MHRA produced FAQs for Risk Adaptive Approach

[MHRA Super Moderator]

4. Is it expected that the trial is given an overall risk rating?

The MHRA scheme uses the Investigational Medicinal Product (IMP) marketing authorisation status to categorise into types A, B and C in relation to the authorisation process and potential documentation required for a trial. This categorisation is not equivalent to a risk rating, though it gives an indication that a trial of type C may involve more potential risks than one of type A. The real risk of the trial is obtained by an evaluation of the potential risks from conducting the trial, not just from the IMP marketing status ? this is why a full bespoke trial specific risk assessment is required. For example a trial may be assessed as type A based on the IMP status; however there may be other risks associated with the trial procedures and/or the use of a vulnerable population that would mean that it was not in fact a low risk trial. It is therefore recommended that a risk assessment process whereby an overall risk score for the trial is generated which leads to generic actions (e.g. a low score = no monitoring; high score = on site monitoring) is used with some caution. Whilst an overall risk score can give a useful indication of the trial?s risk, the aim of the risk-adapted approach is to identify specific vulnerabilities within the trial and take appropriate actions for these. Specific high risk areas within the trial could potentially be overlooked by assigning a risk category to the entire trial. Conversely, the risk assessment process can also identify areas where adaptations from ?traditional? GCP could be implemented, as no particular risk is identified, for example, no requirement to monitor storage conditions for the IMP.

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[MHRA Super Moderator]

5. When should the risk assessment be undertaken?

The risk assessment should be done as early as possible. This allows the sponsor to identify whether the proposed research falls under the CT legislation, whether the sponsor wishes to proceed with sponsorship (possibly for other reasons than patient safety/GCP compliance ? e.g. financial) and also the potential type (A, B, C). The process could be defined such that the risk assessment is undertaken on the research proposal and then further refined once the protocol has been drafted, thus there could be several steps to the process with different individuals involved. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g. identification of trial monitoring requirements so that these can be budgeted for in any funding application).

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[MHRA Super Moderator]

6. Who should conduct the risk assessment?

The relevant personnel undertaking the risk assessment would typically include a medic with understanding of the therapeutic area and the therapeutic use of the proposed investigational medicinal products (IMP) (for example Medical Monitor or Chief Investigator); a pharmacist / toxicologist / pharmacologist who has a detailed understanding of the IMP (this is particularly important for potential type B and C trials); a statistician with relevant experience of medical statistics and a person with an appropriate level of understanding of applicable regulatory, legal and GCP requirements (e.g. Regulatory Affairs / Quality Assurance / Lawyer / Research Governance personnel). In addition it would be usual to include data management personnel, trial monitors or project/study managers in the multidisciplinary team conducting the risk assessment, as these individuals would be important with respect to defining feasible mitigation/adaptations. Finally it may be considered appropriate by the sponsor to include a suitable patient advocate/representative in the risk assessment. It should be clearly documented who has participated in the risk assessment and those involved could change as the planning and conduct of the trial progresses.

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[MHRA Super Moderator]

7. Should the risk assessment be documented?

Yes. This is essential as the risk assessment is an important and useful document which will influence the conduct and management of the trial. Whilst it is for the sponsor to decide upon the best way to document the areas considered, the risks identified and any mitigations/adaptations to traditional GCP as a result, the MHRA recommends a tabular format for the assessment, and an example is provided in the Appendix 2 of the risk-adaptive approach. It is recommended that the risk assessment, (it may also be known as a risk management plan), should not repeat information covered elsewhere, for example information that is in the protocol, patient information sheet, SmPC, investigator?s brochure; as this makes the document lengthy and cross referencing is more useful. It is strongly recommended that the risk assessment is a separate document in its own right. A sponsor, however, may choose to insert the risk assessment in the protocol, but there should be clarity on where it is documented. The placing of the risk assessment in the investigator?s brochure may not be appropriate, as the risk assessment is trial specific review of the proposed trial protocol, but the investigator?s brochure could be used for more than one trial. The documented risk assessment should be subject to appropriate version control.

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[MHRA Super Moderator]

8. What should happen to the risk assessment once it is completed and documented?

The risk assessment should be kept in the trial master file (TMF), but it is important that the sponsor and, where appropriate, site staff are aware of the content of the risk assessment. It is therefore recommended that there is a process to ensure that the risk assessment and any subsequent updates are provided to the relevant personnel. It is strongly recommended that one person has the responsibility for ensuring that the mitigations/actions that are planned from the risk assessment have been implemented and undertaken. For example, ensuring the requirements for specific aspects of monitoring identified in the risk assessment are subsequently captured in the trial monitoring plan (or other trial procedure). This would typically be the responsibility of the Project Manager/Chief Investigator.

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[MHRA Super Moderator]

9. Does the MHRA recommend a specific methodology to be used for quantifying risk?

The sponsor is responsible for selecting or defining a suitable process to define the risk for the various areas assessed. As risk assessment is used in many areas, there are published methodologies that may be suitable for application to clinical trials, but as yet there are no validated methods or tools available specific to clinical trials. It is possible that tools will become available in time. The risk assessment process may be quantitative or qualitative, but it may include an assessment of impact of the hazard and the probability/likelihood of occurrence. Additionally the risk assessment is likely to include a summary of the discussion of the area assessed as this may be the rationale for adaptations away from ?traditional? GCP. The GCP Inspectorate has no preference or requirements for the methodology employed. The Inspectors would be looking at the risk assessment to see that it was comprehensive and thorough and that appropriate actions for risks identified had been documented and subsequently implemented. In the absence of validated tools, the GCP Inspectorate aim to facilitate this with the publication of suitable example risk assessments undertaken by sponsors via this GCP Forum.

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[MHRA Super Moderator]

10. Can the risk assessment be amended?

Yes. In fact it would be expected that the sponsor undertakes a continual review of the risk assessment, which is particularly important when new information becomes available. For example, the risk assessment should be re-examined following a protocol amendment or when new data is obtained (new SmPC, related pre-clinical/clinical trial results are released, a data monitoring committee meeting or interim analysis takes place). If the risk assessment is reviewed and it is not updated, the sponsor should document that the review has taken place. It is important when applying a quality risk management process that systems are in place for identification of new or unanticipated risks and taking appropriate actions. For example, a serious breach may occur and this may result in an amendment to the risk assessment with additional, changed or new mitigating actions required, such as changes to the type and/or frequency of monitoring.

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