Using risk assessment decision tree models to maintain safety and data validity in clinical trials during COVID-19

During the COVID-19 pandemic, challenges to the conduct of clinical trials may arise, e.g. due to travel restrictions or quarantines, interruptions to supply chains, or when site personnel or trial subjects become infected with SARS-CoV-2.

As a consequence, adjustments to clinical trial conduct may be required to ensure safety of the trial participants and maintaining trial data validity, which should be based on a risk assessment (referring section 5.0 of ICH GCP).

In this risk assessment, risks of involvement in a clinical trial should be weighed against the anticipated benefit for trial participants and society (referring principle 2.2 of ICH GCP).

Adequate measures should be implemented which prioritize trial participant safety and data validity. In case of a conflict, safety has to be given priority.

Risk assessments should be based on input by all relevant parties, to evaluate the feasibility and immediate necessity to start or continue a trial, and identify additional risks to trial participants. Key aspects at the trial-, country-, site- and trial subject-level should be considered. On the one hand, sponsors should perform a risk assessment of each individual trial (prioritizing critical tasks in the clinical trial and determining how these are best maintained), and on the other hand investigators should perform a risk assessment of each individual trial participant.

Decision trees may help guide stakeholders through the steps necessary to consider all relevant aspects and determine which risk mitigation measures are most appropriate in view of the overarching ICH GCP principles mentioned above.

The same decision-making approach should be used to decide if trial activities can be resumed when the situation evolves (e.g. restarting recruitment after a temporary halt enrolment for new patients).  Adhering to these guiding principles will help ensure trial participant safety and data validity.

The trial-level decision tree provides guidance to sponsors on how to evaluate the impact of COVID-19 on a trial and determine the applicable approach based on the trial status (whether or not trial participants have been enrolled) and benefit/risk balance assessment. The risk assessment should also include any potential impact of COVID-19 on trial participants who are part of a risk-group for COVID-19 or are receiving treatments that could increase the risk. Outcomes of this trial-level risk assessment may be for example to hold off starting new clinical trials, temporarily halt enrolment of new trial subjects or take risk mitigation actions resulting in amendments to the trial. The decision tree provides support to all stakeholders on how to evaluate COVID-19 impact and determine appropriate risk mitigation actions in line with local legislation and requirements of countries which are currently affected by the COVID-19 pandemic. The decision tree should be revisited as the COVID-19 situation develops and also serves to determine exit strategies for a country recovering from the COVID-19 pandemic.

The site-monitoring level decision tree provides support to all stakeholders (sponsors, CROs) on how to evaluate site-level COVID-19 impact on monitoring / source data quality assurance needs and implement appropriate temporary monitoring adjustments in line with country legislation and site requirements  (e.g. cancel or postpone site monitoring visits, use off-site monitoring, or remote source data verification). This decision tree should be revisited at appropriate intervals in order to lift applicable temporary measures in line with local circumstances.

The subject-level decision tree serves to support to all stakeholders (sponsor, CRO and investigator) on how to evaluate country- and site-level COVID-19 impact to determine appropriate risk mitigation actions, such as remote visit alternatives in line with country legislation and site requirements, e.g. postponing site visits of subjects, using telehealth, home delivery of study supplies, home nursing, local laboratories, or remote site monitoring. At this level, the investigator should also evaluate any potential impact of COVID-19 on trial participants who are part of a risk-group for COVID-19 or are receiving treatments that could increase the risk.  The decision tree should be revisited at appropriate intervals to develop COVID-19 lockdown exit strategies.

All decision and risk mitigation measures require to be properly documented by responsible parties and updated on an ongoing basis as the COVID-19 pandemic evolves. Their impact on the scientific validity of trial data needs to be carefully considered.

While there is an apparent urgency to conduct risk assessments at the beginning of the COVID-19 pandemic outbreak, it is also utterly important to reassess the risk-benefit balance as the situation evolves so that COVID-19 related clinical trial measures can be continuously adjusted in line with local rules and needs, or lifted and halted trial activities re-started once appropriate in COVID-19 recovering countries (with or without continued modifications due to COVID-19).

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