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Animal Rule for Drug Approval Creates a Jungle of Confusion (Nature Medicine)

In 2002, in the aftermath of the 9/11 attacks, the US introduced the 'animal rule' as a way for the country's regulators to approve medical countermeasures to chemical, biological and radiological weapons in instances where conducting human efficacy studies would be unethical or unfeasible. In the rule's first ten years, the US Food and Drug Administration (FDA) has used the provision to approve vitamin B12 injections for cyanide poisoning, an enzyme-blocking pill for nerve gas exposure and a broad-spectrum antibiotic to treat plague. Notably, in all of these cases the drugs had already received FDA approval for other afflictions or had previously received a green light in other countries for use against deadly chemicals.

Now, in a regulatory first, on 14 December the FDA cleared a completely novel product through the animal rule without any such prior approvals: an antibody drug called raxibacumab for the treatment or prevention of respiratory anthrax, caused by inhalation of the bacterium Bacillus anthracis. In fact, although the safety of raxibacumab was demonstrated in more than 300 healthy human volunteers, the only validated efficacy studies available to the FDA were in monkeys and rabbits.

“It's really the first drug that has been approved using the animal rule as the sole mechanism,” says James Swearengen, director of comparative medicine at the National Biodefense Analysis and Countermeasures Center at Fort Detrick, a government research lab in Frederick, Maryland, created by the US Department of Homeland Security. “It's a milestone.”

For Swearengen, the decade-plus it took from enacting the animal rule to approving raxibacumab is simply a reflection of the pace of regulatory science: “Any time you introduce anything new like that at a government level, there's a learning curve,” he says. However, others worry that the dearth of medical countermeasures approved in the post-9/11 era signals a deeper problem—both with the FDA's handling of applications under the animal rule and with the rule itself. “While it's great that we have this drug that's approved, the stockpile is not as full as I would like it to be,” says Gigi Gronwall, an immunologist at the Center for Biosecurity of the University of Pittsburgh Medical Center in Baltimore.

Both Swearengen and Gronwall sat on a committee first convened in 2009 by the US National Academy of Sciences (NAS) that was tasked with judging how reliable animal models are as proxies when it comes to testing the efficacy of bioterrorism countermeasures. Under the existing animal rule, the FDA will accept animal efficacy data when a protective effect is demonstrated in at least two suitable species or in a single animal species if it “represents a sufficiently well-characterized animal model for predicting the response in humans.” Yet, according to Thomas Hartung, an NAS panel member and director of the Center for Alternatives to Animal Testing at the Johns Hopkins Bloomberg School of Public Health in Baltimore, such an ideal model simply doesn't exist. “If there was an animal model good enough to substitute for people, we would not have a 92% failure rate in clinical trials,” he says.

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