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

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.

Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms

“…hSC-derived cells advantageously enable high throughout assessment, strong reproducibility, translation into clinical studies, and potential applications in personalized and precision medicine for many therapeutic areas. Utilization of hSC-derived cells is in agreement with the 3Rs (Replace, Reduce, Refine the need for animal studies) (Beken, Kasper, & van der Laan, 2016;Tornqvist, et al, 2014). The increasing availability of patient-and diverse donor-derived pools of stem cells opens the door to a clinical-trial-in-adish paradigm (Fermini, Coyne, & Coyne, 2018;Sayed, Liu, & Wu, 2016;Shinozawa, et al, 2017) .…”

Bioluminescence Imaging of Spheroids for High‐throughput Longitudinal Studies on 3D Cell Culture Models

“…Therefore, BL cell‐based assays based on two‐dimensional (2D) monolayer cell culture models represent well‐established reliable tools that improved the first steps of drug screening, in compliance with the Replacement, Reduction, Refinement principle . However, cells in 2D cultures often do not reflect the morphology and functionality of their native three‐dimensional (3D) phenotypes; thus, the relevance of information obtained by the 2D assay is reduced .…”

Automated screening for oxidative or methylation-induced DNA damage in human cells

“…When establishing new test methods, it is imperative to implement the 3R principle where possible. Ideally such tests should be animal-free and should rely on human-relevant biological systems (Beken et al, 2016;Knudsen et al, 2019).The comet assay is the gold standard in many laboratories for genotoxicity measurements. With its high sensitivity and broad scope of application, it is an attractive technique for analyzing DNA damage induction and repair in a broad variety of cells.…”