Revista de biometría y bioestadística

Adjustment on the Type I Error Rate for a Clinical Trial Monitoring for both Intermediate and Primary Endpoints

Abstract

Susan Halabi

 In many clinical trials, a single endpoint is used to answer the primary question and forms the basis for monitoring the experimental therapy. Many trials are lengthy in duration and investigators are interested in using an intermediate endpoint for an accelerated approval, but will rely on the primary endpoint (such as, overall survival) for the full approval of the drug by the Food and Drug Adminstration. We have designed a clinical trial where both intermediate (progression free survival, (PFS)) and primary endpoints (overall survival, (OS)) are used for monitoring the trial so the overall type I error rate is preserved at the pre-specified alpha level of 0.05. A two-stage procedure is used. In the first stage, the

Bonferroni correction was used where the global type I error rate was allocated to each of the endpoints. In the next stage, the O'Brien-Fleming approach was used to design the boundary for the interim and final analysis for each endpoint. Data were generated assuming several parametric copulas with exponential marginals. Different degrees of dependence, as measured by Kendall's τ , between OS and PFS were assumed: 0 (independence), 0.1, 0.3, 0.5 and 0.7. The results of the simulations were robust regardless of the copula that were assumed. We controlled for the global type I error and marginal type I rates for both of the endpoints under the null hypothesis. In addition, the global power and individual power for each endpoint were attained at the desired level under the alternative hypotheses. This approach is applied to an example in a prostate cancer trial.