Opportunities to Apply the 3Rs in Safety Assessment Programs

Abstract

Before a potential new medicine can be administered to humans it is essential that its safety is adequately assessed. Safety assessment in animals forms an integral part of this process, from early drug discovery and initial candidate selection to the program of recommended regulatory tests in animals. The 3Rs (replacement, reduction, and refinement of animals in research) are integrated in the current regulatory requirements and expectations and, in the EU, provide a legal and ethical framework for in vivo research to ensure the scientific objectives are met whilst minimizing animal use and maintaining high animal welfare standards. Though the regulations are designed to uncover potential risks, they are intended to be flexible, so that the most appropriate approach can be taken for an individual product. This article outlines current and future opportunities to apply the 3Rs in safety assessment programs for pharmaceuticals, and the potential (scientific, financial, and ethical) benefits to the industry, across the drug discovery and development process. For example, improvements to, or the development of, novel, early screens (e.g., in vitro, in silico, or nonmammalian screens) designed to identify compounds with undesirable characteristics earlier in development have the potential to reduce late-stage attrition by improving the selection of compounds that require regulatory testing in animals. Opportunities also exist within the current regulatory framework to simultaneously reduce and/or refine animal use and improve scientific outcomes through improvements to technical procedures and/or adjustments to study designs. It is important that approaches to safety assessment are continuously reviewed and challenged to ensure they are science-driven and predictive of relevant effects in humans.

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

“…The field of 3Rs (replacement, reduction, refinement) is prolific for the regulation of vaccines and pharmaceutical drugs (Goh et al 2015;Eskes and Whelan 2016;Sewell et al 2016), thanks to constant input from regulators, academics, pharmaceutical companies, and EU funding bodies. As stated by the WHO technical report on non-clinical evaluation of vaccines (WHO 2003): "Product diversity and new approaches, technologies, and methodologies develop over time; therefore, judgment based on the best science available should always form the basis for deciding on the type and extent of nonclinical evaluation for these products."…”

CSL-Tox: An open-source analytical framework for the comparison of short-term and long-term toxicity end points and exploring the opportunities for decreasing in-vivo studies conducted for drug development programs

“…Likelihood ratios were calculated according to equation 3 and 4 respectively. The p-values for the relationships in the 2 by 2 contingency tables were computed using Fisher's exact test and the interpretation of likelihood ratios were adopted from Chien and Khan's work and is listed in Table .2 16 . Only statistically significant likelihood ratios (p-value < 0.05) were considered in the analysis and a cut-off of 5 was drawn to indicate a "high" positive or inverse negative likelihood ratio.…”

Structure–Activity Relationship of Graphene-Based Materials: Impact of the Surface Chemistry, Surface Specific Area and Lateral Size on Their In Vitro Toxicity

“…A dramatically huge number of nanomaterials are available and assessing their toxicity on a case-by-case basis is impossible, as it would be too expensive and timeconsuming. Moreover, many scientists try to reduce the use of animal testing and focus on alternative approaches when in vivo testing is not essential [10]. These alternative approaches emerged in the past decade, including grouping [11] or read across [12].…”