New medicines need not be tested in animals to receive U.S. Food and Drug Administration (FDA) approval, according to legislation signed by President Joe Biden in late December 2022. The change—long sought by animal welfare organizations—could signal a major shift away from animal use after more than 80 years of drug safety regulation.
“This is huge,” says Tamara Drake, director of research and regulatory policy at the Center for a Humane Economy, a nonprofit animal welfare organization and key driver of the legislation. “It’s a win for industry. It’s a win for patients in need of cures.”
In place of the 1938 stipulation that potential drugs be tested for safety and efficacy in animals, the law allows FDA to promote a drug or biologic—a larger molecule such as an antibody—to human trials after either animal or nonanimal tests. Drake’s group and the nonprofit Animal Wellness Action, among others that pushed for changes, argue that in clearing drugs for human trials the agency should rely more heavily on computer modeling, “organ chips,” and other nonanimal methods that have been developed over the past 10 to 15 years.
But pro-research groups are downplaying the law, saying it signals a slow turning of the tide—not a tsunami that will remake the drug approval process overnight. Jim
Newman, communications director at Americans for Medical Progress, which advocates for animal research, argues non-animal technologies are still “in their infancy” and won’t be able to replace animal models for “many, many years.” FDA still retains tremendous discretion to require animal tests, he notes, and he doesn’t expect the agency to change tack anytime soon.
In order for a drug to be approved in the United States, FDA typically requires toxicity tests on one rodent species such as a mouse or rat and one nonrodent species such as a monkey or dog. Companies use tens of thousands of animals for such tests each year. Yet more than nine in 10 drugs that enter human clinical trials fail because they are unsafe or ineffective, providing grist to those who argue that animal experiments are a waste of time, money, and lives.
“Animal models are wrong more often than they are right,” says Don Ingber, a Harvard University bioengineer whose lab developed organ chip technology now being commercialized by the company Emulate, where he sits on the board and owns stock.
Such chips typically consist of hollow channels embedded in silicone-based polymers about the size of a computer thumb drive. The channels are lined with living cells and tissues from organs such as the brain, liver, lung, and kidney. Fluids flow through them to mimic blood flowing through tiny vessels and fluid tracking through tissues, as it does in living organs. In the body, drug damage often shows up in the liver because it breaks down drugs for excretion. A human liver chip can warn of such toxicity when an experimental drug pumped through it damages the cells.
Last month, Lorna Ewart, chief scientific officer at Emulate, Ingber, and colleagues published a study highlighting the potential of this technology. The company’s liver chips correctly identified 87% of a variety of drugs that were moved into humans after animal studies, but then either failed in clinical trials because they were toxic to the liver or were approved for market but then withdrawn or scaled back because of liver damage. The chips didn’t falsely flag any nontoxic drugs.
Other animal alternatives include organoids—hollow, 3D clusters of cells that are derived from stem cells and mimic specific tissues. They have shown promise in predicting liver and cardiac toxicities. Proponents also tout the potential of digital artificial neural networks for rapidly identifying the toxic effects of drugs.
Some drug companies have chafed at FDA’s animal testing requirement, arguing that animal studies cost them millions of dollars, slowing drug development and making the medicines that do reach the market far more expensive. In 2019, Vanda Pharmaceuticals sued the agency, charging that its requirement of additional toxicity testing of an antinausea drug in dogs was unreasonable. A U.S. judge ruled against the company in 2020, citing the animal testing requirement in what was then the law governing FDA’s drug assessments.
Now, that requirement is gone. In eliminating it, Congress seems to have responded to the emergence of nonanimal methods and growing public sentiment against animal research. Senator Rand Paul (R–KY) and Senator Cory Booker (D–NJ), who both call animal research inefficient and inhumane, introduced the changes, which the Senate passed by unanimous consent in September 2022. In December, Biden signed them into law as part of the Consolidated Appropriations Act, which funds the government through this fiscal year.
Wendy Jarrett, CEO of Understanding Animal Research, an animal research advocacy group based in the United Kingdom, doesn’t share animal advocates’ delight at the changes. She says non-animal methods can’t capture all the ways a drug might put human trial participants at risk. “We can drop a new [candidate drug] onto a bunch of liver cells. And we can see that it doesn’t damage them,” she says. “But what we don’t know is whether it’s going to make the person cough, whether it’s going to damage their intestines or their brain.”
FDA’s chief scientist says the agency is in favor of trying to move away from animal testing—when other approaches are ready. “We support alternative methods that are backed by science and provide the necessary data showing whether products are safe and effective,” Namandjé Bumpus says. “We continue to encourage developers working on alternative methods to present their work to the FDA.” She also notes that the agency requested and received $5 million this year to launch an FDA-wide program to develop methods to replace, reduce, and refine animal testing.
Still, it remains unclear just how much the new law will change things at FDA. Although the legislation allows the agency to clear a drug for human trials without animal testing, it doesn’t require that it do so. What’s more, FDA’s toxicologists are famously conservative, preferring animal tests in part because they allow examination of a potential drug’s toxic effects in every organ after the animal is euthanized.
The main impact of the new law is that it opens the way for FDA and a company to have a serious discussion about whether alternatives are adequate, says Steven Grossman, a former deputy assistant secretary of health who advises companies on their FDA applications. “It provides a little additional authority. It says in law: ‘Congress is cool that these discussions are going on.’”