FDA CRL - Sage Therapeutics, Inc.

Agile Therapeutics, Inc. received a Complete Response Letter from the FDA regarding its New Drug Application (NDA 204017) for Twirla, a transdermal contraceptive system. The FDA's review, following the April 2012 NDA submission and subsequent amendments, determined the application could not be approved in its current form. The primary clinical concerns centered on inadequate evidence of efficacy. Two Phase 3 studies demonstrated unacceptably high Pearl Indices, significantly exceeding those of approved hormonal contraceptives. The agency noted substantial problems with study conduct, including low completion rates, poor subject follow-up, non-compliance with drug use and study procedures, and data quality issues, limiting confidence in the results. Product quality deficiencies were also identified across several areas. These included inadequate manufacturing controls and product specifications, insufficient justification for acceptance criteria, and issues with product labeling, specifically regarding strength identification. Further, impurities were not adequately characterized, the post-approval stability protocol needed updating, and a referenced Drug Master File was deemed inadequate. Discrepancies in manufacturing equipment used for clinical versus commercial production also required clarification. To address these concerns, Agile Therapeutics must conduct a new, rigorously overseen Phase 3 study demonstrating acceptable efficacy with the proposed to-be-marketed product, after resolving all product quality issues. This includes updating manufacturing controls, specifications, and labeling, fully characterizing impurities, ensuring the adequacy of the Drug Master File, and providing a comparison of manufacturing processes.