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Original Investigation
May 2, 2019

Analysis of Control Arm Quality in Randomized Clinical Trials Leading to Anticancer Drug Approval by the US Food and Drug Administration

Author Affiliations
  • 1Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona
  • 2Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland
  • 3Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland
  • 4Senior Scholar in the Center for Health Care Ethics, Oregon Health & Science University, Portland
JAMA Oncol. 2019;5(6):887-892. doi:10.1001/jamaoncol.2019.0167
Key Points

Question  How often are anticancer drugs approved by the US Food and Drug Administration (FDA) based on randomized clinical trials designed with a suboptimal control arm?

Findings  In this quality improvement study, 143 anticancer drug approvals granted by the FDA between January 1, 2013, and July 31, 2018, were reviewed; 16 (17%) of 95 anticancer drugs approved for market were approved based on comparing them with suboptimal control arms.

Meaning  Despite the increase in the number of drug approvals by the FDA, a substantial number of anticancer drugs are receiving market authorizations based on data that does not prove their superiority over standard-of-care therapy, thereby leaving both clinicians and patients unsure of the benefit conveyed by these agents.

Abstract

Importance  To date, an empirical evaluation of the quality of control arms in randomized clinical trials (RCTs) leading to anticancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken.

Objective  We sought to estimate the percentage of RCTs that used a control arm deemed suboptimal and led to FDA approval of anticancer drugs from January 1, 2013, to July 31, 2018.

Design, Setting, and Participants  This quality improvement study included 143 anticancer drug approvals granted by the FDA from January 1, 2013, to July 31, 2018. All approvals based on single-arm studies (48 approvals) were excluded. Approvals based on RCTs were further investigated and each trial was analyzed for design, time of patient accrual, control arm, and primary end point. Standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of trial enrollment. The percentage of approvals based on RCTs that used suboptimal control arms was then calculated. The quality of the control arm was deemed suboptimal if the choice of control agent was restricted to exclude a recommended agent, the control arm was specified but the recommended agent was unspecified, and if prior RCT data had demonstrated that the control agent was inferior to an available alternative.

Main Outcomes and Measures  Estimated percentage of RCTs that used suboptimal control arms that led to FDA approval of anticancer agents between January 1, 2013, to July 31, 2018.

Results  A total of 145 studies that led to 143 drug approvals between January 1, 2013, and July 31, 2018, were included. Of these studies, 48 single-arm studies were excluded. The remaining 97 studies led to 95 drug approvals. Of these 95 approvals, 16 (17%) were based on RCTs with suboptimal control arms; 15 were international trials, and 1 was conducted in the United States. The type of approval was regular in 15 trials and accelerated in 1 trial. When categorized by the nature of suboptimal control, 4 (25%) trials omitted active treatment in control arm by limiting investigator’s choice, 11 (63%) trials omitted active treatment in the control arm by using a control agent known to be inferior to other available agents or not allowing combinations, and 1 (13%) trial used a previously used treatment in the control arm with a known lack of benefit associated with reexposure.

Conclusions and Relevance  Although anticancer drug approvals are increasing, a proportion of these drugs are reaching the market without proven superiority to what is considered the standard of care at the time of patient enrollment in pivotal trials. The choice of control arm should be optimized to ensure that new anticancer agents being marketed are truly superior to what most clinicians would prescribe outside a clinical trial setting.

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