Draft guidance, issued by the FDA last week, could remove ambiguity and uncertainty that may have so far limited uptake of new approach methodologies, experts told BioSpace, particularly emphasizing the agency’s recommendations around defining NAMs’ regulatory purpose.
Experts hailed the FDA’s recently released draft guidance on animal testing alternatives as a framework that can cut regulatory risk and remove guesswork for companies considering new approach methodologies.
The new guidance, published last Wednesday, seeks to help drug developers validate new approach methodologies (NAMs) that have the potential to replace in vivo tests.
The new guidance “sends a clear signal that FDA is serious about integrating NAMs into [investigational new drug] submissions,” Michael Phelan, principal consultant at InnovApproach Consulting, told BioSpace via email.
NAMs include a broad range of methods, including complex and 2D in vitro studies as well as in chemico and in silico studies, the FDA noted in the document. All of these methods generate evidence of a molecule’s effects without using animals.
The draft guidance sets general validation principles for NAMs, including context of use, human biological relevance, technical characterization and fit-for-purpose. Through these principles, the FDA aims to make NAM studies more interpretable and reliable in order to limit the need for animal data to inform regulatory decisions.
The FDA has previously outlined the draft’s concepts at conferences and in sponsor interactions, Phelan noted, but he added that documenting the principles will lower perceived regulatory risk and encourage proactive NAM use in clinical trial submissions. To Phelan, the draft text “helps close the gap between what FDA has been saying informally and what sponsors feel comfortable submitting.”
Steven Bulera, chief scientific officer for discovery and safety assessment at Charles River Laboratories, agreed, telling BioSpace via email that the draft guidance provides “an additional layer of regulatory clarity.” This, Bulera added, opens the door for researchers to show that NAMs can generate “reliable, reproducible, human-relevant data that answer specific regulatory questions.”
Until now, developers have relied on the FDA’s Innovative Science and Technology Approaches for New Drugs (ISTAND) program, which the agency introduced in 2020, to advance NAMs. Phelan led the ISTAND submission at Integral Molecular, his former employer. While ISTAND offered a path to market, Kevin Snyder, director of nonclinical innovation and emerging technologies at Certara, told BioSpace the process is “fairly laborious.”
While the draft doesn’t provide new regulatory pathways, it is still a big step in the right direction, said Snyder, who previously served as associate director of nonclinical informatics at the FDA’s Center for Drug Evaluation and Research. “Sponsors now know what information they will need to justify NAM use and can factor that end goal into the designs of their programs from day one.”
Defining the Use Case
The FDA’s advice on context of use (COU) is central to the document’s potential to inform decisions about NAM development, the experts agreed. A COU defines the regulatory purpose of a NAM. The FDA cited supporting choices about patient monitoring in clinical trials and dosage selection as examples of COU cases it would consider in the regulatory process.
The importance of COU “cannot be overstated,” Phelan said. By framing NAMs as tools that answer specific scientific questions to inform regulatory decisions, the FDA is communicating to developers that they need to identify a current gap in drug development and craft their COU around it, he added.
For Snyder, tools that explain the results of animal tests are a strong initial use case for NAMs. Drug developers sometimes see toxicity in animal species but have reason to believe the findings are not relevant to the safety of humans. The draft guidance provides a clear framework for how companies in that situation could use NAMs to demonstrate that the safety signal is specific to the studied animal species. Data from a complex in vitro assay could show the effect of a molecule on a model that more accurately replicates the human organs relevant to the toxicity signal, Snyder continued, thereby allaying the FDA’s concerns.
Bulera agreed with Snyder’s prediction that companies may initially use NAMs to interpret, rather than replace, animal tests. While Health Secretary Robert F. Kennedy Jr. said in a statement that the goal is to replace animal testing with human-relevant, scientifically rigorous methods, Bulera called the transition to NAMs “an evolutionary rather than revolutionary process.”
The FDA is accepting feedback on the draft guidance until May 18.
