Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants

Importance

Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts “filing reviews” to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown.

Objectives

To quantitatively analyze the FDA’s reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents.

Design and Setting

This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019.

Main Outcomes and Measures

Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA’s refusal reasons were also assessed.

Results

The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters.

Conclusions and Relevance

This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants’ disclosure of those reasons was incomplete. This work sheds light on the FDA’s regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.