Advancing the transition from animal models to alternative methods: FDA's initiative and sponsors' opportunities

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Published May 1, 2025 

On April 10, the FDA announced its intention to progressively phase out required animal testing as part of the pre-approval safety assessment of drug products. The announcement includes a scientific roadmap¹ with an initial strategy to reduce and replace animal testing of monoclonal antibodies (mAbs), to be followed by other biological products and then new chemical entities.  

The FDA’s effort aims to improve drug safety and accelerate the investigational drug evaluation process by reducing animal research as well as reducing associated costs of nonclinical studies, which may ultimately lead to lower drug prices. The FDA’s goal is to make animal safety studies in drug development an exception rather than the norm in the next 3-5 years. This approach builds upon decades of policies and initiatives to reduce the reliance on animal testing in drug development, and to increase new approach methodologies (NAMs).^2,3,4  

FDA describes alternatives to animal testing in mAb safety evaluation, and proposes incentives for the use of NAMs:  

• Modeling, AI and ML: The agency encourages developers to leverage computer modeling and artificial intelligence/machine learning applications to predict a drug’s behavior. Advancement in these fields is particularly valuable in screening a vast range of potential therapies, with the goal of more accurate prediction of effect with minimal laboratory experimentation. 
• Organoids and organ-on-a-chip systems: The FDA is promoting the use of lab-grown human “organoids” and organ-on-a-chip systems which are recognized alternatives to traditional animal models. Organoids are 3D tissue structures that mimic the architecture and function of human organs such as the liver, heart, brain and immune organs. Organ-on-a-chip devices go one step further; to replicate complex physiological processes on a miniature scale, they manipulate tiny amounts of fluids and cells and can simulate blood flow and interactions between cell types. Together, these methods, which model human biology, demonstrate huge potential for detection of clinically relevant effects. 
• Regulatory incentives: For companies that submit robust safety data from non-animal tests, the FDA aims to provide regulatory incentives such as streamlined reviews of regulatory submissions.   A shortened review is made possible with elimination of data from certain animal studies. These types of regulatory incentives are anticipated to encourage investment in modernized nonclinical testing platforms. 

FDA will launch a pilot program over the coming year that allows developers of mAb products to use a primarily non-animal-based testing strategy, under close FDA consultation. This proposal is designed to speed up the drug development process, enabling mAb therapies to reach patients more quickly, without compromising safety. 

Why were mAbs selected as a starting point? 

• Limited scientific validity of animal studies: Biological differences between humans and nonclinical species can lead to inaccurate prediction of a clinical response. This is particularly true for mAbs targeting human antigens and novel pathways. These mAbs may produce pharmacological effects and toxicities in rodents that are different from humans due to species-specific variations in target biology and immune responses.  
• Non-predictive immunogenicity response: Animals often have immunogenic reactions to mAbs because they are human proteins; such findings are of little relevance to human safety.  
• Cost and animal savings: Recognizing the increased target sequence homology when compared to humans, non-human primates (NHPs) tend to be used during the safety evaluation of mAbs (as opposed to other species). However, the use of NHPs is expensive and time-consuming; therefore reducing, and eventually eliminating, animal testing for mAbs has the potential to reduce drug development costs and accelerate development. 

FDA’s plan aligns with other global regulators   

The traditional reliance on animal models for preclinical testing and research has long raised ethical concerns, with evidence to suggest that in vivo methods can have limitations in the prediction of the human response. Globally, alternative in vitro methods or NAMs have been gaining momentum to elucidate the efficacy and, more importantly, the safety of medicinal products, offering promising avenues for more accurate risk assessments. While updates to FDA guidances have referred to the potential use of these alternative methods for safety evaluation^5,6,7, this recent announcement more solidly aligns with those of other regulators. For example, the European Medicines Agency (EMA) has established a network of member states and other European countries to define and implement a strategy for the reduction, refinement and replacement of animal use in drug development.⁸ 

Five recommended actions for sponsors in response to FDA’s plan 

1. Include NAMs in nonclinical development programs, using alternative methods developed in-house, tailored to specific need or in vitro methods developed by nonclinical CROs. Sponsors should collaborate closely with their nonclinical CROs to establish whether the NAMs have been validated and understand any feedback from the FDA and other regulators regarding predictivity and acceptability of the proposed NAMs.  
   
   We eagerly await the creation of a shared central database for validated NAMs, which is a work in progress by the FDA in collaboration with the Interagency Co-ordinating Committee on the Validation of Alternative Methods (ICCVAM); the beta version of this database is expected by mid-20251,9.  
   
   From our perspective, in the absence of a fully validated method, sponsors should generate data using their selected NAMs alongside conventional in vivo tests to demonstrate validity of the NMAs.  
2. Incorporate in silico tools and computational modeling into current development programs. Aligned with FDA’s inclusion of the use of in silico methods (alongside information from public databases) in their scientific roadmap, we recommend this approach for sponsors starting to incorporate non-animal methods, and to support the expansion of off-target screening methods. PK/PD modeling is currently utilized by many sponsors to predict human exposure and other ADME parameters. We recommend that companies refine these PK/PD models to enhance accuracy to provide added reassurance with the derivation of exposure margins and their ability to predict the likelihood of safety (and efficacy). Machine learning models have been developed to predict immunogenicity on the basis of Ab sequence and structure10,11. Hence, sponsors should take advantage of pre-existing machine learning and AI programs to predict toxicological profile.   
3. Invest in machine learning/AI-tailored applications to assist with product development. 
   To be competitive and to take advantage of plans to phase out toxicity studies for mAb development in the long term, we recommend that sponsors develop machine learning/AI-tailored applications to assist with product development. Sponsors should also invest in the development of NAM technologies that support their programs with the aim of demonstrating that the data using these platforms are sufficient and that the conduct of an in vivo toxicity study would not likely provide any additional safety information of relevance to humans.  
4. Stay current with the evolving nonclinical regulatory landscape by: 
   • Monitoring the FDA website for upcoming and revised guidances on alternative methods (for instance ICH Guideline S6(R1)12, which was identified by the FDA roadmap for update, in addition to already considering alternative methods)  
   • Consulting with FDA about the incentives that will be offered to companies (for instance, fast-track meeting requests and regulatory reviews). 
   • Engaging FDA early (e.g. in pre-IND meetings) and often, to discuss strategies for the development and incorporation of NAMs. Clear communication between the agency and sponsors will alleviate uncertainty and drive more widespread utilization of these methods, leading to more rapid validation of NAMs.  
5. Partner with a nonclinical CRO experienced with NAMs 
   The acceptability of data generated using these models will require careful consideration of their capabilities and limitations, especially in the early stages, before the alternative methods are formally declared fit for purpose. The decision to reduce or waive in vivo toxicity studies will be made on a case-by-case basis and will depend on the data generated using NAMs as well as the volume of data available to FDA applicable to a given mAb or biological target. While the aim is to reduce or eliminate in vivo studies to support an IND, sponsors should be prepared for situations during this transition where studies of a shorter duration may be proposed. It will be the sponsor’s responsibility to determine whether the findings from the shorter study could accurately predict the results in a study of increased treatment duration. 

Parexel’s Regulatory Consulting experts partner with pharmaceutical companies and academics to implement NAMs as alternatives to animal testing. Our specialized non-clinical experts advise on seeking FDA and other agency guidance on the utilization and acceptance of NAMs, as well as FDA concurrence on procedures for NAM validation. We help sponsors navigate regulatory pathways for product development; and we offer practical support for regulatory authority interactions, including managing processes for meetings and submissions, authoring of study reports, and preparation of meeting packages and other submissions.  

Ready to discuss your alternative approaches to animal models? Our regulatory experts are always available for a conversation. 

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References 

1. Roadmap to Reducing Animal Testing in Preclinical Safety Studies 
2. FDA Modernization Act 3.0 
3. Implementing-alternative-methods FDA 
4. Potential approaches to drive future integration of new NAMs 
5. FDA Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 
6. FDA Guidance for industry: S6 Addendum to Preclinical safety evaluation of Biotechnology-derived pharmaceuticals 
7. FDA Guidance for industry: Human Gene Therapy Products Incorporating Human Genome Editing 
8. European medicines agencies network strategy to 2025: Protecting public health at a time of rapid change 
9. Summary Minutes: Scientific Advisory Committee on Alternative Toxicological Methods Meeting. September 17 – 28, 2024: Final Minutes: 2024 SACATM Meeting 
10. Wang H, Hao X, He Y, Fan L. AbImmPred: An immunogenicity prediction method for therapeutic antibodies using AntiBERTy-based sequence features. PLoS One. 2024 Feb 23;19(2):e0296737. 
11. Zheng J, Wang Y, Liang Q, Cui L, Wang L. The Application of Machine Learning on Antibody Discovery and Optimization. Molecules. 2024 Dec 16;29(24):5923. doi: 10.3390/molecules29245923. PMID: 39770013; PMCID: PMC11679646. 
12. ICH guideline S6 (R1) – preclinical safety evaluation of biotechnology-derived pharmaceuticals  

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