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Tibau A, Molto C, Borrell M, et al. Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration Based on Single-Arm Trials. JAMA Oncol. 2018;4(11):1610–1611. doi:10.1001/jamaoncol.2018.4300
For regulatory approval, the US Food and Drug Administration (FDA) requires evidence of safety and efficacy of new drugs from adequate and well-controlled trials.1 Improved understanding of the molecular basis of cancer, has led to rapid development of new drugs. In combination with regulatory changes providing rapid review and approval of drugs for diseases with unmet need,2 this acceleration has led the FDA to use overall response rates (ORRs) assessed in single-arm trials as the basis for approval.
Fewer than half of randomized clinical trials (RCTs) supporting FDA approval meet substantial clinical benefit thresholds defined using validated scales such as the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).3 In this study, we applied version 1.1 of the ESMO-MCBS4 to single-arm trials that have supported FDA approval.
Data on trials supporting FDA approvals between January 1, 2006, and December 31, 2016, were collected as described previously.3 For single-arm studies, ORR was evaluated using the response evaluation criteria in solid tumors,5 published rules defining when measurable tumors regress, stabilize, or progress in response to treatment. Independent review committee was preferred over investigator assessment. For each trial, ESMO-MCBS grades were applied by 2 of us (C.M. and M.B.). Disagreement was resolved by consensus with a third author (A.T.). Substantial clinical benefit was defined as grade A or B for trials of curative intent and grade 5 or 4 for those of noncurative intent. Data were reported descriptively as proportions, medians, and ranges. Comparisons between groups were assessed using the Mann-Whitney and χ2 tests for continuous and categorical variables, respectively. Data analyses were conducted using SPSS version 21 (IBM Corp). Statistical significance was defined as a 2-sided P < .05. Per the Government of Canada, Panel on Research Ethics, this study was exempt from the requirement for ethical approval in view of its use exclusively of publicly available data.
Of 134 individual studies supporting new anticancer drug approval, 4 reported subgroup analyses and were evaluated independently. Among these 138 data points, ESMO-MCBS could not be applied to 5 studies. Therefore, 133 data points were included in the analysis. The Table shows differences in study characteristics between approvals supported by RCTs and those supported by single-arm studies. Among all data points, 45 (33.8%) met the criteria for substantial clinical benefit using ESMO-MCBS. For single-arm trials, 2 (7.4%) met the threshold for substantial clinical benefit. These included trials evaluating osimertinib for T790M-mutated non–small cell lung cancer and crizotinib for ALK-rearranged non–small cell lung cancer, both scoring 4 on the ESMO-MCBS scale. Of the remaining single-arm trials, 8 (29.6%) scored 3, 8 (29.6%) scored 2, 5 (18.5%) scored 1 and 4 trials (14.8%) scored 0.
The observation of common and durable response to targeted therapy and immunotherapy has raised questions about whether traditional randomized trials are necessary to support drug approval.6 The ability to study a drug’s ORR, especially in clearly defined target populations, makes the single-arm study design appealing as a pathway to approval. The ability to identify target populations has been aided by increasing understanding of the molecular basis of cancer, which has allowed anatomically defined cancers to be subdivided into smaller, molecularly defined subtypes more likely to respond to targeted therapies. Our data confirm that ORR is a common end point in single-arm studies supporting accelerated approval of anticancer therapies. However, a small proportion of single-arm studies met the threshold for substantial clinical benefit defined by ESMO-MCBS, version 1.1. These results are unsurprising because, to meet substantial benefit thresholds using the ESMO-MCBS, a single-arm trial must show substantial efficacy as well as improvement in quality of life or have data from confirmatory postmarketing study. The low proportion of single-arm trials that meet the threshold for substantial benefit may reflect a lack of supporting data or unrealistic thresholds in the ESMO framework.
In conclusion, approximately one-third of trials supporting FDA drug approval meet the threshold for substantial clinical benefit as measured by ESMO-MCBS. Compared with RCTs, approvals supported by single-arm studies are less likely to show substantial benefit using ESMO-MCBS. It is likely that this reflects the high thresholds for substantial benefit used to calibrate the ESMO-MCBS for single-arm trials.
Accepted for Publication: July 13, 2018.
Corresponding Author: Eitan Amir, MD, PhD, Division of Medical Oncology, Princess Margaret Cancer Centre, 700 University Ave, Ste 7-721, Toronto, ON M5G 1Z5, Canada (firstname.lastname@example.org).
Published Online: September 27, 2018. doi:10.1001/jamaoncol.2018.4300
Author Contributions: Drs Tibau and Amir had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Tibau, Molto, Borrell, Del Paggio, Booth, Amir.
Acquisition, analysis, or interpretation of data: Tibau, Molto, Borrell, Barnadas, Amir.
Drafting of the manuscript: Tibau, Molto, Borrell, Del Paggio, Amir.
Critical revision of the manuscript for important intellectual content: Tibau, Molto, Barnadas, Booth, Amir.
Statistical analysis: Molto, Amir.
Administrative, technical, or material support: Tibau, Molto.
Supervision: Tibau, Molto Valiente, Amir.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Alberto Ocana MD, PhD, Translational Research Unit, CIBERONC, Albacete University Hospital, Albacete, Spain; Arnoud Templeton, MD, Department of Medical Oncology, St Claraspital and Faculty of Medicine, University of Basel, Basel, Switzerland; and Luis Del Carpio, MD, Oncology Department, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona, Spain, provided assistance with data interpretation and preparation of the manuscript for this study. None were compensated for their work on this manuscript.