Research Letter
Regulatory and Clinical Outcomes of Nononcology Accelerated Approvals
Ian T. T. Liu, Gemma Reynolds, Aaron S. Kesselheim, et al
JAMA 2025;334;(13):1194-1196. doi:10.1001/jama.2025.10726
The US Food and Drug Administration (FDA) accelerated approval pathway expedites drug approvals based on changes to surrogate or intermediate measures only “reasonably likely” to predict clinical benefit. Therapies granted accelerated approval must undergo confirmatory trials to evaluate their clinical benefits. Since the program’s inception, about 10% of new drugs have used the pathway,1 with 80% of these in oncology.2
Surrogate measures have variable ability to predict how patients feel, function, or survive, challenging their usefulness for regulatory approval.3 This has created controversy for several recent nononcology accelerated approvals, such as aducanumab for Alzheimer disease, tofersen for amyotrophic lateral sclerosis,4 delandistrogene moxeparvovec for Duchenne muscular dystrophy,5 and voxelotor for sickle cell disease.6 To better understand the FDA’s use of the accelerated approval pathway for nononcology products, this study characterizes the pivotal and confirmatory trials supporting agency decision-making.
Methods
For all accelerated approvals of nononcology products from 2013-2024 reported in FDA databases, we identified approved indications, regulatory designations (expedited designations such as fast track and other designations such as for rare diseases) other than accelerated approval, and pivotal trials supporting approval and confirmatory trials leading to conversion to regular approval (or withdrawal). We extracted key trial characteristics including their end points and, for product-indication pairs converted to regular approval and all trials, 2 authors (I.T.T.L., E.R.S.C.) classified end points as surrogate or clinical, resolving disagreement by consensus (eMethods in Supplement 1).1 To compare characteristics between pivotal and confirmatory trials, we generated statistics using Microsoft Excel version 16.9 (Microsoft) and used χ2 and 2-tailed t tests. We followed STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guidelines; this study did not constitute human participants research, so institutional review board approval was not sought.
Results
Among 206 accelerated approvals, 156 (75.7%) were excluded as oncology products, leaving the remaining 50 (24.3%) nononcology products indicated to treat 26 diseases. Among these, 12 (24.0%) were vaccines for infectious diseases, 10 (20.0%) drugs for nonmalignant hematologic diseases, 11 (22.0%) drugs for neurologic diseases, and 5 (10.0%) drugs for infectious diseases (Table 1). Thirty-five (70.0%) received at least 1 FDA expedited designation other than accelerated approval, and 30 (60.0%) carried a rare-disease designation. The median time projected from accelerated approval to planned confirmatory trial submission was 4.64 years (IQR, 2.69-5.70 years).
Table 1. Characteristics of Nononcology Accelerated Approvals, 2013 to 2024
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Overall (N = 50) | Current regulatory statusa | |||
| Ongoing accelerated approval (n = 28) | Converted to regular approval (n = 19) | Withdrawn approvals(n = 3) | ||
| Disease area | ||||
| Vaccine | 12 (24.0) | 6 (21.4) | 6 (31.6) | 0 |
| Neurologic | 11 (22.0) | 8 (28.6) | 2 (10.5) | 1 (33.3) |
| Nonmalignant hematologic | 10 (20.0) | 2 (7.1) | 6 (31.6) | 2 (66.7) |
| Nonvaccine infectious disease | 5 (10.0) | 2 (7.1) | 3 (15.8) | 0 |
| Gastrointestinal | 4 (8.0) | 4 (14.3) | 0 | 0 |
| Kidney | 3 (6.0) | 1 (3.6) | 2 (10.5) | 0 |
| Metabolic | 3 (6.0) | 3 (10.7) | 0 | 0 |
| Musculoskeletal | 2 (4.0) | 2 (7.2) | 0 | 0 |
| FDA designations | ||||
| Any expedited program (priority review, fast track, breakthrough therapy) | 35 (70.0) | 19 (67.9) | 13 (68.4) | 3 (100.0) |
| Priority review | 28 (56.0) | 20 (71.4) | 6 (31.6) | 2 (66.7) |
| Fast track | 16 (32.0) | 11 (39.3) | 2 (10.5) | 3 (100.0) |
| Breakthrough therapy | 14 (28.0) | 8 (28.6) | 4 (21.1) | 2 (66.7) |
| Orphan Drug Act designation | 30 (60.0) | 20 (71.4) | 8 (42.1) | 2 (66.7) |
| Other designation | 2 (4.0) | 2 (7.1) | 0 | 0 |
The 50 accelerated approvals were based on 82 studies and used 22 distinct surrogate or intermediate primary end points. Nineteen approvals (38.0%) were converted to regular approval, 3 (6.0%) withdrawn, and 28 (56.0%) remain ongoing accelerated approvals. Of the 19 conversions to regular approval, 9 (47.4%) were based on clinical outcomes and 10 (52.6%) on surrogate measures, of which 7 (36.8%) were the same end point that supported the original accelerated approval. Conversions and withdrawals were supported by 21 confirmatory trials (Table 2). Median time from accelerated to conversion to regular approval or withdrawal was 3.26 years (IQR, 2.10-5.20 years), while median time since approval for ongoing accelerated approvals was 3.70 years (IQR, 1.06-6.46 years).
Table 2. Characteristics of Pivotal and Confirmatory Trials Associated With Nononcology Accelerated Approvals, 2013-2024
| No. (%) | P value | ||
|---|---|---|---|
| Pivotal trials (n = 82) | Confirmatory trials (n = 21)a | ||
| Phase | |||
| 1 | 2 (2.4) | 1 (4.8) | .003 |
| 2 | 18 (22.0) | 0 | |
| 3 | 57 (69.5) | 15 (71.4) | |
| 4 | 1 (1.2) | 4 (19.0) | |
| Retrospective analysis | 4 (4.9) | 1 (4.8) | |
| No. of intervention groups | |||
| 1 | 12 (14.6) | 6 (28.6) | .02 |
| 2 | 43 (52.4) | 10 (47.6) | |
| 3 | 19 (23.2) | 0 | |
| ≥4 | 8 (9.8) | 5 (23.8) | |
| Comparator structure | |||
| Placebo-controlled | 38 (46.3) | 7 (33.3) | .66 |
| Active comparator | 23 (28.0) | 8 (38.1) | |
| None | 20 (24.4) | 6 (28.6) | |
| Historical controls | 1 (1.2) | 0 | |
| Randomization | |||
| Randomized | 69 (84.1) | 15 (71.4) | .20 |
| Nonrandomized (multigroup) | 2 (2.4) | 0 | |
| Single-group | 11 (13.4) | 6 (28.6) | |
| Blinding | |||
| Double-blind | 50 (61.0) | 14 (66.7) | .15 |
| Single-blind | 12 (14.6) | 0 | |
| Open-label | 18 (22.0) | 5 (23.8) | |
| Retrospective/observational analysis | 2 (2.4) | 2 (9.5) | |
| Primary outcome measureb | |||
| Clinical outcome | 25 (32.1)c | 7 (33.3) | .74 |
| Surrogate measure | 45 (57.7) | 13 (61.9) | |
| Nonefficacy primary end point | 8 (10.3) | 1 (4.8) | |
| Enrollment, median (IQR) | 557 (122-1713) | 503 (126-3301) | .60 |
Discussion
Accelerated approvals cover a wide array of nononcologic diseases, most commonly nonmalignant hematology and neurology conditions, with one-fourth covering vaccines for infectious diseases. Conversion to regular approval occurred a median of 3 years after accelerated approval, with many confirmatory trials also using surrogate measures as primary efficacy end points. No significant differences between pivotal and confirmatory trials were observed across trial size, comparator structure, randomization status, and blinding. It was surprising to find that one-third of pivotal trials reported clinical outcomes as primary efficacy end points, although the FDA decision to grant accelerated approval was instead based on surrogate marker end points. While using surrogates with unproven links to clinical benefit is an expected feature of the accelerated approval program, pivotal and confirmatory trials reported surrogate measures as primary efficacy outcomes at similar rates, and at least one-half of conversions to regular approval were granted using surrogate measures as well, leaving uncertainty as to drugs’ clinical utility despite the change in regulatory status.
The study cohort was restricted to pivotal and confirmatory trials and did not consider any unpublished data or postconversion trials, although these are rare. Confirmatory trials for accelerated approval drugs should more consistently address clinical benefit so patients and clinicians can have confidence in the safety and efficacy of products receiving accelerated approval.
