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Office-led project

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

At a glance

In progress
Current contacts
NC3Rs Scientist
Elisa Passini

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Overview

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 ICH M3(R2) guidelines [1]. Current international ICH M3(R2) guidelines for nonclinical safety studies to support human clinical trials, as well as marketing authorisation for pharmaceuticals, 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). 

Find out more about the Two Species project: Review of the use of two species in regulatory toxicology studies.

Two Species Phase I: ICH S6(R1)

Previously, we have reviewed how and when two species are used within regulatory toxicology studies for molecules following ICH S6(R1) guidelines [2] for the development of biotechnology-derived pharmaceuticals (i.e. biologics). For molecules following ICH S6(R1), 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.

Two Species Phase II: ICH M3(R2)

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.

We have developed a new 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.

The survey will be launched in Spring 2024 and the results will be used to develop evidence-based recommendations.

Interested in taking part in this data-sharing project to build the evidence base for single species toxicity studies?

If your company works with molecules following ICH M3(R2), please get in touch with our Head of Toxicology, Dr Fiona Sewell.

References

  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