A new drug approved by the US Food and Drug Administration (FDA) to treat patients afflicted with the plague was reviewed under a rarely used regulatory pathway meant to sidestep ethical and practical testing concerns.
In 2002, FDA passed the Animal Efficacy Rule ("Animal Rule"), a regulation which permits the approval of some products based on safety testing in humans and efficacy testing in animals.
The rule, located at 21 CFR 314.600-650 (drugs) and 601.90 (biologics), is meant to allow FDA to approve products for "serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances."
The rule is especially important in either of two cases:
- if a biological threat exists to humans, but not in sufficient quantity to permit clinical testing
- if the biological threat is so dangerous that exposing a patient in clinical testing to the agent would be unethical
For example, prior to the 2014 outbreak of Ebola virus disease (EVD) in West Africa, there were very few reported cases of Ebola. This made it all but impossible to study the disease in humans, as there was no natural human reservoir of the disease. Because the disease is so often lethal, it would also have been unethical to introduce the disease in humans to then test the safety and efficacy of a product.
The Animal Rule pathway is therefore a concession between FDA's demand for evidence and the need to ensure the wellbeing of patients. The investigational product is tested in healthy adult patients to assure regulators of its safety, while its efficacy is tested using live animals infected with the agent.
Animal Rule History to Date
To date, FDA has approved just a small handful of products based on the rule, and most of them only within the last few years. For example, FDA approved the first product under the Animal Rule, J&J's Levaquin (levofloxacin, plague), in April 2012. In December 2012, FDA approved the first biologic product under the rule, GSK's raxibacumab (inhalation anthrax). A botulism antitoxin manufactured by Cangene was approved in March 2013.
In all cases, approval was based on FDA's findings that a product was safe for use in healthy humans, indicating that the drug was unlikely to cause harm to sick patients, and data indicating that the drug was effective in animals known to have similar disease pathways as humans. For example, raxibacumab was tested in one trial of monkeys and three trials involving rabbits.
While animal studies aren't a perfect substitute for studies involving humans, regulators have said the rule represents the best chance they have to develop medical countermeasures before they're needed.
The Newest Approval
FDA has now approved another product using its Animal Rule pathway: Bayer Healthcare's Avelox (moxifloxacin).
The drug, approved 8 May 2015, is intended to treat patients with plague, a bacterial infection caused by the enterobacteria Yersinia pestis and best known for wiping out a third of the human population in the 1300s ("the Black Death").
The disease is now relatively rare—there were just 783 reported cases in the world in 2013—but it is especially deadly if left untreated, killing 30-60% of afflicted patients. Plague is also a potential "biological threat agent that could potentially be used as a bioterrorism agent," according to FDA.
Though Avelox has already been approved for use in several other diseases, FDA approved its use for plague under the Animal Rule, the agency said.
"Avelox’s approval was based on an efficacy study conducted in African green monkeys that were infected with Yersinia pestis in a laboratory setting," FDA explained. "Animals were randomly selected to receive a 10-day regimen of Avelox or placebo at least four hours after the onset of fever following exposure to Yersinia pestis. The primary endpoint was survival at the end of the study. All 10 monkeys treated with Avelox survived. None of the 10 monkeys treated with placebo survived."
The drug's safety was established based on a combination of clinical data and post-marketing information from the drug's other approved indications, FDA said. The drug's safety warnings, including a black box indicating Avelox may cause tendinitis and tendon rupture, are adopted from Avelox's other approved indications as well.
FDA Approval Notice for Avelox