A Brief Overview of FDA's Drug Approval Process
Classifying Rx and OTC Drugs
Dispensing Veterinary Prescription Drugs
Compounding Animal Drugs
Extra-Label Use of FDA Approved Drugs In Animals
Information about Extra-Label Use of Specific Drug Products
How to Report Animal Drug Side Effects and Product Problems
A Brief Overview of FDA's Drug Approval Process
Under the Act, the term "drug" means articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary; articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and articles other than food intended to affect the structure or any function of the body of man or other animals. It also includes articles intended for use as a component of a drug.
Once a product is determined to be a drug for animal use, the next step is to determine whether or not it is a new animal drug. The Act defines a new animal drug (in part) as any drug intended for use for animals other than man, the composition of which is not generally recognized, among experts qualified by scientific training and experience, as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling. By virtue of Supreme Court interpretations of the necessary basis for general recognition, there are, for all practical purposes, no animal drugs which are not also new animal drugs. The Animal Drugs @ FDA, accessible from the CVM Home Page contains a searchable database of all FDA-approved animal drugs.
An unapproved new animal drug may be distributed in accordance with 21 CFR Part 511 if the drug will be used for research, i.e., for the collection of data intended to be submitted in support of an NADA approval. Investigational New Animal Drug (INAD) regulations provide that such drugs may be distributed for use only by experts, qualified by scientific training and expertise, to investigate the safety and effectiveness of animal drugs.
Before a new animal drug may receive FDA approval, the sponsor must establish that the new animal drug is safe and effective.
Safe includes safety to the animal, safety of food products derived from the animal, safety to persons administering the drug or otherwise associated with the animal, and safety in terms of the drug's impact on the environment.
Effective means that the product will consistently and uniformly do what the labeling claims it will do.
Drug sponsors submit a New Animal Drug Application (NADA) along with supporting data, including all adverse effects associated with the drug's use. The NADA must also include information on the drug's chemistry; composition and component ingredients; manufacturing methods, facilities, and controls; proposed labeling; analytical methods for residue detection and analysis if applicable; an environmental assessment; and other information. The sponsor of a new animal drug is responsible for submitting all appropriate data to establish effectiveness and safety. If the drug product is intended for use in a food-producing animal, residues in food products must also be established as safe for human consumption.
FDA review of the NADA submitted by drug sponsors is very detailed and comprehensive. FDA scientists will determine whether the data have been developed in accordance with either Good Laboratory Practice Regulations or clinical trial guidance. If the studies were conducted properly, the data are evaluated with respect to drug safety and effectiveness. The animal safety data for a drug product must relate to the dosage levels and routes of administration proposed in the labeling. The primary objective is to determine the safety of the product relative to labeled usage.
At the conclusion of the animal safety review, a summary is prepared which explains why the product is safe or not shown to be safe. If the product has been shown to be safe but some restrictions or constraints on use are needed, all warning and precaution statements to be placed on the label must be enumerated and included in the summary, as well as any expected side effects.
All effectiveness data submitted must relate either directly or indirectly to the specific label and labeling claims made for the product. The sponsor must demonstrate that the product produces the claimed effect.
With respect to human food safety, it is the responsibility of the producer or sponsor of the animal drug to furnish FDA with the scientific information and experimental data that demonstrate that the presence of residues of the animal drug in the edible food products of the animal are safe for the consumer of the food product. The term "residues" applies to the parent drug and/or its metabolites. Detailed guidance on the studies required for animal drug approval is available from the Center for Veterinary Medicine (CVM). To assure that human food of animal origin can be monitored for the presence of drug residues, FDA requires sponsors of drugs for food animal use to provide acceptable analytical methods capable of determining and confirming the animal drug or its metabolites in the animal tissue.
Classifying RX and OTC Animal Drugs
FDA is responsible for determining the marketing status (prescription, over-the-counter, or VFD) of animal drug products based on whether or not it is possible to prepare "adequate directions for use" under which a layperson can use the drugs safely and effectively. Prescription (Rx) products can be dispensed only by or upon the lawful written order of a licensed veterinarian. Safe use includes safety to the animal, safety of food products derived from the animal, safety to the persons associated with the animal, and safety in terms of the drug's impact on the environment.
Effective use of a drug product assumes that an accurate diagnosis can be made with a reasonable degree of certainty, that the drug can be properly administered, and that the course of the disease can be followed so that the success or lack of success of the product can be observed.
The same drug substances can be marketed in a number of different dosage forms, intended for use by different routes of administration, and in different species of animals. Thus, these drug products may be appropriately labeled Rx in some cases and OTC in others. Rx products must bear the legend:
"Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian."
Dispensing Veterinary Prescription Drugs
Since adequate directions for safe and effective lay use cannot be written for animal prescription drug products, such products can only be sold on the prescription or other order of a licensed veterinarian (Section 503(f)). Prior to being sold or dispensed, they must remain in the possession of a person or firm regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of animal prescription drug products. The drug products may be distributed only by persons or firms authorized by State and local laws.
Sale (dispensing, shipping, or otherwise making available for use in animals) of an animal prescription drug product to the layperson may be made only by or on the bona fide prescription or other order of a licensed veterinarian. Sale of a animal prescription drug product to a layperson, except on a prescription or on order of a licensed practitioner, causes the product to be misbranded and subjects the seller to civil and/or criminal provisions of the Act.
A licensed veterinarian may legally use or dispense an animal prescription drug product only within the course of his/her professional practice where a valid veterinarian-client-patient relationship exists. Veterinarians employed by drug manufacturers or distributors may not legally dispense prescription drug products to laypersons unless they meet the above criteria. Similarly, practicing veterinarians or their employees may not legally sell animal prescription drug products to walk-in customers unless the same criteria are met. Federal regulations require that drug manufacturers provide at least the following information on the label of the finished package form of animal prescription drug products:
What information needs to be on the package label of animal Rx drugs?
- the statement, "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian;"
- recommended or usual dosage;
- route of administration, if it is not for oral use;
- quantity or proportion of each active ingredient as well as the information required by section 502(e) of the Act;
- names of inactive ingredients if it is for other than oral use;
- an identifying lot or control number from which it is possible to determine the complete manufacturing history of the drug.
What needs to be included in the veterinarian’s prescription and included on the label of the dispensed product?
- name and address of the dispenser;
- serial number and date of the order or its filling;
- name and address of the veterinarian who prescribed or ordered the drug product;
- directions for use; and
- any necessary warning and precautionary statements including withdrawal times.
Any additional requirements of State or local laws for dispensed animal drug products must also be followed.
To protect themselves and their clients, veterinarians should make efforts to ensure their instructions are followed, especially when they prescribe or recommend drugs for food-producing animals that require a withdrawal period.
Compounding of Animal Drugs
To be legally marketed, new animal drugs must be approved under section 512 of the FD&C Act, conditionally approved under section 571 of the FD&C Act, or included on the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species under section 572 of the FD&C Act. The FD&C Act does not generally distinguish between compounding and other methods of animal drug manufacturing. Animal drugs that are not approved or indexed are considered "unsafe" under section 512(a)(1) of the FD&C and adulterated under section 501(a)(5) of the FD&C Act. Animal drugs compounded from bulk drug substances are new animal drugs.
On May 19, 2015, FDA revoked Compliance Policy Guide, Section 608.400, “Compounding of Drugs for Use in Animals" and published a draft guidance that provided information to compounders of animal drugs and other interested stakeholders on FDA’s enforcement approach with respect to the compounding of animal drugs from bulk drug substances. Compliance Policy Guide 608.400 was withdrawn because it was no longer consistent with FDA’s current thinking. After reviewing the comments submitted to the docket, the FDA decided not to finalize the current draft guidance, and will instead develop and issue a new draft guidance. In developing the new draft, the FDA will carefully consider the issues that are specific to compounding of animal drugs, including the significance of using compounded drugs as a treatment option in various veterinary settings and animal species. Until we publish final guidance on this issue, FDA intends to look at the totality of the circumstances when determining whether to take enforcement action for unlawful animal drug compounding activities.