Multiplicity Adjustments for Clinical Trials with Multiple Doses of an Active Treatment and Multiple Endpoints

• Activity Number: 424
• Type: Contributed
• Date/Time: Wednesday, August 6, 2003 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Hui Quan*+ and Xiaohui Luo and Bruce Binkowitz and Thomas P. Capizzi and Xun Chen and Lynn Xiaoying Wei
• Companies: Merck & Co., Inc. and Merck & Co., Inc. and Merck & Co., Inc. and Merck Research Laboratories and Merck Research Laboratories and Merck & Co., Inc.
• Keywords: closed procedure ; sequential procedure ; strong sense ; weak sense ; error rate ; P value

Abstract

To increase trial efficiency, multiple doses of an active treatment including a placebo control and multiple endpoints are often simultaneously considered in the designs of clinical trials. For these trials, traditional multiplicity adjustment procedures such as Bonferroni, Hochberg, and Hommel procedures can be used to control the family-wise Type I error rate when treating all comparisons, including the comparisons of different doses to control on each endpoint and comparisons of each dose to control on different endpoints at the same level. However, these approaches will not take into account the possible dose-response relationship on each endpoint, are less specific, and may have lower power. To gain power, we may want to consider the problem as a two-dimensional multiplicity problem: one dimension concerns the multiple doses and the other dimension concerns the multiple endpoints. We will discuss procedures which control the entire family-wise error rate in a strong sense for such a two-dimensional problem. Examples and simulations will be provided.