New Drug Development (eBook)

Dr. Rick Turner is an experimental research scientist, clinical trialist, and author. He was awarded his doctoral degree in the field of Cardiovascular Behavioral Medicine in 1984. His innovative genetic research in that discipline led to 50 peer-reviewed papers, five books, and two international research awards. Fifteen years ago Dr. Turner moved into the pharmaceutical industry, holding positions as a Clinical Submissions Scientist at GlaxoSmithKline and as President and Chief Scientific Officer at Turner Medical Communications LLC. He is now Senior Scientific Director, Cardiac Safety Services, at Quintiles, the world’s largest pharmaceutical contract research organization. His work focuses on assessing the cardiac safety of non-cardiac drugs. He has spoken before two FDA Advisory Committees on cardiovascular safety issues, given numerous presentations at international conferences, and published several recent peer-reviewed papers in this field. He is also the senior author of 'Integrated Cardiac Safety: Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance' (Turner and Durham, 2009).

Sample of Published Review Comments for the First Edition of New Drug Development 5
Foreword 7
Preface 9
Acknowledgments 11
Contents 12
About the Author 22
1 New Drug Development 23
1.1 Introduction 23
1.2 Origin and Goals of the Book 24
1.3 The Discipline of Statistics 24
1.4 A Lifecycle Perspective on Drug Development 25
1.5 Design, Conduct, and Analysis 26
1.5.1 Compelling Evidence 26
1.6 Drug Discovery 26
1.7 Nonclinical Development Programs 27
1.8 Clinical Development Programs 27
1.8.1 Ethical Conduct 28
1.8.2 Different Studies in a Clinical Development Program 29
1.9 Manufacturing 30
1.10 Definitions of Clinical Research and Clinical Trials 31
1.10.1 Clinical Research 31
1.10.2 Clinical Trials 32
1.11 Operational Execution 32
1.12 The Central Importance of Biological Considerations 32
2 The Regulatory Environment 33
2.1 Introduction 33
2.1.1 Goals of the ICH 34
2.2 The Food and Drug Administration 34
2.2.1 The Code of Federal Regulations 35
2.3 cGMP, cGLP, and cGCP 36
2.4 Regulatory Aspects of New Drug Development 36
2.5 Sponsor and Regulatory Agency Responsibilities 37
2.6 The Investigational New Drug Application 37
2.6.1 Review of the Investigational New Drug Application 39
2.6.1.1 The Medical/Clinical Review 39
2.6.1.2 The Chemistry Review 39
2.6.1.3 The Pharmacology/Toxicology Review 39
2.6.1.4 The Statistical Review 40
2.7 The New Drug Application 41
2.7.1 Statistical Review of the New Drug Application 41
Further Readings 42
3 Drug Discovery 43
3.1 Introduction 43
3.1.1 Small Molecule Drug Candidates 43
3.1.2 Biopharmaceutical Drug Candidates 44
3.2 Overview of Pharmaceutics, Pharmacokinetics, and Pharmacodynamics 44
3.2.1 Drug Receptors 45
3.2.2 The Pharmacodynamic Phase 45
3.2.3 The Pharmacokinetic Phase 46
3.2.4 The Pharmaceutical Phase 47
3.3 Medicinal Chemistry 47
3.3.1 Drug Molecules 48
3.3.2 Macromolecules, Receptors, and Drug Targets 48
3.3.3 Structure--Activity Considerations and Drug--Receptor Interactions 49
3.4 Cheminformatics, Bioinformatics, and Computer-Aided Molecular Design 50
3.4.1 Bioinformatics 51
3.5 Biologicals 52
3.5.1 Molecular Genetics and Proteins 52
3.5.2 Protein Structures 53
3.5.3 Recombinant DNA Technology 53
3.5.4 Recombinant Proteins As Drugs 54
3.5.5 Discovery and Development of Biopharmaceuticals 55
3.6 Moving to Nonclinical Research 56
Further Readings 56
4 Nonclinical Research 57
4.1 Introduction 57
4.1.1 Reduction, Refinement, and Replacement of Laboratory Animal Studies 57
4.2 Pharmacokinetics 58
4.2.1 Absorption 58
4.2.2 Distribution 59
4.2.3 Metabolism 59
4.2.4 Elimination 60
4.3 Pharmacology 60
4.3.1 Research Pharmacology Studies 60
4.3.1.1 Primary Research Pharmacology Studies 60
4.3.1.2 Secondary Research Pharmacology Studies 61
4.3.2 Safety Pharmacology Studies 61
4.4 Toxicological Studies 61
4.4.1 Toxicodynamics 62
4.4.2 Exploratory Toxicology Studies 62
4.4.3 Pre-FIH Regulatory Toxicology Studies 63
4.4.4 Post-FIH Regulatory Toxicology Studies 63
4.4.5 Dose Range-Finding Toxicology 63
4.4.6 Genotoxicity 64
4.5 Assessment of QT Interval Prolongation 64
4.5.1 Long QT Syndrome: Underlying Molecular Biology 65
4.5.2 Drug-Induced QT Interval Prolongation 66
4.5.3 Associated Nonclinical Testing 67
4.5.4 Short QT Syndrome 67
Further Readings 68
5 Designing Clinical Trials 69
5.1 Introduction 69
5.2 Classification of Clinical Trials 69
5.3 Human Pharmacology Trials 71
5.4 Clinical Pharmacokinetics and Pharmacodynamics 73
5.4.1 Pharmacokinetic Parameters 74
5.4.2 Fasting and Fed Pharmacokinetics 74
5.4.3 Absorption and Bioavailability 75
5.4.4 Distribution 76
5.4.5 Metabolism 76
5.4.6 Elimination/Clearance 77
5.5 Therapeutic Exploratory Trials 77
5.6 Therapeutic Confirmatory Trials 78
5.7 Therapeutic-Use Trials 78
5.8 Study Design 78
5.9 Ethical Aspects of Design 79
5.10 Study Design in Drug Clinical Trials 79
5.10.1 The Parallel Group Design 80
5.10.2 The Cross-over Design 81
5.10.3 Respective Advantages of the Parallel Group and Cross-over Designs 81
5.10.4 Focus on the Parallel Group Design in This Book 82
5.11 Central Principles of Experimental Design in Clinical Trials 82
5.11.1 Replication 83
5.11.2 Randomization 83
5.11.2.1 Simple Randomization 84
5.11.2.2 Block Randomization 84
5.11.2.3 Stratified Randomization 84
5.11.2.4 Cluster Randomization 85
5.11.2.5 Additional Statistical Steps to Address Randomization Issues 85
5.11.2.6 Ethical Concerns Regarding Randomization 85
5.11.3 Local Control 86
5.11.4 Good Design Simplifies and Validates the Accompanying Analyses 86
5.11.5 Sample Size Estimation 87
5.12 The Clinical Study Protocol 87
5.12.1 Inclusion and Exclusion Criteria 88
5.12.2 The Primary Objective 88
Further Readings 89
6 Conducting Clinical Trials I: Experimental Methodology 90
6.1 Introduction 90
6.2 Blood Pressure Measurement in Clinical Trials 91
6.2.1 Hypertension 91
6.2.2 Surrogate Endpoints in Clinical Trials 92
6.2.3 Arterial Blood Pressure 93
6.2.4 Assessing Blood Pressure Change over Time 94
6.2.5 A Cautionary Tale: Blood Pressure Measurement at Your Doctor's Office 95
6.2.6 A Cautionary Tale for Clinical Trial Blood Pressure Measurements 96
6.3 Central Labs 96
6.3.1 Operational Considerations 97
6.4 Core ECG Labs 98
6.5 The Case Report Form 98
Further Readings 99
7 Conducting Clinical Trials II: Operational Execution 100
7.1 Introduction 100
7.2 The Outsourcing Process 101
7.3 Feasibility Evaluations 101
7.3.1 More Extensive Feasibility Evaluations 102
7.3.2 Feasibility Reporting 103
7.4 Standard Operating Procedures 103
7.4.1 Balancing the Degree of Flexibility Within an SOP 104
7.4.2 The Necessity of Implementing and Maintaining SOPs 104
7.5 Project Management 105
7.6 Site and Investigator Recruitment 106
7.6.1 Principal Investigators 106
7.6.2 Responsibilities of Principal Investigators 107
7.6.3 Potential Principal Investigators in Private Practice Settings 107
7.6.4 Potential Principal Investigators at Larger Medical Institutions 107
7.6.5 Principal Investigator Training 108
7.7 Subject Recruitment and Retention 109
7.7.1 Subject Recruitment 109
7.7.2 Subject Retention 110
7.8 Monitoring Clinical Trials 111
7.9 Data Management 112
7.9.1 Data Management Plans 112
7.9.2 Electronic Data Capture 113
7.9.3 Database Development 113
7.10 A New Paradigm: Allying With Sponsors 114
7.11 Underperforming and Non-performing Clinical Trial Sites 114
7.11.1 Limitations of the Current Model 116
7.12 Another New Paradigm: The Site-Specific CRO 116
7.12.1 Synergies of a Sponsor CRO and a Site-Specific CRO Working Together 117
Further Readings 118
8 Statistical Analysis 119
8.1 Introduction 119
8.2 Types of Clinical Data 120
8.2.1 Numerical Variables 120
8.2.2 Categorical Variables 120
8.2.3 Parametric Tests and Nonparametric Tests 121
8.3 Descriptive Statistics: Summarizing Data 121
8.3.1 Measures of Central Tendency 121
8.3.2 Measures of Dispersion Around a Central Value 122
8.4 Inferential Statistics: Hypothesis Testing 123
8.4.1 The Search for Compelling Evidence 123
8.4.2 Variation and Systematic Variation 123
8.4.3 Between-Groups Variation and Within-Groups Variation 124
8.4.4 Comparing Between-Groups Variance and Within-Groups Variance 124
8.4.5 The Term Error Does Not Imply a Mistake 125
8.5 Probability 125
8.5.1 Likely Events Do Not Always Happen 126
8.5.2 Clinical Decision-Making 126
8.5.3 Sampling Theory 127
8.5.4 The Standard Error of the Mean 127
8.6 The Normal Distribution 128
8.6.1 Area Under the Normal Curve 130
8.6.2 Various Areas Under the Normal Curve 131
8.7 Analysis of Association 131
8.7.1 Direction of an Association 132
8.7.2 Degree of Closeness of an Association 132
8.7.3 Correlation Coefficients 132
8.7.4 Determining the Significance of a Product Moment Coefficient 133
8.7.5 The Coefficient of Determination 133
8.7.6 Association Does Not Necessarily Equate to Causation 134
9 Statistical Significance 135
9.1 Introduction 135
9.2 Creating a Research Question and Associated Hypotheses 135
9.2.1 The Research Hypothesis 135
9.2.2 The Null Hypothesis 136
9.3 Precise Expression of the Research Hypothesis and the Null Hypothesis: The Concept of Statistical Significance 136
9.4 Hypothesis Testing 137
9.5 Conducting a Statistical Test and Obtaining a Test Statistic 138
9.6 The Independent Groups t-Test 138
9.6.1 Degrees of Freedom 139
9.6.2 Format of Results from an Independent Groups t-Test 140
9.6.3 The p-Value: Its Definition and Meaning 141
9.6.4 The p-Value and Hypothesis Testing 142
9.6.5 Two More Examples of Results from an Independent Groups t-Test 142
9.7 The Dependent Measures t-Test 143
9.8 Analysis of Variance 145
9.9 One-Factor Independent Groups ANOVA 145
9.9.1 The Test Statistic in ANOVA 146
9.9.2 Calculation of the F-Test 146
9.9.3 A Further Analytical Step: Multiple Comparisons 148
9.10 General Comments on Multiple-Comparison Testing 150
9.10.1 Type I Errors and Type II Errors 150
9.11 Possible Clinical Interpretations of Statistical Results 152
10 Clinical Significance 154
10.1 Introduction 154
10.2 The Logic of Confidence Intervals 154
10.3 Confidence Intervals for a Sample Mean 155
10.3.1 A More Precise Definition of a Confidence Interval 156
10.4 Confidence Intervals for the Difference Between Treatment Group Means 156
10.5 Relationship of the 95 CI and 99 CI to the 0.05 and 0.01 p-Values 157
10.6 The Additional Benefit of Using Confidence Intervals 158
10.6.1 Clinical Relevance and Clinically Relevant Differences 158
11 Sample Size Estimation 161
11.1 Introduction 161
11.2 Ethical Issues in Sample Size Estimation 162
11.3 Variables Involved in Sample Size Estimation 163
11.4 Type I and Type II Errors 164
11.4.1 The Implications of Type I and Type II Errors 164
11.5 Choosing the Variables Needed for Sample Size Estimation 165
11.5.1 Alpha and Beta 165
11.5.2 The Treatment Effect, Its Variance, and the Standardized Treatment Effect 166
11.6 Using the Appropriate Formula to Yield the Sample Size 166
11.7 Influences on the Sponsors Choice of These Values 167
11.8 Choosing the Objective(s) on Which to Base the Sample Size Estimation 168
11.9 Other Issues to Keep in Mind 168
12 General Safety Assessments 170
12.1 Introduction 170
12.2 Operationalizing the Term Drug Safety 170
12.2.1 Perspectives of Regulators and Prescribing Physicians on Safety Data 171
12.3 General Safety Assessments 172
12.3.1 Extent of Exposure 173
12.3.2 Adverse Events 173
12.3.3 Common Laboratory Tests 174
12.3.4 Vital Signs 176
12.4 Acquisition and Management of Safety Data 176
12.4.1 Adverse Events 176
12.4.2 Serious Adverse Event Data 177
12.5 Analysis Populations 178
12.6 Presentation of Safety Data 178
12.6.1 Descriptive Approaches to Safety Data 179
12.6.2 Time-to-Event Analysis 180
12.6.3 Differences Between Approaches to Safety and Efficacy Data 181
Further Readings 181
13 Efficacy Assessment 182
13.1 Introduction 182
13.1.1 Superiority, Equivalence, and Noninferiority Trials 182
13.1.2 Group Sequential and Adaptive Study Designs 183
13.2 Analysis Populations 183
13.2.1 The Intent-to-Treat Population 184
13.2.2 The Per-protocol Population 184
13.2.3 Using Both Analysis Populations 184
13.2.4 Missing Data 185
13.3 Hypothesis Testing Is Integral to All of the Designs Discussed 185
13.4 Superiority Trials 186
13.4.1 Well-Defined Study Objectives and Endpoints 186
13.4.2 Analysis of Covariance 187
13.4.3 Subgroup Analysis 188
13.5 Equivalence Trials 189
13.5.1 Why the Hypothesis Testing Strategy Is Different Here 190
13.5.2 Establishing the Equivalence Margin 191
13.5.3 Hypothesis Construction and Testing 192
13.5.4 Statistical Analysis and Clinical Judgment Working Together 193
13.6 Noninferiority Trials 193
13.6.1 Establishing the Noninferiority Margin 193
13.6.2 Hypothesis Construction and Testing 193
13.6.3 Statistical Analysis and Clinical Judgment Working Together 194
13.7 Group Sequential Designs 194
13.7.1 Interim Analyses in Group Sequential Trials 195
13.7.2 Data Monitoring Committees 195
13.7.3 Statistical Methodology for Interim Analysis 196
13.7.3.1 The O--Brien--Fleming Approach 198
13.7.3.2 Group Sequential Alpha Spending Functions 198
13.7.4 Ethical Considerations in Early Termination 199
13.8 Adaptive Designs 200
13.8.1 Protocol Amendments 200
13.8.2 Increasing Awareness of Adaptive Designs 201
13.8.3 Regulatory Guidance for Adaptive Designs 202
13.9 Bayesian Approaches to Analyzing Clinical Trials 203
13.10 Meta-analysis 203
13.10.1 Introduction to Meta-analysis 204
13.10.2 The Basic Steps 205
13.10.3 Choice of the Summary Statistic Representing the Treatment Effect of Interest 206
13.10.4 Data Analysis 206
13.10.5 Evaluating Robustness 208
13.10.6 Dissemination of Results and Conclusions of a Meta-analysis 208
13.11 Therapeutic Use Trials 209
13.11.1 Large Simple Therapeutic Trials 209
Further Readings 210
14 Cardiac and Cardiovascular Safety Assessments 211
14.1 Introduction 211
14.2 A Three-Component Risk Exclusion Model 212
14.2.1 Confidence Intervals Facilitate the Determination of Thresholds of Regulatory Concern 213
14.2.1.1 Confidence Intervals in Magnitude-of-Change Assessments 213
14.2.1.2 Employment of Confidence Intervals in Relative Risk Assessments 214
14.3 Cardiac Safety Assessment: A Brief History 214
14.4 Obtaining QTc Data from QT Measurements 215
14.5 The Thorough QT/QTc Study 216
14.5.1 Design of the TQT Study 216
14.5.2 TQT Study Conduct 217
14.5.3 Statistical Analysis 218
14.5.4 Ramifications of Interpretations by Sponsors and Regulatory Agencies 219
14.6 FDA Guidance on Excluding Unacceptable Cardiovascular Risk in the Development of Antidiabetic Drugs for Type 2 Diabetes Mellitus 220
14.6.1 Clinical Trials to Be Conducted 220
14.6.2 Choice of Subject Populations 221
14.6.3 Choice of Cardiovascular Endpoints 221
14.6.4 Endpoint Adjudication 221
14.6.5 The Required Meta-analysis 222
14.6.6 A Dedicated Large (Simple) Cardiovascular Trial 223
14.6.7 An Additional Consideration for Safety Meta-analyses 224
14.7 An Example of a Real Safety Meta-analysis 224
14.8 Potential Regulatory Thresholds of Interest for Other Cardiovascular Parameters 225
Further Readings 226
15 Manufacturing Small Molecule Drugs and Biologicals 227
15.1 Introduction 227
15.2 Nonclinical Development 228
15.3 Drug Products for Clinical Trials 228
15.3.1 Need for the Investigative Drug and the Control Drug 229
15.3.2 Blinding of Drug Products for Clinical Trials 229
15.3.3 Packaging and Distributing Clinical Drug Products 230
15.4 Commercial Manufacturing 231
15.5 Quality Control: Building Quality into the Process 231
15.6 Stability Studies 232
15.7 Immediate Release and Modified Release Tablets and Capsules 232
15.8 Recombinant Protein Biologicals 233
15.8.1 Commercial-Scale Manufacturing 234
Further Readings 235
16 Postmarketing Surveillance 236
16.1 Introduction 236
16.2 Limitations of Preapproval Clinical Trials 237
16.3 Individual Differences in Drug Response 238
16.3.1 Hepatic Impairment 238
16.3.2 Renal Insufficiency 239
16.3.3 The Elderly 239
16.3.4 Pediatric Populations 240
16.4 Postmarketing Surveillance 241
16.5 The 2005 CDER Report to the Nation 242
16.6 The Institute of Medicines 2006 Report on Drug Safety 243
16.7 The Food and Drug Administration Amendments Act of 2007 244
16.8 The FDAs 2008 Sentinel Initiative 245
16.8.1 The Science of Safety 245
16.8.2 Active Surveillance 246
Further Readings 246
17 Main Themes and Concluding Comments 247
17.1 Introduction 247
17.2 Ethical Considerations 248
17.3 Design, Methodology, Operations, and Analysis 249
17.3.1 Reducing Bias and Improving Precision 249
17.3.2 Our Definition of Statistics Revisited 250
17.3.3 Numerical Representations of Biological Information 250
17.3.4 Some Thoughts on the p-Value 251
17.4 Confidence Intervals and Clinical Significance 252
17.5 Pharmacokinetics and Pharmacodynamics 252
17.6 Decision-Making 253
17.6.1 The Subjective Nature of Many Decisions 253
17.6.2 Determining Thresholds of Regulatory Concern 255
17.7 BenefitRisk Considerations 255
17.8 Biological Considerations Pervade Our Discussions 255
17.8.1 Biological Underpinnings of Precision Medicine 256
17.8.2 Pharmacogenetics 256
17.8.3 Pharmacogenomics 257
17.8.4 Pharmacoproteomics 257
17.9 Integrated Pharmaceutical Medicine 258
17.10 Concluding Comments 259
References 260
Index 264