Abstract
BackgroundIn clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called ‘group sequential designs’ are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics.MethodsIn this work, we propose a general method to construct ‘optimal’ futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations.ResultsBy construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study ‘wrongly’. Our results clearly demonstrate the benefit of using such ‘optimal’ futility boundaries, especially compared to futility boundaries commonly applied in practice.ConclusionsAs the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.
Highlights
In clinical trials, the opportunity for an early stop during an interim analysis may relevantly save time and financial resources
We restrict our considerations to a controlled clinical trial with one interim analysis and one final analysis resulting in a group sequential design with two stages
Clinical trial example and simulation design The RENAAL study was a randomized, double-blind, placebo-controlled trial conducted to investigate the effect of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy [29]
Summary
The opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. Group sequential designs give the opportunity to stop the study early during an interim analysis, thereby saving time and financial resources. The choice of adequate boundaries to stop the study early for futility has been discussed only briefly in these works This is astonishing as unfavorable futility boundaries may have serious consequences with respect to the performance of the study design
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