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Posted 25 March 2013 | By Alexander Gaffney, RAC,
The US Food and Drug Administration (FDA) announced on 22 March 2013 the approval of Cangene Corporation's Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G, Equine), the seventh product approved under a rarely-used regulatory pathway intended to make sure medical countermeasures are in place to counteract potential bioterrorism events or outbreaks of dangerous pathogens.
Cangene's antitoxin in a sterile solution of purified antibody fragments is intended to counter the effects of exposure to botulism, a paralyzing illness caused by toxins produced by Clostridium botulinum and related species. A briefing submitted to FDA in February 2013 explained that the seven types of toxins produced by strains of botulinum are "among the most potent neurotoxins known to science."
And therein lies the promise of Cangene's product. While there are some botulism antitoxins already approved by FDA, Cangene says its product fills a distinct need. "Currently, no specific, licensed therapies are available to treat all seven known serotypes," it wrote in its submission to FDA. "Given the inability to rapidly detect and identify botulinum neurotoxin (BoNT) serotypes in emergency situations, there is a critical need for a single effective treatment against all BoNT serotypes."
FDA's Blood Products Advisory Committee (BPAC) agreed with that assessment back in February 2013, voting unanimously to support the company's biologics licensing applications (BLA) for the product, all but clearing the way for the product's approval by FDA.
On 22 March 2013, FDA granted Cangene that approval, observing that the product "meets an urgent unmet medical need for the treatment of sporadic cases of life-threatening botulism and provides a medical countermeasure should botulinum nerve toxins be used in a terrorism event."
As with similar medical countermeasure products, Cangene's antitoxin was tested under the Animal Efficacy Rule (the Animal Rule), so-named because it relies solely on animal testing to provide insight into the probably effectiveness of the product in humans.
That paradigm, unique among regulatory pathways, has its roots in clinical trials ethics. Because cases involving botulism are exceedingly rare, a trial to test the efficacy of the antitoxin would otherwise rely on patient purposefully infected with Clostridium botulinum-at best a risky proposition, and at worst a likely death sentence for several participants in the trial. In a bid to avoid those ethical issues, FDA's Animal Rule pathway sets up a compromise: It will grant approval to products intended to be used in rare situations so long as the product is proven to be efficacious in trials involving multiple types of animals, and is shown to be safe in a Phase 1 trial involving healthy human volunteers.
In Cangene's case, the product was tested in guinea pigs and macaques. In a test of all seven C. botulinum serotypes on guinea pigs, all 238 animals survived testing when using Cangene's product. Just 31 animals on the placebo treatment survived, 17 of which were exposed to serotype G.
That isn't to say the data showed flawless efficacy. Just 14 of 30 rhesus macaques survived exposure to Serotype A, though none of the placebo group of 30 animals did. Those animals that did not survive in the treatment group survived more than twice as long as their control group counterparts-a potential benefit for physicians hoping to carry out additional testing and treatment.
Human safety testing did, however, raise some red flags to regulators, which said that six test subjects died during testing, of which three were potentially related to the use of the product. Those deaths went unmentioned in FDA's final approval notice, but the one of the potential causes of death-allergic reactions resulting from serum sickness-was mentioned as being one of the most serious side effects.
Cangene will be held to several postmarketing requirements by FDA, including a three-year patient registry and a pediatric pharmacokinetic study to be completed by June 2017, as well as eight other undefined postmarketing commitments not detailed in FDA's approval letter.
In a statement, Cangene called the approval a "significant milestone for Cangene as well as the US Government," which helped to develop the product under a $427 million contract to bring the product into the US Strategic National Stockpile. The product has been included in the stockpile since 2007.
"The U.S. Department of Health and Human Services and BARDA have been excellent development partners, and we are very proud to have received FDA approval for this important countermeasure to naturally occurring botulism and a significant potential bioterrorism threat," said John Sedor, president and CEO of Cangene. "We look forward to delivering the remaining BAT doses to BARDA over the coming years and to continuing our successful relationship."