Interim futility analysis with intermediate endpoints

Abstract

Background Interim analysis of Phase III trials typically includes testing for both efficacy and futility. Futility testing is commonly performed on the primary outcome at very low levels (e.g., one-sided α=0.0025) at one or two times before final analysis. When overall survival is the primary outcome and events accrue slowly, and if a suitable intermediate endpoint is available, then using this endpoint for interim futility testing may yield a higher probability of stopping early for futility in the absence of any treatment effect. Purpose The purpose of this study is to explore the possibility of incorporating an intermediate endpoint into interim futility testing of Phase III trials. Methods Using a simple two-stage exponential survival model based on recent Southwest Oncology Group Phase III studies in several disease settings, we perform a series of simulation studies. Survival data are simulated under both the null and alternative hypotheses, and analyzed using overall survival, progression-free survival, and a composite endpoint for futility testing. Results In all disease settings examined here, when survival data were simulated under the null hypothesis, the probability of stopping a trial early for futility was substantially increased by incorporating PFS into interim futility analyses. When testing for futility with the composite endpoint, average patient accrual was reduced by 6—11% in a wide variety of disease settings. In the study scenario with the longest survival, the savings in study duration was more dramatic than in patient resources. When data were simulated under the alternative hypothesis, this procedure resulted in a negligible loss of power. Limitations The properties of this procedure outside of the context of cancer clinical trials and/or using a different intermediate endpoint are not examined. These results also do not address its performance in the context of less conservative stopping rules. Conclusions Interim futility monitoring of Phase III trials using a suitable intermediate endpoint may substantially increase the probability of stopping early for futility when there is no treatment effect. These simulation studies suggest that this would lead to meaningful reductions in study duration and patient resources in many disease settings, with no substantial loss of power for the primary test of efficacy. Future work is needed to explore in detail whether modifications to the stopping rules used in this procedure may yield greater savings without compromising power. Clinical Trials 2008; 5: 14—22. http://ctj.sagepub.com