[Federal Register Volume 81, Number 178 (Wednesday, September 14, 2016)]
[Notices]
[Pages 63187-63191]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-21972]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-2635]


The Judicious Use of Medically Important Antimicrobial Drugs in 
Food-Producing Animals; Establishing Appropriate Durations of 
Therapeutic Administration; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, we) is 
soliciting comments regarding the establishment of appropriately 
targeted durations of use of antimicrobial drugs of importance to human 
medicine (i.e., medically important antimicrobial drugs) when they are 
administered in the feed or water of food-producing animals for 
therapeutic purposes. This activity is consistent with previous efforts 
by FDA to protect public health by promoting the judicious use of these 
drugs in food-producing animals.

DATES: Submit either electronic or written comments by December 13, 
2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-D-2635 for ``Establishing Appropriate Durations of Therapeutic 
Administration.'' Received comments will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at http://www.regulations.gov or at the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Cindy Burnsteel, Center for Veterinary 
Medicine (HFV-130), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 240-402-0817, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    On September 18, 2014, the President issued Executive Order 13676 
on ``Combating Antibiotic-Resistant Bacteria'' (https://www.gpo.gov/fdsys/pkg/FR-2014-09-23/pdf/2014-22805.pdf), underscoring the urgent 
need to address the global threat of antimicrobial resistance. The 
National Action Plan for Combating Antibiotic-Resistant Bacteria 
(National Action Plan) (March 2015, https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf) was developed in response to this Executive 
order, and presents a strategy for collaborative action by the U.S. 
Government in coordination with individuals and organizations within 
the human and animal health sectors. The plan establishes specific 
goals and objectives within a 5-year timeframe, outlines steps for 
implementing certain measures, and informs national policy development 
in order to combat the emergence of antimicrobial-resistant bacteria.
    FDA is actively engaged in several ongoing efforts to address 
antimicrobial resistance originating from the use of antimicrobial 
drugs that are important in human medicine (medically important 
antimicrobials) in food-

[[Page 63188]]

producing animals. These efforts have supported and continue to support 
the initiatives of the National Action Plan. Judicious use of medically 
important antimicrobials, which includes implementation of 
interventions (e.g., good husbandry practices) that can reduce the 
spread of antimicrobial resistance, is the cornerstone of Goal 1 in the 
National Action Plan, to ``Slow the Emergence of Resistant Bacteria and 
Prevent the Spread of Resistant Infections.'' FDA's approach to 
ensuring the judicious use of medically important antimicrobial drugs 
in food-producing animals has been presented in two Guidance for 
Industry (GFI) documents, GFI #209, ``The Judicious Use of Medically 
Important Antimicrobial Drugs in Food-Producing Animals'' \1\ (GFI 
#209) and GFI #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'' \2\ (GFI 
#213).
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    \1\ http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM216936.pdf.
    \2\ http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM299624.pdf.
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    GFI #209, published in April 2012, outlines FDA's fundamental 
principles of judicious use. These are: (1) Limiting medically 
important antimicrobial drugs to uses in food-producing animals that 
are considered necessary for assuring animal health and (2) limiting 
such drugs to uses that include veterinary oversight or consultation. 
In GFI #209, FDA stated that it generally considers uses that are 
associated with the treatment, control, or prevention of specific 
diseases to be uses that are necessary for assuring the health of food-
producing animals, in contrast to uses for production purposes (e.g., 
for growth promotion or improved feed efficiency) to enhance the 
production of animal-derived products.
    As discussed in GFI #209, FDA's 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, as is done 
with dosage form drugs (e.g., injectables, tablets, etc.). Therefore, 
FDA is more concerned with medically important antimicrobial new animal 
drugs and combination new animal drug products intended for use in feed 
or water of food-producing animals.
    GFI #213, published in December 2013, is based on the two 
fundamental principles of judicious use described in GFI #209 and 
provides specific recommendations for drug sponsors. These 
recommendations for sponsors of approved medically important 
antimicrobial drugs administered in feed or water to food-producing 
animals include: (1) Removing production indications \3\ (e.g., 
increased rate of weight gain and improved feed efficiency) and (2) 
incorporating veterinary oversight for the remaining therapeutic 
indications.
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    \3\ Production uses are also referred to as ``nontherapeutic'' 
or ``subtherapeutic'' uses, terms that we believe lack sufficient 
clarity (GFI #209).
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    FDA is working collaboratively with the sponsors of affected 
applications to facilitate the revision of product labeling to reflect 
the voluntary withdrawal of approval of production indications. 
Incorporating veterinary oversight is accomplished by changing the 
marketing status from over-the-counter (OTC) use to use by either 
veterinary feed directive (VFD), in the case of drugs administered in 
feed, or by veterinary prescription (Rx), in the case of drugs 
administered in water.
    In Section III of GFI #213, FDA states, ``all antimicrobial drugs 
listed in Appendix A to GFI #152 \4\ (Appendix A) [are considered] 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 [``critically important,'' 
``highly important,'' or ``important''] 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. 
. . . 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.''
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    \4\ GFI #152, ``Evaluating the Safety of Antimicrobial New 
Animal Drugs with Regard to their Microbiological Effects on 
Bacteria of Human Health Concern.'' (http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052519.pdf).
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    The implementation of GFI #213 is a critical step toward improving 
judicious use in veterinary practice, thereby minimizing the selection 
of antimicrobial-resistant microorganisms to help preserve the 
therapeutic effectiveness of medically important antimicrobial drugs. 
As stated previously, incorporating veterinary oversight is 
accomplished by changing the existing OTC marketing status of these 
drugs to either VFD marketing status, in the case of drugs administered 
in feed, or to veterinary Rx status, in the case of drugs administered 
in water. In GFI #213 and outreach related to the 2015 revisions made 
to the VFD regulations (http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/ucm449019.htm), FDA has stated that, in 
addition to veterinary oversight, use of these antimicrobials should be 
linked to a specific etiologic agent and that the antimicrobial should 
be administered for an appropriately targeted period of time, i.e., 
have a defined duration of use.
    As explained in GFI #213, we expect, among other things, that any 
new indications for medically important antimicrobials, including those 
used in feed or in drinking water, have defined durations of use. 
Consistent with this expectation, the recently revised VFD regulations 
in 21 CFR part 558 state that a lawful VFD, among other requirements, 
must document the duration of use of the VFD drug contained in the 
medicated feed (see 21 CFR 558.6(b)(3)(x)).
    Although GFI #213 sets out our expectation that new indications of 
medically important antimicrobial drugs used in or on feed and water 
will have defined durations of use, it does not address what to do with 
respect to some currently approved therapeutics that lack defined 
durations of use. Establishing defined durations of use for currently 
approved therapeutics will support FDA's efforts to foster stewardship 
of medically important antimicrobial drugs in food-producing animals 
and help preserve the effectiveness of these antimicrobials in animal 
and human medicine. Some examples of defined durations of use on the 
labeling of currently approved therapeutics are ``Feed continuously for 
5 days,'' ``Feed continuously for 5 days as the sole ration,'' ``Feed 
from weaning up to 120 pounds,'' and ``Do not feed to

[[Page 63189]]

chickens over 16 weeks (112 days) of age.''
    In section II, FDA invites comment on the establishment of 
appropriately targeted durations of use of medically important 
antimicrobial drugs administered to food-producing animals in feed or 
water for those therapeutics for which a defined durations of use is 
not included on currently approved labeling. Along with labeling that 
is silent on limits to the duration of use, some examples in which the 
duration of use is not defined on currently approved labeling are 
``Feed continuously'' and ``Feed continuously as the sole ration.''
    FDA will consider submitted comments as we develop a process by 
which sponsors of currently approved, medically important antimicrobial 
drugs, administered in feed or water to food-producing animals for 
therapeutic purposes, could establish appropriately targeted durations 
of use. We recognize that, in certain circumstances, some medically 
important antimicrobial drugs may have a range of safe and effective 
durations (see 21 CFR 514.4(b)(2)(i)). Approval of defined durations of 
use may be supported by existing effectiveness data, target animal 
safety data, human food safety studies, clinical pharmacology studies, 
disease pathophysiology, and/or other available information.
    Based on an April 2016 review, FDA identified six species (cattle, 
swine, chickens, turkeys, sheep, and honey bees) for which there are 
approved, medically important antimicrobials administered in medicated 
feed or drinking water for therapeutic purposes that do not currently 
have a defined duration of use included on labeling. We have 
summarized, in tabular form, the species and disease indications for 
which these drugs are approved without defined durations of use (see 
tables 1 through 6). Indications are summarized as disease conditions 
(see column entitled ``Indication/Disease'') and are listed with their 
associated antimicrobial drugs (see column titled ``Ingredient(s)''). 
These tables may assist members of the public who wish to comment on 
establishing appropriately targeted durations of use.

II. Issues for Consideration

    A key objective of FDA is to optimize the use of medically 
important antimicrobials by using a dosage strategy that maximizes drug 
effectiveness, minimizes target animal toxicity, and has an 
appropriately targeted duration of use to minimize the development of 
resistance to antimicrobial drugs of human medical importance. FDA 
invites comments on the questions below to assist in evaluating 
appropriately targeted durations of use for medically important 
antimicrobial drugs administered to food-producing animals in or on 
feed or in drinking water for those therapeutics for which a defined 
duration of use is not included on the currently approved labeling.
    For the species and disease indications listed in tables 1 through 
6, this request for comments is intended to: (1) Obtain additional 
information, especially from the animal agriculture, animal health, and 
veterinary communities, on the underlying diseases for these 
therapeutic indications, including periods when livestock or poultry 
are at risk of developing these diseases; (2) seek input on more-
targeted antimicrobial use regimens for these diseases, and husbandry 
practices that may help avoid the need for these antimicrobials, or 
that may help make more-targeted antimicrobial use regimens more 
effective; and (3) seek comment on strategies for updating affected 
product labeling, as appropriate, that does not currently include a 
defined duration of use.
    When commenting on an appropriately targeted duration of use for a 
medicated feed for use in a food-producing major species, please 
consider the target animal classes described in Appendix III of GFI 
#191, ``Changes to Approved NADAs--New ANDAs vs Category II 
Supplemental NADAs,'' \5\ and the periods when that class of animal is 
at risk of developing that disease. For the diseases/indications and 
antimicrobials listed in tables 1 through 6 for which the duration of 
use is undefined on labeling, please address the following questions 
based on your current practices:
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    \5\ http://www.fda.gov/downloads/animalveterinary/guidancecomplianceenforcement/guidanceforindustry/ucm052460.
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    1. When is the animal/class at risk of developing the disease?
    2. For how long do you administer X antimicrobial for Y indication 
if the labeling says ``feed continuously,'' or is silent on duration of 
use?
    3. What factors influence your decision when determining the 
duration of use?
    4. In addition to the drug labeling, what sources of information do 
you use in making a decision regarding duration of use?
    a. Past personal experience;
    b. drug industry representatives;
    c. extension agents;
    d. producer or veterinary medicine magazines;
    e. online resources;
    f. formularies; and
    g. other.
    5. What pros and cons do you see if durations of use are defined 
for all of these antimicrobials?
    6. What reasonable alternatives to medically important 
antimicrobials, including other pharmaceutical or non-pharmaceutical 
approaches, are available for managing the diseases listed in tables 1 
through 6?
    In the following tables, undefined durations of use means, for 
example, therapeutics that include the statement ``feed continuously,'' 
``feed continuously as the sole ration'' or other similar language on 
their labeling, or that have labeling that is silent on limits to the 
duration of use. Ingredient(s) means a medically important 
antimicrobial ingredient and any feed use combination approvals 
including that ingredient. When more than one ingredient is listed, 
that drug combination is only available in a fixed-ratio, combination 
drug Type A medicated article for use in complete Type C medicated 
feeds.

  Table 1--Antimicrobials With Approved Therapeutic (Treatment/Control/
    Prevention) Indications With Undefined Durations of Use in Cattle
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Anaplasmosis...........................  Chlortetracycline.
Bacterial enteritis....................  Chlortetracycline.
                                         Oxytetracycline.

[[Page 63190]]

 
Liver Abscesses........................  Chlortetracycline.
                                         Tylosin.
                                         Oxytetracycline.
                                         Neomycin With Oxytetracycline.
                                         Virginiamycin.
Pneumonia..............................  Chlortetracycline.
------------------------------------------------------------------------



  Table 2--Antimicrobials With Approved Therapeutic (Treatment/Control/
    Prevention) Indications With Undefined Durations of Use in Swine
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Atrophic rhinitis......................  Tylosin.
                                         Tylosin With Sulfamethazine.
                                         Chlortetracycline.
                                         Sulfamethazine.
Pneumonia..............................  Tylosin With Sulfamethazine.
                                         Oxytetracycline.
GI-Parasites \1\.......................  Hygromycin B.
GI-Bacterial \2\.......................  Tylosin With Sulfamethazine.
                                         Lincomycin.
                                         Chlortetracycline With
                                          Sulfamethazine.
                                         Chlortetracycline.
                                         Oxytetracycline.
Jowl abscesses.........................  Chlortetracycline.
------------------------------------------------------------------------
\1\ An example of Gastrointestinal (GI)-Parasite indication is ``Control
  of infestations of large roundworms (Ascaris suis), nodular worms
  (Oesophagostomum dentatum), and whipworms (Trichuris suis).''
\2\ Examples of Gastrointestinal (GI)-Bacterial indications are: ``For
  treatment of swine dysentery''; ``To help prevent bacterial swine
  enteritis''; and ``Treatment of bacterial swine enteritis
  (salmonellosis or necrotic enteritis caused by Salmonella choleraesuis
  and vibrionic dysentery).''



  Table 3--Antimicrobials With Approved Therapeutic (Treatment/Control/
   Prevention) Indications With Undefined Durations of Use in Chickens
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Infectious Coryza......................  Ormetoprim with
                                          Sulfadimethoxine.
Chronic Respiratory Disease............  Oxytetracycline.
                                         Oxytetracycline.
Necrotic Enteritis/Colibacillosis......  Ormetoprim with
                                          Sulfadimethoxine.
                                         Lincomycin.
                                         Virginiamycin.
Fowl Cholera...........................  Ormetoprim with
                                          Sulfadimethoxine.
Gastrointestinal (GI)-Parasites \1\....  Hygromycin B.
Coccidiosis............................  Ormetoprim with
                                          Sulfadimethoxine.
------------------------------------------------------------------------
\1\ An example of Gastrointestinal (GI)-Parasite indication is, ``As an
  aid in the control of infections of large roundworms (Ascaris galli),
  cecal worms (Heterakis gallinae), and capillary worms (Capillaria
  obsignata).''



  Table 4--Antimicrobials With Approved Therapeutic (Treatment/Control/
   Prevention) Indications With Undefined Durations of Use in Turkeys
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Coccidiosis............................  Ormetoprim with
                                          Sulfadimethoxine.
Fowl Cholera...........................  Ormetoprim with
                                          Sulfadimethoxine.
------------------------------------------------------------------------



[[Page 63191]]



  Table 5--Antimicrobials With Approved Therapeutic (Treatment/Control/
    Prevention) Indications With Undefined Durations of Use in Sheep
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Vibrionic Abortion.....................  Chlortetracycline.
Enterotoxemia..........................  Chlortetracycline.
------------------------------------------------------------------------



  Table 6--Antimicrobials With Approved Therapeutic (Treatment/Control/
  Prevention) Indications With Undefined Durations of Use in Honey Bees
------------------------------------------------------------------------
           Indication/disease                     Ingredient(s)
------------------------------------------------------------------------
Foulbrood..............................  Oxytetracycline.
------------------------------------------------------------------------


    Dated: September 7, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-21972 Filed 9-12-16; 11:15 am]
 BILLING CODE 4164-01-P