The FDA’s announcement that it will phase out in vivo testing requirements for monoclonal antibodies marks a seismic shift. Here’s how industry can adapt.
U.S. regulators in April announced a seismic shift in their approach to preclinical in vivo testing. In a decision with immediate and potentially far-reaching implications for drug development, the FDA stated it would phase out in vivo testing requirements for monoclonal antibodies and expand the policy to other biologics and small molecules as more data are collected.
For decades, preclinical safety and efficacy testing—my area of specialty at WuXi AppTec—has revolved around nonhuman in vivo models. With the FDA’s announcement, drug developers and sponsors must prepare to chart a new course. U.S. regulators list patient safety, animal welfare and more efficient pipelines for novel treatments among the goals of this shift. Officials also envision reduced R&D costs, accelerated time to market and the possibility of setting new standards for ethical and scientific discovery.
Beginning immediately, drug developers will be allowed to use advanced, human-relevant testing platforms—such as advanced computational models, lab-grown organoids and organ-on-a-chip systems—to support investigational new drug (IND) applications. Known collectively as new approach methodologies (NAMs), these alternatives have the potential to predict toxicities and side effects more reliably than in vivo assays. They also provide the flexibility to test drugs on patient-specific cells, opening a world of possibilities in personalized medicine.
The new policy also encourages using real-world safety data from global markets to further streamline drug development. That means electronic health records, patient registries and postmarket surveillance data could be used in safety assessments, providing a more holistic understanding of the drug’s effects. At present, it’s unclear which jurisdictions will qualify and how applications for biologics licenses and new drugs will be managed.
While this shift brings the potential for faster, more efficient and more ethical drug development, the scientific community continues to explore the best ways to implement these changes. Careful validation and regulatory engagement remain important to ensure that patient safety and data reliability are maintained throughout the transition.
What’s Missing From the NAM Toolbox
The idea of moving away from in vivo testing models is not new and appears to have public support. The U.S. Congress worked with the scientific community to pass a 2022 act modernizing the in vivo approach and authorizing validated non-animal alternatives in applications to the FDA. A 2024 survey of more than 2,000 U.S. adults showed that more than 85% support moving away from animal testing in favor of more modern, humane methods.
Nonetheless, relying on NAMs requires rigorous methodological validation that is still far from being achieved. For example, the functional observational battery is a critical section within the FDA’s ICH S7A guidance document and a well-established method to assess neurobehavioral changes in various species across different times and doses. No in vitro assays exist for these neurological assessments. There are in silico options to assess cardiovascular toxicity, but nothing for neuro.
Moreover, general toxicology studies rely on balloon testing to detect histopathological changes in central nervous system tissue. Usually, that means slicing cross-sections of the material as many as seven times and examining each layer closely for potential morphological changes. Combining histopathology, functional observational battery results and other data can help to comprehensively assess toxicity and provide a complete picture of drug safety. It remains unclear how this level of rigor can be achieved without using in vivo testing methods.
NAMs validation also presents other challenges. Current organ-on-a-chip systems (OOCs) and advanced computational models lack standardized protocols, raising concerns about reproducibility. The regulatory roadmap guiding the shift toward in vitro assays emphasizes multisite validation studies, including retrospective analyses and prospective, parallel testing of drugs in animals and NAMs to compare predictive accuracy. While desirable in principle, that process can be especially challenging when assessing complex endpoints like chronic toxicity or immune-related adverse events.
Global Alignment, Industry Readiness and the Path Forward
U.S. regulators’ pivot to NAMs data may encounter practical complications in global drug development. While the FDA is advancing toward in vivo test alternatives, other regulatory bodies have not signaled similar shifts. For example, the European Medicines Agency prohibits animal testing for cosmetics but continues to require it for most monoclonal antibody (mAb) programs. Similarly, China’s NMPA and Japan’s PMDA still mandate in vivo data for mAbs and all investigational new drug submissions. Although these agencies are not expected to challenge the FDA’s decision directly, the lack of harmonization could force sponsors to conduct redundant studies to meet multi-jurisdictional requirements.
Another set of questions concerns industry readiness. Adopting NAMs will require a cultural shift and a significant investment for much of the scientific community. For example, OOC systems have not been widely adopted despite great promise and seemingly clear benefits. Questions about regulatory acceptance and the high cost of manufacturing drive these concerns. Furthermore, some lab testing partners may lack experience maintaining these systems or interpreting the data they generate, requiring sponsors to do extra diligence when choosing a collaborator. Also of concern to the industry is a potential misalignment: while the FDA launched a pilot program this year to test OOCs’ readiness, critical training for regulators in this area will not begin until 2026.
NAMs’ overall success hinges on real-world validation. As part of its implementation roadmap and pilot program, the FDA will track several metrics, including 1) the correlation between NAMs data and clinical outcomes, 2) the overall reduction in animal use hours (the goal is a 50% cut by 2027) and 3) the time to a successful IND for NAMs programs versus traditional ones. It remains to be seen whether the scientific community can build trust in NAMs data or whether clinical setbacks will hinder their success.
Navigating Regulatory and Commercial Risks
Phasing out in vivo assays for mAbs requires rethinking preclinical drug development. Someday, this change could mean higher quality, more-affordable pharmaceuticals that keep patients every bit as safe as those on the market today. Continued progress to that end will depend on the collective efforts of innovators and the wider healthcare community. For that to happen, upfront investments (e.g., in OOC platforms and staff training) could be significant, especially for smaller companies. And for drug developers and sponsors hoping to do business in the U.S., the transition to NAMs is not optional.
Early investment in human-relevant models, robust validation and regulatory engagement will be critical to maintaining a competitive advantage and ensuring access to global markets. Success will also depend on adapting to the challenges ahead and building the expertise to interpret and act on new data sources. Those who can achieve this will help shape a new regulatory reality.
