Multiple Testing in Group Sequential Trials Using Graphical Approaches

Maurer, Willi; Bretz, Frank

doi:10.1080/19466315.2013.807748

Cited by 99 publications

(114 citation statements)

References 35 publications

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“…, F i,T (α)} denotes the F i -induced univariate level-α group-sequential critical boundary for testing H i . Further, it can be shown that Maurer and Bretz 2013).…”

Section: Univariate Critical Boundary For Single-hypothesismentioning

confidence: 99%

“…Several specific forms of error spending functions have been proposed, and a few are commonly used in clinical applications. To accommodate the problem of testing multiple hypotheses, Maurer and Bretz (2013) attempted some slight generalizations of spending functions, and they redefined a family of error spending functions F (α, r) as follows: Parameterized by a prespecified Type I error rate α, 0 < α < 1, F (α, r) is a cumulative Type I error spending function of the information fraction r, 0 ≤ r ≤ 1. They further suggested that mild monotonicity conditions should be imposed: (1) for a given α, F (α, r) is nondecreasing in r, with F (α, 0) = 0 and F (α, 1) = α; and (2) for a given r, F (α, r) is nondecreasing in α.…”

Section: Univariate Critical Boundary For Single-hypothesismentioning

confidence: 99%

“…To utilize these betweenendpoint correlations in perhaps the simplest way possible, we construct a group-sequential parametric procedure that has the same feature as the weighted Bonferroni procedures (Maurer and Bretz 2013) in that it is step-down, sequentially rejective at each analysis time point, requiring at most max (m, T ) tests to finish the testing of m hypotheses. In the following, we outline the algorithm for performing the proposed T -stage groupsequential parametric procedure with m endpoints.…”

Section: Group-sequential Parametric Procedures For Multiple Endpointsmentioning

confidence: 99%

“…Recent years have seen the development of a class of group-sequential closed test procedures based on the weighted Bonferroni test (Maurer and Bretz 2013) for testing multiple endpoints (hypotheses) in clinical trials, where the objective is to reject at least one endpoint (hypothesis) while maintaining strong control of the family-wise error rate at a prespecified level α across all analysis time points and endpoints. Such a class of procedures has the following desirable properties: (1) it conveniently uses marginal test statistics, which are the individual test statistics corresponding to the individual endpoints; (2) it is sequentially rejective at each of the analysis time points; and (3) it provides a generalization in that the popular groupsequential fixed sequence procedure (e.g., Strategy 2 in Hung, Wang, and O'Neill 2007; Strategy 1 and Strategy 2 in Tamhane, Mehta, and Liu 2010) and the recently proposed groupsequential Holm procedure (the method GSHv in Ye et al 2013) are special members of the class.…”

Section: Introductionmentioning

confidence: 99%

“…Although a powerful α-propagation (also called "recycling" or "transferring") rule is incorporated, the class of procedures (Maurer and Bretz 2013) does not consider betweenendpoint correlations, which we refer to as correlations of the test statistics associated with the individual clinical endpoints. In a group-sequential trial with correlated multiple endpoints, power improvement can be achieved by suitably using the between-endpoint correlations.…”

Section: Introductionmentioning

confidence: 99%

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Step-Down Parametric Procedures for Testing Correlated Endpoints in a Group-Sequential Trial

Fu¹

2018

Statistics in Biopharmaceutical Research

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Maurer and Bretz developed a class of group-sequential weighted Bonferroni procedures with multiple endpoints. Performed as a step-down consonant shortcut to the group-sequential closed testing procedure, the class of procedures of Maurer and Bretz is simple to use for testing multiple endpoints in classical groupsequential settings. This class uses the correlations of sequential statistics, but does not leverage the correlations between endpoints. Thus, there is room for power improvement by suitably using the betweenendpoint correlations in a group-sequential trial while maintaining strong control of the family-wise error rate. To this end, we propose a Holm-type step-down exact parametric procedure for situations in which between-endpoint correlations are known a priori or estimable. An adaptive strategy is suggested for situations in which such correlations are unknown. In addition, we briefly discuss a natural group-sequential extension of the partially parametric Seneta-Chen procedure.

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“…, F i,T (α)} denotes the F i -induced univariate level-α group-sequential critical boundary for testing H i . Further, it can be shown that Maurer and Bretz 2013).…”

Section: Univariate Critical Boundary For Single-hypothesismentioning

confidence: 99%

Section: Univariate Critical Boundary For Single-hypothesismentioning

confidence: 99%

Section: Group-sequential Parametric Procedures For Multiple Endpointsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Step-Down Parametric Procedures for Testing Correlated Endpoints in a Group-Sequential Trial

Fu¹

2018

Statistics in Biopharmaceutical Research

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Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas

Tap

Wagner

Schöffski

et al. 2020

JAMA

220

169

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IMPORTANCEPatients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.OBJECTIVE To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.DESIGN, SETTING, AND PARTICIPANTS ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.INTERVENTIONS Patients were randomized 1:1 to receive doxorubicin, 75 mg/m 2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/ placebo monotherapy.MAIN OUTCOMES AND MEASURES Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. RESULTS Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). CONCLUSIONS AND RELEVANCEIn this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.

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Allocating recycled significance levels in group sequential procedures for multiple endpoints

Tamhane

2014

Biometrical J

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Graphical approaches have been proposed in the literature for testing hypotheses on multiple endpoints by recycling significance levels from rejected hypotheses to unrejected ones. Recently, they have been extended to group sequential procedures (GSPs). Our focus in this paper is on the allocation of recycled significance levels from rejected hypotheses to the stages of the GSPs for unrejected hypotheses. We propose a delayed recycling method that allocates the recycled significance level from Stage r onward, where r is prespecified. We show that r cannot be chosen adaptively to coincide with the random stage at which the hypothesis from which the significance level is recycled is rejected. Such an adaptive GSP does not always control the FWER. One can choose r to minimize the expected sample size for a given power requirement. We illustrate how a simulation approach can be used for this purpose. Several examples, including a clinical trial example, are given to illustrate the proposed procedure.

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Multiple Testing in Group Sequential Trials Using Graphical Approaches

Cited by 99 publications

References 35 publications

Step-Down Parametric Procedures for Testing Correlated Endpoints in a Group-Sequential Trial

Step-Down Parametric Procedures for Testing Correlated Endpoints in a Group-Sequential Trial

Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas

Allocating recycled significance levels in group sequential procedures for multiple endpoints

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