Contains Nonbinding Recommendations 
 #213 
 
Guidance for Industry 
 
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 
 
 
 
Submit comments on this guidance at any time.  Submit written comments to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852.  Submit electronic comments to http://www.regulations.gov.  All written 
comments should be identified with the Docket No. FDA-2011-D-0889. 
For further information regarding this document, contact William T. Flynn, Center for 
Veterinary Medicine (HFV-1), Food and Drug Administration, 7519 Standish Place, Rockville, 
MD 20855, 240-276-9084. E-mail: william.flynn@fda.hhs.gov.   
Additional copies of this guidance document may be requested from the Communications Staff 
(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD  20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm  or http://www.regulations.gov. 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
 December 2013  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
I. INTRODUCTION ....................................................................................................................... 3 
II. BACKGROUND ........................................................................................................................ 3 
A. Therapeutic Uses that Help Assure the Health of Animals ........................................... 4 
B. Veterinary Oversight ...................................................................................................... 4 
III. MEDICALLY IMPORTANT ANTIMICROBIAL DRUGS ................................................... 5 
IV. VOLUNTARY ADOPTION OF JUDICIOUS USE PRINCIPLES ........................................ 5 
A. Voluntarily Phasing out Production Uses ...................................................................... 6 
B. Need for Veterinary Oversight of Medically Important Antimicrobial Drugs Used in 
the Feed or Water of Food-Producing Animals ...................................................... 6 
C. Additional Considerations. ............................................................................................. 8 
V. TIMELINE FOR VOLUNTARILY IMPLEMENTING CHANGES ....................................... 8 
VI. SUPPLEMENTAL NEW ANIMAL DRUG APPLICATIONS ............................................ 10 
A. Removing Production Uses/Changing Marketing Status ............................................ 10 
B.  Adding New Therapeutic Indications ......................................................................... 11 
VII. GENERIC DRUGS AND COMBINATIONS ...................................................................... 15 
A. Generic Applications.................................................................................................... 15 
B. Combination New Animal Drugs ................................................................................. 16 
VIII. REFERENCES..................................................................................................................... 18  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
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 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind FDA 
or the public.  You can use an alternative approach if the approach satisfies the requirements of the 
applicable statutes and regulations.  If you want to discuss an alternative approach, contact the 
FDA staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA 
staff, call the number listed on the previous page of this guidance. 
 
I. Introduction 
 
  This guidance is intended for sponsors of approved applications for new animal drugs and 
new animal drug combination products containing medically important antimicrobial new animal 
drugs for use in or on medicated feed or water of food-producing animals.  The guidance 
contains information for sponsors of such new animal drugs and combination products to 
facilitate voluntary changes to the conditions of use for such new animal drugs and combination 
products consistent with FDAs recommendations included in the guidance document entitled 
The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals 
(Judicious Use Guidance, GFI #209).   In particular, the purpose of this guidance is to provide 
sponsors with specific recommendations on how to supplement their approved new animal drug 
applications to align with FDAs GFI #209.  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in FDAs guidances means that 
something is suggested or recommended, but not required. 
 
II. Background 
 
  On April 11, 2012, FDA finalized a guidance document entitled The Judicious Use of 
Medically Important Antimicrobial Drugs in Food-Producing Animals (Judicious Use 
Guidance, GFI #209).  That final guidance represents the Agencys current thinking regarding 
antimicrobial drugs that are medically important in human medicine and used in food-producing 
animals.  Specifically, the final guidance discusses FDAs 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, 
3  Contains Nonbinding Recommendations 
 
the Judicious Use Guidance provides two recommended principles regarding the appropriate or 
judicious use of medically important antimicrobial drugs:  
 
(1) Limit medically important antimicrobial drugs to uses in animals that are considered 
necessary for assuring animal health, and   
(2) Limit medically important antimicrobial drugs to uses in animals that include veterinary 
oversight or consultation.  
 
As noted above, the purpose of this guidance is to provide sponsors with specific 
recommendations on how to voluntarily modify the use conditions of their medically important 
antimicrobial drug products to align with the above two principles.  The voluntary process 
outlined in this guidance would help to phase out the use of medically important antimicrobial 
drugs for production purposes and phase in veterinary oversight of therapeutic uses of these 
drugs. 
A. Therapeutic Uses that Help Assure the Health of Animals  
 As discussed in GFI #209, FDA believes that, in light of the risk that antimicrobial 
resistance poses to public health, the use of medically important antimicrobial drugs for 
production purposes in food-producing animals does not represent a judicious use of these drugs.  
Such uses are typically administered through the feed or water on a herd- or flock-wide basis and 
are currently approved for such uses as increasing rate of weight gain or improving feed 
efficiency.  
  Production uses are not directed at any specifically identified disease, but rather are 
expressly indicated and used for the purpose of enhancing the production of animal-derived 
products.  FDA believes that production use indications such as increased rate of weight gain 
or improved feed efficiency are no longer appropriate for the approved conditions of use for 
medically important antimicrobial drugs.  In contrast, FDA considers uses that are associated 
with the treatment, control, and prevention of specific diseases to be therapeutic uses that are 
necessary for assuring the health of food-producing animals.   
B. Veterinary Oversight  
  New animal drugs and new animal drug combination products are approved with one of 
three types of marketing status: (1) over-the-counter (OTC), (2) veterinary prescription (Rx), or 
(3) veterinary feed directive (VFD).  Products for which adequate directions for use can be 
written for use by lay persons are labeled for OTC marketing status.  When adequate directions 
can not be written in a manner that enables a layperson to use a drug safely and for the purposes 
for which it is intended, the drug is restricted to use under veterinary oversight as an Rx or VFD 
product. 
  FDA believes it is important to include veterinary oversight in the use of antimicrobial new 
animal drugs to assure their appropriate and judicious use.  Veterinarians play a critical role in 
the diagnosis of disease and in the decision-making process related to instituting measures to 
treat, control, or prevent disease.  As discussed in more detail below, FDA believes that the 
4  Contains Nonbinding Recommendations 
 
judicious use of medically important antimicrobial new animal drugs in the feed or water of 
food-producing animals needs the scientific and clinical training of a licensed veterinarian. 
 
III. Medically Important Antimicrobial Drugs 
  FDA uses the concepts set out in its Guidance for Industry (GFI) #152, Evaluating the 
Safety of Antimicrobial New Animal Drugs with Regard to their Microbiological Effects on 
Bacteria of Human Health Concern, in reviewing the human food safety component of new 
animal drug applications for medically important antimicrobial new animal drugs for use in 
food-producing animals. Guidance for Industry #152 includes an appendix that ranks 
antimicrobial drugs into three tiers, critically important, highly important, or important, in 
regard to their human medical importance.  At this time, FDA considers all antimicrobial drugs 
listed in Appendix A to GFI #152 (Appendix A) to be medically important in the context of 
implementing the recommendations outlined in GFI #209 and further discussed in this guidance 
document (GFI #213). We believe that the policy in GFI #209 and GFI #213 applies to all three 
tiers of medically important antimicrobial drugs at this time because each tier (and thus all of the 
drugs listed in Appendix A) contains drugs that have been previously assessed through the public 
processes used to develop GFI#152 and determined to be important for treating bacterial 
infections in people.  
  FDA recognizes that the list of drugs in Appendix A is not static and should be periodically 
reassessed and updated as necessary.  Such reassessment is necessary to take into consideration 
such factors as the development of new antimicrobials for human therapy, the emergence of 
diseases in humans, or changes in prescribing practices in the United States.  FDA intends to 
update Appendix A, as necessary, through a separate process that will also be subject to public 
comment.  However, because Appendix A identifies those antimicrobials that have been 
determined to be medically important to human medicine, FDA believes the existing Appendix 
A provides adequate clarity for purposes of moving forward with the recommendations outlined 
in GFI #209. Therefore, the current list of medically important antimicrobial drug classes that are 
the subject of this guidance includes: aminoglycosides, lincosamides, macrolides, penicillins, 
streptogramins, sulfonamides, and tetracyclines.  
 
IV. Voluntary Adoption of Judicious Use Principles 
  As discussed in the following section, FDA intends to work with affected drug sponsors to 
help them to voluntarily implement the principles described above through modifications to the 
approved conditions of use of their new animal drug products.  FDA believes a voluntary 
approach, conducted in a cooperative and timely manner, is the most effective approach to 
achieve the common goal of more judicious use of medically important antimicrobials in animal 
agriculture.  
  FDA recognizes that it is equally important that the Agency also work with the veterinary 
and animal producer communities, the end users of these products, to ensure that their concerns 
are taken into consideration as these changes are implemented.  One issue of concern is the 
5  Contains Nonbinding Recommendations 
 
ability of producers, particularly those with smaller operations in remote locations, to have 
adequate access to veterinary services.  Therefore, as steps are taken to phase in the voluntary 
changes discussed in this document, FDA is working collaboratively with United States 
Department of Agriculture (USDA) to engage the veterinary community and other stakeholders 
to explore strategic approaches (e.g., new models, pilot programs) to address this issue.   
A. Voluntarily Phasing out Production Uses 
 
  FDA is concerned about the risk that antimicrobial resistance poses to public health from 
the use of medically important antimicrobial drugs in food-producing animals for production 
purposes.  As a consequence of this concern, FDA will be working with affected drug sponsors 
who wish to voluntarily withdraw approved production uses of their medically important 
antimicrobial new animal drugs and combination new animal drug products.  This guidance is 
intended to facilitate the voluntary process by providing useful information for sponsors 
intending to revise their approved labeling through a supplemental new animal drug application.  
In addition, as discussed later in this guidance, FDA is asking affected sponsors to notify the 
Agency within 3 months from the date of publication of this final guidance to inform us of their 
intentions to make these voluntary changes.   
B. Need for Veterinary Oversight of Medically Important Antimicrobial Drugs Used in the 
Feed or Water of Food-Producing Animals  
  Prior to 1993, most antimicrobial drugs were approved for over-the-counter use in food-
producing animals and many of these were administered through medicated feed or drinking 
water.  At that time, the methods used by FDA 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.  In addition, FDAs recommended 
approach for conducting pre-approval microbial food safety assessments has evolved over time 
as the quantity and quality of epidemiologic and other data bearing on antimicrobial resistance 
has improved.  As a result, all antimicrobial new animal drugs for use in food-producing animals 
approved by CVM since 1993 have been labeled with Rx or 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 articles1.  This shift to a 
marketing status requiring veterinary oversight was viewed as an important step to mitigate the 
microbial food safety risks of antimicrobial new animal drugs, particularly for those drugs 
considered to be medically important. 
 
  Based on the available scientific evidence concerning antimicrobial resistance, including 
information about resistance trends associated with the use of medically important antimicrobial 
drugs in food-producing animals, FDA believes that the judicious use of medically important 
antimicrobial drugs intended for use in food-producing animals should involve the scientific and 
                                                 
1 A Type A medicated article is a concentrated new animal drug product used as a component in the manufacture 
of (1) another Type A medicated article, (2) an intermediate Type B medicated feed, or (3) a final formulation 
Type C medicated feed.  See definition at 21 CFR 558.3(b)(2).  
6  Contains Nonbinding Recommendations 
 
clinical training of a licensed veterinarian. This is because judicious use involves accurately 
identifying bacterial disease that is present or likely to be present and selecting the suitable 
antimicrobial drug. 
 
  In the case of prevention, judicious use includes a consideration by the veterinarian of 
relevant factors for determining the risk of a specific bacterial disease and for determining 
whether the use of medically important antimicrobials for prevention purposes is appropriate in a 
particular situation.  The decision by the veterinarian to use a specific approved drug or 
combination drug is based on factors such as the mode of antibacterial action, drug distribution 
in specific tissues, and the duration of effective drug levels at the site of infection. Other 
important factors veterinarians consider when determining the appropriateness of a preventive 
use include whether: (1) there is evidence of effectiveness, (2) such a preventive use is consistent 
with accepted veterinary practice, (3) the use is linked to a specific etiologic agent, (4) the use is 
appropriately targeted to animals at risk of developing a specific disease, and (5) no reasonable 
alternatives for intervention exist.  Numerous risk factors have been documented to increase 
susceptibility to bacterial disease, including environmental factors (such as temperature extremes 
and inadequate ventilation), host factors (such as age, nutrition, genetics, immune status), and 
other factors (such as stress of animal transport).  From FDAs standpoint, the administration of 
a drug to animals when a veterinarian determines that there is a risk of a specific disease, based 
on the presence of such risk factors, could be considered judicious prevention use.  For example, 
if a veterinarian determines, based on the clients production practices and herd health history, 
that cattle being transported or otherwise stressed are more likely to develop a certain bacterial 
infection, preventively treating these cattle with an antimicrobial approved for prevention of that 
bacterial infection would be considered a judicious use.  Another example would be the 
prevention of necrotic enteritis in broiler chickens.  In this case, the preventive use of an 
antimicrobial approved for such use is important to manage this disease in certain flocks in the 
face of concurrent coccidiosis, a significant parasitic disease in chickens.  On the other hand, 
FDA would not consider the administration of a drug to apparently healthy animals in the 
absence of any information that such animals were at risk of a specific disease to be judicious.  
FDA believes that veterinarians are uniquely qualified to determine which specific disease-
causing microorganisms are likely to be present in a particular situation and to determine 
appropriately timed administration to prevent disease based on specific, known risk. 
  For these reasons, in FDAs 1999 proposed rule on veterinary feed directives (64 FR 35966; 
July 2, 1999), the Agency gave antimicrobial resistance as a key example of a reason it can be 
important for medicated feed to be administered under a veterinarians supervision.  FDA stated, 
control of the usage of certain antimicrobials is critical to reducing unnecessary use of such 
drugs in animals and to slowing or preventing the development of bacterial resistance to 
antimicrobial drugs.  
  Accordingly, FDA recommends that affected drug sponsors voluntarily revise the 
conditions of use of their medically important antimicrobial new animal drugs and combination 
new animal drug products to reflect the need for the professional oversight of a licensed 
veterinarian.  This would mean a change from OTC to VFD status for medicated feed products 
and from OTC to Rx status for medicated drinking water products.  A proposed timeline for 
making such changes is discussed in more detail below.  FDA acknowledges that in order to 
facilitate the OTC to VFD change in marketing status, existing requirements related to the 
7  Contains Nonbinding Recommendations 
 
distribution and use of VFD drugs must be updated and streamlined.  Therefore, concurrent with 
the development of this guidance, FDA is actively pursuing revisions to the VFD regulations (in 
21 CFR part 558) through the rulemaking process.  Some of the key changes being considered 
include better alignment between the criteria for appropriate veterinary supervision or oversight 
and those established as part of veterinary licensing and practice requirements and streamlining 
administrative procedures.  To facilitate the transition from OTC to VFD status, FDA believes it 
is critically important that changes such as these be implemented to minimize impacts on 
veterinarians, the animal feed industry, and animal producers.  
  While FDA believes that all medically important antimicrobial new animal drug products 
should be marketed with the appropriate professional oversight restriction, at this time FDA is 
most concerned with medically important antimicrobial new animal drugs and combination new 
animal drug products intended for use in or on the feed or water of food-producing animals.   As 
discussed in GFI#209, FDAs current methodology for assessing antimicrobial risks associated 
with the use of antimicrobial new animal drugs in food-producing animals 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.  Because feed or water use 
antimicrobial drugs are typically administered to entire herds or flocks of food-producing 
animals, such uses pose higher risk to public health than the administration of such drugs to 
individual animals or targeted groups of animals.  For that reason, this guidance is focused on 
those medically important antimicrobial new animal drugs that are approved for use in the feed 
or water of food-producing animals.  
C. Additional Considerations.  
  It is important to note that any extralabel use of medicated feed 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 in an extralabel manner. Therefore, when production 
claims 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. 
 
V. Timeline for Voluntarily Implementing Changes 
  The Agency recognizes the significance of the proposed changes and the potential impacts 
such changes will have on the animal pharmaceutical industry, animal producers, the animal feed 
industry, and the veterinary profession.  For this reason, FDA is currently pursuing a strategy for 
the voluntary adoption of these changes in an effort to minimize the impacts and provide for an 
orderly transition. FDA encourages all sponsors of affected new animal drugs and new animal 
drug combination products to contact the Agency and initiate steps to change product labeling 
and approved conditions of use through the process outlined in this guidance. 
  FDA also believes it is critical to see meaningful progress toward eliminating production 
uses of medically important antimicrobial drugs and bringing the remaining therapeutic uses of 
such drugs in or on the feed or water of food-producing animals under the oversight of 
8  Contains Nonbinding Recommendations 
 
veterinarians.  In order to ensure progress under the cooperative framework outlined in this 
guidance, FDA will monitor progress to assess whether these changes are being adopted along 
the timelines discussed below.  FDA is confident that the objective of phasing in these changes 
can be met through the cooperative process discussed in this guidance, which is why we are 
initially pursuing this voluntary approach. If, after the period of evaluation of the three year 
phase in, we determine that adequate progress has not been made, we will consider whether 
further action under the existing provisions of the FD&C Act may be appropriate.  To assist FDA 
in effectively monitoring rates of adoption in the industry, we request that sponsors of affected 
products (i.e., those products containing antimicrobial new animal drugs of importance to human 
medicine that are administered in medicated feed or drinking water of food-producing animals) 
notify the Agency of their intentions to engage in the voluntary process to modify their product 
labeling within 3 months from the date of publication of this final guidance.  FDA anticipates 
that sponsors of affected products should be able to complete implementation of the changes 
discussed in this final guidance within 3 years of the date of publication.  
  FDA intends to keep the public apprised of progress.  First, FDA is making public on its 
website a listing of all antimicrobial products affected by the guidance.  Second, FDA intends to 
notify affected drug sponsors and, following the 3-month notification period, FDA intends to 
publish summary information to provide an indicator of the level of engagement of affected drug 
sponsors in the voluntary process.  In addition, the public will be notified of completed changes 
to affected products through publication of approval of supplemental new animal drug 
applications.  
  Upon issuance of this final guidance, the Agency will monitor the progress of its strategy 
for the voluntary adoption of the changes outlined, including the progress of measures intended 
to facilitate an orderly and minimally disruptive transition.  Three years from the date of 
publication of this final guidance, FDA intends to evaluate the rate of adoption of the proposed 
changes across affected products.  The Agency will then consider further action as warranted in 
accordance with existing provisions of the FD&C Act for addressing matters related to the safety 
of approved new animal drugs. 
  FDA recognizes that the proposed changes in the use of these antimicrobial drugs have 
significant practical implications for animal producers, veterinary practitioners, animal drug 
sponsors, and feed mills.  In particular, as mentioned previously, implementing changes to 
streamline existing VFD requirements is pivotal to facilitating the transition to greater veterinary 
oversight (i.e., from OTC to VFD marketing status) for many of these products.  Therefore, the 
3-year timeframe for voluntary phase-in noted above is intended to provide sufficient time for 
the necessary changes to the existing VFD requirements to be developed and implemented 
through notice and comment rulemaking.  Although FDA is committed to completing this 
rulemaking process within the 3-year timeframe for implementing the changes discussed in this 
guidance, FDA is prepared to extend the timeframe, as necessary, to ensure that it coincides with 
the implementation of the revised VFD requirements.  
  The 3-year timeframe for voluntary phase-in is also intended to provide time for animal 
drug sponsors to make these changes in an efficient and practical manner, and for other 
stakeholders to prepare for the resulting changes in management/business practices. When 
several approved products are involved (e.g., combination drug approvals containing the same 
9  Contains Nonbinding Recommendations 
 
active ingredients; same active ingredient in different dosage forms), sponsors are encouraged to 
coordinate implementation when practicable. 
   
VI. Supplemental New Animal Drug Applications 
A. Removing Production Uses/Changing Marketing Status  
  The procedures in this section (VI.A) apply to the situation where no new indications are 
being proposed.  In the limited circumstances where a sponsor would be proposing that a new 
therapeutic indication be added, the procedures set forth at section VI.B below for submitting a 
supplemental application should be followed instead.  As always, FDA encourages sponsors to 
consult with FDA prior to submitting supplemental applications to ensure that sponsors are 
targeting their submissions to answer questions that are relevant to the particular drug.  The 
recommendations below, which, as guidance, establish no legally enforceable requirements, 
apply when sponsors who wish to voluntarily pursue judicious use changes are submitting 
supplemental new animal drug applications under 21 CFR 514.8.  
1. Administrative Procedures 
  Sponsors who wish to voluntarily remove production use claims and change the marketing 
status for the remaining approved feed or water uses of affected products should indicate that 
their supplemental application is being submitted in accordance with GFI #213.  Such 
supplemental applications do not need to include additional safety or effectiveness data.  
Sponsors of such applications would either (1) propose to change the marketing status to VFD or 
Rx and voluntarily withdraw the approval for all production uses or (2) for those applications 
without approved production uses, such sponsors would only propose a change in marketing 
status to VFD or Rx.  No new indications would be proposed by the sponsors and in most cases 
the sponsors would only be required to submit revised labeling.   
2. Applicable Supplemental New Animal Drug Application Technical Sections 
  Type A medicated articles and their associated medicated feeds should bear the VFD 
statement found in this Agencys regulations at 21 CFR 558.6(f) and medicated drinking water 
products (e.g., water soluble powders, concentrated solutions, etc.) should bear the Rx statement 
found in section 503(f)(4) of the FD&C Act (21 U.S.C. 353(f)(4)).  The Type A medicated 
article and representative medicated feed labeling (Blue Bird) should be included in the 
supplemental application to verify: 1) the VFD statement found in this Agencys regulations at 
21 CFR 558.6(f) has been appropriately added to all the labeling (Type A medicated article and 
Blue Bird feed labeling), and 2) the indications, mixing directions, feeding directions, etc., have 
been revised to reflect the voluntary withdrawal of the production use(s).  Labeling for 
medicated drinking water products should be included in the supplemental application to verify:  
1) the Rx statement found in section 503(f)(4) of the FD&C Act (21 U.S.C. 353(f)(4)) has been 
appropriately added to the labeling, and 2) the indications, directions for use, etc., have been 
revised to reflect the voluntary withdrawal of the production use(s). 
10  Contains Nonbinding Recommendations 
 
B.  Adding New Therapeutic Indications 
  In some cases, it has been suggested that there could be a therapeutic benefit associated with 
the production use of a drug.  In situations where this could be the case, concerns have been 
raised that removing production uses from approved conditions of use will have negative animal 
health impacts.  In those cases, where scientific evidence demonstrates a therapeutic benefit 
associated with the use of the drug for treating, controlling, or preventing a particular disease, 
sponsors could wish to seek new therapeutic indications to fill the therapeutic needs of animals. 
 
  FDA stresses that such new indications must be based on scientific evidence that such drug 
is safe and effective for the intended therapeutic use.  Such new therapeutic indications should be 
directed at specifically identified diseases and should involve dosage regimens that provide the 
desired therapeutic effect while minimizing overall extent of use.  
1. Administrative Procedures 
  Sponsors who wish to seek new therapeutic indications for use of affected products should 
indicate that their supplemental application is being submitted in accordance with GFI #213. 
Because new therapeutic indications are being proposed, these supplemental applications require 
the inclusion of additional safety and effectiveness data.  These supplemental applications would 
need to include specific information as follows:  
2. Applicable Supplemental New Animal Drug Application Technical Sections 
 
  a. Labeling 
 
  Type A medicated articles and their associated medicated feeds should bear the VFD 
statement found in this Agencys regulations at 21 CFR 558.6(f) and medicated drinking water 
products (e.g., water soluble powders, concentrated solutions, etc.) should bear the Rx statement 
found in section 503(f)(4) of the FD&C Act (21 U.S.C. 353(f)(4)).  The Type A medicated 
article and representative medicated feed labeling (Blue Bird) should be included in the 
supplemental application to verify: 1) the VFD statement found in this Agencys regulations at 
21 CFR 558.6(f) has been appropriately added to all the labeling (Type A medicated article and 
Blue Bird feed labeling), and 2) the indications, mixing directions, feeding directions, etc., have 
been revised to reflect the voluntary withdrawal of the production use(s).  Labeling for 
medicated drinking water products should be included in the supplemental application to verify:   
1) the Rx statement found in section 503(f)(4) of the FD&C Act (21 U.S.C. 353(f)(4)) has been 
appropriately added to the labeling, and 2) the indications, directions for use, etc., have been 
revised to reflect the voluntary withdrawal of the production use(s).  In both cases, the labeling 
would need to reflect the new therapeutic indications for use. 
 
  b. Chemistry, Manufacturing, and Controls 
 
  The recommendations in this section assume there is no change in the chemistry, 
manufacturing and controls (CMC) information for the Type A medicated article or medicated 
drinking water products, including the product formulation, raw materials, manufacturing 
process, controls and packaging.  If there are changes to the CMC information for the Type A 
11  Contains Nonbinding Recommendations 
 
medicated article or medicated drinking water product associated with the new therapeutic 
indication, the sponsor should provide a description of such changes in the supplemental 
application, along with appropriate documentation and data to support the changes.  See 21 CFR 
514.8(b). 
 
Medicated Drinking Water Product  
  If the new indication provides for use of the medicated drinking water product at the same 
concentration or concentration range as currently approved, no additional chemistry, 
manufacturing and controls (CMC) information is required.  If the medicated drinking water 
product will be used to prepare medicated water at a different concentration than currently 
approved, the sponsor should address stability of the medicated drinking water at the new 
concentration (Ref. 1).  
 
Type A Medicated Article 
  If the new indication is for a currently approved species and provides for a medicated feed 
inclusion rate currently approved for that species, no additional CMC information is required.  
 
  If the new indication is for a medicated feed inclusion rate outside of the currently approved 
inclusion rate or range (i.e., lower than the lowest currently approved inclusion rate or higher 
than the highest currently approved inclusion rate for that species), the sponsor should address 
homogeneity, non-segregation, and stability of the drug in representative medicated feeds at the 
higher/lower inclusion rate (Ref. 1).  In addition, the sponsor should demonstrate that the 
approved medicated feed assay method is valid for assay of feeds manufactured at the 
higher/lower inclusion rate or provide a new method that is capable of assaying the feed (Refs. 2, 
3, and 4). 
 
  If the new indication is for a species not currently approved, the sponsor should address 
homogeneity, non-segregation, stability, and medicated feed assay methodology in representative 
medicated feeds at the highest and lowest proposed medicated feed inclusion rates. 
 
  c. Human Food Safety 
 
Toxicology/Residue Chemistry 
  Toxicology information associated with the original approval was considered for currently 
approved antimicrobial new animal drugs, and that information was the basis of the acceptable 
daily intake (ADI) that drove the residue chemistry conclusions (target tissue, tolerance, 
withdrawal times, etc.) for those approvals.  The toxicological assessment is not expected to be 
reconsidered under proposed therapeutic indications with similar conditions of use to those 
corresponding to the production use (see Impact on Human Intestinal Flora below).  If a new, 
proposed therapeutic indication has corresponding conditions of use (same species, with 
dose/duration/formulation/route of administration, etc.) that fit within existing residue chemistry 
parameters and are covered by previous residue chemistry evaluations, we do not anticipate that 
the sponsor will need to provide additional residue chemistry data or information.  Sponsors are 
encouraged to contact CVM if they have any toxicological assessment questions. 
 
  
12  Contains Nonbinding Recommendations 
 
Microbial Food Safety 
Antimicrobial Resistance 
  It should be noted that, at the time of the original approval of older antimicrobial new 
animal drug applications, microbial food safety was most likely not considered in the same way 
or to the same extent as is currently the case.  The Agency is concerned, consistent with the 
general elements of judicious use discussed in section II above and GFI#152, that giving 
antimicrobial drugs to food-producing animals at low levels for long periods of time and in large 
numbers of animals may contribute to antibiotic resistance.  We expect any new indication(s) to 
(1) have an explicitly defined duration of dosing, (2) specify a therapeutic dose level, and (3) be 
available only to those animals that need the drug for the new indication, rather than the entire 
flock or herd when such use is not necessary. 
 
  Generally, these changes are expected to remove injudicious use indications, and to result 
only in the therapeutic use of medically important antimicrobial drugs in or on the feed or water 
of food-producing animals.  In addition, such indications for use should include risk mitigation 
measures intended to reduce antimicrobial resistance when these drugs are used in or on the feed 
or water of food-producing animals. 
 
  To assure these goals have been met, the approval of any new indications for use would also 
necessitate that microbial food safety concerns be addressed consistent with the objectives of 
GFI #152. Prior to submission of an application, sponsors should discuss with CVM the type of 
information needed for this purpose.  This information may include, but is not limited to: 
 
(1) Basic information on the subject antimicrobial new animal drug, including information 
on mechanisms of action, spectrum of activity, resistance mechanisms, transfer of 
resistance, pharmacokinetics and/or pharmacodynamics if known, proposed conditions of 
use and how these could influence resistance development, and information on 
susceptibility among bacteria of human health concern;  
 
(2) Information on the use of the subject antimicrobial new animal drug in or on the feed or 
water of food-producing animals, focusing on numbers of animals treated, class, 
consumption rates for food products from treated animals, and rates of contamination by 
bacteria of human health importance.  
 
(3) Information on the use of the subject antimicrobial drug (or drugs similar to the subject 
drug) in human medicine.  This information should address how loss of susceptibility of 
organisms of human health concern to the subject antimicrobial drug (or drugs similar to the 
subject drug) could impact human clinical medicine. 
 
(4) Information detailing how FDAs general elements of judicious use discussed in section 
II have been addressed.  Specifically, all approved indications should be for treatment, 
control and/or preventive use only, require veterinary oversight, and restrict use to an 
explicitly defined duration of dosing. FDA considers these measures to be significant risk 
mitigations consistent with the goals of GFI #152.  
 
13  Contains Nonbinding Recommendations 
 
  Upon review of this information, the Agency should be able to: 1) identify appropriate risk 
mitigations that would enable us to determine that the proposed use of the drug in food-
producing animals is safe (i.e., a reasonable certainty of no harm to human health); and 2) advise 
on the types of additional information or data needed to address any existing data gaps associated 
with the new, proposed use of the subject antimicrobial new animal drug. 
 
Impact of Antimicrobial Residues on Human Intestinal Flora 
  Based on the expected changes in use patterns for new indications described in the previous 
section, we do not anticipate that this issue will need to be addressed by sponsors.  However, if 
changes in conditions of use (dose/duration/formulation/route of administration) are proposed 
that are expected to increase overall human exposure to residues of antimicrobial new animal 
drugs in animal-derived food products, then sponsors will be asked to address the safety of their 
proposed use with respect to impact of residues or metabolites of antimicrobial new animal drugs 
and compounds with antimicrobial activity on the intestinal flora of human consumers (Ref. 5). 
 
  d. Target Animal Safety 
 
  Regarding previously approved antimicrobial new animal drugs, target animal safety 
information associated with the original approval has already been considered.  As long as any 
new, proposed therapeutic indication has conditions of use that are covered by previous target 
animal safety evaluations (same species, a dose within the approved dosage range, same or 
shorter duration, same route of administration, same formulation), we do not anticipate that the 
sponsor will need to provide additional data or information, unless the Agency becomes aware of  
human or animal health concerns that were not apparent at the time of the original target animal 
safety evaluation. 
 
  e. Evidence of Effectiveness 
 
Sponsors seeking approval of a new therapeutic indication should provide substantial 
evidence in support of the effectiveness of the new animal drug for the proposed new therapeutic 
indication.   As described in 21 CFR 514.4, the sponsor should provide information that will 
allow the Agency to determine that: 
 
   parameters selected for measurement and the measured responses reliably reflect 
effectiveness; 
    the results obtained are likely to be repeatable; 
   valid inferences can be drawn from these sources to the use of the new animal drug in the 
target population; and 
   the new animal drug is effective for the new therapeutic indication under the proposed 
conditions of use.  
 
The type of information required to demonstrate effectiveness will need to be determined on 
a case-by-case basis and be consistent with substantial evidence as described in 21 CFR 514.4.  
The Center will consider data from a wide variety of sources including literature, data generated 
by food animal production facilities or universities, and other existing information for a 
substantial evidence package.  Sponsors should not limit their consideration of potential useful 
14  Contains Nonbinding Recommendations 
 
data to only data that is prospectively generated.  Previously approved therapeutic indications 
that are very similar or related to the new therapeutic indication could also provide inferential 
value in support of the new indication (e.g., a new control of bovine respiratory disease 
indication added to an application that has a previously approved treatment of bovine 
respiratory disease indication with a similar dosage regimen). 
 
  Sponsors are encouraged to discuss approaches to satisfying the requirements of substantial 
evidence of effectiveness with CVM. 
 
  f. Environmental Impact 
 
  By regulation (see 21 CFR 514.1(b)(14)), the Environmental Impact section must include 
either an environmental assessment (EA) (see 21 CFR 25.40), or a claim for categorical 
exclusion (see 21 CFR 25.30, 25.33).  Under 21 CFR 25.15(a), a claim of categorical exclusion 
must include a statement of compliance with the categorical exclusion criteria and must state that 
to the sponsors knowledge, no extraordinary circumstances exist. Environmental Impact 
Considerations and directions for preparing an EA can be found in 21 CFR Part 25. 
 
VII. Generic Drugs and Combinations 
 
Revising the conditions of use in applications for a pioneer single ingredient new animal 
drug products may have an effect on abbreviated (generic) new animal drug applications and 
combination new animal drug applications that reference these single ingredient products.  The 
effects that submission and approval of a supplement for the pioneer drug may have on these 
generic or combination drugs are discussed in this section.  FDA intends to work expeditiously 
with the sponsors of affected generic and combination new animal drug applications to align 
their products with the revised conditions of use specified in the referenced (i.e., pioneer) 
applications for the single ingredient new animal drug products. 
A. Generic Applications 
 
  If the approved conditions of use for a new animal drug application for a medically 
important antimicrobial new animal drug are revised under this guidance by voluntarily 
withdrawing a production use, the approved labeling for any currently approved generic 
application(s) that references the original new animal drug application must generally be revised 
in a similar fashion, as is now standard practice.  FDA will contact affected generic drug 
sponsors when these revisions become necessary.  Consistent with current practice, we expect 
that the generic sponsor will submit a supplemental application to come into compliance with the 
revised labeling of the reference listed new animal drug (RLNAD) within 60 days after FDA 
notifies the generic sponsor that the approved conditions of use for the RLNAD have been 
revised.  In such cases, if the generic labeling is not revised accordingly, the generic application 
holder(s) faces the possibility of suspension of the generic application under section 512(c)(2)(G) 
of the FD&C Act (21 U.S.C. 360b(c)(2)(G)).  With regard to suspension, FDA intends to follow 
the procedures outlined in its regulations at 21 CFR 314.153(b) relating to human generic drug 
15  Contains Nonbinding Recommendations 
 
suspensions until generic new animal drug regulations implementing section 512(c)(2)(G) of the 
FD&C Act (21 U.S.C. 360b(c)(2)(G) are finalized. 
 
  In addition, any future generic sponsor that wants to use such a drug as its referenced listed 
new animal drug cannot include the production use that was voluntarily withdrawn from the 
pioneer application in its generic application because under section 512(n)(1)(F) of the FD&C 
Act (21 U.S.C. 360b(n)(1)(F)) the generic sponsor must submit labeling that is the same as the 
labeling approved for the referenced listed new animal drug with a few exceptions not relevant 
here.  Furthermore, under section 512(c)(2)(A)(vii) of the FD&C Act (21 U.S.C. 
360(c)(2)(A)(vii)), the Agency cannot approve an abbreviated new animal drug application 
unless the labeling proposed for the generic product is the same as the labeling approved for the 
referenced listed new animal drug with a few exceptions not relevant for purposes of this draft 
guidance. 
B. Combination New Animal Drugs 
 
  The term Combination new animal drug is defined in the substantial evidence provisions of 
21 CFR Part 514 to mean a new animal drug that contains more than one active ingredient or an 
animal drug that is applied or administered simultaneously in a single dosage form or 
simultaneously in or on animal feed or drinking water (See 21 CFR 514.4(c)(1)(i)).  Although 
the term combination new animal drug applies both to products intended for use in or on animal 
feed and products intended for use in the drinking water of animals, the majority of approved 
combination new animal drug products are feed use combination drug products.  
 
  Most feed use combination new animal drugs are combinations of individual Type A 
medicated articles that have previously been separately approved.  So, for example, a 3-way feed 
use combination actually involves four approved new animal drug applications, one for the 
combination and one for each of the three individual Type A medicated articles.  The holder of 
an approved feed use combination new animal drug application is typically also the holder of an 
approved application for at least one of the individual Type A medicated articles in the 
combination. 
1. Production Uses. 
  As discussed above, FDA is requesting affected sponsors to voluntarily withdraw 
production uses of their medically important antimicrobial new animal drugs and combination 
new animal drug products.  In those instances where an approved combination new animal drug 
product with a production claim includes a medically important antimicrobial new animal drug 
and the sponsor of the individually approved new animal drug application for a medically 
important antimicrobial new animal drug has voluntarily withdrawn the production use claims,  
FDA expects the sponsor of the affected combination new animal drug product will voluntarily 
follow suit and similarly withdraw the production use claim from the combination new animal 
drug application.  If sponsors of these affected combination new animal drug products do not 
voluntarily withdraw the production use claim from the combination new animal drug 
application, FDA intends to consider further action as warranted in accordance with existing 
provisions of the FD&C Act for addressing matters related to the safety of approved combination 
new animal drugs. 
16  Contains Nonbinding Recommendations 
 
 
2. Remaining Therapeutic Uses. 
 
  As discussed at section IV above, based on a number of factors FDA believes that the 
judicious use of medically important antimicrobial drugs intended for use in food-producing 
animals needs the scientific and clinical training of a licensed veterinarian.  This belief applies 
not only to individual medically important antimicrobial new animal drugs but also to 
combination new animal drug products incorporating such drugs.  However, as previously 
discussed, in recognition of the significant practical implications of revising the marketing status 
for these products, FDA has expressed its intent to pursue a strategy for voluntarily phasing in 
these changes over time in an effort to minimize the impacts and provide for an orderly 
transition.  As explained more fully in section V, FDA is proposing clear timelines for sponsors 
of the affected products to make these changes in order to ensure effective progress under the 
cooperative framework outlined in this guidance.   
 
  However, once a sponsor of an individual Type A medicated article that is also part of a 
combination new animal drug submits a supplement to switch the marketing status of the 
individual product to VFD or Rx, FDA expects the sponsor of the affected combination new 
animal drug product to voluntarily follow suit.  Indeed, for a combination new animal drug 
product containing individual Type A medicated articles intended for use in or on animal feed, 
this outcome is essentially compelled since a voluntary switch to VFD marketing status by one 
or more of the sponsors of the individual Type A medicated articles will automatically trigger the 
requirement for a VFD to be issued before the affected combination new animal drug product 
can be used in or on animal feed.  This is the case because under section 504(a)(1) of the FD&C 
Act, [a]ny animal feed bearing or containing a veterinary feed directive drug shall be fed to 
animals only by or upon a lawful veterinary feed directive issued by a licensed veterinarian in the 
course of the veterinarians professional practice. (21 USC 354(a)(1)).  Thus, the requirement 
for a VFD to be issued applies whenever a VFD drug will be used in feed, regardless of whether 
the VFD drug is being used by itself or in combination with other drugs.  Because a voluntary 
switch to VFD marketing status by one or more of the Type A medicated articles contained in a 
combination new animal drug product results, by operation of law, in the requirement for a VFD 
to be issued before a feed containing the combination new animal drug product can be fed to 
animals, in effect, the combination new animal drug product takes on VFD status also. 
 
  Therefore, we believe that in such instances the combination new animal drug product 
sponsors should also submit their own supplements to formally change the marketing status of 
the affected combination new animal drug products to VFD in a timely manner. 
    
  This outcome is consistent with the Agencys policy, as expressed in the substantial 
evidence notice of proposed rulemaking (62 FR 59835; Nov. 5, 1997) which provides that a 
combination new animal drug should generally bear VFD or Rx marketing status if one or more 
of the new animal drugs that make up the combination product were individually approved with 
VFD or Rx marketing status for any of the intended uses or conditions of use that are also 
applicable to the combination product.  
17  Contains Nonbinding Recommendations 
 
 
VIII. References 
 
1.  FDA 2008.  Guidance for Industry 5: Drug Stability Guidelines 
2.  FDA 2005.  Guidance for Industry 135: Validation of Analytical Procedures for Type C 
Medicated Feeds 
3.  FDA 2007.  Guidance for Industry #136: Protocols for the Conduct of Method Transfer 
Studies for Type C Medicated Feed Assay Methods 
4.  FDA 2007.  Guidance for Industry #137: Analytical Methods Description for Type C 
Medicated Feeds 
5.  FDA 2013.  Guidance for Industry #159: Studies to Evaluate the Safety of Residues of 
Veterinary Drugs in Human Food: General Approach to Establish a Microbiological 
ADI VICH GL36(R) 
6.  FDA 2012. Guidance for Industry #209: The Judicious Use of Medically Important 
Antimicrobial Drugs in Food-Producing Animals 
 
 
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