On power and sample size calculation for QT studies with recording replicates at given time point.

The problem of the impact on power and sample size calculation for routine QT studies with ECG recording replicates under a parallel-group design and a crossover design is examined. Replicate ECGs are defined as single ECG recorded within several minutes of a nominal time (PhRMA, 2003). Formulas for sample size calculations with and without adjustment for covariates such as some pharmacokinetic responses (e.g., AUC or C(max)), which are known to be correlated to the QT intervals, were derived under both the parallel-group design and the crossover design. The results indicate that the approach of replicates may require a smaller sample size for achieving the same power when the correlation coefficient between the recording replicates (or repeated measures) is close to 0 (i.e., these replicate ECGs are almost independent). On the other hand, if the correlation coefficient is close to 1, then there is not much gain regardless of whether replicate ECGs are considered. In this paper, an approach to identifying optimal allocation between the number of subjects and the number of replicates per subject is proposed for achieving the maximum power under a fixed budget constraint. The proposed approach can also be applied to minimize the cost for a given power.