Sample Size Calculations for Population Pharmacodynamic Experiments Involving Repeated Dichotomous Observations

Abstract

Analysis of repeated binary measurements presents a challenge in terms of the correlation between measurements within an individual and a mixed-effects modelling approach has been used for the analysis of such data. Sample size calculation is an important part of clinical trial design and it is often based on the method of analysis. We present a method for calculating the sample size for repeated binary pharmacodynamic measurements based on analysis by mixed-effects modelling and using a logit transformation. Wald test is used for hypothesis testing. The method can be used to calculate the sample size required for detecting parameter differences between subpopulations. Extensions to account for unequal allocation of subjects across groups and unbalanced sampling designs between and within groups were also derived. The proposed method has been assessed via simulation of a linear model and estimation using NONMEM. The results showed good agreement between nominal power and power estimated from the NONMEM simulations. The results also showed that sample size increases with increased variability at a rate that depends on the difference in parameter estimates between groups, and designs that involve sampling based on an optimal design can help to reduce cost.

Key Words:

• Binary observations
• Clinical trials
• Mixed-effects modelling
• Population pharmacodynamics
• Sample size

ACKNOWLEDGMENTS

The research was sponsored by the Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, UK. (CAPKR is supported by the following consortium members; Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and Servier).