FDA Releases Draft Guidance on Refuse-to-File Action

The FDA has released new draft guidance for industry on refuse-to-file (RTF) action taken by the FDA. The document seeks to clarify circumstances under which the FDA’s Center for Drug Evaluation and Research (CDER) may refuse to file a new drug application (NDA), supplemental NDA, or a Biologics License Application (BLA), or supplemental BLA for a product regulated by CDER. The guidance highlights the importance of submitting a complete application to minimize the chance of an RTF action.

The FDA typically either files an NDA or BLA within 60 days of receipt or informs the applicant of an RTF action. The filing of an application signals that the agency has made a threshold determination that the application’s content is sufficiently complete to permit a thorough review of its merits.

FDA regulations describe the possibility that the agency will consider an application incomplete if it is obviously deficient in a way that will make a review impossible, but the agency acknowledges in its new draft guidance that the administrative threshold to determine completeness has increased in recent years. The guidance points to pre-submission meetings between applicants and the FDA as opportunities to reach agreements regarding the content of a complete application, as well as agreement on submission of minor components that may be submitted within a 30-day period after the original application is submitted (though a rolling review period is available for fast-track designations). These additional submissions can add to the complexity of determining an application’s completeness. However, timely reviews of applications—provided for under user fee act agreements—make it imperative that the agency exercise its RTF authority when necessary to optimize the applicant’s and the FDA’s time and resources.

The types of application deficiencies that may result in an RTF action by day 60 are as follows:

• Materially lacking or inadequately organized applications
• Inadequate information for 1 or more indications of a product
• Reliance on a single trial for a demonstration of effectiveness if the FDA has communicated the need for more than 1 trial
• Failure to submit an assessment of studies related to potential abuse of the drug
• Non-electronic submission of required content in cases in which the FDA has specified the need for electronic submission
• Material not received within 30 days of an application’s receipt.

Within 30 days after an RTF notification, an applicant can request an informal conference with the FDA to discuss whether the agency should file an application despite the RTF action.