Moving the U.S. Food and Drug Administration Forward

Abstract

The mission of the U.S. Food and Drug Administration (FDA) includes “protecting the public health by ensuring the safety, efficacy and security of human and veterinary drugs, biological products . . . [as well as] advancing the public health by helping to speed innovations that make medicines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health” (1). The recent emergency use authorization of COVID19 vaccines is a prime example of how the FDA can accomplish this mission with amazing care and efficiency. Yet, the FDA commonly faces substantial challenges, such as bringing forward new treatments of various illnesses, including those that are devastating, progressive, and incurable; responding to the public pressures from patient advocacy groups; advising industry in the proper conduct of clinical trials; staying within budgetary constraints, with more than half of the FDA budget provided by applicant companies; maintaining impartial scientific assessment; and, finally, securing public and scientific community trust through transparency. This last is absolutely critical at a time when social media magnifies any hint of impropriety, whether real or imagined. Each of these issues comes to the forefront when the FDA makes a decision to either approve or disapprove a new drug application. How the FDA comes to a decision must be clear and transparent to permit the public and the scientific community to have trust in its actions. In response to criticism of slow reviews and approvals, the FDA implemented a series of expedited procedures beginning with the FDA Modernization Act of 1997 (2). These approaches include orphan drug designation, fast track, accelerated approval, priority review, and breakthrough therapy designation. Each of these or a combination of these can be applied to specific drug reviews. For example, on 7 June 2021 the FDA approved aducanumab for treatment of Alzheimer disease, despite no member of the expert advisory committee recommending approval on 6 November 2020 because of lack of convincing evidence of clinical benefit. Rather, the FDA used the accelerated approval path, citing that reduction of b -amyloid in the brain could act as a surrogate end point with a reasonable likelihood of clinical benefit (3) despite the director of the FDA neuroscience division stating at the advisory committee meeting, “We re not using the amyloid as a surrogate for efficacy” (4). This disconnect and controversy about whether brain b -amyloid correlates with or predicts clinical benefit (5) led 3 members of the advisory committee to resign and many in the scientific community to question the FDA s overruling the advisory committee recommendation (6). How did the FDA come to this decision? To shed some light on this process, Janiaud and colleagues (7), who include past FDA staff, investigated how the FDA evaluates applications that were initially rejected on the basis of inadequate evidence of efficacy (7). They identified 912 applications submitted between 2013 and 2018, with 117 requiring multiple reviews. Of these, 22 were initially rejected because clinical efficacy was deemed inadequate for various reasons, including disagreement between the FDA and the applicant about clinical meaningfulness of the findings, inconsistent results, anddeficiencies of data integrity or statistical analysis. Some were approved after submission of newpivotal studies andothers after clarification of inconsistent results; 8 were approved by an FDA division director despite unresolved issues. Occasionally, approval followed shifting the application to a different FDAdivisionwithout any change in the evidence. Janiaud and colleagues contrasted these FDA decision processes with legal case law. Case law builds on precedent and cites relevant cases that support each decision. The FDA does not. In fact, the authors found no examples of references to previous FDA decisions in any of the 22 cases that had been initially rejected. No consistent patterns of evidentiary analyses emerged. Further, query into the workings of the FDA continues to be challenging because of inadequate curation of previous decisions in an easily searchable database, a remedy suggested in the article. Janiaud and colleagues take an important first step in trying to demystify the actions of the FDA. Although they investigated only applications that were initially denied because of inadequate evidence of efficacy, other issues remain unexplored, such as how the FDA addresses untoward side effects, how it weighs benefit versus side effects, how it selects when to call for an external expert advisory committee, whether it considers the recommendations of such a committee, and how it weighs public pressures. Prospective rules for transparency must be developed and followed. Breaking the financial tether between the FDA and industry also will help ensure independence. Full funding by Congress could provide a substantial return on investment because FDA decisions have potentially large effects on federal expenditures through Medicare. These corrective steps will permit the FDA to regain and maintain community trust.Weneeda strongand independent FDA.