In the United States, the US Food and Drug Administration (FDA) issues approvals for new drugs and biologics that have demonstrated safety and efficacy in “adequate and well-controlled studies.” Pivotal trials are the most critical of these trials, often identified directly by FDA reviewers as the basis for approval and described in detail in FDA approval packages. Early guidance suggested that at least 2 such trials were required for approval, but the FDA has maintained a flexible interpretation, taking into consideration the ethical acceptability of conducting additional trials or the rarity of diseases when determining the sufficient threshold for safety and efficacy.  As a result, the quantity and quality of evidence supporting recent drug approvals is variable, both in terms of the number of pivotal trials and their design features, such as randomization, blinding, choice of comparators and end points, number of treated patients, and trial duration.

Potentially contributing to this variability is the increasing number of special regulatory programs available to the FDA during the past 30 years, now including Fast Track (1988, in statute 1997), Priority Review (1992), Accelerated Approval (1992), and Breakthrough Therapy designation (2012). Many of these programs codify special evidentiary standards acceptable for FDA approval of certain drugs and biologics, such as the use of surrogate end points (Accelerated Approval) and the acceptability of single trials as the basis of approval (Fast Track), with the goal of promoting earlier market availability of certain therapies, such as those addressing an unmet need or those treating serious or life-threatening conditions. As these new programs are conformed to the regulatory environment in addition to existing programs, such as orphan designation (1983) for rare diseases, it is critical to understand their potential influence on the quality of evidence supporting the new drugs and biologics that clinicians prescribe to their patients.