FDA Moves to Standardize Terminology for Clinical Trial Protocol Deviations

FDA has moved to standardize the terminology used to categorize protocol deviations in clinical studies. In December 2024, FDA issued a draft guidance document entitled “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices.” The guidance defines an “important protocol deviation” as a “protocol deviation… that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject’s rights, safety, or well-being.” While other terms such as “major,” “critical,” and “significant” have sometimes been used to classify such a protocol deviation, FDA recommends using “important” to encompass all these terms. Examples of important protocol deviations that could significantly affect the completeness, accuracy and/or reliability of study data include:
• Enrollment of a trial participant in violation of key eligibility criteria designed to ensure a specific participant population;
• Failure to collect data to evaluate important study endpoints (e.g., primary or secondary endpoints); and
• Premature unblinding of a trial participant’s treatment allocation for reasons other than those specified in the study protocol.

Examples of important protocol deviations that might significantly affect a subject’s rights, safety, or well-being include:
• Failure to conduct study procedures designed to assess participant safety or failure to adequately monitor participants;
• Administration of concomitant treatment prohibited by the study protocol that may increase risks to participants (e.g., drug-drug interactions); and
• Failure to obtain informed consent or meet other applicable requirements under FDA regulations for the protection of human subjects under 21 C.F.R. Part 50.

The guidance document also provides recommendations to assist sponsors, investigators, and IRBs in defining, identifying, evaluating, reporting, and avoiding protocol deviations. For example, FDA recommends that sponsors conduct a risk assessment during protocol development to identify elements that could be more flexible to avoid protocol deviations. Such protocol elements include establishing flexible enrollment criteria, removing unnecessary enrollment criteria, streamlining the study design, conducting certain assessments remotely when possible, and eliminating nonessential activities.

Here is a link to the FDA guidance document.

If the guidance document is finalized, while it will not have the force and effect of law, the standardization of terminology and the “important protocol deviation” definition promise to bring a little more clarity to the categorization of protocol deviations and how to handle them.