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

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 Administration. 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) 0.3, 0.5 and 0.70. This approach is applied to an example in a prostate cancer trial.