Development of gatekeeping strategies in confirmatory clinical trials

• Published in: Biometrical journal Vol. 53; no. 6; pp. 875 - 893
• Main Authors: Dmitrienko, Alex, Millen, Brian A., Brechenmacher, Thomas, Paux, Gautier
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-11-2011; WILEY‐VCH Verlag; Wiley - VCH Verlag GmbH & Co. KGaA
• Subjects: Biometry; Clinical trials; Clinical Trials as Topic - methods; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Error analysis; Familywise error rate; Goals; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Multiple tests; Power; Structural hierarchy; Testing procedures
• ISSN: 0323-3847; 1521-4036
• DOI: 10.1002/bimj.201100036

This paper discusses multiplicity issues arising in confirmatory clinical trials with hierarchically ordered multiple objectives. In order to protect the overall type I error rate, multiple objectives are analyzed using multiple testing procedures. When the objectives are ordered and grouped in multiple families (e.g. families of primary and secondary endpoints), gatekeeping procedures are employed to account for this hierarchical structure. We discuss considerations arising in the process of building gatekeeping procedures, including proper use of relevant trial‐specific information and criteria for selecting gatekeeping procedures. The methods and principles discussed in this paper are illustrated using a clinical trial in patients with type II diabetes mellitus.