MHRA produced FAQs for monitoring

[MHRA Super Moderator]

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?

[MHRA Super Moderator]

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

The UK legislation requires^a 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 must^b 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)

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[MHRA Super Moderator]

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 guidance^a. 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

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[MHRA Super Moderator]

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.
http://www.mhra.gov.uk/home/groups/l.../con111784.pdf

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[MHRA Super Moderator]

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.

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[MHRA Super Moderator]

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.

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[MHRA Super Moderator]

6. Is it possible to have different intensity or focus of the oversight and monitoring activities?

Yes, it is quite appropriate for the monitoring to focus or have more detailed review (intensity) on different areas within a trial or in different trials. The following examples illustrate this:

• There may be a need to undertake 100% source data verification (SDV) of consent in a trial categorised as Type A (where the IMP is used as per normal clinical practice) involving vulnerable subjects or emergency research, but there may be no recording of IMP accountability beyond normal clinical practice resulting in limited or no monitoring of this aspect.
• Samples taken and processed for pharmacokinetic analysis, where this was the primary or an important trial objective, would need a more detailed review of the processing done to ensure that it had been done in accordance with the trial protocol/procedures to ensure their integrity compared with routine samples for haematology/biochemistry or for exploratory analysis, particularly if the routine or exploratory samples were taken as per the normal hospital practice.
• Unlicensed IMP in a trial categorised as Type C would need monitoring of the accountability in more detail than would be expected for IMP in a trial categorised as Type A, where the IMP is used as per normal clinical practice. Additionally, if the IMP needed to have refrigerated or frozen storage conditions this would potentially increase the monitoring focus, though still may not necessitate on-site visits. This could be the case for example if there had been a detailed assessment and approval of the facilities and regular provision of remote storage data to demonstrate compliance.

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[MHRA Super Moderator]

7. Does adaptive monitoring always have to be trial-specific – for example, in relation to the trial risk assessment?

Not necessarily, as the sponsor may have generic procedures for monitoring that build in a flexible and adaptive approach that covers all trials. However, a fully proportionate approach to the management and monitoring of the trial would need a risk assessment to be undertaken in order that the vulnerabilities in a particular trial are identified so suitable mitigating actions can be taken. Without the risk assessment it may be possible that the generic activities are not focussed in the important areas or that resource is wasted undertaking activities that do not significantly improve the quality of the trial (e.g. extensive source data verification), for this reason, it is recommended to undertake a trial specific risk assessment.

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[MHRA Super Moderator]

8. Is it possible that not undertaking any oversight or monitoring is acceptable?

The sponsor must^a ensure that the trial is conducted in accordance with the legislation and principles of GCP. In some trials categorised as Type A, it may be possible that the sponsor oversight can be reduced substantially, but some activity will still be needed; however central or on-site monitoring activities may not be deemed necessary as part of the risk assessment of the trial. This would be very rare and the trial would need to be very low risk for no such monitoring to be justified. The rationale for the oversight and monitoring strategy would be contained in the risk assessment. For example, this may be limited to sponsor oversight of the initiation process and then a detailed questionnaire returned from the investigator as a self assessment process, perhaps with addition of an audit.

Trials that are very small, investigator-led, and primarily related to scientific investigation of the mode of action or scientific other aspects of a licensed IMP rather than general clinical efficacy or safety are more likely to lead to a conclusion that no on-site and no extensive central monitoring is necessary when risk assessed. It is recommended that there is a contingency plan to implement monitoring if this was considered necessary by the oversight activities results.

a. SI 2004/1031 (as amended) Regulation 28 (1) and (2).

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[MHRA Super Moderator]

9. What should the documented oversight and monitoring strategy contain?

It is the responsibility of the sponsor^a to define the processes and procedures to ensure the principles and conditions of GCP are adhered to and the sponsor should therefore be responsible for deciding the risk-based oversight and monitoring strategy for the trial and thus provide or approve the content of any formal procedures (policies, plans, protocol, SOPs etc.) that implement the strategy. It is recommended that where the sponsor is undertaking many trials, there is a procedure in place for the development of the documentation that implements the strategy which would include the necessary content, perhaps in the form of template documents. Items for consideration for inclusion in documentation could include the following examples (not intended as an exhaustive list):

• Within documentation there ought to be a clear link to the risk assessment to identify the areas that matter to the results reliability, subject safety and rights and compliance with the legislation
• How sponsor oversight of (Chief) Investigator (Non-commercial), vendors etc will be undertaken
• Type of monitoring to be utilised (central and/or on-site)
• The standards and any SOPs to be followed and any document templates to be used
• Cross-references to other relevant documents within the suite of documentation implementing the oversight and monitoring strategy (e.g. medical monitoring plan, safety plan, data management plan, committee charters etc.)
• Site assessment and initiation procedures
• Training of site staff plus training of sponsor and CRO personnel involved in monitoring, audit, data management etc.
• Frequency of monitoring activities, e.g. site visits, database interrogation reports
• Communication activities with vendors and site(s)
• Monitor site capacity (i.e. maximum number of sites per monitor in relation to resource/skills)
• Where site visits take place, which departments will be visited (i.e. in addition to the investigator, any ancillary departments, such as pharmacy, laboratories, imaging etc.)
• What data will be reviewed at site (% of SDV needed and on what data)
• Data validation specifications
• Data collection and transfer methods
• Computer systems validation/study build validation – e.g. for data transfers, eCRF, IVRS use
• Procedures for use and monitoring of central laboratories, specialist services (imaging, ECGs etc.)
• Considerations for unblinded monitors and reviewers (if necessary)
• Expectations for availability of the principal investigator (PI) during monitoring visits
• How non-compliance will be recorded and resolved
• Oversight of the investigator and ancillary department site files
• Escalation process:
  
  • For central monitoring, what triggers will be utilised for escalating to on-site monitoring visits, or triggers from site visits for audit etc.
  • For both central and on-site monitoring, how unresolved issues or serious non-compliances are handled that the monitor cannot address
• Supplies management and monitoring processes (IMP and ancillary materials, subcontractors, QP certification etc.)
• SAE reporting processes and associated monitoring responsibilities
• AE and SAE review, signal detection, medical monitoring
• Query Management:
  
  • Data queries from data management activities and found by monitoring at site
  • Protocol queries to medical monitor
  • IMP (including temperature excursion management)
• Documentation and review of monitoring activities:
  
  • Types of reports (monitoring visit report, central monitoring metrics, statistical monitoring etc.)
  • Format of the reports
  • Responsibility for reviewing the reports
  • Timelines for preparing and reviewing reports
• Role and procedures of adjudication, data monitoring, management and steering committees
• Processes for interim analysis (data gathering, analysis and reporting control)
• Sponsor Trial Master File management
• Regulatory and REC approval maintenance (process for amendments, urgent safety measures, serious breach evaluation and reporting)
• Contract and insurance review and maintenance
• Audit plans
• Checks on randomisation processes

a. SI 2004/1031 (as amended) Regulation 28 (1) and (2).

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