Category: Alternatives to Animal Experiments

Historical Roots of Mandated Animal Testing

Animal use in U.S. biomedical research has been both guided and constrained by laws that date back to the 1938 Food, Drug & Cosmetic Act, which effectively required animal data before human trials could begin. Yet almost as soon as that mandate was in place, pressure to curb its excesses arose. In 1959, British scientists William Russell and Rex Burch articulated the now-canonical “3 Rs” (Replace, Reduce, Refine) in The Principles of Humane Experimental Technique, giving regulators and ethicists a common language for alternatives¹.

Through the 1970s and 1980s, advocacy groups such as the Humane Society of the United States, the Physicians Committee for Responsible Medicine, and later PETA turned laboratory animal welfare into a mainstream public concern. Their campaigns helped secure passage of amendments to the U.S. Animal Welfare Act and spurred the first congressional hearings on alternatives to animal testing in drug development.

The scientific establishment followed. In 1997, eleven federal agencies formed the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and Congress cemented its role with the ICCVAM Authorization Act of 2000. ICCVAM’s charter is explicit: accelerate regulatory acceptance of test methods that replace, reduce, or refine animal use without compromising safety or efficacy².

Momentum grew when the National Research Council’s 2007 report, “Toxicity Testing in the 21st Century,” urged a wholesale shift toward human-relevant, high-throughput assays and computational models³. That vision seeded collaborative programs like Tox21, an EPA-, NIH-, and FDA-backed effort that screens thousands of chemicals in robotics-driven, cell-based platforms instead of rodents⁴. Across the Atlantic, the European Union’s phased-in ban on animal-tested cosmetics—culminating in a full marketing ban in 2013—proved that large markets could operate under strict animal-free requirements without stalling innovation⁵.

Why This Marks an Inflection Point

Despite this steady drumbeat, U.S. federal drug-development rules remained largely unchanged—until recently. Over the past 3 years, and especially within the last twelve months, a cascade of legislative and agency actions has transformed decades of advocacy into concrete policy. What once felt aspirational is now operational: sponsors are no longer merely allowed to submit New Approach Methodologies (NAMs); they are increasingly expected to do so. That rapid acceleration marks 2024-2025 as an unmistakable inflection point: one in which scientific maturity, public pressure, and regulatory authority have finally aligned to make human-relevant models the new default for preclinical research.

Over the past three years, the United States has moved from discussion to implementation in modernizing drug-development rules that were once completely reliant on animal testing. Catalyzed by bipartisan legislation, agency-specific pilot programs such as FDA’s ISTAND program, and mounting scientific validation of New Approach Methodologies (NAMs) such as Organ-on-a-Chip technology, a clear through-line has emerged: regulators now expect—and increasingly require—human-relevant tools to inform safety and efficacy in preclinical research. Below is a chronological look at the key milestones, followed by a recap of how Emulate has helped drive and shape this historic shift.

Recent Timeline of Policy Milestones

December 2020 — FDA launches ISTAND Program

Recognizing the need to facilitate the approval of beneficial technologies for drug development that fall outside the scope of existing Drug Development Tool (DDT) qualification programs, in late 2020, the FDA introduced the Innovative Science and Technology Approaches for New Drugs (ISTAND) Program. In their explanation of the ISTAND program, the FDA explicitly listed microphysiological systems such as Organ-Chips as an example technology that would qualify for entry into the program. Ultimately, technologies approved for a context of use through the ISTAND program can be included in IND and NDA applications “without needing FDA to reconsider and reconfirm its suitability.”⁶

December 29, 2022 — FDA Modernization Act 2.0 becomes law

Congress eliminated the Depression-era mandate that animal data be the default gateway to human trials, explicitly authorizing cell-based assays, microphysiological systems (MPS), and sophisticated computer models as equally valid evidence. The amending language accomplishing this was quite simple: the new act removed the phrase “preclinical tests (including tests on animals)” from the original law, and replaced it with “nonclinical tests”. Nonclinical test were further defined as “…a test conducted in vitro, in silico, or in chemico, or a non-human in vivo test that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug, and may include animal tests, or non-animal or human biology-based test methods, such as cell-based assays, microphysiological systems, or bioprinted or computer models.”

While the changes to the original law were simple, their effects were profound. The statute not only empowers sponsors to use NAMs, it also instructs FDA reviewers to consider them on their scientific merits^7,8.

February 6, 2024 — FDA Modernization Act 3.0 introduced

Building on the 2022 breakthrough, the 3.0 bill directs the FDA to create a formal pathway for the qualification, review, and routine acceptance of non-animal methods. If enacted, it would put the agency on a clock to translate legal authority into day-to-day regulatory practice, closing any remaining gaps that slow the adoption of NAMs⁹.

September 24, 2024 — First Organ-on-a-Chip admitted to FDA’s ISTAND Pilot Program

FDA’s ISTAND initiative, created to qualify novel Drug Development Tools, accepted the first Organ-on-a-Chip submission: a liver MPS designed to predict drug-induced liver injury (DILI). This seminal acceptance signaled that complex microfluidic models can progress through the same evidentiary pipeline as traditional models¹⁰.

April 10, 2025 — FDA announces phased elimination of routine animal testing & releases Roadmap

In a pair of same-day actions, the agency published:

1. A policy plan to “reduce, refine, and ultimately replace” animal studies, prioritizing MPS data and AI-driven toxicity modeling in Investigational New Drug (IND) submissions.
2. A detailed Roadmap that lays out short-, mid-, and long-term steps—validation standards, cross-agency collaborations, and pilot incentives—to mainstream NAMs across all Centers.
   Taken together, the documents move the conversation from permission to expectation, stating that animal use should become “the exception rather than the rule.”^11,12

April 29, 2025 — NIH shifts funding priorities toward human-based technologies

America’s largest source of funding for biomedical research launched an initiative to prioritize grant applications that incorporate Organ-Chips, organoids, or computational models—an early indication that future paylines will reward researchers who leave “animal-only” study designs behind¹³.

May 29, 2025 — U.S. Navy ends cat and dog experiments

The Department of the Navy formally stopped all biomedical research on companion animals, citing the availability of advanced human-based platforms and ethical stewardship of federal resources. Although limited in scope, the decision adds military pressure to the broader federal trend away from animal models¹⁴.

July 7, 2025 — NIH bars funding for animal-only studies

Just nine weeks after its technology push, the NIH announced that proposals relying exclusively on animal data will no longer be eligible for agency support. Investigators must integrate at least one validated human-relevant method, accelerating the scientific community’s pivot toward NAMs¹⁵.

Emulate’s Contributions to the Sea Change

1. Giving NAMs a Voice on Capitol Hill
Before Congress voted on the FDA Modernization Act 2.0, Emulate submitted formal testimony underscoring how Organ-on-a-Chip technology can improve translational accuracy while reducing animal use. The company’s perspective helped lawmakers grasp the real-world readiness of NAMs and the economic upside of faster, failure-proof pipelines¹⁶.

2. Generating the Evidence Base
In the largest head-to-head study of its kind, Emulate’s peer-reviewed Nature publication demonstrated that the human Liver-Chip S1 outperforms animal models for predicting DILI, showing 87% sensitivity and 100% specificity for a set of hepatotoxic drugs that animal models had deemed safe. Those data have since been cited by regulators and pharma R&D teams alike as proof that chips can surpass conventional in vivo benchmarks^17,18.

3. Achieving the First-Ever ISTAND Acceptance
The Emulate Liver-Chip S1 became the first Organ-Chip welcomed into FDA’s ISTAND Program—setting a procedural precedent for all future MPS tools. Emulate’s submission not only opened the door for chip qualification; it provided the cross-disciplinary dossier that FDA reviewers will use as a template^19,20.

4. Being the Only Organ-Chip Manufacturer Cited in FDA’s Roadmap
When FDA mapped its strategy to cut animal testing, it highlighted Organ-Chips—specifically referencing Emulate’s platforms—as validated NAMs ready for wider deployment. That acknowledgment elevated the technology from promising to actionable in the eyes of regulators, funders, and biopharma stakeholders^21,22.

5. Convening Thought Leaders Around the New Rules
Shortly after the Roadmap’s release, Emulate hosted a fireside chat with FDA Senior Advisor Dr. Tracy Beth Høeg, Wyss Institute founder Dr. Don Ingber, and Moderna scientist Dr. Samantha Atkins to unpack what the policy means for sponsors. The session offered pragmatic guidance on designing IND packages that lean heavily on human-relevant data—effectively turning policy into a playbook^23,24.

Looking Ahead

From Congress to the lab bench, momentum now aligns toward a future where Organ-on-a-Chip technology, advanced in silico models, and other NAMs form the backbone of drug safety assessment. Through our early advocacy, scientific rigor, and collaborative posture, Emulate is proud to have played a role in shifting the regulatory tides. As agencies implement their roadmaps and funders enforce new criteria, technologies that accurately recapitulate human biology will become indispensable. The era of relying on animal proxies is closing; what follows is a more predictive, ethical, and efficient research ecosystem—one that Emulate is excited to be a part of!

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As the demand for more human-relevant, ethical, sustainable and cost-effective safety and efficacy testing grows, New Approach Methodologies (NAMs) are rapidly becoming the new cornerstone of modern toxicology in drug discovery and development. NAMs represent a shift away from traditional animal models toward more predictive, mechanistically-informed systems that can assess human health risks with greater accuracy. But what exactly are NAMs, how do they work, and why are they capturing the attention of researchers, regulators, and industry leaders worldwide?

Let’s begin by defining what we mean by the term “NAM”. NAM has taken on several different meanings within today’s discourse on alternatives to animal models. While the terms is sometimes used to mean non-animal methods or new alternative methods, for the purposes of this blog, we will use NAMs to mean New Approach Methodologies.

“New Approach Methodologies” was formally coined in 2016 to encompass a broad range of techniques, technologies, and approaches that embrace ethical research principles and are increasingly being adopted for regulatory decision-making by agencies worldwide. In other words, for a new test or assessment method to be considered a NAM, it must be relevant for the regulatory hazard or safety assessment of a chemical, drug, or other substance.

This definition underscores an important point: NAMs aren’t just any new scientific method. They are fit-for-purpose tools that help evaluate safety in a way that regulators can use, moving us toward more predictive, human-relevant, and non-animal approaches.

In this blog post, we’ll explore the landscape of NAMs, break down the different types, explain how they can be used synergistically, and highlight the key factors driving their recent momentum.

What Are New Approach Methodologies (NAMs)?

New Approach Methodologies (NAMs) are a diverse suite of tools and technologies that can be used either alone or in combination with other methods to evaluate chemical and drug safety without relying on animal testing. The term encompasses in vitro, in silico, and in chemico methods, as well as frameworks for integrating data from multiple sources (e.g., Integrated Approaches to Testing and Assessment, or IATA).

NAMs are not a single test or platform. Rather, they include:

• Cell-based assays
• Organ-on-a-Chip systems
• Computational modeling (QSAR, PBPK, AI/ML)
• Omics technologies (transcriptomics, proteomics, metabolomics)
• Adverse Outcome Pathways (AOPs)

By focusing on human-relevant biology, NAMs aim to provide more accurate predictions of human health outcomes, reduce costs, and shorten development timelines—while also minimizing the ethical and scientific limitations of animal models.

Types of NAMs and What They Do

Let’s take a closer look at the most prominent categories of NAMs:

1. In Vitro Models

These models use cultured cells or tissues to assess biological responses to compounds and pharmaceuticals, including chemical and biological entities. Common systems include:

• 2D cell cultures: Widely used for basic toxicity screening.
• 3D spheroids and organoids: Offer more physiologically relevant structure and function.
• Organ-on-a-Chip models: Microengineered systems that mimic organ-level functions, enabling dynamic studies of toxicity, pharmacokinetics, and mechanisms of action.

Organ-on-a-Chip platforms in particular are gaining attention due to their ability to replicate complex tissue-tissue interfaces, fluid flow, and mechanical forces, offering a powerful bridge between cell culture and whole-organism physiology.

2. In Silico Models

Computational approaches simulate biological responses or predict chemical properties based on existing data. They include:

• Quantitative Structure-Activity Relationships (QSARs): Predict a chemical’s activity based on its structure.
• Physiologically Based Pharmacokinetic (PBPK) models: Model how chemicals are absorbed, distributed, metabolized, and excreted in the body.
• Machine Learning/AI: Leverage big data to uncover novel patterns and make toxicity predictions across the pharmaceutical space.

These tools can screen thousands of compounds in silico before any lab testing is done, helping prioritize candidates and reduce unnecessary experimentation.

3. Omics-Based Approaches

Omics technologies analyze large datasets from genomics, proteomics, metabolomics, and transcriptomics to identify molecular signatures of toxicity or disease. They offer:

• Mechanistic insights into how chemicals affect biological systems.
• Biomarker discovery for early indicators of adverse effects.
• Pathway-based analyses aligned with Adverse Outcome Pathways (AOPs).

These methods support a shift toward mechanistic toxicology, focusing on early molecular events rather than late-stage pathology.

4. In Chemico Methods

These techniques assess chemical reactivity without involving biological systems. A common application is testing for skin sensitization, where the ability of a compound to bind to proteins is evaluated directly through assays like the Direct Peptide Reactivity Assay (DPRA).

How NAMs Work Together: The Power of Integrated Approaches

One of the strengths of NAMs lies in their ability to complement each other. By combining in vitro, in silico, and omics data within integrated testing strategies (ITS) or frameworks like Integrated Approaches to Testing and Assessment (IATA), researchers can build a weight-of-evidence to support safety decisions.

For example:

• A computational model might predict that a compound is likely hepatotoxic.
• An Organ-on-a-Chip liver model can then test the compound’s effects on human liver tissue under physiologically relevant conditions.
• Transcriptomic profiling can reveal specific pathways perturbed by the exposure to the compound of interest.
• All this information can be fed into an AOP framework to map out the progression from molecular interaction to adverse outcome.

This synergy not only improves confidence in NAM-derived data but also aligns with regulatory goals to reduce reliance on animal testing while ensuring human safety.

Why Are NAMs Gaining Momentum Now?

Several converging trends are driving the growing interest in NAMs:

1. Scientific Advances

Technological innovations have made it possible to model human biology with unprecedented fidelity. From microfluidic Organ-Chips that more faithfully model human biology to AI-driven toxicity predictions, today’s NAMs offer tools that simply didn’t exist a decade ago.

2. Regulatory Support

Regulatory bodies around the world are actively encouraging the development and acceptance of NAMs. For example:

• US regulatory agencies have shown an unprecedented level of alignment and support for the NAMs in recent months. Both the Food and Drug Administration (FDA) and National Institutes of Health (NIH) have committed to phasing out animal testing and incentivizing the use of NAMs across academia and preclinical drug development. Just as recently as July 7^th, the NIH announced that they would no longer fund animal-exclusive studies, instead requiring all new proposals to include considerations for NAMs.
• The UK government has released their Life Sciences Sector Plan, which outlines their goal of driving the development alternatives to animal models through an infrastructure of translational networks and hubs.
• European agencies like the European Food Safety Authority (EFSA) and the European Chemicals Agency (ECHA) are incorporating NAMs into risk assessment frameworks.
• The Organisation for Economic Co-operation and Development (OECD)—a global entity that comprises 38 member countries—has published guidelines for validated NAMs such as the DPRA, KeratinoSens™, and human Cell Line Activation Test (h-CLAT).

Regulators are working collaboratively and increasingly globally to harmonize acceptance criteria and promote the use of NAMs for pharmaceutical and chemical safety evaluation.

3. Ethical and Social Pressure

Public concern over animal testing continues to grow, especially in cosmetics, food, and consumer products. NAMs offer a scientifically robust and ethically preferable alternative, aligning with principles of the 3Rs: Replacement, Reduction, and Refinement.

4. Economic and Efficiency Gains

NAMs can significantly reduce development costs and timeframes. High-throughput screening and predictive modeling allow companies to quickly eliminate unviable candidates early in development, saving millions in downstream costs.

Conclusion: NAMs Are Here to Stay

New Approach Methodologies are more than a replacement for animal testing—they represent a transformation in how we can better understand and assess the safety and efficacy of compounds and biologics. By integrating in vitro models, computational tools, and omics-based insights, NAMs offer a pathway to faster, more predictive, and human-relevant science.

As regulatory frameworks evolve and validation efforts expand, NAMs will play an increasingly central role in toxicology, risk assessment, and drug development. For industry leaders, researchers, and regulators alike, the time to invest in and adopt NAMs is now.

The time has come to move away from NHPs and embrace more practical, reproducible, and cost-effective models. 

As some of our closest evolutionary relatives, non-human primates (NHPs) like Cynomolgus Macaques, Sabaeus Monkeys, and Rhesus Macaques are well suited to play the role of “human” test subjects in biomedical research. Shared physiological and genetic features mean that NHPs are likely to respond to prospective drugs, for example, in the same way that a human would, enabling researchers to test drugs in human-like subjects before advancing them to clinical trials. In this way, NHPs have served a pivotal role in the development of safe and effective vaccines, medical devices, and blockbuster drugs¹. 

However, the era of NHP use may be coming to an end—and for good reason, too. In the face of an increasingly constricted supply chain, technological breakthroughs, and mounting evidence pointing to the shortcomings of NHPs as human avatars, it is becoming harder for researchers to justify their continued use. 

Are NHPs The Right Models? 

NHPs have long been viewed as the gold standard when it comes to approximating human physiology, due mostly to the significant commonalities among primates in both physiology and genetics. However, these models are far from perfect. Phenotypic and genotypic differences can result in drugs appearing safe in NHPs only to be lethal in humans. 

The models are further weakened by the possibility that some research NHPs are lab born, while others are sourced from the wild. Aside from international laws that aim to protect populations of endangered species, sourcing wild animals is problematic because it introduces variability into the pool of research subjects.  

Wild-born animals can differ from their lab-born counterparts in significant ways. They may have genetic variants that alter drug metabolism. Or, they may be infected with viruses or have altered microbiomes. Together, these variables can lead to inconsistent or non-reproducible results, eroding the robustness of NHP research altogether.  

Collectively, these issues raise the question of whether NHPs are truly a gold standard. Among animal models, they may still be the closest approximation to humans that we can find. But, technological advances may mean that we can look beyond animal models for a more human-relevant system. 

Towards A Human-Relevant Research Model 

While the supply chain of NHPs gets ever smaller, and as their scientific robustness is called further into question, technological and methodological advancements in tissue modeling may bring the era of NHP-dominated research to an end. 

Microfluidic Organ-on-a-Chip technology (Organ-Chips) is an important step in the right direction. Many tissue-specific Organ-Chips have already been developed for various applications, including Liver- and Kidney-Chips for preclinical toxicology screening. 

Organ-Chips are small, transparent devices designed to recapitulate the complexity of in vivo microenvironments, ultimately to help coax cells into behaving as they would in the body. This is achieved by culturing cells in the three-dimensional environment micropatterned to emulate tissue architecture from the target organ. Heterogeneous cells are cultured in this environment with tissue-specific extracellular matrix proteins. Microfluidics enable the functional and mechanical simulation of dynamic fluid flow through the tissue. Lastly, mechanical stimuli are provided when necessary by compressing or relaxing vacuum channels within the device (as may be needed when modeling the human lung, for example). 

Collectively, these features foster an environment where human cells can be readily observed and are more likely to behave as they would in vivo. As such, Organ-Chips are a highly human-relevant model type that may come to be a new gold standard in preclinical drug screening. To this end, the Emulate human Liver-Chip has already been shown to be capable of detecting hepatotoxic compounds that animal models failed to detect². Had the Liver-Chip been used in the preclinical screening of the drugs used in the study, their toxic profiles could have been detected before the drugs entered the clinic, and 242 patient deaths could have been prevented. 

The FDA recognizes the challenges of the current NHP supply constraints and is working with researchers on how to minimize their use in nonclinical studies. The agency recently released guidance on how labs can mitigate the impacts of NHP shortages by replacing NHPs with alternative models, including non-animal models, whenever feasible³. In addition, the FDA Modernization Act 2.0 authorizes alternatives to NHPs, such as cell-based assays, computer models, and microphysiological systems like Organ-Chips, as acceptable models for drug development⁴. While Organ-Chips are not yet ready to assume all the roles played by NHPs, the technology is rapidly evolving, and the current NHP shortages should spur scientists to accelerate their adoption of next-generation alternatives where appropriate. 

Moving Away from NHPs 

As next-generation drug development models become more advanced, researchers should begin to critically examine the performance of the models they use, including NHPs. As many as 90% of drugs that enter human clinical trials fail to make it to market, which is ample indication that current preclinical screening approaches are not providing the necessary information⁵. Because Organ-Chips start with human tissue, they have the potential to provide more precise data to inform drug development and help companies choose agents that are most likely to succeed in trials. 

With the ever-increasing challenges around the use of NHPs creating research bottlenecks, it’s time to reassess longstanding drug development practices. Relying on familiar but flawed approaches is bad for patients, animals, and companies. With technologies like Organ-Chips now available, researchers can lessen their reliance on NHPs while improving their ability to predict human response ahead of clinical trials. Now is the time to move drug development into a human-centric era. 

References  

1. “State of the Science and Future Needs for Nonhuman Primate Model Systems – Meeting 6.” Nationalacademies.org, 2023, www.nationalacademies.org/event/12-01-2022/state-of-the-science-and-future-needs-for-nonhuman-primate-model-systems-meeting-6. Accessed 28 Mar. 2023. 
2. Ewart, Lorna, et al. “Performance Assessment and Economic Analysis of a Human Liver-Chip for Predictive Toxicology.” Communications Medicine, vol. 2, no. 1, 6 Dec. 2022, pp. 1–16, www.nature.com/articles/s43856-022-00209-1, https://doi.org/10.1038/s43856-022-00209-1. 
3. Research, Center for Drug Evaluation and. “Nonclinical Considerations for Mitigating Nonhuman Primate Supply Constraints Arising from the COVID-19 Pandemic.” U.S. Food and Drug Administration, 11 May 2022, www.fda.gov/regulatory-information/search-fda-guidance-documents/nonclinical-considerations-mitigating-nonhuman-primate-supply-constraints-arising-covid-19-pandemic. Accessed 29 Mar. 2023. 
4. Congress, US. “S.5002 — 117th Congress (2021-2022).” Congress.gov, 9 Sept. 2022, www.congress.gov/bill/117th-congress/senate-bill/5002/text. 

5. Sun, Duxin, et al. “Why 90% of Clinical Drug Development Fails and How to Improve It?” Acta Pharmaceutica Sinica B, vol. 12, no. 7, Feb. 2022, https://doi.org/10.1016/j.apsb.2022.02.002.