Drugs for animals face a more complex approval process than those for humans.

It may be long, tortuous, and expensive, but the approval process for new human drugs is pretty straightforward—only one target species to consider (humans) and only one agency to deal with (the FDA). The road to market in the world of veterinary medicine is more complicated: Depending on the compound’s intended purpose, any one of three federal agencies grants final approval—the FDA, the U.S. Department of Agriculture (USDA), or the Environmental Protection Agency (EPA). Animals are further divided into subcategories with their own sets of unique agency requirements. For example, animals that produce milk, eggs, and meat have the potential of carrying residues into the human body. Residues from pharmaceutical products used to treat companion animals like dogs and cats, however, are seldom a concern, as these animals are not likely to wind up on the dinner table. Thus, making sure that human consumers are protected from various drug contaminants in animal products is an important part of the registration process.

Under the current system, the FDA has jurisdiction over drugs, the USDA over “veterinary biologicals” and vaccines, and the EPA over externally applied pesticides such as flea powder. As in human pharmacology, the process from discovery to market approval is risky. Arthur Craigmill, toxicology specialist with the University of California at Davis, points out that only 1 in 200 newly discovered animal drugs actually makes it to the practitioner’s black bag. The rest fall victim to poor efficacy, excessive cost, or unwanted side effects, he says. But these failed drugs usually drop off the radar during basic research—long before promising candidates are identified and the regulatory agencies are contacted. Steven D. Vaughn, director of the Division of Therapeutic Drugs for Food Animals in the FDA Center for Veterinary Medicine (CVM), says that most veterinary drugs that make it to the approval process ultimately pass muster with the Feds. “Far in excess of 50% of these drugs make it,” he said. “Most of the manufacturers are large companies that do their homework in advance.”

Approvals under the FDA
Drug approvals at the FDA are handled by the CVM. In accordance with Title 21 of the Code of Federal Regulations, Parts 500–599, applicants approach the CVM through its Office of New Animal Drug Evaluation (ONADE) and request an Investigational New Animal Drug Application (INADA) that describes the drug and the protocol under which it will be tested. A green light from the ONADE allows applicants to begin gathering data designed to show that their drug fulfills five criteria: efficacy, safety to the animals being treated, safety to humans who eat the animal, safety to the environment, and good manufacturing practices during production.

Unlike human pharmacology, safety (i.e., toxicity) studies of veterinary drugs can be performed directly in the target population. This provides an advantage over human drug studies that infer these parameters through experimental testing in animals. “You can’t do a safety study in people,” explains Randy Lynn, director of regulatory affairs at Blue Ridge Pharmaceuticals in Greensboro, NC. “But in veterinary medicine, you can study these effects in the animal population for which the drug is intended and obtain some precise values.”

According to Lynn, safety studies usually involve administering the drug at 1–5 times the recommended dose (generally identified in preliminary studies in rodents) for at least 3 times the duration recommended for clinical treatment. The animals are monitored for toxic responses during the exposure period and are then sacrificed and examined for tissue or cellular effects.

Once toxic limits have been identified, populations for clinical field trials are assembled—usually by consulting with practicing veterinarians in at least three different geographical regions. Exploring geographic variability is important, says Vaughn, because climate and environmental factors can influence both the nature of the clinical condition and the response to the drug.

Hold the residues, please
Compared with drugs for companion animals, the drug approval process for food animals is more extensive because of the potential for human exposure. These studies can cost millions of dollars, and according to Craigmill, are easily the most expensive part of development for any new animal drug. In addition to in vitro mutagenicity assays such as the Ames test, new drugs are evaluated for toxic, teratogenic, and reproductive effects in laboratory species that may include rats, mice, and dogs. These human food safety studies are used to identify a no-observed-effect level (NOEL), which is the highest dose that produces no ill effect in the exposed animals. A human health protective level is calculated by dividing the NOEL by a safety factor that may be either 100 or 1000, depending on circumstances.

To identify metabolites in edible tissues, researchers use radioactive tracers to track the drug’s distribution as it is broken down and eliminated from laboratory species used in preliminary toxicity studies as well as the animals for which the drug is intended. These dual studies are performed to ensure that the types of metabolites produced are comparable in both species. Explains Jane Owens Clark, senior research investigator at Pfizer, Inc., in Groton, CT, “You want to make sure that you’ve tested the metabolites for toxicity. If a cow produces high levels of a metabolite that the rat doesn’t produce, then the toxicity of that metabolite may not have been sufficiently evaluated.”

Additional studies are also used to determine appropriate “withdrawal periods” for drugs used in food animals. According to Clark, researchers monitor residue levels in edible tissues over time by sacrificing the animals at varying intervals after exposure. These residue data are then compared with the NOEL to determine the time necessary to reach a human health protective level in tissue after the last dose of the drug is given. Finally, once all the appropriate data have been gathered, applicants submit the INADA to the FDA, which must review the material and render an approval decision within 180 days.

Extra-label uses
In addition to drugs passed through the standard approval process, veterinarians can give their patients human drugs for comparable conditions by using “extra-label” prescriptions. Although veterinarians have been prescribing human drugs for years (Lynn suggests that it would be impossible to practice veterinary medicine without them), regulatory approval of the process is fairly recent—it is codified in the Animal Medicinal Drug Clarification Act of 1994. This act provided guidelines for prescribing human drugs to animals and also established a set of formal restrictions: namely that extra-label use is legitimate only in the context of the veterinarian–client–patient relationship and that dose levels must not violate human health protective residue concentrations in food animals. “The agencies have specific regulations designating the drugs you can use and those that you can’t,” says Lynn. “There are quite a few human drugs that are banned for use in food-producing animals.”

Lynn adds that for the most part, veterinarians do not blindly prescribe human drugs without any knowledge of how their patients are likely to respond. Most extra-label prescriptions are made using drugs that have been tested in animals by researchers in universities and other similar settings. These studies provide dosing schedules for target species that wind up in the published literature for reference by practicing veterinarians.

Agency redundancy
One curious issue in the veterinary pharmaceutical arena concerns the potential for overlap among the three federal agencies. In addition to the FDA’s work with animal drugs, animal vaccines are monitored by the Center for Veterinary Biologics (CVB) in the USDA’s Plant and Animal Health Inspection Service while the EPA’s Office of Pesticide Programs handles external veterinary pesticides. In most cases, says Craigmill, there is little question as to which agency has jurisdiction over a given product. But in some instances, the lines of jurisdiction are blurred. One example is formaldehyde—used to treat parasites in fish—which had to gain drug approval from the FDA and veterinary disinfectant approval from the EPA. Albert Morgan, the chief of the operational support staff at the CVB, says that jurisdictional issues tend to arise when a manufacturer applies for approval of a product with a dual claim—anti-parasiticals that are both pesticides and drugs, for example. But he adds that these situations are the exception and that most are easily resolved in meetings with federal regulators.

Questions of jurisdictional responsibility have led some stakeholders to argue for consolidating these activities in a single agency—a solution that makes some federal regulators uneasy. “There is talk about integrating these responsibilities,” says Linda Grassie, a communications specialist with the FDA. “But the FDA doesn’t support these proposals. The laws we apply are very stringent and we don’t want to lose control over the process.”

Ultimately, the approval process does not guarantee that an adverse effect will not be noted at some point in the future. Clinical trials are designed to be statistically robust, but they are not a substitute for widespread use involving millions of animals. Adverse reactions are recorded with the CVM’s Office of Surveillance and Compliance. If a significant number of reactions are reported, the agency notifies manufacturers, who may have to issue warnings to practitioners and conduct additional safety studies. The final test of a product is time. Meanwhile, the veterinary approval process imposes safeguards to reassure the public that marketed products are exhaustively tested.