Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016–2021: An observational study.

Background: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. Methods and findings: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. Conclusions: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies. In this observational study, Yichen Zhang and colleagues explore how comparator arms are used in randomized oncology trials registered in China. Author summary: Why was this study done?: ■ Using inappropriate controls in randomized trials of new cancer drugs can expose patients to harm and produce potentially unreliable results of clinical efficacy. ■ In November 2021, China's Center for Drug Evaluation issued the Guidance on Clinical Value-Oriented Oncology Drug Research and Development. It stated that an active control arm should be selected with consideration of whether it reflects the optimal treatment in current clinical practices. ■ Previous descriptive analysis showed that oncology trials are expanding in China; however, no literature evaluated the quality of their control arms. What did the researchers do and find?: ■ This observational study reports the annual trend and proportion of 453 Phase II/III and Phase III randomized oncology trials registered in China between 2016 and 2021 that adopted a suboptimal control arm. We also calculated the cumulative number of trial participants at risk of exposure to suboptimal treatments. ■ We observed a fluctuating yet overall upward trend in the number of trials and participants that used a suboptimal comparator during our observation period. Overall, 60 trials adopted a suboptimal control arm and the cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021. ■ Trials with a suboptimal control reported higher but statistically non-significant proportions of positive results than those using an optimal control. What do these findings mean?: ■ Trial sponsors, ethical review boards, and oncologists should make collaborative efforts to protect patients from unnecessary harm and drugs with uncertain clinical benefits over the existing standard of care. ■ Regulatory agencies should be cautious when reviewing investigational new drug applications whose supporting trial used a suboptimal control and when making subsequent market authorization decisions. ■ A limitation of this study is the reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. Hence, though oncologists and clinical pharmacists were consulted when assessing the sample trials, our results may have inherent subjectivity. [ABSTRACT FROM AUTHOR]