FDA proposes uniform system for classifying protocol deviations
The US Food and Drug Administration (FDA) has issued draft guidance that proposes a uniform system for classifying protocol deviations in clinical studies to assist sponsors, clinical investigators, and institutional review boards (IRBs) in reporting these deviations for drugs, biological products, and medical devices.The guidance states that “a system that applies consistent classification, reporting, and documentation standards is important to assure the most interpretable and useful information emerges from the reporting of protocol deviations.”
FDA’s regulations do not define protocol deviations or classify the different types of deviations that may arise during clinical investigations. Instead, the agency adheres to the definition provided by the International Council for Harmonisation’s (ICH) E3(R1) guideline adopted in July 2012. The guideline defines a protocol deviation as “any change, divergence, or departure from the study design or procedures outlined in the protocol.”
The ICH guideline also defines important protocol deviations as “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 well-being.” FDA has adopted this definition as well.
Yet since the publication of ICH E3(R1), FDA has received requests for additional guidance on reporting protocol deviations. The guidance is designed to “help clarify sponsor and investigator responsibilities for identifying, mitigating, and reporting protocol deviations and to provide recommendations to IRBs for evaluating protocol deviations.”
FDA proposes that the following protocol deviations be deemed important, as they may impact a subject’s safety: inadequate monitoring of study subjects or failure to collect crucial laboratory assessments for safety monitoring.
Other important protocol deviations include administering concomitant treatment prohibited by the study protocol that may increase risks to participants, failing to obtain informed consent, failing to protect a participant’s private protected health information, failing to withdraw investigational products from trial participants who meet withdrawal criteria, administering the wrong treatment or incorrect dose to trial participants, and failing to adhere to the protocol’s randomization scheme.
FDA also suggests a list of important protocol deviations that can undermine the reliability of conclusions about a drug’s effectiveness. These include enrolling a participant who does not meet critical eligibility criteria meant to ensure a specific participant population, failing to collect data needed to assess important study endpoints (such as primary or secondary endpoints), and prematurely unblinding a participant's treatment for reasons not outlined in the study protocol.
Examples of minor deviations include having a signed consent with a page missing a participant’s initial and failing to perform a study procedure not relevant for safety monitoring or not related to an important study efficacy endpoint.
These protocol deviations may be deemed minor, noncritical, and non-significant deviations.
The deadline for comment is 28 February 2025.
Guidance
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