Review of the use of two species in regulatory toxicology studies: Phase II - molecules following ICH M3(R2)

Phase II of the Two Species project aims to review opportunities to expand the use of a single species in long-term toxicity studies to molecules following the international ICH M3(R2) guidelines [1] for nonclinical safety studies. These guidelines currently require safety and tolerability data from two species – a rodent (e.g. rat or mouse) and a non-rodent (e.g. dog, minipig or non-human primate) – to support human clinical trials, as well as marketing authorisation for pharmaceuticals.

Previously, we have reviewed how and when two species are used within regulatory toxicology studies for molecules following the international ICH S6(R1) guidelines [2] for the development of biotechnology-derived pharmaceuticals (i.e. biologics). For these molecules, a single species can be used for longer-term studies if "similar" toxicities are identified in two species in short-term studies (i.e. supporting the first administration in humans). The evidence collected via survey highlighted opportunities for a single species approach to be used more widely for more molecules following ICH S6(R1), and provided preliminary evidence to support expanding this approach to nonclinical toxicology strategies for other drug modalities (i.e. molecules following ICH M3(R2)) [3]. However, it was recognised that changing the regulatory guidelines in order to apply these opportunities would require more robust evidence demonstrating minimal risk/impact for human risk assessment.

In 2023, we established an international expert working group consisting of 42 organisations to review opportunities to expand the use of a single species in long-term toxicity studies to molecules following ICH M3(R2). The working group includes representatives from pharmaceutical companies, contract research organisations and regulatory bodies in the UK, and elsewhere in Europe, USA and Japan.

In 2024 we ran a survey to collect information on studies carried out to support development of these molecules, to better understand:

• How often similar toxicities are identified in short-term studies across different species.
• How often new or unexpected toxicities manifest in long-term studies, and the differences between rodents and non-rodents.
• The theoretical risk to human safety if using only a single species for long-term studies.

We are analysing the data collected and the results will be available in 2025.

1. ICH S6(R1) Scientific guideline for preclinical safety evaluation of biotechnology-derived pharmaceuticals.
2. ICH M3(R2) Scientific guideline for non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals.
3. Prior H et al. (2020). Opportunities for use of one species for longer-term toxicology testing during drug development: a cross-industry evaluation. Regulatory Toxicology and Pharmacology 113: e104624. doi: 10.1016/j.yrtph.2020.104624