U.S. Food and Drug Administration Reasoning in Approval Decisions When Efficacy Evidence Is Borderline, 2013–2018

The U.S. Food and Drug Administration (FDA) has substantial flexibility in its approval criteria in the context of life-threatening disease and unmet therapeutic need.To understand the FDA's evidentiary standards when flexible criteria are employed.Case series.Applications submitted between 2013 and 2018 that went through multiple review cycles because the evidence for clinical efficacy was initially deemed insufficient.Information was obtained from the approval package (available on Drugs@FDA), including advisory committee minutes, FDA reviews, and complete response letters.Of 912 applications reviewed, 117 went through multiple review cycles; only 22 of these faced additional review primarily because of issues related to clinical efficacy. Concerns about the end point, the clinical meaningfulness of the observed effect, and inconsistent results were common bases for initial rejection. In 7 of the 22 cases, the approval did not require new evidence but rather new interpretations of the original evidence. No FDA decisions cited reasoning used in previous decisions.The conclusions rely on the authors' interpretation of the FDA statements and on a series of "close calls."The FDA has no mechanism to find or tradition to cite similar cases when weighing evidence for approvals, resulting in standalone, bespoke decisions. These decisions show highly variable criteria for "substantial evidence" when flexible evidential criteria are used, highlighted by the recent approval of aducanumab. A precedential tradition and suitable information system are required for the FDA to improve institutional memory and build upon past decisions. These would increase the FDA's decisional transparency, consistency, and predictability, which are critical to preserving the FDA's most valuable asset, the public's trust.U.S. Food and Drug Administration.