Risk Assessments and Monitoring Plans

Risk in clinical trials (such as randomised controlled trials) can be defined as the likelihood of a potential hazard occurring and resulting in harm. This harm could be to the trial participant, or to the organisation conducting the research, or to the reliability of the trial results.

All trials will carry a degree of risk. There may be risk at the study level, for example with the intervention, protocol driven procedures or from the trial conduct itself. For example, there may be side effects associated with the intervention or the tests and procedures used in the trial itself. Risk may also arise at a system or organisational level, with risk which may relate to facilities, to technology or to data security. Risk can relate to the inadequacy of measures to protect the privacy of trial subjects and confidentiality of their personal data. For example, if data is not held securely, there may be a risk that sensitive information about individual participants may be accessed by people who are not authorised to see it, or there may be a risk to data loss which would affect the overall credibility of the data set. By conducting a risk assessment the risks inherent to the individual trial can be identified and an assessment can be made of the likelihood of those risks occurring and resulting in harm.

Risk assessment needs to be conducted early in the planning phase of the trial. This will allow for the protocol, procedures, project plans and trial specific documents to be designed to minimise risk. A risk assessment should be conducted for each trial and will commonly be recorded on the sponsor organisations risk assessment template. This risk assessment template provides an example of the kinds of risks to participants that may be identified and also to the reliability of the results.

Risk to participant safety associated with the Investigational Medicinal Product

In trials of an Investigational Medicinal Product (IMP) the risks associated with the IMP will also need to be assessed. Risks to participant safety will be relative to how much is already known about the IMP being investigated, in the condition under study and in the specific population to be included in the trial. Any potential risks should be assessed relative to the standard care for the relative clinical condition and balanced against the level of risk that a trial subject would be exposed to outside of the trial.

In the UK and European Union, the regulations allow for a risk-adapted approach to the management of trials involving an IMP. This allows for trial management procedures and trial mitigation and monitoring to be simplified or to be less intensive where the IMP being used in the trial is categorised as being of lower risk. For example, more will be understood about the safety profile of a medicine being used in a trial that has been on the market for a number of years than will be understood about a new medicine which has had little clinical exposure in the population under study. There are likely to be differences in the risk of these two examples in relation to participant safety, and the risk assessment could therefore determine a difference in the safety reporting requirements. The assessment should also consider the level of clinical experience with the intervention Part of the assessment of the risk of the IMP should include the anticipated hazards to body systems.

Once the risks associated with the IMP have been identified and evaluated, the trial can be categorised in terms of how far the risk is comparable to the risk of standard care. In the UK, on the basis of the risk assessment, trials of an IMP can be categorised as being either Type A, Type B or Type C, and examples of the types of trials that would fit into each of the categories are described in the tables below.

Categorisation of clinical trials based on potential risk associated with the IMP and its use

Categorisation of Clinical Trials based on Potential Risk Associated with the IMP and its use
Category base on the potential risk associated with the IMP	Examples of types of Clinical Trials
Type A: No higher than that of a standard Medical care	Trials involving medicinal products licensed in any EU Member state if they relate to the licensed range of indications, dosage and form or, they involve off-label use (such as in paediatrics and in oncology etc) if this off-label use is established practice and supported by sufficient published evidence and/or guidelines

Category base on the potential risk associated with the IMP	Examples of types of Clinical Trials
Type B: Somewhat higher than that of standard medical care	Trials involving medicinal products licensed in any EU Member State if: - Such products are used for a new indication (Different patient population/disease group) or - substantial dosage modifications are made for the licensed indication or - If they are used in combination for which interactions are suspected. Trials involving medicinal products not licensed in any EU Member State if: - the active substance is part of a medicinal product licensed in the EU

Category base on the potential risk associated with the IMP

Examples of types of Clinical Trials

Type B: Somewhat higher than that of standard medical care

Trials involving medicinal products licensed in any EU Member State if: - Such products are used for a new indication (Different patient population/disease group) or - substantial dosage modifications are made for the licensed indication or - If they are used in combination for which interactions are suspected. Trials involving medicinal products not licensed in any EU Member State if: - the active substance is part of a medicinal product licensed in the EU

Category base on the potential risk associated with the IMP	Examples of types of Clinical Trials
Type C: Markedly higher than that of standards medical care	Trials involving a medicinal products not licensed in any EU Member State

Evaluation of Risk

Once individual trial risks have been identified, a critical component of the risk assessment process is an evaluation of these risks. Some identified risk may be evaluated as having a limited impact on the safety of trial participants or on the credibility of the data and reliability of the results, and these risks may therefore be acceptable. Evaluation allows for the prioritisation of mitigation for the risks that really matter. The risks that are not acceptable must be mitigated either through changes to the trial design or the implementation of strategies to mitigate the risk.

Strategies for the Mitigation of Risk

Strategies to mitigate risk could include the design of training material which may include specific instructions and flow charts which could be used to assist in standardising the delivery of particularly complex trial specific procedures. These may be used as standalone initiatives or used to support face to face or remote training for trial delivery staff. A programme of planned audit of key areas of risk could in addition be implemented. Standardised written procedures including checklists could be developed for a variety of project management processes such as data management or safety monitoring, and used to provide guidance and training for delivery staff.

Monitoring

Monitoring in clinical trials is defined as ‘the act of overseeing the progress of a clinical trial, and of ensuring it is conducted, recorded and reported in accordance with the protocol and any amendments, Good Clinical Practice (GCP), and the applicable regulatory requirements.’(ICH Topic E6 (R1)). Monitoring is an important strategy in the mitigation of risk and it is the responsibility of the sponsor to ensure that trials are adequately monitored. The sponsor must therefore determine the extent and nature of the monitoring required for individual trials. This determination will be based on the objective, purpose, design, complexity, size, blinding and endpoints of the trial, in addition to the risks of the intervention and trial related activities. This will be identified through the risk assessment and documented in the form of a monitoring plan. ICH GCP defines the main purpose of monitoring to verify that the:

Rights, safety and well-being of trial subjects are protected
Trial data are accurate, complete and verifiable from source documents
Conduct of the trial is in compliance with the approved protocol, GCP and the applicable regulatory requirements

(ICH tripartite guideline for good clinical practice E6 (R1). 1996.) There are a number of different approaches to monitoring and these include:

On-site monitoring – where data and protocol adherence are reviewed through a physical visit to the investigator site by monitoring personnel
Central or remote monitoring – where data and protocol adherence are reviewed from a location remote from the site by monitoring personnel
Oversight committees – there are a variety of different committees which can be appointed to provide oversight of the trial (More information on Oversight Committees will be covered in step 3.7). The Data Monitoring and Ethics Committee (DMEC/DMC) will review emerging safety data and will advise the Trial Steering Committee (TSC) on any safety issues. The TSC will provide overall supervision of the trial and will review trial progress, participant safety and adherence to the protocol. The TSC will make key decisions about the trial.

Monitoring plans

Where the risk assessment identifies any vulnerabilities in the trial that can be mitigated through monitoring, the monitoring strategy should be detailed in a monitoring plan. The strategy may include on-site, or central monitoring, or a combination of the two approaches, in addition to the appointment of oversight committees. The chosen approach should be targeted and justified and the plan should detail what will be monitored, how it will be conducted and the plan for up-escalation. Up-escalation refers to the point at which the issues identified cannot be tolerated, which would trigger an evaluation to determine what action might be needed to correct the issues and prevent them from re-occurring.

An assessment of risk in clinical trials, such as randomised controlled trials, and strategies to mitigate, either through adaptation to trial design and/or implementation of quality control checks such as monitoring, is crucial to the safety of participants and to the reliability of the results. Risk assessment needs to be conducted early in the planning phase of the trial. This will allow for the protocol, procedures, project plans and trial specific documents to be designed to minimise risk. It will allow for mitigation to be planned to ensure that the objectives of good clinical practice and the scientific objectives of the trial are met. Amendments to trials are common and any change could impact on the risk of the trial. Risk assessment should therefore continue to be conducted throughout the lifecycle of the trial.

References: ICH tripartite guideline for good clinical practice E6 (R1). 1996.

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