Andrew Haskell, PhD, MLS, CT(ASCP), CMM, BCM, QLSCM
ISCT North America LRA Committee
ASPR
United States

Lynn Csontos, RAC
ISCT North America LRA Committee
STEMCELL Technologies
Canada

Kevin Bosse, PhD, RAC-US, CABP(H)
Chair, ISCT North America LRA Committee
ISCT North America Regional Executive Committee
Nationwide Children's Hospital
United States

FDA Guidance Leverages New Approach Methodologies to Spare Animal Research Requirements

The FDA Center for Drug Evaluation and Research (CDER) released draft guidance to provide a framework for drug developers to use nonclinical evidence generated in new approach methodologies (NAMs) to support investigational new drug (IND) or biosimilar / biologics license (BLA) applications. This framework may, in certain contexts, reduce or replace specific animal studies when supported by sufficient evidence, which would align with their Roadmap to Reducing Animal Testing in Preclinical Safety Studies. 

The NAMs moniker refers to a category of research methodologies, with examples given in the draft guidance including “complex in-vitro, 2D in vitro, in chemico and in silico studies.” Flashy names like “tissue on a chip” have launched these technologies into their “wild west” stage of development, a rapidly evolving and diverse state allowing for the development of complex systems to support human cell and tissue analogues. In addition to replacing animal use, these methodologies may also be to answer niche scientific questions that traditional animal models may not directly be able to support. As is the case with any new technology, this has left regulatory bodies around the world with a need to quickly determine if and how their policies need to adapt to the new technologies while balancing public safety against the risk of stifling innovation.

While this draft guidance does state that it is highly preferable for NAMs to be qualified and validated (described below) it explicitly indicates that neither is a hard requirement, but that data must still be reliable and convey confidence in the method used. This is an important distinction as it succinctly encourages development and use of groundbreaking NAMs though early adopters may bear a greater burden of the regulatory qualification and validation on the first to use a particular NAM or test.

Qualification is defined in the draft guidance as “a determination that a drug development tool and its proposed context of use (COU) can be relied upon to have a specific interpretation and application in drug development and regulatory review.” Validation, on the other hand, is defined as: “a process by which the accuracy, reliability, and relevance of a procedure are established for a specific COU.” While the guidance does not discuss the qualification process in much detail, it does define the following parameters for consideration during the validation process:

1. Context of Use: A clear definition of the intended use of the NAM and regulatory purpose in the context of a specific drug development decision.
2. Human Biological Relevance: The relationship between NAM data and how it could be used to assess the drug in the context of human testing and predicting “toxicities that cannot be measured in clinical trials.”
3. Technical Characterization: Used to establish scientific confidence in NAM data and to ensure it is robust, reliable, and reproducible to quantify scientific specific endpoints.
4. Fit-for-Purpose: The NAM can assist CDER in regulatory decision making if it meets at least one of the three following objectives:
   1. Replaces a traditional method (for example, an animal study).
   2. Fills a data gap when traditional research methods are insufficient.
   3. Confirms and/or compliments findings from traditional research methods.

While the considerations for the validation process are extensive and numerous examples are provided, the guidance does not directly address method qualification, instead referencing previous guidance and regulations.  To a drug developer, this exclusion creates uncertainty which may delay the implementation of NAM data without predetermined alignment with the Agency. However, we are also encouraged by the lack of strict language that could be prohibitive of exciting NAM innovation, and we celebrate this step forward in the safe development of cell and gene therapies, particularly for rare diseases, while potentially lowering the financial bar and minimizing our reliance on animal sacrifice.

references

1. General Considerations for the Use of New Approach Methodologies in Drug Development: Guidance for Industry (Draft Guidance) (CDER, 2026): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-considerations-use-new-approach-methodologies-drug-development. 
2. Roadmap to Reducing Animal Testing in Preclinical Safety Studies (FDA, 2025): https://www.fda.gov/files/newsroom/published/roadmap_to_reducing_animal_testing_in_preclinical_safety_studies.pdf