Silly Mistakes Lead to Refuse to File From FDA for Breakthrough Therapy
[Thursday, April 11, 2019]

A “strange” news release by Zogenix announced that it received a Refuse-to-File (RTF) for its NDA for Fintepla, a breakthrough therapy designated (BTD) drug for epilepsy. There are many clues in this announcement that could be lessons for others. The strangeness of the news is in the details of the RTF issues: missing chronic non-clinical study, and incorrect version of a clinical dataset in the NDA. The announcement went on the claim that FDA has not requested “additional clinical efficacy and safety studies” indicating that FDA had previously requested chronic non-clinical study and that the company decided to ignore such request when filing its NDA. The announcement went on to say that the company is requesting a Type A meeting with FDA to “clarify and respond to issues identified in the RTF letter” indicating that it cannot simply address the RTF issues and resubmit but needs to renegotiate with FDA for acceptability of its NDA. This episode highlights that breakthrough designation does not mean that FDA would turn a blind eye to sloppiness or let ignorance of its suggestions unpunished. Since this was a BTD drug, one can assume that FDA teams worked closely with Zogenix on the clinical and non-clinical development plan. Such interactions should theoretically have minimized the likelihood of miscommunications and last-minute changes. The fact that a nonclinical study considered critical by FDA was not included in the NDA indicates that the company either did not conduct the requested non-clinical study or that it rushed its NDA while the non-clinical study was not completed. A chronic toxicity study could take more than a year to complete and it is possible that the company did not want to wait for it to submit its NDA. Such issues should have addressed at the pre-NDA meeting. The lack of similar information was not a deterrent for acceptance of the market approval application by European regulators since European regulators generally are more accepting of fewer non-clinical data than FDA. The sloppiness to include incorrect dataset should be easiest to address. Unfortunately for Zogenix, their efforts to develop a promising treatment for epilepsy hit a snag, which will likely get addressed soon. It does not negate the efforts of the development team working on this drug. But any delay in market approval is expensive. And it does provide a valuable lesson in the regulatory process that we all can learn from.