When evaluating risks in clinical trials, people normally evaluate the likelihood, impact and detectability. This is closely following the guidance in ICH E6 R2. For example, perhaps there is an assessment made by the investigators of morphology of the eye and there is a relatively new rating scale used to assess this. A risk might be “inconsistency in applying the rating scale by investigators due to the unusual rating scale might lead to an inability to assess a key secondary endpoint.” It might be decided by the study team that this is likely to happen, if it does happen then the impact would be high and that detecting this during the study is difficult. This risk would score high for all three dimensions and end up as one of the high risks for the study.
The next step is risk management is to look at the high risks and consider how they can be further controlled (or “mitigated”). I teach teams to look at the component risks scores for likelihood, impact and detectability and consider how/whether each of them can be influenced by additional controls.
To reduce likelihood, for example:
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- Protocol changes (e.g. use a more common scale or have a maximum number of participants per site)
- Improved training including an assessment (but not “retraining”!)
- Increasing awareness (e.g. with reminders and checklists)
And to improve detectability (and reduce its score), for example:
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- Implement additional manual checks (e.g. site or remote monitoring)
- Close monitoring of existing or new Key Risk Indicators (KRIs)
- Computational checks (e.g. edit checks in EDC)
- Use of central readers
But what of the impact dimension though? Are there any additional controls that might be able to reduce the impact? Here we need to think more about impact. As issues emerge, they rarely start with their maximum impact. For example, if there is a fire in an office building, it takes time before the building is burnt to the ground. There are actions that can be taken after the emergence of an issue to reduce the overall impact. For a fire in an office building, examples of such actions are: having fire extinguishers available and people trained to use them, having clearly signed fire exits and people who have practiced exiting the building through regular fire drills, and having fire alarms that are regularly tested. These are actions that are implemented before the issue emerges so that when it emerges, they are ready to implement and to reduce the overall impact. They are contingencies.
As I work through possible additional controls with teams, they typically look at the impact and decide there is no way they can affect it. For some risks that might be true but often there are contingencies that might be appropriate.
To reduce the impact the following are example contingency actions:
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- Upfront planning for how to manage missing datapoints statistically
- Planning for the option of a home healthcare visit if an on-site visit is missed
- Preparing to be able to ship investigational product direct to patients if a pandemic strikes
- Back-up sites
In our risk example “inconsistency in applying the rating scale by investigators due to unusual rating scale might lead to an inability to assess a key secondary endpoint,” the impact is the inability to assess a key secondary endpoint. But if we detect this emerging issue early enough, are there any actions we could take (and plan for upfront) that could help stop that maximum impact from being realised? Maybe it is possible to take a picture that could be assessed at a later point if the issue emerges? Or there could be remedial training prepared in case it appears that an investigator’s assessments are too variable?
Of course, not all risks need risk controls. But contingencies are worth considering. In my experience, contingencies are a tool in the risk management toolbox that is not removed often enough. Perhaps by helping teams understand how contingencies fit into the framework of RBQM, we can encourage better use of this tool.
Text: © 2023 Dorricott MPI Ltd. All rights reserved.
Image: © 2023 Keith Dorricott
A great reminder Keith!
Many thanks!