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

by Turner, J. Rick; Durham, Todd A.

Edition: 1st

ISBN13: 9780470229644

ISBN10: 0470229640

Format: Hardcover

Pub. Date: 2008-11-03

Publisher(s): Wiley

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Summary

This book covers cardiac safety assessment of drugs at all stages of the lifecycle from discovery thru postmarket research. The focus is on cardiac safety of those drugs that do not target the cardiovascular system, meaning cardiac safety as a possible side effect of drugs. Such safety issues are the leading cause of drug withdrawals from market and failures during development and trial stages. In this self-contained, reader-friendly approach, the author looks at cardiac safety assessments at all stages of a drug's lifecycle - including drug discovery, non-clinical research, pre-approval clinical trials, and post marketing research - along with guidance and methodology for assessing cardiac safety.

Author Biography

J. Rick Turner, PhD, PGCE, MICR, is Chairman, Department of Clinical Research at Campbell University School of Pharmacy. Dr. Turner has extensive teaching, research, and pharmaceutical credentials and more than a dozen awards and honors, including a Commit to Product Development Award from GlaxoSmithKline. He is the author of seven books and more than 100 journal articles and published abstracts. TODD A. DURHAM, MS, is Senior Director of Biostatistics and Data Management at Inspire Pharmaceuticals. Prior to joining Inspire, Mr. Durham served as Associate Director of Biostatistics at Quintiles, Inc. Mr. Durham has made significant statistical contributions to six NDA submissions and has been involved with five presentations to FDA advisory committees.

Foreword	p. XIII
Preface	p. XV
Acknowledgments	p. XXIII
Abbreviations	p. XXV
Introduction
The Importance of Cardiac Safety Assessments
Introduction	p. 1
Lifecycle Drug Development	p. 2
The International Committee on Harmonisation	p. 6
Regulatory Agencies	p. 9
The Role of Benefit-risk Assessment	p. 11
Benefit-risk Estimates	p. 13
Formalized Drug Safety Is a Relatively Young Discipline	p. 16
Integrated Cardiac Safety	p. 17
Teaching and Learning Objectives of This Book	p. 22
Further Reading	p. 23
The Biological Basis of Adverse Drug Reactions
Introduction	p. 25
Individual Variation in Responses to Drugs	p. 25
Deoxyribonucleic Acid	p. 26
Transmission Genetics and Molecular Genetics	p. 31
The Pioneering Work of Morgan using Drosophila melanogaster	p. 31
Genes and the Human Genome Project	p. 32
Proteomics and Transcriptomics	p. 35
Gene Expression	p. 36
Proteins	p. 39
Cells	p. 40
Cell Membranes	p. 43
Proteins in Cell Membranes	p. 43
Ion Channels	p. 45
Receptors	p. 47
Enzymes	p. 48
Posttranslational Modification	p. 50
Genetic Mutations as Causes of Changes in Three-dimensional Molecular Geometry	p. 51
Mechanisms of Action	p. 53
The Promise of Precision Pharmaceutical Medicine	p. 53
Summary	p. 54
Cardiac Function and Pathology
Cardiac Structure and Function
Introduction	p. 55
The Heart	p. 55
Cardiovascular Parameters of Interest	p. 58
The Autonomic Nervous System	p. 60
The Endocrine System	p. 61
Overview of the Cardiac Conduction System	p. 62
The Cardiac Transmembrane Potential	p. 64
Phases of the Action Potential	p. 65
One Repolarizing Current of Specific Interest in Proarrhythmic Cardiac Safety	p. 68
Protein Trafficking	p. 71
Cardiac Pathophysiology and Disease
Introduction	p. 73
Arrhythmias	p. 73
Cardiac Channelopathies: Inherited LQTS	p. 75
Drug-induced QT Interval Prolongation and TdP: The Causal Link	p. 81
How Do Noncardiac Drugs Lead to Loss of Function in hERG Channels?	p. 82
Dispersion of Repolarization	p. 83
Trafficking Deficiencies in Inherited LQTS	p. 84
Cardiac and Cardiovascular Diseases	p. 87
Hypertension	p. 87
Coronary Heart Disease	p. 88
Heart Failure	p. 90
Sudden Cardiac Death	p. 91
Further Reading	p. 92
Drug Discovery and Nonclinical Development
Drug Discovery and Drug Design
Introduction	p. 93
Medicinal Chemistry	p. 94
Drug Design: Structural Molecular Engineering	p. 95
Bioinformatics	p. 99
Computer-assisted Molecular Design	p. 100
In Silico Modeling and the hERG Channel	p. 101
Further Reading	p. 105
Nonclinical Development
Introduction	p. 111
The Need for Nonclinical Research	p. 111
The Strengths and Limitations of Nonclinical Data	p. 112
Pharmacokinetics	p. 113
Pharmacology Studies	p. 114
Toxicological Studies	p. 116
Investigation of Torsadogenic Liability	p. 117
Methodologies for the Nonclinical Investigation of QT Interval Prolongation	p. 119
"Correcting" QT Interval Measurements for the Concurrent Heart Rate	p. 121
QT Prolongation Is Not the Only Parameter of Interest	p. 122
Additional Nonclinical Considerations and Investigations	p. 123
Attempting to Extrapolate from Nonclinical Data to Human Responses	p. 123
Stem Cell Research and Its Implications for Cardiotoxicity Research	p. 125
Investigation of Torsadogenic Liability for Biologicals	p. 125
What Nonclinical QT Liability Assessments Are Appropriate for Biologicals?	p. 128
Further Reading	p. 132
Preapproval Clinical Development
The Thorough QT/QTc Study
Introduction	p. 135
Benefit-risk Assessments in the Context of the TQT Study	p. 137
Nomenclature Considerations	p. 138
A Brief Recap of Acquired QT Interval Prolongation and TdP	p. 140
Correction of the QT Interval - QTc	p. 141
The ICH Guidance E14	p. 144
Confidence Intervals and Their Employment in Hypothesis Testing	p. 146
Study Design Considerations	p. 149
Data Collection: Measurement of QT Intervals	p. 155
Endpoints Evaluated in the TQT Study	p. 158
Considerations for Statistical Analysis of TQT Study Results	p. 165
The Issue of Multiplicity	p. 172
Sample Size Considerations	p. 175
Adverse Events	p. 175
Interpretations and Implications of TQT Study Results for Future Studies during the Preapproval Clinical Development Program	p. 176
Torsadogenic Liability Evaluation When a Traditional TQT Study Cannot Be Conducted	p. 176
Torsadogenic Liability Evaluations for Biologicals	p. 180
Labeling Implications of QT Liability Assessments	p. 181
Trends Identified from Recent Drug Approvals	p. 181
The Cardiac Safety Research Consortium	p. 182
Short QT Syndrome	p. 184
Further Reading	p. 186
General Safety Assessments
Introduction	p. 193
Statistical Analysis and Interpretation in Drug Development	p. 194
Physical Examinations	p. 198
Clinical Laboratory Tests	p. 198
Vital Signs	p. 202
Adverse Event Data	p. 203
Issues of Multiplicity	p. 222
Regulatory Considerations for Safety Data	p. 223
The Contrast with Regulatory Guidance Concerning Proarrhythmic Cardiac Safety	p. 227
Authors' Perspectives	p. 228
Further Reading	p. 230
Postmarketing Assessment Methodologies
Therapeutic Use Trials and Meta-analyses
Introduction	p. 231
Nomenclature Considerations	p. 232
Limitations of Preapproval Clinical Trials	p. 233
Therapeutic Use Trials	p. 237
Introduction to Meta-analysis	p. 240
The Basic Steps in Meta-analysis	p. 241
Identifying All Relevant Studies: Publication Bias I	p. 242
Establishing Inclusion and Exclusion Criteria: Publication Bias II	p. 244
Data Abstraction and Acquisition: Individual Participant Data	p. 245
Data Analysis	p. 246
Evaluating Robustness	p. 253
Dissemination of Results and Conclusions of a Meta-analysis	p. 254
An Additional Consideration	p. 254
The Cochrane Collaboration	p. 255
Further Reading	p. 256
Assessment Methodologies in Nonexperimental Postmarketing Surveillance
Introduction	p. 259
Using Information from Experimental and Nonexperimental Studies	p. 259
Nomenclature Considerations	p. 261
Adverse Drug Reactions	p. 263
The Nature of Postmarketing Surveillance	p. 266
Spontaneous Reporting and Safety Signals	p. 267
Nonregulatory Organizations' Involvement in Pharmacovigilance	p. 268
The Science of Pharmacovigilance	p. 270
Active Postmarketing Surveillance	p. 271
Epidemiology at the U.S. Food and Drug Administration	p. 271
Assessment Methodologies in Postmarketing Surveillance	p. 272
Methods for the Capture of Postmarketing Surveillance Data	p. 276
Data Mining	p. 278
The ICH Guidance E2E: Pharmacovigilance Planning	p. 278
Future Methodological Developments	p. 279
Acknowledgment	p. 280
Further Reading	p. 280
Postmarketing Proarrythmic Cardiac Safety Assessments
Introduction	p. 285
Examples of Relevant Drug Withdrawals	p. 285
Case Studies	p. 287
A Brief History of the Development of ICH Guidances S7B and E14	p. 289
Preapproval Identification of QT Liability Does Not Necessarily Mean That the Investigational Drug Will Not Be Approved	p. 290
Generalized Cardiac Safety
Introduction	p. 293
Case Study I: Rofecoxib	p. 294
Case Study II: Rosiglitazone	p. 300
Case Study III: Aprotinin Injection	p. 315
Oncology Treatment and Cardiotoxicity	p. 316
General Discussions	p. 318
Further Reading	p. 323
Behavioral Drug Safety
Medication Errors, Adherence, and Concordance
Introduction	p. 329
The "Five Rights" of Safe Medication Use	p. 331
The Institute of Medicine's 2000 Report To Err Is Human	p. 332
Recommendations in To Err Is Human	p. 334
The Institute of Medicine's 2001 Report Crossing the Quality Chasm	p. 339
The Institute of Medicine's 2004 Report Patient Safety	p. 342
The Institute of Medicine's 2007 Report Preventing Medication Errors	p. 344
Adherence to Pharmaceutical Treatment Regimens	p. 346
Concordance	p. 348
Further Reading: Medication Errors	p. 350
Further Reading: Adherence and Concordance	p. 352
Integrative Discussion
Future Directions in Drug Safety
Introduction	p. 357
Future Developments in Torsadogenic Liability Assessment	p. 358
The Prescription Drug User Fee Act	p. 362
Three Related FDA Guidances on Risk Management	p. 363
The FDA Premarketing Risk Assessment Guidance	p. 364
The FDA Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment Guidance	p. 366
The FDA Development and Use of Risk Minimization Action Plans Guidance	p. 367
Reports on the Status of Postmarketing Study Commitments	p. 368
Reporting Adverse Events to Investigational Review Boards	p. 369
FDA's Communication to the Public	p. 372
The Institute of Medicine's Report The Future of Drug Safety	p. 373
The Food and Drug Administration Amendments Act of 2007	p. 375
The FDA's Drug Safety Five-year Plan	p. 377
The FDA's Sentinel Initiative and the Science of Safety	p. 379
Decision Making Related to Benefit-risk Assessments	p. 381
Pharmacogenetics, Pharmacogenomics, and Precision Medicine	p. 383
Biomarkers and Clinical Endpoints	p. 386
Drug Development and Drug Therapy: Benefit-risk Assessments	p. 387
Losing Good Drugs for Bad Reasons	p. 390
Reflections on Central Themes in the Book	p. 391
The FDA's Critical Path Initiative: The Right Path	p. 393
European Drug Safety Activities	p. 394
Concluding Comments	p. 396
Further Reading	p. 396
References	p. 425
Index	p. 457
Table of Contents provided by Ingram. All Rights Reserved.

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