To support the broader adoption of innovative testing methods while maintaining existing safety standards for human drug development, the U.S. Food and Drug Administration (FDA) recently issued a "direct final rule" updating its regulations. The update clarifies that non-animal methods may be used for safety testing of drugs and biological products intended for human use prior to entering human trials, where appropriate.
This update reflects advances in science and technology that have expanded the range of testing methods available in human drug development, including methods utilizing human cells, organ-on-a-chip, computer models, and other advanced technologies.
Dr. Kyle Diamantas, Acting Commissioner of the FDA, stated, "It gives scientists and drug developers greater flexibility to use the testing methods that best answer their scientific questions. Our goal is not to replace one rigid approach with another, but to support rigorous modern science—including continuing animal studies where appropriate, as well as adopting validated alternative methods when they can provide the evidence needed to protect patients."
The rule replaces terms such as "animal tests" and "animal studies" with "nonclinical tests" and "nonclinical studies." Related terms, including "preclinical" and "in vitro," have also been replaced. The rule defines "nonclinical tests" and "nonclinical studies" based on the Food and Drug Omnibus Reform Act of 2022 (FDORA). This Act recognizes that updated methods not using animals, as well as traditional animal studies, are both potential pathways to generate the evidence needed to initiate human research. The rule removes language that could imply animal testing is the only acceptable way to generate safety information for regulatory decisions on human products. It does not eliminate or prohibit animal studies, does not change evidentiary standards, and does not impose new costs or requirements on drug developers.
To demonstrate the practical application of these methods, the FDA has also launched a database featuring specific application cases of "New Approach Methodologies" (NAMs). The initial release includes 25 examples, all drawn from publicly available FDA review materials. The new rule and the database are among several actions taken by the U.S. Department of Health and Human Services (HHS) to advance the use of NAMs in drug development. NAMs are innovative testing methods that may better reflect human biology. When these methods are sufficiently validated and applicable to the relevant product and regulatory question, developers may use NAMs to generate safety information.
The FDA is keeping pace with emerging technologies and strengthening the agency's leadership in regulatory science. Encouraging the use of NAMs also aligns with the Test Case Initiative—an HHS effort aimed at modernizing clinical research and accelerating the development of life-saving therapies. Clearer terminology and regulatory expectations can reduce avoidable uncertainties for sponsors in building nonclinical evidence and preparing Investigational New Drug (IND) applications.
The agency invites the public—including clinicians, parents, caregivers, the scientific community, industry, and others—to provide comments on the rule.
For more information, please refer to the notice in the Federal Register announcing the direct final rule, the companion proposed rule, and the comment period. If the FDA receives significant adverse comments on the direct final rule, the agency will withdraw the rule and proceed with rulemaking through the standard notice-and-comment process using the companion proposed rule. Publishing both simultaneously ensures that rulemaking can proceed efficiently regardless of the outcome.
ChemRadar Insights
Based on the 25 examples released by the FDA, current applications are mainly concentrated in local toxicity areas such as in vitro skin corrosion/irritation, in vitro eye damage, and in vitro skin sensitization. Successful cases in systemic toxicity are currently lacking. It is hoped that with the further development of NAMs, more successful cases of nonclinical trials for systemic toxicity will emerge, providing enterprises with more options.
