FDA CRL - Aveo Pharmaceuticals Inc.

The FDA issued a Complete Response Letter (CRL) on June 6, 2013, to AVEO Pharmaceuticals, Inc. regarding their New Drug Application (NDA 204408) for tivozanib hydrochloride capsules, submitted on September 28, 2012. The application was deemed unapprovable under section 505(b) of the Federal Food, Drug, and Cosmetic Act due to significant clinical and product quality deficiencies. Clinically, a single Phase 3 trial for advanced renal cell carcinoma presented inconsistent results: while progression-free survival (PFS) statistically favored tivozanib, a potential 25% increase in the risk of death (decreased overall survival, OS) was observed. This disparity, coupled with an imbalance in post-study treatments, rendered the trial's risk-benefit assessment uninterpretable and inconclusive. From a product quality standpoint, the proposed dissolution acceptance criterion was not adequately supported by data and deemed unacceptable. The FDA requires AVEO to conduct an additional adequate and well-controlled randomized trial for tivozanib, powered for PFS and sufficiently sized to demonstrate no adverse effect on OS, ensuring applicability to the US population. The company must also implement a revised dissolution acceptance criterion (Q={%} at P minutes) at release and on stability, including the updated specifications in any resubmission. Furthermore, a comprehensive safety update, incorporating all new nonclinical and clinical data, detailed adverse event analysis, and worldwide safety experience, is required. AVEO has one year to resubmit the application, addressing all identified deficiencies.