Efficient and flexible simulation-based sample size determination for clinical trials with multiple design parameters

Abstract: Simulation offers a simple and flexible way to estimate the power of a clinical trial when analytic formulae are not available. The computational burden of using simulation has, however, restricted its application to only the simplest of sample size determination problems, minimising a single parameter (the overall sample size) subject to power being above a target level. We describe a general framework for solving simulation-based sample size determination problems with several design parameters over which to optimise and several conflicting criteria to be minimised. The method is based on an established global optimisation algorithm widely used in the design and analysis of computer experiments, using a non-parametric regression model as an approximation of the true underlying power function. The method is flexible, can be used for almost any problem for which power can be estimated using simulation, and can be implemented using existing statistical software packages. We illustrate its application to three increasingly complicated sample size determination problems involving complex clustering structures, co-primary endpoints, and small sample considerations.