01/21/2025

This is the second of a two-part blog entry, please see part one here.

The guidance breaks down the roles and responsibilities of the investigator, sponsor, and Institutional Review Board (IRB) in regards to monitoring, mitigating, reporting, and evaluating protocol deviations (PDs). The investigator, who is responsible for the conduct of the trial and protection of the rights, safety, and welfare of the participants must report all PDs to the sponsor, highlighting the important PDs. If the investigator intends to make an intentional deviation from the protocol, they must first receive approval from both the sponsor and the IRB. In the case that the intentional deviation is to protect the immediate health and well-being of a study participant, the investigator should report this to the sponsor and IRB as soon as possible but no later than five working days.

Sponsor responsibilities is the longest section of this guidance. Sponsors are responsible for monitoring protocol deviations and should have specific oversight on the critical-to-quality factor where important PDs are most likely to occur. The sponsor also should review all the PDs presented by the investigator and determine if any of them require reclassification and should share any of these reclassifications with the investigator. Sponsors should also ensure that proper corrective and preventative action plans are implemented for each deviation to ensure the issue does not get worse or reoccur in the future. There are steps the sponsor can take to minimize PD occurrence. The guidance gives examples such as:

Establishing flexible enrollment criteria when appropriate to give investigators more discretion and removing unnecessary enrollment criteria.
Using flexible time frames for collection of essential data where feasible,
Eliminating nonessential activities.

The IRB’s role is primarily to evaluate the reported PDs during their periodic reviews of the clinical investigation to assure the protection of the study participant’s safety and well-being. The FDA recommends all important PDs be reported to the IRB as soon as possible and that the IRB also review these PDs in a similar expedited manner. The IRB must also review and determine if any changes or intended deviations from the protocol will have an impact on the study participants rights and safety. All of these reviews and procedures should be clearly outlined in the study protocol.

The entire draft guidance is available on the FDA’s website and supplementary information can also be found in the Federal Register’s Notice. Since this is a draft, anyone who wishes to comment on the guidance can do so here from now until February 28, 2025. To stay up to date with FDA activity such as this as well as other clinical trial related content, visit the Clinical Pathways website and sign up for our blog and newsletter.

The Clinical Pathways Team

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