MHRA produced FAQs for monitoring

[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.

Version 1: 22 February 2013

[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.

Version 1: 22 February 2013

[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).

Version 1: 22 February 2013

[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).

Version 1: 22 February 2013

[MHRA Super Moderator]

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 must^a, however, according to the principles of GCP that must^b 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

[MHRA Super Moderator]

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

[MHRA Super Moderator]

12. Does the strategy documentation have to be followed?

Yes, it must^a, 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