Development of gatekeeping strategies in confirmatory clinical trials

Abstract

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.

Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults

“…Type I error was controlled using a gatekeeping strategy. 27 A hierarchical structure was identified among the hypotheses of interest (ie, the treatment × time interaction) followed by the main effects, followed by specific within- and between-group comparisons. Comparisons were performed only at α = .05 if significance was obtained at α = .05 at the higher level in the hierarchy.…”

‘Third wave’ cognitive therapy versus mentalization-based therapy for major depressive disorder. A protocol for a randomised clinical trial

“…The outcomes will be divided into two classes comprising the primary outcome and all the secondary ones respectively. Dmitrienko et al’s gatekeeping testing procedure with parallel inferences will be used to control the family-wise error rate [46]. All raw P values of all outcome comparisons between the two groups will be presented.…”

Power Calculations in Clinical Trials With Complex Clinical Objectives

“…These general goals can be accomplished within the Clinical Scenario Evaluation (CSE) framework (Benda et al, 2010;Friede et al, 2010). Conceptually similar approaches to quantitative evaluation of multiple analysis strategies were also proposed in Dmitrienko et al (2011a) and Millen and Dmitrienko (2011).…”

“…Let p i denote the p-value for the hypothesis H i , i = 1, 2, 3, 4. Procedure H is based on the following testing algorithm (Dmitrienko et al, 2011a):…”

“…The trial's sponsor could consider extending the Hochberg-based gatekeeping procedure defined above to implement a re-testing strategy; see, for example, Dmitrienko et al (2011a).…”