10.2 Drugs and the Federal Drug Administration

In addition, a licensed veterinary practitioner may use an FDA-approved drug for human use in an animal with an appropriate clinical indication. Using human drugs in animals is often referred to as extralabel drug use. The same term is used for utilizing a drug approved in one species to treat another. Veterinary practitioners are cautioned to use great discretion in treating food animals with extralabel drugs. Greater discretion is needed because if the drugs are not used properly, they could have negative effects on the consumer, such as contaminating drug residues due to inadequate withdrawal times, which may result in some of the following health sequelae for human consumers:

• Acute allergic and toxic reactions. For example, drug residue exposure in the population can have a range of reactions from a rash to anaphylaxis to fatal anaplastic anemia (i.e., chloramphenicol, which is prohibited in food animals in the United States).
• Antimicrobial-resistant pathogens may develop from inappropriate use of antimicrobials, which could potentially be transmitted to consumers.

In federal regulatory terms, this would be an adulteration of human food. The food item is not truthfully labeled by having contaminants that may not be known but irresponsibly remain from improper drug use.

This extralabel use is narrowly restricted to licensed veterinary practitioners. However, extralabel use is even more restricted in aquatic species, especially for food fish. The extralabel use of drugs in food fish must be an FDA-approved drug for aquatic animal use. An example is Aquaflor (florfenicol) antibiotic in medicated feed. A Veterinary Feed Directive (VFD) may be issued for another fish species or disease not covered in the current FDA approval. The Aquaflor medication used in the feed formulation must be for an aquatic species. A similar antibiotic formulation for swine (if one exists) is illegal for the veterinarian to substitute. VFDs will be discussed in more detail later in the chapter.

The veterinarian is responsible for determining the withdrawal period for VFDs used on nonapproved species or disease for the food fish before they can be slaughtered or released from hatcheries to the wild. The withdrawal period is the time from when a drug treatment is terminated to when the drug concentration falls below the tolerance residue by clearance from the body. Tolerance is the legally allowed concentration of a drug residue for individual tissues or other food products. Before the FDA approves a drug for marketing, it must have undergone a rigorous drug approval process and data must be submitted to the FDA that show the drug is safe and effective for the animal, safe for the environment, and safe for consumers when used according to the label. Once tolerance is established, a withdrawal period can be determined. All questions regarding withdrawal times and the use of drugs in food animals when used in an extralabel manner should be directed to the Food Animal Residue Awareness Databank (FARAD).^[3]

Minor Use and Minor Species (MUMS) Medications

MUMS medications are used for minor use and minor species. In 2004, Congress passed the Minor Use and Minor Species Animal Health Act (commonly called the MUMS Act) to help the FDA ensure that innovative treatments are available for clinical indications that are used too infrequently to justify seeking FDA approval. Minor use is addressed when an effective drug is seldom used, such as chemotherapeutics for certain cancers in dogs.

The MUMS Act was the origin of Conditional Drug Approval, explained below, to allow earlier access to drugs fitting the MUMS scenario. Later, the Act was amended to include “non-MUMS” drugs to receive the “Expanded Conditional Approval.”

Conditional Approval

Conditional Approval is given to a drug that the FDA has determined to have a “reasonable expectation of effectiveness” but has not gathered enough data to establish the “substantial evidence” standard for full approval. The Conditional Approval is good for one year and may be extended up to four times while the company gathers enough data to show substantial evidence of effectiveness. The advantage of bringing a drug to market before FDA approval is to allow suitable and needed medications to be available to veterinarians; similarly is true in human medicine. Conditional Approval cannot be prescribed or used in extralabel situations (discussed later).^[4]

Indexing

Indexing is the process of marketing animal drugs to nonfood animals and is best explained by the FDA, as follows: “The purpose of indexing is to allow an additional means of legally marketing new animal drugs intended for use only in minor species and that have not been approved or conditionally approved through the new animal drug approval process or the conditional approval.” ^[5] The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (“the Index”) is a list of new animal drugs intended for use in minor species that have had their safety and effectiveness affirmed through review by an expert panel (i.e., not the FDA). Minor species are all animals that are not one of the following seven major species: horses, dogs, cats, cattle, pigs, turkeys, and chickens. Thus, fish are considered a minor species. Often the target species or treatment use has a population so small that safety and effectiveness trials cannot be done cost-effectively. Indexing is an alternative to the drug approval process for non–food-producing minor species and the early life stages of food-producing minor species. This process is interrelated to the MUMS product process.

The FDA approval process is complex and includes label approval, expiration calculations, withdrawal times, and many more sections. These various areas are beyond the discussion of this introductory chapter but can be addressed in more detail in future chapters.

There are also a few categories of drugs that are not FDA-approved and marketed with FDA knowledge. These drugs include Drugs of Low Regulatory Priority. Under this category, the FDA uses regulatory discretion in enforcing federal laws on some compounds used as drugs. Low Regulatory Priority drugs are not FDA approved yet and are on the market for treating some conditions associated with aquatic animal health. This includes compounds like salt (sodium chloride) used in table salt. When salt is applied to aquatic animals in a nonfood way, the FDA regulates the chemical as a drug because it is used to prevent or treat a nonhealthy condition.

The FDA has a review process that determines the significance of the drug regarding food safety, human health, and environmental consequences. A complete guide to this area of drugs and their regulatory priority is available in the following manual: Center for Veterinary Medicine Program Policy and Procedures Manual 1240.4200.^[6]

Drug Marketing

The FDA assigns a marketing category for approved drugs. The federal government has authority over interstate commerce, which includes the shipment of products. The marketing category includes the following:

• Over the counter (OTC)
• Prescription (Rx)
• Veterinary feed directive (VFD)

Over-the-counter Drugs

If the FDA determines that “directions for use” of an approved drug can be written on the drug’s label so that a nonmedical person can use the drug safely and effectively, it can be sold as an OTC product.^[7]

Prescription Drugs

When an adequate direction is not possible on the label, the drug is marketed as either Rx or VFD. Both the Rx and VFD drugs require veterinary oversight, which is defined as having a valid VCPR. The VCPR is a working relationship of the owner with a licensed veterinary practitioner. The veterinarian should be familiar with the current husbandry and health problems through examination of the animal(s) and inspection of the facility.^[8] Please note the interchangeability in the terms “extralabel” and “off-label” use. One federal agency may refer to one term and another federal agency may use the other. They both describe the same professional prescribing use.

Besides veterinarians’ responsibility for proper Rx drugs, the veterinary practitioner may utilize certain FDA-approved drugs in an extralabel (off-label) manner. Extralabel means the prescribed drug is not FDA approved for a specific animal species or certain clinical indication being treated. Extralabel use is not legally permitted with OTC drugs. Any extralabel use of drugs must be done by or under the direction of a licensed veterinarian. Veterinary practitioners are not legally permitted to off-label FDA-approved drugs for terrestrial animals in aquatic food animals. If an off-label drug is an available option, the product prescribed for food fish must be FDA approved for aquatic species use. The off-label drug may be for another aquatic food species or a different disease not on the approved label if the veterinarian has reason to believe the product will be useful and safe. The veterinarian prescribing an off-label drug is solely responsible and liable for setting the appropriate withdrawal time.

Veterinary Feed Directive Drugs

The VFD drug category was created for the use of drugs as medicated feed. Large numbers of animals can be easily treated by medicating their feed ration. A licensed veterinarian must order VFD drugs. The FDA created this separate category of drugs because various state laws were inconsistent in prescribing medicated feed. Hence, medicated feed orders are not prescriptions. The VFD applies to all medicated feed and water-administered antibiotics for food animals. A VFD is not needed for water treatments such as formalin, H2O2, or salt.

VFDs are not permitted to be used in an extralabel manner in terrestrial and avian species. An exception has been given to aquatic animal medicated feeds due to the lack of FDA-approved drugs for a large number of aquatic species. Extralabel prescriptions and VFDs are restricted to drugs approved for other aquatic animals. Terrestrial and avian drugs are not permitted to be used in aquatic food animals. The FDA requires a stated withdrawal time for livestock slaughtered for food production. The withdrawal period enables the animal to metabolically break down the drug to levels not of public health concern. The veterinarian is strictly responsible for determining the withdrawal time when drugs are prescribed in an extralabel manner.^[9]