting note: state here that all WWORTH SOPs apply OR specify which do apply and detail any others SOP Title Owner (Department / Company / reference)





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1. Division of responsibility between the Monitor and the Trial Co-ordinator

[drafting note: insert here details of which visits the Trial Co-ordinator will undertake, having regard to WWORTH SOP (Monitoring); if this is not relevant state here that the Monitor will undertake all visits.]

2. Timing and Frequency of Interim Monitoring Visits

[drafting note: insert here details of timing and frequency of visits, based on risk assessment of the trial; for example “ the first Monitoring Visit following Site Initiation will take place approximately …… weeks after randomisation of the first participant at Site. Subsequent Monitoring Visits will take place every ….. weeks”. Frequency of monitoring visits may be adjusted depending upon significant monitoring findings.

3. Source Data Verification (SDV)

3.1. On each visit SDV Consent and Eligibility Criteria will be carried out for all participants enrolled since the last visit.

3.2. In addition to the checks specified in 3.1, on each visit SDV will be performed for (10%) of the data in the CRF for (10%) of participants. Different participants will be selected at each visit. [drafting note: Insert 100% or lower proportions according to the trial risk assessment].

4. Report Elements to be covered

4.1. In the Monitoring Visits checks will be carried out and the Report completed for the following elements: [drafting note: specify here the number and timing of checks required on elements of the Monitoring Report (TMF / ISF, Laboratory, Pharmacy, Other, Participant Recruitment.]

5. Close-Out Checks – Archiving Arrangements

[drafting note: specify here the archiving arrangements for the trial, i.e. what will be archived at participating Sites and what will be archived centrally, and how the material is to be prepared for the Monitor’s check. (See WWORTH SOP Trial Close-Out and WWORTRTH SOP Archiving) ]

6. Close-Out Checks - IMP Reconciliation and Retention / Disposal Arrangements

[drafting note: specify here the arrangements for retention and disposal of IMP at the end of the trial and how the material is to be prepared for the Monitor’s check prior to final authorisation of retention / disposal by the Sponsor’s representative (See WWORTH SOP Trial Close-Out)





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Appendix 3: Initiation Tool

Initiation Report

Study Title (short):

ReDA Reference:

EUDRACT Number:

Site:

Type of Site: (please tick) -Chief Investigator (CI) -Initiation of whole study -Trial Master File check -Principal Investigator (PI) -Participating Site

Chief Investigator / Principle Investigator at Site:

Date of Initiation:





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Site Initiation Attendance Log

Study Title (short):

ReDA Reference: EUDRACT Number:

Date of Initiation:

The undersigned attended the Site Initiation visit and were present during discussion of the topics for which the following code numbers are entered against their names (if present throughout, state ‘all’)

1. Overview of the Protocol; 2. Primary and secondary endpoints; 3. Investigator’s Brochure / Summary of Product Characteristics; 4. Participant recruitment, establishment of eligibility, consent and randomisation; 5. Discontinuation and withdrawal; 6. Definition of source data / maintenance of source data records; 7. Applicable Standard Operating Procedures; 8. Pharmacovigilance, adverse event documentation and safety reporting; 9. Data protection and confidentiality; 10. Data collection: Case Report Forms, File Notes, Sample handling; 11. Site File Maintenance including Delegation Log, Minuted Meetings; 12. Pharmacy 13. Laboratory

Name (print) Job Title (print) Topic codes Signature





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Section 1: Review of Trial Master File (TMF) / Trial Site File (TSF)

Yes / No / Not applicable

1. Has the Trial Master File/Investigator Site File been collated in readiness for the Trial, with appropriate dividers and contents page?

2. If some essential documents are to be kept in other departments, e.g. Pharmacy, are there appropriate cross-referenced file notes indicating where everything can be found at Site?

Section 2: Contents of TMF / TSF

Document / designated file section in main (investigator - held) file? If elsewhere on site (e.g. Pharmacy) state where

Yes No NA Comment

1. Contact Information

1.1 Contact details of all personnel involved in trial at this Site

1.2 Daytime and ‘out of hours’ contact information as given to participants

1.3 External personnel contacts (e.g. Sponsor representative, Trials Unit)

2. Participant Logs and Consent Forms

2.1 Participant screening log (chronological list of all screened potential with reasons for non-entry if appropriate)

2.2 Participant enrolment log (all enrolled in trial in trial ID number order)

2.3 Participant identification randomisation code list





____________________________________________________________________________




Yes No NA Comment

2.4 Original signed consent forms with Participant Information Sheet need to be filed in recruitment order

3. Archiving

3.1 - Is the storage and archiving of data described? - Is there a designated person for Archiving?

4. Standard Operating Procedures

4.1 List of all WWORTH SOPs used for trial (i.e. sponsor / co-sponsor general or study-specific-SOPs). Are the trial teams familiar with relevant trial specific SOPs and had training?

5. Protocol and associated documents

5.1 Current approved Protocol signed by CI / PI

5.2 Current approved Participant Information Sheet (local headed paper)

5.3 Current approved Consent Form (local headed paper)

5.4 Current approved GP letter

5.5 Current approved advertisement





____________________________________________________________________________




Yes No NA Comment

5.6 Current trial flow-chart / procedural guide (if applicable) and summary of randomisation procedure

5.7 Eligibility criteria

5.8 Sheets of labels for attachment to participants’ medical records noting fact of trial participation and mentioning do not destroy notes

6. Data collection

6.1 Sample of current approved Case Report Form

6.2 Sample(s) of other current approved data collection instruments (e.g. questionnaires)

6.3 Signed, dated and completed Case Report Forms storage

6.4 Signed, dated and completed questionnaires etc, storage

6.5 Data queries

6.6 File notes documenting CRF corrections or data clarifications

7. Site Personnel

7.1 Up to date, signed and dated CVs and Good Clinical Practice (GCP) training records

7.2 Confidentiality Agreements





____________________________________________________________________________




Yes No NA Comment

7.3 Delegation of Authority and Signature Log

8. Ethics and Clinical Trial Authorisation

8.1 Ethics and MHRA applications (appropriate IRAS Sections)

8.2 Favourable ethical opinion letter and committee composition (are there any issues that are outstanding)

8.3 Clinical Trial Authorisation from MHRA

8.4 Correspondence with Ethics Committee and MHRA about applications; any associated file notes

9. Sponsorship

9.1 Letter of acceptance of sponsorship

9.2 Sponsor’s delegation of roles and responsibilities

10. NHS Permission

10.1 Final approval letter

10.2 Conditional or interim approval letter (if applicable)

10.3 Site Specific Information form (application)

10.4 Correspondence re NHS Permission

10.5 JSRC approval letter

11. Contracts / Agreements / Finance / Indemnity

11.1 Clinical Trial Agreement





____________________________________________________________________________




Yes No NA Comment

11.2 Indemnity and / or insurance policy evidence (if not covered in Clinical Trial Agreement)

11.3 Any other contracts relating to the trial (e.g. IMP supplier)

11.4 Financial records and invoices

11.5 Correspondence and any file notes re agreements, finance etc.

11.6 Any other approvals

12. Pharmacovigilance

12.1 Current Investigator Brochure (IB) / Summary of Product Characteristics (SmPC)

12.2 Serious Adverse Events (SAE) Reports

12.3 Suspected Unexpected Serious Adverse Event Reports and reporting forms

12.4 DSUR submissions to MHRA with copies sent toEthics and R&D

12.5 Notification by Sponsor to Investigators of safety information and Pregnancy reporting procedure.





____________________________________________________________________________




Yes No NA Comment

12.6 Procedure for randomisation and emergency unblinding / Code Breaks (if applicable)

12.7 Code Break envelopes (where applicable)

12.8 Blank SAE forms

12.9 Adverse event reporting and documention

13. Amendments

13.1 Chronological list of amendments with version numbers and dates

13.2 A separate bundle of documents for each amendment, filed in chronological order, comprising:

Copy approval / notification for information – Ethics

Copy approval / notification for information – MHRA

Copy approval / notification for information – R&D

Correspondence and any file notes on the amendment

Completed Version Control Checklist

14. Equipment (if applicable)

14.1 Calibration certificates

14.2 Correspondence and any file notes

14.3 Usage procedures





____________________________________________________________________________




Yes No NA Comment

15. Monitoring

15.1 Monitoring plan and visit schedules

15.2 Site Initiation Report

15.3 Monitoring Summaries, Action Lists and Log


16. Audit (if applicable)

16.1 Audit Reports

16.2 Audit correspondence

17. Pharmacy

17.1 Delegation of authority and signature form

17.2 Pharmacy financial information / invoices

17.3 Shipping records/Chain of Custody

17.4 Sample of label(s) attached to IMP container Which has been MHRA approved?

17.5 Instructions for handling the IMP/Quarantine

17.6 MAIMP Licence of the IMP supplier

17.7 QP Release documentation

17.8 Notification of unblinding

17.9 Record of retrieval / use of Code Break envelopes (if applicable)

17.10 IMP Recall documentation

17.11 Drug accountability/Is the IMP product ready at site?





____________________________________________________________________________




Yes No NA Comment

17.12 Pharmacy correspondence/Protocol amendments and any file notes

18. Laboratory

18.1 Lab accreditation with date

18.2 Normal ranges with date

18.3 Record of retained body fluids / tissue samples/Chain of Custody

18.4 Laboratory correspondence and any file notes

19. Tissue Samples

19.1 Does the trial involve retaining of samples for later analysis in the trial (Human Tissue Act implications)?

19.2 Have procedures for handling of relevant laboratory samples (e.g. freezing, shipment etc.) been prepared?

19.3 For multi-centre trials, are arrangements in place for the collection, transportation, storage and analysis of the samples?





____________________________________________________________________________


Section 3: Laboratory arrangements/Tissue Sample arrangements.

Satisfactory Unsatisfactory (specify under ‘comments’)

Not Applicable

Shipment record-keeping arrangements

Specimen handling arrangements (chain of custody)

Temperature log set up for all fridges or freezers used for the study

Are there Normal Range/Values for medical/lab/technical procedures and tests? ● lab accreditation evidence ●SOPs in place? ●Are there any PDF versions of blood tests which are study specific? ●Staff training files/hand over procedures

3: COMMENTS:

Section 4: Pharmacy arrangements


Not Applicable

Labels for attachment to the IMP container (Good Manufacturing Practice compliant)

Instructions for handling the IMP

Arrangements for IMP storage at appropriate temperature

Shipping record-keeping arrangements

Medication receipt arrangements

Decoding procedures

Patient randomisation codes and emergency code-breaks

Drug accountability forms

IMP supplies have been received by the Site Pharmacy





____________________________________________________________________________


Section 4: Pharmacy arrangements


Not Applicable

4: COMMENTS:

Section 5: Staff


Not Applicable

Evidence of Site CI/PI GCP training within the last 2 years

Evidence of GCP training within the last 2 years for other members of investigator team

Staff other involved departments have received sufficient GCP and protocol training to enable them to fulfil their responsibilities

Evidence that all members of investigator team who are not employees of the Site organisation have honorary contracts of employment. Letters of access and research passports are valid?

Satisfactory attendance at Site Initiation meetings / training

5: COMMENTS:





____________________________________________________________________________


Section 6: Other arrangements


Not Applicable

Provision for storage of paper documentation (lockable cabinets, in a lockable room)

Participant identifiable data to be kept off data collection instruments - investigators aware:

Use only standard approved CRFs etc.;

Do not add ID information (e.g. hospital labels)

Computer files containing identifiable data to be stored on a remote server and are appropriate back-up processes in place for IT systems? ● Are specification and validation

documents in place for IT Systems (e.g. Databases, randomisation program, online data collection)?

● Is the trial database secure? ● Are data collection and storage

systems clear? ● Are trial team familiar with data

retention requirements (security and timescales)?

All equipment to be used for the study calibrated according to Site policy?

All fridges or freezers to be used for study have thermometer to record temperature and satisfactory procedure in the event of failure

6: COMMENTS:





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Section 7: Chief Investigator Co-ordination


Not Applicable

Does the Chief Investigator have sufficient time agreed as part of job plan to oversee this trial?

● Is there a designated Trial Co-ordinator? ● Study cover in the absence of PI/key personnel

Does the Trial Co-ordinator have sufficient time allocated in his/her job plan to carry out co-ordination tasks properly?

The study has been Risk Assessed and has been categorised into a;

Low risk

Medium risk

High risk

The monitoring plan has been agreed and the study will be monitored every............months during the study period. Will the study require a monitoring visit after the first patient has enrolled into study?

7: COMMENTS:





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SECTION 8: MONITOR’S SUMMARY ASSESSMENT Any Comments;

Confirmation A below, sign and give the Report to the Sponsor Representative

Confirmation A I confirm that:

The Site has been prepared for the study;

All required topics have been covered in meetings with involved staff at Site;

Necessary staff, facilities and arrangements are in place.

The Sponsor is advised that the study CAN BEGIN at this Site.

Monitor’s Signature

Date

Name (print)

Report Received by Sponsor’s Representative

Date

Name (print) Signature





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SECTION 9: CONFIRMATION FOLLOWING ACTION LISTS Please list any outstanding actions identified at the initiation meeting. 1 2 3 4 5 6 7 8 9 10 11 12

If actions are required, the Monitor should sign Confirmation B or send a similar personal email to the Sponsor representative for attaching to the Report.

Confirmation B I confirm that NOT all necessary actions have been completed and the Sponsor is advised that the study cannot begin at this Site.

Monitor’s Signature

Date

Name (print)





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SECTION 10: FINAL SIGN-OFF

When the Monitor has confirmed that the study can begin at Site, the Sponsor representative should sign below in acknowledgement that the Report has been accepted. The signed original Report should be retained in the Sponsor File and a copy given to the Site.

Sponsor Representative’s Signature

Date

Name (print)

NOTES:





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Appendix 4: Monitoring Tool

Study Title (short): ReDA reference: EUDRACT Number: Site: Chief / Principal Investigator at Site: Date of visit: Date of previous visit: Teams / Departments visited (delete or add as required): Investigator Team / Pharmacy / Imaging / Laboratory Name and job title of all personnel seen: Duration of meeting between Monitor / Trial Co-ordinator and Site CI/PI (if not present at all, state reason): Name / designation of anyone attending meetings apart from Site personnel listed above and Monitor / Trial Co-ordinator:





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Section 1: Review of Trial Master File / Trial Site File

CI Site – TMF Participating Site – TSF

Documents in Investigator File – note ‘O’ ‘original’ or ‘C’ ‘copy’; if elsewhere on Site state where

Future documents – tick to confirm labelled file section exists in Trial Site File or state where (e.g. Site Pharmacy)



1.

Contact Information

1.1 Contact details of all personnel involved in trial at this Site

1.2 Daytime and ‘out of hours’ contact information as given to participants

1.3 External personnel contacts (e.g. Sponsor representative, Trials Unit)

2.

Participant Logs and Consent Forms

2.1 Participant screening log (chronological list of all screened potential patients. with reasons for non-entry is appropriate)


2.3 Participant randomisation identification code list

2.4 Original signed consent forms with Participant Information Sheet filed in recruitment order

3.

Source data

3.1 Source data location list e.g.; CRF, files, booklets, visit schedules, blood tests, consent forms, copies of letters, SAE forms.

4.

Standard Operating Procedures

4.1 - List of all WWORTH SOPs used for trial

- Sponsor / co-sponsor general or study-specific_SOPs)

4.2 Copies of current versions of documents listed under 4.1





____________________________________________________________________________








5.

Protocol and associated documents

5.1 Current approved Protocol, signed by CI / PI



5.4 Current approved GP letter 5.5 Current approved advertisement 5.6 Current trial flow-chart / procedural

guide (if applicable) and summary of randomisation procedure

5.7 Current eligibility criteria 5.8 Labels for attachment to participants’

medical records noting fact of trial participation

5.9 Therapy regimes 6.

Data collection


6.2 Sample(s) of other current approved data collection instruments (e.g. questionnaires)

6.3 Signed, dated and completed Case Report Forms

6.4 Signed, dated and completed questionnaires etc.

6.5 Data queries 6.6 File notes documenting CRF

corrections or data clarifications





____________________________________________________________________________








7.

Site Personnel

7.1 Up to date, signed and dated CVs and Good Clinical Practice (GCP) training records GCP training at least every 2 years and any other relevant trial specific training

7.2 Confidentiality Agreements (if applicable)


7.4 - Honorary contracts - Letter of access - Research passport

7.5 Staff changes - New staff - Staff leavers

8.

Ethics and Clinical Trial Authorisation


8.2 Favourable ethical opinion letter and committee composition



9.

Sponsorship

9.1 Letter of acceptance of sponsorship 9.2 Sponsor’s delegation of roles and

responsibilities





____________________________________________________________________________








10.

NHS Permission

10.1 Final approval letter 10.2 Conditional or interim approval letter

(if applicable)


10.4 Correspondence re NHS Permission 10.5 JSRC approval letter 11.

Contracts / Agreements / Finance / Indemnity

11.1 Clinical Trial Agreement 11.2 Indemnity and / or insurance policy

evidence (if not covered in Clinical Trial Agreement)

11.3 Any other contracts relating to the trial (e.g. IMP supplier)

11.4 Financial records and invoices 11.5 Correspondence and any file notes re

agreements, finance etc.

12.

Pharmacovigilance

12.1 Current Investigator Brochure (IB) / Summary of Product Characteristics (SmPC)


12.3 Suspected Unexpected Serious Adverse Event Reports

12.4 Development Safety Update Reports (DSUR) to MHRA and Ethics

12.5 Notification by Sponsor to Investigators of safety information





____________________________________________________________________________








12.6 Procedure for randomisation and routine and emergency unblinding / Code Break (if applicable)


12.8 Blank SAE forms 12.9 Adverse event reporting and

documentation

12.10

Progress Reports to Ethics

13.

Amendments

13.1 Chronological list of amendments with version numbers and dates

13.2 A separate bundle of documents for each amendment, filed in chronological order, comprising:

Copy approval / notification for information – Ethics

Copy approval / notification for information – MHRA

Copy approval / notification for information – R&D

Correspondence and any file notes on the amendment

Completed Amendment Checklist if applicable.

14.

Equipment (if applicable)

14.1 Calibration certificates 14.2 Correspondence and any file notes 14.3 Usage procedures 14.4 Expiry dates 15.

Monitoring

15.1 Monitoring Plan and visit schedules





____________________________________________________________________________








15.2 Site Initiation Report if applicable 15.3 Monitoring Visit Reports, Summaries,

Action Lists and Log

15.4 Trial Close-Out Report 15.5 Correspondence and any file notes 16.

Audit (if applicable)

16.1 Audit Report 16.2 Audit correspondence 17.

Pharmacy



17.3 Shipping records 17.4 Sample of label(s) attached

to IMP container

17.5 Instructions for handling the IMP 17.6 MAIMP Licence of the IMP supplier 17.7 QP Release documentation 17.8 Notification of unblinding 17.9 Record of retrieval / use of Code

Break envelopes (if applicable)

17.10

IMP Recall documentation

17.11

Drug accountability

17.12

Pharmacy correspondence and any file notes





____________________________________________________________________________








18.

Laboratory

18.1 Lab accreditation with date 18.2 Normal ranges with date 18.3 Record of retained body fluids

/ tissue samples


18.5 Chain of custody procedures 19.

Other

19.1 Copies of research related publications / reports

19.2 General correspondence and file notes not filed under sections above

19.3 Meeting Minutes

Section 2: Laboratory


Not Applicable

1. Shipment records 2. Specimen handling 3. Temperature monitoring in operation for all fridges or freezers used for the study

4. Ranges and lab accreditation evidence; evidence that ‘out of range’ results are appropriately flagged

5. Chain of custody clearly identified





____________________________________________________________________________


Section 3: Pharmacy


Not Applicable

1. Labels attached to IMP container (Good Manufacturing Practice compliant)

2. Instructions for handling the IMP available to all relevant staff

3. IMP being stored appropriately and at correct temperature, and that temperature excursions are being notified and acted upon.

4. Shipping records 5. Medication receipts 6. Evidence that IMP is being dispensed only on authority of authorised personnel ( Delegation Log / filled prescriptions)

7. Decoding procedures available to all relevant staff

8. Patient randomisation codes and emergency code-breaks appropriately managed

9. Have emergency code-breaks been used? 10. Does participant administration match site accountability records?

11. Has unused medication been returned? 12. Is the amount of returned medication consistent with drug accountability records?

13. Chain of custody procedures clearly identified SECTION 3: COMMENTS:

Section 4: Other


Not Applicable

SECTION 2: COMMENTS:





____________________________________________________________________________


Section 4: Other


Not Applicable

1. Is paper documentation being stored appropriately (lockable cabinets, in a lockable room)?

2. Are data collection instruments free of inappropriate participant identifiable data?

3. Is only standard, approved documentation being used?

4. Are consent forms present for all those listed on the participant log?

5. Is the consent process being carried out as agreed at the initiation visit?

6. Are all consent forms signed and dated by participant, researcher, witness, as appropriate?

7. Are computer files containing identifiable data stored on a remote server?

8. Is there evidence that all Site personnel have up to date GCP training?

9. Are tasks being carried out by appropriate personnel in line with the Delegation Log?

10. Is there evidence that all equipment used for the study is calibrated according to Site policy?

11. Do all fridges or freezers used for study have thermometers and is there evidence of temperature monitoring being done?


Section 5: Participant Recruitment 1. Number of subjects screened

2. Number screening failures

3. Total participants consented

4. Total participants enrolled

5. Total participants ongoing

6. Total participants completed





____________________________________________________________________________


Section 5: Participant Recruitment 7. Total participants withdrawn due to; -Safety reasons -Other reasons

7. Overall Target Recruitment


Section 6: Source Data Verification

1. Number of participants for whom Source Data was verified on this visit (attach completed Appendix 1 form for each such participant)

Section 6: COMMENTS:





____________________________________________________________________________


Section 7: Overall Assessment Please respond briefly in this section; and detail actions to be taken using form in Appendix 2

Yes No Comments

1. Have all issues raised on previous monitoring reports been addressed at the Site?

2. Have you identified adverse events during monitoring that had not been documented?

3. Have reported Serious Adverse Events been reported within required time frame with follow up information?

4. Have you identified any unreported Serious Adverse Events?

5. Have you identified any deviations from the Protocol or non-compliance with legislation?

6. Have you given any action lists to the Site (see Appendix 2)? If yes, add copy to this report and note number of items for action here under ‘comments’

7. Please detail any individual events, or series of events that you consider may be a Serious Breach of the Protocol, GCP or other urgent issues that the Sponsor should review carefully.

8. Are there sufficient staff, time and facilities for the study to continue?

Section 7: COMMENTS

Signature of Monitor / Trial Co-ordinator

Date

Name (printed)

Report received by Sponsor’s representative (enter date)

Signature

Name (print)





____________________________________________________________________________


Monitoring Tool : Annex 1 Individual Participant Records Check Reproduce this Section of the Form for each participant whose records are checked Records Check for Participant ID {insert ID number}:

Yes No Comments

1. Are source data for this participant retained in the appropriate place(s) (cf Source Data Location List)

2. When this participant was recruited were the correct, approved, patient information sheets and consent forms used?

3. Was consent given prior to study procedures?

4. Were all consent procedures prescribed by the Clinical Trial Regulations or the Ethics Committee followed?

5. Is this participant’s informed consent and confirmation of receipt of participant information properly documented and recorded in the health records or other source data file?

6. Was the decision on eligibility of this participant (compliance with inclusion and exclusion criteria) taken on the basis of documented evidence in existence at the date of the decision?

7. Was the decision on eligibility taken by the CI/PI or other authorised person?

8. Do Case Report Forms and other study documents contain any entry error, omission or illegibility?

9. Has the CI/PI or other authorised person made corrections, additions, or deletions appropriately and dated / initialled them?

10. Is there in the health records or other source data file a letter (to GP) informing of patients trial participation?

11. Is there a study label on the cover of the health records stating that the participant is in a clinical trial?





____________________________________________________________________________



Yes No Comments

12. Are study activities recorded in health records?

13. Are reported Serious Adverse Events verifiable against patient records?

14. Are there any adverse events recorded in the health records or other source data file that have not been documented as study data?

15. Are there any serious adverse events recorded in the health records or other source data file that have not been documented and reported in accordance with the protocol and the Clinical Trial Regulations?

16. Is withdrawal from the study documented (where applicable) with reason for withdrawal?

17. Are primary outcome data consistent with source data?

Participant’s Records Check: Comments

Monitoring tool: Annex 2, SITE ACTION LIST If any actions are required the Monitor / Trial Co-ordinator should complete this form and give or send it to the CI/PI or relevant department at the Site as soon as possible after the monitoring visit, copying to the Sponsor at the same time. Add extra rows as required. Investigator / Support Department representative to attend to all actions within prescribed time, sign, date and return to Sponsor at the address below.





____________________________________________________________________________



Yes No Comments

Item no. Issue identified Action required and from whom [e.g. ‘PI’, ‘Pharmacy’, ‘Lab’]

Date by which action required (10 days or sooner)

I confirm that all the above actions that were required to be taken by today’s date have now been completed.

Signed …………………………………………………………………………………………….

Name, Job Title, Role in Trial (print) …………………………………………………………………………………………….

Dated …………………………………………………………………………………….





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Monitoring tool: Annex 3, SPONSOR’S ACTION LIST If immediate actions are required the Monitor / Trial Co-ordinator should complete this form and give or send it to the Sponsor as soon as possible after the monitoring visit. Add extra rows as required. Sponsor to attend to all actions and document within recommended time. NB ‘Serious Breach’ issues to be reported to Sponsor within 24 hours of Monitor / Trial Co-ordinator becoming aware. Item no. Issue identified Action required [Note where

action required by a department of the Sponsor organisation, e.g. Pharmacy]






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Monitoring tool: Annex 4, MONITORING VISIT SUMMARY OF ACTION POINTS The Monitor / Trial Co-ordinator should complete this Summary for the benefit of the Site, after every visit. It should be given or sent to the CI/PI and copied to the Sponsor. If actions are immediately required at Site these should be detailed on Site Action List(s). This Summary should include any other (i.e. non-urgent) items that need to be drawn to the Investigator’s attention, or recommendations for improved practice.

Signature, Date and Printed Name of Monitor / Trial Co-ordinator ABM University Health Board would like to thank North & East Yorkshire R&D Alliance for their permission to reproduce the contents of this SOP.





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WWORTH-SOP17_Monitoring_V2.6 MS edits 140506 Not guaranteed if printed Page 60 of 82

Appendix 5: Pharmacy Monitoring Log

Pharmacy Monitoring Visit for ABMU HB sponsored trials/and non commercial sponsored trials Location of Pharmacy: Pharmacy staff seen: Study Title: C.I. / P.I.: ReDA Reference:

Pharmacy Arrangements Satisfactory Unsatisfactory (Specify under comments)

N/A Comments Monitors signature

Instructions for handling the IMP available to all relevant staff All equipment to be used for study calibrated according to Site policy?

Licence from the IMP supplier IMP supplies have been received by the site pharmacy Evidence that IMP is being dispensed only by authorised personnel

Labels for attachment to the IMP container (Good Manufacturing Practice compliant)

Patient randomisation codes and emergency code-breaks for unblinding

Decoding procedures Shipping records Delegation of Authority and signature form





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Medication receipt arrangements, and chain of custody procedures

Record or retrieval/ use of code break envelopes Is the amount of returned medication consistent with drug accountability

Drug accountability forms Temperature exursions are being notified and acted upon Arrangements for IMP storage at appropriate/correct temperature

Return of unused medication Quarantine area Temperature log completed (are there any discrepancies)

Evidence of GCP training within 2 years List of c.v.’s Training files up to date Pharmacy financial information/ invoices

Pharmacy correspondence file Further Comments: Monitored by: Monitors signature: Date:





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Appendix 6: Laboratory Checklist Good Clinical Practice (GCP) is applicable throughout a clinical trial and the general principles of GCP are applicable to and must be met by clinical laboratories. A clinical laboratory must be ‘adequate’ for purpose and the responsibility to ensure that this is the case resides with the PI. Study Title: C.I / P.I. ReDA reference:

Check Document Notes Laboratory/Department Name Name of any sub-contracted laboratory

Contact name of Head of Lab/Dept CV provided (Mandatory) Contact name for Trial Lead CV provided (Mandatory) Deputy to named Trial Lead CV provided (Mandatory)

List test(s) to be undertaken: Tests within current capability of laboratory

Test sub-contracted

YES/NO/NA YES/NO/NA

(a) (b) (c)





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(d) (e) (f)

Accreditation/Certification YES/NO/NA Copy of certificate filed in ISF/TMF

ISO 9000 ISO 15189 ISO 17025 ISO 45001 CAP (College of American Pathologists) CLIA (Clinical Laboratory Improvement Amendments) GMP (Good Manufacturing Practice) GLP (Good Laboratory Practice) GCLP (Good Clinical Laboratory Practice) Other:

Does the Lab have: YES/NO/NA EVIDENCE Security system(s) with controlled access Backup systems in case of power/equipment failure SOPs in place for all activities to be undertaken Validated computer systems Systems for calibration and maintenance of equipment

Temperature loggers Any discrepancies on freezer log, (evidence of actions taken)

Temperature alarm systems and testing procedures





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Adequate sample storage facilities Systems to register receipt and analysis of samples Procedures for transportation Temperature monitoring during transportation Prompt reporting of results Procedures to retain backup samples Chain of Custody procedures Sample Collection forms in PDF. Delegation of Duties log Current Approved Protocol Evidence/Certificates of equipment checks/calibrations

Laboratory Ranges Provided

Staff training records Evidence of GCP Training Comments:

Quality Assurance Officer undertaking Assessment:

Signature Date Laboratory Contact Signature Date





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Appendix 7: Monitoring Visit Log

C.I./ P.I. Study Site

Study Title

ReDA Number

Visit date Visit purpose Visitor-print name Visitor signature Confirmed by signature (member of investigator team)

ABM University Health Board would like to thank North & East Yorkshire R&D Alliance for their permission to reproduce their information.





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Appendix 8: Monitoring / Audit Visit Report Template

Date of monitoring / audit visit: Study title: Chief/Principle Investigator:

Study location:

R&D/ ReDA Reference:

To be completed by R&D Office For investigator completion

Moni

torin

g

findi

ngs

-Good Clinical Practice (G.C.P.)

recommendations/ guidance

-Sponsor

recommendations/guidance

Corrective and Prevent

ative Actions (C.A.P.A

.’S)

Actions to be completed/commented by C.I./P.I. or delegate.

Returned responses to R&D by:

Actions completed by:.........................

Date:.....................

Comments:

Report prepared by: .............................................. Signature: ............................................................. Date: ……………………………. Report checked by R&D Manager: .................................................. R&D Manager Signature: ………………………………….......... Date: ……………………………….





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Response to the above report required by: ……………………………… Please send response to: Mrs Tina Morgan Research Quality Assurance Officer R&D Department Morriston Hospital Heol Maes Eglwys Swansea SA6 6NL 01792 704056 Email [email protected]






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Appendix 9: Trial Close Out Report Template

TRIAL CLOSE – OUT REPORT TEMPLATE STUDY TITLE (short):

ReDA Reference:

EUDRACT NUMBER:

SITE:

CHIEF/PRINCIPAL INVESTIGATOR AT SITE:

DATE OF VISIT:

DATE OF PREVIOUS VISIT:

IF PARTICIPATING SITE CLOSE-OUT, DATE OF LAST PARTICIPANT AT SITE:

IF WHOLE-TRIAL CLOSE-OUT, DATE OF LAST PARTICIPANT CONTACT ACROSS ALL SITES:

DEPARTMENTS VISITED; -INVESTIGATOR TEAM -PHARMACY -IMAGING -LABORATOR -OTHER (please state)

NAME AND JOB TITLE OF STAFF SEEN:





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DURATION OF MEETING BETWEEN MONITOR AND SITE CI/PI (if not

present at all, state reason):

NAME / DESIGNATION OF ANYONE ATTENDING MEETINGS APART FROM

SITE PERSONNEL LISTED ABOVE:

MONITOR’S NAME:

SECTION 1: FINAL CHECK of WHOLE TRIAL MASTER FILE / INVESTIGATOR SITE FILE

NB. DOCUMENTS E.G. PHARMACY, SHOULD NOW BE BROUGHT TOGETHER AND PUT INTO A SINGLE COMBINED FILING SYSTEM

1.0 CONTACT INFORMATION

TICK IF PRESENT IN FILE

(COMMENTS)

1.1 Contact details of all personnel involved in trial at this site

1.2 Daytime and ‘out of hours’ contact information as given to participants.

1.3 External personnel contacts (e.g. Sponsor representative)

2.0 PARTICIPANT LOGS AND CONSENT FORMS

2.1 Participant screening log


2.3 Participant identification code list

2.4 Original signed consent forms with participant information sheet filed in recruitment order.

3.0 SOURCE DATA

3.1 Source data location list

4.0 STANDARD OPERATING PROCEDURES

4.1 List of all SOPs used for trial (i.e. sponsor / co





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sponsor general or study specific)

4.2 Copies of current versions of documents listed under 4.1

5.0 PROTOCOL AND ASSOCIATED DOCUMENTS

5.1 Current approved Protocol, signed by CI/PI



5.4 Current approved GP letter (if applicable)

5.5 Current approved advertisement (if applicable)

5.6 Current trial flow-chart / procedural guide (if applicable) and summary of randomisation procedure

5.7 Current eligibility criteria extract for clinical team information if used (NB direct extract copied from protocol only, with version control)

5.8 Sheets of labels for attachment to participants medical records noting fact of trial participation

6.0 DATA COLLECTION


6.2 Samples(s) of other current approved data collection instruments (e.g. questionnaires)

6.3 Signed, dated and completed Case Report Forms





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6.4 Signed, dated and completed questionnaires etc.

6.5 Data queries

6.6 File notes documenting CRF corrections or data clarifications

7.0 SITE PERSONNEL

7.1 -Up to date, signed and dated CVs -Good Clinical Practice Certificates (GCP) -Training records

7.2 Confidentiality Agreements (if applicable)


8.0 ETHICS AND CLINICAL TRIAL AUTHORISATION


8.2 Favourable ethical opinion letter and committee composition



9.0 SPONSORSHIP

9.1 Joint Scientific Review Committee acceptance letter

9.2 Letter of acceptance of sponsorship

9.3 Sponsor’s delegation of roles and responsibilities

10.0 NHS Permission

10.1 Final approval letter

10.2 Conditional or interim approval


10.4 Correspondence re NHS





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Permission

11.0 Contracts / Agreements / Finance / Indemnity

11.1 Clinical Trial Agreement (CTA)

11.2 Indemnity and / or insurance policy evidence (if not covered in CTA

11.3 Any other contracts relating to the trial (e.g. IMP Supplier)

11.4 Financial records and invoices

11.5 Correspondence and any file notes re agreements, finance etc

11.6 Service Level Agreement

12.0 Pharmacovigilance

12.1 Current Investigator Brochure (IB) / Summary of Product Characteristics


12.3 Suspected Unexpected Serious Adverse Event Reports (SUSAR’s)

12.4 -DSUR Reports to MHRA and Ethics. -Progress reports to ethics

12.5 Notification by Sponsor to Investigators of safety information

12.6 Procedure for randomisation and unblinding / Code Break (if applicable)


12.8 Blank SAE / AE forms

12.9 Copies of any adverse incident reports made under the normal reporting procedure used by the Health Board.

13.0 Amendments

13.1 Chronological list of





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amendments with version numbers and dates

13.2 A SEPERATE BUNDLE OF DOCUMENTS FOR EACH AMENDMENT, FILED IN CHRONOLOGICAL ORDER, COMPRISING -Copy approval / notification for information – Ethics -Copy approval/ notification for information – MHRA -Copy approval / notification for information – R&D -Correspondence and any file notes on the amendment

14.0 EQUIPMENT

14.1 Calibration certificates and any contracts.


15 MONITORING

15.1 Monitoring Plan

15.2 Site Initiation Report

15.3 Monitoring Visit Reports, Summaries, Action Lists Log

15.4 Trial Close-Out Report


16.0 AUDIT (if applicable)

16.1 Audit Report

16.2 Audit correspondence

17.0 PHARMACY



17.3 Shipping records

17.4 Sample of label(s) attached to IMP container

17.5 Instructions for handling





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the IMP

17.6 MAIMP Licence of the IMP supplier

17.7 QP Release documentation

17.8 Notification of unblinding

17.9 Record or retrieval / use of Code Break envelopes (if applicable)

17.10 IMP Recall documentation

17.11 Drug accountability

17.12 Pharmacy correspondence and any file notes

18.0 LABORATORY

18.1 Lab accreditation with date

18.2 Normal ranges with date

18.3 Record of retained body fluids / tissue samples


19.0 OTHER

19.1 Copies of research related publications / reports

19.2 General correspondence and file notes not filed under sections above

19.3 Meeting minutes

20.0 SUPERSEDED DOCUMENTS

20.1 Superseded Section 4 SOP documents

20.2 Superseded Section 5 Protocol and associated documents

20.3 Superseded Section 6 Data collection

20.4 Superseded Section 7 Site Personnel

20.5 Superseded Section 8 Ethics and Clinical Trial Authorisations

20.6 Superseded Section 9 Sponsorship

20.7 Superseded Section 10





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NHS Permission

20.8 Superseded Section 11 Contracts, Agreements, Finance, Indemnity

20.9 Superseded Section 12 Pharmacovigilance

20.10 Superseded Section 14 Equipment

20.11 Superseded Section 17 Pharmacy

20.12 Superseded Section 18 Laboratory

SECTION 1: COMMENTS DETAIL ANY ERRORS OR EMISSIONS IN TMF / ISF REQUIRING RECTIFICATION

SECTION 2: IMP TICK IF SATISFACTORY

1.Have all relevant Pharmacy documents been provided for inclusion in the combined TMF / ISF

2.Have you carried out a complete final reconciliation check

3. Is all IMP fully accounted for?

4. Is the Site now ready, on instruction from the Sponsor, to carry out the instructions for IMP destruction / retention / disposal as specified in the Protocol and SOP.

Any Comments:





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SECTION 3: PARTICIPANT RECRUITMENT

1.Number of subjects screened

2.Number of screening failures

3.Total participants consented

4. Total participants enrolled

5. Total participants completed

6. Total participants withdrawn

Any Comments:

SECTION 4: SOURCE DATA VERIFICATION

1. Number of participants for whom Source Data was verified on this visit:

(attach completed Appendix 1 form for each such participant)

Any Comments: Note any issues with regard to SDV

Section 5: Monitor’s overall assessment (Please respond briefly in this section, and detail actions to be taken using forms in Annex 2 and 3

YES NO COMMENTS

1. Have all issues raised on previous monitoring reports been addressed?

2. In closing out the trial have you identified adverse events or serious adverse events that have not been documented, reported or followed up appropriately?

3. Have you given an action list to the Site of items requiring attention before Trial Close-Out can be completed (see Annex 2)?. If yes, add copy to this report and note number of items for action here under ‘comments’





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4. Please detail any individual events, or series of events that you consider may be a Serious Breach of the Protocol, GCP or other urgent issues that the Sponsor should review carefully. NB Any serious breach in a ABMUHB Sponsored study MUST be reported to the R&D Department within 24 hours of the breach being identified.

5. Are all arrangements in place and understood by Site personnel for archiving of study materials in accordance with ‘SOP08 Archiving’

6. Is a list of randomisation codes attached to this Close-Out Report to facilitate reconciliation by the Sponsor? If not please comment.





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MONITOR’S GENERAL COMMENTS Please note here anything you wish to report to the Sponsor that has not been

covered above.

SIGNATURE OF MONITOR

DATE

MONITOR’S NAME

REPORT RECEIVED BY SPONSOR’S REPRESENTATIVE (ENTER DATE)

SIGNATURE

NAME (PRINT)

REPORT SIGNED OFF BY SPONSOR’S REPRESENTATIVE

FOLLOWING RESOLUTION OF ALL QUERIES AND CLOSE – OUT OF SITE

(ENTER DATE)

SIGNATURE

NAME (PRINT)





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ANNEX 1 PARTICIPANT RECORDS CHECK (INDIVIDUAL PARTICIPANTS)

Reproduce this section of the form for each participant whose records are checked

RECORDS CHECK FOR PARTICIPANT ID (insert ID number)

YES NO COMMENTS

1. Are source data for this participant retained in the appropriate place(s) (Source Data Location List)

2. When this participant was recruited were the correct, approved, patient information sheets and consent forms used?

3. Was consent given prior to study procedures?

4. Were all consent procedures prescribed by the Clinical Trial Regulations or the Ethics Committee followed?

5. Is this participant’s informed consent process and confirmation of receipt of participant information properly documented and recorded in the health records or other source data file?

6. Was the decision on eligibility of this participant (compliance with inclusion and exclusion criteria) taken on the basis of documented evidence in existence at the date of the decision?

7. Was the decision on eligibility taken by the CI/PI or other authorised person?

8. Do Case Report Forms and other study documents contain an entry error, omission or illegibility?

9. Has the CI / PI or other authorised person made corrections, additions, or deletions appropriately and dated / initialled them?

10. Is there in the health records or other source data file a letter to the G.P. informing of patients trial





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participation?

11. Is there a label on the cover of the medical records stating that the participant is in a clinical trial?

12. Are study activities recorded in health records?

13. Are reported Serious Adverse Events verifiable against patient records?

14. Are there any adverse events recorded in the health records or other source data file that have not been documented as study data?

15. Are there any serious adverse events recorded in the health records or other source data file that have been documented and reported in accordance with the protocol and the Clinical Trial Regulations?

16. Is withdrawal from the study documented (where applicable)?

17. Are primary outcomes data consistent with source data?

PARTICIPANT’S RECORDS CHECK: COMMENTS

ANNEX 2 SITE ACTION LIST

If any actions are required the Monitor / Trial Co-ordinator should complete this form and give or send it to the CI/PI or relevant department at the Site as soon as possible after the close - out visit, copying to the Sponsor at the same time. Add extra rows as required. Investigator / Support Department representative to attend to all actions within prescribed time, sign, date and return to Sponsor at the address below.





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ANNEX 2 SITE ACTION LIST

If any actions are required the Monitor / Trial Co-ordinator should complete this form and give or send it to the CI/PI or relevant department at the Site as soon as possible after the close - out visit, copying to the Sponsor at the same time. Add extra rows as required. Investigator / Support Department representative to attend to all actions within prescribed time, sign, date and return to Sponsor at the address below.

Item no.

Issue identified Action required and from whom [e.g. ‘PI’, ‘Pharmacy’, ‘Lab’]

Date by which action required Please state: (10 days or sooner)..............

I confirm that all the above actions that were required to be taken by (enter date).................. have now been completed.

Signed …………………………………………………………………………………………….

Name, Job Title, Role in Trial (print) …………………………………………………………………………………………….

Dated …………………………………………………………………………………….





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ANNEX 3 SPONSOR’S ACTION LIST

If immediate actions are required the Monitor / Trial Co-ordinator should complete this form and give or send it to the Sponsor as soon as possible after the close - out visit. Add extra rows as required. Sponsor to attend to all actions and document within recommended time. NB ‘Serious Breach’ issues to be reported to Sponsor within 24 hours of Monitor / Trial Co-ordinator becoming aware.

Item no.

Issue identified Action required [Note where action required by a department of the Sponsor organisation, e.g. Pharmacy]


