New Approach Methodologies (NAMs): The Future of Non-Animal Research Models

Table of Contents

Overview
Why Researchers Look Beyond Animal Models
NIH Leadership in Human-Based Research
FDA Efforts to Reduce Animal Testing
International Regulatory Trends
Challenges and Limitations
Recommended Training
Looking Ahead
References

Overview

Animal models play a central role in biomedical research to study diseases and evaluate whether drugs or medical products are safe enough for human use. Animal studies remain part of many regulatory systems around the world. However, scientific advances and policy changes are now creating further opportunities to reduce dependence on animal testing and improve the relevance of research to human health.

Government agencies and global regulatory bodies in the United States and globally are increasingly supporting new approach methodologies (NAMs). Examples of NAMs include tools such as organoids, organ-on-chip systems, and advanced computer modeling.

Organoids are small, three-dimensional structures grown from human stem cells that mimic some features of organs such as the liver, brain, or intestines. Researchers use organoids to study disease progression, infection, toxicity, and drug responses.
Organ-on-chip systems combine engineering and biology to recreate aspects of human organ function on small microfluidic devices. These systems can simulate blood flow, breathing movements, or tissue interactions.
Computer modeling systems can analyze large datasets, identify patterns, and predict biological responses. Researchers are using AI to evaluate toxicity risks, identify drug candidates, and model disease pathways.

These approaches aim to improve the prediction of human responses while also replacing animal use in research and testing. Understanding NAMs is important for researchers, institutions, ethics committees, and regulatory professionals working in biomedical research.

Why Researchers Look Beyond Animal Models

Animal models have contributed significantly to scientific progress. They help researchers understand biological systems, develop vaccines, and study disease mechanisms. However, animal studies also have important limitations. The first major concern is that animal biology does not always predict how humans will respond to a drug or treatment. Studies have shown that many treatments that appear promising in animals later fail in human testing. Differences in genetics, metabolism, immune systems, and physiology can lead to results that fail to translate effectively into human clinical trials.

Ethical concerns are another determining factor. The scientific community has long supported the principles of the “3Rs”: replacement, reduction, and refinement. These principles encourage researchers to replace animals with other alternative methods (when possible), reduce the number of animals used, and refine procedures to minimize pain or distress. The recent emphasis on NAMs reinforces the importance of the 3Rs.

NIH Leadership in Human-Based Research

The National Institutes of Health (NIH) has become a major supporter of human-based research technologies. In recent years, NIH leaders have emphasized the importance of developing methods that better reflect human biology. The NIH Complement-ARIE program is one example of an effort focused on accelerating the development and use of alternative research approaches. In 2025, NIH announced additional efforts to prioritize human-based technologies in research programs to improve translational research. The agency also emphasized that improving human relevance may help address high failure rates in clinical development.

FDA Efforts to Reduce Animal Testing

The U.S. Food and Drug Administration (FDA) is also increasing its focus on reducing animal testing. Although many regulatory pathways still require animal data, the FDA has taken several steps to encourage innovation. FDA strategic roadmaps describe how the agency plans to incorporate NAMs into regulatory science. These efforts include evaluating new testing tools, developing standards for validation, and supporting collaboration between government agencies, industry, and academic researchers. One important area involves drug safety testing. Researchers are exploring whether human-based systems can provide more accurate toxicity information than traditional animal models. FDA initiatives are examining the use of tissue chips, computational toxicology, and other NAMs to support safety assessments. Further, the FDA and NIH also organized a collaborative workshop focused on reducing animal testing and promoting alternative methods.

International Regulatory Trends

The movement toward NAMs is not limited to the United States. Regulatory agencies around the world are exploring alternative approaches. The European Medicines Agency (EMA) has published guidance on the regulatory acceptance of NAMs aimed at reducing animal use. The EMA supports the 3Rs principles and encourages the development of scientifically valid alternative methods. The EMA has emphasized collaboration among regulators, researchers, and industry groups to advance these efforts. Europe has historically been active in promoting alternatives to animal testing, particularly in areas such as cosmetics and chemical safety assessment. Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is also exploring the use of innovative testing approaches. The PMDA has participated in international discussions on regulatory science and new technologies. Japan’s involvement demonstrates that the transition toward alternative methods is becoming a global issue rather than a regional trend.

Challenges and Limitations

Although enthusiasm for NAMs is growing, important challenges remain. Regulators and researchers need strong evidence that alternative methods are reliable and reproducible. A method that works well in one laboratory must also work consistently in other settings. Validation can take years and may require extensive comparison with existing testing approaches. Regulatory agencies must determine whether new tools provide information that is equal to or better than traditional methods.

Human biology is extremely complex. No single model can fully replicate the interactions among organs, immune systems, hormones, and environmental influences. Animal models also have limitations, but they can sometimes capture whole-body interactions that are difficult to recreate in laboratory systems. As a result, many experts believe research will continue to use combinations of animal and non-animal approaches for the foreseeable future. Additionally, modern research often generates large and complex datasets. Integrating information from organoids, computational systems, imaging technologies, and genetic analyses can be difficult.

Researchers must also develop new standards for interpreting and sharing data generated by NAMs.

Recommended Training

As NAMs continue to evolve, professionals may benefit from training in the 3Rs. CITI Program’s 3Rs Certificate Course introduces you to key information about, and tools to use, the 3Rs. The goal is to empower you to make a difference for animals in science by enhancing animal welfare, reducing the total animal numbers while ensuring scientific validity, and replacing animals with scientifically valid alternatives. Additional training on animal care and use is available through CITI Program’s ACU Core and ACU Advanced series.

Looking Ahead

Advances in organoids, tissue chips, AI, and computational science are creating new opportunities to improve the relevance and efficiency of research. Federal agencies such as NIH and FDA are focused on the use of these technologies, while international regulators are developing frameworks for their evaluation and acceptance. At the same time, significant scientific and regulatory challenges remain. Validation, standardization, and infrastructure will all play critical roles in determining how quickly NAMs continue to advance. Rather than viewing NAMs as a complete replacement for animal research today, many experts see them as part of a larger effort to create more predictive, efficient, and humane research systems. As technology continues to evolve, the balance between animal and non-animal methods may continue shifting toward approaches that better reflect human biology and improve translational success.