Comparisons of global tests on intersection hypotheses and their application in matched parallel gatekeeping procedures

ABSTRACT A clinical trial often has primary and secondary endpoints and comparisons of high and low doses of a study drug to a control. Multiplicity is not only caused by the multiple comparisons of study drugs versus the control, but also from the hierarchical structure of the hypotheses. Closed test procedures were proposed as general methods to address multiplicity. Two commonly used tests for intersection hypotheses in closed test procedures are the Simes test and the average method. When the treatment effect of a less efficacious dose is not much smaller than the treatment effect of a more efficacious dose for a specific endpoint, the average method has better power than the Simes test for the comparison of two doses versus control. Accordingly, for inferences for primary and secondary endpoints, the matched parallel gatekeeping procedure based on the Simes test for testing intersection hypotheses is extended here to allow the average method for such testing. This procedure is further extended to clinical trials with more than two endpoints as well as to clinical trials with more than two active doses and a control.

[1]  G. Koch,et al.  Statistical planning in confirmatory clinical trials with multiple treatment groups, multiple visits, and multiple endpoints , 2018, Journal of biopharmaceutical statistics.

[2]  Alex Dmitrienko,et al.  An enhanced mixture method for constructing gatekeeping procedures in clinical trials , 2018, Journal of biopharmaceutical statistics.

[3]  G. Koch,et al.  Statistical planning to address strongly correlated endpoints for inferential subgroups: An innovative approach for an illustrative clinical trial with complex multiplicity issues , 2017, Journal of biopharmaceutical statistics.

[4]  G. Koch,et al.  Analyzing multiple endpoints in a confirmatory randomized clinical trial—an approach that addresses stratification, missing values, baseline imbalance and multiplicity for strictly ordinal outcomes , 2017, Pharmaceutical statistics.

[5]  A. Dmitrienko,et al.  Mixture-based gatekeeping procedures for multiplicity problems with multiple sequences of hypotheses , 2016, Journal of biopharmaceutical statistics.

[6]  M. Thase,et al.  Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. , 2015, The Journal of clinical psychiatry.

[7]  G. Koch,et al.  Multivariate Mann–Whitney Estimators for the Comparison of Two Treatments in a Three-Period Crossover Study with Randomly Missing Data , 2010, Journal of biopharmaceutical statistics.

[8]  Xin Wang,et al.  Stepwise Gatekeeping Procedures in Clinical Trial Applications , 2006, Biometrical journal. Biometrische Zeitschrift.

[9]  Xun Chen,et al.  The application of enhanced parallel gatekeeping strategies , 2005, Statistics in medicine.

[10]  P. Westfall,et al.  Optimally weighted, fixed sequence and gatekeeper multiple testing procedures , 2001 .

[11]  R T O'Neill,et al.  Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance. , 1997, Controlled clinical trials.

[12]  G Wassmer,et al.  Procedures for two-sample comparisons with multiple endpoints controlling the experimentwise error rate. , 1991, Biometrics.

[13]  R. Simes,et al.  An improved Bonferroni procedure for multiple tests of significance , 1986 .

[14]  P. O'Brien.  Procedures for comparing samples with multiple endpoints. , 1984, Biometrics.

[15]  K. Gabriel,et al.  On closed testing procedures with special reference to ordered analysis of variance , 1976 .

[16]  Thorsten Dickhaus,et al.  Simultaneous Statistical Inference , 2014, Springer Berlin Heidelberg.

[17]  Huei Wang,et al.  Performance of some multiple testing procedures to compare three doses of a test drug and placebo , 2005 .

[18]  G. Koch,et al.  A linear model method for rank measures of association from longitudinal studies with fixed conditions (visits) for data collection and more than two groups. , 1998, Journal of biopharmaceutical statistics.