Limitations in Clinical Trials Leading to Anticancer Drug Approvals by the US Food and Drug Administration

Importance While there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain. Objective To assess the percentage of clinical trials with limitations in 4 domains-lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms-that led to FDA approvals from June 30, 2014, to July 31, 2019. Design, Setting, and Participants This observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated. Main Outcomes and Measures Estimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA. Results A total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately. Conclusions and Relevance Two-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards. Question How often are anticancer drugs approved by the US Food and Drug Administration (FDA) based on clinical trials with the following limitations: nonrandomized design, lack of demonstrated survival advantage, inappropriate use of crossover, or the use of suboptimal control arms? Findings In this observational study, 187 trials leading to anticancer drug approvals between June 30, 2014, and July 31, 2019, were reviewed. A total of 125 (67%) trials leading to anticancer drug indications had limitations in at least 1 of the 4 domains of interest. Meaning Despite the increase in the number of drug approvals by the FDA, a substantial number of drugs are authorized based on data that do not demonstrate efficacy over established standards of care. This observational study assesses the percentage of clinical trials with limitations in 4 domains that led to US Food and Drug Administration approvals from June 30, 2014, to July 31, 2019.