Almost one in five anticancer drugs approved by the FDA from 2013 through 2018 were based on randomized clinical trial data using a control arm that was inferior to the then-current standard of care, a new study found.
As an example, for patients with anaplastic large cell lymphoma, the ALCANZA studycompared the then-investigational agent brentuximab vedotin (Adcetris) with an investigator choice of oral methotrexate or bexarotene (Targretin). However, investigator’s choice did not include use of histone deacetylase (HDAC) inhibitors as a comparator, despite the fact that they had already been approved by the FDA by the time the trial initiated enrollment.
“Future regulatory trials 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 in Phoenix, and colleagues wrote in JAMA Oncology.
The study examined 143 anticancer FDA drug approvals from 2013 to 2018, excluding 47 approvals based on a single-arm study. Randomized clinical trials were considered to have a suboptimal control arm if:
- Restrictions were placed on the choice of control to exclude a recommended agent
- The control arm was specific, but not the recommended agent
- Prior randomized clinical data had demonstrated the control agent was inferior to an available alternative
The 98 studies left ultimately led to 96 drug approvals, 16 approvals — or 17% — of which were based on randomized clinical trials with suboptimal control arms. Fifteen of the trials were international and one was based in the U.S.
Results from two of the trials led to accelerated approvals, but the remaining 14 received regular approval and “thereby do not require additional randomized clinical trials to verify clinical benefit,” the researchers noted.
“This is problematic because when an experimental agent has not been proven to be superior to the established standard of care treatment, clinicians are potentially offering patients an agent that may be the equivalent or even inferior to established standard therapy, usually at a higher cost and alternate toxicity profile,” Hilal and colleagues wrote.
Twenty-five percent of these approvals omitted active treatment in the control arm by limiting the investigator’s choice — as in the ALCANZA trial; 63% of 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.
“Suboptimal control arms may accrue events (e.g., progression of disease or death) faster, leading to successful results sooner, and hastening drugs to market,” they explained.
For example, the control arm in the BFORE trial looking at first-line bosutinib (Bosulif) in chronic-phase chronic myeloid leukemia was imatinib (Gleevec), even though nilotinib (Tasigna) and dasatinib (Sprycel) had already demonstrated better major molecular response compared with imatinib.
Finally, 13% of the approvals with suboptimal control arms used a previously used treatment in the control arm with a known lack of benefit associated with re-exposure. One of these trials was the ALTA trial looking at brigatinib (Alunbrig) in metastatic ALK-positive non-small cell lung cancer after crizotinib. ALTA had high-dose crizotinib as the comparator arm, rather than platinum-based doublet therapy, even though this was an unproven strategy.
Rachel Dear, MBBS, FRACP, PhD, of St. Vincent’s Hospital Sydney in Darlinghurst, Australia, called the findings “concerning.” Dear and colleagues recently conducted a similar studylooking at the use of “standard care” controls in 210 clinical trials of breast cancer from 2004 to 2014, and compared these with recommendations from the National Comprehensive Cancer Network (NCCN).
“In our study, we found 29% of randomized breast cancer trials did not have a control group consistent with the world-renowned NCCN guidelines for breast cancer,” Dear said. “Without careful attention to trial design, including an appropriate control arm comparator, trials may produce misleading results, waste research resources, and potentially negatively impact patient care.”
Hilal’s group acknowledged that some of the consideration that goes into assessing a control arm is subjective in nature. “In many instances, one can construct a justification for the control arm,” they wrote.
When contacted for comment, the FDA responded that it “does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
Hilal reported no conflicts of interest. One co-author reported grants from the Laura and John Arnold Foundation and honoraria for grand rounds/lectures from several universities, medical centers, nonprofit groups, and professional societies.
Primary Source
JAMA Oncology
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