01/14/2025
Photo by Cole Ankney on Unsplash
On December 30, 2024, the US Food and Drug Administration (FDA) released the draft guidance for industry titled “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices” to help trial sponsors, investigators, and institutional review boards (IRB) define, identify, and report protocol deviations. Protocol deviations (PD) can be found in all levels of a trial: at the patient level, missing a scheduled visit, site level, storing the investigational product in a temperature outside the protocol-required range, or study level, if treatment assignments are prematurely unblinded. The FDA regulations currently do not have a set definition for PD or a classification system for their severity. Proper identification and reporting of PDs is essential for the FDA’s review of clinical investigations.
In this guidance, the FDA is adopting the definitions used by the International Council for Harmonisation (ICH) in their guidance for industry “E3 Structure and Content of Clinical Study Reports.”
Protocol Deviation: 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.
PDs that are not considered important are commonly classified in reports as minor, non-critical, or non-significant. These can include improper eSignatures that do not meet 21 CFR Part 11 regulations, insufficient quality management systems, or missing endpoint readings that are not relevant for safety monitoring or study efficacy. PDs such as these still need to be accurately recorded, reported, and followed up on to ensure no further deviations occur. However, this can be done in a routine manner and are usually contained in monitoring visit reports that are sent to the sponsor on a protocol-specified basis. Important PDs on the other hand are classified in reports as major, critical, or significant and are required to be reported in a more expedited manner (often 24-48 hours following discovery). Important PDs are those that affect critical-to-quality factors of the trial. Critical-to-quality factors ensure:
The protection, safety, and well-being of the study participants.
The generation of reliable and meaningful results.
And management of risks to those factors using risk proportionate approach.
The trial protocol should clearly define what is considered an important PD to facilitate their identification and reporting. The guidance provides multiple examples of what the FDA considers to be important PDs, or those related to the protection of study participant and the assessment of safety. For example:
Failure to conduct study procedures designed to assess participant safety or failure to adequately monitor participants.
Failure to collect important laboratory assessments for monitoring safety issues.
Failure to administer the study product according to specifications in the protocol.
Failure to protect a participant’s identifiable private protected health information.
Administration of the wrong treatment or incorrect dose to trial participants or implantation of an incorrect device.
As well as those related to the reliability of conclusions on effectiveness:
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).
Premature unblinding of a trial participant’s treatment allocation for reasons other than those specified in the study protocol.
-The Clinical Pathways Team
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