Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy

Abstract

Background: Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Objectives: This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.

Methods: We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.

Results: Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.

Conclusion: Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Keywords: Accelerated approval; Breakthrough therapy; Clinical trial; Drug development; Drug price; Efficacy; European medicines agency; Fast track; Healthcare policy; Innovation; Orphan designation; Pharmaceutical policy; Priority review; Safety; Special designation; US food and drug administration.

Fig. 1

An overview of the FDA’s special review pathways and designations. FDA US food and drug administration, R&D research and development. Own illustration

Fig. 2

Drugs with special FDA approval from 2003 and 2022. FDA US food and drug administration. Own illustration

Fig. 3

Orphan FDA designations and approvals from 1983 until 2021. FDA US food and drug administration. Own illustration

Fig. 4

Drugs with standard and fast track FDA approval from 2003 until 2022. FDA US food and drug administration. Own illustration

Fig. 5

Drugs with standard and accelerated FDA approval from 2003 until 2022. FDA, US food and drug administration. Own illustration

Fig. 6

FDA-approved drugs with standard and priority review from 2003 until 2022. FDA US food and drug administration. Own illustration

Fig. 7

Breakthrough therapy designation requests (a) and FDA approvals (b) from 2012 until 2022. FDA, US Food and Drug Administration. Own illustration

Fig. 8

Impact of the FDA's special designations on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. FDA, US Food and Drug Administration; NR, not reported. The figure illustrates each of the five special designation’s implications on the seven examined dimensions: safety, efficacy/clinical benefit, clinical trial evidence, innovation, economic incentives, development time, and price. Own illustration

Fig. 9

Comparison of special designations and review programs in the US (FDA) and the EU (EMA). EMA European medicines agency; FDA US food and drug administration; PRIME priority medicines, R&D research and development. Own illustration