Draft FDA Guidance – Protocol Deviations

Introduction

A recent draft guidance from the FDA provides clarity on how protocol deviations can better be defined, identified and reported in clinical investigations. Because the term “protocol deviation” is not explicitly defined in FDA regulation, the guidance directs sponsors, clinical investigators and institutional review boards (IRBs) to what constitutes a deviation and how best to proceed once one is identified.

The guidance dives into two primary areas of focus: (1) defining protocol deviations and (2) recommending how to respond to identified deviations.

Defining protocol deviations vs. important protocol deviations

1. Important protocol deviations: A subset of more impactful protocol deviations that could 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. These may have previously been flagged as “major” or “critical”, but the FDA recommends the use of “important” as a catch-all for anything with increased study impact.
2. Protocol devaitions: All other protocol deviatons that do not meet the definition of “important” fall into this category. These include deviations that may have been prior deemed as “minor”, “noncritical” and “non-significant”.

Recommendations:

Types of protocol deviations that sponsors should report to the FDA

• Sponsors are in charge of oversight during clinical investigations and are therefore tasked with detection and management of any protocol deviations that occur. Sponsors should be notified of all protocol deviations that occur for proper record keeping and reporting.
• When submitting a new drug application (NDA) or a biologics license application (BLA), sponsors should include both a discussion of and listing of important protocol deviations. Sponsors should also include this listing in Study Data Tabulation Model Protocol Deviation (DV) domain so that the FDA can better ascertain the impact on data quality.
• In addition to reporting in these instances, the sponsor also must report whether any protocol deviations contributed to the occurrence of serious and unexpected suspected adverse reactions for drug products.

Types of protocol deviations that investigators should report to sponsors and IRBs

• Investigators should report to the sponsor all protocol deviations of which they are aware, using reporting procedures that highlight important protocol deviations.
• The recommendations for investigators reporting protocol deviations to the IRB varies depending on whether a deviation rises to the level of “important”. If important, the deviation should be reported as soon as possible, whereas if not important, the time to report is less urgent.
• For drug investigations, if there is a need for an intentional deviation from the protocol, the investigator must gain sponsor and IRB approval prior to implementing the change unless the need to make the change is urgent due to risk to the study subjects, in which case prior approval is not needed, but subsequent notification is required. 
• For device investigations, all protocol deviations should be kept on record and any deviations due to emergency situations must be reported to the sponsor and IRB within 5 days of the occurrence. For non-emergency scenarios, sponsor and IRB approval must be gained before implementing the change as with drug investigations.

Role of IRBs in evaluating protocol deviations.

• Upon notification of an important protocol deviation having occurred, the IRB must review as soon as possible to determine the larger impact on participant safety and study conduct.

Takeaways

Through consolidating relevant regulatory requirements and commentary from previous guidances to provide more clear cut definitions and recommendations, this guidance provides some highly useful clarity when it comes to defining and responding to protocol deviations. Whether an investigator, sponsor or IRB, this draft guidance can be a great resource to provide direction relating to protocol deviations. 

For any support on how this guidance may impact your day to day operations, MVG Consulting Services is the perfect resource. We’ve been a valued partner throughout many industry changes and our expertise allows us to provide continued guidance to our clients and colleagues when faced with industry changes and updates. With this in mind, please reach out with any inquiries and our team will be happy to help.