FDA’s Drug Designations

Sorting Through the Thicket

Since the COVID pandemic, a confusing panoply of FDA drug designations has crept into public awareness. Let’s sort through and elucidate some of the key designations—expedited approval pathways, a category that encompasses fast track, breakthrough therapy, priority review, and accelerated approval; emergency use authorization; and, the orphan drug designation.

Ideally, these designations reflect processes intended to address a serious unmet need for treatment by expediting FDA review or promoting drug research and development. A new drug currently requires about a decade to work its way through the standard clinical development and regulatory approval processes, a lengthy and costly undertaking that could delay the introduction of urgently needed medications.1,2

Expedited Approval

Most of the expedited drug approval pathways now in use by the FDA have their genesis in the Prescription Drug User Fee Act (PDUFA).  Enacted in 1992, PDUFA, in part, provided additional funds so the FDA would have the internal resources to expeditiously review and adjudicate new drug applications. PDUFA authorized the FDA to collect user or application fees from drug sponsors—that is, manufacturers—to supplement its annual appropriation for salaries and expenses.3 PDUFA also committed the FDA to hone its internal timetables for new drug applications, laying the foundation for the current standard set of expedited review pathways. 

Expedited Approval Pathways—The Big Four

In 2023, approximately two-thirds (65%) of the 55 drugs approved by the FDA were reviewed through at least one of the four standard expedited pathways (Table).4,5 The pathways are not mutually exclusive—a new drug can be covered by more than one designation. 


What About Emergency Use Authorization?

Because it has been used so frequently in recent years, Emergency Use Authorization (EUA) is conspicuous by its absence from the list of standard expedited FDA processes. Indeed, the FDA has issued over 600 EUAs in response to COVID-19 alone.12

Established in 2004, EUA represents a unique authority because it empowers the Secretary of Health and Human Service to permit the FDA to authorize “unapproved medical products or unapproved uses of approved medical products” based on preliminary clinical data of efficacy and safety only during a declared public health emergency.13,14 Examples included certain COVID vaccines and the COVID treatment Paxlovid™, which has since received full FDA approval. The EUA permission for product marketing expires at the end of the public health emergency.

How Does the Orphan Drug Designation Fit in?

To spur the development of drugs to treat patients with rare diseases—that is, those affecting 200,000 or fewer individuals in the U.S.—Congress approved the Orphan Drug Act in 1983.15 This legislation incentivizes manufacturers to pursue drug research and development for rare diseases by offering a series of impressive financial incentives16-18:

  • 50% tax credit for clinical testing costs
  • Waiver of the FDA’s new drug or biologic application fee (approximately value: $2 to $4 million)
  • 7-year product marketing exclusivity

The financial incentives offered under the Orphan Drug Act have become controversial of late in light of recent findings showing that drugs initially approved with an orphan drug designation were just as profitable after launch as drugs for more common conditions without the orphan drug designation.19

Since 1983, approximately 1130 orphan drugs have been approved by the FDA, most (38%) for a cancer indication.20 In 2023, more than half (51%) of the novel drugs approved by the FDA were designated orphan drugs and the vast majority (82%) of those also received at least one type of expedited FDA review.4 In recent years, there has been a steady uptick in the number of drugs seeking initial orphan drug status. Only about a third of all FDA were designated orphan drugs between 2010 and 2013 compared with more than half since 2018.21

Jim Kesslick

Medical Writer

References

  1. Clinical development success rates and contributing factors 2011–2020. Quantitative Life Sciences. February 2021. Accessed April 18, 2024. https://go.bio.org/rs/490-EHZ-999/images/ClinicalDevelopmentSuccessRates2011_2020.pdf
  2. Brown DG, Wobst HJ, Kapoor A, Kenna LA, Southall N. Clinical development times for innovative drugs. Nat Rev Drug Discov. 2022 Nov;21(11):793-794. doi: 10.1038/d41573-021-00190-9
  3. FDA drug approval. United States Government Accountability Office. March 2020. Accessed April 13, 2024. https://www.gao.gov/assets/gao-20-244.pdf
  4. Cavazzoni P. New Drug Therapy Approvals 2023. FDA. Center for Drug Evaluation and Research. January 2024. Accessed April 16, 2024. https://www.fda.gov/media/175253/download?attachment
  5. Salib V. Understanding the FDA’s expedited approval pathways. PharmaNews Intelligence. November 2, 2022. Accessed April 13, 2024. https://pharmanewsintel.com/features/understanding-the-fdas-expedited-approval-pathways
  6. Fast track. FDA. January 4, 2018. Accessed April 13, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
  7. Kepplinger EE. FDA’s Expedited Approval Mechanisms for New Drug Products. Biotechnol Law Rep. 2015 Feb 1;34(1):15-37. doi: 10.1089/blr.2015.9999.
  8. Breakthrough therapy. FDA. January 4, 2018. Accessed April 13, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy
  9. Priority Review. FDA. January 4, 2018. Accessed April 13, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review
  10. Accelerated Approval Program. FDA. December 2, 2022. Accessed April 13, 2024. https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program
  11. Deshmukh AD, Kesselheim AS, Rome BN. Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021. JAMA Health Forum. 2023 Mar 3;4(3):e230217. doi: 10.1001/jamahealthforum.2023.0217
  12. Cohen K, Hackley C, Krishnan A. Emergency use or overuse? The Regulatory Review. Published July 16, 2022. Accessed April 13, 2024. https://www.theregreview.org/2022/07/16/saturday-seminar-emergency-use-or-overuse/
  13. Emergency Use Authorization. FDA. Accessed April 13, 2024. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization
  14. Billingsley A. What Is an Emergency Use Authorization (EUA)? GoodRx. October 28, 2021. Accessed April 13, 2024. https://www.goodrx.com/healthcare-access/medication-education/fda-emergency-use-authorization
  15. The Orphan Drug Act: Legal overview and policy considerations. Congressional Research Service. March 5, 2024. Accessed April 17, 2024. https://crsreports.congress.gov/product/pdf/IF/IF12605
  16. Seoane-Vazquez E, Rodriguez-Monguio R, Szeinbach SL, Visaria J. Incentives for orphan drug research and development in the United States. Orphanet J Rare Dis. 2008 Dec 16;3:33. doi: 10.1186/1750-1172-3-33
  17. Tennant I.  Benefits of FDA Orphan Drug designation: what you need to know. American Gene Technologies. April 6, 2020. Accessed April 17, 2024. https://www.americangene.com/blog/benefits-of-fda-orphan-drug-designation-what-you-need-to-know/
  18. Prescription Drug User Fee Amendments. U.S. Food and Drug Administration. April 17, 2024. Accessed April 19, 2024. https://www.fda.gov/industry/fda-user-fee-programs/prescription-drug-user-fee-amendments
  19. Tu SS, Nagar S, Kesselheim AS, Lu Z, Rome BN. Five-Year Sales for Newly Marketed Prescription Drugs With and Without Initial Orphan Drug Act Designation. JAMA. 2023 May 9;329(18):1607-1608. doi: 10.1001/jama.2023.3079
  20. Fermaglich LJ, Miller KL. A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act. Orphanet J Rare Dis. 2023 Jun 23;18(1):163. doi: 10.1186/s13023-023-02790-7