Controlling Type I Error Rates for Secondary Endpoints through an Alpha Spending Method

Music City Center 

At the interim analysis (IA) of a study, if superiority of the investigational product (IP) over the control on the primary efficacy endpoint is established, superiority of IP over the control on secondary efficacy endpoints will be tested sequentially at the significance level corresponding to the O'Brien-Fleming boundary using the information fraction (IF) of 60%. However, the true IF value for a specific secondary efficacy endpoint depends on the final number of that endpoint event collected at the end of study, which is unknown at the time of IA. We propose to adjust the alpha level at the final analysis to control the overall type I error rate in testing for secondary efficacy endpoints. A simulation study demonstrates that the proposed alpha spending method is expected to effectively control the type I error rates for secondary efficacy endpoints. It also shows that the differences between true IF values and the benchmark value of 60% for secondary efficacy endpoints are limited regardless of treatment effect sizes, which can be attributed to the similarity in risk over time patterns.

Overall Type I Error Control

Alpha Spending Method

Interim Analysis

Information Fraction 

Biopharmaceutical Section