New FDA guidance on validation of new approach methodologies (NAMs): What you need to know

The recently issued by FDA draft guidance on approaches to validate New Approach Methodologies (NAMs)¹ aims to promote the use of NAMs and thereby reduce and replace animal testing in drug development; as well as foster human relevant testing strategies that improve, enhance and accelerate the nonclinical safety evaluation process.  

While NAM validation is not a prerequisite for FDA submission, the validation work demonstrates NAM reliability and fitness for purpose, as well as strengthens regulatory acceptance of the methodology.    

Four core principles of NAM validation  

The draft guidance defines four core validation principles to enhance the reliability and the interpretability of data generated using NAMs: 

1. Context of use: NAM validation is the process by which the accuracy, reliability, and relevance of a method are established for a specific context of use (COU). The COU should clearly identify the intended purpose of the NAM to address a scientific and/or drug development question which supports regulatory decision-making. For example, the COU for a liver-on-a-chip model might be to support hepatotoxicity assessment during clinical trials. Examples of other COUs include establishing a safe start dose or elucidating the mechanism of off-target effects following an adverse event in animals or in humans. 

2. Human biological relevance: The data generated from each NAM should have significance in predicting effects on human health and safety, with a focus on predicting toxicities that will not be measurable in early human studies. Demonstrating adequate human biological relevance will build confidence in the methodology among the agency and industry. Three main recommendations for establishing human biological relevance are: 

• Describe physiological features assessed: Explain the relevance of species, cell types and whether anatomical/physiological characteristics of NAM platform are representative of the in vivo situation in humans. 
• Demonstrate toxicological relevance: Show how relevant toxicological findings can be reliably evaluated in the NAM. For example, demonstrate whether liver toxicity NAMs simultaneously measure markers such as albumin and urea and/or functional assessments (CYP450 expression, transaminase release) over extended periods to simulate repeated administration in the clinical setting. 
• Link to clinical trial endpoints: Describe how biological mechanisms in the NAM apply to human clinical trial outcomes. For example, developmental toxicity NAMs should mimic key stages of fetal development to predict outcomes following administration to women of childbearing potential. 

3. Technical characterization: As with validation for animal-based methods, it is essential to establish scientific confidence in the method by ensuring that the platform is sufficiently robust, reliable, and reproducible. Aligned with the OECD Guidance Document on Good In Vitro Method Practices (GIVIMP)², the guidance provides detailed recommendations across eight key areas of technical characterization: 

4. Fit-for-purpose: A NAM is considered fit-for-purpose when it assists CDER with regulatory decision-making. A fit-for-purpose NAM must accomplish at least one of three objectives: 

• Replace – Provide equivalent or improved proof of activity or safety compared to traditional methods
• Fill data gaps – Supply additional activity or safety information where traditional nonclinical models are unavailable or insufficient 
• Confirm and complement – Provide information equivalent to traditional nonclinical models, thereby confirming and/or complementing traditional findings 

Where traditional animal methods exist, sponsors should demonstrate how the NAM characterizes risk in comparison to the traditional method. The sensitivity, specificity, positive and negative predictivity, and false positive and negative rates for the NAM should be determined and compared to those of the established method. Sponsors should also discuss the benefits and limitations of the NAM, specifically addressing aspects of the study design or methods that may impact reliability, reproducibility, and ability to inform risk assessment for its intended context of use.  

Conclusions 

The new FDA guidance reflects the ongoing paradigm shift within the FDA, other global regulators to use NAMs, and advances sponsors’ understanding of how to increasingly incorporate NAMs into nonclinical development programs. While validation is not a pre-requisite for regulatory acceptance, sponsors must clearly demonstrate that the method is fit for regulatory purpose so that regulatory authorities have confidence in the methodology and the reliability of the data produced.   

Validation of NAMs and their progressive use could reduce the direct costs of research and development by either limiting or avoiding animal use. In addition, NAMs could reduce drug development costs, as well as make nonclinical development more efficient by enabling sponsors to make more informed go/no-go decisions earlier on during development. 

We recommend that sponsors start to include NAMs best suited for their nonclinical program at the earliest opportunity by developing tailored NAMs specific to their own needs, or to work with collaborators (e.g., CROs, academia that are currently developing NAMs that can lend support to their nonclinical package).  

Recognizing the rapidly evolving regulatory and scientific landscape of NAMs, Parexel Regulatory Consulting nonclinical experts partner with both biopharmaceutical companies and academic researchers developing NAMs. We support in review of the NAMs development pathway and communication with regulatory authorities (e.g., on the analysis method and the adequacy and/or suitability of your data to date or required authority feedback on NAM adequacy).  

Ready to discuss your NAM strategy? We can support reviewing your preliminary nonclinical data to assess whether it is ready for a regulator’s lens. Please contact us - our regulatory strategy experts are always available for a conversation.  

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References 

1. FDA Draft Guidance on General Considerations for the Use of 2 New Approach Methodologies in Drug Development Guidance for Industry, March 2026 
2. ​​​​​OECD Guidance Document on Good In Vitro Method Practices (GIVIMP), December 2018 

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