This two-day course focuses on a broad class of multiplicity problems arising in clinical trials and provides a comprehensive review of traditional and advanced methods for addressing multiplicity. The course begins a review of key concepts in multiple hypothesis testing, e.g., inferential goals in multiplicity problems, error rate definitions, closure principle and other principles for constructing MTPs (multiple testing procedures). A detailed summary of commonly used MTPs is provided, including nonparametric procedures with a data-driven or fixed testing sequence, semiparametric and parametric procedures. Additional topics of particular interest include simultaneous confidence intervals in multiplicity problems and sample size calculations in clinical trials with multiple objectives.
The second part of the course deals with more advanced multiplicity problems with several sources of multiplicity, e.g., problems arising in trials with multiple endpoints (first source of multiplicity) and multiple dose-control comparisons (second source of multiplicity). Gatekeeping procedures are commonly used in complex multiplicity problems. These procedures protect the overall Type I error rate and efficiently account for the hierarchical structure of individual tests. The following types of gatekeeping procedures will be discussed:
• Gatekeeping procedures with simple logical relationships (serial and parallel gatekeeping procedures), including general multistage parallel gatekeeping procedures.
• Gatekeeping procedures with general logical relationships among families of hypotheses, including chain procedures (graphical methods) and powerful mixture-based procedures.
The short course offers a well-balanced mix of theory and applications with case studies based on real clinical trials and discusses relevant regulatory considerations. Software tools for implementing popular multiple testing procedures will be presented, including custom SAS macros and R functions.
Dmitrienko, A., Tamhane, A.C. (2007). Gatekeeping procedures with clinical trial applications. Pharmaceutical Statistics. 6, 171-180.
Dmitrienko, A., Bretz, F., Westfall, P.H., Troendle, J., Wiens, B.L., Tamhane, A.C., Hsu, J.C. (2009). Multiple testing methodology. Multiple Testing Problems in Pharmaceutical Statistics. Dmitrienko, A., Tamhane, A.C., Bretz, F. (editors). Chapman and Hall/CRC Press, New York.
Dmitrienko, A., Tamhane, A.C. (2009). Gatekeeping procedures in clinical trials. Multiple Testing Problems in Pharmaceutical Statistics. Dmitrienko, A., Tamhane, A.C., Bretz, F. (editors). Chapman and Hall/CRC Press, New York.
Dmitrienko, A., Tamhane, A.C. (2011). Mixtures of multiple testing procedures for gatekeeping applications in clinical trials. Statistics in Medicine. 30, 1473-1488.
Dmitrienko, A., D’Agostino, R.B., Huque, M.F. (2013). Key multiplicity issues in clinical drug development. Statistics in Medicine. 32, 1079–1111.
Alex Dmitrienko, Ph.D., is President and Founder of Mediana Inc. Alex Dmitrienko has over 20 years of clinical trial experience and has been actively involved in biostatistical research with emphasis on multiple testing procedures, subgroup analysis and adaptive designs in clinical trials. He has published over 80 papers and authored/edited two SAS Press books (Analysis of Clinical Trials Using SAS and Pharmaceutical Statistics Using SAS) and a Chapman and Hall/CRC Press book (Multiple Testing Problems in Pharmaceutical Statistics). Dr. Dmitrienko is a Fellow of the American Statistical Association (2009).
Dr. Dmitrienko has taught over 30 short courses on key topics in clinical trial statistics, including multiple comparisons, subgroup analysis and clinical trial optimization. He is a co-author of a full-day course on the analysis of clinical trials offered at the Joint Statistical Meetings (JSM). This course is the longest continuously running full-day course in JSM’s history. He has received an Excellence in Continuing Education Awards from the American Statistical Association for this short course in 2005.