US Food and Drug Administration Approval of Drugs Not Meeting Pivotal Trial Primary End Points, 2018-2021

In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval to aducanumab for the treatment of Alzheimer disease despite both pivotal trials being stopped for futility with respect to the primary trial end point: change from baseline clinical dementia rating score.¹ Instead, FDA approval was based on an exploratory, surrogate marker: amyloid plaque reduction.² Prior studies have shown an FDA history of approving new drugs and high-risk medical devices when evidence of efficacy is uncertain.^3,4 We sought to systematically determine the frequency of and rationale for FDA approval of drugs based on pivotal trials with null findings for 1 or more primary efficacy end points.

Using the Drugs@FDA database, we conducted a cross-sectional study of all FDA-approved New Drug Applications between 2018 and 2021. From their approval package, we identified all pivotal trials, associated primary efficacy end points, and whether each end point met the prespecified criteria. For each drug not meeting at least 1 prespecified primary end point, we extracted drug, pivotal study, and end point characteristics, then characterized the FDA’s rationale for approval described in approval packages, whether a postmarket study was required or requested, and whether the postmarket study addressed the unmet primary end point.

This study used public, nonidentifiable data that did not constitute human participants research (45 CFR §46.102) and was not submitted for institutional review board review. The study followed the STROBE reporting guideline.

Between 2018 and 2021, the FDA approved 210 new drugs, 21 (10.0%) based on pivotal studies with null findings for 1 or more primary efficacy end points (Table 1). These 21 drugs were approved for 21 unique clinical indications. Of these drugs, 11 (52.4%) were first in class, 10 (47.6%) received orphan designation, and 14 (66.7%) received an expedited review designation. Before approval, an advisory committee was convened for 3 (14.3%) of the drugs.

The 21 drug approvals were supported by 55 pivotal trials; 6 approvals (28.6%) were supported by a single pivotal trial. These 55 trials included 68 primary efficacy end points, 27 of which (39.7%) were null; among these 27 end points, 13 (48.1%) were clinical outcomes, 7 (25.9%) were surrogate markers, 4 (14.8%) were clinical scales, and 3 (11.1%) were composite end points. Four drug approvals—naxitamab-gqgk for high-risk refractory or relapsed neuroblastoma, tazemetostat hydrobromide for epitheloid sarcoma, migalastat hydrochloride for adults with Fabry disease, and asparaginase erwinia chrysanthemi (recombinant) for acute lymphoblastic leukemia and lymphoblastic lymphoma—were based on a single pivotal study with null results for all pivotal primary end points.

The FDA’s most common reasons for approval of the 21 drugs were success in at least 1 other pivotal study (n = 13; 61.9%), positive findings from secondary or exploratory end points in the pivotal study (n = 10; 47.6%), and favorable post hoc analysis (n = 7; 33.3%) (Table 1). The FDA required or requested postmarketing studies for 7 (33.3%) of the drugs to address the null end point or a related clinical end point. Table 2 provides additional details for the 21 drug approvals.

From 2018 to 2021, 10% of drugs approved by the FDA were based on pivotal studies with null findings for 1 or more primary efficacy end points. Study limitations include a focus on pivotal trials, although the agency may have considered other studies or other regulators’ decisions. We were unable to analyze withdrawn or rejected New Drug Applications, as this information is not public.

Our findings underscore the complexity of regulatory decision-making, as exemplified by evidence of effectiveness despite a null primary end point finding (eg, tezacaftor-ivacaftor and triclabendazole). For other drugs (eg, cilastatin sodium, imipenem, and relebactam and istradefylline), the evidence of efficacy was less clear. Greater transparency regarding FDA decision-making could increase clinician, patient, and payer confidence in novel drugs and improve clinical use. Timely completion of postapproval studies addressing areas of clinical uncertainty is also necessary.⁵

Accepted for Publication: November 28, 2022.

Published Online: February 13, 2023. doi:10.1001/jamainternmed.2022.6444

Correction: This article was corrected on April 3, 2023, to fix some incorrect values in the Results for the numbers of pivotal trials, approvals supported by a single pivotal trial, and end points; to fix incorrect values for the numbers of expedited review drugs in Table 1; and to remove incorrectly placed footnotes in Tables 1 and 2.

Corresponding Author: Reshma Ramachandran, MD, MPP, MHS, Yale School of Medicine, 333 Cedar St, SHM IE-64, New Haven, CT 06510 (reshma.ramachandran@yale.edu).

Author Contributions: Dr Ramachandran 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: All authors.

Drafting of the manuscript: Johnston, Ramachandran.

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

Statistical analysis: Johnston, Ramachandran.

Obtained funding: Ramachandran.

Administrative, technical, or material support: Ramachandran.

Supervision: Ramachandran.

Conflict of Interest Disclosures: Dr Ross reported receiving grants from the US Food and Drug Administration; Johnson and Johnson; Medical Device Innovation Consortium; Agency for Healthcare Research and Quality; National Heart, Lung, and Blood Institute; and Arnold Ventures outside the submitted work. Dr Ross also is an expert witness at the request of relator attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Dr Ramachandran reported receiving research support from the Stavros Niarchos Foundation through Yale Law School for a project entitled Re-envisioning Publicly Funded Biomedical Research and Development and the US Food and Drug Administration for a project entitled Best Practices for Adequately Representing Women, Older Adults and Patients Identifying as Racial and Ethnic Minorities in Oncology Research: A Positive Deviance Approach; consultant fees for the ReAct-Action on Antibiotic Resistance Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health, which is funded by the Swedish International Development and Cooperation Agency; and grant support from Arnold Ventures outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from Arnold Ventures to the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (Drs Ramachandran and Ross).

Role of the Funder/Sponsor: The funder 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.

Additional Contributions: The authors thank Vinay K. Rathi, MD, MBA, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, and Sanket S. Dhruva, MD, MHS, University of California, San Francisco, School of Medicine, for their contributions to the initial design of this study. Neither Dr Rathi nor Dr Dhruva were compensated for their feedback, and neither has relevant conflicts of interest to disclose.