Comment from The 3Rs Collaborative

The 3Rs Collaborative, a US-based non-profit dedicated to advancing better science – for both people and animals – believes that progress in scientific research, the 3Rs, and New Approach Methodologies (NAMs) must be measured by improved outcomes for patients and public health. We commend FDA-CDER’s efforts to advance the responsible use of NAMs. The 3RsC defines NAMs as technologies that do not directly involve live animals and generate mechanistic or predictive information to advance biological understanding or inform decisions related to human, animal, or environmental health. They typically rely on target species’ data, cells, tissues, or computational approaches. These technologies may, but do not always contribute to the 3Rs of animal research. Please see LaFollette et al 2026 (https://doi.org/10.1016/j.namjnl.2026.100085). We encourage FDA-CDER to ensure that any future press releases, media statements, and recommendations from FDA reviewers are aligned and mirror the scientifically grounded tone present in this guidance. When press releases, FDA reviewer recommendations, and official guidance do not match, sponsors are left without clarity on what studies are required, policy makers are led to believe that practices are ahead of where they are, and the public are misled as to the current status of drug development and the importance and value of animal models. Overpromising the current capacity of NAMs while dismissing the continued value of animal models risks alienating the very individuals and organizations that need to adopt NAMs, while simultaneously undermining public trust in science. The 3RsC commends the FDA-CDER for its efforts to facilitate broader integration of NAMs in drug development and regulatory submission packages. We encourage FDA-CDER to explicitly acknowledge the role of international harmonization, especially alignment with OECD test guidelines already accepted as fit-for-purpose. This will help reduce duplicative validation burdens on sponsors operating across jurisdictions. We also commend FDA-CDER for: - Encouraging the use of NAMs in regulatory submission where they improve predictivity, reliability, & human relevance of nonclinical test and safety of subsequent clinical trials. - Creating a realistic, scientifically grounded approach to use of NAMs in drug development that requires data to be reliable and there to be confidence in the methodology. - Clearly distinguishing between validation and qualification, in a regulatory context. We appreciate and agree with the following: - Clear guidance on context of use, and for providing examples of context of use for regulatory decision making. - Providing key recommendations for establishing human biological relevance including physiological features, relevant toxicology, and biological mechanisms - Providing key recommendations for technical characterization including key features from Good In Vitro Method Practices (GIVIMP), although Good Laboratory Practice should be the default for safety studies with GIVIMP supporting GLP and not replacing GLP. Harmonization across agencies is strategically essential. This effort reduces duplicative documentation for sponsors already operating under GIVIMP and GLP standards and positions FDA-CDER as a collaborative partner within the international regulatory science community. - Providing fit-for-purpose recommendations including comparator assessment, benefits/limitations and findings. - Delineating 3 potential applications including replacement, filling data gaps, and confirming or complementing traditional methods We recommend that recommendations be expanded for in silico NAMs such as that in silico model validation should reference established frameworks where possible (e.g., OECD principles for QSAR model validation, ECH M15 on PBPK). We recommend that the FDA-CDER run workshops or participate in workshops, presentations and/or roundtables at national meetings of scientific societies, for example the American College of Toxicology and Society of Toxicology, to present examples of successful use of NAMs in regulatory applications. The 3Rs Collaborative appreciates the opportunity to contribute to this dialogue. There is a clear need for funding on all aspects of the 3Rs; research, education, reproducibility, translation, and dissemination. The convergence of regulatory willingness, technological advancement, and organizational support presents an immense opportunity. We remain committed to ongoing partnerships with FDA-CDER and the broader scientific community to advance patient and public health outcomes through the responsible, evidence-driven implementation of the 3Rs. Please consider the 3Rs Collaborative as a resource and partner in these efforts.