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Regulatory Agencies

Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021

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JAMA Oncology
Published Online: December 29, 2022
Special Communication
Sundeep Agrawal, MD1;
Shaily Arora, PharmD1;
Laleh Amiri-Kordestani, MD1;
R. Angelo de Claro, MD1;
Lola Fashoyin-Aje, MD, MPH1;
Nicole Gormley, MD1;
Tamy Kim, PharmD2;
Steven Lemery, MD, MHS1;
Gautam U. Mehta, MD1;
Emma C. Scott, PhD1;
Harpreet Singh, MD1;
Shenghui Tang, PhD1;
Marc R. Theoret, MD1,2;
Richard Pazdur, MD1,2;
Paul G. Kluetz, MD1,2;
Julia A. Beaver, MD1,2
Author Affiliations
  • 1Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
  • 2Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, Maryland
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Abstract

Importance  Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered.

Observations  Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021.

Conclusions and Relevance  Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

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Oncology Research, Methods, Statistics Drug Development Regulatory Agencies
Article Information

Accepted for Publication: September 6, 2022.

Published Online: December 29, 2022. doi:10.1001/jamaoncol.2022.5985

Corresponding Author: Sundeep Agrawal, Center for Drug Evaluation and Research, Office of New Drugs, Office of Oncologic Diseases, US Food and Drug Administration, Silver Spring, MD 20993 (sundeep.agrawal@fda.hhs.gov).

Author Contributions: Dr Agrawal 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. Drs Kluetz and Beaver contributed equally.

Concept and design: Agrawal, Arora, Fashoyin-Aje, Singh, Tang, Beaver, Pazdur, Kluetz.

Acquisition, analysis, or interpretation of data: Agrawal, Amiri-Kordestani, de Claro, Fashoyin-Aje, Gormley, Kim, Lemery, Mehta, Scott, Singh, Tang, Theoret, Pazdur, Kluetz.

Drafting of the manuscript: Agrawal, Scott, Beaver, Pazdur.

Critical revision of the manuscript for important intellectual content: Agrawal, Arora, Amiri-Kordestani, de Claro, Fashoyin-Aje, Gormley, Kim, Lemery, Mehta, Singh, Tang, Theoret, Beaver, Pazdur, Kluetz.

Statistical analysis: Tang.

Administrative, technical, or material support: Agrawal, Arora, de Claro, Kim, Singh, Theoret, Pazdur.

Supervision: Amiri-Kordestani, Fashoyin-Aje, Gormley, Kim, Singh, Theoret, Beaver, Pazdur, Kluetz.

Conflict of Interest Disclosures: Dr Arora completed work on this publication while she was an employee at the US Food and Drug Administration; at the time of publishing, she is an employee at AstraZeneca. No other disclosures were reported.

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