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Sick Call of the Wild:
Increasing the Availability of Drugs for Exotic Animals

"Come on sweetie. Wake up."

Mitchell Bush, D.V.M., is urging his sedated patient awake following exploratory surgery for an abdominal mass. His patient, a 35-pound female maned wolf from South America, has ovarian cancer.

She slowly comes to as her keeper carries her back to her cage. It looks as if she will survive the surgery.

Bush and his staff are pleased. Even though surgery on rare and exotic animals is fairly routine at the National Zoological Park's Conservation and Research Center in Front Royal, Va., it's always risky, considering virtually no anesthetics, antibiotics or other drugs are approved for these animals. Instead, veterinarians like Bush rely on personal experience, published data, and word-of-mouth from other veterinarians to use animal and human drugs already on the U.S. market or approved for use in foreign countries.

"We're dealing with a lot of unknowns," says Bush, who is the center's chief veterinarian. "There's hardly any drug on my shelf that's approved for these animals."

Congress wants to change that. This year, as mandated under the Animal Drug Availability Act of 1996, the Food and Drug Administration plans to propose measures that will encourage drug companies to seek approval of drugs for minor species and minor uses in major species. The purpose is to alleviate the scarcity of safe and effective drugs for these animals.

A minor species is defined as any animal other than dogs, cats, cattle, horses, pigs, chickens, and turkeys. Minor use of a drug includes drugs used to treat minor species and used to treat rare diseases in major species or diseases in major species confined to certain geographic areas. Examples of two drugs FDA approved recently that fall into the "minor use" category are Antizol-Vet (fomepizole) as an antidote to antifreeze intoxication in dogs--usually limited to dogs in the Northern states--and Imizol (imidocarb dipropionate), an antiparasitic for babesiosis in dogs.

FDA's anticipated proposals, if adopted, could benefit a wide range of animals, including zoo animals; common U.S. wildlife, such as deer, fox, squirrels, and raccoons; minor species farmed for food, such as game birds and goats; and many pets, such as birds, fish, ferrets, guinea pigs, and hamsters.

FDA believes that increasing the availability of drugs for these kinds of animals will not only benefit them but humans, as well. "Organisms capable of causing disease in minor species are not confined to such species," a work group in FDA's Center for Veterinary Medicine wrote in a preliminary set of proposals. "It is clearly in the public interest to treat such diseases in minor species before they are transmitted to people or other animals."

To increase the number of approved drugs for minor species, FDA plans to propose measures that would encourage new drug development, more clinical trials both of new drugs and of drugs already approved for major species and humans in minor species, and the submission of new animal drug applications (NADAs) for agency review.

Linda Wilmot, D.V.M., veterinary medical officer and team leader in FDA's Center for Veterinary Medicine, says some of the measures expected to be proposed would follow closely those allowed under FDA's Orphan Products Development Program. The program encourages drug companies to seek approval of drugs for rare human diseases and conditions by offering companies help with study design and by giving financial incentives, such as tax relief, grants, and extended exclusivity periods. In the past, drug companies were reluctant to develop drugs for "orphan diseases" because the small patient populations made investment in research unprofitable. The same holds true for rare animals and rare animal diseases in the current veterinary market, Wilmot says.

Other potential measures, based partly on public comments FDA received in response to a June 1997 Federal Register request and ideas floated by FDA's work group, could be more far-reaching and innovative, she says.

These proposals might, for example:

• encourage drug companies to seek drug approvals by offering them financial incentives--for example, tax credits and longer periods of protection from generic competition
• create a fair marketplace by reducing sale and use of unapproved animal drugs. According to the FDA work group, companies that might consider seeking agency approval for drugs for minor use are now reluctant to invest in the process because they cannot always be assured of protection from competition with unapproved drugs. The work group said FDA's enforcement work needs more resources.

Successfully increasing the number of approved drugs for minor species or minor use will likely depend on the adoption of more than one proposal, Wilmot says.

Minor Players

"Minor" may be a misnomer because these animals are prevalent throughout the United States. More than a million of them alone live in zoos and sanctuaries throughout the country. They represent just about every species, too, says Jane Ballentine, public affairs director for the American Zoo and Aquarium Association. "The scope is international," she says. "You name it, somebody has probably got it."

All wildlife, though abundant in rural and some urban areas, falls in the minor category, as do farm-raised fish (aquaculture). And many U.S. households--about 13 million in 1996, according to the American Veterinary Medical Association--have pets that fall into the minor species category. These pets number about 80 million, according to the AVMA.

Still, the drug market for minor species is limited because, while there is a wide variety of species, the number of animals within each is small and the number for which veterinary services are sought is even smaller. As a result, many veterinary drug companies don't seek drug approval because they fear they won't recoup the cost of developing and testing the drug once it's on the market. "It's just not worth it for the drug company," FDA's Wilmot says.

For instance, between October 1996 and September 1997, FDA approved nearly 80 drugs for the seven major species and only one for a minor species.

Off-Label Use

The 1994 Animal Medicinal Drug Use Clarification Act helped ease the drug scarcity by giving veterinarians the legal right to use approved human and animal drugs in "extra-label," or "off-label," uses. This means that under certain circumstances veterinarians can use approved drugs in other species, for other diseases and conditions, or at different dosage levels from those listed in drug labeling.

For example, Bush has used a penicillin product approved for horses, dogs and cattle to treat a zebra with an infected hoof. Nick Kapustin, D.V.M., senior veterinarian at the Indianapolis Zoo, says human insulin is used to treat diabetes in apes, and he frequently uses an antibiotic approved only for horses "across the board on a variety of species," including kangaroos, wallabies, birds, and many amphibians.

Avery Bennett, D.V.M., an assistant professor of wildlife and zoological medicine at the University of Florida and a veterinary surgeon, says he uses a children's cough syrup and a children's antibiotic in liquid form to treat infections in birds.

And at the National Zoo in Washington, D.C., veterinarians give the giant panda Hsing Hsing an anti-inflammatory medicine, Rimadyl (carprofen), approved for use in dogs, for Hsing Hsing's arthritis.

"If we could no longer use drugs off label, I'd quit the business," Bennett says.

While the 1994 act has extended veterinarians' drug choices, many, including FDA, believe it isn't the solution to the drug scarcity. Problems that still exist, according to FDA, are:

• inability to get drugs to minor species that don't have access to veterinary care. Under the law, only veterinarians can administer off-label drugs to minor species.
• inability of veterinarians to prescribe medicated feed "off label." Off-label use of drugs to medicate feed is prohibited under the act. But for many minor species, such as birds and fish, feed offers the most effective route for administering drugs.
• reluctance of some veterinarians to prescribe drugs for off-label use because of liability concerns
• risk of unsafe and ineffective drugs in animals for which the drugs or their uses have not been approved
• risk posed by drug reformulations created as part of off-label use
• increased risk of drug resistance in animals because of repeated use of one drug.

Also, specialty and exotic pets are becoming more popular. Between 1991 and 1996, an AVMA survey found that the number of households with pets of a minor species--especially ferrets, reptiles and fish--grew 65 percent.

Other reasons FDA and veterinary experts would like to see more applications for minor species' drugs are:

• to meet the expected increase in consumption of fish and seafood from aquaculture (the production of fish and shellfish for food in a closely managed habitat). In the United States, there are only a handful of approved drugs on the market for food fish. According to the AVMA's Aquaculture and Seafood Advisory Committee, the lack of drugs for aquatic species is one reason the United States lags behind the rest of the world in aquaculture production.
• to provide contraception to solve overpopulation problems, such as for deer in urban areas. Currently, there are no contraceptive medicines approved for any animal, although there are some that delay the mating period.
• to protect endangered species from extinction. Bill Lance, D.V.M., Ph.D., founder and president of Wildlife Pharmaceuticals in Fort Collins, Colo., says: "If you lost an animal 30 years ago, it was not a problem. Today, it's a problem. These animals are very valuable. [Veterinarians] can't afford to use [just] any drug on them."

Though some of the expected proposals may take years to implement, Wilmot and other veterinary experts believe they are necessary for ensuring public health. With more drug options, they say, veterinarians will find it easier to reduce pain and suffering by treating diseases in animals of minor species. And the approved labeling will provide more complete information on proper dosing and possible side effects.

"It will give veterinarians a handle on what the drug can do and how it works," Wilmot says.

Veterinarians like Bush at the Conservation Center believe that humans have a role in animal health. "Just as we feed them and clean them, we're obligated to provide their medical care," he says.

"Effective treatments are not just for zoo animals," he adds. "We also need them for animals in the free-living situation, where our intervention can help ward off diseases. We're responsible for these animals' health care, [as well]."

Paula Kurtzweil is a member of FDA's public affairs staff.

Rabbits and Ferrets and Fish, Oh My!

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For more information about medical treatment for animals, visit FDA's Center for Veterinary Medicine on this Website.

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