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.

Background

Identifying ineffective practices that have been used in oncology is important in reducing wasted resources and harm. We sought to examine the prevalence of practices that are being used but have been shown in RCTs to be ineffective (medical reversals) in published oncology studies.

Methods

We cross-sectionally analyzed studies published in three high-impact oncology medical journals (2009-2018). We abstracted data relating to the frequency and characterization of medical reversals.

Results

Of the 64 oncology reversals, medications (44%) represented the most common intervention type (39% were targeted). Fourteen (22%) were funded by pharmaceutical/industry only and 56% were funded by an organization other than pharmaceutical/industry. The median number of years that the practice had been in use prior to the reversal study was 9 years (range 1-50 years).

Conclusion

Here we show that oncology reversals most often involve the administration of medications, have been practiced for years, and are often identified through studies funded by non-industry organizations.