Classifying Protocol Deviations - New FDA Guidance on Protocol Deviations

In clinical trials, protocol deviations are generally unintentional departures from the IRB-approved protocol and are commonly not discovered until after they occur (e.g., an investigator’s failure to perform a protocol-required test is discovered by the study monitor during a routine monitoring visit).

Too many protocol deviations could indicate the protocol issue (the protocol is poorly written), the protocol compliance by the investigators, and the overall quality of the study. Protocol deviations are collected and reviewed throughout the study. At the end of the study, the final list of protocol deviations will be converted into the data set (CDISC SDTM DV data set). The protocol deviations will then be listed and summarized for the inclusion in the clinical study report. According to ICH E3 "Structure and Contents of Clinical Study Reports", protocol deviations will be described in the CSR section 10.3.

For NDA/BLA submissions to CDER, FDA, there is a special requirement for submitting the BIMO (bioresearch monitoring) data sets and listings to assist FDA to select the investigational sites for inspection. Protocol deviations are important part of the BIMO data. According to "BIORESEARCH MONITORINGTECHNICAL CONFORMANCE GUIDE", the protocol deviations need to be provided in listings by subject and by clinical site. 

7. Protocol Deviations 

This by-subject, by-clinical site listing should include all protocol deviations. The listing should include a description of the deviation and identify whether the sponsor considered the deviation to be an important or non-important protocol deviation. 

Protocol deviations need to be classified based on the seriousness of the protocol deviation and the impact on the safety and efficacy evaluation of the protocol deviations. Traditionally, we have classified the protocol deviations into minor and major categories. However, other terms are used for categorizing the protocol deviations: critical protocol deviations, significant protocol deviations, ... 

FDA's new guidance "Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices" (December 2024) sets this straight. Only two categories will be used for protocol deviations: Important protocol deviations and other protocol deviations. 

1. Important Protocol Deviations 

As noted above, in this guidance an important protocol deviation is 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. While other terms such as major, critical, and significant have sometimes been used to classify such protocol deviations, FDA recommends using important to encompass all these terms. 

2. All Other Protocol Deviations 

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. Examples of all other protocol deviations may include small deviations from protocol-specified visit windows; a signed consent with a page missing a participant’s initial; or failure to perform a study procedure not relevant for safety monitoring or not related to an important study efficacy endpoint (e.g., primary or secondary endpoints).