Benchmarking safety pharmacology regulatory packages and best practice
Abstract
Introduction The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19-21, 2007). Methods The survey was distributed by the SPS to 125 pharmaceutical companies. Survey topics included (a) an update on ICH S7A and S7B practices, (b) frontloading Safety Pharmacology studies prior to selection of candidate drugs, (c) abuse and dependence-liability studies and (d) an extended evaluation of industry practises practices as assessed by Contract Research Organizations (CROs). Results Respondents (>94%) include GLP core battery (CV, CNS and respiratory) studies in the drug package submitted to regulatory agencies, and approximately 40% also submit studies on gastrointestinal and renal function. Respondents to the ICH S7B aspects indicate approximately 98% include the hERG assay and QT interval (in vivo) data in submissions, 63% include APD in vitro data and another 23% APD in vivo and other cardiac channel data (26%). SP frontloading is performed by 78% of all responding companies. Respondents indicate that 39% of these non-GLP CV studies are conducted before lead optimization (LO) and 85% during LO and before candidate drug selection. The hERG, CNS selectivity binding screens and rodent behavioral studies are frontloaded by 100%, 90% and 74% of respondents. Responding CROs (26) were surveyed on the services offered including Irwin or Functional Observational Battery (FOB) tests (70%), respiratory studies (85%), in vivo telemeterized dogs (69%) and in vitro CV studies (50%). Only 38% of SP studies are combined with toxicology studies at the CROs. Discussion The survey results indicate that ICH S7A core battery studies are implemented by most of the responding companies with a clear trend of an enhanced submission of renal and GI studies. The impact of ICH S7B is clear since, all respondents assess cardiac repolarization using cellular hERG (I(Kr)) and whole animal (QT interval) assays as a component of their safety assessment. Responses indicate a diversity of approaches for conducting abuse liability studies, which primarily use the methods of self-administration and drug discrimination. While early SP frontloading of studies seems to vary, the methods used appear to be generic to some extent and include in vitro 'off-target' evaluations and in vivo tests to determine the potential for CNS and cardiovascular issues.
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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 Lindgren, et al., 2008
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- Authors
- Lindgren, S., Bass, A. S., Briscoe, R., Bruse, K., Friedrichs, G. S., Kallman, M. J., Markgraf, C., Patmore, L., & Pugsley, M. K.
- Affiliations
- AstraZeneca (Sweden) (SE)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Covance (United States) (US)
- Eli Lilly (United States) (US)
- Johnson & Johnson (United States) (US)
- Corresponding author
- Lindgren, Silvana
- Venue
- Journal of Pharmacological and Toxicological Methods
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 58
- Issue
- 2
- Pages
- 99-109
- ISSN
- 1056-8719 (ISSN-L)
- OpenAlex
- W1993588163
- Cited by
- 109
- References
- 19
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 7 · 2016: 9 · 2015: 9 · 2014: 8 · 2013: 13 · 2012: 4
- FWCI
- 14.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacological and Toxicological Methods (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- safety pharmacology, ICH S7B, cardiac repolarization, QT interval, APD, frontloading, contract research organizations, lead optimization
- MeSH terms
- Data Collection, Drug Industry, Drug Evaluation, Preclinical, Surveys and Questionnaires, Practice Guidelines as Topic, Benchmarking, Drug-Related Side Effects and Adverse Reactions
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