Summary
Cardiac Toxicity – drugs causing heart muscle, valve damage or potentially fatal arrhythmias in patients - has been implicated in 28% of drug withdrawals in the USA over the last 30 years.
The significance for patients, regulators and the pharmaceutical industry is immense. If cardiac toxicity is discovered during a drug’s development the programme will, almost invariably, be terminated. If cardiac toxicity is discovered after launch then the drug may be withdrawn or new labelling will almost certainly be required.
The consequences for the global pharmaceutical industry can be huge, with major drugs being withdrawn and companies being sued for negligence.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. And when cardiac events do occur the exact mechanism involved may remain a mystery.
This unique report covers all aspects of cardiac toxicity, from physiology and pharmacology to regulation by the FDA and EMEA. It looks at:
• Physiology
• Pharmacology
• Pre-clinical determination of cardiac toxicity
• Determination of potential cardiac toxicity in early phase clinical testing (QTc studies)
• The implications for the clinical trial process
• Regulation
• The commercial implications
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 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:
View an overview of the report (pdf)
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Preface
Introduction. Dr R G Hughes - Consultant in Pharmaceutical Development
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 What happens to drugs associated with cardiotoxicity?
1.4 Assessing the size of the cardiotoxicity problem
1.5 Assessing the commercial costs of cardiotoxicity
1.6 To withdraw or re-label?
1.7 Lost sales
1.8 Competitors benefit – temporarily
1.9 Negative publicity
1.10 Share price impact
1.11 The indirect costs of cardiotoxicity
1.11.1 Loss of confidence
1.11.2 Litigation
1.11.3 Patient costs
1.12 Reformulation
1.13 Litigation costs as a result of cardiotoxicity
1.14 Reformulating a molecule to cut cardiotoxicity
1.15 Understanding and addressing the problem of cardiotoxicity in the future
1.16 Looking forward
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
Abbreviations & Glossary
Editors and Contributors
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TABLE OF CONTENTS
