Section 10.2 of the ICH E3 Guideline requests an accounting of important protocol deviations. However, the flowchart in Annex IVa of E3 (Subject Disposition) recommends that data be provided on the number of subjects withdrawn from the study due to “protocol violations.” Neither the term “protocol deviations” nor “protocol violations” has been previously defined by ICH. What is the distinction between a protocol deviation, important protocol deviation, and a protocol violation? Can these terms be clarified? Additionally, does the Guideline allow sponsors’ flexibility in defining what constitutes an important protocol deviation for a trial?

A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol. Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject’s rights, safety, or well-being. For example, important protocol deviations may include enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value of the trial.
Protocol violation and important protocol deviation are sometimes used interchangeably to refer to a significant departure from protocol
requirements. The word “violation” may also have other meanings in a regulatory context. However, in Annex IVa, Subject Disposition of the ICH E3 Guideline, the term protocol violation was intended to mean only a change, divergence, or departure from the study requirements, whether by the subject or investigator, that resulted in a subject’s withdrawal from study participation. (Whether such subjects should be included in the study analysis is a separate question.) To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”, as shown in the example flowchart below. Sponsors may also choose to use another descriptor, provided that that the information presented is generally consistent with the definition of protocol violation provided above.
The E3 Guideline provides examples of the types of deviations that are generally considered important protocol deviations and that should be described in Section 10.2 and included in the listing in Appendix 16.2.2. The definition of important protocol deviations for a particular trial is determined in part by study design, the critical procedures, study data, subject protections described in the protocol, and the planned analyses of study data. In keeping with the flexibility of the Guideline, sponsors may amend or add to the examples of important deviations provided in E3 in consideration of a trial’s requirements. Substantial additions or changes should be clearly described for the reviewer.