Analysis of Virtual Control Groups and Inter-species Concordance using Preclinical Toxicity Data
type: CreativeWork
description: Chapter 1 (Introduction). In line with the US EPA’s “Toxicity Testing in the 21st Century: A Vision and Strategy” and the Replacement, Refinement, and Reduction (3Rs) goals for animals in toxicity testing, the current two species preclinical testing paradigm for small molecules outlined in ICH M3 (R2) is under increasing pressure (Krewski et al., 2010). These pressures reflect not only the ethical concerns around animal testing (Prior et al., 2021) but also the lack of translatability of preclinical findings to humans. For example, despite animal testing forming the cornerstone of modern safety assessment (Greaves, 2012), undetected clinical safety risks (25.5%) were found to be the principal cause of drug attrition upon entering phase I clinical trials between 2000-2010 followed by efficacy (8.9%) (Waring et al., 2015). The high clinical failure rate is particularly pertinent due to the significant cost associated with phase I and II clinical trials (Bender and Cortés-Ciriano, 2020). This lack of translatability has given rise not only to questioning the external validity of increasingly standardised animal tests conducted with small sample sizes (Karp and Fry, 2021), but even whether use of animals for toxicity testing is scientific valid or is based on mere historical precedence (Monticello, 2015; Zbinden, 1993). Such concerns have driven changes in regulatory attitudes, such as the recent passing of the FDA Modernization Act 2021 which would remove the mandate for animal testing to evaluate the safety of drugs in the USA (Buchanan, 2021), and the European Parliament 2021 resolution to phase out animal testing for research, testing and education (Marshall et al., 2022). These developments follow in the wake of the 2006 REACH legislation in Europe and subsequent banning of animal testing for new cosmetic products (Yang et al., 2021), and aim to drive the development of New Approach Methodologies (NAMs) for the toxicity testing of drugs (Ball et al., 2022; Fischer …
abstract: Chapter 1 (Introduction). In line with the US EPA’s “Toxicity Testing in the 21st Century: A Vision and Strategy” and the Replacement, Refinement, and Reduction (3Rs) goals for animals in toxicity testing, the current two species preclinical testing paradigm for small molecules outlined in ICH M3 (R2) is under increasing pressure (Krewski et al., 2010). These pressures reflect not only the ethical concerns around animal testing (Prior et al., 2021) but also the lack of translatability of preclinical findings to humans. For example, despite animal testing forming the cornerstone of modern safety assessment (Greaves, 2012), undetected clinical safety risks (25.5%) were found to be the principal cause of drug attrition upon entering phase I clinical trials between 2000-2010 followed by efficacy (8.9%) (Waring et al., 2015). The high clinical failure rate is particularly pertinent due to the significant cost associated with phase I and II clinical trials (Bender and Cortés-Ciriano, 2020). This lack of translatability has given rise not only to questioning the external validity of increasingly standardised animal tests conducted with small sample sizes (Karp and Fry, 2021), but even whether use of animals for toxicity testing is scientific valid or is based on mere historical precedence (Monticello, 2015; Zbinden, 1993). Such concerns have driven changes in regulatory attitudes, such as the recent passing of the FDA Modernization Act 2021 which would remove the mandate for animal testing to evaluate the safety of drugs in the USA (Buchanan, 2021), and the European Parliament 2021 resolution to phase out animal testing for research, testing and education (Marshall et al., 2022). These developments follow in the wake of the 2006 REACH legislation in Europe and subsequent banning of animal testing for new cosmetic products (Yang et al., 2021), and aim to drive the development of New Approach Methodologies (NAMs) for the toxicity testing of drugs (Ball et al., 2022; Fischer …
author: Wright, Peter
language: eng
keywords: Control incidence rates, Drug development, Histopathology, Preclinical studies, Statistical modeling, Toxicology, Translational, Treatment related, Virtual control group
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/79c779a9-aa11-46b3-aa76-196c6b59b353/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-02-20
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.97106