The FDA has announced plans to phase out animal testing and replace it with methods that are more compatible with humans. This is because most animal studies fail to predict safety issues and efficacy in humans, and new technologies have proven to be more adequate. Although the FDA's roadmap, published on April 10, 2025 [1], was considered groundbreaking and took the industry by storm, didn't we all see it coming? It is perfectly in line with the principle of reduce, refine, and replace (3R) in animal testing, the FDA Modernization Act 2.0[2], and moves toward the already introduced New Approach Methodologies (NAMs) and approval of microdosing studies.
So, what's really new in the FDA press release? Let's get you up to date on this 11-page roadmap with this blog, which only takes 7 minutes to read.
Starting today
The plans are not just any plans; they apply directly to new Investigational New Drug (IND) applications. First, in a pilot phase for selected monoclonal Antibody (mAb) development projects, and then in a transition period to replace animal testing with NAMs via broader policy changes. This roadmap is supported by a growing scientific community and is based on overwhelming evidence that animal data is a poor predictor of drug behavior in humans. 90% of drugs that seemed promising in animal tests failed in human trials. If all goes to plan, drug developers no longer need to invest in an inappropriate measure of clinical success. Instead, they can spend resources on NAMs to obtain better data and develop these NAMs even further.
Objectives of FDA roadmap to phase out animal testing
What are the goals of this FDA roadmap to phase out animal testing?
- Make drug development more ethical and efficient
- Reduce R&D costs
- 3R: Reduce, refine and replace animals in research
- Improve preclinical predictions for outcomes in humans
- Increase development of innovative methods
- Make informed go/no-go decisions before clinical trials
- Bring new therapies to patients faster
- Improve global collaboration
- Combine databases and establish open-access repositories
- Put FDA at the forefront of regulatory innovation
mAbs, biologics, and other compounds
This new approach is effective immediately, starting with monoclonal antibodies, then other biologics, and eventually other compounds. Why?
- The immunogenicity of animals differs from that of humans.
- The conditions in animal laboratories can affect several aspects, so the results may differ from those of tests on humans.
- The development costs of mAbs are high (an average of 144 non-human primates (NHPs) are needed, at a cost of 7.2 million).
- Long-term animal studies extend timelines, leading to delayed patient reach.
New Approach Methodologies (NAM)
NAMs are in vitro, or computational (in silico) methods that can replace animal testing. With the use of NAMs, safety (toxicity and immunogenicity), efficacy, and pharmacology can be evaluated quicker, cheaper, and more accurately. We summarize the listed NAMs below. Keep in mind that often a combination of several NAMs can serve as a sufficient substitute for an animal study. Which integrative strategy to use is not yet clear. This will first be considered on a case-by-case basis and based on further research from the FDA and related agencies and partners.
In-Vitro Microphysiological systems (MPS)
MPS includes cell cultures that can mimic human organ functions, enabling safety testing and evaluation of on- and off-target effects. Researchers can monitor this in real time. The FDA mentioned organoids, cell cultures such as liver, kidneys, spleen, lymph nodes, lungs, heart, intestines, blood, or skin, and organs-on-a-chip. These are single or combinations of organoids on a bioengineered chip that mimic the in-vivo conditions of organs or even human body-on-a-chip microenvironments. The latter enables complex testing of on-target effects and off-target risk assessment. However, ex-vivo human tissue and cell-based screening can also complement organoids.
In-silico
The recent development of AI, machine learning (ML) and computational modeling have expanded in-silico capabilities faster than most could have predicted. This can be used for:
- Physiologically-based pharmacokinetic (PBPK) modeling for ADME (Absorption, Distribution, Metabolism, Excretion) simulation;
- Bioinformatics for screening and predicting on- and off-target binding based on comparisons with vast amounts of existing data;
- Quantitative Systems Pharmacology (QSP) to simulate biological effects and pathways.
In-human microdosing studies
The roadmap also includes an option that allows you to obtain in-human data by performing a microdosing study. This is an already approved approach in ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) regions. This solution is known as Phase 0, exploratory studies, and early Phase 1. TRACER specializes in this method: in-vivo testing of new drugs in patients at a microdose, prior to Phase 1. These exploratory studies have no therapeutic effect, are deemed safe, and can therefore be conducted with minimal animal studies. For example, only a single dose extended toxicity study is sufficient to administer the Investigational Medicinal Product (IMP) in humans. The use of imaging methods in phase 0 studies provides early data on efficacy and safety in patients.
Focus also on other 3Rs in current animal research
For the transition period, before animal experiments are completely replaced, solutions such as transgenic models may be useful. In addition, the 3R in animal studies must be taken into account. For mAbs, routine primate toxicity studies can be reduced from 6 months to 3 months if interim analyses after 1 month and NAM studies show no concerns. For other biological drugs and compounds, toxicity studies can be reduced based on modeling of existing clinical data on drugs or drug classes.
Steps to reduce animal testing
- Using international data, similar to the principle of bridging trials.
- Less animal data will be needed when accompanied by validated NAM results.
- Identify key areas for NAMs, conduct gap analysis, and support further development.
- Validation, standardization, and reproducibility of NAM studies.
- Support the development of an open repository with the goal of building a database containing all available, relevant data, including toxicity and efficacy data in humans and animals. These data can also be used to train AI and ML models.
- Support further development of the database for validated NAMs, called Collection of Alternative Methods for Regulatory Application (CAMERA).
- Preclinical data should be published to avoid duplication of research and make data available for AI and ML.
Evaluation
Twice a year, the FDA will evaluate this new approach based on the time and cost of NAM and animal testing. In this evaluation, the FDA will compare the two for time, cost, accuracy, reliability, and efficacy. The evaluation will be by animal species, by IND and for specific contexts of use. It will also assess changes in cost over time. Further, it will evaluate safety issues, such as toxicities first identified in humans, and correlate NAM data with the overall safety and efficacy of clinical trials. Ultimately, the effect of NAMs on the time between IND and approval and the effect on clinical trials and real-world data after marketing will be reviewed.
Future of preclinical development guidelines
Following evaluations, expected after 3-5 years, new and updated guidelines and standards can be expected. This includes suggestions for ICH guidance documents, which means that other ICH regions will need to reconsider their guidelines/requirements as well. Before new guidance documents are available, animal studies may be reduced or omitted through case-by-case exemptions and waivers.
For you as a drug developer
An exciting new era has arrived, offering more opportunities for you as a drug developer. But how can you find out what the possibilities are and how to apply this new approach to your research, drug or even pipeline?
- Through pre-IND meetings, you can discuss the use of NAMs with the FDA.
- (Re-)evaluate your road to clinical translation.
- Contact TRACER for more information on in-vivo microdosing studies.
FAQ
Here are some frequently asked questions we received on this topic. Do you have another question? Feel free to contact us.
Is the FDA no longer requiring animal testing for new drugs?
Animal testing is required for new drugs unless a validated NAM is deemed sufficient or superior. Although this roadmap is effective immediately, it applies first to mAb development, then to biologics, and eventually to other types of drugs. In the coming period, the FDA will collect more data, establish collaborations, and authorize pilot studies. In subsequent years, the data from these studies will be used to standardize protocols and update existing guidelines, publish new guidelines, and achieve global harmonization.
What is replacing animal testing?
Replacing animal testing is one of the 3 R’s, the other R’s being Reduce and Refine. Replacing can be done with NAMs. Human microdosing studies can also serve as a replacement and lead to reduction. A microdosing study can be conducted with minimal animal studies. The study shows in-human biodistribution of the IMP. If a compound does not reach or bind to the target in a human microdosing study, further research may be discontinued. This new FDA roadmap focuses on replacing animal testing with NAMs.
How can real-world data be used in drug development programs?
Another important aspect of the roadmap is the use of real-world, Phase 4 postmarketing data. Predictions of safety and efficacy can be based on pre-existing data in countries with similar regulatory standards, including ICH regions. A principle already known from bridging studies, but now expanding to building an international, open-access repository. Real-world data reflect aspects like comorbidities and clinical practice. These factors influence outcomes, making them different from clinical trials and animal studies. As the FDA describes in the roadmap, laboratory conditions may be influential.
Abbreviations
| FDA | Food and Drug Administration |
| 3R | Reduce, Refine, and Replace |
| NAM | New Approach Methodologies |
| IND | Investigational New Drug |
| mAb | monoclonal Antibody |
| R&D | Research and Development |
| NHP | Non-Human Primates |
| MPS | Microphysiological systems |
| AI | Artificial Intelligence |
| ML | machine learning |
| PBPK | Physiologically-Based PharmacoKinetic |
| ADME | Absorption, Distribution, Metabolism, Excretion |
| QSP | Quantitative Systems Pharmacology |
| ICH | International Conference on Harmonization |
| IMP | Investigational Medicinal Product |
| CAMERA | Collection of Alternative Methods for Regulatory Application |
Citations
Although this article has been composed with great care and attention, we cannot guarantee its accuracy. If you have any suggestions or additions to this article, please email info@tracercro.com.
No rights can be derived from this publication. This blog does not make claim or promote ownership to any intellectual property, study information, or copyrighted terms wherein.