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Published by: Biopharm Knowledge Publishing
Published: Mar. 28, 2008 - 115 Pages
Table of Contents
- Chapter 1 Assessing the Commercial Implications of Cardiotoxicity
- Jo Pisani and Yann Bonduelle, Pharmaceutical Strategy Consultants, PricewaterhouseCoopers LLP
- 1.0 Introduction
- 1.1 The cardiotoxicity challenge
- 1.2 The impact on stakeholders of cardiotoxicity
- 1.3 Assessing the size of the cardiotoxicity problem
- 1.4 Assessing the commercial costs of cardiotoxicity
- 1.5 Reacting to a cardiotoxic event: What option?
- 1.6 The case of Vioxx direct costs
- 1.7 The case of Fen-Phen: Impact on the obesity market
- 1.8 The case of Celebrex: The indirect costs of cardiotoxicity
- 1.9 The case of Vioxx & Fen-Phen: Litigation costs
- 1.10 The case of Gleevec: Reformulation costs
- 1.11 Understanding and addressing the problem of cardiotoxicity in the future
- 1.12 So what?
- Chapter 2 Introduction to Cardiac Pharmacology
- Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford
- 2.0 A discussion of the pharmacology of the heart and what are the key pharmacologic processes
- 2.1 Introduction
- 2.2 Drug action and the heart
- 2.2.1 Ion channels and what they are and do
- 2.2.2 Which enzymes and other proteins are important?
- 2.2.3 Which proteins are involved in the contractile process?
- Chapter 3 Introduction to electrical activity in the heart
- Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford
- 3.0 Description of the important electrical processes
- 3.1 Equivalent circuit model
- 3.2 Electrogenic transporters and their influence on membrane potential.
- 3.3 Importance of gK1 and its reduction during the action potential plateau
- 3.4 Detailed models of electrical activity in ventricular myocytes
- 3.5 Genes associated with ion channels
- 3.5.1 Description of an electrocardiogram
- Chapter 4 Mechanisms of Cardiac Toxicity
- Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford
- 4.0 QT interval prolongation
- 4.1 QT interval shortening
- 4.1.1 Torsade des Pointes
- 4.1.2 Short and long term functional changes
- 4.1.3 Gene related adverse events
- Chapter 5 Preclinical Determination of Cardiac Toxicity
- Professor D Terrar - Professor of Cardiac Electrophysiology, University of Oxford
- 5.0 In Vitro
- 5.1 hERG testing
- 5.1.1 Advantages of hERG assays
- 5.1.2 Conventional electrophysiology
- 5.1.3 High throughput methods
- 5.1.4 Disadvantages of hERG assays
- 5.2 Purkinje Fibres
- 5.2.1 Myocytes (action potentials and currents)
- 5.2.2 Papillary muscles
- 5.2.3 Langendorf Hearts
- 5.2.4 Cardiac Wedge
- 5.3 In vivo telemetry
- Chapter 6 Determination of Cardiac Toxicity in the Clinic
- Daniel B. Goodman, MD, Medical Director, Entelligent Solutions, Inc
- Eileen M. Daniel, Vice President of Operations, Reliance Clinical Research Services
- 6.0 Introduction
- 6.1 Early Phase Clinical Trials
- 6.1.1 Thorough QT/QTc Study
- 6.1.2 TQTS Design
- 6.1.3 The TQTS in Practice
- 6.1.4 Collection of ECG data in the Clinic
- 6.1.5 Completion of ECG readings
- 6.1.6 Clinical Study Report
- 6.2 Later Phase Trials
- 6.2.1 Oncology
- 6.2.2 Other Cardiac Toxicity
- 6.3 Conclusion
- Chapter 7 Regulatory Aspects of QT/QTc Interval Prolongation
- Thomas E. Donnelly, Ph.D., Senior Vice President of Regulatory Affairs, Quality Assurance and Compliance, Reliance Clinical Research Services
- 7.0 Introduction
- 7.1 ICH Guidance and Thorough QT (TQT) Study
- 7.2 Risk Management Guidance during Development
- 7.3 Regulatory Review of QT/QTc Protocols
- 7.4 Interdisciplinary Review Team for QT Studies
- 7.5 Risk Management Guidance Post-Marketing for Drugs that Prolong the QT/QTc Interval
- 7.5.1 Risk Management General
- 7.5.2 Risk Management with QT/QTc Interval Prolongation
- 7.6 Labeling Issues for Drugs that Prolong the QT/QTc Interval
- 7.7 Regulatory Review of Clinical Safety Data in a Marketing Application
- 7.8 Summary
- Chapter 8 Future Prospects
- Professor D Terrar
- Dr Eileen Daniel
- Dr D Goodman
- Dr T Donnelly
- Dr RG Hughes
- 8.0 Imaging: Optical probes for measuring electrical activity
- 8.1 Imaging: Optical probes for calcium and other ions
- 8.2 Tissue culture cardiac cells
- 8.3 Computational methods
- 8.4 Medium Throughput screening for cardiac toxicity
- 8.5 Commercial prospects
- 8.6 Regulatory prospects
- 8.7 Clinical Challenges
- Chapter 9 References and Useful Reading
- Chapter 10
- Glossary & Abbreviations
- About the Contributors
AbstractCardiac Toxicity - Major cause of drug withdrawal
Cardiac Toxicity has been implicated in 28% of drug withdrawals in the USA over the last 30 years - with twenty major drugs withdrawn in that period. The consequences for the global pharmaceutical industry can be huge, with major drugs being withdrawn and companies being sued for negligence. But often cardiac events are so rare that they may only be found many years after launch and after thousands, or even millions, of patients have been treated.
This unique report covers all aspects of cardiac toxicity, from physiology and pharmacology to regulation by the FDA and EMEA.
It will help you to:
- Understand the physiology and pharmacology of the heart and how cardiac toxicity may be provoked
- See which classes of drugs carry most risk
- Plan for the clinical trial process
- Manage the regulatory process
- Understand the commercial implications
The report is edited by industry expert Dr Graham Hughes and includes a chapter on the commercial implications written by Yanne Bonduelle and Jo Pisani of PwC.
Key industry and academic figures have also contributed significant chapters to the report:
- Professor Derek Terrar Professor of Cardiac Electrophysiology, University of Oxford,
- Thomas E Donelly, PhD Senior Vice President, Reliance Clinical Research Services
- Daniel B. Goodman, MD Medical Director, Entelligent Solutions, Inc
- Eileen M. Daniel Vice President of Operations, Reliance Clinical Research Services
The report is essential reading for anyone in biotech, pharmaceuticals or contract research. It will appeal to Corporate Management, Development, R&D, Pre-clinical and Clinical Safety, Regulatory Compliance, Quality, Marketing and Sales. It gives an up to date, authoritative, detailed and clear explanation of the issues surrounding cardiac toxicity and its implications for the pharmaceutical market.
Get Full Details About This Report >>
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