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Validation of Alternative Methods for Toxicity Testing pp 33–64Cite as

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

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 856))

Abstract

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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Notes

  1. 1.

    Referred to as safety testing in marketing authorisation applications for veterinary medicinal products.

  2. 2.

    With the exception of clinical trials for veterinary medicinal products, which are specifically excluded from the scope of the directive.

  3. 3.

    A ‘procedure’ means any use, invasive or non-invasive, of an animal for experimental or other scientific purposes, with known or unknown outcome, or educational purposes, which may cause the animal a level of pain, suffering, distress or lasting harm equivalent to, or higher than, that caused by the introduction of a needle in accordance with the good veterinary practice (Directive 2010).

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Authors and Affiliations

  1. Division Evaluators, DG PRE Authorisation, Federal Agency for Medicines and Health Products (FAMHP), Victor Hortaplace 40/40, Brussels, 1060, Belgium

    Sonja Beken

  2. Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger Allee 3, Bonn, 53175, Germany

    Peter Kasper

  3. Pharmacology, Toxicology and Biotechnology Department, Medicines Evaluation Board (MEB), Graadt van Roggenweg 500, 3531, AH, Utrecht, The Netherlands

    Jan-Willem van der Laan

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  1. Sonja Beken
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  2. Peter Kasper
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  3. Jan-Willem van der Laan
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Correspondence to Sonja Beken .

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Editors and Affiliations

  1. SeCAM Services & Consultation on Alternative Methods, Magliaso, Switzerland

    Chantra Eskes

  2. European Commission Joint Research Centre (JRC), Ispra, Italy

    Maurice Whelan

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Beken, S., Kasper, P., van der Laan, JW. (2016). Regulatory Acceptance of Alternative Methods in the Development and Approval of Pharmaceuticals. In: Eskes, C., Whelan, M. (eds) Validation of Alternative Methods for Toxicity Testing. Advances in Experimental Medicine and Biology, vol 856. Springer, Cham. https://doi.org/10.1007/978-3-319-33826-2_3

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