Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials  book cover
1st Edition

Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials

ISBN 9780367330682
Published August 8, 2019 by Chapman and Hall/CRC
320 Pages 30 B/W Illustrations

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Book Description

Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials gives a thorough presentation of state-of-the-art methods for early phase clinical trials. The methodology of clinical trials has advanced greatly over the last 20 years and, arguably, nowhere greater than that of early phase studies. The need to accelerate drug development in a rapidly evolving context of targeted therapies, immunotherapy, combination treatments and complex group structures has provided the stimulus to these advances. Typically, we deal with very small samples, sequential methods that need to be efficient, while, at the same time adhering to ethical principles due to the involvement of human subjects.

Statistical inference is difficult since the standard techniques of maximum likelihood do not usually apply as a result of model misspecification and parameter estimates lying on the boundary of the parameter space. Bayesian methods play an important part in overcoming these difficulties, but nonetheless, require special consideration in this particular context. The purpose of this handbook is to provide an expanded summary of the field as it stands and also, through discussion, provide insights into the thinking of leaders in the field as to the potential developments of the years ahead. With this goal in mind we present:

  • An introduction to the field for graduate students and novices
  • A basis for more established researchers from which to build
  • A collection of material for an advanced course in early phase clinical trials
  • A comprehensive guide to available methodology for practicing statisticians on the design and analysis of dose-finding experiments
  • An extensive guide for the multiple comparison and modeling (MCP-Mod) dose-finding approach, adaptive two-stage designs for dose finding, as well as dose–time–response models and multiple testing in the context of confirmatory dose-finding studies. 

John O’Quigley is a professor of mathematics and research director at the French National Institute for Health and Medical Research based at the Faculty of Mathematics, University Pierre and Marie Curie in Paris, France. He is author of Proportional Hazards Regression and has published extensively in the field of dose finding.

Alexia Iasonos is an associate attending biostatistician at the Memorial Sloan Kettering Cancer Center in New York. She has over one hundred publications in the leading statistical and clinical journals on the methodology and design of early phase clinical trials. Dr. Iasonos has wide experience in the actual implementation of model based early phase trials and has given courses in scientific meetings internationally.

Björn Bornkamp is a statistical methodologist at Novartis in Basel, Switzerland, researching and implementing dose-finding designs in Phase II clinical trials. He is one of the co-developers of the MCP-Mod methodology for dose finding and main author of the DoseFinding R package. He has published numerous papers on dose finding, nonlinear models and Bayesian statistics, and in 2013 won the Royal Statistical Society award for statistical excellence in the pharmaceutical industry.



Table of Contents

Phase I designs

Overview of Phase I designs
Graham Wheeler

Model based designs when safety is the primary aim (graded outcomes)
Emily Van Meter

Dose finding methods for non-binary endpoints (TITE)
Ken Cheung and Shing Lee Pediatrics

More advanced Phase I and Phase I/II methodology

Safety and Efficacy: bivariate endpoints
Alex Sverdlov

Combination studies
Ying Yuan

Studies with multiple schedules 
Nolan Wages

Studies in the presence of patient heterogeneity
Mark Conaway

Optimal designs 
Nolan Wages

Practical implementation: protocol development
Alexia Iasonos and John O’Quigley

Dose-Finding Studies in Phase II

Dose-Finding Studies in Phase II: Introduction and Overview
Bjőrn Bornkamp

The MCP-Mod methodology: Practical Considerations and The DoseFinding R package
Xiaolei Xun and Frank Bretz

Designing Phase II Dose-Finding Studies: Sample Size, Doses and Dose Allocation Weights
José Pinheiro and Bjőrn Bornkamp

Two-stage designs in dose-finding
Tobias Mielke and Vladimir Dragalin

Longitudinal dose-response models
Heinz Schmidli and Markus R. Lange

Multiple Test Strategies for Comparing Several Doses with a Control in Confirmatory Trials
Frank Bretz, Franz Kőnig, and Bjőrn Bornkamp

A Regulatory View on Dose-Finding Studies and on the value of Dose-Exposure-Response analysis
Sofia Friberg Hietala, Efthymios Manolis and Flora Musuamba Tshinanu




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"This book provides different perspectives for revisiting drug development in both therapeutic areas. Statisticians involved in early phase clinical trials, whether in academia or in industry, may get benefit from this book. They will find descriptions of some innovative methods that will be helpful in designing dose-finding trials." ~Xavier Paoletti, Biometric Journal