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  1. #1

    MHRA produced FAQs for monitoring

    The following frequently asked questions (FAQs) are presented below:
    1. What is the purpose of overseeing and monitoring a clinical trial?
    2. What are oversight and monitoring activities?
    3. What are the important factors in determining the oversight and monitoring strategy?
    4. How should the oversight and monitoring strategy be documented?
    5. How can the oversight and monitoring strategies be adapted?
    6. Is it possible to have different intensity or focus of the oversight and monitoring activities?
    7. Does adaptive monitoring always have to be trial-specific – for example, in relation to the trial risk assessment?
    8. Is it possible that not undertaking any oversight or monitoring is acceptable?
    9. What should the documented oversight and monitoring strategy contain?
    10. Who should review the oversight and monitoring strategy documentation?
    11. Does the strategy documentation need to be global or country specific?
    12. Does the strategy documentation have to be followed?
    13. Can the strategy documentation be amended?
    14. Are there examples of trial documents that outline oversight and monitoring strategy?
    15. What role do oversight committees have in monitoring a clinical trial?
    16. Is it necessary to perform regular on-site visits?
    17. Is it necessary to perform an investigator site assessment visit?
    18. Is it necessary to perform an investigator site initiation visit?
    19. Is it necessary to perform an investigator site close out visit?
    20. What activities comprise “central monitoring” of a clinical trial and should they be documented?
    21. What is statistical monitoring?
    22. Are there any expectations of which metrics or key performance indicators or methodologies should be used in central/statistical monitoring?
    23. What are the benefits of conducting an on-site visit?
    24. How should non-compliance be dealt with when it is identified?
    25. How important is the accuracy of the clinical trial data?
    26. Is it necessary to perform 100% source data verification (SDV)?
    27. How do I show that the monitoring strategy has been complied with?

  2. #2
    1. What is the purpose of overseeing and monitoring a clinical trial?

    The UK legislation requiresa that the sponsor assures themselves that the trial is being conducted according to the principles of GCP, the legislation, the authorisation from the competent authority, the favourable opinion from the ethics committee and the trial protocol and procedures. There is also a requirement that the monitoring policy mustb be contained in the trial protocol.

    The sponsor’s oversight and monitoring can be regarded to encompass all the activities undertaken by the sponsor during the conduct of the trial that are there to ensure the subjects rights and well being are protected, the reliability of the trial data and hence the trial results and that the trial is conducted in accordance with the legislation. It is the sponsor’s “safety net” to check that the trial protocol, procedures, training etc. that have been implemented in order to get it right first time are functioning correctly.

    a. SI 2004/1031 (as amended) Regulation 28, (1) & (2) and Regulation 29, Schedule 1 Part 2, (4)
    b. SI 2004/1031 (as amended) Schedule 1 Part 2, (7)

    Version 1: 22 February 2013

  3. #3
    2. What are oversight and monitoring activities?

    Oversight and monitoring activities can include a broad range of activities, for example, the use of committees to manage the trial or review the emerging safety data, regular review meetings (e.g. sponsor with CRO/Chief Investigator), central review of clinical trial data, documents and reports, feedback from questionnaires sent to investigators, data management processes, statistical review of the data from the trial, pharmacovigilance signal detection, audits and visits to the investigator site by a trial monitor and auditors to assess the conduct of the trial.

    Oversight is important where the sponsor has delegated functions to other parties, either within the same organisation, for example, a Chief Investigator within the Trust or to an external CRO. The sponsor’s project management or governance should have sufficient number of the above processes in place in order to verify that the functions are being conducted appropriately. The sponsor should be approving documents and processes (protocols, CRFs, SOPs, analysis plans, data management plans etc.) that are being implemented to carry out the delegated functions. The delegated parties would typically be implementing some or all of the detailed processes decided from the monitoring strategy. The oversight would usually involve assessment of the processes that are to be used by those delegated the sponsor’s functions, regular review meetings with personnel, review and approval of specific documentation (e.g. site visit report, regulatory green light documentation) or perhaps visits or co-visits to investigator sites and audit.

    Traditionally, “monitoring” has tended to define and focus on monitors visiting sites as part of quality control and this approach has been extensively used by commercial sponsors consisting of regular on-site visits covering the activities outlined in ICH GCP guidancea. Non-commercial trials have primarily taken a more centralised approach to monitoring activities with less reliance on on-site visits.

    Audit activities are sample based and may occur during or after the trial is completed, or for cause as a result of issues detected by other monitoring activities. The auditor would also assess the effectiveness of the monitoring activities and compliance with the processes outlined in the protocol/monitoring plan/SOPs.

    An emerging consensus is that an approach to take, though not mandatory, is to define the overall oversight and monitoring strategy and the procedures of the trial (e.g. SOPs, protocol) to mitigate the risks to the quality of the trial, i.e. the reliability of the results and protection of trial subjects, using the appropriate methods. This would involve undertaking a thorough risk assessment of the trial to identify the risks and then determine the strategies and procedures to mitigate them. This risk-based approach is consistent with ICH GCP where the “sponsor should determine the extent and nature of the monitoring” a.

    a. ICH GCP Sections 5.18.3 – 5.18.6
    Version 1: 22 February 2013

  4. #4
    3. What are the important factors in determining the oversight and monitoring strategy?

    Monitoring may aim to assess compliance with every detail of the protocol and trial procedures and conduct checks of every data point for consistency with source documents and validity. Such an approach has been used traditionally and is extremely resource-intensive. The key aim is to ensure the rights, safety and well-being of the trial subjects are protected and that the final results of the trial are reliable. It is recommended that a proportionate approach to the management and monitoring of the trial is undertaken based on the trial risk assessment that identifies the areas that matter to achieving the above key aim, i.e. those activities/data that, if incorrect, would have a negative impact on subject safety and trial results. It is not possible to provide an exhaustive list, but the strategy, as considered by risk assessment, is likely to depend upon:

    • Trial categorisation as per the MRC/DH/MHRA risk adapted approach (A, B or C)a
    • Complexity of the trial protocol and procedures – e.g. some trials can have complicated protocols involving several different objectives and collection of extensive data
    • Novelty of the trial – for example, the use of new methods/equipment
    • Endpoint measurements – for example, could be directly collected/transferred electronically, for example if laboratory based
    • Size – multicentre, multinational, number of subjects, data quantity
    • Use of vulnerable subjects, for example consent process involving parents, carers, legal representatives
    • Type of investigator site and experience of site staff
    • Whether electronic data capture is being used – an eCRF allows additional information about who and when data were entered etc. (from the audit trail)
    • Use of commercial or academic contract research organisations, which would involve their assessment
    • Complexity and ease of use of the Case Report Form (CRF)
    • Training needs of monitoring staff, investigators and research teams
    • Type and effectiveness of central monitoring approaches available – e.g. if it is a single site trial there will not be the opportunity to compare data across a number of sites

    a. For further guidance see MRC/DH/MHRA Risk-Adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products.

    Version 1: 22 February 2013

  5. #5
    4. How should the oversight and monitoring strategy be documented?

    The risk assessment would be a document that defines the necessary oversight/monitoring actions and further documentation to implement these would usually be prepared. How this is done is decided by the sponsor. This may be contained in one document, for example the protocol, an SOP, or a monitoring plan which clearly outlines for a particular trial how the trial would be overseen, managed and monitored to ensure compliance with the regulations. In many organisations, the oversight and monitoring strategy is contained in a range of documents, for example SOPs, protocol, monitoring plan, committee charters, data management plan, data validation plan, medical monitoring plan, pharmacovigilance plan etc. It is recommended that there is clarity on how these link together to implement the strategy based on the risk assessment and an overriding document to explain this would be recommended. Such a document would be particularly useful where there is delegation of functions from the sponsor, for example, to CROs in different countries, as it will facilitate consistency. Where these types of documents/plans are being used extensively for trials within an organisation, there should be formal procedures to control the content, version control, maintenance etc. of them.
    Version 1: 22 February 2013

  6. #6
    5. How can the oversight and monitoring strategies be adapted?

    The adaptation of aspects of the conduct of the trial based on a trial categorisation to Type A/B/C and trial specific risk assessment is a broad approach that impacts on all areas of the trial conduct, but beneath this, the activities outlined as the monitoring strategy could include a further flexible or adaptive approach. This ensures that the monitoring tasks undertaken are also risk-based and reflect accumulating information about the compliance of the investigator site(s) or from data/information from outside the trial (e.g. new legislation).

    The document(s) comprising the monitoring strategy (e.g. protocol, SOPs, data management plan, medical monitoring plan, safety plan, monitoring plan etc.) are recommended to have been based on the vulnerabilities identified in the risk assessment, but are also recommended to contain further risk-based flexibility within. For example,
    • the intensity of monitoring/oversight and/or visits is high initially and then decreases when compliance is acceptable,
    • high intensity (visits, contact etc) for unknown/new sites with little trial experience compared with sites used many times by the sponsor,
    • triggering an on-site visit, if central monitoring reveals concerns at a particular site (e.g. a serious breach has occurred).

    There should always be a process and resources made available to escalate the monitoring activities when necessary. Such decisions could be delegated to the monitor to decide the appropriate level and frequency of monitoring based on guidance in the monitoring strategy together with the outcome of monitoring activities and actively overseen by the project manager/chief investigator/trial steering group. The monitoring strategy is recommended to define how adaptations will be decided and the rationale for the change should be documented. In some cases, the monitoring strategy documents may need to be amended if the planned adaptation is beyond the scope of flexibility built into the original strategy.
    Version 1: 22 February 2013

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