Abstract 8489: Study Modifications & Primary Endpoint Reinterpretations Prior to Food & Drug Administration Approval of High-Risk Cardiovascular Devices

Abstract

Introduction: It is known that post-hoc analysis is less reliable and reduces the certainty of research findings. The most rigorous Food & Drug Administration (FDA) review process, for novel and high-risk devices, is called Premarket Approval (PMA). It is unknown to what extent post-hoc analysis is used in PMA applications. Hypothesis: We hypothesized that the PMA review process would involve studies of the highest methodological rigor and that all studies of approved cardiovascular devices would meet their pre-specified primary endpoints. Methods: We examined the Summary of Safety and Effectiveness Data, a document which is intended to present an objective critique of the scientific evidence which the FDA reviews for each device, for all PMA cardiovascular devices approved from 2000 through 2010. Any study modification or post-hoc primary endpoint reinterpretation was recorded by one author and confirmed by at least one additional author. Results: Of the 96 cardiovascular PMAs between 2000-2010 containing a study with at least one primary endpoint, 18 (19%) had some form of study modification or post-hoc primary endpoint reinterpretation. In 10 of these PMAs, a study did not meet at least one pre-specified primary endpoint, but the device was approved on the basis of a post-hoc data review. Pre-specified statistical analyses were changed after study initiation in 3 PMAs. Two PMAs were approved on qualitative merits rather than quantitative data after the FDA deemed the study characteristics no longer applicable at the time of review. Pre-specified controls were changed in 2 PMAs. In 1 PMA each, study design was modified after study initiation, a primary endpoint was redefined after study initiation, or new patients were added to a study after completion of initial enrollment. Conclusions: The most rigorous FDA review process includes numerous forms of study modification and post-hoc primary endpoint reinterpretation. More consistent requirements for pre-specified clinical trial outcomes will help improve the quality and consistency of the approval process and ensure that cardiovascular devices are safe and effective.