New approach methodologies (NAMs): human-relevant alternatives to animal testing

New approach methodologies (NAMs) are testing methods that provide information on the safety or effects of drugs and chemicals without animals, or with fewer of them. They include human cell-based assays, organoids, organs-on-chips, in chemico tests and computer models. In the US, the FDA Modernization Act 2.0 (2022) made such nonclinical tests eligible to support drug applications.

Key takeaways

• NAMs is an umbrella term for human-relevant, non-animal or animal-reducing test methods, not a single technology.
• The FDA Modernization Act 2.0 replaced wording that pointed drug sponsors to animal tests with “nonclinical tests,” a defined category that includes cell-based assays, microphysiological systems and computer models, as well as animal tests.
• The law permits alternatives; it does not ban animal testing.
• The FDA published a Roadmap to Reducing Animal Testing in Preclinical Safety Studies in April 2025 and reported follow-up actions in April 2026.
• Validation, showing that a method reliably predicts human outcomes for a defined purpose, is the main hurdle for any NAM.

What are new approach methodologies? #

New approach methodologies are methods that aim to answer the questions animal tests have traditionally answered (is this compound toxic, does it reach its target, what dose is safe?) using human biology and computation instead. The term is used by regulators and industry as a broad label. What unites NAMs is purpose rather than technique: they are evaluated by whether they give decision-makers reliable, human-relevant information.

NAMs sit within a longer tradition. The 3Rs principle (replace, reduce and refine animal use), set out by William Russell and Rex Burch in 1959 and revisited by Balls in ALTEX (2010), has shaped research ethics for decades. In the European Union, Directive 2010/63/EU on animals used for scientific purposes builds the 3Rs into law. NAMs are, in large part, the toolkit that makes “replace” and “reduce” practical.

Main types of NAMs #

What did the FDA Modernization Act 2.0 change? #

Before 2022, the section of the Federal Food, Drug, and Cosmetic Act governing investigational new drugs referred to “preclinical tests (including tests on animals).” The FDA Modernization Act 2.0, passed by the Senate as S. 5002 and enacted in December 2022 as part of the Consolidated Appropriations Act, 2023, made three key changes:

1. It replaced “preclinical tests (including tests on animals)” with “nonclinical tests.”
2. It replaced a separate reference to “animal” studies with “nonclinical tests.”
3. It added a definition: a nonclinical test is one conducted in vitro, in silico, in chemico, or a non-human in vivo test, before or during clinical trials, and may include animal tests or non-animal or human biology-based methods such as cell-based assays, microphysiological systems, or bioprinted or computer models.

A parallel change applied to toxicity assessments for biosimilar biological products. As Han summarized in Artificial Organs (2023), the law allows alternatives; it does not require them or prohibit animal studies. Sponsors still need to convince the FDA that their data support safety.

What is the FDA’s roadmap to reduce animal testing? #

In April 2025, the FDA published a Roadmap to Reducing Animal Testing in Preclinical Safety Studies. It describes a stepwise strategy for replacing some animal safety studies with validated NAMs where they perform as well as or better than animal models. In an April 2026 press announcement, the agency said it had met its first-year goals and listed actions taken since, including draft guidance on reducing or eliminating nonhuman primate testing in monoclonal antibody development, and described NAMs as including advanced in vitro systems, computational modeling and human-derived platforms.

Policies and guidance in this area are changing quickly, so the current FDA documents are the authoritative reference for anyone planning a regulatory submission. This entry is not regulatory advice.

Why are NAMs needed? #

Supporters point to several reasons:

• Human relevance. Animal physiology differs from human physiology, and some toxicities or efficacy signals do not translate.
• Mechanistic insight. Human cell systems can reveal how a compound acts, not just whether it causes harm.
• Ethics. Reducing animal use is a long-standing goal of research ethics under the 3Rs.
• Speed and scale. Many in vitro and in silico methods can test more conditions faster.

Skeptics and cautious regulators raise counterpoints: isolated tissues miss whole-body effects such as metabolism, immunity and interactions between organs; many methods are not yet validated for specific regulatory decisions; and variability between labs and batches can undermine trust. Most observers expect a mixed approach for some time, with NAMs replacing animal tests for some questions and complementing them for others.

How is a new approach methodology validated? #

A method is only useful to a regulator if it answers a defined question reliably. Validation generally asks a sequence of questions:

1. Context of use. What exact decision is the method meant to inform, for which kind of product?
2. Biological relevance. Does the system contain the cells and mechanisms that matter for that question?
3. Reproducibility. Does the method give consistent results within a lab, and across different labs using the same protocol?
4. Predictivity. When tested on compounds with known human effects, does it identify them correctly, and how often does it raise false alarms?
5. Documentation. Are protocols, materials and data analysis described well enough for others to repeat them?

A NAM does not have to model a whole organism to be valuable. It has to be fit for its stated purpose. A neural assay that reliably flags seizure risk, for example, could be useful even though it says nothing about liver toxicity.

How do brain organoids fit into NAMs? #

Brain organoids grown from induced pluripotent stem cells are among the most complex human in vitro models available. When placed on a high-density microelectrode array, they offer a functional readout: changes in firing rates, network bursts and synchrony after exposure to a compound. That kind of data is relevant to neurotoxicity testing and drug discovery for neurological and psychiatric conditions.

Organoid-based assays face the general NAM challenges in sharper form:

1. Variability between organoids, batches and cell lines.
2. Immaturity, since many organoids resemble fetal rather than adult tissue.
3. Missing components, including blood vessels and, in many protocols, immune cells.
4. Standardization, because readouts depend on culture age, electrode layout and analysis choices such as spike sorting.

Engineering advances such as microfluidics and organoid vascularization aim to address some of these gaps.

What is the connection to organoid intelligence and ethics? #

The same tissue used as a NAM for drug testing is used in organoid intelligence research, where living neural networks are trained through stimulation. The ethics overlap. Using human neural tissue instead of animals can reduce one set of concerns while raising others: donor consent, and questions about whether more complex neural tissue could ever warrant protection. These issues are covered in the ethics of organoid intelligence and, for how to act under uncertainty, in our entry on the precautionary principle.

For human-relevant methods to earn regulatory trust, results must be reproducible across labs, with full records of cell source, culture conditions and protocols. Those records are central to how we are designing the Organoid Programming platform. For a broader view of where these tools are heading, see the future of biocomputing.

Frequently asked questions

What are new approach methodologies (NAMs)?

New approach methodologies are testing methods that generate information about the safety or effects of drugs and chemicals without using animals, or while using fewer of them. Examples include human cell-based assays, organoids, organs-on-chips, in chemico tests and computational models. The term is used by regulators and industry as an umbrella for human-relevant alternatives, rather than as the name of one specific technique.

Did the FDA ban animal testing?

No. The FDA Modernization Act 2.0, signed in December 2022, removed the wording that pointed drug sponsors toward animal tests and replaced it with nonclinical tests, a category that includes animal tests as well as cell-based assays, microphysiological systems and computer models. Animal studies remain permitted and are still used. The change made alternatives legally eligible rather than prohibiting animal work.

What is the FDA roadmap to reduce animal testing?

In April 2025 the FDA published a Roadmap to Reducing Animal Testing in Preclinical Safety Studies, describing a stepwise plan to replace some animal safety studies with validated new approach methodologies where they perform as well or better. In an April 2026 update, the agency described follow-up actions, including draft guidance on reducing or eliminating nonhuman primate testing in monoclonal antibody development.

Are organoids a new approach methodology?

Organoids can serve as NAMs when they are used to answer a testing question, such as whether a compound damages human liver or neural tissue. They fall under the human biology-based methods the FDA Modernization Act 2.0 describes. Their use in regulatory decisions depends on validation: showing that a given organoid assay reliably predicts the human outcome it is meant to measure.

Why are NAMs important for neuroscience?

Human neural tissue differs from rodent tissue, and many drugs for brain disorders that look promising in animals fail in people. Human brain organoids and neurons from stem cells, recorded on microelectrode arrays, can show how a compound changes firing and network activity in human cells. They do not replace whole-brain or behavioral studies, but they add a human-relevant functional readout.

Sources

1. S. 5002, FDA Modernization Act 2.0 (117th Congress), engrossed text. GovInfo.
2. Consolidated Appropriations Act, 2023, Public Law 117-328 (includes the FDA Modernization Act 2.0 provisions). Congress.gov.
3. US Food and Drug Administration (2025). Roadmap to Reducing Animal Testing in Preclinical Safety Studies.
4. US Food and Drug Administration (2026). FDA achieves year 1 goals in reducing animal testing in drug development (press announcement).
5. Han, J. J. (2023). FDA Modernization Act 2.0 allows for alternatives to animal testing. Artificial Organs.
6. Balls, M. (2010). The principles of humane experimental technique: timeless insights and unheeded warnings. ALTEX.
7. Directive 2010/63/EU on the protection of animals used for scientific purposes. EUR-Lex.
8. Bhatia, S. N. & Ingber, D. E. (2014). Microfluidic organs-on-chips. Nature Biotechnology.