Smoothing Corrections for Improving Sample Size Recalculation Rules in Adaptive Group Sequential Study Designs.

Abstract

Background: An adequate sample size calculation is essential for designing a successful clinical trial. One way to tackle planning difficulties regarding parameter assumptions required for sample size calculation is to adapt the sample size during the ongoing trial.This can be attained by adaptive group sequential study designs. At a predefined timepoint, the interim effect is tested for significance. Based on the interim test result, the trial is either stopped or continued with the possibility of a sample size recalculation.

Objectives: Sample size recalculation rules have different limitations in application like a high variability of the recalculated sample size. Hence, the goal is to provide a tool to counteract this performance limitation.

Methods: Sample size recalculation rules can be interpreted as functions of the observed interim effect. Often, a "jump" from the first stage's sample size to the maximal sample size at a rather arbitrarily chosen interim effect size is implemented and the curve decreases monotonically afterwards. This jump is one reason for a high variability of the sample size. In this work, we investigate how the shape of the recalculation function can be improved by implementing a smoother increase of the sample size. The design options are evaluated by means of Monte Carlo simulations. Evaluation criteria are univariate performance measures such as the conditional power and sample size as well as a conditional performance score which combines these components.

Results: We demonstrate that smoothing corrections can reduce variability in conditional power and sample size as well as they increase the performance with respect to a recently published conditional performance score for medium and large standardized effect sizes.

Conclusion: Based on the simulation study, we present a tool that is easily implemented to improve sample size recalculation rules. The approach can be combined with existing sample size recalculation rules described in the literature.