Modifying the design of ongoing trials without unblinding.

Abstract

Conventional group sequential designs provide an objective basis for reducing the sample size of a trial if the difference between the treatments is much more or much less than anticipated. The flexibility of group sequential designs can be enhanced by allowing the sample size to increase when the variability turns out greater than expected. This can be accomplished by examining the variability before unblinding the data at the first stage of the trial. Depending on the result of this examination, the trial may continue as planned, or the design may change in various ways, for example, by increasing the sample size or by changing the number of stages or the scheduling of the interim analyses. The effect of this adaptive flexibility on the error rates turns out as one would expect from the findings for fixed-sample designs: no material impact on the type I error rate and an effect on the power that depends on the final total sample size.