On April 10, 2025, the US FDA announced that it has a long-term plan to eliminate conventional animal testing in drug development, starting with monoclonal antibodies (mAbs).[1] Instead, within 3-5 years, the expectation will be to leverage an integrated safety assessment approach, combining information from a comprehensive battery of New Approach Methodologies (NAM). These methodologies could include in vitro and ex vivo human-based systems; advanced Artificial Intelligence supported by in silico computer-based modeling and simulation (M&S); microdosing and imaging in human volunteers; and refined, targeted, and customized in vivo methods, in addition to many others. FDA’s vision and details on the use of NAMs in drug development was also released on April 10, 2025, as a “Roadmap to Reducing Animal Testing in Preclinical Safety Studies.”[2]  

An overview of the 3R’s 

The FDA and other global regulatory health authorities have long embraced the 3R’s of animal research (replace, reduce, and refine). One great example is the FDA’s 505(b)(2) New Drug Application (NDA) pathway. This pathway allows novel drug products to leverage data from other approved drugs (in the US and abroad), greatly reducing and sometimes altogether avoiding animal testing for approval. In 2019, we published a detailed peer-review article outlining this process based on our long history of leveraging existing animal and human data to streamline drug development programs and reduce or eliminate animal testing under the 505(b)(2) pathway.[3]  

The FDA and ICH have embraced the practical use of NAMs in other areas of drug development, such as using vitro and ex vivo methods to replace animals for ocular safety testing for dermal products and in silico Quantitative Structure-Activity Relationship (QSAR) modeling for mutagenic impurities under ICH Guideline M7(R2).[4-6] Although there has been tremendous progress on the development of a wide array of NAMs, their adoption for formal regulatory use has been relatively slow since there is a requirement that they need to be qualified and validated. This aspect of NAM development is critical to ensure that the information they generate can be relied upon to make robust safety determinations and ensure that drugs have appropriate benefit:risk ratios, without causing unnecessary harm to patients.   

Legislation with delayed implementation  

In 2021, the FDA Modernization Act 2.0 was passed, requiring the FDA to consider alternatives to animal testing, such as in vitro, in silico, and in chemico tests and models, by amending the Federal Food, Drug, and Cosmetic Act (FFDCA).[7] This was a landmark change in philosophy. However, from a practical standpoint, animal testing in drug development has remained fairly consistent since the Act was passed with only incremental changes in the adoption of NAMs for regulatory purposes primarily due to the high hurdle in qualifying and validating NAMs. FDA’s renewed focus on NAMs, starting with their use to eventually eliminate animal testing for mAbs, will likely accelerate the use and regulatory acceptance of NAMs in drug development as emphasized in the FDA’s roadmap.  

Navigating the changes: Takeaways from the roadmap 

For sponsors developing mAbs, the FDA’s roadmap highlights some NAMs to investigate and consider incorporating in the development process, including using 3D human tissue models to understand specificity and biological activity, in vitro methods to characterize potential for cytokine storm, and leveraging available clinical data on similar antibodies (e.g., from approved products in other countries) to inform doses and development. The roadmap also notes a potential pathway to reduce long-term toxicity testing durations in non-human primates from the typical 6 months to 3 months, if there are no concerning signals in the 1-month toxicity study. Finally, one of the policy recommendations in the roadmap discusses providing incentives for companies that utilize NAMs, such as fast-track meeting requests and review. While no clear incentive program was announced in the roadmap, this potential is something to monitor and take advantage of if these kinds of programs are implemented.  

The importance of holistic approaches  

Although there may be many unknown gaps with eliminating animal testing and the types of NAMs that are needed to provide robust safety assessments, it is an exciting time to leverage the immense amount of preclinical and clinical data, knowledge, and tools to refine and expedite drug development. As NAMs are adopted, it will be critical to have expert toxicologists guide preclinical drug development that can bridge multiple disciplines ranging from designing and interpreting in vitro and ex vivo assays, running and leveraging in silico computer models, utilizing existing animal and human data, among other holistic approaches. All of this information will then need to be integrated into comprehensive Weight-of-Evidence (WOE) assessments to justify initially the safety of the drug to enter the clinic and then the overall benefit:risk of the drug for formal marketing approval. The WOE process along with the use of NAMs is becoming more accepted for various regulatory purposes, such as waiving a 2-year rat carcinogenicity study in accordance with ICH S1B(R1) and the use of alternative assays and a WOE approach to determine the reproductive and developmental toxicity testing strategies under ICH S5(R3).[8-9] 

Overall, the FDA’s push to use NAMs in drug development and regulatory decision-making is a positive move towards the 3R’s. This is in alignment with FDA’s adoption of Model Informed Drug Development (MIDD) approaches to streamline and accelerate drug development.[10] In order to reach the FDA’s ultimate vision, it will be critical to ensure NAMs are qualified, designed, and run to high standards and the results integrated into robust WOE assessments to ensure the protection of human volunteers and appropriate benefit:risk in patients. 

Premier is committed to monitoring this evolving regulatory landscape to support sponsors through the design and conduct of their nonclinical programs under this new paradigm. We remain ingrained in the regulations to ensure sponsors can optimize their programs and leverage the benefits that might be available to them via new initiatives. 

For questions on NAMs and the impact to your program, contact us. 

 

About Premier Consulting

Premier Consulting, a business unit of Premier Research, is a strategic product development and global regulatory consulting brand dedicated to supporting the specialized needs of emerging biotech and medtech companies. Like them, we are dedicated to the patient journey and are driven by the challenges of bringing new life-saving technologies to market. We deliver end-to-end strategy, regulatory, nonclinical, CMC, quality, and commercial solutions that are best in class. With a customer-centric culture, we pair efficiency with quality as we guide sponsors every step of the way to commercialization. We tailor development plans to meet the most rigorous global regulatory requirements and deliver results for sponsors — and the patients they serve.

Authors:
William Salminen, PhD, DABT, PMP, Vice President, Regulatory Toxicology and Clinical Pharmacology

Madelyn Huang, PhD, Toxicologist

Andrew Emanuel, Principal Toxicologist

REFERENCES:

[1] FDA News Release (April 10, 2025): FDA Announces Plan to Phase Out Animal Testing Requirement for Monoclonal Antibodies and Other Drugs. https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs.

[2] FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studies (April 10, 2025). https://www.fda.gov/media/186092/download.

[3] Salminen et al. (2019). Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway. https://www.sciencedirect.com/science/article/abs/pii/S135964461830120X?via%3Dihub.

[4] ICH = International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. https://www.ich.org/.

[5] US FDA Center for Drug Evaluation and Research (CDER) Guideline (2015): Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route. https://www.fda.gov/media/72246/download.

[6] ICH Harmonised Guideline M7(R2) (2023): Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. https://database.ich.org/sites/default/files/ICH_M7%28R2%29_Guideline_Step4_2023_0216_0.pdf

[7] H.R.2565 – 117th Congress (2021-2022): FDA Modernization Act of 2021 | Congress.gov | Library of Congress.

[8] ICH Harmonised Guideline S1B(R1) (2022): Testing for carcinogenicity of pharmaceuticals. https://database.ich.org/sites/default/files/S1B-R1_FinalGuideline_2022_0719.pdf.

[9] ICH Harmonised Guideline S5(R3) (2020): Detection of reproductive and developmental toxicity for human pharmaceuticals. https://database.ich.org/sites/default/files/S5-R3_Step4_Guideline_2020_0218_1.pdf.

[10] FDA. Focus Areas: Model-Informed Product Development. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-model-informed-product-development#:~:text=MIPD%20encompasses%20model-informed%20drug%20development%20%28MIDD%29%2C%20an%20approach,sources%20to%20inform%20drug%20development%20or%20regulatory%20decision-making.