Use of New Approach Methodologies in Drug Development: Perspectives on FDA’s Recent Draft Guidance

By Rachel Ham, MS, Medical Writer II; Rachel Rozakis, PharmD, Associate Director, Clinical Pharmacology; Connor Slattery, PharmD Candidate, Intern, Clinical Pharmacology, Modeling and Simulation; and Marcus S. Delatte, PhD, Vice President, Regulatory Strategy

In March 2026, the FDA released a highly anticipated draft guidance, General Considerations for the Use of New Approach Methodologies in Drug Development Guidance for Industry, to provide a validation framework for New Approach Methodologies (NAMs), to improve predictive toxicology, and to reduce animal testing. After 2022 legislation clarified that non-animal alternatives could be used to support an investigational new drug (IND) application or a biosimilar biologics license application (BLA), FDA solicited feedback from the Science Board to develop the guidance. The release of this guidance marks one of many achieved milestones in FDA’s 2026 Roadmap to Reducing Animal Testing in Preclinical Safety Studies, which outlined a strategy to modernize drug development.

The recommendations for encouraging nonclinical NAM validation discussed in this guidance have been provided by the FDA following 20 years of qualifying translational biomarkers, determining a qualification process for drug development tools (DDT), and establishing ISTAND as a permanent DDT qualification program. In addition to existing DDT qualification programs for biomarkers, clinical outcome assessments, and animal models, ISTAND was established for NAM tools, such as microphysiological systems, novel nonclinical assays, artificial intelligence-based algorithms for patient evaluation, and novel digital health technologies (e.g., wearables).

What are New Approach Methodologies (NAMs)?

NAMs include a broad range of methods such as complex in vitro models (CIVMs), 2D in vitro cell culture studies, in chemico cell-free biochemical assays, and in silico techniques. CIVMs include 3D organoids, microphysiological systems (e.g., liver-on-a-chip), tissue slices, and hydrogel-based tissue matrices. 2D in vitro monolayer cell cultures have been used for many decades, but new techniques such as utilizing induced pluripotent stem cells and adding chemical adjuvants can be classified as NAMs. In chemico cell-free biochemical assays are used for safety evaluations of drug products with biological materials, such as proteins or DNA. Finally, in silico techniques include quantitative structure activity relationship (QSAR) models, physiologically based pharmacokinetic (PBPK) models, and mechanistic toxicological models. During the pilot period of ISTAND, 93% of the submissions were for either in vitro (CIVMs and 2D cell-based assays) or in silico methods, leading the FDA to prioritize these development areas.

Advantages and Challenges of NAMs in Drug Development

NAMs offer several advantages that include reducing product development costs and animal use and approaching safety in a human-centric manner. NAMs that closely model human biology may identify drug toxicities or mechanisms of action for areas lacking adequate models. However, challenges to widespread adoption of NAMs still remain, including unknown predictivity, incomplete understanding of toxicity mechanisms, and a lengthy validation process.

Key Recommendations in FDA’s 2026 Draft Guidance on NAMs

NAM Qualification vs. Validation

The 2026 draft guidance defines validation as a process by which the accuracy, reliability, and relevance of a procedure are established for a specific context of use (COU). Qualification is a determination that a DDT and its proposed COU can be relied upon to have a specific interpretation and application in drug development and regulatory review. Details on DDT qualification are provided in FDA’s Qualification Process for Drug Development Tools guidance, updated in 2020. In drug development programs, qualification is useful, but validation is critical for establishing the reliability of NAMs.

NAM Validation Considerations

Context of Use

The FDA initially defined COU in the E16 Biomarkers Qualification Guidance (August 2011). A COU should precisely define the NAM’s intended use and regulatory purpose to address a specific drug development decision, such as filling a data gap, and to fulfill at least one development objective.

Human Biological Relevance

Adequate demonstration of human biological relevance of a NAM is critical to ensure confidence in its methodology. The FDA recommends establishing biological relevance of a NAM based on the description of physiological features assessed and biological mechanisms investigated within it, and the demonstration of the relevance of toxicological findings collected.

Technical Characterization

FDA offers recommendations for characterizing certain types of NAMs that are aligned with insights from the 2018 OECD Guidance Document on Good In Vitro Method Practices.

The recommendations include:

• Describing test methods (e.g., dosage, frequency, test substance), statistical methods, cell types, and biological variability
• Demonstrating sensitivity and specificity
• Defining cell culture media and reagents
• Providing study details to address specific considerations for microphysiological systems and organ-on-a-chip technologies.

The level of detail provided helps to ensure reproducibility and transparency and increase confidence in the NAM.

Fit-for-Purpose

A NAM is fit-for-purpose if it supports regulatory decision making. Ideally, a NAM will serve one of the following purposes:

• Replace or improve a traditional method, such as an animal study
• Fill a data gap, such as by providing information about mechanisms of toxicity or action
• Confirm or complement findings from a traditional study, such as by revealing why an animal species is irrelevant to human biology.

Demonstrating fit-for-purpose may be achieved by comparing the NAM with a traditional method, demonstrating its benefits and limitations, and describing how it will contribute to the development program.

Implications of FDA’s Draft Guidance on NAMs for Drug Development

In efforts to reduce animal use, the FDA will review fit-for-purpose NAMs (including unvalidated assays), especially those that adequately address specific toxicological concerns. As the FDA gains confidence in NAMs, specific assays can be validated to reduce or replace previous nonclinical safety studies, including animal studies.

This new draft guidance on NAMs demonstrates FDA support of these methods and provides clear expectations for implementation. Additionally, the FDA is actively encouraging submission of NAMs in drug development programs, indicating increased regulatory visibility of these innovative methods, which may lead to a surge in the number of validated NAMs, a reduction in the use of animals, and an increase in the emphasis on mechanistic approaches in toxicology.

NAMs in Drug Development: Looking Ahead

The FDA is making its current thinking publicly known and encouraging the use and validation of NAMs, which should decrease sponsor uncertainty about appropriate use of these assays.

While this draft guidance offers useful considerations, there are many areas of safety concern that lack defined toxicological endpoints, which limit the applications of NAMs in certain safety pharmacology studies. Despite this and other limitations, NAMs place greater emphasis on mechanistic approaches to toxicology and represent another tool to inform product risk assessments.