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Single-arm trials often miss ‘substantial benefit’ mark
Single-arm trials that paved the way for FDA approval of anticancer drugs seldom met validated criteria for a substantial clinical benefit, according to a retrospective study.
“Improved understanding of the molecular basis of cancer has led to rapid development of new drugs,” Ariadna Tibau, MD, PhD, of the department of oncology at Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona in Spain, and colleagues wrote. “In combination with regulatory changes providing rapid review and approval of drugs for diseases with unmet need, this acceleration has led the FDA to use overall response rates assessed in single-arm trials as the basis for approval.”
In a previous study, researchers found that fewer than half of randomized clinical trials supporting FDA approvals met thresholds defined by the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).
In this study, Tibau and colleagues assessed single-arm trials and randomized clinical trials from 2006 to 2016 that have supported FDA approvals using ESMO-MCBS.
Researchers defined substantial clinical benefit as grade A or grade B for trials of curative intent, and grade 5 or grade 4 for those of noncurative intent.
The analysis included 134 studies supporting new anticancer drug approvals and four subgroup analyses that researchers evaluated independently. ESMO-MCBS could not be applied to five studies.
Overall, 33.8% of trials met the criteria for substantial clinical benefit using ESMO-MCBS. However, of the 27 single-arm trials included in the analysis, only two (7.4%) met the substantial benefit threshold, each scoring 4 on the scale.
Those trials included the study of osimertinib (Tagrisso, AstraZeneca) among patients with T790M-mutated non-small cell lung cancer and crizotinib (Xalkori, Pfizer) among patients with ALK-rearranged NSCLC.
“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 post-marketing study,” the researchers wrote. “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.”
Of the remaining single-arm trials:
- 29.6% had a score of 3;
- 29.6% had a score of 2;
- 18.5% had a score of 1; and
- 14.8% had a score of 0.
“Compared with randomized clinical trials, approvals supported by single-arm studies are less likely to show substantial benefit using ESMO-MCBS,” researchers wrote “It is likely that this reflects the high thresholds for substantial benefit used to calibrate the ESMO-MCBS for single-arm trials.” – by Cassie Homer
Disclosures: The authors report no relevant financial disclosures.