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How the FDA Can Reduce Animal Testing

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How the FDA Can Reduce Animal Testing

The agency should support sophisticated in vitro and computational approaches that can curtail—and potentially even replace—the practice. January 11, 2022
Technology and Innovation
Politics and law

As a senior executive appointee to the Food and Drug Administration in the Trump administration, I saw certain officials place politics above scientific progress on animal testing. If the FDA prioritizes science, health, and ethics over political considerations, it should support the development of sophisticated in vitro and computational approaches to curtail animal testing.

Old rules govern the FDA’s current approach to this issue. In 1962, Congress passed the Kefauver–Harris Amendments (KHA) to the Federal Food, Drug and Cosmetic Act. Among other requirements to “modernize” scientific methodologies, this now-dusty law empowered the FDA to mandate animal-testing requirements for new drug approvals. Additionally, Sec. § 312.20 in the Code of Federal Regulations outlines the requirements for Investigational New Drug (IND) applications, and the FDA also requires comprehensive animal studies for the approval of new drugs in humans. Last year, in appropriations, the FDA was directed to update its regulations to allow for non-animal methodologies. The agency was to report back on its progress by September 30, but it missed this deadline.

The existing regulations are extremely specific. Drug-makers are directed to use animal tests to discern pharmacology (how a drug exerts its effects) and toxicology (the dose at which it causes adverse events), as well as radiation absorption and reproductive effects. The regulations allow no flexibility to explore or implement newer methods that may be more predictive for humans. The FDA alone holds the power to initiate any change. Companies must follow these regulatory rules to move an investigational medication through the review process and eventually obtain FDA approval.

Beyond the regulations, other FDA guidance documents enumerate and prioritize animal testing. Guidance documents are meant to be non-binding recommendations that reflect the agency’s thinking on a topic but do not hold the weight of regulations—or do they? Recently, Vanda Pharmaceuticals tried to avoid conducting a nine-month study on dogs, stating that the study, which would kill dozens of beagles, had no scientific justification. But FDA reviewers would not budge, referencing their own guidance documents.

The number of annually required animal tests is staggering. Over 110 million mice and rats are killed every year in the name of science in the U.S., as are other animals, including monkeys, rabbits, pigs, guinea pigs, cats, and dogs.

And the benefits are not always apparent. When the KHA was passed, it was the scientific standard of its time. Sixty years later, scientists have learned that the results of animal tests are not necessarily useful or predictive in humans. Approximately 90 percent of early-phase clinical trials fail after extensive animal testing has already been conducted. Despite this, the FDA requires animal tests to be performed for almost every IND it reviews, regardless of utility.

Animal tests are often unnecessary. Aside from the many animal species and breeds involved, the variety of metabolic pathways and drug metabolites in animals leads to variation in efficacy, toxicity, disease latency, and dosing schedules. Often, the results are only loosely relevant to human beings. For example: isotretinoin, also known as Accutane, causes birth defects in rabbits, monkeys, and humans, but not in mice or rats. Corticosteroids are known to cause congenital abnormalities in many animal species but not in humans. Thalidomide is not teratogenic (affecting the development of an embryo or fetus) in animals but is in humans. Many of the studies required by the FDA are nonsensical, including eye- and skin-irritation tests of drugs approved only for oral administration. The National Institutes of Health acknowledges that “approximately 30 percent of promising medications have failed in human clinical trials because they are found to be toxic despite promising preclinical studies in animal models.”

All this can lead to atrocious results. It was reported recently that the National Institute of Allergy and Infectious Diseases granted $424,455 in taxpayer funds for a study that locked beagles in cages alone in the desert for nine days to attract parasite-ridden sand flies, then starved those sand flies, and then let them feed on live, restrained beagles’ heads. The beagles were reportedly “vocalizing in pain” despite being heavily sedated during the experiment.

As a Pfizer investigational medicine research scientist in the early 2000s, I was charged with overseeing “LD50” tests in animals. My colleagues and I would have to determine the lethal dose—the amount that would kill 50 percent of the animals after a single dose. Often, this meant force-feeding canines and rodents multiple grams of experimental drugs before first-in-human (FIH) trials that dose humans with mere milligrams of the drug—a tiny fraction of the dose we gave to animals. We would then work our way up logarithmically until we found the maximum tolerated dose. This was done to satisfy FDA mandates.

Major advances have been made in drug testing since the existing regulations were written. These include pre-clinical, non-animal methodologies. Consider “Organ-on-a-Chip” (OOC) technology. As a former senior executive White House appointee to the FDA, I was tasked with advising the FDA commissioner and the White House on ways to modernize and speed up drug development. One of my proposals was advancing OOC technologies, which potentially did both. OOCs are made by programming or culturing human cells obtained from relevant human organs (heart, liver, kidney, brain, gastrointestinal) in a microenvironment “chip,” where micro-doses of experimental drugs can be applied. OOCs can then be linked to form model human systems, adding additional complexity. Since human cells are used to populate these OOCs, this in vitro technology circumvents—and could one day substantially reduce—the cruelty and experimental limitations inherent to animal testing.

The ethical and technological advantages of such innovations are obvious. OOCs have the potential to predict safe doses more clearly and quickly than animal tests. Alternatives to animal testing already enjoy bipartisan support. And such innovations have public-health and efficiency benefits.

Unfortunately, some FDA officials are reluctant to change. During my time there, I spent months preparing a detailed proposal in which funding would be provided to a few pharmaceutical companies to implement OOCs in tandem with existing animal testing. The goal was to test the hypothesis, supported by certain comparative studies, that OOCs could speed pre-clinical drug development by more accurately predicting safety and efficacy in humans. To my astonishment, I was obstructed every step of the way by career leadership bureaucrats at the FDA. One of these, Patrizia Cavazzoni, had a reputation of refusing to work with Donald Trump’s political appointees; she was “leap frog” promoted by President Biden shortly after his inauguration. Cavazzoni and her team wouldn’t even consider listening to my research or science-based recommendations.

Americans overwhelmingly disapprove of animal testing and would likely come together on curbing it, especially if they knew about technologically superior alternatives like OOC. Over the past seven decades, technology has advanced dramatically, and so has our view of the role of animals in society. To keep up with the latest technology, the FDA should work to reduce its reliance on animal tests by embracing—not ignoring— innovative alternatives.

Photo by Anna Moneymaker/Getty Images

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