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Examining The Second Species Requirement in ICH M3


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Objectives

A two-day hybrid workshop will be hosted by faculty and members of the Toxicology Policy Program at Johns Hopkins Bloomberg School of Public Health and Cruelty Free International to discuss whether the ICH M3 (R2) guidance on second species testing should be re-examined, drawing lessons from ICH S1B(R1). Participants will critically examine the scientific, ethical and regulatory case for moving toward a single-species approach.

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.

Session 1: Lessons from ICH S1

Designing a robust review - what a credible, regulator-led evaluation must include

  • What worked in S1’s prospective evaluation

  • What challenges emerged (subjectivity, regulator/sponsor differences, data gaps)

  • What an M3 review might need to evaluate the two-species paradigm

  • Pros/cons of prospective vs. retrospective approaches in the M3 context

Session 2: Evidence Needs & Evaluation Pathways

Identify data needs

  • Types of analyses ICH should conduct using proprietary data

  • Criteria for assessing when the second species adds meaningful value

  • How to incorporate mechanistic understanding, relevance, and NAMs

  • Key scientific questions that an ICH M3 working group should address

Session 3: Regulatory Options & Practical Pathways for Flexibility

Identify actionable outputs for ICH

  • Operational considerations (global alignment, review processes)

  • Drafting key elements of a “blueprint” for an ICH-led review

  • Consensus on priority questions and study design recommendations

Deliverables:

  • A published workshop report outlining study design(s), metrics, and data needs for a potential ICH review of M3.

  • An evidence-based options list for reducing or refining the two- species requirement while maintaining human safety.

  • A roadmap for next steps, including pilot studies and data-sharing mechanisms.

Date and Location

The two-day workshop will be held in person at Johns Hopkins University Bloomberg Center in Washington DC or online on the following dates:

Day 1: May 21st, 2026: 9:00AM - 4:00PM EST

Day 2: May 22nd, 2026: 9:00AM - 12:30PM EST

In-Person Location: 555 Pennsylvania Ave NW, Washington, DC 20001

Register below!

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. NC3Rs. Review of the use of two species in regulatory toxicology studies (ICH M3). National Centre for the Replacement, Refinement and Reduction of Animals in Research. Available from: https://nc3rs.org.uk/our-portfolio/review-use-two-species-regulatory-toxicology-studies-ichm3

  3. 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

  4. 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.

  5. 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.

  6. 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.

Scientific Advisory Committee:

  • Warren Casey (NIH)

  • Thomas Hartung (JHU CAAT)

  • Sally Thompson Iritani (University of Washington; 3Rs Collaborative)

  • Szczepan Baran (Baran Café)

  • Nathalie Printemps (Corteva; EPAA)

  • Paul Locke (JHU TPP)