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Overview

Now viewed as its own scientific discipline, clinical trial methodology encompasses the methods required for the protection of participants in a clinical trial and the methods necessary to provide a valid inference about the objective of the trial. Drawing from the authors' courses on the subject as well as the first author's more than 30 years working in the pharmaceutical industry, Clinical Trial
Methodology
emphasizes the importance of statistical thinking in clinical research and presents the methodology as a key component of clinical research.

From ethical issues and sample size considerations to adaptive design procedures and statistical analysis, the book first covers the methodology that spans every clinical trial regardless of the area of application. Crucial to the generic drug industry, bioequivalence clinical trials are then discussed. The authors describe a parallel bioequivalence clinical trial of six formulations incorporating group sequential procedures that permit sample size re-estimation. The final chapters incorporate real-world case studies of clinical trials from the authors' own experiences. These examples include a landmark Phase III clinical trial involving the treatment of duodenal ulcers and Phase III clinical trials that contributed to the first drug approved for the treatment of Alzheimer's disease.

Aided by the U.S. FDA, the U.S. National Institutes of Health, the pharmaceutical industry, and academia, the area of clinical trial methodology has evolved over the last six decades into a scientific discipline. This guide explores the processes essential for developing and conducting a quality clinical trial protocol and providing quality data collection, biostatistical analyses, and a clinical study report, all while maintaining the highest standards of ethics and excellence.

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Editorial Reviews

From the Publisher
This comprehensive text introduces the key areas of clinical trial methodology from the perspective of the biostatistician in the pharmaceutical industry. … Throughout, the text benefits from a highly structured and logical flow … the arguments made in the book are grounded in many years of practical experience in drug development and at the very least will act as a prompt for in-depth discussion or critical review of one’s own perceptions. … Clinical Trial Methodology will be of substantial value to early career pharmaceutical industry statisticians.
—Christopher J. Weir, Pharmaceutical Statistics, 2012

… informative discussions of mechanisms such as IND and NDA … are unique strengths of this book, distinguishing it from the many other clinical trial texts available. … Case studies … are presented carefully … The authors’ writing style is disciplined, careful, and informative. … this is a helpful and informative book, a nice reference to have for most biostatisticians working on clinical trials.
—Mithat Gönen, Journal of Biopharmaceutical Statistics, 21, 2011

The book is an excellent overview predicated on the first author’s seasoned experiences in designing, analyzing, and communicating the results of clinical trials across a broad number of medical disciplines. … A nice introductory feature is the history of drug law and regulation, which helps to frame the subsequent statistical discussion nicely. … The real-world examples that dominate the last few chapters are fantastic. … There is nothing like a series of examples from an experienced clinical trialist to whet the appetite of those involved in the noble enterprise of medical (and more specifically pharmaceutical) research with the goal of improving the public’s health. This book does an admirable job in giving the regulatory and statistical foundations for clinical trials, coupled with real-world examples of how statistical methodology has guided the development of important medicines. …
—Gregory Enas

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Product Details

  • ISBN-13: 9781584889175
  • Publisher: Taylor & Francis
  • Publication date: 7/19/2010
  • Series: Chapman & Hall/CRC Biostatistics Series
  • Edition description: New Edition
  • Edition number: 1
  • Pages: 420
  • Product dimensions: 6.30 (w) x 9.40 (h) x 1.10 (d)

Meet the Author

Karl E. Peace is the Georgia Cancer Coalition Distinguished Cancer Scholar, founding director of the Center for Biostatistics, and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.

Din Chen is the Karl E. Peace Endowed Eminent Scholar Chair in Biostatistics and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.

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Table of Contents

Preface

1 Overview of Clinical Trial Methodology 1

1.1 Clinical Trials 1

1.2 Clinical Trial Methodology 1

1.2.1 Randomization and Control 1

1.2.2 Kefauver-Harris Amendment and Its Impact on Clinical Trial Methodology 2

1.2.3 Categorization of Clinical Trial Methodology 3

1.3 Summary of Clinical Trial Methodology 4

References 7

2 Overview of the Drug Development Process and Regulation of Clinical Trials 9

2.1 Introduction 9

2.2 The Drug Development Process 10

2.2.1 Pre-Investigational New Drug Exemption Application 10

2.2.2 Investigational New Drug Exemption Application 10

2.2.3 Phases of Clinical Trials 11

2.2.4 The New Drug Application 13

2.2.5 Post-FDA NDA Review Activities 14

2.3 History of Drug Regulation 15

2.3.1 The Pure Food and Drugs Act---1906 15

2.3.2 The Sherley Amendment---1912 15

2.3.3 The Food and Drug Administration---1930 15

2.3.4 The Food, Drug, and Cosmetic Act---1938 15

2.3.5 The Durham-Humphrey Amendment Act---1951 16

2.3.6 The Kefauver-Harris Drug Amendments---1962 16

2.3.7 The Fair Packaging and Labeling Act---1966 16

2.3.8 The DESI Review---1970 16

2.3.9 The FDA Package Insert Requirement---1970 17

2.3.10 FDA Review of OTC Products---1972 17

2.3.11 The National Research Act---1974 17

2.3.12 The Medical Device Amendments---1976 17

2.3.13 The Good Laboratory Practices---1978 18

2.3.14 Good Clinical Practice Guidelines---1978 18

2.3.15 Protection of Human Subjects and IRB Standards---1981 18

2.3.16 The Federal Anti-Tampering Regulations---1983 19

2.3.17 The Orphan Drug Act---1983 19

2.3.18 The Hatch-Waxman Act---1984 19

2.3.19 The IND/NDA Rewrite---1983-1987 20

2.3.20 Drugs for Life-Threatening Illnesses---1987 20

2.3.21 Inclusion of Older Patients in Clinical Trials---1989 20

2.3.22 Accelerated Approval---1992 21

2.3.23 The Prescription Drug User Fee Act---1992 21

2.3.24 MedWatch---1993 21

2.3.25 The Food and Drug Modernization Act---1997 21

2.3.26 PDUFA Renewed---1997, 2002, and 2007 22

2.3.27 The Gender Guideline---1993 22

2.3.28 The Demographic Rule---1998 22

2.3.29 Best Pharmaceuticals for Children Act---2002 22

2.3.30 Pediatric Research Equity Act---2003 22

2.3.31 Drug Safety Oversight Board---2005 23

2.3.32 Other Regulations and Guidances 23

2.4 Principles of Adequate and Controlled Investigations 23

2.5 Content and Format of the IND 26

2.6 Content and Format of the NDA 28

2.6.1 Overall Summary 29

2.6.2 Technical Sections 29

2.6.3 Integrated Summaries 32

2.6.3.1 Integrated Summary of Efficacy 32

2.6.3.2 Integrated Summary of Safety 33

2.6.3.3 Integrated Summary of Benefit to Risk 34

2.7 Organizational Structure of the FDA 35

2.7.1 Overview of FDA Responsibilities 35

2.7.2 Centers and Offices of the FDA 35

2.7.3 Center for Biologics Evaluation and Research 36

2.7.4 Center for Devices and Radiological Health 37

2.7.5 Center for Drug Evaluation and Research 37

2.8 The FDA Review Process 39

2.9 Labeling and the Package Insert 41

2.10 Pharmaceutical Company Organization and Role of the Biostatistician 43

2.10.1 Pharmaceutical Company Organization Overview 43

2.10.2 Role of the Biostatistician 44

2.11 Concluding Remarks 45

References 49

3 Ethical Considerations in the Design and Conduct of Clinical Trials 55

3.1 Introduction 55

3.2 History and Evolution of Ethical Considerations in Clinical Trials: Key Milestones 56

3.2.1 The Nuremberg Code 56

3.2.2 The Declaration of Helsinki 58

3.2.3 The Belmont Report 59

3.2.4 21 CFR Parts 50 and 56 60

3.2.5 45 CFR Part 46 60

3.2.6 International Conference on Harmonization on Good Clinical Practices 61

3.3 Independent Review Boards 61

3.3.1 Investigational Review Board 61

3.3.2 Data Safety Monitoring Board 62

3.4 Clinical Trial Ethics: Who Should Practice? 62

3.4.1 Protocol Development 62

3.4.1.1 The Physician 63

3.4.1.2 The Biostatistician 63

3.4.1.3 Regulatory Affairs Expert 64

3.4.2 Clinical Trial Operations 64

3.4.2.1 Investigator and Site Personnel 64

3.4.2.2 Field Monitoring 65

3.4.3 Clinical Data Management 65

3.4.4 Biostatistical Analysis 65

3.4.5 Clinical Trial Study Report 66

3.4.6 Dissemination of Results 67

3.5 Informed Consent, Sample Size and Power 67

3.6 Common Ethical Principles of Various Codes and Regulations 69

3.7 Concluding Remarks 70

References 70

4 Sample Size Considerations in Clinical Trials Pre-Market Approval 73

4.1 Introduction 73

4.2 Phases of Clinical Trials and Objectives 73

4.2.1 Phase I Trials 74

4.2.2 Phase II Trials 74

4.2.3 Phase III Trials 75

4.3 The Clinical Development Plan: Pre-Market Approval 75

4.4 Sample Size Requirements 76

4.4.1 Protocol Objectives as Specific Statistical Questions 76

4.4.2 Endpoints 78

4.4.3 Statistical Methods 79

4.4.4 Statistical Design Considerations 80

4.4.5 Numbers in Phase I Program 82

4.4.6 Numbers in Phase II Program 82

4.4.7 Numbers in Phase III Program 83

4.4.8 Other Sample Size Considerations 83

4.4.8.1 Relative Size of Trials and Detectable Differences 83

4.4.8.2 Three-Arm Efficacy Trial: Dose of New Drug, Placebo, and Dose of Marketed Drug 86

4.4.8.3 Interim Analyses 87

4.5 Examples 89

4.5.1 H2-Receptor Antagonist Duodenal Ulcer SNDA Program 89

4.5.2 Two Identical Studies in the Prevention of NSAID-Induced Gastric Ulceration 91

4.6 Philosophical Issues 96

4.6.1 Axioms of Drug Development 96

4.6.2 Sample Size: Efficacy or Ethical Imperative? 97

4.6.3 Larger versus Smaller Trials 98

4.6.4 One-Sided versus Two-Sided Tests 99

4.6.5 Amalgamation of Phase IIB and Phase III Trials 99

4.7 Concluding Remarks 100

References 100

5 Sequential, Group Sequential, Stochastic Curtailment, and Adaptive Design Procedures in Clinical Trials 103

5.1 Introduction 103

5.2 Sequential Procedures 103

5.3 Group Sequential Procedures 104

5.3.1 Definitions 104

5.3.2 Computational Aspects of the Contributions from Each Planned Interim Analysis to Overall P-Value and Power 106

5.3.3 A Three-Stage, Two-Treatment Trial 110

5.3.4 Application 112

5.3.4.1 Conditional Partitioning of α or α Spending Method 112

5.3.4.2 Pocock's Method 113

5.3.4.3 The O'Brien/Fleming Method 113

5.3.4.4 Minimum Detectable Difference 114

5.3.4.5 Power 115

5.3.5 Summary 115

5.4 Stochastic Curtailment 116

5.4.1 Introduction 116

5.4.2 Methods 117

5.4.3 Application 120

5.5 Adaptively Designed Clinical Trials 121

5.5.1 Introduction 121

5.5.2 Group Sequential Design 122

5.5.3 Sample-Size Reestimation Design 122

5.5.4 Drop-Loser Design 123

5.5.5 Adaptive-Randomization Design 124

5.5.6 Biomarker-Adaptive Design 124

5.5.7 Multiple Adaptive Designs 124

5.6 Concluding Remarks 125

References 126

6 Biostatistical Aspects of the Protocol 129

6.1 The Background or Rationale 129

6.2 Objective 129

6.3 Plan of Study 130

6.3.1 Study Population 130

6.3.2 Study Design 131

6.3.2.1 Type of Study 131

6.3.2.2 Treatment Group Specification and Assignment 131

6.3.2.3 Packaging to Achieve Blinding 131

6.3.2.4 Concomitant Medication 132

6.3.2.5 Procedures 132

6.3.3 Problem Management 132

6.4 Statistical Analysis Section 132

6.4.1 Study Objectives as Statistical Hypotheses 133

6.4.1.1 Primary, Secondary, Safety, or Other Objectives 133

6.4.1.2 Translating Protocol Objectives into Statistical Hypotheses 133

6.4.2 Endpoints 134

6.4.3 Statistical Methods 135

6.4.4 Statistical Monitoring Procedures 135

6.4.5 Statistical Design Considerations 136

6.4.6 Subset Analyses 137

6.5 Administration 138

6.5.1 Review and Consent Requirements 138

6.5.2 Record Keeping 139

6.5.3 Monitoring 139

6.6 Protocol References Section 140

6.7 Concluding Remarks 140

References 140

7 The Statistical Analysis Plan 143

7.1 Introduction 143

7.2 Protocol Objective 143

7.3 Efficacy Data Collected and Protocol Schema 143

7.4 Primary and Secondary Efficacy Endpoints 144

7.4.1 Primary Efficacy Endpoint 144

7.4.2 Secondary Efficacy Endpoints 145

7.5 Objectives, Translated as Statistical Hypotheses 145

7.5.1 Primary Efficacy Objective as a Statistical Hypothesis 145

7.5.2 Secondary Efficacy Objectives as Statistical Hypotheses 145

7.5.2.1 Percent of Patients with Acute Kidney Injury by Study Day 56 146

7.5.2.2 Cumulative Percent of Patients Surviving by Study Day 56 146

7.5.2.3 SOFA Score at Study Day 28 146

7.5.2.4 SOFA Score at Study Day 56 147

7.6 Protocol Design Features 147

7.6.1 Experimental Design 147

7.6.2 Treatment or Intervention Groups 147

7.6.3 Randomization 148

7.6.4 Blinding 148

7.6.5 Number of Patients 148

7.6.6 Number of Protocol Centers 148

7.7 Statistical Analyses 148

7.7.1 Trial Populations for Statistical Analyses 149

7.7.2 Demographics, Baseline Characteristics, Eligibility, and Disposition 149

7.7.3 Efficacy Analyses 150

7.7.3.1 Primary Efficacy Analyses 150

7.7.3.2 Secondary Efficacy Analyses 150

7.7.3.3 Analyses of Generalizability across Subpopulations 151

7.7.4 Interim Analyses 151

7.8 Concluding Remarks 151

References 152

8 Pooling of Data from Multicenter Clinical Trials 153

8.1 Introduction 153

8.2 Multicenter Clinical Trial Experimental Setting 154

8.3 Pre-Study Planning 155

8.4 Multicenter Clinical Trial Conduct 155

8.5 Biostatistical Analysis 156

8.5.1 Design-Based Analysis Strategy 156

8.5.1.1 Weighted Means and Variances 156

8.5.1.2 Inference on Treatment Effect 158

8.5.2 Model-Based Analysis Strategies 160

8.5.2.1 Fixed Center and Treatment Effects: No Interaction or No Significant Interaction 160

8.5.2.2 Center and Treatment as Fixed Effects: Significant Interaction 160

8.5.2.3 Random Center and Fixed Treatment Effects 161

8.6 Concluding Remarks 161

8.6.1 Design-Based Inference 162

8.6.2 Model-Based Inference 162

References 163

9 Validity of Statistical Inference 165

9.1 Introduction 165

9.2 Planning the Investigation 166

9.2.1 Research Question and Endpoints 166

9.2.2 Hypothesis Testing Framework 167

9.2.3 The Number of Subjects 167

9.2.4 Procedures for Conducting the Investigation 168

9.2.5 Data Collection, Computerization, and Quality Assurance 168

9.2.6 Statistical Methods 169

9.3 Conducting the Investigation 170

9.4 Statistical Analyses, Interpretation, and Inference 170

9.5 Reporting Results of Investigations 172

9.6 Concluding Remarks 172

References 173

10 Bioequivalence Clinical Trials 175

10.1 Introduction 175

10.2 Absorption, Distribution, Metabolism, and Excretion (ADME) 175

10.3 Bioavailability 176

10.3.1 Basis for Estimating Bioavailability 176

10.3.2 Relative Bioavailability 177

10.3.3 Absolute Bioavailability 177

10.4 Factors that Affect Bioavailability 178

10.4.1 Formulation or Dosage Form 178

10.4.2 Routes of Administration 178

10.4.3 State of the Biological System 178

10.5 Blood Level Clinical Trials 179

10.6 Bioequivalence 179

10.6.1 Bioavailability Parameters or Endpoints Needed for Bioequivalence 180

10.6.2 Decision Criterion for Concluding Bioequivalence 181

10.7 Design of Bioequivalence Trials 182

10.7.1 The Objective of Bioequivalence 182

10.7.2 Experimental Design Considerations 183

10.7.2.1 The Type of Experimental Design 183

10.7.2.2 Drug Elimination Period 184

10.7.2.3 Times of Collection of Blood Samples 184

10.7.2.4 Specific Experimental Designs 184

10.7.3 Endpoints 193

10.7.4 Sample Size Determination 193

10.7.5 Randomization and Blinding 196

10.7.6 The Statistical Analysis Section 197

10.7.6.1 Computation of Endpoints for Each Subject 197

10.7.6.2 Statistical Analysis of Concentrations and Bioavailability Endpoints 198

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