DESIGN FOR SAMPLE-SIZE REESTIMATION WITH INTERIM DATA FOR DOUBLE-BLIND CLINICAL-TRIALS WITH BINARY OUTCOMES

Estimation of sample size in clinical trials requires knowledge of par ameters that involve the treatment effect and variability, which are u sually uncertain to medical researchers. The recent release within the European Union of a Note for Guidance from the Commission for Proprie tary Medical Products (CPMP) highlights the importance of this issue. Most previous papers considered the case of continuous response variab les that assume a normal distribution; some regarded the portion up to the interim stage as an 'internal pilot study' and required unblindin g. In this paper, our concern is with the case of binary response vari ables, which is more difficult than the normal case since the mean and variance are not distinct parameters. We offer a design with a simple stratification strategy that enables us to verify and update the assu mption of the response rates given initially in the protocol. The desi gn provides a method to re-estimate the sample size based on interim d ata while preserving the trial's blinding. An illustrative numerical e xample and simulation results show slight effect on the type I error r ate and the decision making characteristics on sample size adjustment. (C) 1997 by John Wiley & Sons, Ltd.