Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021

The US Food and Drug Administration (FDA) accelerated approval program expedites regulatory approval of certain medications for patients with serious illness using efficacy evidence from surrogate markers that are reasonably likely to predict clinical benefits. As required by law, drug manufacturers agree to evaluate clinical benefits in a follow-up trial. The FDA sets a time frame for completion, but confirmatory trials are sometimes delayed.^1-3 We sought to systematically characterize the frequency of delayed confirmatory trials relative to deadlines set by the FDA.

In this cross-sectional study, we used public FDA data to identify follow-up trial requirements and the deadline agreed on between FDA and manufacturer for drugs granted accelerated approval from January 1, 2012, to July 31, 2021. We compared the time granted by characteristic (therapeutic area and small molecule vs biologic) using Wilcoxon rank sum tests at a significance level of P < .05. Trials were categorized as late if the requirement was fulfilled (met or released by the FDA) or the indication withdrawn by the manufacturer after the agreed on deadline, or if the requirement remained unfulfilled after the deadline, as of September 15, 2021. We also identified manufacturer-reported delays among incomplete requirements as of September 15, 2021. This study followed the STROBE reporting guideline. Per the Common Rule (45 CFR §46), institutional review board review and approval were not sought because this study does not constitute human participant research. Results were analyzed in Excel (Microsoft) and SAS, version 9.4 (SAS Institute Inc).

We included 177 follow-up trial requirements among 140 new indications (range, 0-4 requirements per indication). The median time allowed to complete confirmatory trials was 3.5 years from the date of approval (IQR, 1.8-5.8 years), with significant variation by therapeutic area (Table). The time granted for completion remained steady over the study period and did not vary between biologics and small molecule drugs (median 3.3 [IQR, 1.8-5.4] years vs 3.8 [IQR, 1.8-6.1] years; P = .63).

One-hundred trials (57%) were completed or due before September 15, 2021, of which 54 (54%) were late (Figure). An additional 14 studies (8%) were reported to the FDA as delayed by the manufacturer before the due date. Trials for nononcologic indications (93% [15 of 16]) were more likely to be late than those for oncologic indications (46% [39 of 84]). Trials for small molecule drugs (62% [40 of 65]) were more likely to be late than those for biologics (40% [14 of 35]).

Of the 54 late requirements, 27 were fulfilled by September 15, 2021, a median 1.0 year (IQR, 0.7-1.9 years) after the deadline and 3 were withdrawn a median of 1.4 years (range, 0.9-3.3 years) after the deadline. Twenty-four incomplete late requirements were a median of 1.8 years (IQR, 0.6-2.2 years) past their deadlines as of September 15, 2021.

Accelerated approval expedites the marketing of medications based on uncertain efficacy evidence, but the process depends on timely follow-up trials. We found that more than half of so-called confirmatory studies were not completed in the agreed-on time. In contrast with a recent Office of the Inspector General Report⁴ of incomplete confirmatory trials, our study includes late completed trials and manufacturer-reported delays. Limitations include shorter follow-up for more recent accelerated approvals and inability to identify reasons for trial delays.

Incomplete confirmatory clinical trials harm patients who are prescribed expensive drugs despite uncertain clinical benefits.⁵ However, drug manufacturers face few consequences for delays. The Consolidated Appropriations Act for 2023⁶ included accelerated approval reforms, such as granting the FDA greater authority to ensure confirmatory trials are under way before approval, mandating progress reports every 6 months by manufacturers, and clarifying procedures for withdrawal if follow-up trials do not find clinical benefit. It will be important to monitor whether these changes lead to fewer delays or whether additional authority is needed to assure that confirmatory trials are completed in a timely manner for the benefit of patients.

Accepted for Publication: January 23, 2023.

Published: March 31, 2023. doi:10.1001/jamahealthforum.2023.0217

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Deshmukh AD et al. JAMA Health Forum.

Corresponding Author: Benjamin N. Rome, MD, MPH, Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120 (brome@bwh.harvard.edu).

Author Contributions: Dr Deshmukh had full access to all 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: All authors.

Drafting of the manuscript: Deshmukh.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Deshmukh, Rome.

Obtained funding: Kesselheim.

Supervision: Kesselheim, Rome.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by a grant from Arnold Ventures (Kesselheim, Rome).

Role of the Funder/Sponsor: The funding organization 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.

Data Sharing Statement: See the Supplement.