New Drug Development J Rick Turner New Drug Development An Introduction to Clinical Trials: Second Edition 123 J Rick Turner Cardiac Safety Services Quintiles 4820 Emperor Boulevard Durham, NC 27703, USA rick.turner@quintiles.com ISBN 978-1-4419-6417-5 e-ISBN 978-1-4419-6418-2 DOI 10.1007/978-1-4419-6418-2 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010930851 © Springer Science+Business Media, LLC 2010 All rights reserved This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Sample of Published Review Comments for the First Edition of New Drug Development The author has the uncanny ability to reveal the essence of a complex topic without bogging down in superficialities (Journal of Clinical Research Best Practices) The book gives a refreshing run through of the drug discovery and development process and it is probably the book you need to have to learn about this fascinating field (Journal of Applied Statistics) This volume would provide an excellent introduction for anyone entering the pharmaceutical industry It would also make superb background reading in medical statistics for MSc students (International Statistical Review) v For Karen, Charlie, Mishadow, Misty, and Mac Foreword While passion in any worthwhile pursuit is to be commended, passion about a process that affects the lives of many millions of people throughout the world is particularly so Pharmaceutical products improve health and quality of life on a scale that is unrivaled by any other medical intervention Before these drugs are prescribed by physicians, they go through an extremely rigorous process that investigates their safety and their efficacy: This is the process of new drug development This investigation is conducted under the governance of regulatory agencies throughout the world In the United States, the Food and Drug Administration (FDA) shoulders this responsibility Nonclinical investigation in animals and clinical investigation in humans must be conducted in a specified manner, and all results must be submitted to the FDA in appropriately formatted documentation to achieve marketing approval Although Dr Turner’s exposition is simple and straightforward, successful new drug development is a complex process that requires the integration of careful study design, careful experimental methodology, diligent execution of all operational aspects of conducting clinical trials, and proper statistical analysis and interpretation That is, a clinical trial requires a design that is capable of answering a carefully constructed research question, collection of optimum quality data, the use of appropriate statistical analysis, and interpretation of the numerical results in the context of the research question and study design Indeed, attempting to conduct a research study without full and prior consideration of study design, experimental methodology, operational execution, and statistical analysis would be much like attempting to pilot an airliner without due consideration of the type of aircraft flown (design), its intended destination and route of flight (methodology), one’s ability to successfully fly the aircraft under existing conditions (execution), and how information gathered in flight will be assessed and incorporated to achieve a safe outcome (analysis) before filling the plane with passengers (study subjects) and departing Such a flight would almost certainly have a highly unfavorable finish, with little likelihood of arriving safely or successfully at its intended destination So too would a research study that was hastily designed and executed without full consideration and implementation of the fundamentals of clinical research so eloquently presented in this book ix x Foreword From the scientific perspective, an inappropriate study design is generally incapable of providing a valid answer to a research question, no matter the proposed methodology or how carefully the study is executed and analyzed Similarly, the perfect design may provide false or misleading information if the research methodology or study execution is flawed or the statistical analysis is improperly conducted or misinterpreted From the ethical perspective, research subjects voluntarily take part in clinical trials with the expectation that their participation will provide information that is useful and generalizable to a much larger group of people This is one of the “benefits” that is weighed against the “risks” of their being exposed to a drug under development If the clinical trial is designed or conducted in such a manner that the data collected not permit the best possible information to be obtained or the study data are improperly analyzed or misinterpreted, the subjects’ expectations have been seriously violated Further, if poorly designed, conducted, or analyzed research leads to a drug failing to be approved for marketing when in reality it is safe and effective, patients who could have benefited from the drug will have been unfairly denied the opportunity to receive it To make the chapters addressing the analysis of data collected during clinical trials suitable for a wide readership, they contain no complicated statistical computation and no complex statistical formulas are presented Rather, the author addresses the issues conceptually, and explains, in an accessible and convincing manner, that study design, conduct, and analysis are of central and paramount importance in the research conducted by the pharmaceutical and biotechnology industries The new drug development process requires the interdisciplinary collaboration of hundreds of clinical research professionals, and successful new drug development requires all of these individuals to conduct their part with full awareness of the personal responsibilities involved The book’s journey from drug discovery to postmarketing surveillance is a fascinating one, and I believe that reading this book will prove informative to everyone involved with or interested in the process of new drug research and will enhance understanding of the importance of this work The first edition of this book received excellent reviews The addition of chapters addressing drug cardiac safety and the operational aspects of running clinical trials makes this edition even more comprehensive I strongly recommend it to all of my colleagues engaged in the wonderful and privileged field of developing new drugs that improve the human condition Students and practitioners of clinical research, pharmacy, medicine, nursing, and allied health professions will also find it an extremely useful guide to the development of the pharmaceutical drugs they encounter in their professional lives The views expressed are those of the writer individually, and not necessarily those of GlaxoSmithKline, his employer London, UK RTP, NC, USA Jack Modell, MD Preface This new edition of New Drug Development has retained the sections that were particularly well received in the first edition, added chapters discussing the latest developments in the realm of drug safety, and expanded its coverage of clinical trials considerably The book still adopts a lifecycle approach to drug development, since an understanding of the research that precedes and follows clinical trials is extremely helpful in placing these trials in the larger framework of integrated pharmaceutical medicine Accordingly, overviews of medicinal chemistry, drug discovery and design, and nonclinical research precede the coverage of clinical trials, and an overview of postmarketing surveillance follows them Drug manufacturing is also considered, since clinical trials require the drug products being tested However, this edition is first and foremost a book about clinical trials that are conducted to bring a new drug to market A different presentation style has been adopted in this edition While still reader-friendly, the first edition was more academic in nature, written as a scholarly textbook and therefore containing several hundred references throughout the text In contrast, this edition presents factual knowledge with a minimum of referencing, thereby improving the flow of ideas and concepts and making it even more reader-friendly The primary target audience is entry-level professionals in the pharmaceutical, biopharmaceutical, and contract research organization (CRO) industries, along with seasoned clinical research professionals who wish to refresh their knowledge in areas outside their immediate area of expertise The book prepares you for discussions with many members of study teams, including statisticians and biomedical data scientists, clinical research associates, clinical monitors, clinical trial investigators, clinical trial administrators, managers, and coordinators, project managers, data managers, clinical scientists, regulatory affairs professionals, clinical operations specialists, medical writers, nurses, pharmacists, and medical safety officers You will benefit considerably from being able to converse with all of these colleagues, and you will therefore become a more valuable employee to your company This edition is also well suited for students of medicine, pharmacy, and nursing, and for physician assistants and allied health professionals Further readings are suggested at the end of chapters for those who wish to pursue individual topics in more detail xi xii Preface Numerical information utilized in the drug development process takes many forms Its collection and analysis vary from context to context, and its interpretation facilitates informed decision-making Study design, experimental methodology, and operational execution are concerned with the collection of optimum quality data Analysis and interpretation are concerned with producing results and interpreting their meaning Since the discipline of Statistics (notated with a capital S) is concerned with both design and analysis, the book provides a conceptual introduction to Statistics and illustrates its important role in the new drug development process For readers who may start to feel a little queasy at the very mention of the word Statistics, please rest assured that this is absolutely not a traditional Statistics book It adopts a conceptual approach, not a computational one, explaining the statistical thinking that goes into the successful planning of clinical trials Of course, once a clinical trial has been planned, it must be executed (run) successfully too The operational complexities of running clinical trials are immense, and the well-coordinated participation of many clinical research professionals is critical The roles and responsibilities of these individuals are introduced in the following chapters Throughout the discussions of the various topics included, I have focused on three key messages First, optimum quality study design is fundamental to good trials If studies are designed well, the data acquired can be analyzed in a straightforward manner Second, optimum quality operational execution is necessary to run good trials and to collect optimum quality data for analysis: poor quality data can still be analyzed, but the answers provided to the research questions asked will also be of poor quality Third, the purpose of new drug development is to produce drugs that can be used safely and effectively to treat patients We are privileged to be engaged in an endeavor that makes a huge difference to the health and well-being of millions of people Thank you for your interest in this edition: I very much hope that you enjoy reading it Chapel Hill, NC J Rick Turner ... and clinical trials points us in the direction of biology and the biological significance of a drug? ??s effects Clinical research and clinical trials investigate topics of clinical relevance, and,.. .New Drug Development J Rick Turner New Drug Development An Introduction to Clinical Trials: Second Edition 123 J Rick Turner Cardiac Safety Services... uniformity meant that nonhuman animal (nonclinical) and human (clinical) studies had to be repeated, resulting in additional and unnecessary use of animal, human, and material resources It also meant