In a groundbreaking press release on April 10th, 2025, the FDA announced its decision to phase out animal testing requirements for monoclonal antibodies, followed by other drugs – signaling a clear shift towards the use of more relevant human approaches for preclinical safety and toxicity testing.
Associated with their announcement was a 5-year roadmap outlining their plan to reduce animal studies from the norm to exceptions in the standard drug development process.
This historic and pivotal moment also included much-anticipated regulatory guidance and incentives for using data from New Approach Methodologies (NAMs), including Microphysiological Systems (MPS) and in silico approaches, for regulatory applications with immediate effect.
Why has the FDA loosened its grip on animal testing for mAbs?
Several key factors behind the FDA animal testing phase-out for monoclonal antibodies (mAbs) are cited as reasons behind this decision including:
Advancing Public Health
Improve drug safety and accelerate the evaluation process by using more effective, human-relevant methods
Reducing Animal Experimentation
Due to their limitations in accurately modeling human health and disease and their predictivity for whether a drug may be safe or effective in humans.
Cost Efficiency
Leveraging AI-based computational models and lab-grown human organ-on-a-chip/ organoids, to reduce R&D costs and lower drug prices
Ethical Considerations
The shift aligns with broader ethical concerns about animal testing and promotes more humane testing methods
In this first blog in a series of three, we explore highlights from the FDA’s roadmap and why mAbs were chosen as the starting point. We dig into the topic of NAMs and plans to ensure that they offer the same degree of safety as animals before focusing down on the important role of predictive human MPS in the successful outcome of this process.
What does the FDA animal testing phase-out for monoclonal antibodies (and other drugs) roadmap look like?
There’s no doubt that the FDA’s implementation roadmap for reducing toxicity testing in animals in favor of a NAMs-based approach is ambitiously proactive. Their roadmap plans are outlined in a document released alongside the press release, which can be read in full here, however the short- and long- term highlights are summarized below.
Short-term (1-3 year) priorities
Leveraging existing international data, encouraging NAM IND data submissions in parallel with animal data, developing an international open-access data repository of toxicology data from animals and humans, reducing timelines for primate mAb and other drug toxicity testing, and tracking quantifiable changes.
Long-term (3-5 year) efforts
Aim to make animal studies the exception rather than the norm by switching to a “NAM-based default” for pre-clinical safety & toxicity testing.
Despite the initial shock regarding the boldness of the FDA’s decision, when you investigate the detail, their initial focus on monoclonal antibodies represents a cautious first step. mAbs are relatively safe and well-tolerated by humans. But they (and any other new human-specific drug modalities) pose development challenges due to inter-species differences that render the use of animals less suited or even unsuited for their testing. This can result in adverse effects being discovered in the clinic, or during post-approval marketing. But there’s more than just safety concerns behind their decision.
Why did the FDA choose to focus on phasing out animal use for mAbs first?
Monoclonal antibodies specifically target molecules and cells in the body, making them highly effective for treating a plethora of diseases. They are well-characterized and have a long half-life, meaning they can provide sustained therapy over extended periods. And importantly, compared to traditional therapeutics, generally have fewer side effects due to their specificity. For reasons such as these, the mAbs clinical pipeline represents the largest of all new modality classes, with 2,700 mAbs in clinical trials as treatments for a wide variety of diseases according to a 2024 report from BCG.
Although mAbs have a relatively good safety profile, the FDA specifically calls out reasons why mAbs represent a promising area for reducing preclinical animal use in their roadmap. These include the shortcomings of animal models, which render testing workflows vulnerable, plus practical considerations centered around “skyrocketed” costs, as quoted below.
Immunogenicity & interspecies differences
“Animals often mount immune responses to human mAbs, which can alter exposure and confound toxicity interpretation. However, animal immunogenicity is not predictive of human immunogenicity due to interspecies differences in immune systems. In addition to inherent biological differences, stress of laboratory life and use in research can impact immune function, inflammatory responses, metabolism, and disease susceptibility and progression.
Moreover, some safety risks may go undetected in animals – a notable example is the mAb TGN1412, which caused a life-threatening cytokine release syndrome in human volunteers despite appearing safe in preclinical monkey studies. That tragedy highlighted the limitations of animal models for certain immune-activating mAbs and spurred efforts to develop in vitro assays to better predict human-specific responses”.
Practical challenges
“The cost of drug development can vary by therapeutic class, with a market report noting the cost to develop a mAb at $650-$750 million and taking up to 9 years. Typical mAb development programs typically use 144 non-human primates (NHPs). In recent years, costs of NHPs have skyrocketed, up to $50,000 per NHP. The time and cost of long-term animal studies slow down delivery of new therapies to patients.”
This is where it gets interesting, by forcing the hand to “plug” this weakness – alongside animals initially – testing workflows can be made even safer than today!
Before animals are fully replaced, the FDA plan also allows time for lessons to be learnt, gaps to be identified and NAMs to become further developed, validated and entrenched into workflows. Plus, the FDA acknowledges the importance of updating international guidelines so that companies do not face different rules in different regions to alleviate adoption barriers.
This approach also begins the important process of reducing both the cost, and the time required to bring novel mAb therapeutics to patients to lower the price of drugs, whist also preparing workflows for the inclusion of additional drug types going forward.
What are NAMs and how do we ensure that they deliver the same degree of drug safety as animals?
In their roadmap, the FDA provides an overview of key NAM categories and their applicability to drug development. There are many definitions for NAMs but the FDA refers to them as:
“tools to assess safety, efficacy, and pharmacology of drugs and therapeutics without traditional animal models. NAMs include in vitro human-based systems such as organs-on-chips, “in silico”, or computer-based modeling, as well as other innovative platforms that can collectively evaluate immunogenicity, toxicity, and pharmacodynamics with high relevance to human biology. The FDA and the broader scientific community recognize NAMs as a means to obtain faster and more accurate human risk assessments while reducing animal use”.
The FDA acknowledges that the transition to a NAMS-based approach will require careful planning, robust science, and collaboration. It lists specific actions that the FDA is considering for validating and integrating NAMS safely into their regulatory process.
They also recognize that, while computational models can be used to predict human-relevant outcomes, in vitro test systems will be needed to confirm and improve predictions. Amongst the in vitro-derived systems cited by the FDA are organoids and microphysiological systems (MPS), often called organ-on-a-chip (OOC).
MPS can be thought of as next-generation organoids because they more accurately recapitulate human organs. The differences between organoids and MPS are explored in more detail in our blog “Taking organoids to the next level”, however, the most important differentiators are the incorporation of microfluidic flow, mechanical forces, and multi-cell primary human co-cultures on a bioengineered chip to recapitulate the in vivo environment.
Compared to self-assembling organoids cultured in static conditions, MPS deliver higher functioning microtissues that deliver greater assay sensitivity, the reporting of clinically relevant biomarkers for enhanced in vitro to in vivo extrapolation (IVIVE), plus prolonged culture longevity (for up to a month using PhysioMimix® OOC solutions) to facilitate repeat-dosing studies in vitro. Furthermore, they can be interconnected to form multi-organ networks that simulate pharmacodynamic effects systemically, human processes such as drug absorption and metabolism, or used to understand interactions between organs, such as inflammation, which drive disease and cause unexpected toxicities.
Many of the organ systems affected by mAbs are available, including liver, heart, lung and kidney. However, despite these technological advances, certain scientific challenges are yet to be overcome before animal tests can be fully replaced. For example, in vitro or in silico models are not able to represent a complete biological system, and further advances are required in the field to recreate the full complement of the human immune system.
Despite these challenges, it is important to acknowledge that, although animal use is a current mainstay of drug development, when first utilized they were never fully validated before being adopted. By comparison, the ongoing validation of non-animal methods, including MPS, for predicting human drug responses is highly rigorous. It is also a well-understood fact that, for certain read-outs, animal responses are no better than the toss of a coin on whether a drug may be safe or effective in humans. Frequently, different answers will be reported by different species, which makes the final assessment of drug safety difficult. In addition to safety concerns, this lack of clarity also causes safe human therapeutics to be unnecessarily dropped from the pipeline out of caution.
In our extensive experience, MPS-based PhysioMimix assays are more predictive of human responses than animal tests (see example publications and application notes for more info). Our findings are echoed by the FDA’s CDER group who concluded that data derived using PhysioMimix is appropriate for use in drug safety and metabolism applications, evidencing its enhanced performance versus standard techniques. Their publication (Rubino et al., 2021) substantiates CN Bio’s position as a leader in the field with reliable and robust cutting-edge technology, ready for widespread adoption across the pharmaceutical industry.
To provide further confidence in the human predictivity of MPS models, we are also developing animal equivalent MPS models/assays. They enable developers to recreate in vivo outcomes in vitro alongside human assays to prevent good assets from being abandoned. However, rather than just using these to troubleshoot, our future vision for MPS-based cross-species assays is for upstream lead optimization to reduce unnecessary in vivo animal use.
Despite the positive outcomes of our MPS validation tests using “fallen angels” it is also imperative to remember that, like animals, no one NAMs method will be 100% accurate or applicable for every question, especially given the fact that no human is identical. Therefore, we believe it is important to adopt a broad range of NAMs to predict human behavior. The skill to acquire here is determining which combination of alternative approaches should be used in combination to determine a drug’s safety. At CN Bio we will continue to explore and demonstrate the advantages of combining MPS plus in silico tools ourselves, with further announcements planned later this year.
Concluding thoughts
So, as we wrap up this first (of three) blog post FDA announcement, three things are certain. Firstly, it is well known fact that drug development failures are due to lack of efficacy or unexpected safety issues that were not evident in standard in vitro or animal tests. Secondly, the largest global regulator has sent a clear message regarding their plans to phase out animal testing to save significant costs (up to $7.2M for NHP use alone/mAb) and reduce development cycle times. Thirdly, the FDA’s timeline to modernize drug development workflows is short.
The key way for pharmaceutical companies to enhance the human predictivity of workflows and keep pace with these changes is to invest in several NAM approaches. By becoming familiar with the types of data they generate and understanding where their limitations lie, you can decide which combinations of NAMs-based tests are required to fully investigate the safety and efficacy of a new drug entity.
So, having explored the FDA animal testing phase-out for monoclonal antibodies (and other drugs) roadmap, and what is being done to ensure that the collective use of NAMs offer the same degree of safety as animals before their use is reduced and replaced – are you ready to get started now and incorporate OOC/MPS into your workflows to avoid being left behind?
Contact us here, to find out how we can support your journey with PhysioMimix so that you can reap the cost and time-saving benefits earlier.
In part two of this blog series, we take a deeper dive into how MPS address the shortcomings of animal models for mAbs development and the role that CN Bio is taking to support the switch to a NAMs-based approach. Continue reading here.