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Clinical Trials

A Methodologic Perspective

Third Edition

Steven Piantadosi

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Preface to the Third Edition

The third edition of this work reflects three trends. The most important trend is the continued evolution of clinical trials as a scientific tool. Changes in therapeutic approaches based on knowledge of gene function, cell pathways, and disease mechanisms, for example, have in recent years fundamentally altered therapeutic questions and the designs that assess them. This is very evident in fields such as cancer, where it is commonplace to talk about precision medicine and targeted therapy as products and goals of increased biological knowledge. Most other medical disciplines are experiencing similar evolution. Detailed biological knowledge yields sharper therapeutic questions, and often requires refined clinical trial designs. This evolution will certainly continue into the future.

The second trend underlying this third edition derives from my uneasiness with the apparent imbalance of theory and empiricism in clinical trials. Too many clinical investigators appear to mis-learn the lessons of clinical trials, and carry inflexible views and voids in place of workable principles. Trials in late development are strongly empirical, but the role of biological theory is dominant in translation and early development. This edition places greater emphasis on the balanced interplay of ideas that is essential to understand the wide application of clinical trials.

A third trend motivating this edition relates to the training of clinical researchers. Since I first began teaching this subject in the 1980's, the structure of medical education has changed very little. Clinical investigator training at many institutions has stalled in a compromise somewhere between therapeutics and public health. Despite the huge body of work on methods for therapeutic research specifically, the training of high quality clinical investigators remains endangered by weak curricula, impossible funding and competition for their time, over-regulation, and skeptical views of their science. The implication of all these trends is that more time, effort, and clarity is needed in teaching the science of clinical trials. It is my hope that this edition will make some progress in each of these areas.

Colleagues have continued to support this work by giving me their valuable time in discussion and manuscript review. I am grateful to many of them for such help. Chris Szekely, Ph.D. at Cedars Sinai Medical Center reviewed many chapters and references in detail. Chengwu Yang, M.D, M.S., Ph.D. at Hershey Medical Center was also kind enough to review chapters and provide advice based on classroom experience. Special thanks to Jim Tonascia, Ph.D. and Shing Lee, Ph.D. for constructive advice.

Students in my class Design and Analysis of Clinical Trials, first at Johns Hopkins, and since 2007 in the Specialty Training and Research (STaR) Program at the University of California Los Angeles from 2007 to 2014 provide the best motivation for writing through their needs and curiosity. My UCLA classes in 2013 and 2014 read and commented on new chapters and late revisions. I would also like to thank the faculty, students, and sponsors from several teaching workshops who provided many practical questions and examples for interesting clinical trial designs over the years. These include the Clinical Trial Methods in Neurology Workshop in Vail, Colorado in 2007–2012, and the AACR Methods in Cancer Biostatistics Workshop held in Sonoma in 2007 and 2009, and Tahoe in 2015, which sharpened my focus on the role and needs of biostatisticians in clinical cancer research. Similarly, our annual Clinical and Translational Research Workshop at Cedars-Sinai Medical Center draws students and faculty together in didactics and mentoring for trial development. Those and similar teaching venues stimulate clarity and flexibility from a clinical trialist.

My current role as Director of a Cancer Institute has not lessened my interest in methodologic topics that also extend outside cancer, or my belief that such diversification improves understanding overall. My local environment teaches the importance of evolving methodology to keep pace with scientific questions, and the high value of clinical and translational research for the improved lives of patients and advancement of science. My hope is that this book contributes to those goals across disciplinary boundaries.

Steven Piantadosi

Los Angeles, California

2017

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About the Companion Website

This book is accompanied by a companion website:

  1. www.wiley.com/go/Piantadosi/ClinicalTrials3e

The website includes: