172. Cardiovascular Safety

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172. Cardiovascular Safety

CATEGORY: Fitness, Workout & Exercise 500 Courses

COURSE NUMBER: 01

FEES: 555/- INR only

CERTIFICATE VALIDITY: Lifetime

CERTIFICATES DELIVERY: In 48 hours

Syllabus

Part I: Introduction
1 The Central Role of Cardiovascular Safety
in Drug Development and Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Notable Events Driving Assessments of Drug
Safety and Effi cacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4 Cardiovascular Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4.1 Proarrhythmic Cardiac Safety . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.4.2 Cardiovascular Safety Considerations
in Oncology Drug Development and Therapeutic Use . . . . . . . 8
1.4.3 Blood Pressure Responses
to Noncardiovascular Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.4.4 Cardiovascular Safety of Antidiabetic
Drugs for Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.5 Postmarketing Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.6 Clinical Research Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.6.1 Components of Clinical Research Methodology . . . . . . . . . . . 11
1.6.2 The Discipline of Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.6.3 Ethical Considerations and Responsibilities . . . . . . . . . . . . . . 12
1.7 Biological Knowledge Is of Critical Importance . . . . . . . . . . . . . . . . . 14
1.8 The Cardiac Safety Research Consortium:
The Power of Precompetitive Collaboration . . . . . . . . . . . . . . . . . . . . 15
1.8.1 Collaboration with DIA: The Cardiac
Safety Education Collaborative . . . . . . . . . . . . . . . . . . . . . . . . 15
1.9 A Few Words About the Chapters in Part II and Part III . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Part II: A Primer of Biological and Physiological Considerations
2 Drug Structures and the Biological Basis of Drug Responses . . . . . . . . 23
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2 Small-Molecule Drugs: New Molecular Entities
and Drug Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2.1 Pharmacophores and Toxicophores . . . . . . . . . . . . . . . . . . . . . 24
2.2.2 Drug Discovery and Drug Design . . . . . . . . . . . . . . . . . . . . . . 25
2.2.3 Structural Molecular Engineering: A Case Study . . . . . . . . . . 27
2.3 A Brief Introduction to Biopharmaceuticals . . . . . . . . . . . . . . . . . . . . 28
2.4 Individual Variation in Responses to Drugs . . . . . . . . . . . . . . . . . . . . . 29
2.5 Deoxyribonucleic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.5.1 Bases, Nucleotides, and Polynucleotide Strands . . . . . . . . . . . 30
2.5.2 The Double Helix and Replication . . . . . . . . . . . . . . . . . . . . . 30
2.6 Transmission Genetics and Molecular Genetics . . . . . . . . . . . . . . . . . 31
2.6.1 Morgan’s Research Employing Drosophila melanogaster . . . 31
2.7 Human Genetic and Genomic Considerations . . . . . . . . . . . . . . . . . . . 32
2.7.1 Proteins, the Proteome, and Proteomics . . . . . . . . . . . . . . . . . 33
2.7.2 The Structure of Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.8 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.9 Cells and Cell Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.10 Ions and Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.10.1 Focus on the hERG Cardiac Potassium Ion Channel . . . . . . . . 38
2.10.2 Ion Channel (Protein) Traffi cking . . . . . . . . . . . . . . . . . . . . . . 39
2.11 Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.11.1 Metabolic Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.12 Continued Discussion of Biopharmaceuticals . . . . . . . . . . . . . . . . . . . 41
2.12.1 Recombinant DNA Technology . . . . . . . . . . . . . . . . . . . . . . . . 41
2.12.2 A Case Study: Genetically Engineered Insulin . . . . . . . . . . . . 42
2.13 Manufacturing Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.13.1 Manufacturing Recombinant
Protein Biopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3 Cardiovascular Structure, Function, and Pathophysiology . . . . . . . . . . 51
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.2 The Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.2.1 The Cardiac Cycle and the Action Potential . . . . . . . . . . . . . . 52
3.3 Cardiovascular System Parameters of Interest . . . . . . . . . . . . . . . . . . . 54
3.3.1 Stroke Volume and Cardiac Output . . . . . . . . . . . . . . . . . . . . . 54
3.3.2 Total Peripheral Resistance of the Systemic Vasculature . . . . 55
3.3.3 Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.4 Cardiac and Cardiovascular Diseases and Occurrences
of Clinical Concern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3.4.1 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.4.2 Torsades de Pointes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

3.4.3 Cardiac Channelopathies I: Long QT Syndrome . . . . . . . . . . . 58
3.4.4 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.4.5 Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.4.6 Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.5 Cardiac Channelopathies II: Short QT Syndrome . . . . . . . . . . . . . . . . 61
3.5.1 Origins of Regulatory Interest in Drug-Induced
QT Interval Shortening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.5.2 Current Thinking on This Issue . . . . . . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Part III: A Primer Of Statistical Considerations
4 Analyzing and Reporting Efficacy Data . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.2 Categorization of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.3 Statistical Signifi cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.3.1 The Role of Probability in Effi cacy Assessment . . . . . . . . . . . 75
4.3.2 Systematic Infl uence and Randomization . . . . . . . . . . . . . . . . 77
4.3.3 A Case Study: The United Kingdom Medical
Research Council’s Streptomycin Trial . . . . . . . . . . . . . . . . . . 79
4.3.4 An Illustrative Example of an Effi cacy
Analysis to Determine Statistical Signifi cance . . . . . . . . . . . . 79
4.3.5 Factors Infl uencing the Attainment of
Statistical Signifi cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

4.4 Analyzing Data from Clinical Trials Employing
More than Two Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.4.1 A Further Analytical Step: Multiple Comparisons . . . . . . . . . 85
4.4.2 Type I and Type II Errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
4.4.3 Well-Defi ned Study Objectives and Endpoints . . . . . . . . . . . . 88
4.5 Clinical Signifi cance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4.5.1 Confi dence Intervals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
4.5.2 Other Confi dence Levels of Interest . . . . . . . . . . . . . . . . . . . . 92
4.5.3 One-Sided Confi dence Intervals . . . . . . . . . . . . . . . . . . . . . . . 93
4.5.4 Relationship Between Confi dence Intervals
and Probability Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
4.6 Noninferiority Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.6.1 The Noninferiority Margin . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.6.2 Hypothesis Construction and Testing . . . . . . . . . . . . . . . . . . . 95
4.6.3 Case Study 1: Noninferiority Established
for New Drug A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4.6.4 Case Study 2: Noninferiority Not Established
for New Drug B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4.6.5 Employment of Noninferiority Margins
in Proarrhythmic Safety Assessments . . . . . . . . . . . . . . . . . . . 97
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

5 Analyzing and Reporting Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.2 FDA’s Premarketing Risk Assessment Guidance . . . . . . . . . . . . . . . . 99
5.2.1 The Utility of Safety Data for Prescribing
Physicians and Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.2.2 Drug Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5.3 General Safety Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
5.3.1 Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
5.3.2 Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
5.3.3 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.3.4 Common Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.3.5 Examples of Safety Tables Included in Clinical
Study Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
5.3.6 Shift Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.3.7 Responders’ Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.4 A Key Reason for the Nature of General Safety Descriptions. . . . . . 109
5.5 The Intersection–Union and Union–Intersection Tests . . . . . . . . . . . 109
5.5.1 The Thorough QT/QTc Study . . . . . . . . . . . . . . . . . . . . . . . . 109
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
6 Meta-analysis, Group Sequential Study
Designs, Centralized Endpoint Adjudication,
and Composite Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.2 Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6.2.1 More Informative Nomenclature: The Term
Meta-methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6.3 The Fundamentals of Meta-methodology . . . . . . . . . . . . . . . . . . . . . 117
6.3.1 Determining the Studies to Be Included . . . . . . . . . . . . . . . . 117
6.3.2 Identifi cation of all Potentially Relevant Studies . . . . . . . . . . 118
6.3.3 Data Extraction and Acquisition . . . . . . . . . . . . . . . . . . . . . . 118
6.3.4 Executing the Actual Meta-analysis . . . . . . . . . . . . . . . . . . . 119
6.3.5 Testing for Homogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.3.6 Evaluating Robustness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.3.7 Disseminating the Results, Interpretations,
and Conclusions to Various Audiences . . . . . . . . . . . . . . . . . 122
6.3.8 Additional Challenges in Meta-methodology . . . . . . . . . . . . 122
6.3.9 A Potential FDA Guidance for Industry . . . . . . . . . . . . . . . . 122
6.4 Group Sequential Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
6.4.1 Interim Analyses in Group Sequential Trials . . . . . . . . . . . . . 123
6.4.2 Data Monitoring Committees . . . . . . . . . . . . . . . . . . . . . . . . 124
6.4.3 Statistical Methodology for Interim Analysis . . . . . . . . . . . . 125

6.4.4 Subtle Difference in the Multiple Comparisons
Approach in this Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.4.5 The O’Brien–Fleming Approach . . . . . . . . . . . . . . . . . . . . . . 127
6.4.6 Group Sequential Alpha Spending Functions . . . . . . . . . . . . 127
6.4.7 Ethical Considerations in Early Termination . . . . . . . . . . . . . 128
6.5 Centralized Endpoint Adjudication . . . . . . . . . . . . . . . . . . . . . . . . . . 129
6.6 Composite Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Part IV: Proarrhythmic Cardiac Safety
7 The Proarrhythmic Cardiac Safety Regulatory
Landscape Circa 2005–2015: Drug-Induced hERG
Channel Block and the Thorough QT/QTc Study . . . . . . . . . . . . . . . . . 137
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7.2 A Brief History of Proarrhythmic Cardiac Safety . . . . . . . . . . . . . . . 138
7.3 Nonclinical Proarrhythmic Cardiac Safety
Investigations: ICH S7B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
7.3.1 An Example of a Battery of Nonclinical Tests . . . . . . . . . . . 141
7.4 Preapproval Clinical Investigations of Proarrhythmic Liability . . . . 142
7.4.1 Collection of High-Fidelity Digital
ECG Waveforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
7.4.2 The Core ECG Lab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
7.4.3 Analyzing ECG Waveforms in a Core ECG Lab . . . . . . . . . . 144
7.4.4 Adjusting QT Measurements for Heart Rate . . . . . . . . . . . . . 145
7.5 Further Discussion of ICH E14 and the TQT Study . . . . . . . . . . . . . 147
7.5.1 Statistical Analyses Discussed in ICH E14 . . . . . . . . . . . . . . 148
7.5.2 Nomenclature Considerations . . . . . . . . . . . . . . . . . . . . . . . . 150
7.6 Additional Considerations Pertaining to TQT Studies . . . . . . . . . . . 150
7.6.1 Being “as Thorough as Possible” When a
Formal TQT Study Is Infeasible . . . . . . . . . . . . . . . . . . . . . . 150
7.6.2 Correcting for Heart Rate Is Not as Simple as
It May Initially Appear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
7.6.3 Potential Replacements for the Active
Pharmacological Control Treatment Arm . . . . . . . . . . . . . . . 152
7.6.4 Study Design Considerations: Optimizing
Statistical Power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
7.7 Limitations of this Paradigm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
7.7.1 Thoughts from FDA Regulators. . . . . . . . . . . . . . . . . . . . . . . 155
7.8 QTc–Concentration Relationship Analysis as an
Adjunct to the TQT Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
7.9 Other Potential Indices of Proarrhythmic Liability . . . . . . . . . . . . . . 156
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

8 QTc Exposure–Response Modeling as a Primary Methodology
for Proarrhythmic Cardiac Safety Assessments . . . . . . . . . . . . . . . . . . 165
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
8.2 Advantages of Exposure–Response Modeling as a Primary
Methodology in Clinical Proarrhythmic Cardiac
Safety Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
8.3 Discussions of Exposure–Response
Modeling in the Second Revision of the ICH E14
“Questions & Answers” Document . . . . . . . . . . . . . . . . . . . . . . . . . . 167
8.4 An Illuminating Retrospective Study
of QTc Exposure–Response Modeling . . . . . . . . . . . . . . . . . . . . . . . 168
8.5 Prospective Evaluation of Exposure–Response Modeling:
The IQ/CSRC Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
8.5.1 Design of the IQ/CSRC Prospective Study . . . . . . . . . . . . . . 170
8.5.2 Results of the IQ/CSRC Prospective Study . . . . . . . . . . . . . . 170
8.6 Concerns Expressed Following the Publication of
the Results of the IQ/CSRC Study . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
8.7 Details of ICH E14 Q&A R3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
8.7.1 Important Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
8.7.2 Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
8.7.3 Other Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
8.7.4 Comparison of Previously Noted Concerns
with the Text of ICH E14 Q&A R3 . . . . . . . . . . . . . . . . . . . . 174
8.8 Anticipating Many Discussions of ICH E14 Q&A R3 . . . . . . . . . . . 175
8.8.1 A Recently Reported Study of Interest . . . . . . . . . . . . . . . . . 176
8.9 A Provocative Consideration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
8.10 Concluding Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
9 The Comprehensive In Vitro Proarrhythmia Assay Initiative . . . . . . . 181
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
9.2 Advantages of the Proposed Paradigm . . . . . . . . . . . . . . . . . . . . . . . 182
9.3 Cardiac Ionic Currents of Particular Interest . . . . . . . . . . . . . . . . . . . 183
9.4 Electrophysiological Principles Underlying CiPA . . . . . . . . . . . . . . . 184
9.4.1 Early After-Depolarizations . . . . . . . . . . . . . . . . . . . . . . . . . . 185
9.5 CiPA’s Core In Vitro Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
9.6 CiPA’s In Silico Modeling Component . . . . . . . . . . . . . . . . . . . . . . . 187
9.7 Effects on hiPSC-CMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
9.8 Updates from the CiPA Working Groups . . . . . . . . . . . . . . . . . . . . . . 189
9.8.1 The Ion Channel Working Group . . . . . . . . . . . . . . . . . . . . . 189
9.8.2 The In Silico Working Group . . . . . . . . . . . . . . . . . . . . . . . . 190
9.8.3 The Myocyte Working Group . . . . . . . . . . . . . . . . . . . . . . . . 191
9.8.4 The Clinical Translation Working Group . . . . . . . . . . . . . . . 191
9.9 Challenges Remaining to Be Addressed . . . . . . . . . . . . . . . . . . . . . . 191

9.10 Anticipating Many Discussions of CiPA in the Literature. . . . . . . . . 192
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Part V: Additional Domains of Cardiovascular Safety
10 Oncology Drug Therapy: Cardiotoxicity and the
Discipline of Cardio-oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
10.2 Cardiac Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
10.2.1 Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
10.2.2 Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . 204
10.2.3 Radionuclide (Nuclear) Imaging . . . . . . . . . . . . . . . . . . . . . 204
10.3 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
10.3.1 Cardiac Troponin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
10.4 Examples of the Cardiotoxicity of Oncologic Drugs . . . . . . . . . . . . 206
10.4.1 QT Interval Prolongation/Torsades . . . . . . . . . . . . . . . . . . . 206
10.4.2 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
10.4.3 Cardiomyopathy and Left Ventricular Dysfunction . . . . . . . 209
10.5 Therapeutic Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

10.5.1 Strategies for the Prevention of Anthracycline-
and Trastuzumab-Induced Cardiotoxicity . . . . . . . . . . . . . . 210

10.5.2 Therapeutic Management of Hypertension . . . . . . . . . . . . . 211
10.6 Early Detection of Cardiotoxicity: Heart Failure . . . . . . . . . . . . . . . 212
10.7 The Discipline of Cardio-oncology . . . . . . . . . . . . . . . . . . . . . . . . . 213
10.7.1 Prevention or Mitigation of Cardiovascular
Damage and Its Relationship to Oncologic
Agents’ Effi cacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
11 Blood Pressure Responses to Noncardiovascular
Drugs in Development and Therapeutic Use . . . . . . . . . . . . . . . . . . . . . 223
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
11.2 Drug-Induced Blood Pressure Changes . . . . . . . . . . . . . . . . . . . . . . 224
11.3 Preapproval Investigations of Drug-Induced
Blood Pressure Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
11.3.1 Nonclinical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . 224
11.3.2 Clinical Investigations of Drug-Induced
Blood Pressure Responses . . . . . . . . . . . . . . . . . . . . . . . . . . 226

11.4 Learning from the Employment of Ambulatory
Blood Pressure Monitoring in the Clinical Development
of Antihypertensive Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
11.5 What Might a Regulatory Landscape Look Like Here? . . . . . . . . . 230
11.5.1 Incorporation of Ambulatory
Blood Pressure Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . 230

11.6 Treatment of Drug-Induced Blood Pressure Increases . . . . . . . . . . 231
11.6.1 Learning from the Employment of Ambulatory
Blood Pressure Monitoring in Routine
Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
12 The Genesis of Cardiovascular Safety Regulatory
Landscapes for New Antidiabetic Drugs for Type 2 Diabetes . . . . . . . . 239
12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
12.1.1 Prospective Exclusion of Unacceptable
Cardiovascular Risk for New Antidiabetic
Drugs for Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . 241
12.2 Publication of a Meta-analysis Involving Rosiglitazone . . . . . . . . . 241
12.2.1 Details and Critique of the Meta-analysis . . . . . . . . . . . . . . 241
12.3 FDA Advisory Committee Meetings Following
the Publication of the Meta-analysis and Their Consequences . . . . 243
12.4 Reanalysis of the RECORD Trial and Its Consequences . . . . . . . . 245
12.5 FDA Drug Safety Communication in December 2015 . . . . . . . . . . 247
12.6 Comment on the “Rosiglitazone Case Study”
Before Proceeding to Chap. 13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
13 Satisfying the Regulatory Requirements for New
Antidiabetic Drugs for Type 2 Diabetes Most Expeditiously . . . . . . . . 251
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
13.2 The FDA and EMA Regulatory Landscapes . . . . . . . . . . . . . . . . . . 252
13.2.1 The FDA Guidance for Industry . . . . . . . . . . . . . . . . . . . . . 252
13.2.2 The EMA Guideline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
13.2.3 Rationale for our Focus on the FDA Requirements . . . . . . . 253
13.3 Clinical Implications of the FDA Guidance for Industry . . . . . . . . 253
13.4 Approaches to Satisfy the 1.8 and 1.3 Safety Margins . . . . . . . . . . 256
13.4.1 Meta-analysis and a Cardiovascular
Safety Outcome Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
13.4.2 Meta-analysis of Cardiovascular Events from
Phase II and Phase III Trials to Discharge the 1.8
Threshold and a Cardiovascular Safety Outcome
Trial to Discharge the 1.3 Threshold . . . . . . . . . . . . . . . . . . 257
13.4.3 Meta-analysis Inclusive of Interim Data
from a Cardiovascular Safety Outcome
Trial to Discharge the 1.8 Threshold and a
Cardiovascular Safety Outcome Trial to
Discharge the 1.3 Threshold . . . . . . . . . . . . . . . . . . . . . . . . 258

13.4.4 Single Cardiovascular Safety Outcome Trial to
Discharge Both the 1.8 and 1.3 Thresholds . . . . . . . . . . . . . 259
13.5 Statistical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
13.5.1 Meta-analysis and Heterogeneity . . . . . . . . . . . . . . . . . . . . . 260
13.5.2 Adaptive Methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
13.5.3 Restricted Mean Survival Time Analysis. . . . . . . . . . . . . . . 263
13.6 Points to Consider . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
13.6.1 Confi dentiality of Interim Results from
Cardiovascular Safety Outcome Trials . . . . . . . . . . . . . . . . 265
13.7 Emerging Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Part VI: Additional Considerations In General Drug Safety
And Therapeutic Use
14 Postmarketing Cardiovascular Safety Considerations . . . . . . . . . . . . . 279
14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
14.2 Limitations of Preapproval Clinical Trials . . . . . . . . . . . . . . . . . . . . 280
14.3 Therapeutic Use Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
14.3.1 Experimental Therapeutic Use Trials . . . . . . . . . . . . . . . . . 282
14.3.2 Nonexperimental Therapeutic Use Trials . . . . . . . . . . . . . . 282
14.4 Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
14.5 Pharmacoepidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
14.6 Postmarketing Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
14.6.1 Spontaneous Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
14.6.2 Active Postmarketing Surveillance . . . . . . . . . . . . . . . . . . . 285
14.7 Registries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
14.7.1 A De Novo Prospective Registry/Observational Study . . . . 285
14.7.2 A Prospective Registry/Observational Study Built
on an Existing Registry Platform . . . . . . . . . . . . . . . . . . . . . 286
14.7.3 A Prospective Registry/Observational Study Built
on an Electronic Health Record Platform . . . . . . . . . . . . . . 286
14.7.4 A Retrospective Analysis Built from Data Warehouses . . . 286
14.7.5 Relative Strengths and Weaknesses of
These Methodologies Compared with a Prospective
Randomized Cardiovascular Outcome Study . . . . . . . . . . . 287
14.7.6 The Sentinel Initiative, the Science of Safety,
and Mini-Sentinel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
14.8 Evidence-Based Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
14.8.1 Scientifi c Evidence and Clinical Judgment . . . . . . . . . . . . . 289
14.9 Inappropriate Prescriptions of QT-prolonging Drugs
and Opportunities for Clinical Pharmacists to Reduce Them . . . . . 289
14.10 Recognition of QTc Prolongation in Clinical Practice . . . . . . . . . . 291
14.11 Publication Bias? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

14.12 Treatment of Drug-Induced QT Prolongation and Torsades . . . . . . 294
14.12.1 QT Prolongation Without Observed
Episodes of Torsades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
14.12.2 Torsades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
15 A Safety Perspective on Additional Aspects
of Drug Development and Therapeutic Use . . . . . . . . . . . . . . . . . . . . . . 305
15.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
15.2 Regulatory Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
15.2.1 Contributors to the Development of
Regulatory Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
15.3 Rare Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
15.4 Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
15.5 Pain Medication: Abuse of Prescription Opioids . . . . . . . . . . . . . . . 309
15.6 Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
15.7 Reporting Randomized Clinical Trials . . . . . . . . . . . . . . . . . . . . . . 313
15.7.1 The CONSORT Extension Statement
Addressing Drug Harms . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
15.7.2 Imperfections in Reporting Randomized
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
15.7.3 Public Registration of Clinical Trials . . . . . . . . . . . . . . . . . . 316
15.7.4 Evidence-Based Medicine and the Challenge
of Generalizability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
15.8 Concluding Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Further Readings by Topic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
Regulatory Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
Rare Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Pain Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Reporting Randomized Clinical Trials . . . . . . . . . . . . . . . . . . . . . . 326
General Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Afterword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

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