Good Clinical Practice Guide
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Thread: MHRA produced FAQs for monitoring

  1. #11
    10. Who should review the oversight and monitoring strategy documentation?

    The review of the documentation should be undertaken by appropriately qualified individuals within the sponsor organisation. Where there are several documents prepared by different areas, it is recommended that there is a cross-functional review to ensure consistency and compliance with the overall risk–based strategy.

    There is no requirement to send additional documentation outlining the oversight and monitoring strategy to the MHRA or the REC as part of the approval process, as there is no requirement for this to be approved by the MHRA or REC, and there are currently no plans for this to be introduced in the future. The protocol musta, however, according to the principles of GCP that mustb be adhered to, contain the monitoring policy though this may not contain the level of detail that other sponsor documentation (plans/SOPs etc.) contains.

    a. SI 2004/1031 (as amended) Schedule 1, Part 2 (7)
    b. SI 2004/1031 (as amended) Regulation 28 (1) and (2)

    Version 1: 22 February 2013

  2. #12
    11. Does the strategy documentation need to be global or country specific?

    For multi-country trials, global documentation for the trial is acceptable, but it may be necessary to include specific procedures to mitigate any country-specific risks that were identified from the risk assessment – for example, differences in clinical practice, local regulations etc. Furthermore, it may be necessary to include some site-specific actions, for example, there may be additional monitoring checks to be undertaken at the chief investigator’s site (e.g. if the sponsor has delegated numerous functions) or the site may be responsible for undertaking a specific trial activity or where a site-specific risk may have been identified.
    Version 1: 22 February 2013

  3. #13
    12. Does the strategy documentation have to be followed?

    Yes, it musta, together with any procedures described in the protocol (for example setting up of data monitoring committee etc.) and/or standard operating procedures. Any deviations should be documented, justified and any potential impact on the trial quality identified.

    a. SI 2004/1031 (as amended) Regulation 28 (1), 29(a) and Schedule 1, Part 2, (4)
    Version 1: 22 February 2013

  4. #14
    13. Can the strategy documentation be amended?

    Yes, it can and may need to be as part of a flexible and adaptive approach to monitoring. It is recommended that the justification for the amendment is documented and that the documentation is version controlled. It is also recommended that the strategy is reviewed when other important documents are amended, for example, the protocol, the risk assessment or the investigator’s brochure or when significant trial events occur (e.g. the addition of extra sites).
    Version 1: 22 February 2013

  5. #15
    14. Are there examples of trial documents that outline oversight and monitoring strategy?

    The example risk assessment for a trial co-sponsored by the University of Edinburgh and NHS Lothian provides an example of a monitoring strategy: see Example 3 at the following link:

    The MHRA is willing to publish further examples (ideally linked to examples of risk assessments published on the MHRA GCP Forum) here to assist sponsors in developing processes and procedures. Sponsors, who wish to provide examples for consideration for publication, should contact the MHRA GCP Inspectorate:
    Version 2: 05 March 2013
    The examples are not intended to be definitive approaches. They are not endorsed or recommended by the MHRA
    Last edited by MHRA Super Moderator; 14th Nov 2014 at 12:07 PM. Reason: Cross-reference added.

  6. #16
    15. What role do oversight committees have in monitoring a clinical trial?

    In the conduct of a trial, it may be appropriate, if considered as mitigation from the risk assessment, to set up committees as part of the oversight/monitoring strategy. Such committees could be set up on national, regional or global basis dependent on the trial and the remit of the committee.

    One type would be a committee that would oversee the trial conduct, i.e. a Trial Management Committee (TMC), which may be expanded to also involve members independent of the trial, to then form a Trial Steering Committee (TSC). These committees would typically oversee that the trial is appropriately managed to ensure compliance and deal with any issues identified during its conduct. One of their functions would be monitoring that appropriate systems and procedures were in place, the trial was adequately resourced and that progress of the trial was on track. They would be involved in reviewing the monitoring strategy and may make the decisions on any escalation activities that have been identified as being necessary to address non-compliance or any adaptations to the monitoring plan. The TSC may be acting in a more strategic manner than the TMC who would be more operationally focussed. Such committees may not be necessary in the case of a small trial conducted at one site under the direct control of an investigator or organisations may have a project manager and project team that is essentially acting as a TMC.

    An independent trial data monitoring committee (DMC) may also be set up primarily to review the safety data for a trial at regular intervals to assess whether the trial is to continue or not or whether amendments need to be made. They may review un-blinded data and also be involved in reviewing efficacy data for sequential trials.

    Further guidance on such committees can be found in the EMA guidance EMEA/CHMP/EWP/5872/03.
    Version 1: 22 February 2013

  7. #17
    16. Is it necessary to perform regular on-site visits?

    The UK legislation does not require regular on-site visits. The MHRA GCP Inspectorate believes that ICH GCPb underestimates the role that central monitoring can take as it states that monitoring without on-site visits should only be in “exceptional circumstances”. If the risk assessment undertaken has not identified the need for on-site visits to mitigate vulnerabilities and assure that the trial would be undertaken to the requirements of the legislation and GCP, subjects are protected and the results would be reliable; then this would provide suitable justification for an “exceptional circumstance”. Furthermore, the ICH GCPb statement that, “in general there is a need for on-site monitoring before, during and after the trial” is not recommended to be interpreted that on-site visits for assessment, initiation and on-going monitoring and closeout must always be performed. Reports from such activities, however, musta be retained. A need for on-site visit(s) may arise from information gained during the trial conduct. Where routine on-site visits are not part of the monitoring strategy, it is recommended that provision to undertake a triggered or “for cause” on-site visit is in place if circumstances arise via central monitoring activities that necessitate such an escalation activity to undertake corrective and preventative actions to maintain compliance. If only one planned monitoring visit is to be undertaken per site post initiation, it is recommended that this is done soon after the trial commences so that preventative actions can be implemented at an early stage.

    a. SI 2004/1031 (as amended) Regulation 31A (3)
    b. ICH GCP Section 5.18.3

    Version 1: 22 February 2013

  8. #18
    17. Is it necessary to perform an investigator site assessment visit?

    There should be some form of assessment of the trial investigator site undertaken and this together with the decision to proceed with use of the site should be documented, but this does not necessarily mean conducting an actual visit. An assessment could be either a feasibility or information-gathering exercise (e.g. of facilities, resources, staff [CVs], accreditation status for example, as part of a research network, SOPs etc, recommendations from CROs etc) and perhaps via telephone or video-conference to establish the suitability of the site. It may be necessary, however, that even after this process, a visit is needed to confirm the suitability for the trial. The investigator site may be well-known to the sponsor and may have been used for similar previous trials. In such situations, there could be a review of existing information about the site, for example previous monitoring or audit reports to supplement a feasibility review to confirm the continuing suitability of the investigator site. The complexity of the trial may affect the need for a site assessment visit, for example, a trial categorised as Type A may be no different to normal clinical practice and thus the need for an assessment visit would be reduced. It is recommended the risk assessment for the trial considers the investigator site selection process.
    Version 1: 22 February 2013

  9. #19
    18. Is it necessary to perform an investigator site initiation visit?

    The site research team musta be suitably trained to undertake the trial activities. There should be a documented process to demonstrate that the sponsor has ensured that the investigator site research team is suitably trained, set up and ready to conduct the trial. Whilst this is often done with a specific initiation visit and sometimes a meeting of investigators, this may not always be necessary. Specific training could be done centrally via telephone or video-conferencing or using web-based approaches. Training and initiation packages could be sent to the site containing manuals/instructions and checklists to complete and return. The level of training needed would be dependent upon the experience of the site staff and the complexity of the trial. The level of instruction given to the trial site staff at this stage and during the initial stages of conducting the trial is likely to influence the compliance level of the site. Remote training may have risks as it will be reduced in length and may be harder for the trainer to identify any lack of understanding, particularly if it is done without any interaction (e.g. web presentation). The sponsor is recommended to retain evidence of the training given and ideally, evidence of the effectiveness, i.e. the understanding of the site staff, of the training provided. Again, it is recommended that the risk assessment considers the need for site initiation and training. It is also recommended that there is the means to address the training of new staff or re-training of existing staff if the need arises.

    a. SI 2004/1031 (as amended) Regulation 28 (1) and (2), Schedule 1, Part 2, (2)
    Version 1: 22 February 2013

  10. #20
    19. Is it necessary to perform an investigator site close out visit?

    The close out visit by a monitor would primarily be to ensure all the trial documentation and source data is appropriately filed and stored for future retrieval if necessary, to ensure that all trial materials and IMP is accounted for and returned/destroyed, that all the necessary trial data and documentation have been collected and that there are no outstanding monitoring issues or data queries. Some or all of this could be undertaken remotely, with the investigator site staff undertaking tasks under instructions from the sponsor, for example completing checklists for the contents of the investigator file. If the site has been visited before, then the archiving storage should have been assessed and no further visit needed or alternatively, the archiving could be arranged at an archiving vendor by the sponsor (see TMF FAQs). Again, it is recommended that the risk assessment considers the need for close down visits and how the investigator TMF and source data will be available for the required retention time, as this musta be available for at least 5 years.

    a. SI 2004/1031 (as amended) Regulation 31A
    Version 1: 22 February 2013

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