Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon’s design

Abstract Background The non-inferiority (NI) hypothesis is not usually considered in the early phases of clinical development. A proof-of-concept phase II study that allows for the analysis of NI, if superiority criteria cannot be met, may balance between multiple endpoints and additional parameters, which will result in more informed decisions in regard to the therapeutics’ potential value. Methods A total of 12,768 two-stage Simon’s design trials were constructed based on different assumptions of rejection response probability, minimum desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. Agreement between calculated and simulated values was analyzed with Bland-Altman plots. Results The level of agreement was equivalent between calculated and simulated values in two-stage superiority designs and ones in which switching to NI was allowed. Conclusion Switching to NI analysis, when superiority criteria are not achieved, may be useful for weighing additional factors such as clinical benefit duration, safety, cost, or biomarker strategy while assessing activity and early efficacy rate. Implementation of this strategy can be achieved through simple adaptations to existing designs for one-arm phase II clinical trials.