Sample size adjustment based on promising interim results and its application in confirmatory clinical trials

摘要

Background: For a carefully planned and well-designed Phase 3 confirmatory trial, there is still a potential risk of failing to meet the study objective due to possible differences between Phase 2 and Phase 3 studies. As illustrated by the ENGAGE trial, potential sample size increase at an interim analysis can mitigate the risk for an otherwise underpowered study. Many approaches for sample size adjustment (SSA) require certain modifications to the conventional statistical method, such as changing critical values or using a weighted Z-statistic for final hypothesis testing. Without modification, the type I error rate can be inflated, primarily caused by sample size increase for nonpromising interim observation that is close to null or no treatment effect. As illustrated by the TOPICAL trial, increasing sample size for nonpromising interim result could waste limited resource on ineffective treatment. The modifications in these approaches are therefore unnecessary costs of flexibility/interpretability for unnecessary scenarios of sample size increase.