Are New Approach Methods (NAMs) On Track to Be the Tests of Choice for Predictive Toxicology?

Based on listening and talking with a diverse range of industry colleagues, attending several conferences, reading the FDA monoclonal antibodies (mAbs) announcement and roadmap, watching the FDA/NIH workshop on the state of phasing out the use of animal testing, and the FDA’s engagement with 3Rs, the world of in vitro toxicology has been speeding up faster than I've seen before, and it is clear New Approach Methods (NAMs) are playing a more central role in predictive toxicology.

Here is some evidence to support my perspective.

The FDA Monoclonal Antibodies Announcement and Roadmap A lot has been said about the FDA announcement and accompanying roadmap for mAbs that outlines the agency’s plan to phase out animal testing requirements for them and other drugs (U.S. Food and Drug Administration, 2024). There are opportunities for NAMs to inform on the safety of mAbs, which will result in the replacement of some NHP studies.

The FDA & NIH Workshop on Reducing Animal Testing

This workshop provided further detail on the broader changes occurring across agencies regarding in vitro toxicology and non-animal test methods (U.S. Food and Drug Administration, 2025a). A recording of this workshop is available on YouTube. Related details can also be found in the FDA announcement on mAbs.

Joint MHRA/NC3Rs/ABPI Workshop: Incorporation of NAMs to Support the Development of New Medicines During this collaborative workshop, representatives from the FDA, MHRA, and EMA expressed enthusiasm about NAM-related technologies they have seen presented at conferences. However, they noted that such methods are still not appearing in regulatory submissions despite there being no clear reason they cannot be included (NC3Rs, 2024). Even though there are barriers to NAM adoption, it is not necessarily the regulatory agencies causing them (Sewell et al., 2024). New approach methodologies (NAMs): Identifying and overcoming hurdles to accelerated adoption. Toxicology Research, 13(2), tfae044

The WC13 and SACATM Meetings

At both the 13th World Congress on Alternatives and Animal Use in the Life Sciences (WC13) and the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) meetings in September 2025, the FDA and NIH reiterated their expectation that regulatory submissions should include NAMs. They emphasized the importance of supporting data on biological relevance and reliability, along with a clear explanation of the weaknesses of traditional in vivo methods (WC13, 2025, NIEHS, 2025).

The FDA's Engagement with the 3Rs and NAM Implementation

The FDA’s recent initiatives underscore a regulatory shift toward modern, human-relevant testing strategies. Through its focus on NAMs, including organ-on-a-chip systems (OoCs), in silico modeling, and other advanced nonclinical tools that the agency continues to demonstrate its commitment to the 3Rs: replace, reduce, and refine (U.S. Food and Drug Administration, 2025b; U.S. Food and Drug Administration, 2025c).

Emerging Evidence and Examples of NAM Applications

These developments indicate a future where a battery of tests will replace animal studies for each regulatory endpoint. For example, a simple in vivo measurement such as a change in liver weight can now be replicated using a hepatic co-culture microfluidic device (MPS). This system enables the detection of hypertrophy and hyperplasia using traditional pathology observations or cell painting. LaFollette, J. R., et al. (2025). The use of MPS in Three Rs and regulatory applications: Perspectives from developers on stakeholder responsibilities. Alternatives to Laboratory Animals, 53(1), 26–41.

Clinical biomarkers of disease used in animal studies, such as cytokines, can also be measured in Complex In Vitro Models (CIVMs), strengthening the mechanistic understanding of toxicity.

NAMs Defined and Described

NAMs are defined as tests that do not use live animals but include a wide range of validated regulatory methods. “New” does not necessarily refer to a novel technology; rather, it represents a new way of addressing a regulatory question. NAMs include complex 3D co-culture models such as MucilAir™ (upper airway), ALIsens® (alveolar airway), OoCs, microfluidic devices (MPS), and computational models (e.g., artificial intelligence and machine learning). The in vitro systems are often collectively referred to as Complex In Vitro Models (CIVMs). All NAMs must include a regulatory Context of Use (CoU), the specific regulatory question they are designed to answer (LaFollette et al., 2025). The CoU informs the development of appropriate test batteries by identifying the molecular initiating events (MIEs) and key events (KEs) that define an adverse outcome pathway (AOP). A CoU is then built around these KEs and integrated into Integrated Approaches to Testing and Assessment (IATAs) or Defined Approaches (DAs). The test batteries may include in vitro, in chemico, and in silico methods.

Summary of Key References

• LaFollette, J. R., et al. (2025). The use of MPS in Three Rs and regulatory applications: Perspectives from developers on stakeholder responsibilities. Alternatives to Laboratory Animals, 53(1), 26–41. https://doi.org/10.1177/02611929241310566

• NC3Rs. (2024). Incorporating NAMs in medicines development: Insights from regulators, industry, and academia. https://nc3rs.org.uk/news/incorporating-nams-medicines-development-insights-regulators-industry-and-academia

• Sewell, F., et al. (2024). New approach methodologies (NAMs): Identifying and overcoming hurdles to accelerated adoption. Toxicology Research, 13(2), tfae044. https://doi.org/10.1093/toxres/tfae044

• U.S. Food and Drug Administration. (2024). FDA announces plan to phase out animal testing requirement for monoclonal antibodies and other drugs. https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs

• U.S. Food and Drug Administration. (2025a). FDA-NIH workshop: Reducing animal testing. https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/fda-nih-workshop-reducing-animal-testing-07072025

• U.S. Food and Drug Administration. (2025b). Focus area: Novel technologies to improve predictivity of non-clinical studies and replace, reduce, and refine animal use. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-novel-technologies-improve-predictivity-non-clinical-studies-and-replace-reduce-and

• U.S. Food and Drug Administration. (2025c). Implementing alternative methods at the FDA. https://www.fda.gov/science-research/advancing-alternative-methods-fda/implementing-alternative-methods

• WC13. (2025). 13th World Congress on Alternatives and Animal Use in the Life Sciences. https://www.wc13rio.org

• National Institute of Environmental Health Sciences (NIEHS). (2025). SACATM meeting agenda, September 2025. https://ntp.niehs.nih.gov/sites/default/files/2025-07/agendasacatm20250911_508.pdf