FDA issues Draft Guidance on Handling Protocol Deviations in Clinical Trials

The FDA has issued a draft guidance that provides recommendations to help sponsors, investigators, and institutional review boards (IRBs) define, identify, and report protocol deviations in clinical trials.

Definitions for Protocol Deviations and Important Protocol Deviations

According to the agency, protocol deviations are generally unintentional departures from the IRB-approved protocol and are commonly not discovered until after they occur. A system for classifying the various types of deviations that may occur during the conduct of a clinical trial (including classification, reporting, and documentation standards) is important to assure the most interpretable and useful information emerges from the reporting of protocol deviations. To address these considerations, the draft guidance defines the following: 

• 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 well-being.” (ICH E3(R1)).

All other protocol deviations that do not meet the definition of an important protocol deviation may encompass the commonly used terms minor, noncritical, and non-significant deviations. According to the guidance, the term protocol encompasses both written protocols and their related plans and procedures (e.g., monitoring plan, statistical analysis plan).

Morover, the draft guidance includes recommendations on the Roles and Responsibilities in Monitoring, Mitigating, and Reporting Protocol Deviations (i.e., for sponsors, investigators and IRBs).

More information is available in FDA's draft guidance document Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices.