In Assessing New Drugs, One Size Does Not Fit All

Articulating the context of use for New Approach Methodologies

Since the passage of the FDA Modernization Act 2.0 in December 2022, there has been a rapid acceleration in the development of NAMs or New Approach Methodologies. NAMs cover a broad range of technologies including in silico modeling, cell-based assays, and the development of next-generation animal models. The increased focus on developing and implementing NAMs has been driven by some key macrotrends such as favorable legislation, increased societal pressures, supply chain challenges with sourcing animals and significant scientific and technological improvements.

Regulatory agencies in the US and Europe are continuing to make significant investments in the development of NAMs. These include increased funding and the passage of legislation to incentivize drug developers to use in vitro assays to evaluate the safety and toxicity of new therapies. Additionally, there is more engagement among the current generation of young scientists and veterinarians to manage the use of animal models by finding alternative methods to generate biologically actionable data, while being ethically responsible. The widespread prevalence of social media platforms has played a critical role in spreading awareness about animal use in drug development programs, which in turn has incentivized biotech and pharma companies to be more thoughtful on using animals in preclinical efficacy and toxicology studies.

The increased development and adoption of NAMs has also been driven by limited sourcing of large animal models which has resulted in increased costs and extended timelines for safety studies. This has shifted the mindset of drug developers and CROs to search for alternative methods and when required, maximize the data obtained from each animal in small cohorts. While these macrotrends are strong drivers for the development of NAMs, it is important to make sure that alternative methods generate data that are equivalent or superior to animal model data and that the datasets are large enough to identify statistically significant effects of therapeutics.

Identifying the Right Model to Answer a Specific Question

In vitro models cover a broad range of platforms thar range from simple 2D cell lines to highly engineered organ-chip systems that have complex microfluidics to mimic vasculature. In vitro models have several advantages over animal models such as being all human, which removes species variability issues and a controlled testing environment, which reduces data variation and improve data analysis and interpretation. However, in vitro platforms have limitations including the inability to reproduce systemic effects or highly complex biologic processes and limited timelines that may not allow for longitudinal studies. Each platform has unique pros and cons and contexts of use to answer specific scientific questions. At first glance, it seems that the more complex in vitro models such as organ-chip or plate-based microphysiological systems (MPS) would be the optimal choice as they recapitulate many hallmarks of the in vivo state and would likely generate more translational data. However, as model complexity increases, the costs, timelines, and workflow complexity also increase, which is detrimental to the drug development process. Given that complex is not always better, drug developers should carefully consider the context of use for each assay and clearly outline the objective of the study, which will depend on the drug discovery stage. Once the objective is clear, then the appropriate model or platform can be identified.

Examples of Context of Use for Discovery and Safety Applications

For example, it is well known that mouse models of neurodegenerative diseases are not very translational to human disease so a human induced pluripotent stem cell-based model might be the better option to evaluate the efficacy of therapeutic candidates using specific endpoints, such as changes in neuronal electrical activity. It is important to note, however, that while human iPSC-derived neurons are more easily available and mimic human neurons, the culture system does not fully recapitulate the in vivo CNS environment. If the objective of the study is to identify candidates that improve neuronal function, then the iPSC-based cell model is the optimal platform, but the lead candidates would need to be further evaluated in a more physiologically relevant platform such as an MPS system.

Another example of context of use is genotoxicity assessment where the ability of new therapies to damage DNA is assessed using well-established endpoints such as the micronucleus assay and COMET assay. Traditionally, genotoxicity assays use animal models and different tissues including liver and blood cells are tested for DNA damage. There is a strong interest to replace in vivo genotoxicity assays with a battery of in vitro tests using the established micronucleus and COMET assay endpoints. Additional endpoints like whole genome sequencing and biomarkers for DNA damage to assess global mutagenicity are well suited for an in vitro system. Since the study objective and context of use are clearly defined for genotoxicity assays, a cost efficient and rapid in vitro assay is a viable replacement for an in vivo study.

The drug development community is actively evaluating NAMs to reduce, refine and occasionally replace animal models. It is essential to clearly define the study goals of each step and thoughtfully establish the context of use for the assays of choice.

Check out the Alternative Methods Advancement Project (AMAP) and learn more about the scientific and technological innovations Charles River is using to lead the industry into the next frontier of drug discovery and development.

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