Abstract
This cohort study assesses rates at which orphan drugs approved by the US Food and Drug Administration were also approved for supplemental (follow-on) indications.
Introduction
The Inflation Reduction Act (IRA) requires Medicare price negotiation for selected drugs beginning in 2026.1 The law is expected to lower drug prices, but observers have debated the extent to which it will influence future innovation.2,3 The IRA exempts orphan drugs4 (ie, drugs for rare diseases) from negotiations, although this exemption applies only to orphan drugs with a single approved indication. As a consequence, drug companies will have reduced incentives to pursue additional uses of their orphan products. To inform debates around how the IRA may affect development of treatments for rare diseases, we examined how many orphan drugs approved by the US Food and Drug Administration (FDA) have had supplemental (follow-on) approved indications.
Methods
We identified novel orphan drug approvals (2003 through 2022) from FDA’s New Molecular Entity (NME) Drug and New Biologic Approvals database.5 We reviewed each drug’s FDA label current in April 2023 to determine whether FDA had approved the drug for a follow-on indication, and if so, for how many indications. We categorized each follow-on indication as orphan vs nonorphan, and calculated the time from a drug’s initial approval to the follow-on indication approval. This study was exempt from institutional review by the Tufts Medical Center.
To better understand the types of conditions addressed by follow-on indications, we identified whether the FDA included the approval in 1 or more expedited review programs (which the FDA reserves for therapies targeting serious illness and unmet clinical needs): accelerated approval, priority review, fast track, and/or breakthrough therapy.6
Results
FDA approved 282 novel orphan drugs from 2003 to 2022. FDA labels were unavailable for 2 drugs, leaving 280 drugs for analysis. The FDA approved 63 orphan drugs (23%) for at least 1 follow-on indication, including 29 (10%) for multiple follow-on indications (Table 1). Overall, the FDA approved 152 separate follow-on indications; 92 (61%) of these follow-on indications were also for orphan drug conditions. The mean (SD) time from novel orphan drug approval to follow-on indication was 53 (43) months (median [IQR], 46 [57] months) (Table 2). The FDA included 58 (38%) follow-on indications in one expedited review program, 46 (30%) in 2 programs, and 17 (11%) in 3 programs; none were included in all 4 programs.
Table 1. Novel Orphan Drug Approvals and Follow-On Indications.
| Characteristics | Follow-on indications, No. (%) | ||||
|---|---|---|---|---|---|
| All years (2003-2022) | 2003-2007 | 2008-2012 | 2013-2017 | 2018-2022 | |
| Total novel orphan drugs approvals, No. | 280 | 32 | 47 | 74 | 127 |
| Follow-on indications | |||||
| None | 217 (78) | 24 (75) | 32 (68) | 49 (66) | 112 (88) |
| 1 | 34 (12) | 4 (13) | 8 (17) | 10 (14) | 12 (9) |
| 2 | 14 (5) | 2 (6) | 2 (4) | 7 (9) | 3 (2) |
| 3 | 4 (1) | 0 | 2 (4) | 2 (3) | 0 |
| ≥4 | 11 (4) | 2 (6) | 3 (6) | 6 (8) | 0 |
Table 2. Follow-On Indications for Novel Orphan Drug Approvals.
| Characteristic | Expedited program approvals, No. (%) | ||
|---|---|---|---|
| Total follow-on indications (N = 152) | Orphan follow-on indications (n = 92) | Nonorphan follow-on indications (n = 60) | |
| Time to follow-on, mean (SD), mo | 53.1 (42.5) | 56.8 (45.1) | 47.3 (37.7) |
| Time to follow-on, median (IQR), mo | 46.4 (18.0-75.3) | 48.0 (25.4.9-85.2) | 38.8 (2.7-72.0) |
| Total expedited programs per approved drug | |||
| None | 31 (20) | 20 (22) | 11 (18) |
| 1 | 58 (38) | 34 (37) | 24 (40) |
| 2 | 46 (30) | 29 (32) | 17 (28) |
| 3 | 17 (11) | 9 (10) | 8 (13) |
| 4 | 0 | 0 | 0 |
| Expedited review program | |||
| Priority | 89 (59) | 57 (62) | 32 (53) |
| Fast-track | 17 (11) | 9 (10) | 8 (13) |
| Accelerated | 42 (27) | 23 (25) | 19 (32) |
| Breakthrougha | 53 (38) | 30 (35) | 23 (43) |
Abbreviation: FDA, US Food and Drug Administration.
Out of a total 140 FDA-approved follow-on indications after the breakthrough therapy program was established in 2012. Orphan follow-on indications were out of 86 and nonorphan indications out of 54.
Discussion
Efforts to address prescription drug costs must balance the benefits of lower drug prices with downsides in terms of reduced future innovation. We provide new data to help understand the potential consequences of incentives inherent in the IRA for drug companies to curtail efforts to pursue future follow-on indications for orphan drugs. FDA approved roughly one quarter of orphan drugs from 2003 to 2022 for at least 1 follow-on indication, and the agency considered the majority of these indications in expedited review programs.
How much the IRA will affect future innovation is unknown and a source of controversy. Estimates of how many fewer drugs will be developed are wide-ranging.2,3 The law may lead pharmaceutical manufacturers to develop more single-indication orphan drugs (which are not subject to negotiations) rather than follow-on indications. Our analysis suggests that the potential foregone follow-on indication approvals for serious illness and unmet needs could be nontrivial. Such potential losses should be considered against the gains to consumers and society that come with lower drug prices.
Study limitations include that we did not account for the clinical outcomes of follow-on indications, we did not account for the fact that drugs approved for a single use may also be used for off-label indications, and we did not address other incentives created by the IRA.
Data Sharing Statement
References
- 1.The Inflation Reduction Act. Internal Revenue Service website. Updated June 29, 2023. Accessed May 12, 2023. https://www.irs.gov/inflation-reduction-act-of-2022
- 2.Congressional Budget Office . Estimated Budgetary Effects of Public Law 117-169, to Provide for Reconciliation Pursuant to Title II of S. Con. Res. 14. September 7, 2022. Accessed May 12, 2023. https://www.cbo.gov/publication/58455
- 3.Philipson TJ, Durie T. Issue brief: the impact of HR 5376 on biopharmaceutical innovation and patient health. The University of Chicago. November 29, 2021. Accessed May 12, 2023. https://cpb-us-w2.wpmucdn.com/voices.uchicago.edu/dist/d/3128/files/2021/08/Issue-Brief-Drug-Pricing-in-HR-5376-11.30.pdf
- 4.Food and Drug Administration . Designating an Orphan Product: Drugs and Biological Products. July 8, 2022. Accessed May 22, 2023. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products
- 5.Food and Drug Administration . Center for Drug Evaluation and Research (CDER). New Molecular Entity (NME) Drug and New Biologic Approvals database. March 13, 2023. Accessed May 12, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/compilation-cder-new-molecular-entity-nme-drug-and-new-biologic-approvals
- 6.Food and Drug Administration . Guidance for industry: Expedited programs for serious conditions—drugs and biologics. FDA public notice. May 30, 2014. Accessed May 12, 2023. https://www.federalregister.gov/documents/2014/05/30/2014-12534/guidance-for-industry-on-expedited-programs-for-serious-conditions-drugs-and-biologics-availability
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Supplementary Materials
Data Sharing Statement
