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1、NEW DRUG DEVELOPMENT I THE WlLEY BICENTENNIAL-KNOWLEDGE FOR GENERATIONS 1 8 0 7 WLW*2 0 0 7:G a c h generation has its unique needs and aspirations.When Charles Wiley first opened his small printing shop in lower Manhattan in 1807,it was a generation of boundless potential searching for an identity.
2、And we were there,helping to define a new American literary tradition.Over half a century later,in the midst of the Second Industrial Revolution,it was a generation focused on building the future.Once again,we were there,supplying the critical scientific,technical,and engineering knowledge that help
3、ed frame the world.Throughout the 20th Century,and into the new millennium,nations began to reach out beyond their own borders and a new international community was born.Wiley was there,expanding its operations around the world to enable a global exchange of ideas,opinions,and know-how.For 200 years
4、,Wiley has been an integral part of each generations journey,enabling the flow of information and understanding necessary to meet their needs and fulfill their aspirations.Today,bold new technologies are changing the way we live and learn.Wiley will be there,providing you the must-have knowledge you
5、 need to imagine new worlds,new possibilities,and new opportunities.Generations wme and go,but you can always count on Wiley to provide you the knowledge you need,when and where you need it!4 NEW DRUG DEVELOPMENT DESIGN,METHODOLOGY,AND ANALYSIS J.Rick Turner Department of Clinical Research Campbell
6、University School of Pharmacy Morrisville,North Carolina B I C R N T E N N I A L WILEY-INTERSCIENCE A John Wiley&Sons,Inc.,Publication Copyright 0 2007 by John Wiley&Sons,Inc.All rights reserved.Published by John Wiley&Sons,Inc.,Hoboken,New Jeney.Published simultaneously in Canada.No part of this pu
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12、ormation on ow other products and services or for technical support,please contact our Customer Care Depament within the United States at(800)762-2974,outside the United States at(317)572-3993 or fax(317)572-4002.Wiley also publishes its books in a variety of electronic formats.Some content that app
13、ears in print may not be available in electronic format.For information about Wiley products,visit our web site at .Wiley Bicentennial Logo:Richard J.Pacific0 Library of Congress Caraloging-n-Publicatn Data:Turner,J.Rick.p.;cm.New drug development:design,methodology,and analysis/J.Rick Turner.Includ
14、es bibliographical references and index.ISBN 978-0-470-07373-5(cloth:alk.paper)1.Drug development.2.Pharmacy.I.Title.DNLM:1.Clinical Trials.2.Pharmaceutical Preparations-chemical Synthesis.3.Drug Industry-methods.4.Statistics.QV 771 T948n 20071 RS189.T8779 2007 6 15.1 9 4 2 2 2007008032 Printed in t
15、he United States of America.I 0 9 8 7 6 5 4 3 2 1 For Karen,Misty,and Mishadow This Page Intentionally Left BlankCONTENTS FOREWORD PREFACE xi11 xv PART I INTRODUCTION CHAPTER 1.NEW DRUG DEVELOPMENT 1.1 Introduction 1.2 Origin and Goals of the Book 1.3 The Discipline of Statistics 1.4 A Lifecycle Per
16、spective on New Drug Development I.5 Design,Methodology,and Analysis 1.6 Drug Discovery 1.7 Nonclinical Development 1.8 Clinical Development 1.9 Pharmaceutical Manufacturing 1.10 1.1 1 Definitions of Clinical Research and Clinical Trials The Fourth Central Character in This Book-Biology CHAPTER 2.TH
17、E REGULATORY ENVIRONMENT FOR NEW DRUG DEVELOPMENT 2.I Introduction 2.2 2.3 cGMP,cGLP,and cGCP 2.4 2.5 2.6 2.7 The New Drug Application 2.8 The Common Technical Document The Food and Drug Administration Regulatory Aspects of New Drug Development Sponsor and Regulatory Agency Responsibilities The Inve
18、stigational New Drug Application PART I1 DRUG DISCOVERY AND NONCLINICAL RESEARCH CHAPTER 3.DRUG DISCOVERY 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Introduction Overview of Pharmaceutics,Pharmacokinetics,and Pharmacody namics Medicinal Chemistry Cheminformatics,Bioinformatics,and Computer-Aided Molecular Design F
19、uture Trends in Small-Molecule Drug Development B iopharmaceuticals Clinical Trials for Small-Molecule and Biopharmaceutical Drug Candidates 3 4 4 6 6 7 7 8 11 12 13 17 18 20 20 21 22 25 27 31 32 36 39 40 41 45 vii Vlll CONTENTS CHAFTER 4.NONCLINICAL RJZSEARCH 4.1 Introduction 4.2 Pharmacokinetics 4
20、.3 Pharmacology 4.4 Toxicological Studies 4.5 Design,Methodology,and Analysis Considerations PART I11 DESIGN,METHODOLOGY,AND ANALYSIS CHAPTER 5.DESIGN AND METHOLWLWY IN CLINICAL TRIALS 5.1 Introduction 5.2 Design 5.3 Methodology 5.4 5.5 5.6 5.7 The Clinical Study Protocol 5.8 5.9 Clinical Data Manag
21、ement 5.10 Monitoring Clinical Trials 5.1 1 Project Management 5.12 Ethical Aspects of Design and Methodology Study Design in Drug Clinical Trials Central Principles of Experimental Design in Clinical Trials Collecting Data:The Case Report Form Blood Pressure and Blood Pressure Measurement CHAPTER 6
22、.STATISTICAL ANALYSIS 6.1 Introduction 6.2 Types of Clinical Data 6.3 Descriptive Statistics:Summarizing Data 6.4 Inferential Statistics:Hypothesis Testing 6.5 Probability 6.6 The Normal Distribution 6.7 Analysis of Association CHAPTER 7.STATISTICAL SIGNIFICANCE:EMPLOYMENT OF HYPOTHESIS m T I N G 7.
23、1 Introduction 7.2 7.3 7.4 Hypothesis Testing 7.5 7.6 The Independent Groups&Test 7.7 The Dependent Measures t-Test 7.8 Analysis of Variance 7.9 One-Factor Independent Groups ANOVA Creating a Research Question and Associated Hypotheses Precise Expression of the Research Hypothesis and the Null Hypot
24、hesis:The Concept of Statistical Significance Conducting a Statistical Test and Obtaining a Test Statistic 47 47 50 53 56 61 61 61 62 62 66 71 73 74 76 77 77 83 84 86 87 90 93 96 101 101 1 02 103 104 104 110 111 112 CONTENTS I X 7.10 General Comments on Multiple-Comparison Testing 117 7.1 1 Possible
25、 Clinical Interpretations of Statistical Results 118 CHAPTER 8.CLINICAL SIGNIFICANCE:EMPLOYMENT OF CONFIDENCE INTERVALS 8.1 Introduction 121 8.2 The Logic of Confidence Intervals i21 8.3 Confidence Intervals for a Sample Mean 122 8.4 Confidence Intervals for the Difference Between Treatment Group Me
26、ans 123 8.5 Relationship of the 95%CI and 99%CI to the 0.05 and 0.01 p-Values 124 8.6 The Additional Benefit of Using Confidence Intervals 124 CHAPTER 9.SAMPLE-SIZE ESTIMATION 9.1 Introduction 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 Ethical Issues in Sample-Size Estimation Variables Involved in Sample-Size
27、Estimation Type I And Type I1 Errors Choosing the Variables Needed for Sample-Size Estimation Using the Appropriate Formula to Yield the Sample Size Influences on the Sponsors Choice of These Values Choosing the Objective(s)on Which to Base the Sample-Size Estimation Other Issues to Keep in Mind PAR
28、T IV LIFECYCLE CLINICAL DEVELOPMENT CHAPTER 10.SAFETY ASSESSMENT IN CLINICAL TRIALS 10.1 Introduction 10.2 Classification of Clinical Trials 10.3 10.4 Human Pharmacology Trials 10.5 Therapeutic Exploratory Studies 10.6 Therapeutic Confirmatory Clinical Trials 10.7 Therapeutic Use Trials 10.8 The Ter
29、m“Dose”10.9 Clinical Pharmacokinetics and Pharmacodynamics 10.10 Pharmacokinetic Parameters 10.1 1 Mechanisms of Genetic Influences on Metabolism 10.12 Investigation of Pharmacokinetics in Special Populations 10.13 Types of Safety-Related Data 10.14 Acquisition of Safety Data 10.15 Common Laboratory
30、 Tests 10.16 Analysis Populations Used for Safety Data 10.17 Presentation of Data in Regulatory Clinical Study Reports The Wide Variety of Clinical Assessments Conducted 127 128 129 130 131 133 133 134 135 139 139 140 142 143 144 144 144 145 146 149 150 153 156 158 159 160 X CONTENTS C H A P T E R 1
31、 1.EFFICACY ASSFSSMENT IN CLINICAL TRIALS 1 1.1 Introduction 165 11.2 Analysis Populations for Efficacy Analyses 166 1 1.3 Hypothesis Testing Is Integral to All of the Designs Discussed Here 168 1 1.4 Superiority Trials 169 1 1.5 Equivalence Trials 173 1 1.6 Noninferiority Trials 177 1 1.7 Bioequiva
32、lence Studies 179 11.9 Adaptive Designs 186 1 1.10 Bayesian Approaches to Analyzing Clinical Trials 189 11.8 Group Sequential Designs 180 CHAPTER 12.PHARMACEUTICAL AND BIOPHARMACEUTICAL DRUG MANUFACTURING 12.1 Introduction 12.2 Nonclinical Development 12.3 12.4 Commercial Manufacturing 12.5 12.6 Sta
33、bility Studies 12.7 12.8 Producing Recombinant Protein Biopharmaceuticals Drug Products for Clinical Trials Quality Control:Building Quality into the Process Immediate Release and Modified Release Tablets and Capsules CHAPTER 13.POSTMARKWG SURVEILLANCE AND EVIDENCE-BASED MEDICINE 13.1 Introduction 1
34、3.2 13.3 Postmarketing Surveillance 13.4 13.5 Effectiveness 13.6 13.7 Evidence-Based Medicine Limitations of Preapproval Clinical Trials The Institute of Medicines 2006 Report on Drug Safety Publishing Clinical Research in Peer-Reviewed Clinical Journals PART V INTEGRATIVE DISCUSSION CHAPTER 14.UNIF
35、YING THEMES AND CONCLUDING COMMENTS 14.1 Introduction 14.2 Ethical Considerations 14.3 Design,Methodology,and Analysis 14.4 Pharmacokinetics and Pharmacodynamics 14.5 Decision Making 14.6 Pharmacogene tics 14.7 Pharmacogenomics 191 192 192 194 195 196 196 197 20 1 202 203 205 206 207 212 217 217 218
36、 222 222 225 227 CONTENTS XI 14.8 Pharmacoproteomics:Proteomics and Drug Therapy 228 14.9 The Costs of Pharmaceutical Development 235 14.10 FDAs Critical Path Report and Critical Path Opportunities List 236 14.1 1 Coming Full Circle:Revisiting the Books“Opening Quotes”238 14.12 Concluding Comments 2
37、39 APPENDIX.ADDITIONAL RESOURCES FOR TRAINING EXECUTIVES AND PROFESSORS Main Resources 242 Websites 244 Supplemental Materials 243 REFERENCES INDEX ABour THE AUTHOR 245 259 27 1 This Page Intentionally Left BlankFOREWORD While passion in any worthwhile pursuit is to be commended,passion about a proc
38、ess 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 rigorou
39、s 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
40、 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.At the heart of this investigation and documentation is research methodology,addr
41、essed in this volume via discussion of its constituent components of study design,experimental methodology,and statistical analysis.Dr Turners exposition is deceptively simple:Successful new drug development requires the integration of careful study design,careful experimental methodology,and carefu
42、l 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
43、 research question.Who would doubt the veracity of this position?Unfortunately,while researchers in this field are very likely to agree in spirit,research in new drug development too often does not conform to these simple ideals.Yet,attempting to conduct a research study without full and prior consi
44、deration of study design,experimental methodology,and statistical analysis would not be unlike attempting to pilot an airliner without due consideration of the type of aircraft flown(design),its intended destination and route of flight(methodology),and how information gathered in flight will be asse
45、ssed and incorporated to achieve a safe and successful outcome(analysis)before filling the plane with passengers(study subjects)and departing.Such a flight would almost certainly have a highly unfavorable outcome,with little likelihood of successfully arriving at its intended destination.So too woul
46、d 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.From the scientific perspective,an inappropriate study design is generally incapable of answering a research question,
47、no matter how careful the subsequent methodology and analysis.Additionally,the perfect design will not provide optimum information if the research methodology is flawed or an inappropriate statistical analysis is conducted.From the ethical perspective,research subjects voluntarily take part in clini
48、cal trials with the understanding that their participation xiii XIV FOREWORD 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 tri
49、al is conducted in such a manner that the data collected do not permit the best possible information to be obtained,the subjects expectations have been violated.Further,if poor research leads to a drug failing to be approved for marketing when in reality it is safe and efficacious,patients who would
50、 have benefited from the drug will be denied that opportunity.The text of this volume contains 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 design,