For a number of years, the FDA and other regulatory agencies have been concerned about the number of animals used in drug research, particularly with regard to toxicology studies. This concern is not only based on animal welfare considerations, it is also based on the increasing realization that animal toxicology data does not always predict human toxicity.

Here, we discuss these challenges and the FDA’s new roadmap for reducing animal testing in preclinical safety studies.

Animal toxicity often does not predict human toxicity

There have been a number of drugs that appeared safe in animals while under development but were later shown to be toxic in humans.

Some examples include:

• Fialuridine: No significant toxicity was observed in mice, rats, or dogs, but in a Phase II clinical trial, several cases of fatal hepatic failure occurred. The reason for this was later shown to be species-specific differences in how nucleoside analogs affect mitochondrial function.1
• Troglitazone: No significant toxicity recorded in rats, mice, or dogs, but several reports of liver failure were reported post-approval, which ultimately led to the withdrawal of troglitazone from the U.S. market in 2000. It was later determined that toxic reactive metabolites were formed in humans, but not in animals.2
• Rofecoxib: In non-clinical species, there were no safety signals observed. Post-approval, an increased risk of myocardial infarction and stroke were observed during long-term use. The reason for this difference in response is thought to be that rofecoxib may increase the susceptibility of human low-density lipoprotein and cellular membrane lipids to oxidative damage, which then may lead to plaque instability and thrombus formation in humans.3

According to the FDA, over 90% of drugs that appear safe and effective in animals do not ultimately receive FDA approval in humans largely due to safety and/or efficacy concerns.4 Conversely, some medications that are generally considered safe in humans may never have passed animal testing. Such physiological differences underscore why animals may not always provide adequate models of human health and disease.5

A new roadmap: Reducing animal testing in preclinical studies

In April 2025, the FDA published its Roadmap to Reducing Animal Testing in Preclinical Safety Studies.6 The roadmap outlines a long-term plan to reduce or possibly eliminate animal toxicology testing, starting with monoclonal antibodies, by using what is termed the “New Approach Methodologies (NAMs),” which include the use of human tissue-based systems, such as organs-on-chips, in silico modeling, and other innovative approaches.

• Organs-on-chips (OoC): Systems that contain engineered or natural miniature tissues grown inside microfluidic chips.7
• In silico modeling: Using computational modeling to leverage existing data to predict safety, immunogenicity, and pharmacokinetics, reducing the need for new animal testing. Key tools include PBPK modeling, AI/ML, and so on.8

Other approaches mentioned include ex vivo human tissues, high-throughput cell-based screening, microdosing and imaging in human volunteers, and refined in vivo methods. The Roadmap highlights that these methods all address one or more aspects of animal testing, and thus it will be essential to use an integrative strategy.

Key questions for success

Key questions that need to be answered in order for these approaches to be successful include:

1. How predictive are NAMs with regard to determining drug safety?
2. How are NAMs best utilized during the early stages of development, including how studies are to be designed?
3. How consistent are the results across various manufacturers of NAMs?

Unlike animals, new approach methodologies (such as organs-on-chips) may differ significantly in terms of cell types, genetics, and composition of the overall structure.

Final takeaways

The FDA has laid out an ambitious long-term strategy for reducing or even eliminating animal testing initially for monoclonal antibodies, with the potential to extend this to small molecules and therapeutic proteins. The success of this strategy will depend in part on close cooperation between industry stakeholders and the FDA, as well as other regulatory bodies in the ICH.

Interested in learning more?

Join Cytel’s Michael Fossler, Nelia Padilla, and Mammoth Preclinical’s Edwin Garner for their upcoming webinar, “FDA’s Roadmap to Reducing Animal Testing in Monoclonal Antibody Development” on December 9 at 9 am ET:

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