| Description |
1 online resource (xxvi, 333 pages) : color illustrations |
| Contents |
Intro -- Foreword -- Preface -- About the Authors -- Acknowledgments -- Contents -- Part I: Introduction -- Chapter 1: The Central Role of Cardiovascular Safety in Drug Development and Therapeutic Use -- 1.1 Introduction -- 1.2 Drug Safety -- 1.3 Notable Events Driving Assessments of Drug Safety and Efficacy -- 1.4 Cardiovascular Safety -- 1.4.1 Proarrhythmic Cardiac Safety -- 1.4.2 Cardiovascular Safety Considerations in Oncology Drug Development and Therapeutic Use -- 1.4.3 Blood Pressure Responses to Noncardiovascular Drugs -- 1.4.4 Cardiovascular Safety of Antidiabetic Drugs for Type 2 Diabetes -- 1.5 Postmarketing Surveillance -- 1.6 Clinical Research Methodology -- 1.6.1 Components of Clinical Research Methodology -- 1.6.2 The Discipline of Statistics -- 1.6.3 Ethical Considerations and Responsibilities -- 1.7 Biological Knowledge Is of Critical Importance -- 1.8 The Cardiac Safety Research Consortium: The Power of Precompetitive Collaboration -- 1.8.1 Collaboration with DIA: The Cardiac Safety Education Collaborative -- 1.9 A Few Words About the Chapters in Part II and Part III -- References -- Further Reading -- Part II: A Primer of Biological and Physiological Considerations -- Chapter 2: Drug Structures and the Biological Basis of Drug Responses -- 2.1 Introduction -- 2.2 Small-Molecule Drugs: New Molecular Entities and Drug Molecules -- 2.2.1 Pharmacophores and Toxicophores -- 2.2.2 Drug Discovery and Drug Design -- 2.2.3 Structural Molecular Engineering: A Case Study -- 2.3 A Brief Introduction to Biopharmaceuticals -- 2.4 Individual Variation in Responses to Drugs -- 2.5 Deoxyribonucleic Acid -- 2.5.1 Bases, Nucleotides, and Polynucleotide Strands -- 2.5.2 The Double Helix and Replication -- 2.6 Transmission Genetics and Molecular Genetics -- 2.6.1 Morgan's Research Employing Drosophila melanogaster |
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2.7 Human Genetic and Genomic Considerations -- 2.7.1 Proteins, the Proteome, and Proteomics -- 2.7.2 The Structure of Proteins -- 2.8 Receptors -- 2.9 Cells and Cell Membranes -- 2.10 Ions and Ion Channels -- 2.10.1 Focus on the hERG Cardiac Potassium Ion Channel -- 2.10.2 Ion Channel (Protein) Trafficking -- 2.11 Enzymes -- 2.11.1 Metabolic Enzymes -- 2.12 Continued Discussion of Biopharmaceuticals -- 2.12.1 Recombinant DNA Technology -- 2.12.2 A Case Study: Genetically Engineered Insulin -- 2.13 Manufacturing Considerations -- 2.13.1 Manufacturing Recombinant Protein Biopharmaceuticals -- References -- Further Reading -- Chapter 3: Cardiovascular Structure, Function, and Pathophysiology -- 3.1 Introduction -- 3.2 The Heart -- 3.2.1 The Cardiac Cycle and the Action Potential -- 3.3 Cardiovascular System Parameters of Interest -- 3.3.1 Stroke Volume and Cardiac Output -- 3.3.2 Total Peripheral Resistance of the Systemic Vasculature -- 3.3.3 Blood Pressure -- 3.4 Cardiac and Cardiovascular Diseases and Occurrences of Clinical Concern -- 3.4.1 Arrhythmias -- 3.4.2 Torsades de Pointes -- 3.4.3 Cardiac Channelopathies I: Long QT Syndrome -- 3.4.4 Hypertension -- 3.4.5 Myocardial Infarction -- 3.4.6 Heart Failure -- 3.5 Cardiac Channelopathies II: Short QT Syndrome -- 3.5.1 Origins of Regulatory Interest in Drug-Induced QT Interval Shortening -- 3.5.2 Current Thinking on This Issue -- References -- Further Reading -- Part III: A Primer of Statistical Considerations -- Chapter 4: Analyzing and Reporting Efficacy Data -- 4.1 Introduction -- 4.2 Categorization of Clinical Trials -- 4.3 Statistical Significance -- 4.3.1 The Role of Probability in Efficacy Assessment -- 4.3.2 Systematic Influence and Randomization -- 4.3.3 A Case Study: The United Kingdom Medical Research Council's Streptomycin Trial |
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4.3.4 An Illustrative Example of an Efficacy Analysis to Determine Statistical Significance -- 4.3.5 Factors Influencing the Attainment of Statistical Significance -- 4.4 Analyzing Data from Clinical Trials Employing More than Two Treatments -- 4.4.1 A Further Analytical Step: Multiple Comparisons -- 4.4.2 Type I and Type II Errors -- 4.4.3 Well-Defined Study Objectives and Endpoints -- 4.5 Clinical Significance -- 4.5.1 Confidence Intervals -- 4.5.2 Other Confidence Levels of Interest -- 4.5.3 One-Sided Confidence Intervals -- 4.5.4 Relationship Between Confidence Intervals and Probability Levels -- 4.6 Noninferiority Trials -- 4.6.1 The Noninferiority Margin -- 4.6.2 Hypothesis Construction and Testing -- 4.6.3 Case Study 1: Noninferiority Established for New Drug A -- 4.6.4 Case Study 2: Noninferiority Not Established for New Drug B -- 4.6.5 Employment of Noninferiority Margins in Proarrhythmic Safety Assessments -- References -- Further Reading -- Chapter 5: Analyzing and Reporting Safety Data -- 5.1 Introduction -- 5.2 FDA's Premarketing Risk Assessment Guidance -- 5.2.1 The Utility of Safety Data for Prescribing Physicians and Patients -- 5.2.2 Drug Labeling -- 5.3 General Safety Descriptions -- 5.3.1 Extent of Exposure -- 5.3.2 Vital Signs -- 5.3.3 Adverse Events -- 5.3.4 Common Laboratory Tests -- 5.3.5 Examples of Safety Tables Included in Clinical Study Reports -- 5.3.6 Shift Analysis -- 5.3.7 Responders' Analysis -- 5.4 A Key Reason for the Nature of General Safety Descriptions -- 5.5 The Intersection-Union and Union-Intersection Tests -- 5.5.1 The Thorough QT/QTc Study -- 5.5.1.1 Establishing Assay Sensitivity -- 5.5.1.2 Evaluating the Therapeutic and Supratherapeutic Doses of the Drug -- 5.5.1.3 Control of Multiplicity Issues in Thorough QT/QTc Trials -- References -- Further Reading |
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Chapter 6: Meta-analysis, Group Sequential Study Designs, Centralized Endpoint Adjudication, and Composite Endpoints -- 6.1 Introduction -- 6.2 Meta-analysis -- 6.2.1 More Informative Nomenclature: The Term Meta-methodology -- 6.3 The Fundamentals of Meta-methodology -- 6.3.1 Determining the Studies to Be Included -- 6.3.2 Identification of all Potentially Relevant Studies -- 6.3.3 Data Extraction and Acquisition -- 6.3.4 Executing the Actual Meta-analysis -- 6.3.5 Testing for Homogeneity -- 6.3.6 Evaluating Robustness -- 6.3.7 Disseminating the Results, Interpretations, and Conclusions to Various Audiences -- 6.3.8 Additional Challenges in Meta-methodology -- 6.3.9 A Potential FDA Guidance for Industry -- 6.4 Group Sequential Designs -- 6.4.1 Interim Analyses in Group Sequential Trials -- 6.4.2 Data Monitoring Committees -- 6.4.3 Statistical Methodology for Interim Analysis -- 6.4.4 Subtle Difference in the Multiple Comparisons Approach in this Context -- 6.4.5 The O'Brien-Fleming Approach -- 6.4.6 Group Sequential Alpha Spending Functions -- 6.4.7 Ethical Considerations in Early Termination -- 6.5 Centralized Endpoint Adjudication -- 6.6 Composite Endpoints -- References -- Further Reading -- Part IV: Proarrhythmic Cardiac Safety -- Chapter 7: The Proarrhythmic Cardiac Safety Regulatory Landscape Circa 2005-2015: Drug-Induced hERG Channel Block and the Thorough QT/QTc Study -- 7.1 Introduction -- 7.2 A Brief History of Proarrhythmic Cardiac Safety -- 7.3 Nonclinical Proarrhythmic Cardiac Safety Investigations: ICH S7B -- 7.3.1 An Example of a Battery of Nonclinical Tests -- 7.4 Preapproval Clinical Investigations of Proarrhythmic Liability -- 7.4.1 Collection of High-Fidelity Digital ECG Waveforms -- 7.4.2 The Core ECG Lab -- 7.4.3 Analyzing ECG Waveforms in a Core ECG Lab -- 7.4.4 Adjusting QT Measurements for Heart Rate |
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7.5 Further Discussion of ICH E14 and the TQT Study -- 7.5.1 Statistical Analyses Discussed in ICH E14 -- 7.5.2 Nomenclature Considerations -- 7.6 Additional Considerations Pertaining to TQT Studies -- 7.6.1 Being "as Thorough as Possible" When a Formal TQT Study Is Infeasible -- 7.6.2 Correcting for Heart Rate Is Not as Simple as It May Initially Appear -- 7.6.3 Potential Replacements for the Active Pharmacological Control Treatment Arm -- 7.6.4 Study Design Considerations: Optimizing Statistical Power -- 7.7 Limitations of this Paradigm -- 7.7.1 Thoughts from FDA Regulators -- 7.8 QTc-Concentration Relationship Analysis as an Adjunct to the TQT Study -- 7.9 Other Potential Indices of Proarrhythmic Liability -- References -- Further Reading -- Chapter 8: QTc Exposure-Response Modeling as a Primary Methodology for Proarrhythmic Cardiac Safety Assessments -- 8.1 Introduction -- 8.2 Advantages of Exposure-Response Modeling as a Primary Methodology in Clinical Proarrhythmic Cardiac Safety Assessment -- 8.3 Discussions of Exposure-Response Modeling in the Second Revision of the ICH E14 "Questions & Answers" Document -- 8.4 An Illuminating Retrospective Study of QTc Exposure-Response Modeling -- 8.5 Prospective Evaluation of Exposure-Response Modeling: The IQ/CSRC Study -- 8.5.1 Design of the IQ/CSRC Prospective Study -- 8.5.2 Results of the IQ/CSRC Prospective Study -- 8.6 Concerns Expressed Following the Publication of the Results of the IQ/CSRC Study -- 8.7 Details of ICH E14 Q & A R3 -- 8.7.1 Important Considerations -- 8.7.2 Decision-Making -- 8.7.3 Other Uses -- 8.7.3.1 Providing Insight into Regimens Not Studied Directly -- 8.7.3.2 Predicting QTc Effects of Intrinsic and Extrinsic Factors that Affect PK -- 8.7.4 Comparison of Previously Noted Concerns with the Text of ICH E14 Q & A R3 -- 8.8 Anticipating Many Discussions of ICH E14 Q & A R3 |
| Summary |
With the advent of multiple new therapeutic agents for a variety of important diseases has come an increasing realization that many of these drugs can have adverse effects on the heart and vascular system. As this book so elegantly details the mechanisms by which harm occurs are highly complex, many times predictable, but always clinically relevant. Notable experts in the field of cardiovascular medicine, such as Drs. Turner, Karnad, and Kothari, have turned their attention to this thorny problem, and begun to dissect the diverse mechanisms by which cardiac harm can occur with a variety of non-cardiac drugs. This is no easy task, given the complexity of the diseases we treat, and the wide spectrum of new therapies we seek to apply. However, it is an issue with which all health care providers must become familiar in order to prescribe appropriate therapy while safeguarding patients against avoidable and life-threatening cardiac adverse effects. This compendium represents the state-of-the-art in the evolving field of cardiac safety and is vital reading for those interested in developing new chemical entities, as well as those who prescribe them and monitor patients for their hazard. As such, I recommend this book as essential reading for students, scientists, and health care providers at all levels of training. Peter R. Kowey, MD, FACC, FAHA, FHRS Lankenau Institute for Medical Research & Thomas Jefferson University |
| Bibliography |
Includes bibliographical references |
| Notes |
Online resource; title from PDF title page (SpringerLink, viewed August 9, 2016) |
| Subject |
Drugs -- Side effects.
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Drug development.
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Drugs -- Design.
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Cardiovascular Diseases -- etiology
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Drug Design
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Cardiotoxicity -- prevention & control
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Drug Evaluation, Preclinical
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Drug-Related Side Effects and Adverse Reactions
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MEDICAL -- Pharmacology.
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Drugs -- Design
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Drug development
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Drugs -- Side effects
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| Form |
Electronic book
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| Author |
Karnad, Dilip R., author
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Kothari, Snehal, author
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| ISBN |
9783319403472 |
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3319403478 |
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