51 Lisa A. Tell, Margaret Oeller, Tara Marmulak, and Ronette Gehring Antibiotics, antiparasitics, nonsteroidal antiinflammatory drugs, and exogenous hormones are among the essential components in the armamentarium of a food animal veterinarian to combat disease, alleviate animal pain, and minimize economic losses. In the United States, many of these veterinary products are US Food and Drug Administration (FDA) approved for use in a large number of major food-producing animals but not for the minor food-producing animals. According to the FDA, the major food-producing animals are cattle (meat and milk), swine, chickens (meat and eggs), and turkeys. The minor food-producing animals are those that do not fall into the major food-producing animal category with the most popular being goats (both dairy and meat), sheep, deer, commercially raised game birds, and food fish and shellfish. This category also includes less obvious food-producing species such as rabbits, ratites, and honey bees. In the USA, horses are a major animal species; however, they are considered companion animals and are not customarily used for human food as in some other countries. In Europe, the European Medicines Agency has defined the major food-producing animals to be cattle (meat and milk), sheep (meat); pigs; chickens (meat and eggs), and salmonids. Minor food-producing animals include minor ruminants (meat and milk), deer (including reindeer), other avian species (meat and eggs), other fish species, and other mammalian species (horse and rabbit). In other countries, the minor food-producing animal category has the potential to be considerably larger because a greater variety of species are consumed such as small rodents, canids, invertebrates, and various avian species. In recent years, there has been an increased interest in consuming more meat and other products from minor food-producing animals, especially aquaculture species. As this interest grows, so will the expectations to provide safe food items for human consumption. Maintaining the overall health of minor food-producing animals is similar to managing the health of major food-producing animals, and typically requires some use of veterinary pharmaceuticals. However, in contrast to the major food-producing animals, few drugs have FDA approval for use in minor food-producing animals. One of the major challenges for getting veterinary products approved for use in minor food-producing animals is the reduced economic return due to small market size. Additionally, some of the minor food-producing animals are less tractable (e.g., cervids and bison), and there is wide variation in breeds/species with respect to size and pharmacokinetics. In general, there is a large number of species and incredible diversity within this category. For aquatic species, such as finfish, mollusks, and crustaceans, not only are there species differences, but environmental considerations (salinity, pH, temperature), physiological differences (heterothermy), and management practices that also impact metabolism and excretion of drugs. This chapter addresses the unique issues associated with the regulatory requirements for getting a drug approved for use in a minor food-producing animal, the availability of veterinary pharmaceuticals for use in minor food-producing animals, and highlights legislation that has helped address the veterinarian’s need for medications to treat these animals. In addition, government programs and scientific approaches used to meet the therapeutic needs for treating minor food-producing animals are discussed. There are many veterinary pharmaceuticals marketed today that may be administered to minor food-producing animals. The ideal scenario for a veterinarian wanting to treat a minor food-producing animal is having an FDA-approved drug labeled for the intended use in question. One example would be an anthelmintic approved for treating specific gastrointestinal parasites in sheep. This product will have been demonstrated to FDA’s satisfaction to be safe for sheep, safe for the person administering the drug to the sheep, safe for anyone who later consumes meat from the treated sheep, and safe for the environment, both during the drug’s use and its disposal. It will also have been shown to be effective for the labeled use and that it is consistently manufactured to standards of strength and purity. Such a product is labeled with intended uses, doses, and withdrawal times that are appropriate for use in sheep. In contrast to the major food-producing animals, there are not many FDA-approved drugs labeled for use in minor food-producing animals. This is mainly because the development of new drugs for use in animals is a very expensive and time-consuming process, especially for drugs to be used in animals intended for human consumption, and the minor food-producing animal markets are too small to readily recover the pharmaceutical sponsor’s investment. FDA-approved drugs for minor food-producing animals (as of July 2017) are summarized in Tables 51.1–51.5. There is also a searchable database of approved new animal drugs available on the FDA website. Please note that even if approved, a particular product may not be commercially available. This can be for a variety of reasons including closing of manufacturing facilities, or the discontinuation of less lucrative product lines when two companies merge. Table 51.1 Veterinary pharmaceuticals approved by the Food and Drug Administration as of July 2017 for use in small ruminants that are considered minor food-producing animals in the United States of America Goats Sheep Vibrionic abortion Claim withdrawn Goats Sheep Zoo/wild goats Bighorn sheep Drench Bolus Powder Powder Liquid Goats Sheep Rumen atony Curare antagonist Premix (for feed) Powder Respiratory infection Colibacillosis Claim withdrawn Uterine contractions Milk letdown Drench Premix (for feed) Pellet Liquid Goats Sheep aListed indications are broad. For specific indications, the drug label or Code of Federal Regulations should be consulted. Table 51.2 Veterinary pharmaceuticals approved by the Food and Drug Administration as of July, 2017 for use in cervids/other ruminants that are considered minor food-producing animals in the United States of America Bison (American) Reindeer Hypodermosis Warbles Diprenorphine hydrochloride Etorphine hydrochloride Deer Elk Deer Elk aListed indications are broad. For specific indications, the drug label or Code of Federal Regulations should be consulted. Table 51.3 Veterinary pharmaceuticals approved by the Food and Drug Administration as of July, 2017 for use in avian species that are considered minor food-producing animals in the United States of America Pheasants Quail Pheasants Quail Premix (for feed) Powder Ducks Partridge (Chukar) Bacterial infection Coccidiosis aListed indications are broad. For specific indications, the drug label or Code of Federal Regulations should be consulted. Table 51.4 Veterinary pharmaceuticals approved by the Food and Drug Administration as of May, 2014 for use in aquaculture species in the United States of America Coldwater disease Furunculosis Streptococcal septicemia Columnaris disease Finfish eggs Shrimp (Penaeid) Antiprotozoal Antifungal Bacterial hemorrhagic septicemia and Pseudomonas disease Catfish Salmonids Enteric septicemia of catfish Furunculosis aListed indications are broad. For specific indications, the drug label or Code of Federal Regulations should be consulted. Table 51.5 Veterinary pharmaceuticals approved by the Food and Drug Administration as of May, 2014 for use in miscellaneous minor food-producing animals Premix (for feed) Water soluble powder aListed indications are broad. For specific indications, the drug label or Code of Federal Regulations should be consulted. For a drug to be approved for use in a minor food-producing animal, the sponsor must demonstrate to the satisfaction of the scientific reviewers at FDA’s Center for Veterinary Medicine (CVM) that it is safe and effective for its intended use. CVM is the component of FDA responsible for the regulation of veterinary drugs, including the evaluation of such drugs prior to approval. The information that a sponsor needs to present to support a New Animal Drug Application (NADA) includes the following as outlined in regulations published in the Code of Federal Regulations (21 CFR 514): These components are discussed in detail in Chapter 55 of this book. The FDA also provides a variety of guidance documents to assist sponsors in understanding the various requirements. Of particular note for sponsors seeking drug approval for a minor species use is Guidance #61 FDA Approval of New Animal Drugs for Minor Uses and for Minor Species. This document is being revised at the time of writing this chapter and will be published under the new title, Special Considerations, Incentives, and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species. Guidance documents are available on the FDA website. Compared to the drug approval process for major food-producing animals, the drug approval process is not significantly easier for products intended for use in a minor food-producing species. The same high standards must be met. However, there are a few advantages afforded to products intended for use in a minor food-producing animal. These include the possibility of a waiver from user fees, the ability to apply conclusions reached from the radiolabeled residue study in the major food-producing animal to the human food safety evaluation for the minor food-producing animal, the possibility of a categorical exclusion from the need to provide an environmental assessment, and the possibility that fewer sites will be needed for effectiveness clinical trials. The US Congress recognized the drug availability problem for both major and minor animal species when it passed the Animal Medicinal Drug Use Clarification Act (AMDUCA) in 1994 (Public Law No. 103–396; Monti, 2000). This law addressed the fact that FDA generally approves veterinary drugs for narrow intended uses. For example, a broad-spectrum antibiotic that would be safe and effective for the treatment of a wide variety of bacterial infections may only be approved for use in cattle for the treatment of respiratory disease caused by specific bacteria. From a practical standpoint, the pharmaceutical sponsor cannot demonstrate safety and effectiveness for every possible intended use of the product. This means that veterinarians frequently administer the drug for indications that are not on the label. In other words, they use the drug for different diseases, at different doses, by different routes of administration, and in different animal species than what is indicated on the label. AMDUCA legalized this practice for veterinarians within a set of limitations described in the Code of Federal Regulations (21 CFR 530). In general, veterinarians, within the context of a valid veterinarian–client–patient relationship, may use approved dosage form products (but not medicated feeds) outside their labeling. This is allowed only when there is no approved drug for the intended use; other approved drugs are not effective for such use, when the dose is not effective for that use, or in cases where an approved formulation is not appropriate. When using a drug outside of its labeling for a food-producing animal, the veterinarian is responsible for using the drug in a manner that will not result in a violative residue in any food product derived from that animal. The veterinarian must establish a withdrawal period based on some scientific information, although there are few resources for establishing such times. The withdrawal period may be based on data in published literature, extrapolated from the pharmacokinetic profile of the drug, or determined through consultation with organizations such as the Food Animal Residue Avoidance and Depletion Program (FARAD). There are also certain drugs not eligible for extralabel use in food-producing animals. These are listed in the CFR at 530.41. This list includes a fairly new ban on the extralabel use of most cephalosporins. This ban applies only to the major species – cows, pigs, chickens, and turkeys.
Considerations for Treating Minor Food-Producing Animals with Veterinary Pharmaceuticals
The Use of Veterinary Pharmaceuticals in Minor Food-Producing Animals: Special Considerations and Challenges
The Approval Process for Veterinary Pharmaceuticals for Use in Minor Food-Producing Animals
Drug
Formulation
Species
Indicationa
Albendazole
Liquid suspension
Sheep
Internal parasites
Goats
Liver flukes
Ceftiofur sodium
Injection
Respiratory infection
Chlortetracycline
Premix (for feed)
Sheep
Decoquinate
Premix (for feed)
Coccidiosis
Fenbendazole
Liquid suspension
Goats
Internal parasites
Fenbendazole
Premix (for feed)
Internal parasites
Flurogestone acetate
Vaginal sponge
Sheep
Estrus synchronization
Follicle stimulating hormone
Injectable—IV, IM, SQ
Sheep
FSH deficiency
Ivermectin
Drench/liquid
Sheep
Internal parasites
Lasalocid
Premix (for feed)
Sheep
Coccidiosis
Levamisole hydrochloride
Sheep
Internal parasites
Monensin sodium
Premix (for feed)
Goats
Coccidiosis
Morantel tartrate
Premix (for feed)
Goats
Internal parasites
Methoxyflurane
Inhalation
Sheep
Anesthetic
Moxidectin
Drench
Sheep
Internal parasites
Neomycin sulfate
Colibacillosis
Neomycin sulfate
Premix (for feed)
Sheep
Colibacillosis
Neostigmine methylsulfate
Injectable—SQ
Sheep
Oxytetracycline
Sheep
Oxytetracycline hydrochloride—Polymyxin B Sulfate
Ointment
Sheep
Superficial ocular infections
Oxytocin
Injection—IM, IV, SQ
Sheep
Penicillin G procaine
Injectable—IM
Sheep
Respiratory infection
Pituitary luteinizing hormone
Injectable—IV, SQ
Sheep
Pituitary hypofunction
Progesterone
Intravaginal device (CIDR)
Sheep
Out-of-season breeding
Proparacaine hydrochloride
Liquid
Sheep
Ophthalmic anesthetic
Sodium chloride gelatin
Oral liquid
Sheep
Shock/hypovolemia
Sodium selenite/ Vitamin E
Injectable—IM, SQ
Sheep
Selenium deficiency
Tetracycline
Injectable—IM
Sheep
Bacterial infection
Thiabendazole
Internal parasites
Thialbarbitone sodium
Powder—injectable IV
Sheep
General anesthetic
Tilmicosin phosphate
Injection
Sheep
Respiratory infection
Zeranol
Implant—SQ
Sheep
Weight gain/feed efficiency
Drug
Formulation
Species
Indicationa
Ivermectin
Injection
Injectable – IM, IV
Wildlife
Immobilization
Xylazine hydrochloride
Injectable—IM, IV
Sedation
Yohimbine hydrochloride
Injectable—IV
Xylazine antagonist
Drug
Formulation
Species
Indicationa
Amprolium
Premix (for feed)
Pheasants
Coccidiosis
Bacitracin methylene disalicylate
Premix (for feed)
Weight gain/feed efficiency
Bacitracin methylene disalicylate
Water-soluble powder
Quail
Ulcerative enteritis
Bacitracin zinc
Premix (for feed)
Weight gain/feed efficiency
Bacitracin zinc
Water-soluble powder
Quail
Ulcerative enteritis
Carnidazole
Tablets
Pigeons
Trichomoniasis
Chlortetracycline
Premix (for feed)
Ducks
Fowl cholera
Iodinated casein
Premix (for feed)
Ducks
Weight gain/feathering
Lasalocid
Premix (for feed)
Partridge (Chukar)
Coccidiosis
Monensin sodium
Premix (for feed)
Quail (Bobwhite)
Coccidiosis
Novobiocin
Premix (for feed)
Ducks
Bacterial infection
Salinomycin sodium
Quail
Coccidiosis
Sulfadimethoxine ormetoprim
Premix (for feed)
Thiabendazole
Premix (for feed)
Pheasants
Gapeworm
Drug
Formulation
Species
Indicationa
Florfenicol
Premix (for feed)
Catfish
Enteric septicemia of catfish
Florfenicol (now fully approved)
Premix (for feed)
Catfish
Columnaris disease
Florfenicol
Premix (for feed)
Freshwater-rearedSalmonids
Florfenicol
Premix (for feed)
Freshwater-reared finfish
Formalin
Water treatment
Human chorionic gonadotropin
Injection
Finfish (male and female broodstock)
Spawning aid
35% Hydrogen peroxide
Water treatment
Freshwater-rearedSalmonids
Bacterial gill disease
35% Hydrogen peroxide
Water treatment
Freshwater-reared finfish eggs
Saprolegniasis
35% Hydrogen peroxide
Water treatment
Freshwater-reared cool water finfish and channel catfish
External columnaris disease
Oxytetracycline dihydrate
Premix (for feed)
Lobsters
Gaffkemia
Oxytetracycline dihydrate
Premix (for feed)
Salmonids
Ulcer diseases
Oxytetracycline dihydrate
Premix (for feed)
Salmonids and catfish
Oxytetracycline hydrochloride
Water treatment
Finfish
Skeletal marking
Sulfadimethoxine ormetoprim
Premix (for feed)
Sulfamerazine
Premix (for feed)
Trout
Furunculosis
Tricaine methanesulfonate
Water treatment
Fish
Temporary immobilization
Drug
Formulation
Species
Indicationa
Lasalocid
Premix (for feed)
Rabbits
Coccidiosis
Lincomycin hydrochloride
Water soluble powder
Honey bees
American foulbrood
Oxytetracycline
Honey bees
American and European foulbrood
Sulfaquinoxaline
Premix (for feed)
Rabbits
Coccidiosis
Tricaine methanesulfonate
Water Treatment
Amphibians
Temporary immobilization
Tylosin tartrate
Water soluble powder
Honey bees
American foulbrood
Legislation and Policies Supporting the Availability of Veterinary Pharmaceuticals in Minor Food-Producing Animals
Animal Medicinal Drug Use Clarification Act
Compliance Policy Guide 615.115