Cardiac Safety of Noncardiac Drugs

It is generally easy to define the efficacy of a new the- peutic agent. However, what is even more difficult and more challenging yet more important is to define its safety when administered to millions of patients with multi-faceted d- eases, co-morbidities, sensitivities and concomitant medi- tions. The commonest cause of new drug discontinuations, cause for disapproval from marketing and removal from the market after approval is a drug¿s effect on cardiac repolari- tion which is essentially identified by increasing the duration of the QTc interval duration on the standard 12-lead elect- cardiogram (ECG). Cardiac Safety of Noncardiac Drugs: Practical Guide- Joel Morganroth, MD lines for Clinical Research and Drug Development is designed to present the current preclinical, clinical, and re- latory principles to assess the cardiac safety of new drugs based primarily on their effects on the ECG. Practical gu- ance to define cardiac safety at all stages of clinical research and drug development are featured and discussed by inter- tionally recognized experts with academic, industrial, and regulatory experience. Each chapter contains the best ava- able evidence, the author¿s personal opinions, areas of c- troversy, and future trends. Although some of the areas are highly specialized, this book has been designed for a broad audience ranging from medical and graduate students to cli- cal nurses, clinical trial coordinators, safety officers, data managers, statisticians, regulatory authorities, clinicians, and Ihor Gussak, MD, PhD scientists.

Includes supplementary material: sn.pub/extras

Part I. Introduction
Cardiac Safety of Noncardiac Drugs: Historical Recollections
Raymond John Lipicky
Part II. Preclinical and Pharmacogenomic Cardiac Safety Evaluations
Molecular Physiology of Ion Channels That Control Cardiac Repolarization
Jeanne M. Nerbonne and Robert S. Kass
Cellular, Molecular, and Pharmacologic Mechanisms Underlying Drug-Induced Cardiac Arrhythmogenesis
Charles Antzelevitch
hERG Assay, QT Liability, and Sudden Cardiac Death
Arthur M. Brown
Pharmacogenomics in Drug Development: When and How to Apply
Richard Judson and Arthur J. Moss
Part III. Clinical Methodologies and Technical Aspects of Assessing Cardiac Safety of Investigational Drugs: Focus on Cardiac Repolarization
Assessment of Ventricular Repolarization From Body-Surface ECGs in Humans
Jean-Philippe Couderc and Wojciech Zareba
ECG Acquisition and Signal Processing: 12-Lead ECG Acquisition
Justin L. Mortara
Digital 12-Lead Holter vs Standard Resting Supine Electrocardiogram for the Assessment of Drug-Induced QTc Prolongation: Assessment by Different Recording and Measurement Methods
Nenad Sarapa
Holter Monitoring for QT: The RR Bin Method in Depth
Fabio Badilini and Pierre Maison-Blanche
Part IV. Application of Electrocardiology in Clinical Research
Fundamentals of ECG Interpretation in Clinical Research and Cardiac Safety Assessment
Ihor Gussak, Robert Kleiman, and Jeffrey S. Litwin
Design and Conduct of the Thorough Phase I ECG Trial for New Bioactive Drugs
Joel Morganroth
Use of ECGs in Support of Cardiac Safety in Phase II and III Clinical Trials
Martin P. Bedigian
Cardiac Arrhythmia Assessment in Phase IV Clinical Studies
Gerald A. Faich and Annette Stemhagen
Statistical Analysis Plans for ECG Data: Controlling the Intrinsic and Extrinsic Variability in QT Data
Alan S. Hollister and Timothy H Montague
Interpretation of Clinical ECG Data: Understanding the Risk From Non-Antiarrhythmic Drugs
Rashmi R. Shah
Part V. Regulatory Considerations
The FDA's Digital ECG Initiative and Its Impact on Clinical Trials
Barry D. Brown
Quality Control and Quality Assurance for Core ECG Laboratories
Amy M. Annand-Furlong
ECG Digital Communities and Electronic Reporting of Cardiac Safety Data: New Technologies for Reporting Digital ECG Data in Clinical Research Settings
Scott Grisanti and Robert Brown
Index