Abstract
The FDA Modernization Act 2.0 allows companies to submit nonanimal data using certain alternative technologies to demonstrate the safety and efficacy of investigational drugs prior to human trials. Animal rights supporters hope the law represents a shift away from animal use, but researchers caution that organ-chips and other innovations, although potentially valuable, cannot replace animal models to test drugs in development.
The FDA Modernization Act 2.0, passed in December, allows companies to use nonanimal testing methods to help demonstrate the potential safety and efficacy of investigational drugs and biologics prior to clinical trials. Animal rights advocates hail the legislation as a shift away from reliance on animals, while research groups caution that new technologies are not yet capable of replacing animal models.
“There have been major innovations in biotechnology in recent years that can predict toxicities in humans and potentially provide a better gauge in the approval process while also being more humane,” says Wayne Pacelle, president of the Center for a Humane Economy in Bethesda, MD.
Alternative technologies, such as 3D cell culture and organoids, can help reduce animal use by ruling out potentially harmful treatments early in the drug discovery process, agrees P. Jack Hoopes, DVM, PhD, director of the Center for Comparative Medicine and Research at Dartmouth College in Hanover, NH. However, the technologies are not yet sophisticated enough to simulate the complexity of animal responses or predict safety in humans.
As a result, Hoopes and other researchers maintain that the FDA should and likely will continue to request animal data before moving novel drugs into clinical trials.
“There is still a significant risk of doing serious harm… when you bypass animal models before going into the clinic,” says Henry Friedman, MD, deputy director of The Preston Robert Tisch Brain Tumor Center at Duke University in Durham, NC, and chair of the Foundation for Biomedical Research. “Companies can now come to the FDA with alternative data as a starting point, but the FDA will continue to ask for animal data in almost all cases because that data is frequently pivotal to safe extrapolation into patients.”
The new law authorizes the use of certain alternatives to animal testing, including cell-based assays and computer modeling. The FDA actively supports emerging innovations in preclinical testing, including organ-chips, which create in vivo microenvironments inside microchips that simulate the mechanics and physiology of human organ systems.
The agency has been working with the biotech company Emulate to test organ-chips. In a recent study, Emulate's liver-chip—combined with machine learning—correctly identified 13 of 15 drugs that had previously proved hepatotoxic in clinical trials despite having been tested in animals (Commun Med [Lond] 2022;2:154).
Investigators say their findings show how organ-chips might be used during the lead optimization phase of drug discovery. Compounds that produce a toxic signal in the liver-chip could be deprioritized in early studies, thus reducing the need to use animals to assess drugs that are likely to fail.
While organ-chips can be helpful tools for screening drug candidates, they cannot demonstrate how novel drugs will be metabolized, which is critical to determine the best dose, says Matthew Bailey, president of the National Association for Biomedical Research.
Emulate’s liver-chip combines multiple human cell types in a dynamic microenvironment designed to support in vivo–like gene expression, functionality, and physiology. Elements shown above: 1) epithelial channel; 2) extracellular matrix; 3) hepatocytes; 4) stellate cells; 5) membrane; 6) immune cells; 7) endothelial cells; 8) endothelial channel.
To illustrate the critical role of animal studies, Marina Emborg, MD, PhD, at the Wisconsin National Primate Research Center, University of Wisconsin (UW)–Madison, cites a study that tested a drug combination's ability to cross the blood–brain barrier in animals with Parkinson disease (PLoS One 2012;7:e39036). The strategy was not neuroprotective, and the research revealed adverse effects.
“When we did a full autopsy of the animals, we found proliferative, precancerous lesions in the pancreas, which were unexpected,” says Emborg. “It's a good example of why we need to do first-in-class drug testing in animals.”
Advanced computer algorithms and mathematical models can help predict dose and treatment safety.
“However, with many standard therapies, such as radiation, there can be very serious late effects that are not observable using mathematical, cell culture, or even mouse models,” Hoopes says. “These complications are pathologically complex and variable, so using models that are similar to humans in size and physiology remains the most effective way to identify serious complications that may occur years after treatment.”
Animal testing is also important to assess the effects of immunotherapies to treat various cancers, says Igor Slukvin, MD, PhD, also of UW–Madison.
“We often see different effects in vitro than we see using animal models,” he says. “Despite recent advances in organ-on-chip technologies, reproducing the whole-body interorgan physiology on a chip remains a significant challenge.”
In practice, the new legislation adds a list of nonanimal methods that the FDA considers scientifically valid for preclinical testing, says Bailey. However, the agency still strongly recommends demonstrating drug safety in at least one rodent species and one nonrodent species.
“In science, all information is good information, which is why we find these newer technologies to be excellent adjuncts to—but not full replacements for—animal testing,” says Bailey. –Janet Colwell
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