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US Food and Drug Administration Accelerated Approval Program for Nononcology Drug Indications Between 1992 and 2018
Kenji Omae1,2, Akira Onishi3, Ethan Sahker4,5
1Department of Innovative Research and Education for Clinicians and Trainees, Fukushima Medical University Hospital, Fukushima, Japan.
Importance:
The US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking.
Objective:
To evaluate the accelerated approval program for nononcology drug indications over a period of 26 years.
Design, Setting, And Participants:
This retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022.
Main Outcomes And Measures:
The study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication.
Results:
The FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication.
Conclusions And Relevance:
Although the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.
Insights
The US Food and Drug Administration
Area of Science:
- Pharmacovigilance and Drug Safety
- Regulatory Science
- Clinical Trials and Drug Development
Background:
- The US Food and Drug Administration (FDA) utilizes accelerated approval for serious or life-threatening illnesses, particularly in oncology.
- Evaluation of the FDA's accelerated approval program has been extensive in oncology but limited for nononcology drug indications.
Purpose of the Study:
- To conduct a comprehensive evaluation of the FDA's accelerated approval program for nononcology drug indications over a 26-year period.
- To assess the long-term outcomes of accelerated approval for nononcology drugs, including conversion to regular approval, safety modifications, and confirmatory trial completion.
Main Methods:
- A retrospective cohort study analyzed publicly available data on FDA nononcology drug indications granted accelerated approval between June 1992 and May 2018.
- Data on preapproval and confirmatory trials were collected and analyzed to determine regulatory outcomes and timelines.
Main Results:
- The FDA granted accelerated approval for 57 nononcology indications, with 75% converting to regular approval at a median of 53.1 months.
- Safety-related label modifications (boxed warnings) occurred in 47% of indications, and 20% of required confirmatory trials were not fulfilled.
- Clinical efficacy was not verified in 10% of trials, though only 2% of indications were withdrawn due to failed trials.
Conclusions:
- While accelerated approval expedites drug access, nononcology indications often require extensive post-approval evaluation, sometimes exceeding a decade.
- Safety-related label changes are common, and confirmatory trial completion and efficacy verification can be delayed, highlighting the need for robust post-market surveillance.
- The findings underscore the complexity and lengthy duration of comprehensive drug evaluation for nononcology indications approved via the accelerated pathway.
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