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Reviewing The Use Of Two Species In Toxicity Testing For Human Pharmaceuticals

Objectives

Regulatory agencies typically require toxicity testing in both a rodent and a non-rodent species before new drugs can proceed to human trials. Given rapid advancements in human-relevant science, what new approaches might augment or substitute the traditional two-species model?

This hybrid workshop, hosted by faculty and members of the Toxicology Policy Program at Johns Hopkins Bloomberg School of Public Health and Cruelty Free International, will critically examine the scientific, ethical and regulatory case for moving toward a single-species approach – especially for longer-term toxicity studies (e.g. 3 to 6+ months). We will build on recent advances, including the ICH S1 guideline revision, which introduced a new approach to reducing animal testing for carcinogenicity, and emerging modern, human-relevant non-animal methods (NAMs), to explore how regulatory flexibility could drive meaningful change.

To focus our work, we’ll be considering four key questions:

  1. What lessons from ICH S1 should guide us in deciding if a similar study for M3 is warranted?

  2. Is this issue a high enough priority for ICH to pursue now?

  3. Should the aim be to drop the second species across all studies, or only in specific contexts (e.g., long-term studies)?

  4. What data would be needed (sources, number, and type of compounds) to make a credible case for change?

Context:

 

The recent revision of the ICH S1 guideline introduced a WoE approach that allows the two-year rodent carcinogenicity study to be waived under certain conditions. This change followed a comprehensive review of the study’s scientific value, setting an important precedent for evidence-based updates to longstanding regulatory testing requirements. In contrast, the ICH M3 guideline, which mandates toxicity testing in two animal species for small molecule pharmaceuticals, has not been updated in many years despite advances in science and increasing public and political pressure to reduce animal testing. Notably, there is growing concern about testing on dogs and non-human primates, species often used as the second test species. These pressures are reflected in global strategies aimed at phasing out animal tests, including the FDA’s most recent roadmap to reduce animal testing and the goals outlined in the FDA Modernization Act. This workshop will build on the ICH S1 example to explore whether a similar rigorous review of the second species test is warranted. The workshop will also consider how modern, human-relevant NAMs, alongside regulatory flexibility, can drive meaningful change.

Who Should Attend?

  • Toxicologists, drug development experts, regulatory scientists, and professionals in animal-free science

  • Researchers and developers working on NAMs e.g., microphysiological systems (MPS), in silico models and other human-relevant alternatives to systemic toxicity testing

  • Stakeholders interested in evidence-based reform of international regulatory guidelines

What You’ll Do:

As a participant, you will:

  • Join hybrid sessions either in-person at Johns Hopkins University or online

  • Engage in expert presentations, discussions and breakout groups

  • Help shape a formal proposal to ICH for revising outdated testing guidelines

  • Contribute to a peer-reviewed report summarizing the workshop outcomes

Deliverables:

  • Publish a comprehensive, peer-reviewed workshop report to summarize outcomes, support updates to international guidelines and provide a foundation for continued progress in this area.

  • Preparation of a proposal for the ICH to undertake a formal review of its two-species requirement (ICH M3), including clear, evidence-based recommendations for potential revisions.

  • Development of a conceptual WoE framework to guide regulatory decisions on waiving the second species test.

  • Greater understanding and alignment among key stakeholders – including regulators, industry, and scientific experts – on advancing the use of NAMs within the scope of ICH M3.

Date and Location

Workshop sessions will begin in 2026 and will be free to attend. Please email Loza Taye at  ltaye1@jh.edu to be added to the mailing list or for more information.

Resources:

To prepare for the workshop, you may find these documents helpful:

  1. Food and Drug Administration, HHS. International Conference on Harmonisation; Guidance on M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals; availability. Notice. Fed Regist. 2010 Jan 21;75(13):3471-2. PMID: 20349552.

  2. Bourcier T, McGovern T, Cavaliero T, Ebere G, Nishikawa A, Nishimura J, Ogawa K, Pasanen M, Vespa A, Van der Laan JW. ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup. Front Toxicol. 2024 Apr 11;6:1353783. doi: 10.3389/ftox.2024.1353783. PMID: 38665214; PMCID: PMC11043531

  3. Bailey J, Thew M, Balls M. An analysis of the use of dogs in predicting human toxicology and drug safety. Altern Lab Anim. 2013 Nov;41(5):335-50. doi: 10.1177/026119291304100504. PMID: 24329742.

  4. Bailey J, Thew M, Balls M. Predicting human drug toxicity and safety via animal tests: can any one species predict drug toxicity in any other, and do monkeys help? Altern Lab Anim. 2015 Dec;43(6):393-403. doi: 10.1177/026119291504300607. PMID: 26753942.

  5. Prior H, Baldrick P, de Haan L, Downes N, Jones K, Mortimer- Cassen E, Kimber I. Reviewing the Utility of Two Species in General Toxicology Related to Drug Development. Int J Toxicol. 2018 Mar;37(2):121–4. doi: 10.1177/1091581818760564. Epub 2018 Mar 27. PMCID: PMC5881785.