FDA warns of “important” clinical trial protocol deviations

FDA defines a protocol deviation as a “generally unintentional” departure from IRB-approved protocol, noting they are commonly not discovered until after they occur. For example, an investigator’s failure to perform a protocol-required test being discovered by the study monitor during a routine monitoring visit would be a protocol deviation. It may also include an intentional departure from the IRB-approved protocol for a single participant even when prior approval for the deviation is obtained; for example, when an investigator seeks and receives sponsor and IRB approval to enroll a participant above the maximum age criteria. In addition, modifications to protocol-specified procedures that occur without prior IRB approval and submission to FDA of a protocol amendment to implement the modification are deemed protocol deviations.

FDA’s latest draft guidance emphasizes the agency’s desire for uniform definitions of “protocol deviations” and “important protocol deviations,” and adopts the definitions from ICH E3(R1) for these terms across all centers:

• Protocol deviations – any change, divergence, or departure from the study design or procedures defined in the protocol
• Important protocol deviations – a subset of protocol deviations 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 wellbeing.

The draft guidance also highlights the agency’s concern over “important” deviations as they affect critical to quality factors for the trial. Such “important” deviations may: lead FDA to the conclusion that a study is not adequate and well-controlled; affect protection of trial participants or the assessment of safety; or reduce the reliability of conclusions on efficacy. Consequently, sponsors should proactively identify critical to quality factors during the study design phase and build them into the protocol discussion of important protocol deviations. Examples of important protocol deviations provided in the guidance include the following:

• Failure to conduct study procedures designed to assess participant safety or failure to adequately monitor participants; for example, failure to (1) collect important laboratory assessments for monitoring safety issues, or (2) administer the study product according to specifications in the protocol.
• Administration of concomitant treatment prohibited by the study protocol that may increase risks to participants (e.g., drug-drug interactions).
• Failure to obtain informed consent or meet other applicable requirements under FDA regulations for the protection of human subjects.
• Failure to protect a participant’s identifiable private protected health information.
• Failure to withdraw investigational product administration from trial participants who meet withdrawal criteria.
• Administration of the wrong treatment or incorrect dose to trial participants.
• Failure to adhere to the protocol-specified randomization scheme.
• 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.
• Premature unblinding of a trial participant’s treatment allocation for reasons other than those specified in the study protocol.

In general, the guidance emphasizes thoughtful clinical trial protocol design as a means to minimize important protocol deviations. Specifically, before or during protocol development, sponsors should conduct a risk assessment to identify protocol elements that can be made more flexible (or even eliminated entirely) to avoid the occurrence of protocol deviations.

The draft guidance also outlines the duties of sponsors, investigators, and IRBs in monitoring, mitigating, and reporting protocol deviations. The guidance states that “investigators should report to the sponsor all protocol deviations of which they are aware.” This may be accomplished, for instance, by requiring investigators to report important protocol deviations to the sponsor within a defined timeframe, while allowing all other deviations to be reported when the site monitor visits the trial site. Regardless of a study’s prespecified protocol deviation reporting procedures, investigators should report protocol deviations in a way that highlights important protocol deviations. 

Further recommending differential responses to “important” protocol deviations, the draft guidance specifies that sponsors should “provide training on identifying important protocol deviations.” For protocol deviations that are not classified as important, “sponsors should document and evaluate the deviations to determine if the types and numbers of these protocol deviations warrant reclassification.” For IRBs, “FDA recommends that protocol deviations that are classified as important be submitted by the investigator to the IRB when they are identified.”

Additionally, sponsors should include a discussion of any important protocol deviations in the body of the clinical study reports submitted as part of a new drug application (NDA) or a biologics license application (BLA). For device studies, sponsors should include in their premarket approval applications, disclosures of any investigator deviations from the investigational plan.

FDA’s regulations also require sponsors to report to FDA certain adverse reactions, events, and effects, and the draft guidance recommends that sponsors note in the mandatory reports when protocol deviations contributed to the events. For example, the sponsor may note in its report to FDA that prior to the occurrence of the safety event, a safety laboratory test to monitor for a potential drug safety event was not collected as required by the protocol.

Next steps

FDA has invited comments on the draft guidance through February 28. If you have any questions about protocol deviations, clinical investigations more generally, or may wish to submit a comment on the draft guidance, feel free to contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Robert Church, Heidi Gertner, Blake Wilson, and Eman Al-Hassan.