Cancer Drug Approvals Based on Clinical Trials That Do Not Prove Superiority

A study published in JAMA Oncology found that a substantial number of recently approved anticancer drugs are supported by data that do not prove the drug’s superiority over the standard of care.

Researchers analyzed data for 143 anticancer drugs approved by the U.S. Food and Drug Administration between January 1, 2013, and July 31, 2018. Researchers excluded approvals that were based on single-arm studies (n=47). The remaining 98 studies led to 96 drug approvals.

For drugs approved by randomized, controlled trials (RCTs), researchers analyzed design, time of patient accrual, control arm, and primary endpoint. Standard of care was determined by evaluating the literature and published guidelines one year prior to the start of trial enrollment.

Researchers considered the control arm suboptimal if restrictions were placed on the practitioner’s choice of a control drug that excluded a recommended agent; if the control drug was specified but was not the recommended agent; if the approach that was followed was not normally used in clinical practice; or if an earlier RCT showed that the control agent used in the trial was inferior to another alternative.

More than 15% of approvals based on trials with suboptimal controls

Of the 96 anticancer approvals, 16 (17%) were based on RCTs with suboptimal control arms. “When the threshold for determining the standard of care therapy was extended to two years prior to start of accrual of an RCT of interest, 14 of the 16 clinical trials had control arms considered suboptimal,” the researchers noted.

Four trials (25%) omitted active treatment in the control arm by limiting investigator’s choice, 10 trials (63%) 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 two trials (13%) used a previously used treatment in the control arm with a known lack of benefit associated with re-exposure. For the majority (69%) of the trials, progression-free survival was the primary endpoint.

In addition, just one trial was conducted in the United States, as the other 15 were international trials. Fourteen trials led to a regular approval and two led to an accelerated approval.

“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,” the authors concluded.