The recent decision by the U.S. Food and Drug Administration (FDA) to reduce certain mandatory animal testing requirements marks a significant turning point in drug development policy. This shift encourages the adoption of New Approach Methodologies (NAMs) for preclinical testing and signals increasing regulatory and scientific confidence in alternatives such as organoids, computational models, and other non-animal platforms. Also noteworthy, this goal is echoed by the European Medicines Agency (EMA), the U.S. Environmental Protection Agency (EPA), the National Institutes of Health (NIH), and industry.1–4 This decision brings the direction taken with the FDA Modernization Act 2.0 from 2022 to the next level.5 While the initiative represents a move away from exclusive reliance on animal models, it’s important to clarify both its immediate scope and its long-term implications.
Some stakeholders—especially those tied to contract research organizations (CROs) with deep roots in traditional in vivo testing—may express concern about the impact of this change. However, the reality is more nuanced: mouse models and other animal studies are not being discarded but rather redefined within a more flexible regulatory framework. Continued innovation in traditional efficacy models, coupled with strategic investment in NAMs, will be essential for navigating the evolving landscape while maintaining scientific rigor.
Director, Center for Alternatives to Animal Testing (CAAT)
The evolving role of animal models
While the FDA’s revised mandate broadly addresses “animal studies,” its most immediate impact pertains to toxicity testing in large animals such as dogs and non-human primates. By contrast, rodent models used in efficacy testing—especially in fields like oncology and immunology—remain vital tools for elucidating mechanisms of action, pharmacokinetics, and early safety signals. Biologics, including monoclonal antibodies, still rely heavily on these models for translational insights that current alternatives cannot yet fully replicate. Near-term demand for small-animal efficacy models is expected to remain steady, offering reassurance to stakeholders that these tools are not being phased out, but is limited to cases where no alternative exists. With increasing amounts of interest in human-specific biologicals, human-specific virus infections, and rare genetic diseases, traditional animal studies are losing ground.
As regulatory emphasis grows on reducing animal use, CROs will likely face increasing demand for human-relevant platforms such as microphysiological systems (MPS), organoids, and in silico models. Organizations already investing in NAMs will enjoy competitive advantages, while others may need to pivot quickly to build capabilities in these emerging areas. As validation progresses, CROs will be expected to evolve from service providers to co-developers of innovative, translational tools that can drive safer, faster oncology drug development.
Momentum for NAMs
This shifting regulatory environment is fueling momentum for NAMs, particularly in non-animal toxicity testing.6 Organoid-based assays and in silico approaches are gaining traction as scientifically credible, human-relevant tools that support the 3Rs—Replacement, Reduction, and Refinement—enabling more adaptive, targeted preclinical strategies. Over time, sponsors are expected to adopt hybrid testing approaches that combine NAMs with traditional models to meet evolving scientific and regulatory demands.
For broader FDA acceptance, NAMs must demonstrate scientific rigor, predictive validity, and relevance to human biology—particularly in complex areas like oncology. Regulators increasingly prioritize mechanistic insight, performance-based validation, and transparency over adherence to rigid protocols. Encouragingly, the FDA has already accepted NAM-based approaches in select contexts, such as reduced chronic toxicity testing for monoclonal antibodies. The agency also encourages early engagement with developers and supports integrated testing strategies, computational toxicology, and standardized practices such as Good In Vitro Method Practices (GIVIMP), all of which underscore growing regulatory openness to well-substantiated alternatives. This puts the European development of a roadmap to phase out animal testing under considerable pressure: With four percent of the world population, the U.S. represents 53% of the world market for drugs and 67% for new medicines.7
Organoids and AI innovation
Toxicology studies—particularly those focusing on acute and repeat-dose toxicity, immunogenicity, and developmental neurotoxicity—are among the most amenable to animal-reduction strategies, as many endpoints can be modeled effectively in vitro. Pharmacokinetic and pharmacodynamic (PK/PD) profiling also stands to benefit from advanced tools such as organ-on-chip systems and AI-driven extrapolation models. Although efficacy studies remain more complex due to biological variability, innovative platforms like tumor-on-chip systems and patient-derived organoids—especially when integrated with multi-omics and bioinformatics—are emerging as promising complements, and potential alternatives to traditional animal models.
Organoids and ex vivo systems serve as critical bridges between conventional in vitro assays and in vivo models, offering physiologically relevant and often patient-specific insights—especially in oncology. When paired with AI-driven simulations—including predictive toxicology, digital twins, and virtual clinical trials—these platforms allow researchers to model complex biological processes with enhanced scalability and reproducibility. AI also enables the integration of diverse data sources, including genomics, imaging, and functional assays, to generate robust, human-relevant predictions. Together, these innovations hold strong potential to reduce or even replace animal use without compromising translational impact.
Scientific flexibility
By integrating advanced technologies such as organoid platforms, patient-derived xenografts (PDX), and in silico models, CROs can design preclinical studies that are more efficient, human-relevant, and scientifically sound. These non-animal systems are not intended to replace animal models entirely but to strengthen early decision-making with high-resolution insights into efficacy, safety, and drug response. We called this earlier “in vivitrosi,” the integrated use of these evidence streams.8 When combined with traditional approaches, NAMs reduce redundancy, enhance translatability, and may help accelerate regulatory approval timelines.
As regulatory expectations evolve, adaptability will be essential. A platform-agnostic approach—one that draws from both traditional and innovative tools—ensures that each study meets the highest standards of scientific integrity and regulatory relevance. The industry’s ability to deliver predictive, reproducible science will define the future of drug development. Those embracing innovation while maintaining scientific rigor will be best positioned to lead in shaping a modern, ethical, and effective preclinical research ecosystem.
References
1. Edwards M, Blanquie O, and Ehmann F. Insights into new approach methodology innovation: An EMA perspective. Nature Reviews Drug Discovery. March 24, 2025.
2. Dinan S. Zeldin to pursue new ban on animal testing at EPA. The Washington Times. April 10, 2025.
3. National Institutes of Health. NIH to prioritize human-based research technologies. April 29. 2025.
4. Beilmann M et al. Applications of new approach methodologies for nonclinical safety assessment of drug candidates. Nature Reviews Drug Discovery. May 2, 2025.
5. Zushin P-J. Mukherjee S, and Wu J. FDA Modernization Act 2.0: transitioning beyond animal models with human cells, organoids, and AI/ML-based approaches. Journal of Clinical Investigation 2025, 133(21): e175824.
6. Hartung T. The Turning Point: April 2025 Marks Historic Shift in US Animal Testing Policy, in press.
7. Hansell L and Hartung T. Roadmap to Reduce Animal Testing – The EU Talks, the US Acts! Frontiers Policy Lab 2025.
8. Caloni F, De Angelis I and Hartung T. Replacement of animal testing by integrated approaches to testing and assessment (IATA): a call for in vivitrosi. Archives of Toxicology 2022, 96:1935-1950. doi: 10.1007/s00204-022-03299-x.
Thomas Hartung, MD, PhD, is director of the Center for Alternatives to Animal Testing (CAAT) and holds the Doerenkamp-Zbinden Endowed Chair in Evidence-Based Toxicology at the Johns Hopkins Bloomberg School of Public Health, where he has been a faculty member since 2009. Hartung is also a member of the scientific advisory board at Crown Bioscience.
