FDA guidance would cut back on using monkeys for safety testing of monoclonal antibodies

The US Food and Drug Administration (FDA) has issued guidance for sponsors in reducing testing of single-target monoclonal antibodies in monkeys from six months to three months, or even eliminating such testing altogether.

The eight-page draft guidance – Monoclonal Antibodies: Streamlined Nonclinical Safety Studies – was released for comment on Tuesday. It offers recommendations for sponsors assessing long-term safety of monoclonal antibodies that have one target – monospecific antibodies – through streamlined approaches with less reliance on animals. It does not apply to multispecific antibodies, antibody-drug conjugates, or antibody constructs.

“When finalized, the guidance is intended to assist sponsors in avoiding unnecessary use of animals, particularly non-human primates (NHPs), in furtherance of the 3R principles of reducing, refining, and replacing the use of animal testing,” the agency explained in the Federal Register notice.

Knowledge-based risk assessments will fill gaps for regulatory assessments of new products, bringing more humane treatment for animals and greater efficiencies in product development, according to FDA.

“Risk assessments may leverage advanced methodologies,” Richard Pazdur, MD, director of the agency’s Center for Drug Evaluation and Research said in a statement about the guidance. “This evolution in our approach reflects both scientific progress and our responsibility to use the most effective tools for drug evaluation.”

In the guidance document, FDA noted that unlike small molecules, monospecific antibodies are not metabolized through hepatic biotransformation and therefore generally don’t have the same metabolite safety concerns.

“Because of these product characteristics, knowledge of target biology and expression profile may inform approaches for assessing patient safety, and studies in animals (when warranted) could be streamlined,” FDA explained.

In general, studies evaluating effects of chronic administration of monospecific antibodies in non-human primates, dogs and mini-pigs should be no longer than three months, according to the guidance.

“When an assessment of long-term safety is warranted (e.g., a monospecific antibody being administered weekly continuously to humans over many months), sponsors should decide whether a 3-month (or longer duration) toxicology study in animals will generate relevant information,” FDA advised.

The shorter testing plan should be supported by a weight-of-evidence (WoE) risk assessment that may include a range of information, including the following:

Mechanism of action and pharmacology data
A literature-based assessment of potential toxicities associated with the molecular target
Toxicology and pharmacokinetic (PK) data in pharmacologically relevant species
Results of an assay to detect human-relevant off-tissue binding and potential secondary effects
Clinical safety and PK data (Phase 1/2)
Toxicity findings in animals and humans from other monospecific antibodies against the same target.
Other nonclinical data, e.g. new approach methodologies, transgenic models and data using surrogates

Sponsors are encouraged to discuss their plans for nonclinical safety testing of monospecific antibodies with the agency prior to starting.

“For exceptional cases when a 3-month study and WoE risk assessment may be inadequate sponsors should consult the appropriate FDA review division regarding whether a 6-month toxicology study is warranted,” the agency wrote.

There will also be cases where no animal testing is appropriate or feasible, for example if the monospecific antibody does not bind to the molecular target being evaluated in any nonclinical species or when animal data with other monospecific antibodies against the same target have not been predictive of human toxicities.

FDA also guided that animal toxicology studies should use pharmacologically relevant species and that short- and long-term rodent studies may suffice for nonclinical data when the antibody under evaluation has similar pharmacological activity in rodents and non-rodents.

The recommendations apply broadly all clinical indications except oncology, the agency wrote in the guidance document.

“Oncology-specific guidances provide additional flexibility appropriate for oncology indications specifically,” FDA explained. “This flexibility is not described in this guidance.”

In the agency’s statement, FDA Commissioner Marty Makary, MD, wrote that the release is part of the delivery of its roadmap for eliminating animal testing requirements in drug evaluation and accelerating the development of meaningful treatments and cures. (RELATED: FDA, NIH officials look to curb animal testing in drug development, Regulatory Focus 8 July 2025)

Nonclinical testing of a monoclonal antibody product typically involves 100 macaque monkeys at the cost of around $50,000 per animal.

“Yet many products that clear toxicity testing in animals do not receive FDA approval, predominantly due to safety or efficacy issues in humans,” the agency noted.

Modern risk assessments integrate human-relevant models – including computational toxicology, organoid systems, and real-world human safety data – will help make drug development more efficient, minimizing animal testing, according to the statement.

“Modern science has given us far more effective and humane ways of evaluating drug safety than animal testing,” Makary said. This reform may reduce the amount of time it takes to bring a drug to market and lower research and development costs, which can translate into lower drug prices.”

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FDA guidance would cut back on using monkeys for safety testing of monoclonal antibodies

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