FDA Sets Framework for Non-Animal Methods in Preclinical Testing

The FDA has released a draft guidance outlining how drug developers can use non-animal testing approaches, referred to as new approach methodologies (NAMs), when generating preclinical safety and pharmacology data. The guidance is titled, “General Considerations for the Use of New Approach Methodologies in Drug Development.”

These data are required before investigational drugs can move into human clinical trials. The guidance focuses on how alternative methods can support decisions about whether a drug is reasonably safe to test in people.

Drug developers are still required to submit nonclinical evidence before starting human trials. What is evolving is how that evidence can be generated. The guidance explains how data from laboratory models, computational tools and other human-relevant systems can be assessed for regulatory use alongside or in place of traditional animal studies.

NAMs include methods such as cell-based systems, three-dimensional tissue models, organ-on-chip platforms and computer-based simulations. These approaches aim to better reflect human biology and may improve how drug-related risks and mechanisms are identified before clinical testing.

The guidance builds on a 2022 legislative update that clarified non-animal data can be used to support investigational new drug applications and biologics license applications, where appropriate.

A central focus of the document is how to evaluate whether these methods are reliable. The FDA emphasizes that a method does not need to be fully validated to be considered. In some cases, a NAM may still contribute useful information when combined with other data sources. This combined assessment is often referred to as a “weight of evidence” approach, meaning multiple lines of data are reviewed together to understand potential risks.

To guide regulatory use, the FDA outlines four key considerations. These include defining the specific question the method is meant to answer, showing that the model reflects relevant aspects of human biology, demonstrating that results are consistent and reproducible, and confirming that the data can inform regulatory decisions.

Related: FDA’s New Adverse Event Monitoring Platform Promises Streamlined Operations and $120M in Savings

The guidance also distinguishes between validation and qualification. Validation focuses on whether a method produces reliable and meaningful data for a specific use. Qualification is a separate regulatory process that establishes how a tool can be used more broadly in drug development. The FDA notes that validation is critical for interpreting results, even when a tool has not gone through formal qualification.

NAMs may serve different roles in development programs. They can replace certain studies, provide additional insight where existing models fall short or help explain findings observed in earlier testing. For example, laboratory-based skin models have been accepted in some cases to evaluate irritation or sensitization, reducing the need for animal testing in those areas.

The document does not recommend specific technologies or define when NAMs should be used. It provides general principles that can be applied across therapeutic areas and study types. The FDA also encourages sponsors to engage early with review divisions when considering these methods, particularly for questions tied to specific diseases, organs or safety endpoints.

The NAMs draft guidance follows earlier FDA actions aimed at reducing reliance on animal testing in preclinical safety studies, including a roadmap outlining how non-animal methods can be incorporated into regulatory decision-making.

In December 2025, the FDA issued a separate draft guidance describing reduced use of non-human primates in certain monoclonal antibody development programs.

Recent research shows growing use of non-animal approaches such as organ-on-a-chip systems. In February 2026, researchers at Texas A&M University and collaborators evaluated a liver-on-a-chip system and found it could reproduce species-specific drug toxicities and better detect drug-induced liver injury than standard cell-based models. The system also supported longer-term liver cell function, which may help identify delayed toxic effects not captured in conventional in vitro studies.

Separately, researchers at Missouri University of Science and Technology developed a method to produce organ-on-a-chip devices using commercially available 3D printers, aiming to reduce cost and simplify use in research settings. These technologies are still being evaluated for broader use, with factors such as cost, scalability and standardization influencing adoption.

Alongside the NAMs draft, the agency also announced an update to its guidance on pyrogen and endotoxin testing. These tests detect fever-causing contaminants, such as bacterial toxins, in drugs and medical products before release for patient use. The update clarifies how manufacturers can transition to recombinant, non-animal reagents for endotoxin testing.

If you want your company to be featured on Xtalks.com, please email [email protected].