Pharmaceutical research is in the early stages of a transition that promises to advance drug development as profoundly as the introduction of mass spectrometry in the 1990s. The FDA, the European Medicines Agency (EMA) and ICH are encouraging drug and biologic developers to reduce, replace or refine animal testing with advanced, human-relevant methods referred to as New Approach Methodologies (NAMs).
Animal-based drug safety studies often fail to predict human responses. Human-centric models have demonstrated strong predictive value for toxicology depending on drug class according to a recent JAMA editorial.
Integrating NAMs into safety studies has also been shown to produce more directly relevant data and potentially lowers preclinical testing costs compared to animal studies. Six-month toxicology studies may use over 40 nonhuman primates per study. At up to $50,000 per animal, the expenses are substantial.
While many safety and toxicology teams generally support NAM use, replacing an animal study with a NAM isn’t a simple switch: Scientists currently lack standardized processes to create and verify organoids. Good Cell Culture Practice (GCCP) guidelines are designed to bring more uniformity to how organoids are made, but interlaboratory variability in culture conditions and materials remains a documented challenge. At the same time, a repeatable, provable process to confirm an organoid’s health, baseline fitness and functional viability before introducing the drug is lacking.
“You cannot have confidence in a test result until you have confidence in the biological material going into the test,” said Mark Garner, PhD, director of the Translational and Clinical Research Segment at Agilent Technologies. “Traditional cell assays don't tell you the health, baseline fitness or functional viability of the organoid before the drug is introduced. If you don't know the health of the cells you're starting with, it’s hard to trust the results.”
Real-time functional assays evaluate a cell’s metabolism in the moment. With them, preclinical teams have assurance from well to well, or from experiment to experiment, that the cells are metabolically fit to test a drug candidate. Agilent Technologies offers advanced cell analysis instrumentation to conduct these assays, as well as robust multiomics solutions to help preclinical teams chart a clear path from cellular phenotype to molecular mechanism.
The black box of NAM-based safety studies
New Approach Methodologies (NAMs) refers to laboratory techniques, cell tests and computer models used to evaluate chemical safety and toxicity without relying on animals. Studies show NAMs are intended to improve on animal testing's poor predictive record. As a frame of reference, only 8–10% of oncology drugs that demonstrate efficacy in animal models ultimately receive FDA approval, often because of unforeseen toxicity or lack of efficacy in humans.
Scientists are integrating NAMs gradually, due in part to lack of historical data, lack of repeatable processes and the complexity of human-relevant analytical methods. Organoids provide an example of that complexity. A type of NAM, organoids closely mimic human organs — so much so that a cardiac organoid will beat like a human heart. Because they include multiple cell types, they’re difficult to grow and complicated to analyze. Their complexity and diversity is one reason the industry has not arrived at a standardized process to verify cell health.
The emerging solution: regulatory and technological support
The FDA has issued multiple papers that center on the 3Rs principles of animal research: replace, reduce, refine. The agency introduced general validation principles in a March 2026 guidance document, which it followed with a comprehensive progress report a month later.
In Europe, the EMA has also voiced its support of NAM use. Its Committee for Medicinal Products for Human Use (CHMP) qualifies NAM protocols and methods within a specific context of use upon submission of a fully robust, comprehensive validation package.
In late 2020, the FDA launched the ISTAND program, which provides a dedicated regulatory pathway for formally qualifying drug development tools which will be used in NAMs for drug discovery and development filings. Once qualified, sponsors can cite the technology without having to independently justify the platform every time. To date, the FDA has accepted 25 submissions into the ISTAND program, including 15 tis sue- and cell-based technologies for preclinical safety assessment.
“I expect drug companies will be much more comfortable putting ISTAND-qualified NAMs in their filings because it establishes a context of use and sponsors won't have to justify or revalidate that use,” said Garner. “The program speaks to how seriously the FDA is taking this, and it will only help accelerate NAM use by giving us officially accepted, standardized tools.”
How Agilent helps move NAMs forward
Agilent’s product portfolio supports NAM innovation by enabling pharma scientists to make precise, information-rich measurements on organoids, spheroids and other 3D cell culture structures — rapidly and at high throughput.
The Agilent Seahorse XF analyzers track a cell's metabolic response to a drug candidate in real time, including with the Seahorse XF Mito Tox Assay kit used to screen for drug-induced mitochondrial dysfunction using relevant cell types. The Seahorse XF Flex analyzer enables real-time metabolic analysis with 3D study models, such as organoids and tissue materials.
The Agilent xCELLigence RTCA assays enable assessment of cell barrier integrity, cytotoxicity, cardiotoxicity and cellular responses over time. For assessing organoid growth, Agilent BioTek automated cell imaging systems and Gen5 data analysis software round this out by enabling reproducible, image-based measurements of organoid size, morphology and structural changes with powerful imaging and quantitative data from 2D and 3D cell cultures to whole organism imaging.
The general NAM umbrella also includes multiomics approaches — including genomics, transcriptomics, proteomics, and metabolomics — for studies that involve how a drug affects gene expression or mutation. SureScan microarray solutions, SureSelect NGS library preparation and target enhancement systems, and Agilent LC/MS systems allow researchers to detect biomarkers associated with efficacy or adverse effects. Integrating these data helps pinpoint early indicators of toxicity, guiding safer and more effective drug development.
Together, these technologies help researchers connect functional cellular responses with molecular mechanisms, generating the multidimensional evidence required for confidence in NAM-based safety assessments.
When standardization creates a new standard
As NAM standardization evolves, historical data emerges and products in the ISTAND program become fully qualified, the industry may shift in the way that pharmacokinetic testing shifted when mass spectrometry became the default decades ago. A technology once viewed as novel became the trusted baseline that reduced costly late-stage failures. Scientists are building that trust with NAMs.
“Having that standardization is going to catalyze the field taking off,” said Garner. “The risk that biopharma companies and scientists are taking is quite large in the sense that they don't want to fail, and there aren’t many examples of success to emulate. Standardization breeds success. People see that success, they adopt it, and that generates more success. The industry must know a new technology will work before it adopts it.”
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