Non-clinical evaluation of ventricular repolarization (ICH S7B): results of an interim survey of international pharmaceutical companies
Abstract
Introduction The propensity of drugs to cause a potentially fatal arrhythmia, torsades des pointes (TdP), is a significant public health issue. The draft International Conference on Harmonization (ICH) S7B guidelines describe a battery of non-clinical studies to evaluate a drug's potential to prolong ventricular repolarization (VR); an accepted surrogate/risk factor for TdP. A worldwide survey of pharmaceutical industry practices, related to ICH S7B was conducted. The findings were presented at the 4th Annual Meeting of the Safety Pharmacology Society (SPS) meeting (Cincinnati, OH, Sept., 2004). Methods The survey was distributed by the SPS to 119 pharmaceutical companies; 29 surveys were returned. Survey topics included: (a) General Strategy and Testing for Risk of QT prolongation, (b) Study Timing and Relationship to Development, and (c) Application of GLPs. Results Respondents indicate that the basis for assessing prolongation of VR was to: remove compounds with an arrhythmic risk to humans (86%), to satisfy regulatory expectations (79%), or to avoid obstacles in the clinical development of a compound (86%). Development of a compound based on prolongation of VR was halted for 52% of respondents (compared to 45% in a 2003 survey). Models used to evaluate changes in VR included: human ether a go-go related gene (hERG) (93%), action potential duration (APD) (68%; compared to 80% in the 2003 survey), and in vivo QT (100%). The distribution of assays being requested by regulatory agencies includes the hERG (83%), APD (28%), and in vivo QT (79%). In spite of uncertainty regarding the final requirements of ICH S7B, organizations continue to implement (36%) and validate (60%) their electrophysiology laboratories. Summary The survey results indicate that pharmaceutical companies are testing for VR prolongation of drug candidates and that institutions have established in-house or outsourced capabilities to evaluate this potential risk, even in the absence of final guidelines.
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Three separate surveys of the pharmaceutical industry revealed that canine was the most commonly used animal model for evaluating QT interval prolongation of novel compounds.
“Three separate surveys of the pharmaceutical industry revealed that canine was the most commonly used animal model for evaluation and determination of QT interval prolongation of novel compounds (Friedrichs, Patmore, & Bass, 2005; Hammond, et al., 2001; Lindgren, et al., 2008).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Friedrichs, et al., 2005
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Small and large animal models in cardiac contraction research: advantages and disadvantages
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Benchmarking safety pharmacology regulatory packages and best practice
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- Authors
- Friedrichs, G. S., Patmore, L., & Bass, A.
- Affiliations
- IQVIA (United Kingdom) (GB)
- Corresponding author
- Friedrichs, Gregory S.
- Venue
- Journal of Pharmacological and Toxicological Methods
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 52
- Issue
- 1
- Pages
- 6-11
- ISSN
- 1056-8719 (ISSN-L)
- OpenAlex
- W2021775591
- Cited by
- 63
- References
- 13
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacological and Toxicological Methods (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- ICH S7B, ventricular repolarization, QT prolongation, torsades de pointes, safety pharmacology, hERG, action potential duration, GLP compliance, drug development, regulatory testing
- MeSH terms
- Data Collection, Drug Industry, Drug Evaluation, Preclinical, Humans, International Cooperation, Long QT Syndrome, Torsades de Pointes, Tachycardia, Ventricular, Practice Guidelines as Topic, Drug-Related Side Effects and Adverse Reactions
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