Changing standard of care during a randomized trial: examples, considerations and guidelines

Improvements in cancer treatment are guided by randomized clinical trials (RCTs) that reliably assess the therapeutic impact of adding experimental treatments into clinical practice. The fundamental value of RCTs is that the difference in outcomes between the experimental and control arms provides an unbiased estimate of the risk-benefit ratio for the experimental treatment. However, the clinical relevance of trial results depends on the control arm accurately reflecting the appropriate standard of care (SOC) in the intended-use population. Due to the accelerating pace of cancer treatment development, it is becoming more common for the SOC to change during an ongoing randomized trial. This increasingly dynamic SOC landscape may have a nontrivial impact on the conduct and interpretation of future RCTs, and thus it is important to appreciate these issues and, when possible, prospectively address them when designing and conducting clinical trials. We review common scenarios where the SOC changes and provide recommendations on how to design a trial to minimize the impact of such changes when the trial is ongoing.