Planned Protocol Deviations- Should Sponsors Notify FDA?

During a routine monitoring visit of a physician-sponsored IDE study, it was noted that the site was receiving “waivers” from the Sponsor to enroll subjects who did not meet one of the anatomical exclusion criteria. A rational was provided on why the subjects were being enrolled in the study. The site submitted the planned protocol deviations to the IRB and received IRB approval prior to enrolling the subjects. The Sponsor did not seek prior approval from the FDA, but did notify them of the deviations via the Annual Progress Report (APR).

From the FDA’s perspective, did the Sponsor do enough?

I contacted the FDA at the email address where they accept and answer questions to ask them this very question. (gcp.questions@fda.hhs.gov)  I received the following prompt response from Soma Kalb, PhD, Director of the IDE program.

FDA expects that deviations from a study protocol should be rare and that investigators and sponsors should exercise due diligence in avoiding them. Please refer to FDA Guidance “Design Considerations for Pivotal Clinical Investigations of Medical Devices” (2013), Section 9.2 Study Conduct -  http://1.usa.gov/1PLPZBl

Study deviations that are “eligible for reporting in the IDE annual report are those that would not affect: a) the validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol; b) the scientific soundness of the investigational plan; or c) the rights, safety or welfare of the subjects involved in the investigation” (812.35(a)(3)(ii)) and 812.35(a)(4)). Please refer to FDA Guidance “Changes or Modifications During the Conduct of a Clinical Investigation” (2001), Page 4, (4) Changes submitted in annual report - 
http://1.usa.gov/1onV7Bp

In rare circumstances, there may be a reason to plan a deviation from the protocol. When a deviation is planned ahead of time, such as when a subject is proposed to be enrolled as part of the study cohort even though they do not meet the enrollment criteria, and the sponsor agrees with the investigators request, the sponsor should submit a “request for study deviation” IDE supplement for FDA’s review and consideration. A sponsor’s approval of such a planned deviation is not sufficient and such a deviation should not be implemented unless FDA has granted prior approval (812.35(a)(1)) and IRB approval when appropriate (Part 56.110 and 56.111). FDA approval of the IDE supplement also provides the investigator assurance that FDA will not cite the deviation in a future inspection.

The takeaway message from the FDA is that the Sponsor should have submitted and received approval from the FDA for the planned protocol deviations. Reporting the deviations via the APR was good, but doesn’t protect them from being cited for those deviations in the event of an FDA audit.