Conversely, potentially valuable therapies have occasionally been abandoned because of adverse findings in animals that were not relevant to humans. These challenges have contributed to the growing interest in New Approach Methodologies (NAMs), a collective term for innovative technologies designed to generate more human-relevant evidence for biomedical research and drug development. Among these technologies, organoids have emerged as one of the most promising platforms. [1-3]
Organoids are three-dimensional cellular structures derived from stem cells or primary tissues that self-organize into miniature versions of organs. They can reproduce key structural and functional aspects of tissues such as the liver, intestine, kidney, pancreas, lung, brain, and retina, including disease-specific and cancerous variants. Compared with conventional two-dimensional cell cultures, organoids better preserve tissue architecture, cellular diversity, and physiological functionality, making them particularly valuable for disease modelling, drug discovery, toxicity testing, and precision medicine. [1-4]
What makes organoids especially significant is their ability to address a central challenge in translational medicine: predicting how a treatment will behave in humans before it reaches patients. This capability is becoming increasingly important as regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) move toward frameworks that place greater emphasis on human-relevant evidence. [5-13]
Why organoids matter
The primary strength of organoids lies in their biological relevance. Animal models have played a critical role in biomedical research for decades, but species differences in metabolism, signaling pathways, tissue structure, and disease progression often limit their predictive value for human outcomes. Organoids reduce this translational gap by using human-derived cells that more closely reflect human tissue behavior. [1-3]
Their utility is particularly evident in areas where patient-specific biology is important. Patient-derived organoids can be used to study rare genetic diseases, tumor heterogeneity, mechanisms of drug resistance, and organ-specific toxicities. They also support personalized medicine approaches by enabling researchers to test treatment responses directly in patient-derived tissues before therapeutic interventions are initiated. [2,3]
Furthermore, organoids fit naturally within broader NAM strategies. They can be combined with organ-on-chip technologies, advanced imaging systems, transcriptomics, artificial intelligence (AI)-driven image analysis, and computational modelling to generate integrated evidence packages. This integration is increasingly attractive to regulators because it provides mechanistic insights and human-relevant data that are often difficult to obtain from animal studies alone. [1,2]
NAMs beyond animal replacement
NAMs are frequently described as alternatives to animal testing, but their purpose extends far beyond replacing laboratory animals. Their ultimate goal is to improve the scientific quality, relevance, and predictive power of preclinical evidence.
Human-derived methodologies can reveal mechanisms of toxicity, efficacy, and disease progression that may not be observable in animal models. This is particularly important for diseases that are uniquely human or involve highly patient-specific biological processes. Organoids exemplify this shift by providing living human tissue systems that can be generated from healthy donors, patients with specific diseases, or genetically engineered cell lines. [1-3]
As a result, organoids are increasingly viewed as core components of future biomedical research rather than niche laboratory tools. They provide a biologically complex human model system that bridges the gap between traditional cell culture and clinical reality. [1-4]
The FDA shifts the baseline
The most visible regulatory developments in NAM adoption have occurred in the United States. A major milestone was the passage of the FDA Modernization Act 2.0, which removed language that had effectively established animal testing as the default prerequisite for entering human clinical trials. The legislation explicitly opened the door for scientifically justified alternatives, including organoids, organ-on-chip systems, computational modelling, and other NAMs. [8]
Building on this foundation, the FDA announced in 2025 a roadmap to phase out animal testing requirements for monoclonal antibodies and selected other therapeutic products. Importantly, the agency specifically identified organoids, advanced cell-based systems, and computational approaches as critical technologies for future safety and efficacy assessments. [5]
The FDA further strengthened this position in 2026 through draft guidance outlining how NAMs should be evaluated for regulatory applications. The guidance emphasizes principles such as reproducibility, human biological relevance, technical characterization, and fit-for-purpose validation. [6,7] These principles closely align with ongoing efforts within the organoid community to improve standardization, quality control, and reproducibility.
For developers of organoid technologies, this represents a significant shift. The FDA is no longer debating whether human-relevant models have value; instead, it is actively developing pathways for their regulatory implementation. Organoids are therefore moving from research tools to recognized contributors within the regulatory decision-making process. [5-8]
Can drugs be approved without animal testing?
The answer is increasingly yes, although important hurdles remain. Neither the FDA nor other major regulatory agencies currently advocate the complete elimination of animal testing across all therapeutic areas. However, regulators are becoming more willing to accept alternative evidence packages when sponsors can demonstrate that NAMs provide reliable, relevant, and scientifically justified data for a particular regulatory question. [5-8]
The shift should therefore not be interpreted as the end of animal testing, but rather as a transition toward a more evidence-based and flexible framework. The central question is no longer whether data originate from an animal study, an organoid experiment, or a computational model. Instead, the focus is increasingly on whether the evidence is scientifically robust and predictive of human outcomes. [5-8]
This development is particularly favorable for organoids because they generate human-specific data early in the development process, potentially reducing the need for certain animal studies while improving translational predictability. [1-3]
EMA moves more gradually
In Europe, the regulatory trajectory is similar, although the approach has been more gradual and qualification-oriented. The EMA has long supported the principles of the 3Rs (Replacement, Reduction, and Refinement of animal use) and has consistently encouraged the development of alternative methods where scientifically appropriate. [10-13]
Rather than pursuing highly visible policy changes, the EMA has focused on establishing qualification procedures, validation frameworks, and standardization initiatives that can support the long-term adoption of NAMs. Recent EMA reports and scientific perspectives identify organoids, organ-on-chip systems, computational approaches, and AI-supported methodologies as key technologies that may transform medicines development and safety assessment in the coming years. [9-11]
A major European focus is the establishment of standards. Reproducibility and interoperability are considered prerequisites for regulatory acceptance. This is particularly relevant for organoids, where differences in cell sources, culture conditions, extracellular matrices, and analytical methods can affect experimental outcomes. [12]
The European Commission's Joint Research Centre recently published a roadmap for the standardization of organ-on-chip technologies, while EMA initiatives continue to explore qualification pathways for innovative methodologies. [10-12] Although the EMA's pace may appear slower than that of the FDA, its emphasis on validation and standardization is likely to be critical for sustainable regulatory adoption.
Remaining challenges
Despite the growing enthusiasm surrounding organoids and NAMs, important challenges remain. The first challenge is standardization. Organoid systems can vary considerably between laboratories, protocols, operators, and cell sources. Regulatory agencies require confidence that experimental findings can be reproduced consistently across sites and over time. [1,6,12]
The second challenge is quality control. Advanced imaging methods, transcriptomic profiling, functional assays, and AI-assisted analyses are increasingly being incorporated into organoid workflows. However, harmonized quality standards are still evolving. Robust characterization strategies will be essential to ensure confidence in regulatory applications. [1,4,6]
A third challenge concerns context of use. No single organoid model can address every biological question. Liver organoids may be highly informative for hepatotoxicity testing, while kidney, intestinal, or neural organoids may be more appropriate for other applications. Regulatory acceptance will depend on demonstrating suitability for specific purposes rather than universal applicability. [6,9]
Another important challenge is scalability and manufacturing standardization. While many organoid systems perform well at laboratory scale, regulatory acceptance and industrial implementation require robust, reproducible, and scalable production processes. Variability in culture conditions, handling procedures, and operator-dependent workflows can affect organoid quality and experimental outcomes. Recent advances in automated culture platforms and dynamic bioreactor systems have demonstrated the potential to improve process control, increase production capacity, and reduce batch-to-batch variation. Such developments are expected to play an important role in enabling the wider adoption of organoids in drug development, toxicity testing, and future regenerative medicine applications. [14]
Finally, there is the challenge of biological complexity. Even advanced organoid systems cannot yet fully replicate interactions among organs, immune systems, microbiomes, endocrine signalling pathways, and whole-body physiology. Rather than diminishing their value, this limitation highlights the importance of integrating organoids with complementary NAM technologies such as organ-on-chip systems and computational models. [1,2,9]
A human-centered future
The future of drug development is unlikely to be defined by a simple replacement of animals with organoids. Instead, it will emerge as an integrated ecosystem in which organoids, organ-on-chip technologies, computational modelling, AI-driven analytics, and clinical data collectively contribute to decision-making.
Within this ecosystem, organoids provide a crucial biological anchor: a human tissue model that can be experimentally manipulated, observed, and directly linked to patient biology. Their ability to generate mechanistic, human-relevant data makes them one of the most promising technologies within the broader NAM landscape. [1-4]
The current moment therefore represents a genuine regulatory turning point. The FDA is actively creating pathways for alternative methods, while the EMA is developing the qualification and standardization frameworks necessary for broader implementation. Although their approaches differ, both agencies are moving toward a more human-centered form of regulatory science. [5-13]
For organoids, this represents a defining opportunity. They are no longer merely promising experimental systems. They are becoming essential tools for translational research, precision medicine, and safer, more predictive drug development. As regulatory frameworks continue to evolve, the models that succeed will be those that demonstrate scientific rigor, reproducibility, and a clear connection to human biology. Increasingly, organoids meet those criteria.
References
1. Wang D, Villenave R, Stokar-Regenscheit N, et al. Human organoids as 3D in vitro platforms for drug discovery: opportunities and challenges. Nat Rev Drug Discov. 2026;25:204–226.
2. Piraino F, Costa M, Meyer M, et al. Organoid models: the future companions of personalized drug development. Biofabrication. 2024;16(3):032001.
3. Gopallawa I, Gupta C, Jawa R, et al. Applications of organoids in advancing drug discovery and development. J Pharm Sci. 2024;113:2659–2667.
4. Marsee A, Roos FJM, Verstegen MMA, et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell. 2021;28:816–832.
5. U.S. Food and Drug Administration. FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs. 2025.
6. U.S. Food and Drug Administration. General Considerations for the Use of New Approach Methodologies in Drug and Biological Product Development. Draft Guidance. 2026.
7. U.S. Food and Drug Administration. Advancing Alternative Methods at FDA.
8. Van Norman GA. The FDA Modernization Act 2.0 and the future of non-animal drug development. JACC Basic Transl Sci. 2024.
9. Cavero I, Holzgrefe H, Renga B, et al. Insights into new approach methodology innovation: an EMA perspective. Nat Rev Drug Discov. 2025.
10. European Medicines Agency. Qualification of Novel Methodologies for Medicine Development.
11. European Medicines Agency. New Approach Methodologies Horizon Scanning Report. 2025.
12. European Commission Joint Research Centre. Setting Out a Roadmap for Standardisation of Organ-on-Chip Technology. 2025.
13. European Medicines Agency. 3Rs Working Party and Innovation Task Force Presentations on New Approach Methodologies. 2024–2025.
14. Ye S, Marsee A, van Tienderen GS, Rezaeimoghaddam M, Sheikh H, Samsom RA, de Koning EJP, Fuchs S, Verstegen MMA, van der Laan LJW, van de Vosse F, Malda J, Ito K, Spee B, Schneeberger K. Accelerated production of human epithelial organoids in a miniaturized spinning bioreactor. Cell Reports Methods. 2024;4(11):100903.
About the author
Bart Spee, PhD — Co-founder, Orgonex
Bart co-founded Orgonex out of Utrecht University, where his research on liver organoid biobanking and bioreactor-based expansion underpins the RPMotion platform.
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