STOPPING GUIDELINES FOR CLINICAL-TRIALS WITH MULTIPLE TREATMENTS

Stopping guidelines are widely used in long-term clinical trials involving two treatments. These allow planned interim analyses of the accumulating data to be undertaken whilst preserving the type I error rate for the treatment comparison. Their philosophy is extended to the case of trials with multiple treatments so that at any interim analysis, treatments may be considered for dropping from the trial if they are significantly inferior to all treatments that will remain. The proposed guidelines are designed to preserve the error rate in determining that treatment or group of treatments which is, in reality, best. Using simulation studies, stopping guidelines developed for two-arm trials are shown to be directly usable in multiple-arm studies when the treatments studied are all experimental and so in direct competition. When one treatment is the standard of care, a modification gives a better ethical perspective by also permitting treatments to be dropped when they are deemed inferior to the standard. Results are presented for normally distributed responses in trials involving three or four treatments and using stopping boundaries of the form proposed by O'Brien and Fleming. In conclusion, I discuss some of the additional considerations that are important in employing stopping guidelines in trials with multiple treatments.