Getting Back on Track with NAMs at FDA
Has FDA lost it’s way with NAMs? NAMs or New Alternative Methodologies is the term used by FDA for new regulatory tools to improve predictivity and help replace, reduce and/or refine animal testing.
FDA’s recent report “Advancing New Alternative Methodologies at FDA” is chock full of project updates from FDA’s various offices, centers, cross-agency working groups and external partnerships. Many of the projects described showcase tissue chips (microphysiological systems) for addressing drug attrition (liver, cardiac, reproductive and thrombogenesis) as well as disease and toxicity mechanisms (e.g., respiratory toxicants, radiation, viral infection).
Applications for direct reduction of animal testing, however, don’t seem to be advancing very fast.
To be sure, the mechanistic discoveries enabled by NAM technologies described in the report are important.These include advancing our understanding of respiratory toxicants in air-liquid-interface epithelial tissues, radiation-induced pneumonitis, and in mechanisms that control drug disposition in tissues.
In contrast, anemic phrases litter the descriptions of projects aiming to apply NAMs for risk assessment.
“potentially predicting”
“should be useful when”
“may benefit”
“investigating the use”
“a promising alternative”
“may identify translational biomarkers”
“under development”
“may provide information”
“investigating this technology”
“requires careful assessment of research results”
This is not very encouraging for those of us who believe that human-based in vitro and phenotypic assays can make an impact on safer and more effective drugs.
So what may be missing and how can we get back on track?
Going back to the report itself, note the recommendation to move “towards the use of mechanisms of action as the organizing principle for risk assessment”.
“Worldwide research continues to create alternative technologies that could replace—or at least reduce—animal testing. In its 2007 report Toxicity Testing in the 21st Century: A Vision and a Strategy, the National Research Council of the National Academies of Science Engineering and Medicine advocated for a shift away from traditional animal testing towards the use of mechanisms of action as the organizing principle for risk assessment.
In 2011, FDA’s Advancing Regulatory Science Plan identified transforming toxicology as one of its key priorities. The focus was—and continues to be—on promoting a better understanding of toxicity mechanismsby evaluating safety and risk assessment data at multiple biological levels, including genes, proteins, biochemical pathways and cell/organ function.”
– Advancing New Alternative Methodologies at FDA (2021)
Perhaps FDA can consider placing a stronger emphasis on mechanism-based NAMs. In the past, press reports often promoted the suggestion that certain NAM technologies (e.g., organ-on-a-chip) could simply be swapped in for animal studies. Unfortunately, it’s not that simple. Predicting in vivo effects (and bringing in human relevance) requires expert systems that integrate results from many mechanistic assays and information sources.
To build such systems, the biological setting (e.g., organs and tissues) needs to be understood well enough to identify key control points. This is where advanced cellular systems like tissue chips can play a big role. Once these key control points have been identified, high throughput assays with good performance characteristics are then developed. These mechanism-based assays can then be used to generate data used in the expert system. Such assays may already exist but their importance yet to be discovered.
Mechanism-based expert systems have been highly successful for predicting bioavailability and pharmacokinetics. Predicting toxicity outcomes will likely be no different.
Photo by Mathias P.R. Reding on Unsplash.
