The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

Abstract

The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.

Generating comparative evidence on new drugs and devices before approval

“…Although expedited programs differ in their scope and focus, which range from putting deadlines on regulatory review times to approving products on the basis of earlier-stage data than what is typically required, their shared objective is to provide faster access to new products. 28 One rationale for introducing such programs is to meet patient demand for potentially effective therapies for life-threatening diseases for which there is no existing treatment. 29,30 Studies have confirmed that drugs that qualify for expedited programs have shorter development times and receive regulatory approval faster.…”

Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study

“…Contributing to this may be the varying quality of clinical trial evidence available at the time of approval and resulting uncertainty around the extent of clinical benefit. 27 28 29 As more evidence accumulates after approval, the assessment of therapeutic value may also evolve.…”

The US Food and Drug Administration’s expedited approval programs: Addressing premarket flexibility with enhanced postmarket evidence generation

“…In addition, we appreciated Dr. Woodcock's clarification that all New Drug Applications 'are required by law to contain all information and studies that sponsoring companies have conducted or are aware of.' 8 The language we used in our review, suggesting that 'it is possible that drug sponsors only submit individual trials with the largest treatment effects to the FDA', 1 was poorly worded.…”

“…13 We agree that trial participants should reflect the population of patients that are expected to benefit from the therapeutic agent being evaluated. 1 However, it is also worth noting that precision medicine enables drugs to be approved for narrower indications based on smaller trials. While these more 'precise' approvals can effectively address unmet medical needs, there are potential concerns as well if the drugs are then prescribed for broader indications, beyond those formally evaluated by the FDA.…”