Strength of Statistical Evidence for the Efficacy of Cancer Drugs: A Bayesian Re-Analysis of Trials Supporting FDA Approval

Abstract

ABSTRACTObjectiveTo quantify the strength of statistical evidence of randomised controlled trials (RCTs) for novel cancer drugs approved by the Food and Drug Administration (FDA) in the last two decades.MethodsWe used data on overall survival (OS), progression-free survival (PFS), and tumour response (TR) for novel cancer drugs approved for the first time by the FDA between January 2000 and December 2020. We assessed strength of statistical evidence by calculating Bayes Factors (BFs) for all available endpoints, and we pooled evidence using Bayesian fixed-effect meta-analysis for indications approved based on two RCTs. Strength of statistical evidence was compared between endpoints, approval pathways, lines of treatment, and types of cancer.ResultsWe analysed the available data from 82 RCTs corresponding to 68 indications supported by a single RCT and seven indications supported by two RCTs. Median strength of statistical evidence was ambiguous for OS (BF= 1.9; IQR 0.5-14.5), and strong for PFS (BF= 24,767.8; IQR 109.0-7.3*106) and TR (BF= 113.9; IQR 3.0-547,100). Overall, 44 indications (58.7%) were approved without clear statistical evidence for OS improvements and seven indications (9.3%) were approved without statistical evidence for improvements on any endpoint. Strength of statistical evidence was lower for accelerated approval compared to non-accelerated approval across all three endpoints. No meaningful differences were observed for line of treatment and cancer type.LimitationsThis analysis is limited to statistical evidence. We did not consider non-statistical factors (e.g., risk of bias, quality of the evidence).DiscussionBFs offer novel insights into the strength of statistical evidence underlying cancer drug approvals. Most novel cancer drugs lack strong statistical evidence that they improve OS, and a few lack statistical evidence for efficacy altogether. These cases require a transparent and clear explanation. When evidence is ambiguous, additional post-marketing trials could eliminate uncertainty.SUMMARY BOXWhat is already known about the topicNovel cancer drugs are approved based on limited evidence.Between 2000 and 2020, novel cancer drugs were typically approved based on a single pivotal trial, with only half of these being randomised controlled trials and many relying on surrogate endpoints to demonstrate efficacy.What this study addsUsing a newly developed Bayesian survival analysis strategy, we provide novel insights into the strength of statistical evidence given the limited data available at approval. Most novel cancer drugs lack strong statistical evidence that they improve overall survival, and a minority lack evidence for efficacy altogether.