Tag: law

It’s called a “liver-chip.” Researchers grew human liver cells on a small chip-like device, hoping to use it to predict when a drug might cause liver injury. Not only did it do so — flagging a set of small molecule drugs with known hepatoxicity with 87{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} specificity — but it also outperformed conventional animal models.

In the study, recently reported in Nature, the chip also detected 7 of 8 drugs that had been deemed safe in animal tests but were eventually proven to be toxic to the liver when used clinically.

The researchers, who are primarily with the biotechnology company Emulate, said they believe the use of liver-chips could save an estimated $3 billion annually for the drug industry. They also estimate that adopting the use of four other organ-chip models, which address the most common toxicities that derail products, could generate $24 billion in savings via increased efficiency and productivity.

That type of success may be a harbinger of the future of biomedical research and drug, biologic, and vaccine development. Animal advocates have high hopes that the FDA Modernization Act 2.0, signed into law by President Joseph Biden on December 29, 2022, will speed up the acceptance and use of nonanimal methods, such as the liver chip, for toxicology, safety, and effectiveness testing. For now, the new law only applies to pharmaceuticals, biologics, and vaccines but not devices.

The law allows developers to use nonanimal models, such as cell-based assays, organ chips, organoids, and computer modeling, to prove safety and efficacy during the approval of new drugs. It further removes a requirement for animal studies as part of the process for licensing a biological product that is biosimilar or interchangeable with another biological product.

Theoretically, it’s a big switch. Until now, the FDA has required the testing of products in at least two animal species before it can advance to human trials. It is also the culmination of years of effort to significantly reduce the use of animals in research and development.

Surprisingly, however, it only took a single congressional session to pass the law, which had significant bipartisan support, said Wayne Pacelle, president of Animal Wellness Action, a Washington-based nonprofit that lobbies for animal welfare. “The fact that we essentially got this passed almost unanimously is a watershed,” Pacelle told Medscape Medical News.

He said members of Congress had been influenced by the increasing move away from animal testing in the cosmetics and chemicals industries, where the Environmental Protection Agency (EPA) ordered an end to animal use by 2035.

Pacelle also pointed to what he called a “broadly merging consciousness about animals and their well-being,” whether it be improved welfare for farm animals, the removal of elephants from circuses, or a rejection of leather and fur. “There is a rising tide of consciousness, and the science industry is not immune from that,” said Pacelle.

Animal Research Still Necessary?

However, some researchers — and the FDA — say none of the alternative methods is reliable enough to be used regularly.

An FDA spokesperson told Medscape Medical News that animal research is still necessary in many areas because “current nonanimal methods cannot always predict effects that occur in highly complex interacting systems such as the human body.”

In addition, some say that while it may be possible to decrease the numbers of animals being used, it will never be possible to completely eliminate their use.

“I am a passionate believer in the safe, secure, honorable way of doing research involving animals that does not produce any kind of unacceptable harm to them,” Henry Friedman, MD, chairman of the Foundation for Biomedical Research, a nonprofit group that advocates for animal research, told Medscape Medical News.

“But I’m totally of the belief that the notion there will be a day when we won’t need animal models is absolute nonsense,” added Friedman, who is a pediatric and adult neuro-oncologist and the James B. Powell, Jr, Distinguished Professor of Pediatric Oncology at the Duke University School of Medicine.

Many animal advocates are unyielding. Animal Wellness Action and its sister organization, the Center for a Humane Economy, are calling on the FDA to completely eliminate animal testing from drug development by 2030.

There is a moral and ethical imperative to do so, said John Gluck, PhD, professor emeritus of the University of New Mexico and a faculty affiliate with the Kennedy Institute of Ethics at Georgetown University.

Animals’ “lives aren’t ours,” Gluck told Medscape Medical News. “They have a set of capabilities that are relevant to pursuing a life that has evolved over millions of years,” he said. “We’re taking hold of those capabilities without sufficient respect for those capabilities,” he said.

Although the pharmaceutical and biotechnology industries have been actively developing and using nonanimal models, no one expects any immediate changes where it matters most ― at the FDA.

The law is just “the first step in this entire process,” said Aysha Akhtar, MD, MPH, co-founder and CEO of the Center for Contemporary Sciences, a Gaithersburg, Maryland-based nonprofit that promotes animal alternatives.

“More than anything, this sent a message throughout the entire community that, look, we are ready to start moving on, we are ready to start making a change,” said Akhtar, who was a medical officer at the FDA for 10 years. “It’s not going to happen overnight but is going to start to incentivize the further use of these other methods,” she added.

FDA Slow to Change

FDA has been slow out of the gate, agreed Tamara Drake, director of research and regulatory affairs for the Center for a Humane Economy. “Our biggest resistance in the beginning with this legislation was the FDA,” she told Medscape Medical News.

While Drake said the agency has since made a “turnabout,” it is still moving at what she calls “a snail’s pace” in terms of evaluating nonanimal technologies.

“We don’t believe they are moving with the urgency that’s required to fix this broken drug development paradigm,” she said. The agency plans to evaluate two to four alternatives a year, she said, adding that is not enough when all of the major drug and biotech companies are already employing the technologies.

From the agency’s point of view, the law “does not change the regulatory process for drugs and does not eliminate animal testing,” said an FDA spokesperson, Veronika Pfaeffle. “The FDA will continue to ensure clinical investigations of drugs are reasonably safe for initial use in humans,” she added.

“The amendment does not change the fact that FDA reviewers have wide latitude to tell companies what kind of data they want to see,” said Matthew R. Bailey, president of the National Association for Biomedical Research, a nonprofit that represents 340 universities, medical and veterinary schools, pharmaceutical and biotechnology companies, and professional societies on legislative and regulatory matters pertaining to laboratory animal research.

Bailey also said that manufacturers have long been able to submit nonanimal data to the FDA. The agency will likely want to see animal data for the foreseeable future because neither the FDA nor manufacturers “want to be accused of killing people at the clinical trial stage due to negligence,” Bailey told Medscape Medical News.

Rachael Anatol, senior vice president of science and regulatory affairs at BIO, a trade organization, called the FDA Modernization Act “a step in the right direction.”

However, she said, “It will take some time to see a significant real-world impact. It will be critical for companies to demonstrate to FDA that alternative methods can provide the same assurances as animal models with respect to human safety or tolerability of new drugs and biological products. And for the market to fully shift to nonanimal alternatives, the FDA will need to provide assurance that these new methods will be accepted.”

The agency notes that its budget for fiscal year 2023 includes $5 million to support the New Alternative Methods Program, aimed at encouraging the evaluation, qualification, and acceptance of nonanimal alternatives.

In addition, the FDA may begin to feel more pressure to harmonize with policy and regulations being formulated in Europe. The European Union already prohibits the use of animals in the development of cosmetics, and in September, members of the European Parliament called for an expedited plan to eliminate animals in any research or testing.

95{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} Failure Rate

Many believe animal models are outmoded and are not reliably predictive of what a drug — especially a small-molecule therapeutic — will do when it gets into a human.

“Unfortunately, the way we do small molecules, at least in the pharmacologic area, has been fraught with a lot of failures,” said Danilo A. Tagle, PhD, director of the Office of Special Initiatives at the National Institute of Health’s (NIH’s) National Center for Advancing Translational Sciences (NCATS).

Tagle cites a “90{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} failure rate” of drug candidates on going from screening to use in humans, due mostly to the lack of accurate predictive testing in cell culture and animal models.

The low success rate “adds cost and adds time, and then at the same time it also puts patients at risk,” Tagle told Medscape Medical News. “Even when these drugs are approved for human trials, more often than not, they are found to be either toxic or ineffective,” he said.

NCATS has estimated that the failure rate can be as high as 95{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} and that it costs a minimum of $1 billion to bring a drug to market.

“What that failure rate really means is that 90{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} to 95{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} of all drugs and vaccines that have been found safe and effective in the animal tests end up being unsafe or ineffective in humans,” said Akhtar. “That’s a glaring, glaring statistic.”

Using animals as surrogates may have worked 100 years ago, when there was less knowledge, but developers today “are looking at the subtle nuances of molecular physiology, biochemistry, and neurophysiology,” she said. “At this molecular subtle level, even minor differences between species can profoundly impact study results,” Akhtar said.

“For scientific and human health reasons, we should not be using other species to try to understand human biology, because there’s just too many differences between species,” she added

On the other hand, many drugs and vaccines that may have held promise in humans have likely been discarded because they were not safe or effective in animals, said Akhtar, adding that animal models may not represent the most effective use of resources. It all “suggests that there is a lot of room for improvement in drug development process,” she added.

Friedman acknowledges a high failure rate but says a certain winnowing — via animal models — is necessary.

“The notion that animal work doesn’t predict response in humans is in general something you can say, but in some cases, it does predict benefit,” he said.

More importantly, it helps predict toxicity, said Friedman. “I don’t want to kill people. I don’t want to hurt patients with novel therapies. I don’t want to hurt animals either.”

Animal Suffering

The Duke-developed modified poliovirus therapy for glioblastoma could not have happened without the use of long-tailed macaques, said Friedman. “It took a decade to produce the kind of the data that led the FDA to say that it was safe to proceed” to human trials, said Friedman.

The university — like most institutions — keeps close tabs on how many animals it uses, their care, and how they are used, as required by the US Department of Agriculture (USDA), Friedman said.

The USDA requires reporting on how many animals are being held but are not used in research, how many are used for research, and how many are subjected to pain with or without pain relief. These reports are available to the public.

The animals used in research run the gamut from rodents to rabbits, pigs, sheep, dogs, cats, llamas, and nonhuman primates. In fiscal 2019, almost 800,000 animals were used, although this count does not include mice and rats. About 50,000 were subjected to pain but were not given any sort of pain relief.

The England-based nonprofit Fund for the Replacement of Animals in Medical Experiments (FRAME) reports that 3 million experiments were carried out on animals in the United Kingdom in 2021. Of those procedures, 96{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} were carried out on mice, rats, birds, and fish, said FRAME.

Researchers worldwide follow the “three Rs” — which call for the replacement, reduction, and refinement of animal use. While most institutions and companies may do so, horror stories still surface.

In July 2022, the US Department of Justice forced Envigo, a company that breeds and sells animals for research, to surrender some 4000 beagles that had been kept in inhumane conditions in Maryland.

Gluck wonders about the impact of poor animal husbandry or housing conditions that on the surface may seem acceptable but in fact are less than ideal. A rodent living in a typical cage in a typical lab is living in an environment that is 280,000-fold smaller than what it has evolved to live in, said Gluck.

A rhesus monkey is living in a metal mesh cage that is 7-million-fold smaller than the environment it evolved to live in, he said. Aside from the suffering, “what does that do to our science?” said Gluck. Most likely, it distorts the science, he said.

Alternatives on the Horizon

Since its founding a decade ago, the National Center for Advancing Translational Sciences has been looking into how to improve the science of the drug development process, with an eye on creating new efficiencies and, as part of that, reducing or eliminating the use of animals, said Tagle.

NCATS — with a small budget of about $35 to $40 million a year — has been digging deep into tissue chips (also called organs-on-a-chip), computational models, and other technologies in partnership with the FDA, the EPA, NASA, the Department of Defense, and industry and academic partners, said Tagle.

Tissue chips mimic the structure and function of a specific organ and include the heterogeneous collection of every cell in an organ. “We also capture the microenvironment of the tissue,” said Tagle, adding that researchers can subject the chips to stretching or mechanical load.

“Their environment is very similar to what’s happening in the human body,” and the cells are all derived from humans representing a variety of ages, races, genders, and ethnicities, Tagle said.

NCATS has been working with the FDA to validate the chips, and it funded testing centers at the Massachusetts Institute of Technology (MIT) and Texas A&M University. In 2021, under NCATS orders to become self-sustaining, MIT spun off its testing unit into a new start-up, Javelin Biotech, and Texas A&M created the Texas A&M Tissue Chip Validation (TEX-VAL) Consortium.

The NIH center is also funding eight projects that will use tissue chips to identify safety issues early on in human clinical trials and to potentially inform effectiveness. Use of the chips could potentially eliminate the need for a placebo arm, said Tagle.

But the technology is still being polished, he noted. “We’re not at that stage yet where we can practically claim that we have tissue chips that can replace animals. At best, they are a supplement or complementary to animal data, but there will come a time when we can probably say yes, we can replace animals with this technology,” Tagle said

In addition, tissue chips are just one of many animal alternatives being developed. A 2020 study by GlaxoSmithKline researchers, for instance, noted the potential of artificial intelligence (AI) to revolutionize drug discovery.

The report noted that Pfizer, Sanofi, Genentech, and GlaxoSmithKline were employing AI, machine-learning, and deep-learning methods to search for new drug candidates and that the “prediction of hepatotoxicity is one of the most notable areas in which these modeling efforts are being applied.”

Cultural Barriers Persist

Cultural hurdles may prove to be a greater challenge than technologic issues. Most current scientists received training in animal methods, and it becomes a “self-perpetuating paradigm,” said Akhtar. Many younger scientists are coming in with a fresh perspective and may use some of the new tools right from the start, she said.

But efforts to reverse those perspectives may be effective for those in favor of animal research. In 2019, the American Academy of Neurology (AAN) surveyed US-based student members to gauge their attitudes toward animal research. Most of the participants were male, and it was a small survey of 168 students.

The AAN researchers found that after viewing a video suggesting that animal research created multiple benefits for human health, students had a much more positive attitude toward the use of animals. Prior to seeing the video, 4.3{bf0515afdcaddba073662ceb89fbb62b6b1bf123143c0e06b788e1946e8c353f} agreed with the statement, “animal research cannot be justified and should be stopped,” but after seeing the video, none agreed with that statement, suggesting this “simple educational intervention” might influence attitudes in this “crucial population,” the investigators, led by David Q. Beversdorf, MD, chair of the AAN’s Animal Research Task Force, concluded.

Gluck said that students regularly challenged him on his use of animals in his own research when he was at the University of New Mexico. His faculty was less interested in pursuing the moral or ethical questions, he said. “Getting faculty, including myself at that time, to talk about alternatives to the animals that were a crucial part of our experimental designs just seemed absurd,” said Gluck.

Researchers tended to merge together into a “thought collective,” with those using monkeys attending the same conferences and having the same beliefs about their work, he said. Scientists who worry about tenure are also unlikely to rock the boat and lobby for the use of alternatives, especially when universities have invested heavily in labs and animal care infrastructure, Gluck noted.

“We’ve been stuck in a particular conceptual mode of doing research,” he said. But he believes that change will come as the weight of the evidence for alternatives becomes more robust.

Pacelle said that while it may be unrealistic to demand that no animals be used in drug development, “everyone should agree, including the research industry, that that must be our goal.

“There are moral costs with the use of animals in our society,” he said. “They feel pain, the physical pain, emotional pain of trauma. The only kind of logical rationale is we are sacrificing them for the greater good. But if we can do better and use alternatives, then everyone should be on board with that strategy,” said Pacelle.

Using as few animals as possible is a laudable goal, said Friedman. “But don’t ask me to choose between the rights and the moral obligation to take care of animals compared to the moral obligations to take care of patients,” he said. “I don’t think that’s a choice. My oath is to take care of patients. I’ll do everything I can to help them.”

The study was funded by Merck. Smith has received grant funding from Merck. Jones reports no relevant financial relationships. Gluck consults (without compensation) for various animal advocacy organizations.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on Twitter @aliciaault.

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