Under the US Food and Drug Administration’s (FDA’s) accelerated approval program, therapeutic agents that address serious or life-threatening disease can receive conditional approval on the basis of trials that use surrogate markers that are reasonably likely to predict clinical benefit.1 Although drug sponsors are required to conduct postapproval trials to confirm clinical benefit, the amount of time sponsors are granted by the FDA to complete these studies has come under increased scrutiny after the recent accelerated approval of aducanumab for Alzheimer disease,2 which included a 9-year deadline for the completion of the confirmatory trial. Better understanding whether postapproval trial durations, which are generally expected to measure clinical outcomes and be longer than pivotal trials focused on surrogate markers, justify the study timelines set by the FDA is critical because these drugs can remain on the market for an extended period without confirmatory evidence. Therefore, we compared the duration of postapproval trials with that of the pivotal trials used as the basis for the FDA’s approval, as well as FDA-established postapproval trial results reporting deadlines, for all indications receiving accelerated approval from January 1, 2009, through December 31, 2018.
In this cross-sectional study, we used the Drugs@FDA database to identify all new drugs and biologics granted accelerated approval by the FDA from January 1, 2009, through December 31, 2018. This study did not require institutional review board approval because it was based on publicly available information, in accordance with 45 CFR §46. Informed consent was not needed because no patient data were used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. For each therapeutic agent, we used previously described approaches to identify pivotal and postapproval trials designed to confirm efficacy,3-5 classify postapproval trials as either new or ongoing at the time of approval,4 identify FDA-established postapproval trial results reporting deadlines,4,6 and locate ClinicalTrials.gov registrations and publications.4 We used FDA labels/letters and medical reviews, ClinicalTrials.gov registrations, and publications to identify pivotal and postapproval trial primary outcomes and the timing of their ascertainment (ie, median duration of follow-up or response for event-driven trials). For indications with more than 1 pivotal study and/or postapproval trial, we calculated the median of the trial durations. For each indication, we then calculated the difference between the durations of the postapproval and pivotal trials. As suggested during the peer review of this manuscript, we also estimated trial durations by taking the difference between the actual or estimated study start and primary completion dates available for all trials registered on ClinicalTrials.gov. These data analyses were conducted from July 1 to September 1, 2021, using Excel (Microsoft, Inc).
From Jauary 1, 2009, through December 31, 2018, the FDA approved 41 new therapeutic agents for 45 indications via the accelerated approval program. Of these, information on trial duration could be ascertained for 31 therapeutic agents (76%) approved for 32 indications (76%). Of 32 indications approved, 21 (66%) were for drugs, 11 (34%) were for biologics, and 27 (84%) were for therapeutic agents related to cancer and hematology (Table 1).
Overall, the median pivotal trial duration was 10 months (range, 0-42 months) and the postapproval trial duration was 17 months (0-72 months) (median difference, 5 months [range, −6 to 36 months]) (Table 2). The median time from approval to FDA-established postapproval trial results reporting deadlines for sponsors was 50 months (3-116 months), a median of 30 months (range, −19 to 106 months) more than the postapproval trial durations.
Median pivotal and postapproval trial durations were consistent across indications for which the FDA required new postapproval trials vs results reporting or extended follow-up of ongoing postapproval trials and for indications for which postapproval trials used surrogate markers vs clinical outcomes as primary end points (Table 2). Among 37 indications with information on study start and completion dates on ClinicalTrials.gov, the median difference between pivotal and postapproval trial durations based on these data was 1 month (range, −85 to 97 months).
The findings of this cross-sectional study suggest that, for therapeutic agents receiving accelerated approval by the FDA from January 1, 2009, through December 31, 2018, median postapproval trial durations were not much longer than pivotal trial durations. These findings raise questions about the use of the accelerated approval program for certain therapeutic agents, especially if postapproval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate end points.
Limitations of this study include the reliance on publicly available data, the inability to account for postapproval trial recruitment challenges or other reporting deadline changes, and that these results may not be generalizable across all therapeutic areas. Nevertheless, this study’s findings suggest that prolonged results reporting deadlines may not be justified given the marginal differences in pivotal and postapproval trial durations of therapeutic indications recently receiving accelerated approval by the FDA.
Accepted for Publication: September 5, 2021.
Published: November 9, 2021. doi:10.1001/jamanetworkopen.2021.33601
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wallach JD et al. JAMA Network Open.
Corresponding Author: Joshua D. Wallach, PhD, MS, Department of Environmental Health Sciences, Yale School of Public Health, Laboratory of Epidemiology and Public Health, 60 College St, Fourth Floor, Room 411, New Haven, CT 06510 (firstname.lastname@example.org).
Author Contributions: Dr Wallach had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Wallach, Ramachandran, Ross.
Drafting of the manuscript: Wallach.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Wallach.
Obtained funding: Wallach.
Conflict of Interest Disclosures: Dr Wallach reported receiving funding from the US Food and Drug Administration (FDA). Dr Bruckner reported receiving grants from HealthWatch UK to conduct research into clinical trial transparency via TranspariMED and being the founder (an unpaid role) of the TranspariMED campaign. Dr Ross reported receiving research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing; from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology; from the FDA for the Yale University–Mayo Clinic Center Center for Excellence in Regulatory Science and Innovation program; from the Agency for Healthcare Research and Quality; from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH); and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International. All funding and support were outside the scope of the present study. No other disclosures were reported.
Funding/Support: This study was supported by award K01AA028258 from the National Institute on Alcohol Abuse and Alcoholism of the NIH (Dr Wallach).
Role of the Funder/Sponsor: The NIH National Institute on Alcohol Abuse and Alcoholism had no role had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, US Department of Veterans Affairs, or US government.
Additional Information: Requests for the data set can be made to Dr Wallach at email@example.com.
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