Antimicrobial drugs have been widely used in human and veterinary medicine for more than 50 years, with tremendous benefits to both human and animal health. However, the use of antimicrobial drugs in animal agriculture has garnered a significant amount of attention in recent years due to the threat bacterial resistance to antibiotics in both humans and animals poses to public health.
The U.S. Food and Drug Administration (FDA) has provided guidance on the use of antimicrobial drugs in animal agriculture for several decades. On Dec.11, 2013, FDA released Guidance for Industry #213 (GFI #213) and a Proposed Rule that would amend Veterinary Feed Directive (VFD) guidelines, each of which are examined in this article.
What is GFI #213?
Essentially, GFI #213 is non-binding guidance regarding the use of antimicrobial drugs in animal agriculture. This guidance instructs antimicrobial drug manufacturers to remove production-related claims—meaning to promote growth or increase feed efficiency—from their product labels. Instead, the manufacturers are to market these products only for their therapeutic effects—meaning to treat illness.
Notably, it is illegal under the Federal Food, Drug and Cosmetic Act (FFDCA) to use medicated feed or antimicrobial drugs for extralabel uses. Additionally, producers will be required to obtain a prescription, or VFD, from a veterinarian for antimicrobial drugs. A VFD cannot be obtained for uses not contained on the product’s label. Finally, FDA has proposed amendments to VFD guidelines to streamline the implementation of these new non-binding requirements for using antimicrobial drugs throughout the animal agriculture supply chain.
It is worth noting that lawmakers have also given attention to the issue of antimicrobial drug use in animals. In March of 2011, and again in 2013, Representative Louise Slaughter (D-NY), a microbiologist, introduced the Preservation of Antibiotics for Medical Treatment Act. The law would, among other things, amend the FFDCA to heighten the standard for approval of a new animal drug that is considered a medically important antimicrobial. The bill resides with the House Energy & Commerce Subcommittee on Health and is unlikely to receive a hearing or vote anytime soon. The purpose of the legislation is likely overtaken by this recent action by FDA as well.
Antimicrobial Drugs, Food Animals and the FDA
Antimicrobial drugs used in animal agricultural are generally regulated by the FDA. Prior to the mid-1990s, most antimicrobial drugs were approved for over-the-counter (OTC) use in food-producing animals and many of these were administered through medicated feed or drinking water. According to recent statements by the FDA, the methods used to assess the microbial food safety aspects of new animal drug applications for antimicrobials intended for use in food-producing animals were not as rigorous as those used today, in part because less scientific data about the public health ramifications of antimicrobial resistance existed at that time.
Today, all new antimicrobial drugs for use in food-producing animals approved by the FDA Center for Veterinary Medicine are labeled with veterinary prescription (Rx), veterinary feed directive (VFD) or over-the-counter (OTC) marketing status. Only OTC marketing status does not require veterinarian oversight to purchase and use the drugs.
Veterinary Feed Directive
Prior to implementation of the VFD, FDA had only two options for regulating the distribution of animal drugs: OTC and Rx drugs used in animal feeds were generally approved as OTC drugs. In 1996, Congress enacted the Animal Drug Availability Act (ADAA) to facilitate the approval and marketing of new animal drugs and medicated feeds.
In passing the ADAA, Congress created a new regulatory category for certain animal drugs used in animal feed called veterinary feed directive drugs (VFD) drugs. VFD drugs are new animal drugs intended for use in or on animal feed, which are limited to use under the professional supervision of a licensed veterinarian in the course of the veterinarian’s professional practice.
Under current VFD regulations, all animal drugs approved for use in or on animal feed are assigned to one of two categories, depending on their potential to create unsafe drug residues in edible tissues. Category I drugs having the lowest potential and Category II drugs having the highest potential. In order to reduce the potential of creating unsafe drug residues, access to Category II drugs is restricted to licensed feed mills because these facilities are, according to the FDA, technically better suited to handle these drugs in a concentrated form.
Currently, any drug that falls within the VFD is considered a Category II drug. For animal feed containing a VFD drug to be used in animals, a licensed veterinarian must first issue an order, called a veterinary feed directive, providing for such use.
The Proposed Rule that FDA released on Dec.11, includes technical amendments to the Code of Federal Regulations (21 C.F.R., parts 514 and 588), which will essentially make the VFD drug regulations more “user-friendly.” The rule would provide greater flexibility to veterinarians by deferring to the veterinary profession and individual states for the specific criteria for acceptable veterinary professional conduct; increase flexibility for those purchasing VFD drugs; remove the mandatory categorization of all VFD drugs as Category II drugs; and ease recordkeeping requirements for both veterinarians and those to whom they are prescribing the antimicrobials.
As FDA states in the rule, the “primary purpose…is to improve the efficiency of the VFD program, while still ensuring that VFD drugs are used in a manner that affords adequate protection for human and animal health.”
Voluntary Removal of Label for Growth Promotion
FDA recommends in GFI #213 that animal pharmaceutical manufacturers, in conjunction with the principals advanced in GFI #209, cease labeling antimicrobial drugs for growth promotion. This is a voluntary, non-binding request. It is important to note that any extra-label use of medicated feed or antimicrobial drugs is not permitted by law (see sections 512(a)(2) and (a)(4)(A) of the FD&C Act). Neither veterinarians nor their clients may use, or direct the use of, a medicated feed or antimicrobial drug in an extralabel manner. Therefore, when production claims (claims that antimicrobials promote growth) for medically important antimicrobials are voluntarily removed from the approved labeling of these drugs, consistent with the judicious use principles of GFI #209, any further use of a drug without a production claim in medicated feed for production purposes will be considered an extralabel use and, thus, illegal. Consequently, producers will be required to obtain a prescription, or VFD, for antimicrobial drugs from a veterinarian.
FDA has asked that animal pharmaceutical manufacturers notify the Agency within three months from the date of publication of GFI #213 of their intentions to make these voluntary labeling changes. After the three-month notification period, there will be a three-year implementation period, after which time FDA will evaluate the rate of voluntary adoption by drug sponsors of the proposed changes across affected products. If companies have not come into compliance, even though the Guidance is non-binding, FDA has suggested it would take regulatory action.
Evolution of FDA Policy
The release of GFI #213 is at least the third occasion on which FDA has shared its thinking on the use of antimicrobial drugs in animal agriculture. In 2003, FDA published GFI #152, which advanced the position of the Agency that increasing the exposure of bacterial populations to antimicrobial drugs increases the risk of generating resistance to those antimicrobial drugs. GFI #152 also provided a classification of medically important antimicrobial drugs. On April 11, 2012, FDA published GFI #209 with two non-binding principles related to the judicious use of antimicrobial drugs in animal agriculture. The latest guidance, GFI #213, is intended for use in further implementing the recommendations advanced in GFI #209 and #152.
In general, GFI #152 is premised on the concept that increasing the exposure of bacterial populations to antimicrobial drugs increases the risk of generating resistance to those antimicrobial drugs. Pursuant to this principle, the administration of medically important antimicrobial drugs to entire herds or flocks of food-producing animals (e.g., for production purposes) would represent a use that poses a qualitatively higher risk to public health than the administration of such drugs to individual animals or targeted groups of animals (e.g., to prevent, control, or treat specific diseases).
Today, FDA considers all antimicrobial drugs listed in Appendix A of GFI #152 (Appendix A) to be “medically important” because they have been determined to be important for treating bacterial infections in people.
GFI #209, formally titled, “The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals,” discusses FDA’s concerns regarding the development of antimicrobial resistance in human and animal bacterial pathogens when medically important antimicrobial drugs are used in food-producing animals in an injudicious manner. In addition, GFI #209 provides two recommended principles regarding the appropriate or judicious use of medically important antimicrobial drugs:
Principle 1: Limit medically important antimicrobial drugs to uses in animals that are considered necessary for assuring animal health; and
Principle 2: Limit medically important antimicrobial drugs to uses in animals that include veterinary oversight or consultation.
FDA recommends several steps to minimize the development of antimicrobial resistance including voluntary measures that would limit medically important antimicrobial drugs to uses in food-producing animals that are considered necessary for assuring animal health and that include veterinary oversight or consultation.
Net Effect of FDA’s Action
FDA estimates there are roughly 25 pharmaceutical manufacturers that will be affected. Animal health industry stakeholders, including the Animal Health Institute and the American Veterinary Medical Association, have responded approvingly of the action. Several major pharmaceutical manufacturers for animals have already indicated their willingness to comply as well. At least part of this is due to the voluntary nature of FDA’s actions. Rather than issuing mandates, FDA has taken the approach of working with industry to develop a mutually agreeable policy – one that would not unduly disrupt the production of antimicrobial drugs or livestock.
The non-binding nature of the guidance documents grant industry and FDA flexibility in making such changes. If FDA pursued formal regulatory action, they would have to review and approve (or reject) each of the 200 or so antimicrobials on the market. In the tight fiscal times of late, FDA has been hampered by budget shortfalls. Making this sort of regulatory action voluntary allows FDA to rely upon industry resources for some of the burden of implementation, rather than expending its own scarce resources to take strict enforcement action.
The net effect and the intent of this recent action by FDA will be to limit the use of antimicrobial drugs in food animals. FDA’s hope is that curtailing the use of such drugs for production purposes in animals, and limiting use strictly to therapeutic purposes, will decrease overall usage and thus reduce the threat of developing “super bug” illnesses with resistance to antibiotics in humans and animals alike.
Editor’s Note: Scott L. Halbur is attorney with Faegre Baker Daniels LLP, a firm with over 750 professionals in the U.S., U.K. and China. He is a member of the firms Food & Agriculture Industry focus and handles food and agribusiness litigation, including products liability, mass torts, biotechnology, agricultural contracts and regulatory disputes. Bradley A. McKinney is a public policy specialist with FaegreBD Consulting, based in Washington D.C. He is a member of the health and biosciences team, where he specializes in food and agricultural policy and regulation and works on related trade, inspections and labeling issues. Brad advises food, agriculture and life science companies on federal legislation and policies that affect their businesses, including the Farm Bill and the Food Safety Modernization Act, and advocates for their interests before the White House, Congress and federal government agencies.