Animal testing is not required for drug licensing, but high-tech substitutes are not readily available

For generations, people have associated the words “sweat rat” and “guinea pig” with scientific research. Animal testing remains standard and necessary for drug approval.

Just before Christmas, Congress ended the requirement that all new drugs be tested in two species—typically mice and mammals such as rabbits or primates—before they can be tested on humans.

The change will not end animal testing overnight. Research tools and computer algorithms developed in the last 10 to 15 years still have gaps. And regulators won’t immediately change their decades-old approach to ensuring safety and efficacy.

But the legislation, officially called the FDA Modernization Act 2.0, marks the end of 40 years of lobbying by scientific research and animal rights activists over human cells and technology.

“There’s a point where the technology is advanced enough and the understanding is advanced enough,” said Benjamin Friedman, a bioengineer at the Washington School of Medicine.

Animal studies help provide a margin of safety that the drug is likely to be effective and probably not too dangerous — but they can’t be fooled. 90% of drugs that are safe and effective in animals do not work as intended in humans. Sometimes, drugs that appear to be safe in animal testing may not be.

“It’s an open secret that the current system, based on the use of animals for the first round, has failed,” said Cathy Guillermo, senior vice president of Animal Ethical Medicine, which has long championed animal testing. .

How are animals disposed of?

Rachel Anatole, senior vice president of science and regulatory affairs at the Biotechnology Innovation Organization (BIO), a trade group, said the Food and Drug Administration would not allow drugmakers to suddenly stop using animals in drug development.

Drug companies must demonstrate to the FDA that they will not sacrifice safety or efficacy by replacing animal testing, said Anatole, who recently left the regulatory agency.

“Making the agencies comfortable and reliable about this is going to be a stumbling block,” she said.

The FDA did not respond to multiple requests for comment on the change.

She said the first drugs that could be seen to be different were the “me too” products that were similar to those on the market.

Another early benefit from the congressional action is that Botox could be a test for botulinum toxin used for medical and cosmetic purposes, said Danilo Tagle, director of the National Office of Special Initiatives for the Advancement of Translational Sciences. National Institutes of Health Division.

Botulinum toxin is one of the most deadly substances known to contaminate food. Each year, millions of mice are treated with the lethal botulinum toxin to test the potency of each toxin component, Tagle said.

Now, he’s working with the Food and Drug Administration to replace those mice with cells in a dish. The replacement process does not happen for a year or two, and it does not bring millions of more rats in the world – the animals are not bred for this purpose.

But replacing animals in lab experiments saves time and money, poses less risk to lab workers and eliminates the need to dispose of infected animals, he said.

Devices that replace laboratory animals

The technology to completely replace animal testing “doesn’t exist yet,” Anatole said. But researchers can now take skin or blood cells from a patient with a disease of interest, grow the cells in the lab, and quickly test hundreds of drugs to see if they can reverse any mistakes.

Scientists are also creating “organoids” by mixing cell types from a specific organ, such as a kidney, to simulate disease and how drugs might affect them.

A similar technology called “organ-on-a-chip” allows researchers to better represent the environment in the body by mimicking blood flow past these organoids.

Friedman grows miniature models of kidney and lung disease.

“They’re not organs, but they have tissue-like properties,” said Friedman, whose latest study was published Dec. 23. Mini-organisms can show symptoms of disease, drugs are used to see if they change those symptoms and the results are analyzed. They said it would be difficult to work at the cellular level in animals.

Researchers are beginning to connect these simulated organs—suggesting what might happen if a drug is swallowed, digested, injected into the bloodstream and into the liver, Friedman said.

But for now, these cellular models are supplements, not replacements, for animal models.

“There’s a bit of a gap between what happens in the dish and what happens if you put a drug or treatment into the body,” Friedman said. It is still something that needs to be done.

Moving away from animal models would be especially helpful for diseases where animal models are expensive or impossible to develop, and small patient populations make it difficult to justify such work, Tagle and Friedman said.

Using cells from patients instead can shave a year or two off the drug development process.

Artificial intelligence, machine learning and computer simulations are also becoming more and more practical, bio experts said.

Biotech companies, especially large ones with big money for research and development, are investing in artificial intelligence and machine learning technologies, hoping they will be cost-effective over time, said Nick Shipley, the biotech’s chief advocacy officer.

“It has a lot of promise, which is why companies continue to invest, but it’s not quite there yet,” he said.

Why is this happening now?

The move away from animal testing is also driven by cost.

In addition to ethical issues with primates, pandemic shutdowns, particularly in China, have made it harder and more expensive to find research monkeys in recent years, Shipley said.

“There are moral, ethical and financial reasons to move this away from animal testing,” he said.

John Murphy, BIO’s chief policy officer, added that each primate now costs between $4,000 and $5,000 to buy, not including housing and feeding costs. “It’s a pain point,” he said.

In the year A 2019 study of pharmaceutical experts found that replacing animals could save 10% to 26% of drug development research costs, although Murphy and Shipley doubt the savings will be that high.

Cultural change

Scientists are trained to turn to animals when investigating human diseases.

“The first thing I think about is, ‘What animal model am I going to use?'” says Paula Cannon, a virologist at the University of Southern California’s Keck School of Medicine who studies HIV and Covid-19. Rhesus macaques are commonly used in HIV research because their experience is similar to that of humans.

But there is growing awareness among scientists as well as the FDA and companies that animal models have scientific and ethical limitations, he said.

“It used to be a lot of box-checking. The FDA wants us to do this in 500 mice, so let’s do it,” she said. “Now people say is this the right model? Is this really going to tell us anything?”

Even as researchers try to reduce the harm they do to animals, they realize that they impose an ethical price on their studies, says Richard Bourne, a neurobiologist who teaches social issues in biology at Harvard Medical School, including the ethics of animal testing.

It asks students to consider whether animals should be used for research and whether federal tax dollars should pay for that research. Born previously used primates in some studies of the visual system.

Moving away from animals also requires action on the part of both drugmakers and regulators, biotech executives said.

Companies must prove to the FDA that they have viable alternatives to animal testing, but they won’t make that move until the FDA gives assurances that it accepts those alternatives, Shipley said.

They don’t throw things against the wall hoping the FDA likes it, he said. “They want some indication from the FDA (first).”

The market will only move to reduce or eliminate animal testing when the FDA provides some incentive, Murphy added.

“As long as people feel that the FDA is going to keep going back to what’s been done, I don’t think they’re going to see as much interest or investment as there should be.”

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