FDA releases draft guidance on alternatives to animal testing in drug development

18 Mars 2026

The purpose of FDA's draft guidance is to provide drug developers with a validation framework of alternatives to animal testing for nonclinical safety, here referred to as new approach methologies (NAM), such as in vitro and in silico methods.

The document emphasises that a NAM does not need to be formally validated before FDA’s drug review centres (primarily the Center for Drug Evaluation and Research) can evaluate it as part of a drug development programme. In other words, the FDA is willing to assess the scientific merit of a non-animal method and determine whether it is scientifically appropriate for the intended regulatory purpose, even in the absence of formal validation of this method.

A NAM will be evaluated in the context of the weight of evidence, that is prior knowledge (human biology, literature) and existing evidence (in vitro, in silico, clinical).

To determine the reliability and regulatory interpretability of NAM‑generated data, FDA outlines the evaluation principles that its review centres will apply when assessing NAM studies:

1- Context of use (COU)

The COU must articulate the precise intended use and regulatory function of the NAM. It must frame a clearly answerable question that enables CDER to determine how the resulting data can be used to support a regulatory decision. Cited examples of COU include supporting dosage selection and identifying off-target events.

2- Human biological relevance

Key recommendations in this regard are describing the physiological features that will be assessed by the NAM (species of origin, cell types, anatomical and physiological characteristics), demonstrating how toxicological findings can reliably be evaluated in the NAM, and describing how the biological mechanisms investigated in the NAM are applicable to outcomes measured in human clinical trials. For example, a NAM intended to assess drug-induced liver injury is expected to contain cell types relevant for liver (hepatocytes, stellate cells, Kupffer cells), recapitulate hepatocellular physiological features (albumin production, metabolic competence), capture mechanisms responsible for toxicity and enable measurement of markers (urea and albumine secretion) and functional assessment of endpoints (CYP450 expression, transaminase release).

3- Technical characterization

Some of the key recommendations, aligned with the OECD Guidance document on good in vitro method practices, include description of test method details, statistical method, predictive performance, biological variability, and other general and specific considerations relative to the test method.

4- Fit for purpose

To demonstrate that a NAM is fit-for-purpose, that is able to assist CDER in regulatory decision-making, recommendations include presentation of data comparing the NAM to the established method to demonstrate that the risk is characterized as least as well, description of how finding from the NAM contribute to the overall determination of risks and discussion on its benefits and limitations in regard to reliability, reproducibility and ability to inform a risk assessment for its intended COU.

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