What FDA's COVID-19 Clinical Trial Guidance Still Gets Right

FDA issued its guidance on conducting clinical trials during the COVID-19 public health emergency in March 2020 and updated it through August 2021. It was written under pressure and without the usual comment period, for an unanticipated and unprecedented situation.

Despite the challenges of the pandemic, FDA drafted a coherent set of principles for managing trial disruption. These principles are still important in the years following the shutdown.

The Core Framework

Good Clinical Practice (GCP) applies even in extraordinary circumstances - but preparing for the unexpected will keep your clinical trial on track.

Two (2) commitments anchor everything else:

• Participant safety comes first. Protocol deviations were acceptable — but only after sponsors, investigators, and IRBs assessed whether safety could still be maintained. Switching to virtual visits, shipping IP to a patient's home, or delaying an assessment all required a genuine risk-benefit evaluation, not just a logistical convenience.

• If it isn't documented, it didn't happen. Every deviation, every contingency measure, every affected participant needed to be captured. The specific reason related to COVID-19 for each deviation had to be documented and to flow through to the clinical study report.

Four Things Worth Carrying Forward

1. Remote monitoring is only legitimate when it's systematic

The guidance was notably forward-leaning here. Sponsors could use centralized and remote approaches when on-site visits weren’t feasible, using a risk-based framework.

The requirement: document remote monitoring with the same rigor as on-site visits, and let a comprehensive risk assessment drive the decision of whether to follow up in person. The IDE monitoring regulations don't prescribe a method. A well-documented remote program satisfies them.

2. Protocol deviations need a narrative, not just a log.

The guidance asked sponsors to explain the cause of the deviation and its connection to COVID-19, then to include a systematic analysis of how contingency measures affected safety and efficacy results. A deviation that touches a primary endpoint deserves more than a footnote in a deviation table.

3. Switching to remote assessments introduces variability.

FDA was explicit in this guidance: if assessment methods differ across participants or sites (e.g., telephone for some, video for others), variability in data collection methods can affect the measured endpoints and potentially the type I and type II error rates. The SAP needs to account for variability in data collection methods before the database lock, not after.

4. Missing data requires prospective planning.

One of the guidance's clearest statistical instructions: address how protocol deviations will be handled in prespecified analyses in the SAP. Sensitivity analyses should be prespecified. The handling of participants who discontinued, missed visits, or received care outside the protocol should be defined before anyone looks at the data. Treat missing data as a design problem, not an analysis problem.

On IDE Change Reporting

Under 21 CFR 812.35(a), IDE sponsors generally must report changes to the investigational plan before implementation. The guidance created narrow exceptions for emergency changes to protect participant safety; however, those deviations still had to be reported to the FDA within 5 working days. The guidance acknowledged the timeline might be difficult to meet and permitted consolidation. The obligation itself didn't pause.

The Takeaway

The next disruption to a clinical trial won't be COVID-19. But the framework for responding to it should look a lot like this: assess safety first, document everything, plan ahead statistically, and communicate with FDA early.

The guidance is still worth reading as a working reference to keep your clinical trial on track, even in unprecedented times.

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BSC® has supported sponsors through trial disruptions, protocol deviations, and FDA submissions for nearly 40 years. If you're navigating a trial disruption or preparing your SAP for contingency scenarios, we’re glad to help.