Are You in Compliance with FDA Post-approval Study Requirements?

On May 27, 2021, the FDA issued two draft guidances for studies of devices after approval or clearance. The draft guidances would impose much shorter timelines for both post-approval studies and postmarket surveillance studies, changes that could lead to more warning letters for non-compliance.

The FDA draft guidance for procedures for post-approval studies (PAS) will supersede a guidance from June 2009 and is applicable to approved PMA devices. The draft emphasizes issues such as post-approval study status categories, study timelines and enrollment milestones. The agency and the sponsor would collaborate on study milestones when a PAS is included in a device approval order, and the sponsor would have to enroll the first subject within six months of the FDA’s approval of the PAS.

The other enrollment milestones for PAS studies are 20% of subjects enrolled within 12 months, and 50% enrolled within 18 months. The study would have to be fully enrolled within 24 months under this draft guidance, all of which will help to ensure the study is completed in a timely manner.

The FDA will work with the sponsor during the review of the device submission so the PAS can be approved when the device is approved. Otherwise, the sponsor would have to file the PAS proposal as a PMA supplement within 30 days of the approval. If more than one PAS study is to be filed, each of those studies would be filed as separate PMA supplements. Any changes to a PAS after the device is approved would also be filed as a supplement.

There are several differences in the deadlines for this draft PAS guidance and the 2009 final guidance, such as that the FDA’s review of the sponsor’s study proposal will be completed within 60 days. If there are deficiencies with the study protocol that are not addressed, that protocol will be classified as protocol overdue. While warning letters for failure to comply with PAS requirements are not common, the agency has issued such warning letters as recently as May 2020.

The risk for manufacturers is further elevated by the threat of regulatory actions for studies that have not been completed on time. For instance, the PMA could be withdrawn by the FDA, or the agency could order a Section 522 postmarket surveillance study in addition to the PAS, but seizure, injunction, prosecution, and civil monetary penalties are among the other regulatory levers available to the agency.

Unlike the PAS draft, the draft guidance for Section 522 studies is applicable to both class II and class III devices. These studies can be imposed on devices with anticipated uses in pediatric populations, even if pediatric patients are not included in the indications for use. In addition to PMA and 510(k) devices, these studies may be required for humanitarian device exemption applications and petitions for a de novo device designation. The manufacturer may request a review of a Section 522 order if it disagrees with the need for such a study.

The enrollment milestones are less stringent in the Section 522 draft guidance than in the PAS draft guidance, such as that the sponsor has 15 months to begin a Section 522 study, while a PAS study must begin enrollment within six months. Section 522 studies must reach the 20% enrollment mark within 18 months to reach the 20% enrollment requirement in the Section 522 draft whereas a PAS study must this requirement within 12 months. Section 522 studies must reach the 50% enrollment milestone within 21 months, rather than 18 months for the PAS guidance, but full enrollment is expected by 24 months in this guidance, the same timeline used in the PAS guidance.

Manufacturers have more options when it comes to the design of Section 522 studies compared to PAS studies, such as the use of retrospective cohort studies and enhanced surveillance studies. However, the manufacturer must file the final surveillance report within three months of the last subject has completed the last follow-up visit. Manufacturers should be advised that a failure to complete Section 522 studies will make the manufacturer subject to the same enforcement actions listed in the PAS study draft guidance.