On March 18, 2026, the FDA released a new draft guidance on Alternatives to Animal Testing in Drug Development. If you’ve been watching the new approach methodologies (NAMs) space, you know the conversation has been building for a few years, and what this guidance does is finally give sponsors something operational to work with when structuring NAMs-derived data for an Investigational New Drug (IND) submission. For R&D teams who know NAMs needs to be part of their preclinical strategy but haven’t settled on an approach yet, this is a good moment to act on it.
The short version:
- The FDA has formalized a validation framework for NAMs in IND submissions
- The biggest blocker is no longer buy-in, it’s model selection and use case definition
- The practical path is incremental: run NAMs alongside animal studies before replacing them
- Human iPSC-derived systems are gaining traction
- Early FDA engagement matters more than most teams expect
What did the FDA communicate, and what changed?
The draft guidance builds on the FDA Modernization Act 2.0 (2022) and the agency’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies, continuing a push that has been consistent for several years toward reducing reliance on animal models and giving sponsors a clearer path for submitting human-relevant data. What’s different about this update is that it moves beyond signaling intent and into something IND sponsors can use, shifting the internal conversation at pharma and biotech companies from wondering whether the FDA will accept NAMs data to figuring out how to build a package that meets their expectations. For teams that have been experimenting with NAMs, this is the point where building around them starts to make practical sense.
What is the FDA asking for?
The guidance outlines four validation principles for NAMs:
- Context of use
- Human biological relevance
- Technical characterization
- Fit-for-purpose standards
These make expectations explicit rather than introducing new requirements; and having them formalized gives teams something concrete to build toward and gives internal stakeholders something to point to when making the case for investing in human-relevant models. They are general principles, though, and for anything program-specific, you will still need to engage directly with the relevant FDA review division, which will have a much more precise view of what will hold up for your indication.
So where do you start?
In our experience, most teams are not blocked by buy-in or budget. They are stuck on deciding which model to use for which purpose. The NAMs landscape spans organoids, organ-on-chip systems, microphysiological models, computational approaches and advanced in vitro assays, and the right starting point depends on your program, your organ system of interest and the specific question you are trying to answer.
The consistent advice coming out of the field is to resist the urge to replace animal studies overnight and instead run NAMs alongside existing studies first, building internal evidence and familiarity with the data until you have a track record to draw on rather than a hypothesis to defend. Early FDA engagement is worth prioritizing too, especially if you are planning to include NAMs data in a submission, since the review division conversation will tell you far more about what will hold up for your program than the general guidance can.
Where do iPSC-derived cells fit in?
Human iPSC-derived cells are at the center of many of the platforms making progress with regulators, for a simple reason: they address the FDA’s core objection to animal models directly. As FDA Commissioner Marty Makary noted, animal testing has a “poor track record of predicting safety and efficacy in humans,” and iPSC-derived models built from human cells generate the kind of human-specific readouts that close that gap, across tissue types and at the reproducibility that regulatory submissions require.
Reproducibility is the part of this conversation that doesn’t get enough attention. Batch variability that is tolerable in a research context becomes a liability when you are building a regulatory package, and the FDA’s technical characterization and fit-for-purpose criteria will land squarely on this. It’s worth asking hard questions of any supplier about how they have solved for it.
When choosing a model, focus on three questions:
- What is the disease biology you need to capture? The model has to reflect the human tissue where your drug acts, and animal proxies for these cell types often don’t translate.
- What is the endpoint? A disease modeling study has different requirements than a pharmacodynamic package supporting an IND, and the model should fit the question rather than the other way around.
- Can the supplier demonstrate reproducibility at scale? Batch variability that is acceptable in a research context becomes a real liability in a regulatory package, and the FDA’s technical characterization criteria will land squarely on this.
What does Trailhead recommend as a first move?
Find a question that your current animal model answers poorly and identify a human-relevant model that addresses it. Then run the two models in parallel and see what the data tells you.
At Trailhead, we work with teams on this kind of early scoping, helping align model choice with the biology being studied and the questions being asked.
This becomes particularly important as programs move toward IND-enabling work, where expectations around reproducibility and clearly defined use cases increase.
Our HD-DoE® platform produces TrailBio® iPSC-derived cells with the reproducibility and functional consistency that regulatory-supporting studies require, across endothelial, hematopoietic and CNS-relevant cell types.
For teams that are early in the process, our Trailblazers of NAMs Grant Program is designed to remove barriers to getting started, providing access to iPSC-derived cells and support to help evaluate and optimize a NAMs approach within your system. If you’re ready to talk through where to begin, we’re easy to reach.