In our last article, we explored how selecting the right model depends on the scientific question and the stage of research. We summarized the strengths and limitations of animal- and human-derived cells and discussed why moving toward more human-relevant models is best approached in a strategic manner.
Among the human-relevant models gaining traction are new approach methodologies (NAMs), a diverse group of methods that aim to advance research and development while reducing the use of animals. As many readers will already be familiar with NAMs, this article focuses on how they are being applied in nonclinical toxicology today, where they add value, and what is needed for robust scientific and regulatory decision-making. For those interested in learning more about the foundational concepts underpinning NAMs, a detailed review can be found elsewhere (1 and references within).
Asking the Right Question
Instead of asking whether NAMs are ‘ready’ to replace animal models across drug development, a more useful question is where are NAMs most appropriate for a specific drug candidate, mechanism, indication or safety question. This perspective was reinforced at the Northern California Regional Chapter Spring Symposium 2026, “Innovations in Toxicology: End-to-End Strategies in Nonclinical Drug Development”, where the overall tone emphasized pragmatic, case-by-case integration of new toxicology approaches into development and regulatory decision-making. A recurring theme was that NAMs are most useful when treated as bespoke tools, applied where biology, human pathophysiology, decision context and regulatory pathway are aligned.
NAMs in Modern Preclinical Toxicology
The field of nonclinical toxicology has traditionally relied on animal models to assess safety, identify target tissue or organ toxicity and support regulatory submissions. Animals offer whole-organism context, established workflows, and a long history of use in regulatory settings. However, they also present well-known limitations, especially when it comes to predicting human-relevant responses.
NAMs offer a complementary approach. Human cell-based systems, organoids, microphysiological systems and in silico AI-driven models can provide biological insights into toxicity pathways and human-relevant biomarkers. These methods can support earlier detection of potential safety risks and, in some cases, improve the human relevance of safety assessments.
T-cell engagers provide one example. These therapies bring T cells into close proximity with target cells, triggering immune-mediated killing. Because this mechanism depends on human immune cell biology, target expression, receptor engagement and epitope recognition, animal models may not provide the most relevant readout. In this context, assays using high-quality human primary blood cells can help researchers evaluate potency, cytokine release, immune activation and target-dependent effects in a system that more closely reflects the human therapeutic setting (2).
A second example is cardiotoxicity assessment. Cardiac safety remains a major concern in drug development, and human iPSC-derived cardiomyocytes are increasingly used to evaluate drug-induced effects on human cardiac cells in vitro. These models can support the assessment of electrophysiological, contractility, mitochondrial and structural effects, helping to reveal potential cardiac toxicities earlier in drug development (3, 4). While they do not replace the full regulatory cardiac safety package, they illustrate how human-relevant NAMs can complement established assays and provide mechanistic insight into toxicity that may be difficult to capture using traditional models alone.
These examples show how human-relevant assays strengthen safety assessments when paired with a clear biological or regulatory question. They can help de-risk programs before expensive in vivo studies and provide mechanistic insights that strengthen interpretation of downstream results. However, many NAMs do not yet capture the full complexity of whole-organism physiology, including systemic interactions, immune responses, and long-term or cumulative effects. Because of this, they are not always sufficient on their own, particularly in later-stage or regulatory contexts.
Scientific Progress vs. Regulatory Reality
The increasing attention around NAMs reflects decades of gradual scientific progress. For example, advances in stem cell biology, genome editing and tissue engineering have expanded the range and quality of human-relevant models available to researchers. In parallel, regulatory agencies are actively encouraging the development and evaluation of NAMs, and in certain contexts, allowing them to serve as supplements to traditional animal studies (5-8).
However, it’s not a simple question of whether regulators ‘accept’ NAMs. The more important point is whether a chosen NAM strategy is appropriate for the specific drug target and regulatory framework for “that” drug target. Regulatory expectations remain context-dependent and legacy driven. In many cases, NAM-derived data must still be interpreted alongside, or supported by, data from historically established and validated animal models. Legacy data are also an important consideration. Much of the historical evidence used to support nonclinical decision-making and IND-enabling packages has been generated using animal models. As a result, introducing new NAMs into established development pathways can be challenging, even when the aspiration to replace animal models is strong.
How does Decision-Making Differ Between Academic and Industry Settings?
Selecting a model is often treated as a scientific decision, when in practice it is also a strategic one. In nonclinical toxicology, model choice affects not only the data generated, but also how that data will be interpreted, challenged, and ultimately accepted. These decisions involve input from scientists, project teams, regulatory specialists, and organizational leadership.
In industry, implementation of NAMs often needs to be driven at a senior strategic level. Laboratory scientists may recognize the value of a human-relevant model, but model choice can affect timelines, regulatory strategy, resourcing, risk tolerance, and the overall preclinical data package. For this reason, broader use of NAMs requires organizational alignment as well as early engagement with regulators on how the data will be used and interpreted.
Academic scientists may approach NAMs differently. Here, NAMs may be particularly useful for validating human biology, exploring mechanisms, or strengthening translational relevance, while traditional model organisms may still provide important biological insights. NAMs may also have important applications beyond drug development, particularly in environmental, agricultural, and chemical toxicology. For example, NAM-based approaches are being explored in developmental neurotoxicity (DNT), where traditional animal studies are complex and difficult to translate directly to human risk. In these settings, NAMs may help screen chemicals, prioritize further testing, and provide mechanistic insight into human-relevant toxicity (9).
Building a Structured Framework:
Successfully integrating NAMs into nonclinical toxicology requires a structured decision-making framework. A useful starting point is to define the primary objective of the work, whether that is drug candidate safety assessment, efficacy, risk evaluation, regulatory strategy, or clinical trial design. The level of acceptable uncertainty is another key factor. In early discovery, there is often greater flexibility to use emerging models and explore new approaches to validate a drug target and its mechanism of action for a particular disease; in later stages, particularly when decisions involve regulatory agency alignment, the tolerance for uncertainty or risk is much lower.
Teams must also weigh human relevance and the broader regulatory context. Where species differences are likely to affect interpretation, human-derived models may provide critical insight. If data will be used to support formal submissions, teams should consider whether the chosen approach is likely to be accepted, and whether additional supporting data may be required.
NAMs and animal models do not need to be mutually exclusive; many strategies involve integrating data from different systems to build a more comprehensive understanding. The outcome is not a single “correct” model, but a fit-for-purpose approach that reflects the scientific question, the available tools, the level of confidence required, and the regulatory context in which the data will be used.
Strategic Positioning of NAMs:
NAMs are likely to play an increasingly important role in nonclinical toxicology, but their impact will depend on whether they are used in the right context. The key question is not whether a NAM is inherently better than an animal model, but whether it is appropriate for the specific drug candidate, mechanism, indication, safety concern, and regulatory alignment. When NAMs are selected on this basis, and when there is early alignment with regulatory authorities on how the data will be generated, interpreted, and integrated with other evidence, they can support more human-relevant decisions during drug development.
Stay tuned for our next article in this series, where we will dive into an exciting emerging application of NAMs!
Related Articles:
The Right Model at the Right Time for the Right Scientific Question
Chips and Beyond: The Attraction of 3D Organoid Models in Drug Discovery
References:
- Sewell F, Alexander-White C, Brescia S, et al. New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption. Toxicol Res (Camb). 2024 Mar 25;13(2):tfae044.
- Cao Y, Polacheck W. New Approach Methodologies: What Clinical Pharmacologists Should Prepare For. Clin Pharmacol Ther. 2025 Dec;118(6):1269-1272.
- Raniga K, Nasir A, Vo NTN, et al. Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2024 Mar 7;31(3):292-311.
- Funakoshi S, Yoshida Y. Recent progress of iPSC technology in cardiac diseases. Arch Toxicol. 2021 Dec;95(12):3633-3650.
- Herron TJ, Brüning-Richardson A, Gough JE, et al. Alternatives to animal testing are the future – it’s time that journals, funders and scientists embrace them. Nature. 2025 Oct;646(8086):799-801.
- Han JJ. FDA Modernization Act 2.0 allows for alternatives to animal testing. Artif Organs. 2023 Mar;47(3):449-450.
- European Medicines Agency (EMA). New Approach Methodologies: EU-IN Horizon Scanning Report. EMA/56850/2025 Rev.1. February 2025. Available from: https://www.ema.europa.eu
- Osborne OJ, Botham P, Mulholland C, et al. Food for thought – Paving the way for a UK roadmap towards optimum consumer safety: Development, Endorsement and Regulatory acceptance of New Approach Methodologies (NAMs) in Chemical Risk Assessment and Beyond. Regul Toxicol Pharmacol. 2024 Nov;153:105701.
- Blum J, Bartmann K, de Paula Souza J, Fritsche E. Developmental neurotoxicity as a case example for a six-step framework for the sustainable regulatory implementation of NAMs. Curr Opin Toxicol. 2025;42:100528.
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Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.
