Guidance

Risk-Adapted Approach to clinical trials and Risk Assessments

Published 28 January 2022

Risk Assessment Process

It is recommended that a risk assessment is undertaken for all clinical trials. Identification of potential risks to trial participants and to the reliability of the trial results on a trial basis and taking actions to mitigate those risks can only be beneficial for the quality of any clinical trial. In the UK Phase 1 Accreditation scheme, Phase 1 units are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials for this reason. It is essential that trials that have a risk-adapted approach applied have a risk assessment undertaken.

Where sponsors are conducting many trials, a documented process for how the risk assessment should be undertaken is advisable to ensure the consistency of the approach taken by the organisation. The risk assessment must be specific to the proposed trial and whilst the process may include templates or a guide on the areas to consider in the risk assessment, care should be taken to examine the potential risks of the proposed trial, which may present new areas that have not been considered in previous trials. This is why it is a bespoke approach.

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.

When and how to undertake the risk assessment

The risk assessment should be done as early as possible. This allows the sponsor to identify whether the proposed research falls under the Clinical Trials 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).

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.

A multidisciplinary team, as described above is expected to conduct the risk assessment. It is up to the sponsor to decide if any additional review is required, this could be by senior management, other project teams/key individuals or could be in the form of an independent peer review. The MHRA would recommend that the need for or type of review is proportionate to the risks identified in the trial.

Documentation of the risk assessment is essential as this 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 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.

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. 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

Retention and distribution of the Risk Assessment

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.

Revision of the Risk Assessment

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.

Investigator site staff experience and training in clinical trials/GCP etc

This area is also a crucial aspect of the risk assessment process and must also be considered. This is recommended not only to be undertaken at a generic level, considering the risk and mitigations that are required across the trial for all sites, for example processes for initiation, but also at a site-specific level; looking specifically at the information gained about the site during an appropriate suitability assessment (e.g. questionnaire return, audit or pre-selection visit). This would then focus on any site-specific mitigations (e.g. additional training for site staff, additional oversight/monitoring) that may be required to be put in place or conversely, if the site is well known to the sponsor from previous experience and this has been documented; this may lead to a reduction in required oversight activities.

A site’s facilities and personnel resources may change over time and this may impact on the site-specific aspects of the risk assessment and thus be important in the ongoing review.

For multi-country trials, a global risk assessment for the trial is acceptable, but part of the risk assessment areas would be to assess any country-specific risks for example differences in clinical practice, local regulations etc.

Submission of risk assessment to the MHRA and the REC

There is no requirement to submit risk assessments to the MHRA or the REC, and there are no current plans for this to change. If helpful, a separate safety monitoring plan may be developed, as the product of undertaking the risk assessment primarily concerning the risks of the IMP(s). As such, this would be part of the overall risk assessment. This document is not required to be submitted with the CTA, however any safety monitoring should be described in the protocol. It should be noted that information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the REC application. The guidance suggests that the CI/sponsor’s assessment of the IMP risk category is included in the CTA application and gives an example of how this could be presented. There should be a rationale for the trial type (A, B or C) as part of the risk assessment. The example table in the risk-adapted approach is suitable to document this. A full bespoke risk assessment is also required.

A risk assessment based on the potential risks associated with the use of the IMP should be made by the sponsor. Background documentation on how to do this is provided on the MHRA website. The MHRA does not normally advise on the IMP risk stratification or on the eligibility of individual clinical trials for the notification scheme prior to an application being made by a sponsor, but sponsors are encouraged to formally engage with the MHRA early on in the development process if novel or adaptive approaches are planned to be used.

Benefits of the risk assessment process

Whilst undertaking the risk assessment is an additional activity, its benefits in terms of application of risk-adapted approaches are likely to be much greater than the impact of undertaking it. For example, subsequent activities and documentation requirements may be reduced as a result. It is probable that sponsors are already undertaking such a risk analysis anyway and it needs to be formalised in procedures. Additionally, the risk assessment will allow a more detailed assessment of necessary management, monitoring and governance arrangements needed for the trial and this would be beneficial in improving the quality of the trial and the safety of clinical trial participants.

GCP Inspections

Where applicable (i.e. risk adapted approach is being used) GCP Inspectors will review risk assessments. As a key document for defining the management activities for the trials, GCP inspectors will review this and the supporting process in some detail. The risk assessment, where it is documented well, will provide the rationale behind trial management/monitoring and GCP activities applied, or not, to the trial. For example, as described in the safety management or monitoring plans and also the resultant documentation that is available for reconstructing the trial conduct that is filed in the Trial Master File.

Examples of risk assessments

The MHRA GCP Inspectorate has set up a collaborative group to produce example documentation relating to the risk-adapted approach. The risk assessments are not intended to be definitive templates or tools but are provided as examples of what risk assessments may look like and organisations may use the examples to help develop their own risk assessment processes. The examples are not intended to be definitive approaches, but have undergone review by the Inspectorate and the CTU.

Example 1 – Type A

The following risk assessment has been developed on a trial with IMP status of Type A by working with the trial research fellow on behalf of the co-sponsors, which are the Liverpool Women’s NHS Foundation Trust and the University of Liverpool. MHRA would like to thank the research fellow and the trial sponsors for their assistance and support given to the collaborative group and for sharing their documentation.

This example is divided into three sections. The first, a risk assessment that would be undertaken at a trial proposal stage from governance and overall safety aspects, the second is the risk assessment of the IMP and development of a safety monitoring plan and the third is the bespoke trial risk assessment to be used to create a trial monitoring plan. It is clear how the risks of the IMP have been evaluated from the SPC and a safety monitoring plan developed that shows some adaptations from ‘traditional’ GCP in terms of AE recording and SAE reporting, but remains in compliance with the legislation.

The plan would then be reflected in the trial protocol and reviewed and approved as part of the CTA. The bespoke risk assessment then shows how vulnerabilities have been identified (e.g. the blood sampling, consent), but also some adaptation from ‘traditional’ GCP (e.g. IMP labelling, storage and accountability) and some areas for consideration in the development of the monitoring plan. A synopsis of the protocol is also included for reference.

Example 1: Type A Protocol Synopsis

Example 1: Type A Risk Assessment

There are also some blogs available our website which explore this example further part 1 and part 2.

Example 2 – Type A

The following risk assessment has been developed on a trial with IMP status of Type A by working with the trial manager from the South East Wales Trial Unit (SEWTU) on behalf of the sponsor, which is Cardiff University. MHRA would like to thank the trial manager and the trial sponsor for their assistance and support given to the collaborative group and for sharing their documentation.

This example contains a risk assessment that evaluates the IMP type and then consists of a bespoke risk assessment. It is clear how the risks of the IMP have been evaluated as no more than normal clinical practice based on the SPC. The proposed pharmacovigilance processes have been summarised and the safety monitoring plan will be in the protocol. This shows some adaptations from ‘traditional’ GCP in terms of AE recording, but remains in compliance with the legislation. The risk assessment identifies some vulnerabilities, though not rated as “high” (e.g. consenting, privacy, inexperienced staff and use of additional fluoride), but also some adaptation from ‘traditional’ GCP (e.g. IMP labelling, storage and accountability) and some areas for consideration in how the trial is to be monitored. A synopsis of the protocol is also included for reference.

Example 2: Type A Protocol Synopsis

Example 2: Type A Risk Assessment

Example 3 – Type B

The following risk assessment has been developed on a trial with IMP status of Type B by working with the University of Edinburgh Research Governance & QA Office. The trial is co-sponsored by the University of Edinburgh and NHS Lothian. The MHRA would like to thank the individuals from the Research Governance & QA Office and the trial sponsors for their assistance and support given to the collaborative group and for sharing their documentation.

This example is divided into various sections:

• The first section details the risks, and associated mitigations and management strategies, associated with various aspects of the planning and conduct of the trial (investigational product, study participants, study design and methods, and study organisation). The trial population is patients with paracetamol poisoning. Risks and mitigations associated with the consent process in this emergency setting are included.
• Appendix 1 (Facilitation/Sponsorship Risk Adaptions) summarises areas of trial management/oversight where risk adaption has been applied.
• Appendix 2 (Monitoring Strategy Template) outlines a range of options for monitoring (under headings of investigational product, study participants, study design and methods, and study organisation). The template is a tool that enables the focus and intensity of monitoring to be tailored on a trial-specific basis depending on the IMP status and trial-specific risks and mitigations. The “Outcome” table on pages 14-15 indicates which aspects of the monitoring strategy have been applied to this trial.

Example 3: Type A Protocol Synopsis

Example 3: Type A Risk Assessment