Kyowa Pharmaceutical, Inc. – FDA CRL

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter to Kyowa Pharmaceutical, Inc. regarding its New Drug Application (NDA 22-075) for istradefylline tablets (20mg, 40mg), submitted on March 29, 2007. The application was deemed not approvable under section 505(d) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.125(b) due to significant deficiencies. Clinically, while some studies showed effectiveness in reducing “OFF” time for advanced Parkinson’s Disease, other well-controlled studies did not, and the drug failed to demonstrate meaningful benefit on critical secondary outcomes or global patient measures, unlike other approved treatments. This raised substantial concerns about the drug's overall clinical utility and the identification of a suitable patient population. Nonclinical issues involved the detection of dose-related brain mineralization in rat studies, for which the company provided insufficient data, methodology, or expert opinions, compounded by a poorly organized electronic submission. To pursue future approval, Kyowa Pharmaceutical must conduct an additional, adequately designed controlled clinical trial demonstrating a decrease in “OFF” time in maximally treated advanced PD patients. Furthermore, comprehensive nonclinical data, including expert opinion on brain mineralization, must be provided, along with Phase 4 commitments for drug interaction studies (Pgp inhibition and CYP1A2 induction potential), all presented in an organized manner.