We address a multistage clinical trial to assess a sequence of hypotheses in the noninferiority and also rare events setting. Three successive hypotheses are used to evaluate whether the new treatment meets the criteria for new drug approval. Sample sizes for a five stage trial for all hypotheses are calculated using Poisson and Logrank sample size methods. Three strategies and corresponding analysis plans are developed to evaluate the sequential hypotheses. Simulations show the design is satisfactory with respect to controlled Type I error, sufficient power, and early success at interim analyses.
Li, Siying; Koch, Gary G.; and Schwartz, Todd A. DrPH, "A Multistage Non‐inferiority Study Analysis Plan to Evaluate Successively More Stringent Criteria for a Clinical Trial with Rare Events" (June 2012). The University of North Carolina at Chapel Hill Department of Biostatistics Technical Report Series. Working Paper 27.