The Rise Of NAMs

By Ray Dogum, Chief Editor, Drug Discovery Online

The ultimate predictor of toxic outcomes in humans treated with novel compounds is, unsurprisingly, human testing – formally known as clinical trials. Thankfully, over time, we collectively recognized it’s terribly unethical to systematically administer untested new drugs, chemicals, and biologics on humans first. The drug industry conducts preclinical studies to produce data that convinces regulators a drug is safe enough to put into humans.

Animal Trials Before Human Lives

Since 1938, under the mandate of the U.S. Federal Food, Drug, and Cosmetic Act, scientists have relied on animal models as biological proxies for predicting human toxicological responses to compounds. In 1946, the Nuremberg Code and later the Helsinki Declaration included language stating that human experiments should be based on results from animal studies and an understanding of the natural history of the disease.

Animal testing has undoubtedly prevented dangerous substances from becoming commercially available as pharmaceutical and commercial products. Mammalian models still have significant relevance to many researchers, especially for measuring toxicity of therapeutics that aren’t monoclonal antibodies (mAbs), as mAbs are generally considered less toxic than small molecules and other drug modalities. In April of 2025, the FDA announced its plan to thoughtfully phase out animal testing requirements, starting with investigational new drug (IND) applications for  mAbs. We’re still waiting for the outcomes of these new policies, but most industry experts are feeling optimistic.

The big question remains, are there testing options that can better protect the public than animal tests?

Short answer is yes.

In a previous article, I outline the FDA’s massive shift away from animal testing, toward New Approach Methodologies (NAMs) adoption. The concept of incorporating NAMs in preclinical studies is not new. What is new is the growing public support we’re seeing from regulators and the biotech industry more broadly. 

Interestingly, the UK banned animal testing in 1998 for cosmetic product ingredients, while the EU banned them in 2013. Currently, there are only 12 US states which have banned it in the cosmetic industry, making it unlawful to sell cosmetics knowingly developed using animal testing.

One could argue that the profound benefits of developing life-saving medicines justify the ethical cost of animal testing far more than the comparatively superficial risks associated with marketing untested cosmetic products. The former often involves injecting, ingesting, or otherwise inserting substances into the body to treat or cure disease, while the latter pertains to substances “intended to be rubbed, poured, sprinkled, sprayed on, introduced into, or otherwise applied to the human body for the purposes of cleansing, beautifying, or altering appearance.” [FD&C Act, sec. 201(i)]

Given the complex modes of administration and protocols currently in place for animal studies, one begs the question.

What kind of non-animal studies are currently validated by the FDA as in vivo replacements? Well, there are a few categories of NAMs to consider – namely in vitro models, in silico models.

In Vitro Human-Derived Models

These include 2D and 3D cell cultures, organoids, high-throughput screening assays, and other lab-based systems using human cells to assess biological effects without using animals.

A growing model system that’s increasing its share in the in vitro category is microphysiological systems (MPS), also known as organs-on-chips (OoC) or tissue chips, these replicate human organs to model disease, drug responses, and toxicity. They work by using microfluidic devices containing networks of hair-fine microchannels that guide and manipulate minute volumes (picoliters up to milliliters) of solution mimicking human organs or tissue.

MPS is still relatively new to the drug discovery process, and many are still being validated for widespread use in industry. There are also interesting combinations of organ-on-chips to mimic something called body-on-a-chip that may be able to provide insights into how a drug may impact a human body more holistically.

Dozens of OoC companies are furiously working to become accepted into drug discovery workflows and validated for use by the FDA. Current organ models available on the market include those representing the brain, bone marrow, colon, duodenum, kidney, liver, lung, lymphoid tissue, and vagina.

Organoids are part of an important class of NAMs endorsed by the FDA for their ability to model human tissue architecture and function using pluripotent stem cells, including iPSCs and ESCs. These 3D constructs enable mechanistically relevant assessments of drug efficacy and toxicity, and are increasingly accepted in IND submissions. For example, iPSC-derived liver organoids have demonstrated predictive capacity for hepatotoxicity by recapitulating albumin, urea, and CYP enzyme profiles comparable to primary human hepatocytes. Similarly, brain organoids are being used to evaluate neurotoxicity and off-target effects, while tumor organoids co-cultured with immune cells have informed T cell engager selectivity and cytokine release risk.

Other organoids show immense opportunity modeling cells from the human stomach, intestine, lung, thyroid, kidney, hippocampus, cerebella, optic cup.

The growing organoids-as-a-service market is creating new opportunities for drug discovery pipeline companies as they can more cheaply and efficiently begin critical preclinical experiments.

In Silico Models

These are computational or bioinformatic approaches, including AI/ML models, Quantitative Structure-Activity Relationship (QSAR), and Physiologically Based Pharmacokinetic (PBPK) modeling, used to simulate biological processes and predict outcomes. In silico tools also enable integration of multi-omics data and real-world evidence to refine target validation and biomarker discovery.

Their adoption aligns with FDA’s strategic initiatives to modernize regulatory science and reduce reliance on animal testing by using data to enable human-relevant, predictive simulations.

Bonus NAMs to Consider

• Ex Vivo Perfused Organ Models (POMs): The use of real human donated organs suspended in nutrient-rich fluid and all the necessary components to keep the organ alive and functioning during translational experiments.
• Non-mammalian animal models like C. elegans, zebrafish (Danio rerio), fruit flies (Drosophila melanogaster), sea urchins, planarians, and xenopus may be considered NAMs in some specific scenarios.

More NAM systems are being developed in labs every day. This field is rapidly becoming a top choice for young scientists, especially as they look toward the frontiers of scientific discovery. The deeper you explore the expansive field of NAMs, the more you come to appreciate the intricate bioengineering required to fulfill their intended purpose – simulate the human body.

The adoption of NAMs continues to grow and new markets are bringing innovative tools to drug hunters. It’s clear that this shift toward NAMs won’t happen overnight and NAM developers still need to prove their methods are reliable enough to replace widely accepted animal tests. 

If you’re working on developing and validating NAMs, or perhaps you are planning to leverage NAMs to accelerate your drug development, I’d love to hear from you. Find me on LinkedIn and let’s start a conversation.