THE FDA ISTAND Program: The Path to Regulatory Adoption of NAMs

New Approach Methodologies (NAMs) have been used in drug development for decades. Despite their widespread use and clear advantages for improving human health and reducing animal experimentation, NAMs have faced significant headwinds for use in regulatory submissions. Recent guidelines, public announcements, and policy changes have demonstrated that global regulators, led by the US FDA, are ready to change that dynamic. The most powerful example of this change is the FDA’s ISTAND Program (Innovative Scientific and Technology Approaches for New Drugs).

Changing Global Perspectives: The Roadmap to Reduce Animal Testing

Published in April of 2025, the FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies has signaled a dramatic shift in the FDA’s willingness to rapidly reduce, refine, and replace animals in drug research. The roadmap outlines the plan for a transition from animals to NAMs through six key scientific and technical steps, including:

·       Map endpoints and use cases of NAMs

·       Support development of NAM technologies

·       Establish validation and qualification pathways

• This specifically references the “pilot” ISTAND program

·       Develop regulatory guidance and standards

·       Training, communication, and culture change

·       Monitor outcomes and iteratively refine

Validation Versus Qualification

Step three of the Roadmap discusses Validation and Qualification. But like many technical documents, it does not distinguish between the two terms.

Validation is the process of evaluating the performance of a NAM, both against benchmarks to establish utility and over replicates to verify reproducibility. Qualification is a status provided by a regulator after reviewing validation data and other relevant criteria to demonstrate the utility of the NAM for a specific “Context of Use” (COU). For drugs, qualification results in the NAM being classified as a “Drug Development Tool” (DDT) with its data suitable for INDs, NDAs, or BLAs without the need for the technology to be reconsidered or reconfirmed.

Validation is like learning to drive a car. Qualification is like getting your driver’s license.

How Does ISTAND Work?

The ISTAND Program was announced in 2020 as a pilot to provide a pathway for NAMs to pursue qualification. ISTAND is open to any type of applicant, including for-profit companies, research institutions, and individuals. It is modeled after the Biomarker Qualification program under the Drug Development Tool Qualification initiative. ISTAND was made a permanent program on 31 July 2025.

Receiving a qualification through ISTAND is a three-step process. First, a brief Letter of Intent (LOI) is submitted to request entry to the program, including a proposed COU. If accepted, applicants are invited to submit a Qualification Plan (QP) containing all method information, validation data, and other planned validation experiments. If accepted, the applicant then submits a Full Qualification Package (FQP), containing the results of the experiments and all other relevant data. If accepted, the FDA issues a letter indicating the NAM has been approved for its specific COU.

As of November 2025, twelve applicants have been publicly disclosed. Three have been rejected, seven have had their LOI accepted, and two have had both their LOI and QP accepted. A summary of the technologies, their status, and timelines for completion is shown below.

A summary of publicly available ISTAND application results, as of November 2025.

Our Guest Author, Michael Phelan's, Experiences in ISTAND

I was the head of the first technology accepted into the FDA ISTAND Program; Integral Molecular’s Membrane Proteome Array. As the first applicants through the program, we maintained regular communication with the FDA, which provided us with considerable insight into the program’s structure and expectations. Although all these experiences can’t be condensed into a single blog post, I often think of three key takeaways:

·      Context of use is the foundation of every submission. The COU must be precise and useful for regulators. All data and experiments must focus on satisfying the COU.

·       Transparency is non-negotiable. Except for their Executive Summaries, the details of the QP and FQP are confidential. Regulators expect full transparency, including disclosure of proprietary methods and all limitations.

·       Scientific rigor is critical for success. Your submissions will be reviewed widely by FDA personnel, including clinicians, pharmacologists, toxicologists, biostatisticians, and NAMs' research scientists. From biology to statistics, your submission must be able to stand up to intense scrutiny.

What’s Next?

On October 28, Integral Molecular announced the submission of its FQP. As the first FQP to be reviewed, there is no definitive timeline for when approval might occur. Based on previous QP timelines, acceptance is anticipated in mid-to-late 2026. I expect this approval will mark an inflection point in the adoption of NAMs. It will mark the first NAM qualified for drug development, and it will provide regulators with the baseline of acceptable submission criteria for future ISTAND applications. It will also allow for governmental endorsements of NAMs in drug approval. Most importantly, it will establish the new standard for what is required to commercialize NAM technologies successfully.

Hot on the heels of the FDA, global governmental and non-governmental programs are rapidly developing their own guidelines for the validation and qualification of NAMs. With clearer NAMs' guidance, an attractive proposition to drug developers, competition to develop the most robust and beneficial NAMs' regulatory frameworks will intensify rapidly.  

The NAMs revolution is starting. Are you ready?

Written by Michael Phelan, PhD Principal Consultant, InnovApproach Consulting

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