Turner New Drug Development

An Introduction to Clinical Trials: Second Edition
2. Auflage 2010
ISBN: 978-1-4419-6418-2
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 256 Seiten

New Drug Development: Second Edition provides an overview of the design concepts and statistical practices involved in therapeutic drug development. This wide spectrum of activities begins with identifying a potentially useful drug candidate that can perhaps be used in the treatment or prevention of a condition of clinical concern, and ends with marketing approval being granted by one or more regulatory agencies. In between, it includes drug molecule optimization, nonclinical and clinical evaluations of the drug’s safety and efficacy profiles, and manufacturing considerations. The more inclusive term lifecycle drug development can be used to encompass the postmarketing surveillance that is conducted all the time that a drug is on the market and being prescribed to patients with the relevant clinical condition. Information gathered during this time can be used to modify the drug (for example, dose prescribed, formulation, and mode of administration) in terms of its safety and its effectiveness. The central focus of the first edition of this book is captured by its subtitle, 'Design, Methodology, and Analysis'. Optimum quality study design and experimental research methodology must be employed if the data collected—numerical representations of biological information—are to be of optimum quality. Optimum quality data facilitate optimum quality statistical analysis and interpretation of the results obtained, which in turn permit optimum quality decisions to be made: Rational decision making is predicated on appropriate research questions and optimum quality numerical information. The book took a non-computational approach to statistics, presenting instead a conceptual framework and providing readers with a sound working knowledge of the importance of design, methodology, and analysis. Not everyone needs to be an expert in statistical analysis, but it is very helpful for work (or aspire to work) in the pharmaceutical and biologics industries to be aware of the fundamental importance of a sound scientific and clinical approach to the planning, conduct, and analysis of clinical trials.

Autoren/Hrsg.

Turner, J. Rick

Inhaltsverzeichnis

1;Sample of Published Review Comments for the First Edition of New Drug Development ;5
2;Foreword;7
3;Preface;9
4;Acknowledgments;11
5;Contents;12
6;About the Author;22
7;1 New Drug Development;23
7.1;1.1 Introduction;23
7.2;1.2 Origin and Goals of the Book;24
7.3;1.3 The Discipline of Statistics;24
7.4;1.4 A Lifecycle Perspective on Drug Development;25
7.5;1.5 Design, Conduct, and Analysis;26
7.5.1;1.5.1 Compelling Evidence;26
7.6;1.6 Drug Discovery;26
7.7;1.7 Nonclinical Development Programs;27
7.8;1.8 Clinical Development Programs;27
7.8.1;1.8.1 Ethical Conduct;28
7.8.2;1.8.2 Different Studies in a Clinical Development Program;29
7.9;1.9 Manufacturing;30
7.10;1.10 Definitions of Clinical Research and Clinical Trials;31
7.10.1;1.10.1 Clinical Research;31
7.10.2;1.10.2 Clinical Trials;32
7.11;1.11 Operational Execution;32
7.12;1.12 The Central Importance of Biological Considerations;32
8;2 The Regulatory Environment;33
8.1;2.1 Introduction;33
8.1.1;2.1.1 Goals of the ICH;34
8.2;2.2 The Food and Drug Administration;34
8.2.1;2.2.1 The Code of Federal Regulations;35
8.3;2.3 cGMP, cGLP, and cGCP;36
8.4;2.4 Regulatory Aspects of New Drug Development;36
8.5;2.5 Sponsor and Regulatory Agency Responsibilities;37
8.6;2.6 The Investigational New Drug Application;37
8.6.1;2.6.1 Review of the Investigational New Drug Application;39
8.6.1.1;2.6.1.1 The Medical/Clinical Review;39
8.6.1.2;2.6.1.2 The Chemistry Review;39
8.6.1.3;2.6.1.3 The Pharmacology/Toxicology Review;39
8.6.1.4;2.6.1.4 The Statistical Review;40
8.7;2.7 The New Drug Application;41
8.7.1;2.7.1 Statistical Review of the New Drug Application;41
8.7.2;Further Readings;42
9;3 Drug Discovery;43
9.1;3.1 Introduction;43
9.1.1;3.1.1 Small Molecule Drug Candidates;43
9.1.2;3.1.2 Biopharmaceutical Drug Candidates;44
9.2;3.2 Overview of Pharmaceutics, Pharmacokinetics, and Pharmacodynamics;44
9.2.1;3.2.1 Drug Receptors;45
9.2.2;3.2.2 The Pharmacodynamic Phase;45
9.2.3;3.2.3 The Pharmacokinetic Phase;46
9.2.4;3.2.4 The Pharmaceutical Phase;47
9.3;3.3 Medicinal Chemistry;47
9.3.1;3.3.1 Drug Molecules;48
9.3.2;3.3.2 Macromolecules, Receptors, and Drug Targets;48
9.3.3;3.3.3 Structure--Activity Considerations and Drug--Receptor Interactions;49
9.4;3.4 Cheminformatics, Bioinformatics, and Computer-Aided Molecular Design;50
9.4.1;3.4.1 Bioinformatics;51
9.5;3.5 Biologicals;52
9.5.1;3.5.1 Molecular Genetics and Proteins;52
9.5.2;3.5.2 Protein Structures;53
9.5.3;3.5.3 Recombinant DNA Technology;53
9.5.4;3.5.4 Recombinant Proteins As Drugs;54
9.5.5;3.5.5 Discovery and Development of Biopharmaceuticals;55
9.6;3.6 Moving to Nonclinical Research;56
9.6.1;Further Readings;56
10;4 Nonclinical Research;57
10.1;4.1 Introduction;57
10.1.1;4.1.1 Reduction, Refinement, and Replacement of Laboratory Animal Studies;57
10.2;4.2 Pharmacokinetics;58
10.2.1;4.2.1 Absorption;58
10.2.2;4.2.2 Distribution;59
10.2.3;4.2.3 Metabolism;59
10.2.4;4.2.4 Elimination;60
10.3;4.3 Pharmacology;60
10.3.1;4.3.1 Research Pharmacology Studies;60
10.3.1.1;4.3.1.1 Primary Research Pharmacology Studies;60
10.3.1.2;4.3.1.2 Secondary Research Pharmacology Studies;61
10.3.2;4.3.2 Safety Pharmacology Studies;61
10.4;4.4 Toxicological Studies;61
10.4.1;4.4.1 Toxicodynamics;62
10.4.2;4.4.2 Exploratory Toxicology Studies;62
10.4.3;4.4.3 Pre-FIH Regulatory Toxicology Studies;63
10.4.4;4.4.4 Post-FIH Regulatory Toxicology Studies;63
10.4.5;4.4.5 Dose Range-Finding Toxicology;63
10.4.6;4.4.6 Genotoxicity;64
10.5;4.5 Assessment of QT Interval Prolongation;64
10.5.1;4.5.1 Long QT Syndrome: Underlying Molecular Biology;65
10.5.2;4.5.2 Drug-Induced QT Interval Prolongation;66
10.5.3;4.5.3 Associated Nonclinical Testing;67
10.5.4;4.5.4 Short QT Syndrome;67
10.5.5;Further Readings;68
11;5 Designing Clinical Trials;69
11.1;5.1 Introduction;69
11.2;5.2 Classification of Clinical Trials;69
11.3;5.3 Human Pharmacology Trials;71
11.4;5.4 Clinical Pharmacokinetics and Pharmacodynamics;73
11.4.1;5.4.1 Pharmacokinetic Parameters;74
11.4.2;5.4.2 Fasting and Fed Pharmacokinetics;74
11.4.3;5.4.3 Absorption and Bioavailability;75
11.4.4;5.4.4 Distribution;76
11.4.5;5.4.5 Metabolism;76
11.4.6;5.4.6 Elimination/Clearance;77
11.5;5.5 Therapeutic Exploratory Trials;77
11.6;5.6 Therapeutic Confirmatory Trials;78
11.7;5.7 Therapeutic-Use Trials;78
11.8;5.8 Study Design;78
11.9;5.9 Ethical Aspects of Design;79
11.10;5.10 Study Design in Drug Clinical Trials;79
11.10.1;5.10.1 The Parallel Group Design;80
11.10.2;5.10.2 The Cross-over Design;81
11.10.3;5.10.3 Respective Advantages of the Parallel Group and Cross-over Designs;81
11.10.4;5.10.4 Focus on the Parallel Group Design in This Book;82
11.11;5.11 Central Principles of Experimental Design in Clinical Trials;82
11.11.1;5.11.1 Replication;83
11.11.2;5.11.2 Randomization;83
11.11.2.1;5.11.2.1 Simple Randomization;84
11.11.2.2;5.11.2.2 Block Randomization;84
11.11.2.3;5.11.2.3 Stratified Randomization;84
11.11.2.4;5.11.2.4 Cluster Randomization;85
11.11.2.5;5.11.2.5 Additional Statistical Steps to Address Randomization Issues;85
11.11.2.6;5.11.2.6 Ethical Concerns Regarding Randomization;85
11.11.3;5.11.3 Local Control;86
11.11.4;5.11.4 Good Design Simplifies and Validates the Accompanying Analyses;86
11.11.5;5.11.5 Sample Size Estimation;87
11.12;5.12 The Clinical Study Protocol;87
11.12.1;5.12.1 Inclusion and Exclusion Criteria;88
11.12.2;5.12.2 The Primary Objective;88
11.12.3;Further Readings;89
12;6 Conducting Clinical Trials I: Experimental Methodology;90
12.1;6.1 Introduction;90
12.2;6.2 Blood Pressure Measurement in Clinical Trials;91
12.2.1;6.2.1 Hypertension;91
12.2.2;6.2.2 Surrogate Endpoints in Clinical Trials;92
12.2.3;6.2.3 Arterial Blood Pressure;93
12.2.4;6.2.4 Assessing Blood Pressure Change over Time;94
12.2.5;6.2.5 A Cautionary Tale: Blood Pressure Measurement at Your Doctor's Office;95
12.2.6;6.2.6 A Cautionary Tale for Clinical Trial Blood Pressure Measurements;96
12.3;6.3 Central Labs;96
12.3.1;6.3.1 Operational Considerations;97
12.4;6.4 Core ECG Labs;98
12.5;6.5 The Case Report Form;98
12.6;Further Readings;99
13;7 Conducting Clinical Trials II: Operational Execution;100
13.1;7.1 Introduction;100
13.2;7.2 The Outsourcing Process;101
13.3;7.3 Feasibility Evaluations;101
13.3.1;7.3.1 More Extensive Feasibility Evaluations;102
13.3.2;7.3.2 Feasibility Reporting;103
13.4;7.4 Standard Operating Procedures;103
13.4.1;7.4.1 Balancing the Degree of Flexibility Within an SOP;104
13.4.2;7.4.2 The Necessity of Implementing and Maintaining SOPs;104
13.5;7.5 Project Management;105
13.6;7.6 Site and Investigator Recruitment;106
13.6.1;7.6.1 Principal Investigators;106
13.6.2;7.6.2 Responsibilities of Principal Investigators;107
13.6.3;7.6.3 Potential Principal Investigators in Private Practice Settings;107
13.6.4;7.6.4 Potential Principal Investigators at Larger Medical Institutions;107
13.6.5;7.6.5 Principal Investigator Training;108
13.7;7.7 Subject Recruitment and Retention;109
13.7.1;7.7.1 Subject Recruitment;109
13.7.2;7.7.2 Subject Retention;110
13.8;7.8 Monitoring Clinical Trials;111
13.9;7.9 Data Management;112
13.9.1;7.9.1 Data Management Plans;112
13.9.2;7.9.2 Electronic Data Capture;113
13.9.3;7.9.3 Database Development;113
13.10;7.10 A New Paradigm: Allying With Sponsors;114
13.11;7.11 Underperforming and Non-performing Clinical Trial Sites;114
13.11.1;7.11.1 Limitations of the Current Model;116
13.12;7.12 Another New Paradigm: The Site-Specific CRO;116
13.12.1;7.12.1 Synergies of a Sponsor CRO and a Site-Specific CRO Working Together;117
13.12.2;Further Readings;118
14;8 Statistical Analysis;119
14.1;8.1 Introduction;119
14.2;8.2 Types of Clinical Data;120
14.2.1;8.2.1 Numerical Variables;120
14.2.2;8.2.2 Categorical Variables;120
14.2.3;8.2.3 Parametric Tests and Nonparametric Tests;121
14.3;8.3 Descriptive Statistics: Summarizing Data;121
14.3.1;8.3.1 Measures of Central Tendency;121
14.3.2;8.3.2 Measures of Dispersion Around a Central Value;122
14.4;8.4 Inferential Statistics: Hypothesis Testing;123
14.4.1;8.4.1 The Search for Compelling Evidence;123
14.4.2;8.4.2 Variation and Systematic Variation;123
14.4.3;8.4.3 Between-Groups Variation and Within-Groups Variation;124
14.4.4;8.4.4 Comparing Between-Groups Variance and Within-Groups Variance;124
14.4.5;8.4.5 The Term Error Does Not Imply a Mistake;125
14.5;8.5 Probability;125
14.5.1;8.5.1 Likely Events Do Not Always Happen;126
14.5.2;8.5.2 Clinical Decision-Making;126
14.5.3;8.5.3 Sampling Theory;127
14.5.4;8.5.4 The Standard Error of the Mean;127
14.6;8.6 The Normal Distribution;128
14.6.1;8.6.1 Area Under the Normal Curve;130
14.6.2;8.6.2 Various Areas Under the Normal Curve;131
14.7;8.7 Analysis of Association;131
14.7.1;8.7.1 Direction of an Association;132
14.7.2;8.7.2 Degree of Closeness of an Association;132
14.7.3;8.7.3 Correlation Coefficients;132
14.7.4;8.7.4 Determining the Significance of a Product Moment Coefficient;133
14.7.5;8.7.5 The Coefficient of Determination;133
14.7.6;8.7.6 Association Does Not Necessarily Equate to Causation;134
15;9 Statistical Significance;135
15.1;9.1 Introduction;135
15.2;9.2 Creating a Research Question and Associated Hypotheses;135
15.2.1;9.2.1 The Research Hypothesis;135
15.2.2;9.2.2 The Null Hypothesis;136
15.3;9.3 Precise Expression of the Research Hypothesis and the Null Hypothesis: The Concept of Statistical Significance;136
15.4;9.4 Hypothesis Testing;137
15.5;9.5 Conducting a Statistical Test and Obtaining a Test Statistic;138
15.6;9.6 The Independent Groups t-Test;138
15.6.1;9.6.1 Degrees of Freedom;139
15.6.2;9.6.2 Format of Results from an Independent Groups t-Test;140
15.6.3;9.6.3 The p-Value: Its Definition and Meaning;141
15.6.4;9.6.4 The p-Value and Hypothesis Testing;142
15.6.5;9.6.5 Two More Examples of Results from an Independent Groups t-Test;142
15.7;9.7 The Dependent Measures t-Test;143
15.8;9.8 Analysis of Variance;145
15.9;9.9 One-Factor Independent Groups ANOVA;145
15.9.1;9.9.1 The Test Statistic in ANOVA;146
15.9.2;9.9.2 Calculation of the F-Test;146
15.9.3;9.9.3 A Further Analytical Step: Multiple Comparisons;148
15.10;9.10 General Comments on Multiple-Comparison Testing;150
15.10.1;9.10.1 Type I Errors and Type II Errors;150
15.11;9.11 Possible Clinical Interpretations of Statistical Results;152
16;10 Clinical Significance;154
16.1;10.1 Introduction;154
16.2;10.2 The Logic of Confidence Intervals;154
16.3;10.3 Confidence Intervals for a Sample Mean;155
16.3.1;10.3.1 A More Precise Definition of a Confidence Interval;156
16.4;10.4 Confidence Intervals for the Difference Between Treatment Group Means;156
16.5;10.5 Relationship of the 95 CI and 99 CI to the 0.05 and 0.01 p-Values;157
16.6;10.6 The Additional Benefit of Using Confidence Intervals;158
16.6.1;10.6.1 Clinical Relevance and Clinically Relevant Differences;158
17;11 Sample Size Estimation;161
17.1;11.1 Introduction;161
17.2;11.2 Ethical Issues in Sample Size Estimation;162
17.3;11.3 Variables Involved in Sample Size Estimation;163
17.4;11.4 Type I and Type II Errors;164
17.4.1;11.4.1 The Implications of Type I and Type II Errors;164
17.5;11.5 Choosing the Variables Needed for Sample Size Estimation;165
17.5.1;11.5.1 Alpha and Beta;165
17.5.2;11.5.2 The Treatment Effect, Its Variance, and the Standardized Treatment Effect;166
17.6;11.6 Using the Appropriate Formula to Yield the Sample Size;166
17.7;11.7 Influences on the Sponsors Choice of These Values;167
17.8;11.8 Choosing the Objective(s) on Which to Base the Sample Size Estimation;168
17.9;11.9 Other Issues to Keep in Mind;168
18;12 General Safety Assessments;170
18.1;12.1 Introduction;170
18.2;12.2 Operationalizing the Term Drug Safety;170
18.2.1;12.2.1 Perspectives of Regulators and Prescribing Physicians on Safety Data;171
18.3;12.3 General Safety Assessments;172
18.3.1;12.3.1 Extent of Exposure;173
18.3.2;12.3.2 Adverse Events;173
18.3.3;12.3.3 Common Laboratory Tests;174
18.3.4;12.3.4 Vital Signs;176
18.4;12.4 Acquisition and Management of Safety Data;176
18.4.1;12.4.1 Adverse Events;176
18.4.2;12.4.2 Serious Adverse Event Data;177
18.5;12.5 Analysis Populations;178
18.6;12.6 Presentation of Safety Data;178
18.6.1;12.6.1 Descriptive Approaches to Safety Data;179
18.6.2;12.6.2 Time-to-Event Analysis;180
18.6.3;12.6.3 Differences Between Approaches to Safety and Efficacy Data;181
18.6.4;Further Readings;181
19;13 Efficacy Assessment;182
19.1;13.1 Introduction;182
19.1.1;13.1.1 Superiority, Equivalence, and Noninferiority Trials;182
19.1.2;13.1.2 Group Sequential and Adaptive Study Designs;183
19.2;13.2 Analysis Populations;183
19.2.1;13.2.1 The Intent-to-Treat Population;184
19.2.2;13.2.2 The Per-protocol Population;184
19.2.3;13.2.3 Using Both Analysis Populations;184
19.2.4;13.2.4 Missing Data;185
19.3;13.3 Hypothesis Testing Is Integral to All of the Designs Discussed;185
19.4;13.4 Superiority Trials;186
19.4.1;13.4.1 Well-Defined Study Objectives and Endpoints;186
19.4.2;13.4.2 Analysis of Covariance;187
19.4.3;13.4.3 Subgroup Analysis;188
19.5;13.5 Equivalence Trials;189
19.5.1;13.5.1 Why the Hypothesis Testing Strategy Is Different Here;190
19.5.2;13.5.2 Establishing the Equivalence Margin;191
19.5.3;13.5.3 Hypothesis Construction and Testing;192
19.5.4;13.5.4 Statistical Analysis and Clinical Judgment Working Together;193
19.6;13.6 Noninferiority Trials;193
19.6.1;13.6.1 Establishing the Noninferiority Margin;193
19.6.2;13.6.2 Hypothesis Construction and Testing;193
19.6.3;13.6.3 Statistical Analysis and Clinical Judgment Working Together;194
19.7;13.7 Group Sequential Designs;194
19.7.1;13.7.1 Interim Analyses in Group Sequential Trials;195
19.7.2;13.7.2 Data Monitoring Committees;195
19.7.3;13.7.3 Statistical Methodology for Interim Analysis;196
19.7.3.1;13.7.3.1 The O--Brien--Fleming Approach;198
19.7.3.2;13.7.3.2 Group Sequential Alpha Spending Functions;198
19.7.4;13.7.4 Ethical Considerations in Early Termination;199
19.8;13.8 Adaptive Designs;200
19.8.1;13.8.1 Protocol Amendments;200
19.8.2;13.8.2 Increasing Awareness of Adaptive Designs;201
19.8.3;13.8.3 Regulatory Guidance for Adaptive Designs;202
19.9;13.9 Bayesian Approaches to Analyzing Clinical Trials;203
19.10;13.10 Meta-analysis;203
19.10.1;13.10.1 Introduction to Meta-analysis;204
19.10.2;13.10.2 The Basic Steps;205
19.10.3;13.10.3 Choice of the Summary Statistic Representing the Treatment Effect of Interest;206
19.10.4;13.10.4 Data Analysis;206
19.10.5;13.10.5 Evaluating Robustness;208
19.10.6;13.10.6 Dissemination of Results and Conclusions of a Meta-analysis;208
19.11;13.11 Therapeutic Use Trials;209
19.11.1;13.11.1 Large Simple Therapeutic Trials;209
19.11.2;Further Readings;210
20;14 Cardiac and Cardiovascular Safety Assessments;211
20.1;14.1 Introduction;211
20.2;14.2 A Three-Component Risk Exclusion Model;212
20.2.1;14.2.1 Confidence Intervals Facilitate the Determination of Thresholds of Regulatory Concern;213
20.2.1.1;14.2.1.1 Confidence Intervals in Magnitude-of-Change Assessments;213
20.2.1.2;14.2.1.2 Employment of Confidence Intervals in Relative Risk Assessments;214
20.3;14.3 Cardiac Safety Assessment: A Brief History;214
20.4;14.4 Obtaining QTc Data from QT Measurements;215
20.5;14.5 The Thorough QT/QTc Study;216
20.5.1;14.5.1 Design of the TQT Study;216
20.5.2;14.5.2 TQT Study Conduct;217
20.5.3;14.5.3 Statistical Analysis;218
20.5.4;14.5.4 Ramifications of Interpretations by Sponsors and Regulatory Agencies;219
20.6;14.6 FDA Guidance on Excluding Unacceptable Cardiovascular Risk in the Development of Antidiabetic Drugs for Type 2 Diabetes Mellitus;220
20.6.1;14.6.1 Clinical Trials to Be Conducted;220
20.6.2;14.6.2 Choice of Subject Populations;221
20.6.3;14.6.3 Choice of Cardiovascular Endpoints;221
20.6.4;14.6.4 Endpoint Adjudication;221
20.6.5;14.6.5 The Required Meta-analysis;222
20.6.6;14.6.6 A Dedicated Large (Simple) Cardiovascular Trial;223
20.6.7;14.6.7 An Additional Consideration for Safety Meta-analyses;224
20.7;14.7 An Example of a Real Safety Meta-analysis;224
20.8;14.8 Potential Regulatory Thresholds of Interest for Other Cardiovascular Parameters;225
20.9;Further Readings;226
21;15 Manufacturing Small Molecule Drugs and Biologicals;227
21.1;15.1 Introduction;227
21.2;15.2 Nonclinical Development;228
21.3;15.3 Drug Products for Clinical Trials;228
21.3.1;15.3.1 Need for the Investigative Drug and the Control Drug;229
21.3.2;15.3.2 Blinding of Drug Products for Clinical Trials;229
21.3.3;15.3.3 Packaging and Distributing Clinical Drug Products;230
21.4;15.4 Commercial Manufacturing;231
21.5;15.5 Quality Control: Building Quality into the Process;231
21.6;15.6 Stability Studies;232
21.7;15.7 Immediate Release and Modified Release Tablets and Capsules;232
21.8;15.8 Recombinant Protein Biologicals;233
21.8.1;15.8.1 Commercial-Scale Manufacturing;234
21.8.2;Further Readings;235
22;16 Postmarketing Surveillance;236
22.1;16.1 Introduction;236
22.2;16.2 Limitations of Preapproval Clinical Trials;237
22.3;16.3 Individual Differences in Drug Response;238
22.3.1;16.3.1 Hepatic Impairment;238
22.3.2;16.3.2 Renal Insufficiency;239
22.3.3;16.3.3 The Elderly;239
22.3.4;16.3.4 Pediatric Populations;240
22.4;16.4 Postmarketing Surveillance;241
22.5;16.5 The 2005 CDER Report to the Nation;242
22.6;16.6 The Institute of Medicines 2006 Report on Drug Safety;243
22.7;16.7 The Food and Drug Administration Amendments Act of 2007;244
22.8;16.8 The FDAs 2008 Sentinel Initiative;245
22.8.1;16.8.1 The Science of Safety;245
22.8.2;16.8.2 Active Surveillance;246
22.8.3;Further Readings;246
23;17 Main Themes and Concluding Comments;247
23.1;17.1 Introduction;247
23.2;17.2 Ethical Considerations;248
23.3;17.3 Design, Methodology, Operations, and Analysis;249
23.3.1;17.3.1 Reducing Bias and Improving Precision;249
23.3.2;17.3.2 Our Definition of Statistics Revisited;250
23.3.3;17.3.3 Numerical Representations of Biological Information;250
23.3.4;17.3.4 Some Thoughts on the p-Value;251
23.4;17.4 Confidence Intervals and Clinical Significance;252
23.5;17.5 Pharmacokinetics and Pharmacodynamics;252
23.6;17.6 Decision-Making;253
23.6.1;17.6.1 The Subjective Nature of Many Decisions;253
23.6.2;17.6.2 Determining Thresholds of Regulatory Concern;255
23.7;17.7 BenefitRisk Considerations;255
23.8;17.8 Biological Considerations Pervade Our Discussions;255
23.8.1;17.8.1 Biological Underpinnings of Precision Medicine;256
23.8.2;17.8.2 Pharmacogenetics;256
23.8.3;17.8.3 Pharmacogenomics;257
23.8.4;17.8.4 Pharmacoproteomics;257
23.9;17.9 Integrated Pharmaceutical Medicine;258
23.10;17.10 Concluding Comments;259
24;References;260
25;Index;264