Disagreements Within the US Food and Drug Administration Regarding Approval of Novel Therapeutic Agents, 2011-2015

This cross-sectional study examines the frequency of disagreements within the US Food and Drug Administration (FDA) regarding approval of novel therapeutic agents.


Introduction
Thirty days after a novel therapeutic agent, a new molecular entity, or original biologic is approved, the US Food and Drug Administration (FDA) must publicly disclose its approval package, including scientific reviews completed by FDA disciplines (eg, pharmacology, statistical, and medical reviewers) and any available assessments by agency leadership. 1 Although reports of internal disagreement have surfaced, 2 it is unclear how often such disagreements occur. Disagreements document differing points of view or engaged discussion and may, thus, capture important scientific debates or signal challenging decisions within the agency. We sought to determine the frequency of disagreements within the FDA regarding approval of novel therapeutic agents.

Methods
This cross-sectional study did not require institutional review board approval or patient informed consent because it was based on publicly available information and involved no patient records, in   The number in parentheses reflects the number of disagreements in which the discipline (or leadership) was the party recommending against approval. These numbers do not include within-discipline dissents, in which 1 reviewer recommended against approval but the discipline as a whole ultimately supported approval. Between May and September 2019, we identified all approval packages for novel therapeutic agents approved by the FDA from January 2011 to December 2015 using the Drugs@FDA database.
Disagreements were defined as instances where multiple reviewers and/or leadership (whether part of the same discipline or not) disagreed about approving a drug, the indicated patient population (eg, patient age), and/or the parameters of the drug's approval (eg, postmarketing requirements). We searched for disagreements in 2 ways. First, we reviewed the Summary Review, the Office Director Memo, the Cross-Disciplinary Review, and the Medical Review, which tend to describe the recommendations and disagreements. Second, we used key word searches to identify disagreements located elsewhere in the package.

Results
From 2011 through 2015, the FDA published 174 approval packages for novel therapeutic agents (  Table 2). Among the 12 disagreements regarding approval, 11 were approved with a postmarketing requirement or risk evaluation and management strategy.

Discussion
Among all approval packages for novel therapeutics approved by the FDA from 2011 to 2015, disagreements were common over new drug approvals, populations indicated, and the specific parameters of the approval. Given the complexity of determining drug safety and efficacy and the challenge of extrapolating to broad populations from a limited number of small, narrowly defined clinical trials, 3 disagreements within the FDA are not surprising and likely represent differing points of view that may inform pharmacovigilance efforts, as well as public discourse. 4 Our study was limited to disagreements recorded within approval packages. Where disagreements may be unrecorded, our analysis may underestimate their prevalence. We also did not assess whether disagreements were discussed by advisory committees or associated with particular outcomes (eg, safety warnings discovered after approval).
Nevertheless, our findings have important implications for the FDA's recent move to publish only integrated reviews in lieu of reviews by each discipline and agency leadership. 5 It raises questions about whether disagreements within the agency will continue to be published in compliance with the law. 1,6