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Control Arm Quality in Randomized Oncology Trials Leading to FDA Approval

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Key Points

  • It was judged that 17% of randomized controlled trials resulting in 96 recent drug approval featured a suboptimal control arm.
  • The most common reasons were omission of active treatment by using a control agent known to be inferior to other available agents or not allowing combinations in the control arm.

In a study reported in JAMA Oncology, Hilal et al found that 17% of recent cancer drug approvals based on randomized controlled trials featured a suboptimal control arm.

Study Details

The study involved analysis of a total of 145 studies that led to 143 drug approvals between January 2013 and July 2018. Of these, 47 were single-arm studies and were excluded from analysis. The remaining 98 studies led to 96 drug approvals.

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 randomized controlled trial data had demonstrated that the control agent was inferior to an available alternative.

Suboptimal Control Arms

Of the 96 approvals based on randomized controlled trials, 16 (17%) were based on trials deemed to have suboptimal control arms. Of these, 15 were international trials and 1 was conducted solely in the United States. A total of 14 trials resulted in regular approval and 2 led to accelerated approval.

The reasons for considering the control arm treatment suboptimal consisted of: omission of active treatment by limiting investigator’s choice of treatment in 4 trials (25%); omission of active treatment by using a control agent known to be inferior to other available agents or not allowing combinations in 10 trials (63%); and use of a previously used treatment with a known lack of benefit associated with reexposure in 2 trials (13%).

The investigators concluded, “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.”

Talal Hilal, MD, of the Mayo Clinic, Phoenix, is the corresponding author for the JAMA Oncology article.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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