The U.S. Food and Drug Administration today issued a draft guidance intended to help drug developers validate new approach methodologies (NAMs) to be used instead of animal testing in drug development, and to bring safe, effective drugs to market sooner based on human-centric data.  

This marks another major milestone in the implementation of the FDA’s roadmap to reducing animal testing, and reflects the FDA's commitment to moving away from using animal testing as the default method for gaining drug safety information. The draft guidance describes the Center for Drug Evaluation and Research’s (CDER’s) general recommendations to consider for validating NAMs when nonclinical NAMs data are provided in support of a drug application or regarding an order issued under section 505G of the FD&C Act for an OTC monograph.

“This draft guidance advances our commitment to replace animal testing with human-relevant, scientifically rigorous methods” said HHS Secretary Robert F. Kennedy Jr. “Clear validation expectations will help modern tools earn regulatory confidence and speed safer, more effective therapies to patients.”

Under the FDA’s regulations, drug sponsors must submit nonclinical pharmacology and toxicology data before investigational drugs can proceed to clinical trials. While many studies have traditionally been conducted in animals, CDER routinely reviews data from NAMs when the methodology demonstrates reliability and scientific validity.

"Technological advances are allowing us to move beyond animal testing in drug development, which has a poor track record of predicting safety and efficacy in humans," said FDA Commissioner Marty Makary, M.D., M.P.H. "This guidance will facilitate the adoption of modern alternatives to animal testing in regulatory submissions."

Examples of NAMs include innovative testing approaches such as complex and two-dimensional in vitro (laboratory) studies; three-dimensional models such as organoids, spheroids and organs on chips; chemical reactivity studies; computer simulations or in-silico modeling; and studies using “phylogenetically lower” animals such as zebrafish or C. elegans. There are now several examples of validated NAMs outperforming unvalidated animal models in predicting human responses to drugs. NAMs can identify toxicities, demonstrate how the investigational drug works, improve predictivity of nonclinical studies, and enhance the safety of future clinical trials.

This draft guidance establishes four core validation principles for NAMs:

• Context of Use: Clear definition of NAMs’ intended regulatory purpose
• Human Biological Relevance: Demonstration of how NAMs can assess toxicity  
• Technical Characterization: Establishment of scientific confidence through robust, reliable, and reproducible methods
• Fit-for-Purpose: Assurance that NAMs help in regulatory decision-making (e.g., drug review and potential approval)

While the guidance provides general validation considerations for NAMs used in drug development, it does not address specific methodologies or drug discovery applications. FDA encourages drug developers to consult with the appropriate FDA review division when considering NAMs, particularly for indication-, disease-, organ-, and endpoint-specific applications.

“It is time for the FDA to shift the drug development paradigm away from the current default of using animals to predict human responses to one where these data are obtained through human-centric models which can more reliably, efficiently and ethically predict human drug reactions prior to clinical trials,” said Acting CDER Director Tracy Beth Hoeg, M.D., Ph.D.

The expanded use of NAMs was a key recommendation in the MAHA Commission’s Strategy Report to “reduc[e] reliance on animal studies that often fail to replicate complex human conditions.” Today’s announcement also follows draft guidance released in December 2025 regarding the reduction of testing on non-human primates for certain monoclonal antibodies.  

In addition to the draft guidance on NAMs, the FDA is announcing a level 2 revision of the final guidance titled, “Guidance for Industry Pyrogen Endotoxins Testing – Questions and Answers,” to clarify our current thinking on Pyrogen Endotoxins Testing. This action aligns with USP Chapter 〈86〉 Bacterial Endotoxins Test Using Recombinant Reagents published in May 2025 and provides clarity to manufacturers seeking to transition to the use of recombinant reagents for bacterial endotoxin testing of drugs and devices regulated by FDA. The final guidance is available at: Pyrogen and Endotoxins Testing: Questions and Answers. For further information about the draft guidance see our web update regarding the level 2 update at: FDA Clarifies Current Thinking on Pyrogen and Endotoxins Testing. 

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