Journal ArticleDOI
Key multiplicity issues in clinical drug development.
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TLDR
This paper provides a review of concepts that play a central role in defining and solving multiplicity problems (error rate definitions) and introduces main classes of multiple testing procedures widely used in clinical trials (nonparametric, semiparametric, and parametric procedures).Abstract:
Much progress has been made over the past decade with the development of novel methods for addressing increasingly more complex multiplicity problems arising in confirmatory Phase III clinical trials. This includes traditional problems with a single source of multiplicity, for example, analysis of multiple endpoints or dose–placebo contrasts. In addition, more advanced problems with several sources of multiplicity have attracted attention in clinical drug development. These problems include two or more families of objectives such as multiple endpoints evaluated at multiple dose levels or in multiple patient populations. This paper provides a review of concepts that play a central role in defining and solving multiplicity problems (error rate definitions) and introduces main classes of multiple testing procedures widely used in clinical trials (nonparametric, semiparametric, and parametric procedures). The paper also presents recent advances in multiplicity research, including gatekeeping procedures for clinical trials with multiple sets of objectives. The concepts and methods introduced in the paper are illustrated using several case studies on the basis of real clinical trials. Software implementation of commonly used multiple testing and gatekeeping procedures is discussed. Copyright © 2012 John Wiley & Sons, Ltd.read more
Citations
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Journal ArticleDOI
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC
Mark A. Socinski,Robert M. Jotte,Federico Cappuzzo,Francisco Orlandi,Daniil Stroyakovskiy,Naoyuki Nogami,Delvys Rodriguez-Abreu,Denis Moro-Sibilot,Christian A. Thomas,Fabrice Barlesi,Gene Grant Finley,Claudia Kelsch,Anthony Lee,Shelley Coleman,Yu Deng,Yijing Shen,Marcin Kowanetz,Ariel Lopez-Chavez,Alan Sandler,Martin Reck +19 more
TL;DR: The addition of atezolizumab to bevacIZumab plus chemotherapy significantly improved progression‐free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD‐L1 expression and EGFR or ALK genetic alteration status.
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Traditional multiplicity adjustment methods in clinical trials
TL;DR: This tutorial discusses important statistical problems arising in clinical trials with multiple clinical objectives based on different clinical variables, evaluation of several doses or regiments of a new treatment, analysis of multiple patient subgroups, etc.
Journal ArticleDOI
Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.
George R. Saade,Kim A. Boggess,Scott Sullivan,Glenn Markenson,Jay D. Iams,Dean V. Coonrod,Leonardo Pereira,M. Sean Esplin,Larry Cousins,Garrett K. Lam,Matthew K. Hoffman,Robert D. Severinsen,Trina Pugmire,Jeff S. Flick,Angela C. Fox,Amir J. Lueth,Sharon R. Rust,Emanuele Mazzola,ChienTing Hsu,Max T. Dufford,Chad Bradford,Ilia Ichetovkin,Tracey C. Fleischer,Ashoka D. Polpitiya,Gregory C. Critchfield,Paul Kearney,J. Jay Boniface,Durlin E. Hickok +27 more
TL;DR: A serum-based molecular predictor identifies asymptomatic pregnant women atrisk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention.
Journal ArticleDOI
Multiplicity Considerations in Clinical Trials.
TL;DR: Addressing Multiple Comparisons in Clinical Trials Making multiple comparisons increases the likelihood that a chance association could be interpreted as causal and a number of statistical approaches are considered.
Journal ArticleDOI
Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate to Severe Ulcerative Colitis
William J. Sandborn,Marcoli Cyrille,Mark Berner Hansen,Brian G. Feagan,Edward V. Loftus,Gerhard Rogler,Severine Vermeire,Martha L. Cruz,Jun Yang,Michael Boedigheimer,Lubna Abuqayyas,Christine M. Evangelista,Barbara A. Sullivan,Walter Reinisch +13 more
TL;DR: Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe ulcerative colitis in a randomized, phase 2b, placebo-controlled, double-blind study.
References
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Journal ArticleDOI
A Simple Sequentially Rejective Multiple Test Procedure
TL;DR: In this paper, a simple and widely accepted multiple test procedure of the sequentially rejective type is presented, i.e. hypotheses are rejected one at a time until no further rejections can be done.
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A Multiple Comparison Procedure for Comparing Several Treatments with a Control
TL;DR: In this article, a multiple comparison procedure for comparing several treatments with a control is presented, which is based on the Multiple Comparison Procedure for Comparing Several Treatments with a Control (MCPC).
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A sharper Bonferroni procedure for multiple tests of significance
TL;DR: In this article, a simple procedure for multiple tests of significance based on individual p-values is derived, which is sharper than Holm's (1979) sequentially rejective procedure.
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Rectangular Confidence Regions for the Means of Multivariate Normal Distributions
TL;DR: For rectangular confidence regions for the mean values of multivariate normal distributions, this paper proved that a confidence region constructed for independent coordinates is, at the same time, a conservative confidence region for any case of dependent coordinates.
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