FDA and You: Food Animal Practice in the Age of Judicious Use of Antimicrobial Drugs
Rick Tubbs, DVM, MS, MBA
To shamelessly steal the slogan of Auburn’s new head football coach: “It’s a new day”. It
appears that after 40 years of debating the topic, it truly is a new day relative to FDA’s approach
to feed additive antimicrobials, growth promotion and feed efficiency label claims, and the role
of the veterinarian in the application of these products on the farm. In true bureaucratic fashion,
and possibly holding true to the football analogy as well, do not expect the “new day” to arrive
quickly nor without pain (well, at least without discomfort).
A Brief History Lesson
In the FDA’s Guidance for Industry #209 “The Judicious Use of Medically Important
Antimicrobial Drugs in Food-Producing Animals” (which we will discuss again later in the
paper), at least 29 papers are summarized and their conclusions presented. These papers range
from those prepared by various governmental commissions and professional organizations to
peer-reviewed scientific journal articles. The first was a 1969 U.K. report, the Report of the
Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine, or the
“Swann Report”. The joint committee (the Secretary of State for Social Services, the Secretary
of State for Scotland, the Minister of Agriculture, Fisheries and Food, and the Secretary of State
for Wales) concluded that “the administration of antimicrobials to food-producing animals,
particularly at subtherapeutic levels, poses a hazard to human and animal health.” Not to be
outdone, in April 1970, FDA commissioned a 10 member task force, made up of scientists from
FDA, NIH, USDA, and CDC along with 5 university and industry consultants, to do a
comprehensive review of the use of feed antibiotics. One result of this Task Force report was the
codification of requirements “for data to address microbiological safety concerns for
subtherapeutic uses of antimicrobials in food-producing animals” as outlined in the Code of
Federal Regulations (21 CFR 558.15).
In 1977 FDA proposed to withdraw new animal drug approvals for subtherapeutic1 uses of
penicillin and tetracyclines in animal feeds, it appears at least in part due to the conclusions
reached in the aforementioned papers. The rational was that these classes of compounds, at that
time were commonly used in human medicine, and had not been shown to be safe when used in
animal feeds in the manner described. The FDA proposal was criticized based on the lack of
epidemiological data relative to making a clear connection (connecting the dots in today’s
vernacular) between bacteria of animal origin, transmission of such organisms to humans, human
illness as a result of that transmission and lack of response of those organisms to antibiotics
administered to humans. (Indeed, even today, while the evidence is much stronger for the
possibility of such an occurrence, the probability remains extremely low). Interestingly, it was
Congress, at the time that directed FDA to put the withdrawal action on hold and conduct further
studies relative to the use of antimicrobials in animal feeds and their potential adverse effects on
human health. Thus began the 40-year battle that seems to currently be straggling to something
of a conclusion.
As a result of the directive from Congress in 1977, FDA contracted with the National Academy
of Science to conduct a study and charged them to do 4 things:
1. Study the human health effects of the subtherapeutic use of penicillin and tetracycline
in animal feed;
2. Review and analyze published and unpublished data relevant to assessing human
health consequences of such use;
3. Assess the scientific feasibility of additional epidemiological studies; and
4. Make recommendations about additional research needed
The study report was issued in 1980. The report concluded that research, on both subtherapeutic
as well as therapeutic use of antimicrobials in the feed of food-producing animals, had been
limited with issues surrounding poorly constructed and poorly controlled studies, the number of
animals used and the length of time of the studies that were available for review. The NAS study
correctly concluded that no definitive conclusions could be reached relative to the subject in
question. The study did give a precaution, however, that is somewhat prescient in light of
concerns that linger even today: “The lack of data linking human illness with subtherapeutic
levels of antimicrobials must not be equated with proof that the proposed hazards do not exist.
The research necessary to establish and measure a definitive risk has not been conducted and,
indeed, may not be possible”.
In the ensuing years, myriad reports, summaries and peer-reviewed journal articles have been
published, both directly and indirectly related to the subject of subtherapeutic use of antibiotics
in animal feed. As epidemiological techniques have improved and technological advances have
occurred, it has become apparent that in specific cases, with specific organisms and specific
antibiotics, resistance can and does occur subsequent to the use of these compounds in animal
feeds. The probability (risk) relative to human illness as a result of this occurrence remains
extremely low, and FDA has attempted to address concerns over the risk on a compound-bycompound basis. Examples of this approach include the removal of the fluoroquinolone class of
antibiotics from use in poultry in 2005 and the prohibition of extra-label uses of cephalosporins
in cows, pigs, chickens and turkeys. In the face of increasing public and advocacy group
pressures, however, it appears that FDA is making a change in the way they have dealt with this
issue for the past 40 years.
Legislative, Legal and Advocacy Pressures on FDA
The most visible efforts legislatively have been led by the late Senator Edward Kennedy and by
Congresswoman Louise Slaughter and Senator Diane Fienstein. The Preservation of Antibiotics
for Medical Treatment Act (PAMTA) has been introduced repeatedly in the past several
Congresses, with little traction to date. Failure to pass PAMTA has not deterred
Congresswoman Slaughter’s efforts to curtail antibiotic use in food-producing animals, however.
Prior to the recent reauthorization of the Animal Drug User Fee Act (ADUFA), she sent a letter
to over 60 entities in the food chain, ranging from producers to fast food companies, asking for
details about their policies regarding the use of antibiotics in animals feeds, as well as the
amount of antibiotics used under certain use conditions (“without any antibiotics”, “therapeutic
reasons” and “routine use of antibiotics”). In general the companies cited FDA regulations
concerning antibiotic use and did not choose to answer the specifics of Representative
Slaughter’s inquiry. Following that, opponents of antibiotic use in food-producing animals
attempted (unsuccessfully) to attach specific reporting requirements to the reauthorization of
ADUFA. Animal health product sponsors are currently required by ADUFA to report calendar
year antibiotic sales. The new attachments, had they been successful, would have required much
more specific categorical reporting.
In addition to the legislative efforts to curb antibiotic use, legal challenges have been raised as
well. The Natural Resources Defense Council (NRDC) received a summary judgment from a
US Magistrate Judge in New York in its case versus the FDA relative to the 1977 NOOH (notice
of opportunity for hearing) regarding its intent to withdraw growth promotion approvals for
penicillin and the tetracyclines. At the time, in 1977, over 20 drug sponsors requested hearings
to defend the growth promotion claims, but based on the Congressional intervention mentioned
earlier, no hearings were held. NRDC has argued that FDA deemed the routine use of these
compounds unsafe in 1977 and has apparently not changed its position, so the agency should be
required to finish the job it started almost 40 years ago. The judge ordered that the process
should continue and FDA should conduct the hearings they put on hold in 1977. FDA has
appealed the decision.
The Current Regulatory Process
In response to these legislative, legal, and advocacy group challenges, and armed with the more
recent solid data that antimicrobial resistance to antibiotics can occur as a result of
subtherapeutic use of those compounds in animal feeds, and in spite of the tenuous connection of
this use to the real risk of human illness, FDA has laid out a path to remove growth promotion
and feed efficiency claims, and increase veterinary oversight in the use of feed additive
antimicrobials.
Guidance for Industry #209 The Judicious Use of Medically Important Antimicrobial
Drugs in Food-Producing Animal.
In April 2012, FDA produced this guidance document. Ostensibly, guidance documents are
meant to represent FDA’s current thinking on a topic. They are not meant to be binding on FDA
or the public, and alternative approaches that satisfy the requirements of applicable statutes and
regulations may be used. In reality, guidance documents provide the framework for how FDA
operates and if “guidance” does not move industry in the desired direction, regulations may
follow. Such is the case with Guidance Document 209, as it is intended to move the industry
toward “voluntary” removal of growth promotion and feed efficiency claims for feed additive
antimicrobials. Guidance 209 lays out two principles by which FDA will determine judicious
use:
1. The use of medically important2 antimicrobial drugs in food-producing animals
should be limited to those uses that are considered necessary for assuring animal
health.
a. “In light of the risk that antimicrobial resistance poses to public health, FDA
believes the use of medically important antimicrobial drugs in food-producing
animals for production purposes (e.g., to promote growth or improve feed
efficiency) represents an injudicious use of these important drugs.”
b. “In contrast, FDA considers uses that are associated with the treatment,
control, or prevention of specific diseases, including administration through
feed or water, to be uses that are necessary for assuring the health of foodproducing animals. Disease prevention involves the administration of an
antimicrobial drug to animals, none of which are exhibiting clinical signs of
disease, in a situation where disease is likely to occur if the drug is not
administered.”
2. The use of medically important antimicrobial drugs in food-producing animals should
be limited to those uses that include veterinary oversight or consultation.
a. “In addition to instituting voluntary measures that would limit the use of
medically important antimicrobial drugs in food-producing animals to uses
that are considered necessary to assure the animals’ health, FDA also believes
it is important to phase-in the voluntary practice of including veterinary
oversight or consultation in the use of these drugs.”
Guidance Document #209 also lays out FDA’s rational for moving in the direction described in
the two principles. The current regulatory framework and the activities that FDA is currently
pursuing are based on the issuance, in the watershed year of 2003, FDA’s Guidance for Industry
#152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to their
Microbiological Effects on Bacteria of Human Health Concern.” This GFI effectively divided
the status of antibiotic approvals into pre- and post-2003 status. For approvals that occurred post
2003, FDA appears to be very comfortable with the process as described in GFI #152. For those
compounds, product sponsors would have developed products with the Guidance document
“taken into consideration by drug sponsors upstream in the drug development process and, in
effect, steers product development in a direction that is most consistent with the guidance.”
However, “on the post-approval side, FDA may examine certain currently-approved products to
determine whether such products appear consistent with GFI #152.”
In order to facilitate the move toward “voluntary” removal of growth promotion and feed
efficiency labels and the implementation of the 2 judicious use principles outlined in GFI #209,
FDA has issued two other documents that will be important to the process:
Guidance for Industry #213 New Animal Drugs and New Animal Drug Combination
Products Administered in or on Medicated Feed or Drinking Water of Food-Producing
Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use
Conditions with GFI #209.
At this point GFI #213 is a draft document for which the comment period is closed. FDA is now
considering the comments they received and plans to issue the final document soon. This
document lays out the pathway by which existing feed and water products will be brought under
the RX or VFD categories, assuring veterinary oversight in the process of the use of these
products in food-producing animals. In this document, FDA explains the evolution of their
thinking on marketing status of new animal drug approvals, referencing another pivotal year,
1993. Before 1993, feed and water based medications were mostly approved for over-thecounter use in food-producing animals. Since 1993, FDA has approved antimicrobial new
animal drugs for use in food-producing animals for RX of VFD marketing status (“with the
exception of approvals of generic copies of existing OTC products and approvals of combination
medicated feeds using existing OTC antimicrobial Type A medicated articles”). This was the
first step in the move to increased veterinary oversight of feed and water medication with the
current proposals laid out in GFI #209 the next step in the process.
The proposed timeline is that, within 3 months of publication of the final version of GFI #213
(anticipated to occur sometime this year), sponsors of affected products will notify FDA of their
intentions to voluntarily comply with the necessary changes to their product labels, that is the
voluntary removal of growth promotion and feed efficiency label claims or the addition of new
label claims consistent with “therapeutic” uses. Sponsors do have the option of seeking new
therapeutic indications for their products (keeping in mind FDA’s definition of therapeutic as
inclusive of treatment, prevention and control). It appears unlikely that many drug sponsors will
pursue this option, however, due to the process required to gain new label claims, including
producing additional safety and effectiveness data consistent with the new label claims. Within
3 years of the final publication of the Guidance Document, FDA expects product sponsors to
implement these changes.
The other document of importance in moving this process forward is the Proposed Rule on
the Veterinary Feed Directive, published in The Federal Register in April 2012. In this
document, FDA lays out the process by which they intend to streamline and improve the
VFD process in order to make it workable with the intentions of GFI #209 and GFI #213.
In order to get feedback from producers and veterinarians, FDA, with the assistance of USDA,
held a series of “listening sessions” around the country in the spring of 2013. During these
sessions, both producers and veterinarians expressed concerns about the cumbersome nature of
the current VFD system, the potential of adding more burdensome paperwork, access of small
producers and producers in remote locations to veterinary services, turnaround time of
paperwork and delivery of product in the face of disease outbreaks, and the distribution system,
amongst other concerns.
What does this mean for food-animal practitioners and their clients?
In 3 years, there will be no growth promotion or feed efficiency label claims.
All feed-additive products will have claims for treatment, prevention or control.
All feed-additive products will be marketed under the VFD category and all water medications
will be marketed under the RX category.
Paperwork will increase.
Expect some distribution channels to discontinue handling water and feed medications.
Depending on your relationship with your clientele, veterinarians will have increased input, if
not oversight, into the use of antimicrobials in the feed and water of food-producing animals.
Responsibility and potential liability will increase.
There will be some “hiccups” in the system.
Summary of Important Dates and Documents
1977. FDA issues NOOH for penicillins and tetracyclines in feed.
1993. Approval of Feed and Water Medications as RX or VFD.
2003. Guidance #152. Modern Pre-Approval Safety Evaluation Process applied to all approvals
since then and available to re-assess approvals before that time.
2012. Guidance Document #209
Draft Guidance #213
VFD update proposal.
Footnotes
In the ensuing years since 1977, FDA has transitioned from the term “subtherapeutic” and
“nontherapeutic” as lacking sufficient clarity, and instead has preferred the term “production
uses” in reference to compounds “typically administered through the feed or water on a herd- or
flock-wide basis and are approved for such uses as increasing weight gain or improving feed
1
efficiency…..not intended to manage a specific disease that may be ongoing or at risk of
occurring, but rather are expressly indicated and used for the purpose of enhancing the
production of animal-derived products (e.g., increasing rate of weight gain or improving feed
efficiency)”. This FDA definition would contrast with how Slaughter and other advocacy groups
use the term “subtherapeutic” to refer to any use other than treatment (e.g., treatment and
control).
FDA defines “medically important” drugs as those that have use in human medicine and are
also used in food-producing animals, and ranks their importance in Appendix A to GFI #152
Appendix A, as “critically important”, “highly important” or “important”. The rank is
determined based on 5 criteria:
2
1. Antimicrobial drugs used to treat enteric pathogens that cause food-borne disease
2. Sole therapy or one of few alternatives to treat serious human disease or drug is
essential component among many antimicrobials in treatment of human disease
3. Antimicrobials used to treat enteric pathogens in non-food-borne disease
4. No cross-resistance within drug class and absence of linked resistance with other drug
classes
5. Difficulty in transmitting resistance elements within or across genera and species of
organisms
Critically important antimicrobial drugs meet BOTH criteria 1 and 2. Highly important
antimicrobial drugs meet EITHER criteria 1 or 2. Important antimicrobial drugs meet Either
criterion 3 and/or 4 and/or 5.