The Evolution, Scientific Reasoning and Use of ICH S2 Guidelines for Genotoxicity Testing of Pharmaceuticals

Müller, Lutz; Tweats, David; Galloway, Sheila M.; Hayashi, Makoto

doi:10.1007/978-1-4614-5950-7_6

Cited by 5 publications

(1 citation statement)

References 98 publications

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“…The impetus to update ICH S2A and B began shortly after they were completed, especially because of the need to re‐examine the top concentration and toxicity limits for the in vitro mammalian cell assays, [e.g., Müller and Sofuni, ] but the EWG for this purpose did not begin meeting until 2006; the revised ICH S2(R1) guidance was adopted in 2011. Some of the successes and tribulations of the process have been described by ICH S2 EWG members [Müller et al, ].…”

Section: How International Guidelines For Human Pharmaceuticals Are Dmentioning

confidence: 99%

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

Galloway

2017

Environ and Mol Mutagen

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The process of developing international (ICH) guidelines is described, and the main guidelines reviewed are the ICH S2(R1) guideline that includes the genotoxicity test battery for human pharmaceuticals, and the ICH M7 guideline for assessing and limiting potentially mutagenic impurities and degradation products in drugs. Key aspects of the guidelines are reviewed in the context of drug development, for example the incorporation of genotoxicity assessment into non-clinical toxicity studies, and ways to develop and assess weight of evidence. In both guidelines, the existence of "thresholds" or non-linear dose responses for genotoxicity plays a part in the strategies. Differences in ICH S2(R1) protocol recommendations from OECD guidelines are highlighted and rationales explained. The use of genotoxicity data during clinical development and in assessment of carcinogenic potential is also described. There are no international guidelines on assessment of potentially genotoxic metabolites, but some approaches to safety assessment are discussed for these. Environ. Mol. Mutagen. 58:296-324, 2017. © 2017 Wiley Periodicals, Inc.

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Section: How International Guidelines For Human Pharmaceuticals Are Dmentioning

confidence: 99%

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

Galloway

2017

Environ and Mol Mutagen

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Regulatory Acceptance of Alternative Methods in the Development and Approval of Pharmaceuticals

Beken¹,

Kasper

Laan

2016

Advances in Experimental Medicine and Biology

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Animal studies may be carried out to support first administration of a new medicinal product to either humans or the target animal species, or before performing clinical trials in even larger populations, or before marketing authorisation, or to control quality during production. Ethical and animal welfare considerations require that animal use is limited as much as possible. Directive 2010/63/EU on the protection of animals used for scientific purposes unambiguously fosters the application of the principle of the 3Rs when considering the choice of methods to be used.As such, today, the 3Rs are embedded in the relevant regulatory guidance both at the European (European Medicines Agency (EMA)) and (Veterinary) International Conference on Harmonization ((V)ICH) levels. With respect to non-clinical testing requirements for human medicinal products, reduction and replacement of animal testing has been achieved by the regulatory acceptance of new in vitro methods, either as pivotal, supportive or exploratory mechanistic studies. Whilst replacement of animal studies remains the ultimate goal, approaches aimed at reducing or refining animal studies have also been routinely implemented in regulatory guidelines, where applicable. The chapter provides an overview of the implementation of 3Rs in the drafting of non-clinical testing guidelines for human medicinal products at the level of the ICH. In addition, the revision of the ICH S2 guideline on genotoxicity testing and data interpretation for pharmaceuticals intended for human use is discussed as a case study.In October 2010, the EMA established a Joint ad hoc Expert Group (JEG 3Rs) with the mandate to improve and foster the application of 3Rs principles to the regulatory testing of medicinal products throughout their lifecycle. As such, a Guideline on regulatory acceptance of 3R testing approaches was drafted that defines regulatory acceptance and provides guidance on the scientific and technical criteria for regulatory acceptance of 3R testing approaches, including a process for collection of real-life data (safe harbour). Pathways for regulatory acceptance of 3R testing approaches are depicted and a new procedure for submission and evaluation of a proposal for regulatory acceptance of 3R testing approaches is described.

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Influence of 3-aminobenzamide, an inhibitor of poly(ADP-ribose)polymerase, in the evaluation of the genotoxicity of doxorubicin, cyclophosphamide and zidovudine in female mice

Yadav

Khan

Shekh

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

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The Evolution, Scientific Reasoning and Use of ICH S2 Guidelines for Genotoxicity Testing of Pharmaceuticals

Cited by 5 publications

References 98 publications

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

Regulatory Acceptance of Alternative Methods in the Development and Approval of Pharmaceuticals

Influence of 3-aminobenzamide, an inhibitor of poly(ADP-ribose)polymerase, in the evaluation of the genotoxicity of doxorubicin, cyclophosphamide and zidovudine in female mice

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