New Drug Development: Design, Methodology, and Analysis......Page 3
Contents......Page 9
Foreword......Page 15
Preface......Page 17
PART I INTRODUCTION......Page 25
1.1 Introduction......Page 27
1.3 The Discipline of Statistics......Page 28
1.5 Design, Methodology, and Analysis......Page 30
1.7 Nonclinical Development......Page 31
1.8 Clinical Development......Page 32
1.9 Pharmaceutical Manufacturing......Page 35
1.10 Definitions of Clinical Research and Clinical Trials......Page 36
1.11 The Fourth Central Character in This Book—Biology......Page 37
2. 1 Introduction......Page 41
2.2 The Food and Drug Administration......Page 42
2.4 Regulatory Aspects of New Drug Development......Page 44
2.5 Sponsor and Regulatory Agency Responsibilities......Page 45
2.6 The Investigational New Drug Application......Page 46
2.7 The New Drug Application......Page 49
2.8 The Common Technical Document......Page 51
PART II DRUG DISCOVERY AND NONCLINICAL RESEARCH......Page 53
3.1 Introduction......Page 55
3.2 Overview of Pharmaceutics, Pharmacokinetics, and Pharmacodynamics......Page 56
3.3 Medicinal Chemistry......Page 60
3.4 Cheminformatics, Bioinformatics, and Computer-Aided Molecular Design......Page 63
3.5 Future Trends in Small-Molecule Drug Development......Page 64
3.6 Biopharmaceuticals......Page 65
3.7 Clinical Trials for Small-Molecule and Biopharmaceutical Drug Candidates......Page 69
4.2 Pharmacokinetics......Page 71
4.3 Pharmacology......Page 74
4.4 Toxicological Studies......Page 77
4.5 Design, Methodology, and Analysis Considerations......Page 80
PART III DESIGN, METHODOLOGY, AND ANALYSIS......Page 83
5.3 Methodology......Page 85
5.5 Study Design in Drug Clinical Trials......Page 86
5.6 Central Principles of Experimental Design in Clinical Trials......Page 90
5.7 The Clinical Study Protocol......Page 95
5.8 Collecting Data: The Case Report Form......Page 97
5.9 Clinical Data Management......Page 98
5.10 Monitoring Clinical Trials......Page 100
5.12 Blood Pressure and Blood Pressure Measurement......Page 101
6.1 Introduction......Page 107
6.2 Types of Clinical Data......Page 108
6.3 Descriptive Statistics: Summarizing Data......Page 110
6.4 Inferential Statistics: Hypothesis Testing......Page 111
6.5 Probability......Page 114
6.6 The Normal Distribution......Page 117
6.7 Analysis of Association......Page 120
7.2 Creating a Research Question and Associated Hypotheses......Page 125
7.3 Precise Expression of the Research Hypothesis and the Null Hypothesis: The Concept of Statistical Significance......Page 126
7.4 Hypothesis Testing......Page 127
7.6 The Independent Groups &Test......Page 128
7.7 The Dependent Measures t-Test......Page 134
7.8 Analysis of Variance......Page 135
7.9 One-Factor Independent Groups ANOVA......Page 136
7.10 General Comments on Multiple-Comparison Testing......Page 141
7.11 Possible Clinical Interpretations of Statistical Results......Page 142
8.2 The Logic of Confidence Intervals......Page 145
8.3 Confidence Intervals for a Sample Mean......Page 146
8.4 Confidence Intervals for the Difference Between Treatment Group Means......Page 147
8.6 The Additional Benefit of Using Confidence Intervals......Page 148
9.1 Introduction......Page 151
9.2 Ethical Issues in Sample-Size Estimation......Page 152
9.3 Variables Involved in Sample-Size Estimation......Page 153
9.4 Type I and Type II Errors......Page 154
9.5 Choosing the Variables Needed for Sample-Size Estimation......Page 155
9.7 Influences on the Sponsor’s Choice of These Values......Page 157
9.8 Choosing the Objective(s) on Which to Base the Sample-Size Estimation......Page 158
9.9 Other Issues to Keep in Mind......Page 159
PART IV LIFECYCLE CLINICAL DEVELOPMENT......Page 161
10.2 Classification of Clinical Trials......Page 163
10.3 The Wide Variety of Clinical Assessments Conducted......Page 164
10.4 Human Pharmacology Trials......Page 166
10.5 Therapeutic Exploratory Studies......Page 167
10.8 The Term “Dose”......Page 168
10.9 Clinical Pharmacokinetics and Pharmacodynamics......Page 169
10.10 Pharmacokinetic Parameters......Page 170
10.11 Mechanisms of Genetic Influences on Metabolism......Page 173
10.12 Investigation of Pharmacokinetics in Special Populations......Page 174
10.13 Types of Safety-Related Data......Page 177
10.14 Acquisition of Safety Data......Page 180
10.15 Common Laboratory Tests......Page 182
10.16 Analysis Populations Used for Safety Data......Page 183
10.17 Presentation of Data in Regulatory Clinical Study Reports......Page 184
11.1 Introduction......Page 189
11.2 Analysis Populations for Efficacy Analyses......Page 190
11.3 Hypothesis Testing Is Integral to All of the Designs Discussed Here......Page 192
11.4 Superiority Trials......Page 193
11.5 Equivalence Trials......Page 197
11.6 Noninferiority Trials......Page 201
11.7 Bioequivalence Studies......Page 203
11.8 Group Sequential Designs......Page 204
11.9 Adaptive Designs......Page 210
11.10 Bayesian Approaches to Analyzing Clinical Trials......Page 213
12.1 Introduction......Page 215
12.3 Drug Products for Clinical Trials......Page 216
12.4 Commercial Manufacturing......Page 218
12.5 Quality Control: Building Quality into the Process......Page 219
12.7 Immediate Release and Modified Release Tablets and Capsules......Page 220
12.8 Producing Recombinant Protein Biopharmaceuticals......Page 221
13.1 Introduction......Page 225
13.2 Limitations of Preapproval Clinical Trials......Page 226
13.3 Postmarketing Surveillance......Page 227
13.4 The Institute of Medicine's 2006 Report on Drug Safety......Page 229
13.5 Effectiveness......Page 230
13.6 Publishing Clinical Research in Peer-Reviewed Clinical Journals......Page 231
13.7 Evidence-Based Medicine......Page 236
PART V INTEGRATIVE DISCUSSION......Page 239
14.2 Ethical Considerations......Page 241
14.3 Design, Methodology, and Analysis......Page 242
14.5 Decision Making......Page 246
14.6 Pharmacogenetics......Page 249
14.7 Pharmacogenomics......Page 251
14.8 Pharmacoproteomics: Proteomics and Drug Therapy......Page 252
14.9 The Costs of Pharmaceutical Development......Page 259
14.10 FDA’s Critical Path Report and Critical Path Opportunities List......Page 260
14.11 Coming Full Circle: Revisiting the Book’s “Opening Quotes”......Page 262
14.12 Concluding Comments......Page 263
Appendix. Additional Resources for Training Executives and Professors......Page 265
Main Resources......Page 266
Supplemental Materials......Page 267
Websites......Page 268
References......Page 269
Index......Page 283
About the Author......Page 295