There is growing scientific recognition that animal models often fail to reliably predict human health and disease. More than 90 percent of drug candidates that appear safe and effective in animals ultimately do not receive FDA approval, largely due to safety or efficacy failures in humans. Animal-based data have also been particularly poor predictors of clinical success in complex, multifactorial diseases such as cancer, Alzheimer’s disease, endometrisosis, and sepsis.
In December 2025, the Senate passed the FDA Modernization Act 3.0 by unanimous consent, building on reforms enacted in 2022 and formally advancing the FDA’s transition toward “nonclinical” testing. This approach includes both traditional animal studies and new approach methodologies (NAMs) such as organoids, in silico, and other innovative platforms. These technologies aim to better capture immunogenicity, toxicity, and pharmacodynamic responses in humans, providing a potential path to address the long-standing limitations of animal models.
What does the new legislation mean?
The FDA Modernization Act 2.0 removed the decades-old statutory requirement that animal testing be conducted as part of Investigational New Drug applications. FDA Modernization Act 3.0 now goes further, instructing the FDA to establish a formal process for qualifying nonclinical testing methods, including NAMs, as defined in the 2022 law.
The agency must report within two years on which methods have been qualified, how they were evaluated, and how many animals were ultimately spared through their use. The legislation also directs the FDA to expedite review of applications that incorporate qualified NAMs, creating both an incentive for sponsors and a mechanism to rapidly generate real-world regulatory experience.
“It has been nearly three years since Congress eliminated the legal requirement that animal testing be conducted as part of the new drug development process,” said Senator Cory Booker in a press release. “The FDA Modernization Act 3.0 will help lock in these reforms, ensuring that FDA regulations mirror current law and reflect the best available science.”
These requirements arrive as the FDA has already begun implementing changes under Commissioner Martin Makary. In April 2025, the agency released a roadmap to reduce animal testing, initially focusing on monoclonal antibodies. The roadmap emphasized AI-based computational models, organ-on-chip systems, and organoid-based testing, which Makary described as part of a “paradigm shift” in nonclinical evaluation.
As Senator Rand Paul noted in the press release, the bill aims to replace “outdated animal testing” with “modern, humane, and scientifically advanced testing methods,” while accelerating the delivery of life-saving treatments.
The promise — and limits — of NAMs
Market enthusiasm reflects this momentum.
Grand View Research projects that the organ-on-a-chip market will grow from roughly $157 million in 2024 to nearly $1 billion by 2030, while the organoid market could reach $2.72 billion by 2030.
However, many researchers caution that enthusiasm should not outpace evidence. While organoids, organs-on-chips, and computational models have demonstrated value in early discovery and target validation, they still struggle to replicate the complex, systemic responses that whole organisms provide.
“There is currently no full replacement for animal models in biomedical research and drug development,” the National Association for Biomedical Research previously argued in response to the FDA announcing plans to phase out animal testing requirements. “We all want better and faster ways to bring lifesaving treatments to patients,” NABR President Matthew R. Bailey said in the press release. “But no AI model or simulation has yet demonstrated the ability to fully replicate all the unknowns about many full biological systems. That’s why humane animal research remains indispensable.”
That skepticism is echoed by Carl Schoellhammer, a Biopharma Strategy Consultant at DeciBio, who told DDN that the FDA’s reforms are often misunderstood. “Everyone’s made the noise that the FDA won’t require animal testing. That’s not what the FDA did,” he said. “The FDA effectively said you can skip animal testing — if you convince us that it’s sufficiently safe to do so. That is a huge ‘if,’ and, in practice, will rarely happen.”
The FDA effectively said you can skip animal testing — if you convince us that it’s sufficiently safe to do so. That is a huge ‘if,’ and, in practice, will rarely happen.
—Carl Schoellhammer, DeciBio
In Schoellhammer’s view, the reforms are more likely to reduce early-stage mouse studies than eliminate animal testing entirely. “If a non-human primate study shows animals dying, I don’t want that step skipped and that product going straight to humans,” he said. “Animal studies are still critical.”
Towards a hybrid future
Many experts now argue that the future lies not in outright replacement, but in integration. Alternative models may help de-risk compounds earlier, identify human-relevant toxicity sooner, and reduce animal numbers — without abandoning in vivo studies altogether.
One emerging approach focuses on extracting more information from each animal study through continuous, real-time biological measurement. Bill Rader, CEO of Efferent, argues that the core limitation of many alternatives is not accuracy at a single moment but the inability to capture biology over time.
“What organoids, organs-on-chips, and computational models still lack is continuous, integrated physiology — the dynamic interplay between immune, metabolic, and stress responses that often drives drug success or failure,” Rader told DDN. Rather than attempting to fully replicate these systems in vitro, Efferent’s platform uses a small, implantable sensor containing engineered reporter cells that is placed subcutaneously in animal models. This enables researchers to monitor pathway-specific biological responses continuously over the course of a study, reducing the need for large cohorts and repeated terminal sampling.
What organoids, organs-on-chips, and computational models still lack is continuous, integrated physiology — the dynamic interplay between immune, metabolic, and stress responses that often drives drug success or failure.
—Bill Radar, Efferent Labs
For Rader, the goal is not wholesale replacement, but integration. “It’s not about replacing everything with one model,” he said. “It’s about filling the gaps between in vitro systems and whole-animal biology.”
Rader sees a future where multiple platforms are combined, but only if their outputs can be meaningfully integrated. “Adding platforms together isn’t enough,” he said. “Organoids, chips, and computational models often generate fragmented data at different scales and timeframes. Our platform can provide a continuous in vivo reference point that helps contextualize and interpret signals across systems.”
In this sense, FDAMA 3.0 is less about replacing one model with another than about creating a regulatory framework that can accommodate hybrid, evidence-weighted approaches. Realizing its goals will require sponsors to take calculated risks — submitting data from emerging NAMs alongside enhanced animal studies. The shift envisioned by FDAMA 2.0 and 3.0 is unlikely to be driven by any single company or technology, but by coordinated experimentation across biotech and pharma, as regulators and developers test how far integrated systems can go — and where animals may still remain indispensable.
