Valen Johnson and I recently posted a working paper on a method for stopping trials of ineffective drugs earlier. For Bayesians, we argue that our method is more consistently Bayesian than other methods in common use. For frequentists, we show that our method has better frequentist operating characteristics than the most commonly used safety monitoring method.
This graph plots the probability of concluding that an experimental treatment is inferior when simulating from true mean survival times ranging from 2 to 12 months. The trial is designed to test a null hypothesis of 6 months mean survival against an alternative hypothesis of 8 months mean survival. When the true mean survival time is less than the alternative hypothesis of 8 months, the Bayes factor design is more likely to stop early. And when the true mean survival time is greater than the alternative hypothesis, the Bayes factor method is less likely to stop early.
The Bayes factor method also outperforms the Thall-Simon method for monitoring single-arm trials with binary outcomes. The Bayes factor method stops more often when it should and less often when it should not. However, the difference in operating characteristics is not as pronounced as in the time-to-event case.
The paper also compares the Bayes factor method to the frequentist mainstay, the Simon two-stage design. Because the Bayes factor method uses continuous monitoring, the method is able to use fewer patients while maintaining the type I and type II error rates of the Simon design as illustrated in the graph below.
The graph above plots the number of patients used in a trial testing a null hypothesis of a 0.2 response rate against an alternative of a 0.4 response rate. Design 8 is the Bayes factor method advocated in the paper. Designs 7a and 7b are variations on the Simon two-stage design. The horizontal axis gives the true probabilities of response. We simulated true probabilities of response varying from 0 to 1 in increments of 0.05. The vertical axis gives the number of patients treated before the trial was stopped. When the true probability of response is less than the alternative hypothesis, the Bayes factor method treats fewer patients. When the true probability of response is better than the alternative hypothesis, the Bayes factor method treats slightly more patients.
Design 7a is the strict interpretation of the Simon method: one interim look at the data and another analysis at the end of the trial. Design 7b is the Simon method as implemented in practice, stopping when the criteria for continuing cannot be met at the next analysis. (For example, if the design says to stop if there are three or fewer responses out of the first 15 patients, then the method would stop after the 12th patient if there have been no responses.) In either case, the Bayes factor method uses fewer patients. The rejection probability curves, not shown here, show that the Bayes factor method matches (actually, slightly improves upon) the type I and type II error rates for the Simon two-stage design.
Related: Adaptive clinical trial design