Integrated Cardiac Safety : Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing Surveillance.

By: Turner, J. RickContributor(s): Durham, Todd AMaterial type: TextTextPublisher: Hoboken : John Wiley & Sons, Incorporated, 2008Copyright date: ©2009Edition: 1st edDescription: 1 online resource (500 pages)Content type: text Media type: computer Carrier type: online resourceISBN: 9780470411285Subject(s): Cardiovascular toxicology | Drugs -- Safety measures | Drugs -- Side effects -- Testing | Heart -- Effect of drugs onGenre/Form: Electronic books.Additional physical formats: Print version:: Integrated Cardiac Safety : Assessment Methodologies for Noncardiac Drugs in Discovery, Development, and Postmarketing SurveillanceDDC classification: 616.1/23061 LOC classification: RC677 -- .T87 2009ebOnline resources: Click to View
Contents:
Intro -- Integrated Cardiac Safety -- Contents -- Foreword -- Preface -- Acknowledgments -- Abbreviations -- PART I INTRODUCTION -- Chapter 1. The Importance of Cardiac Safety Assessments -- 1.1 Introduction -- 1.2 Lifecycle Drug Development -- 1.3 The International Committee on Harmonisation -- 1.4 Regulatory Agencies -- 1.5 The Role of Benefit-risk Assessment -- 1.6 Benefit-risk Estimates -- 1.7 Formalized Drug Safety Is a Relatively Young Discipline -- 1.8 Integrated Cardiac Safety -- 1.9 Teaching and Learning Objectives of This Book -- 1.10 Further Reading -- Chapter 2. The Biological Basis of Adverse Drug Reactions -- 2.1 Introduction -- 2.2 Individual Variation in Responses to Drugs -- 2.3 Deoxyribonucleic Acid -- 2.4 Transmission Genetics and Molecular Genetics -- 2.5 The Pioneering Work of Morgan using Drosophila melanogaster -- 2.6 Genes and the Human Genome Project -- 2.7 Proteomics and Transcriptomics -- 2.8 Gene Expression -- 2.9 Proteins -- 2.10 Cells -- 2.11 Cell Membranes -- 2.12 Proteins in Cell Membranes -- 2.13 Ion Channels -- 2.14 Receptors -- 2.15 Enzymes -- 2.16 Posttranslational Modification -- 2.17 Genetic Mutations as Causes of Changes in Three-dimensional Molecular Geometry -- 2.18 Mechanisms of Action -- 2.19 The Promise of Precision Pharmaceutical Medicine -- 2.20 Summary -- PART II CARDIAC FUNCTION AND PATHOLOGY -- Chapter 3. Cardiac Structure and Function -- 3.1 Introduction -- 3.2 The Heart -- 3.4 Cardiovascular Parameters of Interest -- 3.5 The Autonomic Nervous System -- 3.6 The Endocrine System -- 3.7 Overview of the Cardiac Conduction System -- 3.8 The Cardiac Transmembrane Potential -- 3.9 Phases of the Action Potential -- 3.10 One Repolarizing Current of Specific Interest in Proarrhythmic Cardiac Safety -- 3.11 Protein Trafficking -- Chapter 4. Cardiac Pathophysiology and Disease -- 4.1 Introduction.
4.2 Arrhythmias -- 4.3 Cardiac Channelopathies: Inherited LQTS -- 4.4 Drug-induced QT Interval Prolongation and TdP: The Causal Link -- 4.5 How Do Noncardiac Drugs Lead to Loss of Function in hERG Channels? -- 4.6 Dispersion of Repolarization -- 4.7 Trafficking Deficiencies in Inherited LQTS -- 4.8 Cardiac and Cardiovascular Diseases -- 4.9 Hypertension -- 4.10 Coronary Heart Disease -- 4.11 Heart Failure -- 4.12 Sudden Cardiac Death -- 4.13 Further Reading -- PART III DRUG DISCOVERY AND NONCLINICAL DEVELOPMENT -- Chapter 5. Drug Discovery and Drug Design -- 5.1 Introduction -- 5.2 Medicinal Chemistry -- 5.3 Drug Design: Structural Molecular Engineering -- 5.4 Bioinformatics -- 5.5 Computer-assisted Molecular Design -- 5.6 In Silico Modeling and the hERG Channel -- 5.7 Further Reading -- Chapter 6. Nonclinical Development -- 6.1 Introduction -- 6.2 The Need for Nonclinical Research -- 6.3 The Strengths and Limitations of Nonclinical Data -- 6.4 Pharmacokinetics -- 6.5 Pharmacology Studies -- 6.6 Toxicological Studies -- 6.7 Investigation of Torsadogenic Liability -- 6.8 Methodologies for the Nonclinical Investigation of QT Interval Prolongation -- 6.9 "Correcting" QT Interval Measurements for the Concurrent Heart Rate -- 6.10 Qt Prolongation Is Not the Only Parameter of Interest -- 6.11 Additional Nonclinical Considerations and Investigations -- 6.12 Attempting to Extrapolate from Nonclinical Data to Human Responses -- 6.13 Stem Cell Research and Its Implications for Cardiotoxicity Research -- 6.14 Investigation of Torsadogenic Liability for Biologicals -- 6.15 What Nonclinical QT Liability Assessments Are Appropriate For Biologicals? -- 6.16 Further Reading -- PART IV PREAPPROVAL CLINICAL DEVELOPMENT -- Chapter 7. The Thorough QT/QTc Study -- 7.1 Introduction -- 7.2 Benefit-risk Assessments in the Context of the TQT Study.
7.3 Nomenclature Considerations -- 7.4 A Brief Recap of Acquired Qt Interval Prolongation and TdP -- 7.5 Correction of the QT Interval - QTc -- 7.6 The ICH Guidance E14 -- 7.7 Confidence Intervals and Their Employment in Hypothesis Testing -- 7.8 Study Design Considerations -- 7.9 Data Collection: Measurement of QT Intervals -- 7.10 Endpoints Evaluated in the TQT Study -- 7.11 Considerations for Statistical Analysis of TQT Study Results -- 7.12 The Issue of Multiplicity -- 7.13 Sample Size Considerations -- 7.14 Adverse Events -- 7.15 Interpretations and Implications of TQT Study Results for Future Studies During The Preapproval Clinical Development Program -- 7.16 Torsadogenic Liability Evaluation When a Traditional TQT Study Cannot Be Conducted -- 7.17 Torsadogenic Liability Evaluations for Biologicals -- 7.18 Labeling Implications of QT Liability Assessments -- 7.19 Trends Identified from Recent Drug Approvals -- 7.20 The Cardiac Safety Research Consortium -- 7.21 Short QT Syndrome -- 7.22 Further Reading -- Chapter 8. General Safety Assessments -- 8.1 Introduction -- 8.2 Statistical Analysis and Interpretation in Drug Development -- 8.3 Physical Examinations -- 8.4 Clinical Laboratory Tests -- 8.5 Vital Signs -- 8.6 Adverse Event Data -- 8.7 Issues of Multiplicity -- 8.8 Regulatory Considerations for Safety Data -- 8.9 The Contrast with Regulatory Guidance Concerning Proarrhythmic Cardiac Safety -- 8.10 Authors' Perspectives -- 8.11 Further Reading -- PART V POSTMARKETING ASSESSMENT METHODOLOGIES -- Chapter 9. Therapeutic Use Trials and Meta-analyses -- 9.1 Introduction -- 9.2 Nomenclature Considerations -- 9.3 Limitations of Preapproval Clinical Trials -- 9.4 Therapeutic Use Trials -- 9.5 Introduction to Meta-analysis -- 9.6 The Basic Steps in Meta-analysis -- 9.7 Identifying All Relevant Studies: Publication Bias I.
9.8 Establishing Inclusion and Exclusion Criteria: Publication Bias II -- 9.9 Data Abstraction and Acquisition: Individual Participant Data -- 9.10 Data Analysis -- 9.11 Evaluating Robustness -- 9.12 Dissemination of Results and Conclusions of a Meta-analysis -- 9.13 An Additional Consideration -- 9.14 The Cochrane Collaboration -- 9.15 Further Reading -- Chapter 10. Assessment Methodologies in Nonexperimental Postmarketing Surveillance -- 10.1 Introduction -- 10.2 Using Information from Experimental and Nonexperimental Studies -- 10.3 Nomenclature Considerations -- 10.4 Adverse Drug Reactions -- 10.5 The Nature of Postmarketing Surveillance -- 10.6 Spontaneous Reporting and Safety Signals -- 10.7 Nonregulatory Organizations Involvement in Pharmacovigilance -- 10.8 The Science of Pharmacovigilance -- 10.9 Active Postmarketing Surveillance -- 10.10 Epidemiology at the U.S. Food and Drug Administration -- 10.11 Assessment Methodologies in Postmarketing Surveillance -- 10.12 Methods for the Capture of Postmarketing Surveillance Data -- 10.13 Data Mining -- 10.14 The ICH Guidance E2E: Pharmacovigilance Planning -- 10.15 Future Methodological Developments -- 10.16 Acknowledgment -- 10.17 Further Reading -- Chapter 11. Postmarketing Proarrythmic Cardiac Safety Assessments -- 11.1 Introduction -- 11.2 Examples of Relevant Drug Withdrawals -- 11.3 Case Studies -- 11.4 A Brief History of the Development of ICH Guidances S7B and El4 -- 11.5 Preapproval Identification of QT Liability Does Not Necessarily Mean That the Investigational Drug Will Not Be Approved -- Chapter 12. Generalized Cardiac Safety -- 12.1 Introduction -- 12.2 Case Study I: Rofecoxib -- 12.3 Case Study II: Rosiglitazone -- 12.4 Case Study III: Aprotinin Injection -- 12.5 Oncology Treatment and Cardiotoxicity -- 12.6 General Discussions -- 12.7 Further Reading -- PART VI BEHAVIORAL DRUG SAFETY.
Chapter 13. Medication Errors, Adherence, and Concordance -- 13.1 Introduction -- 13.2 The "Five Rights" of Safe Medication Use -- 13.3 The Institute of Medicine's 2000 Report To Err Is Human -- 13.4 Recommendations in To Err Is Human -- 13.5 The Institute of Medicine's 2001 Report Crossing the Quality Chasm -- 13.6 The Institute of Medicine's 2004 Report Patient Safety -- 13.7 The Institute of Medicine's 2007 Report Preventing Medication Errors -- 13.8 Adherence to Pharmaceutical Treatment Regimens -- 13.9 Concordance -- 13.10 Further Reading: Medication Errors -- 13.11 Further Reading: Adherence and Concordance -- PART VII INTEGRATIVE DISCUSSION -- Chapter 14. Future Directions in Drug Safety -- 14.1 Introduction -- 14.2 Future Developments in Torsadogenic Liability Assessment -- 14.3 The Prescription Drug User Fee Act -- 14.4 Three Related FDA Guidances on Risk Management -- 14.5 The FDA Premarketing Risk Assessment Guidance -- 14.6 The FDA Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment Guidance -- 14.7 The FDA Development and Use of Risk Minimization Action Plans Guidance -- 14.8 Reports on the Status of Postmarketing Study Commitments -- 14.9 Reporting Adverse Events to Investigational Review Boards -- 14.10 FDA's Communication to the Public -- 14.11 The Institute of Medicine's Report The Future of Drug Safety -- 14.12 The Food and Drug Administration Amendments Act of 2007 -- 14.13 The FDA's Drug Safety Five-year Plan -- 14.14 The FDA's Sentinel Initiative and the Science of Safety -- 14.15 Decision Making Related to Benefit-risk Assessments -- 14.16 Pharmacogenetics, Pharmacogenomics, and Precision Medicine -- 14.17 Biomarkers and Clinical Endpoints -- 14.18 Drug Development and Drug Therapy: Benefit-risk Assessments -- 14.19 Losing Good Drugs for Bad Reasons -- 14.20 Reflections on Central Themes in the Book.
14.21 The FDA's Critical Path Initiative: The Right Path.
Summary: The serious nature of cardiovascular adverse drug reactions occurring in patients makes assessment of a drug's cardiac safety profile a high priority during both development and post-approval monitoring. Integrated Cardiac Safety provides necessary guidance and methodology for professionals assessing cardiac safety of drugs throughout all stages of the drug's life, from discovery and development through postmarketing research. This self-contained, reader-friendly text is valuable to professionals in the pharmaceutical, biotechnology, and CRO industries, pharmacologists, toxicologists, government officials, and students.
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Intro -- Integrated Cardiac Safety -- Contents -- Foreword -- Preface -- Acknowledgments -- Abbreviations -- PART I INTRODUCTION -- Chapter 1. The Importance of Cardiac Safety Assessments -- 1.1 Introduction -- 1.2 Lifecycle Drug Development -- 1.3 The International Committee on Harmonisation -- 1.4 Regulatory Agencies -- 1.5 The Role of Benefit-risk Assessment -- 1.6 Benefit-risk Estimates -- 1.7 Formalized Drug Safety Is a Relatively Young Discipline -- 1.8 Integrated Cardiac Safety -- 1.9 Teaching and Learning Objectives of This Book -- 1.10 Further Reading -- Chapter 2. The Biological Basis of Adverse Drug Reactions -- 2.1 Introduction -- 2.2 Individual Variation in Responses to Drugs -- 2.3 Deoxyribonucleic Acid -- 2.4 Transmission Genetics and Molecular Genetics -- 2.5 The Pioneering Work of Morgan using Drosophila melanogaster -- 2.6 Genes and the Human Genome Project -- 2.7 Proteomics and Transcriptomics -- 2.8 Gene Expression -- 2.9 Proteins -- 2.10 Cells -- 2.11 Cell Membranes -- 2.12 Proteins in Cell Membranes -- 2.13 Ion Channels -- 2.14 Receptors -- 2.15 Enzymes -- 2.16 Posttranslational Modification -- 2.17 Genetic Mutations as Causes of Changes in Three-dimensional Molecular Geometry -- 2.18 Mechanisms of Action -- 2.19 The Promise of Precision Pharmaceutical Medicine -- 2.20 Summary -- PART II CARDIAC FUNCTION AND PATHOLOGY -- Chapter 3. Cardiac Structure and Function -- 3.1 Introduction -- 3.2 The Heart -- 3.4 Cardiovascular Parameters of Interest -- 3.5 The Autonomic Nervous System -- 3.6 The Endocrine System -- 3.7 Overview of the Cardiac Conduction System -- 3.8 The Cardiac Transmembrane Potential -- 3.9 Phases of the Action Potential -- 3.10 One Repolarizing Current of Specific Interest in Proarrhythmic Cardiac Safety -- 3.11 Protein Trafficking -- Chapter 4. Cardiac Pathophysiology and Disease -- 4.1 Introduction.

4.2 Arrhythmias -- 4.3 Cardiac Channelopathies: Inherited LQTS -- 4.4 Drug-induced QT Interval Prolongation and TdP: The Causal Link -- 4.5 How Do Noncardiac Drugs Lead to Loss of Function in hERG Channels? -- 4.6 Dispersion of Repolarization -- 4.7 Trafficking Deficiencies in Inherited LQTS -- 4.8 Cardiac and Cardiovascular Diseases -- 4.9 Hypertension -- 4.10 Coronary Heart Disease -- 4.11 Heart Failure -- 4.12 Sudden Cardiac Death -- 4.13 Further Reading -- PART III DRUG DISCOVERY AND NONCLINICAL DEVELOPMENT -- Chapter 5. Drug Discovery and Drug Design -- 5.1 Introduction -- 5.2 Medicinal Chemistry -- 5.3 Drug Design: Structural Molecular Engineering -- 5.4 Bioinformatics -- 5.5 Computer-assisted Molecular Design -- 5.6 In Silico Modeling and the hERG Channel -- 5.7 Further Reading -- Chapter 6. Nonclinical Development -- 6.1 Introduction -- 6.2 The Need for Nonclinical Research -- 6.3 The Strengths and Limitations of Nonclinical Data -- 6.4 Pharmacokinetics -- 6.5 Pharmacology Studies -- 6.6 Toxicological Studies -- 6.7 Investigation of Torsadogenic Liability -- 6.8 Methodologies for the Nonclinical Investigation of QT Interval Prolongation -- 6.9 "Correcting" QT Interval Measurements for the Concurrent Heart Rate -- 6.10 Qt Prolongation Is Not the Only Parameter of Interest -- 6.11 Additional Nonclinical Considerations and Investigations -- 6.12 Attempting to Extrapolate from Nonclinical Data to Human Responses -- 6.13 Stem Cell Research and Its Implications for Cardiotoxicity Research -- 6.14 Investigation of Torsadogenic Liability for Biologicals -- 6.15 What Nonclinical QT Liability Assessments Are Appropriate For Biologicals? -- 6.16 Further Reading -- PART IV PREAPPROVAL CLINICAL DEVELOPMENT -- Chapter 7. The Thorough QT/QTc Study -- 7.1 Introduction -- 7.2 Benefit-risk Assessments in the Context of the TQT Study.

7.3 Nomenclature Considerations -- 7.4 A Brief Recap of Acquired Qt Interval Prolongation and TdP -- 7.5 Correction of the QT Interval - QTc -- 7.6 The ICH Guidance E14 -- 7.7 Confidence Intervals and Their Employment in Hypothesis Testing -- 7.8 Study Design Considerations -- 7.9 Data Collection: Measurement of QT Intervals -- 7.10 Endpoints Evaluated in the TQT Study -- 7.11 Considerations for Statistical Analysis of TQT Study Results -- 7.12 The Issue of Multiplicity -- 7.13 Sample Size Considerations -- 7.14 Adverse Events -- 7.15 Interpretations and Implications of TQT Study Results for Future Studies During The Preapproval Clinical Development Program -- 7.16 Torsadogenic Liability Evaluation When a Traditional TQT Study Cannot Be Conducted -- 7.17 Torsadogenic Liability Evaluations for Biologicals -- 7.18 Labeling Implications of QT Liability Assessments -- 7.19 Trends Identified from Recent Drug Approvals -- 7.20 The Cardiac Safety Research Consortium -- 7.21 Short QT Syndrome -- 7.22 Further Reading -- Chapter 8. General Safety Assessments -- 8.1 Introduction -- 8.2 Statistical Analysis and Interpretation in Drug Development -- 8.3 Physical Examinations -- 8.4 Clinical Laboratory Tests -- 8.5 Vital Signs -- 8.6 Adverse Event Data -- 8.7 Issues of Multiplicity -- 8.8 Regulatory Considerations for Safety Data -- 8.9 The Contrast with Regulatory Guidance Concerning Proarrhythmic Cardiac Safety -- 8.10 Authors' Perspectives -- 8.11 Further Reading -- PART V POSTMARKETING ASSESSMENT METHODOLOGIES -- Chapter 9. Therapeutic Use Trials and Meta-analyses -- 9.1 Introduction -- 9.2 Nomenclature Considerations -- 9.3 Limitations of Preapproval Clinical Trials -- 9.4 Therapeutic Use Trials -- 9.5 Introduction to Meta-analysis -- 9.6 The Basic Steps in Meta-analysis -- 9.7 Identifying All Relevant Studies: Publication Bias I.

9.8 Establishing Inclusion and Exclusion Criteria: Publication Bias II -- 9.9 Data Abstraction and Acquisition: Individual Participant Data -- 9.10 Data Analysis -- 9.11 Evaluating Robustness -- 9.12 Dissemination of Results and Conclusions of a Meta-analysis -- 9.13 An Additional Consideration -- 9.14 The Cochrane Collaboration -- 9.15 Further Reading -- Chapter 10. Assessment Methodologies in Nonexperimental Postmarketing Surveillance -- 10.1 Introduction -- 10.2 Using Information from Experimental and Nonexperimental Studies -- 10.3 Nomenclature Considerations -- 10.4 Adverse Drug Reactions -- 10.5 The Nature of Postmarketing Surveillance -- 10.6 Spontaneous Reporting and Safety Signals -- 10.7 Nonregulatory Organizations Involvement in Pharmacovigilance -- 10.8 The Science of Pharmacovigilance -- 10.9 Active Postmarketing Surveillance -- 10.10 Epidemiology at the U.S. Food and Drug Administration -- 10.11 Assessment Methodologies in Postmarketing Surveillance -- 10.12 Methods for the Capture of Postmarketing Surveillance Data -- 10.13 Data Mining -- 10.14 The ICH Guidance E2E: Pharmacovigilance Planning -- 10.15 Future Methodological Developments -- 10.16 Acknowledgment -- 10.17 Further Reading -- Chapter 11. Postmarketing Proarrythmic Cardiac Safety Assessments -- 11.1 Introduction -- 11.2 Examples of Relevant Drug Withdrawals -- 11.3 Case Studies -- 11.4 A Brief History of the Development of ICH Guidances S7B and El4 -- 11.5 Preapproval Identification of QT Liability Does Not Necessarily Mean That the Investigational Drug Will Not Be Approved -- Chapter 12. Generalized Cardiac Safety -- 12.1 Introduction -- 12.2 Case Study I: Rofecoxib -- 12.3 Case Study II: Rosiglitazone -- 12.4 Case Study III: Aprotinin Injection -- 12.5 Oncology Treatment and Cardiotoxicity -- 12.6 General Discussions -- 12.7 Further Reading -- PART VI BEHAVIORAL DRUG SAFETY.

Chapter 13. Medication Errors, Adherence, and Concordance -- 13.1 Introduction -- 13.2 The "Five Rights" of Safe Medication Use -- 13.3 The Institute of Medicine's 2000 Report To Err Is Human -- 13.4 Recommendations in To Err Is Human -- 13.5 The Institute of Medicine's 2001 Report Crossing the Quality Chasm -- 13.6 The Institute of Medicine's 2004 Report Patient Safety -- 13.7 The Institute of Medicine's 2007 Report Preventing Medication Errors -- 13.8 Adherence to Pharmaceutical Treatment Regimens -- 13.9 Concordance -- 13.10 Further Reading: Medication Errors -- 13.11 Further Reading: Adherence and Concordance -- PART VII INTEGRATIVE DISCUSSION -- Chapter 14. Future Directions in Drug Safety -- 14.1 Introduction -- 14.2 Future Developments in Torsadogenic Liability Assessment -- 14.3 The Prescription Drug User Fee Act -- 14.4 Three Related FDA Guidances on Risk Management -- 14.5 The FDA Premarketing Risk Assessment Guidance -- 14.6 The FDA Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment Guidance -- 14.7 The FDA Development and Use of Risk Minimization Action Plans Guidance -- 14.8 Reports on the Status of Postmarketing Study Commitments -- 14.9 Reporting Adverse Events to Investigational Review Boards -- 14.10 FDA's Communication to the Public -- 14.11 The Institute of Medicine's Report The Future of Drug Safety -- 14.12 The Food and Drug Administration Amendments Act of 2007 -- 14.13 The FDA's Drug Safety Five-year Plan -- 14.14 The FDA's Sentinel Initiative and the Science of Safety -- 14.15 Decision Making Related to Benefit-risk Assessments -- 14.16 Pharmacogenetics, Pharmacogenomics, and Precision Medicine -- 14.17 Biomarkers and Clinical Endpoints -- 14.18 Drug Development and Drug Therapy: Benefit-risk Assessments -- 14.19 Losing Good Drugs for Bad Reasons -- 14.20 Reflections on Central Themes in the Book.

14.21 The FDA's Critical Path Initiative: The Right Path.

The serious nature of cardiovascular adverse drug reactions occurring in patients makes assessment of a drug's cardiac safety profile a high priority during both development and post-approval monitoring. Integrated Cardiac Safety provides necessary guidance and methodology for professionals assessing cardiac safety of drugs throughout all stages of the drug's life, from discovery and development through postmarketing research. This self-contained, reader-friendly text is valuable to professionals in the pharmaceutical, biotechnology, and CRO industries, pharmacologists, toxicologists, government officials, and students.

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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2018. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.

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