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

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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postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021.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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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.

Pazdur  R .  Endpoints for assessing drug activity in clinical trials.   Oncologist. 2008;13(suppl 2):19-21. doi:10.1634/theoncologist.13-S2-19PubMedGoogle ScholarCrossref
US Food and Drug Administration. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Accessed May 4, 2021. https://www.fda.gov/media/71195/download
Estey  E , Hoth  D , Simon  R , Marsoni  S , Leyland-Jones  B , Wittes  R .  Therapeutic response in phase I trials of antineoplastic agents.   Cancer Treat Rep. 1986;70(9):1105-1115.PubMedGoogle Scholar
Decoster  G , Stein  G , Holdener  EE .  Responses and toxic deaths in phase I clinical trials.   Ann Oncol. 1990;1(3):175-181. doi:10.1093/oxfordjournals.annonc.a057716PubMedGoogle ScholarCrossref
Horstmann  E , McCabe  MS , Grochow  L ,  et al.  Risks and benefits of phase 1 oncology trials, 1991 through 2002.   N Engl J Med. 2005;352(9):895-904. doi:10.1056/NEJMsa042220PubMedGoogle ScholarCrossref
Roberts  TG  Jr , Goulart  BH , Squitieri  L ,  et al.  Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.   JAMA. 2004;292(17):2130-2140. doi:10.1001/jama.292.17.2130PubMedGoogle ScholarCrossref
Waligora  M , Bala  MM , Koperny  M ,  et al.  Risk and surrogate benefit for pediatric phase I trials in oncology: a systematic review with meta-analysis.   PLoS Med. 2018;15(2):e1002505. doi:10.1371/journal.pmed.1002505PubMedGoogle ScholarCrossref
Adashek  JJ , LoRusso  PM , Hong  DS , Kurzrock  R .  Phase I trials as valid therapeutic options for patients with cancer.   Nat Rev Clin Oncol. 2019;16(12):773-778. doi:10.1038/s41571-019-0262-9PubMedGoogle ScholarCrossref
Schwaederle  M , Zhao  M , Lee  JJ ,  et al.  Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis.   JAMA Oncol. 2016;2(11):1452-1459. doi:10.1001/jamaoncol.2016.2129PubMedGoogle ScholarCrossref
Chakiba  C , Grellety  T , Bellera  C , Italiano  A .  Encouraging trends in modern phase 1 oncology trials.   N Engl J Med. 2018;378(23):2242-2243. doi:10.1056/NEJMc1803837PubMedGoogle ScholarCrossref
Prowell  TM , Theoret  MR , Pazdur  R .  Seamless oncology—drug development.   N Engl J Med. 2016;374(21):2001-2003. doi:10.1056/NEJMp1603747PubMedGoogle ScholarCrossref
Dahlberg  SE , Shapiro  GI , Clark  JW , Johnson  BE .  Evaluation of statistical designs in phase I expansion cohorts: the Dana-Farber/Harvard Cancer Center experience.   J Natl Cancer Inst. 2014;106(7):dju163. doi:10.1093/jnci/dju163PubMedGoogle ScholarCrossref
US Food and Drug Administration. Guidance for industry: expedited programs for serious conditions—drug and biologics. Accessed August 12, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics
Blumenthal  GM , Kluetz  PG , Schneider  J , Goldberg  KB , McKee  AE , Pazdur  R .  Oncology drug approvals: evaluating endpoints and evidence in an era of breakthrough therapies.   Oncologist. 2017;22(7):762-767. doi:10.1634/theoncologist.2017-0152PubMedGoogle ScholarCrossref
US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. Accessed June 1, 2022. https://www.accessdata.fda.gov/scripts/cder/daf/
US Food and Drug Administration. Advanced prostate cancer: developing gonadotropin-releasing hormone analogues. Accessed June 1, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/advanced-prostate-cancer-developing-gonadotropin-releasing-hormone-analogues-guidance-industry
Blumenthal  GM , Pazdur  R .  Response rate as an approval end point in oncology: back to the future.   JAMA Oncol. 2016;2(6):780-781. doi:10.1001/jamaoncol.2015.6352PubMedGoogle ScholarCrossref
Kurzrock  R , Stewart  DJ .  Equipoise abandoned? randomization and clinical trials.   Ann Oncol. 2013;24(10):2471-2474. doi:10.1093/annonc/mdt358PubMedGoogle ScholarCrossref
Simon  R , Blumenthal  GM , Rothenberg  ML ,  et al.  The role of nonrandomized trials in the evaluation of oncology drugs.   Clin Pharmacol Ther. 2015;97(5):502-507. doi:10.1002/cpt.86PubMedGoogle ScholarCrossref
Beaver  JA , Howie  LJ , Pelosof  L ,  et al.  A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review.   JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618PubMedGoogle ScholarCrossref
US Food and Drug Administration. Guidance for industry: postmarketing studies and clinical trials—implementation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. Accessed August 12, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postmarketing-studies-and-clinical-trials-implementation-section-505o3-federal-food-drug-and
Code of Federal Regulations. Applications for FDA Approval to market a new drug. Accessed March 31, 2022. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-H/section-314.510
Fleming  T , Sekeres  M , Lieberman  G ,  et al. Development paths for new drugs with large treatment effects seen early. Accessed June 1, 2022. https://www.focr.org/sites/default/files/Panel4FINAL11411.pdf
US Food and Drug Administration. Xalkori (crizotinib). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202570s016lbl.pdf
US Food and Drug Administration. Erivedge (vismodegib). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203388lbl.pdf. Accessed June 1, 2022.
US Food and Drug Administration. Koselugo (selmetinib). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf
US Food and Drug Administration. Keytruda (pembrolizumab). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf
US Food and Drug Administration. Elzonris (tagraxofusp-erzs). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761116s000lbl.pdf
US Food and Drug Administration. Lumoxiti (moxetumomab). Accessed June 1, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761104s000lbl.pdf
Howlader  N , Forjaz  G , Mooradian  MJ ,  et al.  The effect of advances in lung-cancer treatment on population mortality.   N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa1916623PubMedGoogle ScholarCrossref
Singh  H , Pazdur  R .  Contribution of early clinical benefit end points to decreased lung cancer mortality rates.   JAMA Oncol. 2021;7(6):829-830. doi:10.1001/jamaoncol.2020.8090PubMedGoogle ScholarCrossref
Richardson  NC , Kasamon  Y , Pazdur  R , Gormley  N .  The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.   Lancet Oncol. 2022;23(5):563-566. doi:10.1016/S1470-2045(22)00200-5PubMedGoogle ScholarCrossref
Shah  M , Rahman  A , Theoret  MR , Pazdur  R .  The drug-dosing conundrum in oncology—when less is more.   N Engl J Med. 2021;385(16):1445-1447. doi:10.1056/NEJMp2109826PubMedGoogle ScholarCrossref
Pazdur  R .  Response rates, survival, and chemotherapy trials.   J Natl Cancer Inst. 2000;92(19):1552-1553. doi:10.1093/jnci/92.19.1552PubMedGoogle ScholarCrossref
Beaver  JA , Pazdur  R .  “Dangling” accelerated approvals in oncology.   N Engl J Med. 2021;384(18):e68. doi:10.1056/NEJMp2104846PubMedGoogle ScholarCrossref
US Food and Drug Administration; Oncologic Drugs Advisory Committee. Notice of meeting: establishment of a public docket: request for comments posted. Accessed June 1, 2022. https://www.federalregister.gov/documents/2021/03/12/2021-05202/oncologic-drugs-advisory-committee-notice-of-meeting-establishment-of-a-public-docket-request-for
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