In a move welcomed by animal welfare organisations, new medicines no longer need to be tested on animals to receive US Food and Drug Administration (FDA) approval, according to new legislation, a change signalling a major shift from animal use after more than 80 years of drug safety regulation.
In place of the 1938 stipulation that potential drugs be tested for safety and efficacy in animals, the law now allows the FDA to promote a drug or biologic – a larger molecule such as an antibody – to human trials after either animal or non-animal tests, writes the journal Science.
The non-profit Animal Wellness Action, among others that pushed for changes, argues that in clearing drugs for human trials, the agency should rely more heavily on computer modelling, “organ chips”, and other non-animal methods that have been developed over the past 10 to 15 years.
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 years”. The FDA still retains tremendous discretion to require animal tests, he notes, and he doesn’t expect the agency to change tack anytime soon.
But Tamara Drake, director of research and regulatory policy at the Centre for a Humane Economy, a non-profit animal welfare organisation and key driver of the legislation, said, “This is huge. It’s a win for industry and for patients in need of cures.”
For a drug to be approved in the US, the FDA typically requires toxicity tests on one rodent species, like a mouse or rat, and one non-rodent species, such as a monkey or dog. Companies use tens of thousands of animals annually for such tests. Yet more than nine in 10 drugs in 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 commercialised by the company Emulate, where he sits on the board and owns stock.
Such chips typically comprise hollow channels embedded in silicone-based polymers the size of a computer thumb drive. The channels are lined with living cells and tissues from organs like 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 various 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 or then withdrawn/scaled back because of liver damage. The chips didn’t falsely flag any non-toxic drugs.
Other animal alternatives include organoids, hollow, 3D clusters of cells derived from stem cells and which 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 anti-nausea drug in dogs was unreasonable. A US 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 has gone. In eliminating it, Congress seems to have responded to the emergence of non-animal methods and growing public sentiment against animal research. The changes, which the Senate passed by unanimous consent in September 2022, were signed into law in December by President Joe Biden.
Wendy Jarrett, CEO of Understanding Animal Research, an animal research advocacy group in the UK, doesn’t share animal advocates’ delight at the changes. She says non-animal methods can’t capture all the ways a drug might risk human trial participants’ lives.
“We can drop a new (candidate drug) on to a bunch of liver cells, and 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, or damage their intestines or brain.”
FDA’s chief scientist says the agency supports 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 encourage developers working on alternative methods to present their work to the FDA.”
She said the agency requested and received $5m this year to launch an FDA-wide programme to develop methods to replace, reduce and refine animal testing.
Still, it remains unclear just how much the new law will change things at the FDA. Although the legislation allows the agency to clear a drug for human trials without animal testing, it doesn’t require it to 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 euthanised.
Study details
Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology
Lorna Ewart, Athanasia Apostolou, Skyler Briggs, Christopher Carman, Jake Chaff, Anthony Heng, Sushma Jadalannagari, Jeshina Janardhanan, Kyung-Jin Jang, Sannidhi Joshipura, Mahika Kadam, Marianne Kanellias, Ville Kujala, Gauri Kulkarni, Christopher Le, Carolina Lucchesi, Dimitris Manatakis, Kairav Maniar, Meaghan Quinn, Joseph Ravan, Ann Catherine Rizos, John Sauld, Josiah Sliz, William Tien-Street, Daniel Levner et al.
Published in Communications Medicine on 6 December 2022
Abstract
Background
Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realised in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential to improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips’ predictive value have not yet been reported.
Methods
870 Liver-Chips were analysed to determine their ability to predict drug-induced liver injury caused by small molecules identified as benchmarks by the Innovation and Quality consortium, who has published guidelines defining criteria for qualifying preclinical models. An economic analysis was also performed to measure the value Liver-Chips could offer if they were broadly adopted in supporting toxicity-related decisions as part of preclinical development workflows.
Results
Here, we show that the Liver-Chip met the qualification guidelines across a blinded set of 27 known hepatotoxic and non-toxic drugs with a sensitivity of 87% and a specificity of 100%. We also show that this level of performance could generate over $3 billion annually for the pharmaceutical industry through increased small-molecule R&D productivity.
Conclusions
The results of this study show how incorporating predictive Organ-Chips into drug development workflows could substantially improve drug discovery and development, allowing manufacturers to bring safer, more effective medicines to market in less time and at lower costs.
Science article – FDA no longer needs to require animal tests before human drug trials (Open access)
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