Type I error and power in trials with one interim futility analysis

Futility analysis reduces the opportunity to commit Type I error. For a superiority study testing a two‐sided hypothesis, an interim futility analysis can substantially reduce the overall Type I error while keeping the overall power relatively intact. In this paper, we quantify the extent of the reduction for both one‐sided and two‐sided futility analysis. We argue that, because of the reduction, we should be allowed to set the significance level for the final analysis at a level higher than the allowable Type I error rate for the study. We propose a method to find the significance level for the final analysis. We illustrate the proposed methodology and show that a design employing a futility analysis can reduce the sample size, and therefore reduce the exposure of patients to unnecessary risk and lower the cost of a clinical trial. Copyright © 2004 John Wiley & Sons, Ltd.     

Increasing the sample size at interim for a two‐sample experiment without Type I error inflation

For the case of a one‐sample experiment with known variance σ²=1, it has been shown that at interim analysis the sample size (SS) may be increased by any arbitrary amount provided: (1) The conditional power (CP) at interim is ?50% and (2) there can be no decision to decrease the SS (stop the trial early). In this paper we verify this result for the case of a two‐sample experiment with proportional SS in the treatment groups and an arbitrary common variance. Numerous authors have presented the formula for the CP at interim for a two‐sample test with equal SS in the treatment groups and an arbitrary common variance, for both the one‐ and two‐sided hypothesis tests. In this paper we derive the corresponding formula for the case of unequal, but proportional SS in the treatment groups for both one‐sided superiority and two‐sided hypothesis tests. Finally, we present an SAS macro for doing this calculation and provide a worked out hypothetical example. In discussion we note that this type of trial design trades the ability to stop early (for lack of efficacy) for the elimination of the Type I error penalty. The loss of early stopping requires that such a design employs a data monitoring committee, blinding of the sponsor to the interim calculations, and pre‐planning of how much and under what conditions to increase the SS and that this all be formally written into an interim analysis plan before the start of the study. Copyright © 2009 John Wiley & Sons, Ltd.     

A bayesian group sequential analysis procedure

In this work a method is developed for determining the expected sample size, 2nN, required by a group sequential test using a Bayesian approach. This method is proved to be superior to some recently developed methods. It gives a specific technique to determine the maximum number of groups, N, as well as the group, size, 2n. The proposed method allows a very early termination of the experiment when the alternative hypothesis is true, i.e. when i there is real difference between the treatments under consideration.     

Tests for homogeneity of variance

Six procedures which convert tests of homogeneity of variance into tests for mean equality for independent groups are compared. The tests are the analysis of variance (ANOVA) and Welch F statistics. The Welch statistics are included since it was anticipated that ANOVA would not provide a robust test when samples of unequal sizes are obtained from non-normal populations. However, the Welch tests are not found to be uniformly preferrable. In addition, a prior recommendation for Miller's jackknife procedure is not supported for the unequal sample size case. The data indicates that the current tests for variance heterogeneity are either sensitive to non-normality or, if robust, lacking in power. Therefore, these tests cannot be recommended for the purpose of testing the validity of the ANOVA homogeneity assumption.