MHRA produced FAQs for monitoring

[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

[MHRA Super Moderator]

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

[MHRA Super Moderator]

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: http://forums.mhra.gov.uk/showthread...=2153#post2153

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: GCP.inspectors@mhra.gsi.gov.uk

Version 2: 05 March 2013

The examples are not intended to be definitive approaches. They are not endorsed or recommended by the MHRA