Several oncology societies have developed tools to quantify the magnitude of clinical benefit of drugs for the treatment of solid tumors. These include the American Society of Clinical Oncology Value Framework (ASCO-VF), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), the National Comprehensive Cancer Network (NCCN) Evidence Blocks, and the ASCO Cancer Research Committee criteria (ASCO-CRC).

The magnitude of clinical benefit does not influence regulatory approval of cancer drugs. Approval by regulatory agencies such as the US Food and Drug Administration (FDA) requires substantial evidence of safety and efficacy from adequate and well-controlled trials irrespective of the magnitude of such benefit. Advances in the understanding of the molecular basis of cancer have led to rapid development of new drugs and an increasing number of cancer drug approvals based on non-randomized trials. Despite this, randomized controlled trials (RCTs) remain the gold standard to evaluate the benefits and risks of new cancer therapies.

However, RCTs have limitations, including the increasing use of intermediate endpoints which have not been validated as true surrogates for definitive outcomes, and the choice of control group therapy which may not always reflect contemporary standard of care.

While there is extensive literature exploring the associations between the magnitude of clinical benefit and characteristics of new drugs, as well as the clinical trial design supporting their approval, much less is known about the influence of control group therapy on the output of clinical benefit frameworks. Knowledge of the impact of control group therapy could aid in the design of clinical trials (such as expected effect size and influence on quality of life (QoL) assessment), inform drug reimbursement decisions by payers, and provide feedback to the developers of value frameworks. In this article, we quantify the proportion of RCTs meeting thresholds for substantial clinical benefit at the time of FDA marketing approval and assess the association between characteristics of control group therapy and magnitude of clinical benefit. We hypothesized that the magnitude of clinical benefit difference will be greater in trials in which control group therapy has minimal or no overlap with the experimental group.