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FDA and the Veterinarian
To the Veterinarian: The Center for Veterinary Medicine (CVM) within the Food and Drug Administration (FDA) helps to ensure the safety of the food supply and assists in providing for the health care needs of animals through the approval and post-approval monitoring of safe and effective animal drugs, medical devices for animals, and oversight of animal feeds. Veterinarians also help to ensure food safety and provide for the health care needs of animals through appropriate and responsible use of FDA-regulated products. Because of the similarities of mission between FDA and veterinarians, this booklet was written to provide a source of information on CVM activities which may be of interest to veterinarians. Our success at CVM depends on the knowledge, abilities and ethics of veterinarians to use FDA-regulated products responsibly within their practice. We hope this booklet will serve as a catalyst for greater communication between CVM and the veterinary profession. Introduction Two recent statutes expand the veterinarian's authority in the area of drug use: the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), and the Animal Drug Availability Act of 1996 (ADAA). Under the provisions of AMDUCA, veterinarians now have the authority to use approved animal drugs in an extra-label manner, and they may prescribe approved human drugs for use in animals, under certain specified conditions. The ADAA was enacted to help streamline the animal drug approval process. In addition to adding flexibility to the way FDA regulates animal drugs, ADAA authorized a new category, Veterinary Feed Directive (VFD) drugs, which may be used in animal feeds. The VFD category allows the approval and use of sophisticated new animal drugs in animal feed, on a veterinarian's order, while incorporating safeguards to ensure the safe use of such drugs. Section 512 of the Act, the basic statutory provision governing new animal drugs, provides that a new animal drug is unsafe unless there is in effect an approval of a new animal drug application and unless the use of a drug and its labeling conform to the approved application. An unsafe new animal drug is adulterated and subject to the enforcement provisions of the Act. Virtually all animal drugs are "new animal drugs" within the meaning of the Act, and are subject to section 512. Although an animal drug may avoid the approval requirement if it is not a new animal drug or is grandfathered, the burden is on the marketer to prove that one of these exceptions applies. To assist in carrying out its statutory responsibilities, the FDA has promulgated regulations and developed written regulatory policies. New regulations are published in the FEDERAL REGISTER [1]. All FDA regulations are codified in Title 21 of the CODE OF FEDERAL REGULATIONS [2]. FDA regulations and policies may change in response to new circumstances or new information that becomes available. Because regulations are always subject to legal challenge, they must be scientifically and legally defensible. Most regulatory issues can be adequately and appropriately resolved through dialogue in various forms. The FDA encourages such open, frank discussions. While the Food and Drug Administration is responsible for regulating animal drugs, feeds/foods, devices, and most animal health products, there are some classes of animal products that fall under the jurisdiction of other Federal agencies. A quick guide as to which agency has responsibility for these products is provided below. There is no requirement that pet food products have premarket approval by FDA, however, pet foods are subject to the requirements of the Act and pet food manufacturers are subject to individual annual product registration in most states. State laws may require that pet food labels bear, in addition to the mandatory information required by Federal law, a label statement of "guaranteed analysis" for minimum protein and fat content, and maximum fiber and moisture content, a nutritional adequacy statement, and feeding directions. Additional information concerning state registration and labeling requirements may be obtained from the individual states where the products will be distributed or from the Official Publication of the Association of American Feed Control Officials, Inc. c/o Sharon Senesac, Assistant Secretary, AAFCO, P.O. Box 478, 104 East McConnell Street, Oxford, Indiana, 47971. Pet foods are also subject to the labeling requirements of the Fair Packaging and Labeling Act, which governs certain aspects of consumer product labeling. Definitions for certain nutrient content claims, such as "lite" or "light," have been developed in conjunction with AAFCO. In the future, additional definitions may be developed in a manner consistent with those developed for human foods. As with human food, pet foods must not be adulterated or misbranded. Pet foods may not contain any poisonous or deleterious substances or residues of pesticides in excess of established tolerances. They may not be stored in any containers which may render the contents injurious to health because of any poisonous or deleterious substance and may not contain any color additives or food additives which are unsafe. To ensure safety, canned pet food must be manufactured and registered in accordance with the FDA regulations for low-acid canned foods. Pet food labeling may not be false or misleading in any particular. Damage or inferiority may not be concealed in any manner. Pet food may not be sold under the name of any other food and may not have any valuable constituents omitted or extracted. Regulations which apply to pet foods are published in Title 21, Parts 501,573, and 582 of the CODE OF FEDERAL REGULATIONS. The term "veterinary biologics" includes all viruses, serums, toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, and the antigenic or immunizing components of microorganisms intended for use in the diagnosis, treatment, or prevention of disease in animals. The Veterinary Biologics Staff, Animal and Plant Health Inspection Service, U.S. Department of Agriculture, is responsible for regulating veterinary biologics for purity, safety, potency and effectiveness. By statutory definition, a medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component part, or accessory, which is intended for use in the diagnosis of disease, or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals and which does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its principal intended purposes. There are currently no requirements for FDA pre-market approval of medical devices intended for animal use. Veterinary medical devices and diagnostic aids are, however, subject to the general provisions of the Act that relate to misbranding and adulteration. For example an animal medical device is misbranded if the labeling is false or misleading (21 U.S.C. 352(b)). A veterinary medical device may be considered misbranded if the manufacturer or distributor does not have data which establish the safety and effectiveness of the claims made for the product. A medical device is illegal if it is dangerous to animal or human health when used in the manner prescribed, recommended, or suggested in labeling (21 U.S.C. 352(j)). The FDA relies on veterinarians and other users to report unsafe veterinary medical devices. Articles such as screening test kits for drug residues are regulated as veterinary medical devices. One example of screening tests is the test used to screen milk for the presence of drug residues. As with other veterinary medical devices, screening tests must bear adequate directions for use, the labeling may not be false or misleading, and the manufacturer should have data adequate to demonstrate that use of the screening kit in accord with label directions will yield consistent and reliable results. If adequate directions cannot be written for lay use, the veterinary medical device is deemed unsafe for use except under the supervision of a licensed veterinarian. The FDA, therefore, requires that the label bear the statement: "Caution: Federal law restricts this device to sale by or on the order of a licensed veterinarian" (21 CFR 801.109). Examples of veterinary medical devices which are required to bear the prescription legend include transcutaneous electronic nerve stimulators, pulse magnetic field devices, and lasers. Germicidal preparations for use on inanimate objects, as well as rodenticides, and most insecticides are subject to the Federal Insecticide, Fungicide, and Rodenticide Act, administered by the Pesticide Regulation Division of the Environmental Protection Agency (EPA), Washington, D.C. 20460. However, some products used to control external pests are intended to act systemically and, therefore, are regulated as drugs by the FDA and not as pesticides by the EPA. For example, topically applied flea control products are usually regulated by EPA, whereas orally administered flea control products generally fall under FDA's jurisdiction. In those situations where violative residues of pesticides are detected in animal-derived human food products, FDA has the responsibility for regulatory enforcement. Information about EPA pesticide programs can be found on their web site. Animal Grooming Aids Under the FD&C Act, the term "drug" means articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia 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. 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 by scientific data and information that the new animal drug is safe and effective. Effective means that the product will consistently and uniformly do what the labeling claims it will do. 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. The sponsor of a new animal drug is responsible for submitting all appropriate data and information 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. The sponsor must also develop analytical methods to detect and measure drug residues in edible animal products. It is the responsibility of the drug sponsor to submit the necessary data and information. The sponsor may select outside investigators to conduct clinical trials of the drug as long as they are qualified by scientific training and experience, and agree to comply with the investigational protocol and all applicable regulations. FDA has established regulations for the conduct of non-clinical investigations, such as toxicology studies, and guidance for conducting and monitoring clinical trials. When the sponsors believe that sufficient data have been collected to establish the safety and effectiveness of their drug product, they may apply for approval. A New Animal Drug Application (NADA) is submitted 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 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. Examples of some questions that must be answered concerning the safety of the drug product to the animal are:
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 caution 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. Basically, the petitioner must demonstrate that the product produces the claimed effect. As a minimum, the data must have four basic attributes:
Under the provisions of the Food and Drug Act, the FDA is responsible for assuring the drugs are safe for use in animals and the human food derived from animals is safe for consumption by the public. However, it must be recognized that the presence of animal drugs or their metabolites in food is only one source of chemical residues to which the public may be exposed. Other sources of chemical residues in the food supply can result from the use of pesticides and industrial chemicals, as well as certain naturally occurring contaminants such as aflatoxin, pathogenic microbes and their toxic by-products. Thus, the control of animal drug residues is a sub-set of a larger chemical residue control problem. 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 demonstrates 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. The scientific studies required by FDA to evaluate the human food safety of animal drug residues comprise a range of detailed studies in drug residue chemistry, drug metabolism, as well as extensive toxicological evaluation of drug residues. Detailed guidance on the studies required for animal drug approval is available from the Center for Veterinary Medicine (CVM). In evaluating the human food safety of animal drug residues, it is the goal of CVM to base its safety conclusions on the data from well designed studies that are based on sound science that has been competently performed. In order to assure that human food of animal derivation 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. These analytical methods, that are part of the drug approval process, must be demonstrated to reliably measure and confirm the animal drug or metabolite in the tissue of interest. The demonstration of acceptable performance by an analytical method is accomplished by a multi-laboratory evaluation according to the criteria that have been established by CVM. The CVM multi-laboratory procedure for the evaluation of analytical methods is also known as a method trial. Specific technical information on the performance of a acceptable method trial including performance criteria is available upon request from CVM. Classifying RX and OTC Animal Drugs FDA has the responsibility for determining the marketing status (prescription, over-the-counter, or VFD[3]) 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. An animal drug which is not safe for animal use except under the professional supervision of a licensed veterinarian because of:
is an Rx drug if it is not possible to prepare "adequate directions for use" under which a layperson can use the drugs safely and effectively. Such products can be dispensed only by or upon the lawful written order of a licensed veterinarian. Products for which adequate directions for lay use can be written must be labeled for over-the-counter (OTC) use under existing law. 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 veterinary prescription drug products, such products can only be sold to or 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 veterinary 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) to the layperson of a veterinary prescription drug product may be made only by or on the bona fide prescription or other order of a licensed veterinarian. The FDA has interpreted the word "prescription" to apply only to the practitioner's direction to a pharmacist. Because some states authorize persons other than pharmacists to dispense prescription drug products on a veterinarian's instructions the term "other order" is used when instructions are for a legally authorized dispenser who is not a pharmacist. In both cases the instructions and their intent are the same and the dispenser may not dispense an Rx drug product without a veterinarian's explicit authorization. Sale of a veterinary prescription legend 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 a veterinary prescription drug product only within the course of his/her professional practice where a valid veterinarian-client-patient relationship [4] 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 veterinary 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 veterinary prescription drug products:
When issuing a prescription or other order, the veterinarian must inform the dispenser as to the information to be placed on the labeling of the dispensed product which must include at a minimum the information listed below:
Any additional requirements of state or local laws for dispensed veterinary 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. Drugs in Animal Feeds (Medicated Feeds) Anyone who adds drugs to feed is subject to the Federal Food, Drug, and Cosmetic Act. Just as each label claim for a new animal drug must be approved, so too must the drug be specifically approved for administration in animal feed. Approvals are issued only for the uses, claims and drug levels which have been shown to be safe and effective by adequate and well-controlled studies. When the new animal drug application for use of the compound in animal feed is approved, a notice, which upon publication is effective as a regulation is published in the FEDERAL REGISTER. The feed must be labeled in accordance with the regulations. A drug may only be mixed into feed for uses and at potency levels specifically permitted in 21 CFR Part 558. The person or firm mixing a medicated feed must be registered with the FDA as a drug manufacturer and hold an approved medicated feed mill license (Form FDA 3448) unless exempted by regulation from registering and the requirement to hold a feed mill license. If a drug has been added to animal feed for uses or at levels not specified in the regulations, a violation of the FD&C Act has occurred. Any individual authorizing the violation, as well as the individual illegally mixing the feed may be subject to regulatory action. Additionally, the feed itself may be subject to seizure. The Animal Drug Availability Act of 1996 (ADAA) amended the FD&C Act to establish a new category of drugs, veterinary feed directive (VFD) drugs. A drug intended for use in or on feed, which is limited by an approved application to use under the professional supervision of a licensed veterinarian is a VFD drug. Proposed regulations covering the use and distribution of VFD feeds (medicated feeds containing VFD drugs) were published in the FEDERAL REGISTER of July 2, 1999. In the past, drugs used in animal feeds were approved as OTC drugs. While the FD&C Act did not prohibit approval of prescription drugs for use in animal feeds, such approvals were impractical because some states' pharmacy laws required a licensed pharmacist to dispense the drugs, while other states prohibited feed manufacturers from possessing and dispensing prescription drugs. The VFD solves this problem by allowing the veterinarian to order the use of VFD drugs in feed without the involvement of a pharmacist in the manufacture of medicated animal feed. The required involvement of a veterinarian satisfies FDA's concerns that the drugs be used only in appropriate circumstances and under greater control than OTC drugs. The VFD process is straightforward in practice. A veterinarian, operating within the confines of a veterinarian-client-patient relationship, examines and diagnoses animal conditions and determines whether a condition warrants use of a VFD drug. If it does, the veterinarian will issue a signed VFD containing information specified by regulation. The veterinarian keeps a copy of the VFD and provides the completed and signed original and a copy to the client. The client keeps the copy and gives the original VFD to the feed manufacturer. The VFD authorizes the VFD feed to be shipped to the client's animal feeding operation. While not specifically required, we believe the drug manufacturer will provide preprinted "fill in the blank" triplicate VFD forms to the veterinary profession for the sake of efficiency and accuracy. This has been done with tilmicosin, the one approved VFD drug to date. The ADAA has a statutory requirement that anyone intending to distribute VFD feeds notify CVM prior to beginning distribution. Distributor includes the VFD feed manufacturer or anyone in the distribution chain who ultimately supplies VFD feed to an animal producer. This could include the veterinarian if he is the source of VFD feed. A VFD feed may not be distributed to a client without a signed VFD. However, VFD feed may be sent down the distribution chain if the consignee provides the distributor with a signed "acknowledgment letter affirming that it will only ship the VFD feed to a VFD holder or to another distributor who supplies a similar acknowledgment letter. Feed manufacturers or any distributor may stockpile VFD feeds in anticipation of orders. CVM recognizes that there are instances when direct contact among the veterinarian, client and feed distributor is not practical. To counter this problem and facilitate rapid movement of VFD feeds, CVM is proposing to allow facsimile transmission of the VFD. Another area of concern is the length of time a VFD may be valid (expiration date) and the number of refills or reorders that may be allowed. Limits must be placed on length of time a VFD is valid and/or amount of animals that can be treated. These areas will be addressed in the final VFD regulations. Responsibility for Illegal Residues in Meat, Fish, Milk, and Eggs FDA is responsible for programs and regulatory actions aimed at preventing illegal drug residues in human food products derived from treated animals. (For regulatory purposes, live animals are considered unprocessed food.) Illegal drug residues in edible products can constitute a hazard to the health of persons consuming such food. Failure to observe label withdrawal periods before slaughter or processing, or failure to withhold milk is the principal cause of illegal drug residues. Other causes may include failure to follow other label directions, poor feed manufacturing practices, and human negligence. FDA is also charged with ensuring that contaminants of feed origin do not result in unsafe contamination in human food of animal origin. Regardless of the cause, it is FDA's policy to hold responsible any individual in the production and marketing chain who can be shown to have caused (by an act of commission or omission) illegal residues or other contaminants in edible animal products [5] . Livestock dealers may also be subject to enforcement action if they market animals containing illegal residues and have failed to take reasonable precautions to prevent the sale of adulterated food. If justified by the facts, legal charges will be considered against these individuals. If a veterinarian prescribes, dispenses, or treats an animal(s) with a drug which results in the occurrence of an illegal drug residue in edible products from the treated animal, the veterinarian may be held responsible for having caused a violation of law. In general, compounding an animal drug from an active pharmaceutical ingredient (bulk drug) is not permitted by the Act unless covered by an approved new animal drug application. This is true even if the compounder is a veterinarian or a pharmacist. Two courts of appeal have held that bulk drugs may not be sold to veterinarians for compounding unapproved new animal drugs. Nevertheless, CVM acknowledges the medical need for compounding may exist within certain areas of veterinary practice. The contemporary practice of veterinary medicine requires products to treat hundreds of conditions and diseases in dozens of species. However, business and market realities in the animal health industry can only provide a fraction of products necessary for these indications. Consequently, veterinarians continue to require products to treat diseases or conditions in animals for which no FDA-approved product is available. Veterinarians must by necessity on occasion utilize products that are compounded to meet a specific medical need. Thus, the agency may exercise its enforcement discretion to permit compounding in certain instances but only rarely, such as to treat poisoning. The Compounding Policy can be found in the Agency's Compliance Policy Guides Manual . Extra-label Use of New Animal Drugs in Food-Producing Animals "Extra-label use" is defined as "actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to, use in species not listed in the labeling, use for indications (disease and other conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of administration other than those stated in the labeling, and deviation from labeled withdrawal time based on these different uses." Under the provisions of the Animal Medicinal Drug Use Clarification Act of 1994, the FDA recognizes the professional judgement of veterinarians, and allows the extra-label use of drugs by veterinarians under certain conditions (21 CFR 530). Extra-label use of drugs may only take place with the scope of a valid veterinarian/client/patient relationship (VCPR) [4]. In the absence of a valid VCPR, if an approved new animal drug is used for a use for which it is not labeled, it is deemed unsafe under Section 512 (a)(1)(B). Advertising or promotion of extra-label uses in animals of approved new animal drugs or approved human drugs is not permitted and is subject to regulatory action. An approved new animal drug or human drug intended to be used for an extra-label purpose in an animal is not unsafe under section 512 of the Act and is exempt from the labeling requirements of section 502(f) of the act if such use is by or on the lawful written or oral order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship and such use complies with 21 CFR Part 530. Extra-label use is limited to treatment modalities when the health of an animal is threatened, or suffering or death may result from failure to treat. Extra-label use of drugs may be considered by food animal veterinarians only when:
The following additional conditions must be met for a permitted extra-label use, in food-producing animals, of an approved human drug, or of an animal drug approved only for use in animals not intended for human consumption:
Extra-label use of an approved human drug in a food-producing animal is not permitted under this part if an animal drug approved for use in food-producing animals can be used in an extra-label manner for the particular use. The prescribed or dispensed extra-label drug (prescription legend or over-the-counter) must bear labeling information which is adequate to assure the safe and proper use of the product. At a minimum, the following label information is recommended:
Extra-label use of drugs in treating food-producing animals is allowable only by licensed veterinarians within the context of a valid veterinarian-client-patient relationship, and does not include drug use in treating food-producing animals by the layman (except under the supervision of a licensed veterinarian). Lay persons cannot be expected to have sufficient knowledge and understanding concerning animal diseases, pharmacology, toxicology, drug interactions, and other scientific parameters to use drugs in any way other than as labeled. Limitations to Extra-Label Use Provisions of AMDUCA In addition to uses which do not comply with the provision set forth in Sec. 530.10, the following specific extra-label uses are not permitted and result in the drug being deemed unsafe within the meaning of section 512 of the act:
FDA may prohibit the extra-label use of an approved new animal or human drug or class of drugs in food-producing animals if FDA determines that:
Veterinary Use of Human-Labeled Drug Products FDA is aware that human-labeled drug products have been promoted and distributed by manufacturers, distributors, and pharmacies for use in animals and that such drugs are being prescribed, dispensed, and administered by veterinarians for animal use. Promotion of human-labeled drug products for veterinary use by these sources has included advertising animal use in veterinary publications; distribution of labeling and promotional materials, suggesting or recommending use of these products in animals; or oral statements from sales personnel describing or recommending use in animals. Such promotion causes the drugs to be misbranded under Section 502 (f)(1), or adulterated new animal drugs under Section 501(a)(5), or both. Furthermore, such promotion may subvert the new animal drug approval process by creating a disincentive for drug manufacturers to seek such approval. FDA is very concerned about the use of human-labeled drugs in food-producing animals because of the increased potential of illegal drug residues in meat, milk, and eggs. Human-labeled drug products have not undergone testing for residue depletion from edible tissues, thus, appropriate withdrawal times to avoid illegal residues in food can only be estimated. Nevertheless, there are legitimate and important veterinary needs for human-labeled drugs in the treatment of disease or to prevent pain in food-producing animals in instances where there simply are no animal drug products available that would avoid animal suffering or death [6]. Examples include analgesics and anesthetics for pain, sedation, and surgery, insulin for ketosis, and antidotes for poisoning. Most veterinary use of human-labeled drug products occurs in non-food animal practice (companion, sporting, exotic, etc.). Many diseases of pets and other non-food animals cannot be treated in accordance with current standards of veterinary practice without the use of human-labeled drugs because approved drug products bearing veterinary labeling often do not exist. FDA has generally refrained from taking enforcement actions in this area because there is no expected adverse impact upon the public health. In rare circumstances, when the health of the treated animals is harmed, regulatory attention by FDA would be considered or, preferably, referred to the State veterinary licensing authority for investigation. Dispensing pharmacists are required to label dispensed drugs in accordance with the prescribing veterinarian's instructions, including the name and address of the dispenser, the serial number and date of the order or of its filing, the name of the licensed veterinarian, directions for use, and any cautionary statements. Use of human-labeled drug products in food-producing animals should be limited to those cases where appropriate veterinary-labeled therapy does not exist. It is unacceptable to use a human-labeled product for common disease conditions in food animals because approved veterinary-labeled drug products, e.g., antibacterials, anti-inflammatory agents, etc. are available. The food animal veterinarian assumes greater responsibility when he or she uses a human-labeled drug rather than a veterinary drug. Use of human-labeled drugs may be considered by food animal veterinarians only when they have made a careful and definitive diagnosis and evaluation of the condition for which the drug is to be used, and are operating within the confines of a valid veterinary/client/patient relationship; made a deliberate determination that there is no other appropriate veterinary-labeled therapy; i.e., there is no marketed veterinary-labeled drug product specifically labeled for the disease condition to be treated or the veterinary drug has been found clinically ineffective by the veterinarian in the animals to be treated; and taken adequate steps to prevent the occurrence of illegal residues in edible animal products. This should include a review of the best available toxicological and tissue distribution and tissue residue depletion data and establishment of an extra long drug withdrawal period prior to marketing meat, milk, or eggs. The animal owner or manager should be given explicit written withdrawal instructions. The practitioner should have a high degree of confidence that the client will follow the drug withdrawal instructions. Regulatory action will be considered when an illegal residue occurs even if the veterinarian followed the foregoing precautions. Lay persons, e.g., owners, who administer human-labeled drugs either to food-producing or non-food animals without the supervision of a licensed veterinarian operating within the framework of a valid veterinarian/client/patient relationship will be subject to regulatory action. Veterinarians are expected to follow cautionary handling and disposal provisions, if any, specified in human drug labeling to protect handlers and the environment. The highest priority for regulatory attention is illegal tissue residues from human-labeled drugs, and manufacturers, distributors, and pharmacies who promote the substitution of human-labeled drug products for animal drugs for economic reasons. Reporting Adverse Drug Reactions Users of new animal drug products are encouraged to notify the product's sponsor of any unexpected or adverse reactions resulting from the use of that product. The sponsor is responsible for establishing and maintaining records concerning experiences with the drugs and for submitting reports of those experiences to FDA. Among the data which must be submitted are reports of injury, toxicity, sensitivity reaction, unexpected incidence or severity of side-effects associated with use, or failure of the drug to exhibit expected pharmacological action. FDA scientists analyze these data to determine if any modifications are needed in the drug's labeling, dosage level, etc., to prevent future adverse reactions. In extreme instances, the adverse reactions may be so severe as to require withdrawal of approval of the drug. However, because of the extensive premarketing approval process, this rarely occurs. FDA also encourages direct reporting of adverse drug reactions by veterinarians. The reports should be submitted on Form FDA 1932a, Veterinary Adverse Reaction, Lack of Effectiveness, or Product Defect Report. This is a pre-addressed, postage-paid form which is filled out and dropped in the mail by the veterinarian. Copies of the form are usually available from state veterinary medical associations, clinics of colleges of veterinary medicine, USDA Extension Service veterinarians, and FDA offices. FDA may occasionally need more detailed information about an incident, and the veterinarian may be called by a FDA staff veterinarian. In any event all forms are acknowledged by letter and another form is sent for future use. Adverse reactions may be reported by telephone during normal working hours (7:00 a.m. to 4:00 p.m. Eastern Standard/Daylight Time) by calling 888-FDA-VETS (888-332-8387) or after hours by dialing 888-FDA-VETS (888-332-8387) and leaving a message. In the second case a message is recorded and the call is returned by a veterinarian the following working day. Types of FDA Regulatory Actions The objective of FDA regulatory programs is to assure compliance with the Federal Food, Drug, and Cosmetic Act (the FD & C Act). Specific enforcement activities include actions to correct and prevent violations, remove violative products or goods from the market, and punish offenders. The type of enforcement activity FDA uses will depend on the nature of the violation. The range of enforcement activities include issuing a letter notifying the individual or firm of a violation and requesting correction, to criminal prosecution of the individual or firm. Adulteration or misbranding is usually the result of an individual failing to take steps to assure compliance with the law. Such an individual may be liable for a violation of the Act and, if found guilty, be subject to the penalties specified by the law.
The FDA field offices have primary responsibility for conducting inspections or investigations and collecting samples which may lead to recommendations for enforcement/regulatory action. The type of action recommended will depend upon the nature of the violation and the public health concern, Agency policy, previous history of violations by the firm, and other factors. Personnel from FDA headquarters generally review recommendations for enforcement actions and must concur in the recommendation. Criminal Fines for FD & C Act Violations Misdemeanor fines under the FD&C Act may reach $500,000 under some circumstances. The Criminal Fine Enforcement Act of 1994 (Public Law 98-596) provides for fines for violations of Federal law. Although it is not part of the FD&C Act, the Criminal Fine Enforcement Act of 1994 applies to all fines levied under the FD&C Act, as well as other statutes that contain provisions enforced by FDA. The following fines are applicable for each offense:
Interaction with the Food and Drug Administration The Food and Drug Administration is most effective in carrying out its mission under a policy of openness and free communication. All parties are best served when there is clear understanding of the FDA's regulations and policies and how they are administered. By operating under this policy, FDA hopes to create confidence in, and support for, programs that are intended to promote and protect the health and well-being of all. FDA encourages anyone to contact the Agency for assistance, to supply information, or to report a problem with a product. To help direct requests to the proper location for a rapid response, we offer the following guidance: Information on approved drugs, regulations, policies, copies of guidelines, or CVM publications can be found on the CVM website. If you wish to request information by mail, or to submit suggestions or comments, address your letter to:
To request copies of a specific FDA document:
To report an adverse drug reaction:
To report a violation of the Federal Food, Drug, and Cosmetic Act, contact your nearest FDA office or
A comprehensive ORA Field Directory is located on the FDA Home Page. Adulteration: A violation of the Federal Food, Drug, and Cosmetic Act which includes products that are defective, unsafe, not shown to be safe, filthy, or produced under insanitary conditions. It also includes products which are manufactured under procedures and controls which do not comply with Current Good Manufacturing Practice regulations as well as new animal drug products which are not the subject of an NADA approval. Detailed definitions of adulteration are in the Act itself, and have been developed in regulations and by the courts. Adverse Drug Reaction: An unexpected side effect, injury, toxicity, sensitivity reaction, or unexpected incidence or severity of side effects associated with use of a new animal drug product. The failure of a new animal drug product to exhibit expected pharmacological action also is an adverse drug reaction. Animal Feed: An article which is intended for use for food for animals other than man and which is intended for use as a substantial source of nutrients in the diet of the animal. It is not limited to a mixture intended to be the sole ration of the animal. Biologics: see Veterinary Biologics Device: An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its principal intended purposes. Drug: means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 343(r)(1)(B) and 343(r)(3) of this title or sections 343(r)(1)(B) and 343(r)(5)(D) of this title, is made in accordance with the requirements of section 343(r) of this title is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 343(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement. Electronic Animal Identification Products: Implantable transponders which contain unique information for use in animal identification. A reader compatible with the transponder is used to make the final identification. These transponders are implanted into inedible portions of the animal (e.g., ear) and if the implant is rendered for animal feed, the Center is regulating the transponder as a food additive. Extra-Label Use: Refers to the actual or intended use of an approved new animal drug in a manner that is not in accordance with the approved label directions. Food Additive: Any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, processing, preparing, treating, packaging, transporting, or holding food; and including source of radiation intended for any such use), if such substance is not generally recognized, among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures...to be safe under the conditions of its intended use... (see 21 U.S.C. 321 (s) for complete definition). Labeling: All labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers or (2) accompanying such article. Medicated Animal Feed: An article intended for use as food for animals, other than man, bearing, containing, or purporting to bear or contain any kind of animal drug/drug combination. Misbranding: A drug or device shall be deemed to be misbranded (a) if its labeling is false or misleading in any particular; (b) if in package form unless it bears a label containing (1) the name and place of business of the manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of weight, measure, or numerical count; (c) If any word, statement, or other information required by or under authority of the Act to appear on the label is not prominently placed thereon with such conspicuousness and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use... The complete definition of misbranding can be found the Act (21 U.S.C. 502). New Animal Drug: Any drug intended for use for animals other than man which, among other things, is not generally recognized by qualified experts as safe and effective for use under the condition prescribed, recommended, or suggested in the labeling thereof. Veterinary Biologics: Vaccines, bacterins, diagnostics, etc, which are used to prevent, treat, or diagnose animal diseases. These products generally work through some immunological method or process. [1] [2] [3] [4] [5] [6] Compliance Policy Guide 7125.35, Human-Labeled Drugs Distributed and Used in Animal Medicine (7/20/92). HHS Publication No. (FDA) 00-6046 - February 2000
Web Page Updated by hd - July 9, 2008, 3:32 PM ET
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