Withdrawal of Notices of Opportunity for a Hearing; Penicillin and Tetracycline Used in Animal Feed, 79697-79701 [2011-32775]
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Federal Register / Vol. 76, No. 246 / Thursday, December 22, 2011 / Notices
79697
TABLE 3—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN—Continued
Number of
respondents
21 CFR section
Total ..............................................................................
Number of
disclosures
per
respondent
Total annual
disclosures
Average
burden per
disclosure
........................
........................
........................
........................
Total hours
61,329
1 Five
percent of establishments that fall under the Clinical Laboratory Improvement Amendments of 1988 that transfuse blood and components and FDA-registered blood establishments (0.05 × 4,059 + 1,706).
2 Notification of donors determined not to be eligible for donation based on failure to satisfy eligibility criteria.
3 Notification of donors deferred based on reactive test results for evidence of infection due to communicable disease agents.
Dated: December 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011–32778 Filed 12–21–11; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket Nos. FDA–1977–N–0019 (formerly
1977N–0230), FDA–1977–N–0014 (formerly
977N–0231), FDA–1977–N–0022 (formerly
1977N–0316), and FDA–1977–N–0224
(formerly 1977N–0317)]
Withdrawal of Notices of Opportunity
for a Hearing; Penicillin and
Tetracycline Used in Animal Feed
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA or the Agency) is
withdrawing two 1977 notices of
opportunity for a hearing (NOOH),
which proposed to withdraw certain
approved uses of penicillin and
tetracyclines intended for use in feeds
for food-producing animals based in
part on microbial food safety concerns.1
(Refs. 1 and 2) FDA is taking this action,
and closing the corresponding dockets,
because: FDA is engaging in other
ongoing regulatory strategies developed
since the publication of the 1977
NOOHs with respect to addressing
microbial food safety issues; FDA would
update the NOOHs to reflect current
data, information, and policies if, in the
future, it decides to move forward with
withdrawal of the approved uses of the
new animal drugs described in the
NOOHs; and FDA would need to
prioritize any withdrawal proceedings
(for example, take into account which
withdrawal(s) would likely have the
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SUMMARY:
1 FDA’s approval to withdraw the approved uses
of the drugs was based on three statutory grounds:
(1) The drugs are not shown to be safe (21 U.S.C.
360b(e)(1)(B)); (2) lack of substantial evidence of
effectiveness (21 U.S.C. 360b(e)(1)(C)); and (3)
failure to submit required reports (21 U.S.C.
360b(e)(2)(A)).
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most significant impact on the public
health) if, in the future, it decides to
seek withdrawal of the approved uses of
any new animal drug or class of drugs.
FDA is also withdrawing the companion
proposed rules to these NOOHs. (Refs.
3 and 4)
DATES: This notice is effective December
22, 2011.
ADDRESSES: Submit electronic
comments to https://www.regulations.
gov. Submit written comments to the
Division of Dockets Management (HFV–
305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852.
FOR FURTHER INFORMATION CONTACT:
William Flynn, Center for Veterinary
Medicine (HFV–1), Food and Drug
Administration, 7519 Standish Pl.,
Rockville, MD 20855, (240) 276–9000,
email: William.flynn@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
Questions regarding the use of
antimicrobial drugs in food-producing
animals have been raised and debated
for many years. (Ref. 5) 2 Following a
report that was issued by the British
government in 1969 on the use of
antibiotics in veterinary medicine and
animal husbandry, known as the
‘‘Swann Report,’’ the Commissioner of
Food and Drugs established a task force
to review the use of antibiotic drugs in
animal feeds. The task force, established
in 1970, included specialists on
infectious diseases and animal science
from FDA, the National Institutes of
Health, the U.S. Department of
2 The term ‘‘antimicrobial’’ refers broadly to drugs
with activity against a variety of microorganisms
including: Bacteria, viruses, fungi, and parasites.
Antimicrobial drugs that have specific activity
against bacteria are referred to as antibacterial or
antibiotic drugs. However, the broader term
‘‘antimicrobial,’’ commonly used in reference to
drugs with activity against bacteria, is used in this
document interchangeably with the terms
antibacterial or antibiotic. Antimicrobial resistance
is the ability of bacteria or other microbes to resist
the effects of a drug. Antimicrobial resistance, as it
relates to bacterial organisms, occurs when bacteria
change in some way that reduces or eliminates the
effectiveness of drugs, chemicals, or other agents
designed to treat bacterial infections. (Ref. 5)
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Agriculture, and the Centers for Disease
Control and Prevention, as well as
representatives from universities and
industry. The task force identified three
primary areas of concern (human health
hazard, animal health hazard, and
antibiotic effectiveness) and guidelines
were established to show whether the
use of any antibiotic or antibacterial
agent in animal feed presents a hazard
to human and animal health. (Refs. 1
and 6) The task force also made certain
recommendations concerning
restrictions on the use of antibiotic
drugs in animal feeds at growth
promotion and subtherapeutic levels.
(Ref. 6)
In 1972, FDA published the
conclusions and recommendations of
that task force and proposed to require
sponsors to submit specific data for
antibiotic drugs in animal feeds
intended for subtherapeutic or growth
promotion use when such drugs are also
used in human clinical medicine. (Ref.
6) In 1973, FDA finalized this proposal
in 21 CFR 135.109 (re-codified at 21
CFR 558.15 in 1974).3 (Refs. 7, 8, and 9)
This section provided that FDA would
propose to revoke approved uses in
animal feed of antibiotic and
sulfonamide drugs unless certain data
were submitted which satisfactorily
addressed the outstanding safety and
effectiveness issues.
By 1974, FDA had begun to review
the data submitted by the sponsors of
the antibiotic products and requested
that the National Advisory Food and
Drug Committee (NAFDC) review the
data and make recommendations on the
subtherapeutic uses of penicillin and
tetracyclines. A subcommittee (the
Antibiotics in Animal Feeds
subcommittee) was appointed to work
in conjunction with expert consultants
to address these issues. With respect to
the penicillin-containing drugs, the
subcommittee recommended FDA
immediately withdraw approval of the
subtherapeutic uses of penicillin. The
3 Since that time, portions of 21 CFR 558.15 have
been removed because those portions of the
regulation were determined to be redundant or
obsolete. (See 75 FR 16001, March 31, 2010.)
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NAFDC accepted the subcommittee’s
recommendation and recommended to
FDA that it ‘‘immediately withdraw
approval for the subtherapeutic uses of
penicillin, i.e., growth promotion/feed
efficiency, and disease control.’’ 4 (Ref.
1) FDA accepted these
recommendations. (Ref. 1)
With respect to the tetracyclinecontaining drugs, the subcommittee
recommended that FDA: (1) Discontinue
use for growth promotion and/or feed
efficiency in all animal species for
which effective substitutes are available;
(2) permit their use for disease control
where effective alternate drugs are
unavailable; and (3) control the
distribution of the tetracyclines to
restrict their use. NAFDC did not accept
the subcommittee’s first two
recommendations, and instead
recommended that FDA make no
changes in the permitted use of
chlortetracycline and oxytetracycline in
animal feed. (Ref. 2) The NAFDC did
adopt the subcommittee’s third
recommendation that the addition of the
tetracycline in feeds be restricted. (Ref.
2) FDA considered these
recommendations and decided to
propose withdrawal of approval of
subtherapeutic uses of tetracyclines in
animal feeds except for those conditions
of use for which there are no safe and
effective substitutes. (Ref. 2)
This process culminated in the 1977
publication of two NOOHs in the
Federal Register on proposals by the
Bureau of Veterinary Medicine (now
Center for Veterinary Medicine) to
withdraw all uses of penicillin in
animal feed, and all subtherapeutic uses
of tetracycline in animal feed except for:
(1) Oxytetracyline, as an aid in the
control of fowl cholera caused by
Pasteurella multocida in chickens and
infectious synovitis caused by
Mycoplama synoviae in chickens and
turkeys; and (2) chlortetracycline (a) as
an aid in the maintenance of weight
gains in the presence of respiratory
diseases, such as shipping fever, in
combination with sulfamethazine in
beef cattle, (b) as an aid in the control
of infectious synovitis caused by M.
pasteurella in chickens and turkeys, (c)
for the control of active infections of
anaplasmosis in beef cattle, and (d) as
an aid in reducing the incidence of
virbrionic abortion in breeding sheep.
(Ref. 1 and 2) 5 These NOOHs were
4 Generally, FDA no longer considers disease
control or prevention to be subtherapeutic uses.
5 These matters were assigned Docket Numbers
77N–0230 and 77N–0316, respectively. Since the
original dockets were opened, FDA started using a
different numbering convention. Docket Number
77N–0230 is now Docket Number FDA–1977–N–
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published on August 30, 1977
(penicillin) and October 21, 1977
(tetracycline).
At the same time, FDA also published
two companion proposed rules
proposing to amend the regulations to
delete those provisions referencing the
approved penicillin and tetracycline
uses that would be affected by a
withdrawal. (Refs. 3 and 4) FDA did not
withdraw any approved use of
penicillin or tetracyclines intended for
use in feeds for food-producing animals
as a result of these NOOHs, or finalize
the proposed companion rules, and
some new animal drug approvals for the
use of these new animal drugs in feeds
for food-producing animals remain in
effect.
Although FDA initially granted some
hearing requests to provide sponsors
with the opportunity to present
evidence on the safety of the NOOH
products, Congress intervened before
any hearing was held, directing FDA to
hold in abeyance the implementation of
its proposed withdrawal actions
pending the outcome of further research
related to the use of antibiotics in
animal feed. (Refs. 10, 11, and 12)
II. Discussion
At this time, FDA is withdrawing the
1977 NOOHs because: (1) FDA is
engaging in other ongoing regulatory
strategies developed since the
publication of the 1977 NOOHs with
respect to addressing microbial food
safety issues; (2) FDA would update the
NOOHs to reflect current data,
information, and policies if, in the
future, it decides to move forward with
withdrawal of the approved uses of the
new animal drugs described in the
NOOHs; and (3) FDA would need to
prioritize any withdrawal proceedings
(for example, take into account which
withdrawal(s) would likely have the
most significant impact on the public
health) if, in the future, it decides to
seek withdrawal of the approved uses of
any new animal drug or class of drugs.
Although FDA is withdrawing the
1977 NOOHs, FDA remains concerned
about the issue of antimicrobial
resistance. Today’s action should not be
interpreted as a sign that FDA no longer
has safety concerns or that FDA will not
consider re-proposing withdrawal
proceedings in the future, if necessary.
FDA has not ruled out the prospect of
future regulatory action, either with
respect to the antimicrobial new animal
drugs covered by the 1977 NOOHs or
any others. However, as discussed
further in this document, FDA intends
0019, and Docket Number 77N–0316 is now Docket
Number FDA–1977–N–0022.
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to focus its efforts for now on the
potential for voluntary reform and the
promotion of the judicious use of
antimicrobials in the interest of public
health. Importantly, this strategy leaves
open the possibility of pursuing
withdrawal proceedings at a later time
if FDA’s proposed strategy does not
yield satisfactory results.
1. FDA Is Engaging in Other Ongoing
Regulatory Strategies Developed Since
the Publication of the 1977 NOOHs
With Respect to Addressing Microbial
Food Safety Issues
Since the 1977 NOOHs published,
FDA has continued to investigate the
safety concerns associated with
subtherapeutic uses of antibiotics
intended for use in feeds for foodproducing animals. As mentioned
previously, Congress directed FDA to
hold proceedings with respect to the
1977 NOOHs in abeyance and instead to
conduct more research on the issues in
question. (Ref. 10, 11, and 12) In
response, FDA contracted with the
National Academy of Sciences (NAS) to
conduct a study of the safety issues
related to the use of antibiotics in
animal feed. (Refs. 5 and 13) In
particular, FDA asked the NAS to: (1)
Study the human health effects of the
subtherapeutic use of penicillin and
tetracycline in animal feed; (2) review
and analyze published and unpublished
epidemiological and other data
necessary to assess human health
consequences of such use; (3) assess the
scientific feasibility of additional
epidemiological studies; and (4) make
recommendations about additional
research needed. (Refs. 5 and 9)
The NAS issued its report in 1980,
concluding that a very limited amount
of epidemiological research had been
completed on either the subtherapeutic
or therapeutic use of antimicrobials in
animal feeds and that existing data
could neither prove nor disprove the
postulated hazards to human health
from subtherapeutic antimicrobial use
in animal feed. (Refs. 5 and 9) The
report stated that ‘‘[t]he 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.’’ (Refs. 5 and 13)
In 1984, FDA contracted with the
Seattle-King County Health Department
to complete a study intended to provide
additional information regarding
potential public health concerns
regarding the use of antimicrobial drugs
in animal feed. The study focused on
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the relationship between the occurrence
of Salmonella spp. (Salmonella) and
Campylobacter jejuni (C. jejuni) in foods
of animal origin and the occurrence of
human illness caused by those two
organisms. The study report indicated
that the bacteria obtained from human
cases and those obtained from retail
poultry had similar antibiotic
susceptibility patterns, including
similar levels of resistance to
tetracycline. (Refs. 5 and 14)
In 1987, FDA asked the Institute of
Medicine to conduct an independent
review of the human health risks
associated with the subtherapeutic uses
of penicillin and tetracycline in animal
feed. (Refs. 5 and 15) The IOM
established a committee which
developed a risk-analysis model using
data on Salmonella infections that
resulted in human death. (Refs. 5 and
15) The Committee did not find a
substantial body of direct evidence
establishing conclusively the presence
of a human health hazard resulting from
the use of subtherapeutic concentrations
of penicillin and the tetracyclines in
animal feeds. (Refs. 5 and 15)
Nonetheless, the Committee found a
considerable body of indirect evidence
implicating both the subtherapeutic and
therapeutic use of antimicrobials as a
potential human health hazard, and
made recommendations for further
study of the issue.6 (Refs. 5 and 15)
During the 1990’s, FDA continued to
investigate the potential risks associated
with the use of antibiotic drugs
intended for use in feeds for foodproducing animals and how to mitigate
risks associated with such use. In 1999,
FDA published a concept paper titled,
‘‘Proposed Framework For Evaluating
and Assuring the Human Safety of the
6 FDA’s draft guidance titled ‘‘The Judicious Use
of Medically Important Antimicrobial Drugs in
Food-Producing Animals’’ (Draft GFI #209) contains
information on additional key studies relevant to
this issue. For example, in 1997, the World Health
Organization (WHO) issued a report which
concluded that all uses of antimicrobials lead to the
selection of resistant forms of bacteria and that
‘‘low-level, long-term exposure to antimicrobials
may have greater selective potential than shortterm, full-dose therapeutic use.’’ (Ref. 17) The WHO
report contained several recommendations,
including a recommendation that the use of
antimicrobial drugs for growth promotion in
animals be terminated if these drugs are also
prescribed for use as anti-infective agents in human
medicine or if they are known to induce crossresistance to antimicrobials used for human
medical therapy. (Ref. 17) It also recommended that
national practices of antimicrobial use in animals
be reviewed, and policies be developed to reduce
the risks of selection and dissemination of
antimicrobial resistance. (Ref. 17) Further, in 1999
the National Research Council issued a report that,
among other things, recommended that further
development and use of antibiotics in both human
and animal medicine have oversight by an
interdisciplinary panel of experts. (Ref. 18)
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Microbial Effects of Antimicrobial New
Animal Drugs Intended for Use in FoodProducing Animals’’ (‘‘Framework
Document’’). (Ref. 19) Among other
things, the Framework Document called
for revisions to the pre-approval safety
assessment for antimicrobial new
animal drugs, and the categorization of
antimicrobial drugs based on their
importance to human medicine. (Ref.
19)
In 2003, FDA published a final
guidance for industry (GFI #152),
outlining an approach for conducting a
qualitative risk assessment to evaluate
human food safety with respect to the
potential microbiological effects of
antimicrobial new animal drugs on
food-borne bacteria of human health
concern. (Ref. 20) The importance of a
drug for human medical therapy is a key
factor to be considered in the
evaluation. (Ref. 20) Since 2003, FDA
has applied the principles contained in
GFI #152 when assessing antimicrobial
resistance risks for antimicrobial drugs
as part of the new animal drug approval
process. In some cases, this has had the
effect of limiting the claims for which
such drugs are approved while still
protecting animal and human health.
Recognizing that already-approved
antimicrobial new animal drugs also
have antimicrobial resistance risks
associated with their use, FDA began to
look at the safety of some of these
already approved drugs. However,
because the process of reviewing safety
information for antimicrobial drugs
approved before 2003 (and pursuing
withdrawal proceedings if appropriate
in some cases) would take many years
and would impose significant resource
demands on the Agency, FDA began
thinking about alternate approaches to
address safety concerns. As a result, in
June 2010 FDA proposed a different
strategy to promote the judicious use of
medically important antimicrobials in
food-producing animals in a draft
guidance for industry titled ‘‘The
Judicious Use of Medically Important
Antimicrobial Drugs in Food-Producing
Animals’’ (draft GFI #209). (Ref. 5)
Generally speaking, judicious uses
would be those uses that are appropriate
and necessary to maintaining the health
of humans and animals.
Draft GFI #209 proposes two
principles aimed at ensuring the
judicious use of medically important
antimicrobials in food-producing
animals. The first principle described in
the draft guidance is that the use of
medically important antimicrobial drugs
in food-producing animals should be
limited to those uses that are considered
necessary for assuring animal health.
(Ref. 5) As set out in the draft guidance,
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79699
FDA does not consider production uses
of such drugs to be necessary for
assuring animal health because, unlike
other uses, 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 animalderived products (e.g., promoting faster
weight gain or improving feed
efficiency). (Ref. 5) The second
principle set out in the draft guidance
is that the use of medically important
antimicrobial drugs in food-producing
animals should be limited to those uses
that include veterinary oversight or
consultation. (Ref. 5) This principle
speaks to the need for the scientific and
clinical training of licensed
veterinarians to assure that medically
important antimicrobials are used in a
judicious manner.
Based on feedback the Agency
received following the issuance of draft
GFI #209, FDA believes that the animal
pharmaceutical industry is generally
responsive to the prospect of working
cooperatively with the Agency to
accomplish the principles
recommended in draft GFI #209. FDA
intends to work with sponsors who
approach FDA and are interested in
working cooperatively with the Agency
to phase out production uses of
medically important antimicrobials, and
to achieve an orderly transition of
medically important antimicrobials
currently approved for over-the-counter
use in food-producing animals to a
marketing status that involves
veterinary oversight (i.e., veterinary feed
directive (VFD) status for feed use drugs
and prescription status for drugs
approved for use through other routes of
administration).
As part of the proposed strategy, FDA
issued an advance notice of proposed
rulemaking (ANPRM) on March 29,
2010 (75 FR 15387), to seek public
comment on whether and to what extent
efficiency improvements should be
made to the current VFD process as set
forth in FDA’s regulation at 21 CFR
558.6. (Ref. 21) FDA received numerous
public comments in response to the
ANPRM and is taking those comments
into account in considering possible
revisions to this regulation.
FDA believes that the strategy set out
in draft GFI #209 represents another
pathway to achieving the same goals
contemplated by the 1977 NOOHs, i.e.,
the judicious use of medically important
antimicrobial drugs. FDA believes that
by implementing this strategy and
proceeding in part under the statutory
authority provided under the Animal
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Drug Availability Act of 1996 (ADAA) 7
to designate drugs as VFD drugs
(authority which was not available in
1977), it will achieve its goal of
promoting the judicious use of
antimicrobial drugs in a more timely
and resource-efficient manner than
could be accomplished otherwise.8
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2. FDA Would Update the NOOHs To
Reflect Current Data, Information and
Policies If, in the Future, it Decides To
Move Forward With the Withdrawal of
the Approved Uses of the New Animal
Drugs Described in the NOOHs
Although FDA is optimistic that its
proposed strategy to achieve the
judicious use of all medically important
antimicrobials, as set out in draft GFI
#209, will be successful, it has not
foreclosed the possibility of using the
withdrawal provisions in the Federal
Food, Drug, and Cosmetic Act, if
necessary, in the future. This applies
not only to the classes of antimicrobial
drugs covered by the 1977 NOOHs, but
also any other production use claims
(i.e., growth promotion/feed efficiency
uses) for a medically important
antimicrobial new animal drug or class
of drugs intended for use in foodproducing animals. However, if FDA
were to pursue withdrawal of approval
of any production use claims, it would
first publish a notice in the Federal
Register giving the sponsor(s) of the
affected new animal drug(s) notice of
the proposed withdrawal(s) and an
opportunity for a hearing.
If, at some future time, FDA decides
to proceed with the withdrawal of the
production uses of penicillins and
tetracyclines intended for use in feeds
for food-producing animals that were
the subject of the 1977 NOOHs, it would
publish a new Federal Register notice
giving sponsors an opportunity for a
hearing on the matter. A new notice
would be appropriate for many reasons.
7 ADAA (Pub. L. 104–250), which was signed into
law on October 9, 1996, introduced several
amendments to the Federal Food, Drug, and
Cosmetic Act that provided FDA with more
flexibility in how it regulates animal drugs and
animal feeds. One such amendment made by the
law was to add a new ‘‘veterinary feed directive’’
category of new animal drugs to allow the approval
and use of drugs in animal feed on a veterinarian’s
order while incorporating safeguards to help ensure
the safe use of the drug.
8 FDA’s experience with contested, formal
withdrawal proceedings is that the process can
consume extensive periods of time and significant
amounts of Agency resources. For example, when
FDA withdrew a class of animal drugs called
nitrofurans in 1991, the proceedings took nearly 20
years. In another proceeding, the withdrawal of
diethylstilbestrol (‘‘DES’’) in animals became final
in 1979, 7 years after issuance of an NOOH. More
recently, the withdrawal of enrofloxacin for use in
poultry took almost 5 years and cost FDA
approximately $3.3 million.
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First, more than three decades have
passed since the original notice
appeared in the Federal Register. FDA
would publish a new Federal Register
notice to ensure all current sponsors of
the approved new animal drugs are
properly notified and have an
opportunity to request a hearing.
Second, not all uses proposed to be
withdrawn in the 1977 NOOHs are still
approved. The 1977 NOOH which
proposed withdrawal of all penicillincontaining premixes intended for use in
animal feed also included the thenapproved therapeutic uses of penicillin
in feed. The stated grounds for
proposing to withdraw approval of the
therapeutic uses of the penicillincontaining premixes were that there was
not substantial evidence of effectiveness
of these products for the claimed
therapeutic uses. However, there are no
currently approved therapeutic uses of
penicillins in animal feed.
Third, the body of scientific
information relevant to the use of
penicillins and tetracyclines in animal
feeds has grown since 1977. If the
Agency were to pursue the NOOHs,
FDA would need to provide notice to
the sponsors that the information
available since 1977 would be used to
support the proposal to withdraw the
approved uses of the drugs.
For example, in the early 1990’s FDA
began collaborating with other
government agencies to track antibiotic
resistance in foodborne bacteria through
a national public health surveillance
system, known as the National
Antimicrobial Resistance Monitoring
System or ‘‘NARMS,’’ established to
monitor antimicrobial susceptibility
among enteric bacteria from humans,
retail meats, and food animals. (Ref. 22)
Also, since the 1977 NOOHs published,
there have been numerous reports,
including those by the National
Academy of Sciences (Ref. 13), the
Institute of Medicine (Ref. 15), the
World Health Organization (Ref. 17),
and the National Research Council (Ref.
18), that have reviewed available
information and made
recommendations. In addition, there
have been advances in our
understanding of the genetics of
resistance (e.g., ways in which bacteria
accumulate multiple resistance genes).
Fourth, FDA would need to provide
notice regarding which approved uses
were the subject of the NOOH. In the
past, FDA has referred to
‘‘subtherapeutic’’ uses at various times
to include: (1) ‘‘Increased rate of gain,
disease prevention, etc.’’ (Ref. 7); (2)
‘‘any use of an antibacterial drug
continuously in feed for longer than 14
days’’ (Ref. 23); and (3) ‘‘lower levels
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than therapeutic levels needed to cure
disease.’’ (Refs. 1 and 2) FDA’s thinking
on this issue has evolved over the last
three decades, and FDA now generally
considers disease control and
prevention claims to be judicious uses
(in other words, therapeutic uses),
especially when the drug is
administered at the direction and under
the oversight of a licensed veterinarian.
(Ref. 5)
3. FDA Would Need To Prioritize Any
Withdrawal Proceedings (for Example,
Take Into Account Which Withdrawal(s)
Would Likely Have the Most Significant
Impact on the Public Health) if, in the
Future, It Decides To Seek Withdrawal
of the Approved Uses of Any New
Animal Drug or Class of Drugs
To the extent that FDA decides to
move forward with withdrawal
proceedings for any medically
important antimicrobial drugs intended
for use in feeds for food-producing
animals, it would need to prioritize
which withdrawal(s) to propose first
based on various considerations,
including which withdrawal(s) would
have the most significant impact on the
public health. It is possible that FDA
would conclude that its judicious use
goals would better be achieved by first
pursuing withdrawals of drugs other
than penicillins and tetracyclines. FDA
notes that it would need to conduct
such an evaluation regardless of the
statutory grounds contemplated for the
withdrawal action.
III. Conclusion
At this time, FDA is withdrawing the
1977 NOOHs because: (1) FDA is
engaging in other ongoing regulatory
strategies developed since the
publication of the 1977 NOOHs with
respect to addressing microbial food
safety issues; (2) FDA would update the
NOOHs to reflect current data,
information, and policies if, in the
future, it decides to move forward with
withdrawal of the approved uses of the
new animal drugs described in the
NOOHs; and (3) FDA would need to
prioritize any withdrawal proceedings
(for example, take into account which
withdrawal(s) would likely have the
most significant impact on the public
health) if, in the future, it decides to
seek withdrawal of the approved uses of
any new animal drug or class of drugs.
Although FDA is withdrawing the
1977 NOOHs, FDA continues to view
antimicrobial resistance as a significant
public health issue. Today’s action
should not be interpreted as a sign that
FDA no longer has safety concerns
about the use of medically important
antibiotics in food producing animals or
E:\FR\FM\22DEN1.SGM
22DEN1
Federal Register / Vol. 76, No. 246 / Thursday, December 22, 2011 / Notices
that FDA will not consider re-proposing
withdrawal proceedings in the future, if
necessary. FDA has not ruled out the
prospect of future regulatory action,
either with respect to the antimicrobial
new animal drugs covered by the 1977
NOOHs or any others. However, for
now, FDA’s efforts will focus on
promoting voluntary reform and the
judicious use of antimicrobials in the
interest of best using the agency’s
overall resources to protect the public
health. Importantly, this strategy leaves
open the possibility of pursuing
withdrawal proceedings at a later time
if FDA’s proposed strategy does not
yield satisfactory results.
As indicated previously, as part of the
withdrawal of the two 1977 NOOHs, the
Agency will close their corresponding
dockets. However, we encourage
interested persons to submit comments
to the docket established in connection
with draft GFI #209. The docket number
associated with draft GFI #209 is FDA–
2010–D–0094.
jlentini on DSK4TPTVN1PROD with NOTICES
IV. Penicillin and Tetracycline Uses in
Animal Feed
FDA is withdrawing the 1977 NOOHs,
and the related companion proposed
rules, because: (1) FDA is engaging in
other ongoing regulatory strategies
developed since the publication of the
1977 NOOHs with respect to addressing
microbial food safety issues; (2) FDA
would update the NOOHs to reflect
current data, information, and policies
if, in the future, it decides to move
forward with withdrawal of the
approved uses of the new animal drugs
described in the NOOHs; and (3) FDA
would need to prioritize any withdrawal
proceedings (for example, take into
account which withdrawal(s) would
likely have the most significant impact
on the public health) if, in the future, it
decides to seek withdrawal of the
approved uses of any new animal drug
or class of drugs.
V. References
The following references are on
display in the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20857, and may be
seen by interested persons between
9 a.m. and 4 p.m., Monday through
Friday (except on Federal holidays). We
have verified all Web site addresses, but
we are not responsible for any
subsequent changes to the Web sites
after this document publishes in the
Federal Register.
1. 42 FR 43772 (August 30, 1977).
2. 42 FR 56264 (October 21, 1977).
3. 42 FR 43770 (August 30, 1977).
4. 42 FR 56254 (October 21, 1977).
VerDate Mar<15>2010
19:17 Dec 21, 2011
Jkt 226001
5. Draft GFI #209, ‘‘The Judicious Use of
Medically Important Antimicrobial Drugs in
Food-Producing Animals,’’ June 28, 2010;
https://www.fda.gov/downloads/Animal
Veterinary/GuidanceCompliance
Enforcement/GuidanceforIndustry/
UCM216936.pdf.
6. 37 FR 2444 (February 1, 1972).
7. 38 FR 9811 (April 20, 1973).
8. 21 CFR 135.109 (revised as of April 1,
1974).
9. 21 CFR 558.15 (revised as of April 1,
1975).
10. H. Rept. 95–1290, ‘‘Agriculture, Rural
Development and Related Agencies
Appropriation Bill, 1979,’’ June 13, 1978.
11. H. Rept. 96–1095, ‘‘Agriculture, Rural
Development and Related Agencies
Appropriation Bill, 1981,’’ June 17, 1980.
12. S. Rept. 97–248, ‘‘Agriculture, Rural
Development and Related Agencies
Appropriation Bill, 1982,’’ October 23
(legislative day, October 14), 1981.
13. National Academy of Sciences/National
Research Council, ‘‘The Effects on Human
Health of Subtherapeutic Uses of
Antimicrobials in Animal Feeds,’’ 1980, pp.
53–54.
14. 1984 Seattle-King County Study:
‘‘Surveillance of the Flow of Salmonella and
Campylobacter in a Community.’’
15. National Academy of Sciences/Institute
of Medicine, ‘‘Human Health Risks With the
Subtherapeutic Use of Penicillin or
Tetracyclines in Animal Feed,’’ 1988.
16. 68 FR 47272, 47275 (August 8, 2003).
17. 1997 World Health Organization
(WHO) Report, ’’ The Medical Impact of
Antimicrobial Use in Food Animals,’’ https://
whqlibdoc.who.int/hq/1997/WHO_EMC_
ZOO_97.4.pdf
18. 1999 National Research Council (NRC)
Report: ‘‘The Use of Drugs in Food Animals–
Benefits and Risks.’’
19. A Proposed Framework for Evaluating
and Assuring the Human Safety of the
Microbial Effects of Antimicrobial New
Animal Drugs Intended for Use in FoodProducing Animals, https://www/fda/gov/
AdvisoryCommittees/CommitteesMeeting
Materials/VeterinaryMedicineAdvisory
Committee/ucm126607.htm.
20. Final Guidance for Industry #152,
‘‘Evaluating the Safety of Antimicrobial New
Animal Drugs With Regard to Their
Microbiological Effects on Bacteria of Human
Health Concern,’’ October 23, 2003.
21. 75 FR 15387 (March 29, 2010).
22. https://www/fda/gov/AnimalVeterinary
SafetyHealth/AntimicrobialResistance/
NationalAntimmicrobialResistance
MonitoringSystem/default.htm.
23. 41 FR 8282 (February 25, 1976).
Dated: December 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011–32775 Filed 12–21–11; 8:45 am]
BILLING CODE 4160–01–P
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79701
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2011–N–0411]
Bristol-Myers Squibb Co. et al.;
Withdrawal of Approval of 70 New
Drug Applications and 97 Abbreviated
New Drug Applications; Correction
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice; correction.
The Food and Drug
Administration (FDA) is correcting a
notice that appeared in the Federal
Register of June 8, 2011 (76 FR 33310).
The document announced the
withdrawal of approval of 70 new drug
applications (NDAs) and 97 abbreviated
new drug applications (ANDAs) from
multiple applicants, effective July 8,
2011. The document indicated that FDA
was withdrawing approval of the
following three ANDAs after receiving a
request from the ANDA holder, A.H.
Robins Co., c/o Wyeth Pharmaceuticals,
Inc., P.O. Box 8299, Philadelphia, PA
19101–8299: ANDA 086661,
DONNATAL (phenobarbital,
hyoscyamine sulfate, atropine sulfate,
scopolamine (HBr)) Elixir; ANDA
086676, DONNATAL (phenobarbital,
hyoscyamine sulfate, atropine sulfate,
scopolamine (HBr)) Tablets; and ANDA
086677, DONNATAL (phenobarbital,
hyoscyamine sulfate, atropine sulfate,
scopolamine (HBr)) Capsules. Before
withdrawal of these ANDAs became
effective, PBM Pharmaceuticals, Inc.,
acquired the rights to the ANDAs and
informed FDA that it did not want them
withdrawn. Because the basis for
withdrawal would have been a request
from the ANDA holder and the request
was timely withdrawn, the approval of
ANDAs 086661, 086676, and 086677 is
still in effect.
SUMMARY:
FOR FURTHER INFORMATION CONTACT:
Florine Purdie, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 6366,
Silver Spring, MD 20993–0002, (301)
796–3601.
In FR Doc.
2011–14164 appearing on page 33310,
in the Federal Register of Wednesday,
June 8, 2011, the following correction is
made:
On page 33313, in Table 1, the entries
for ANDAs 086661, 086676, and 086677
are removed.
SUPPLEMENTARY INFORMATION:
E:\FR\FM\22DEN1.SGM
22DEN1
]]>Agencies
[Federal Register Volume 76, Number 246 (Thursday, December 22, 2011)]
[Notices]
[Pages 79697-79701]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-32775]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket Nos. FDA-1977-N-0019 (formerly 1977N-0230), FDA-1977-N-0014
(formerly 977N-0231), FDA-1977-N-0022 (formerly 1977N-0316), and FDA-
1977-N-0224 (formerly 1977N-0317)]
Withdrawal of Notices of Opportunity for a Hearing; Penicillin
and Tetracycline Used in Animal Feed
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or the Agency) is
withdrawing two 1977 notices of opportunity for a hearing (NOOH), which
proposed to withdraw certain approved uses of penicillin and
tetracyclines intended for use in feeds for food-producing animals
based in part on microbial food safety concerns.\1\ (Refs. 1 and 2) FDA
is taking this action, and closing the corresponding dockets, because:
FDA is engaging in other ongoing regulatory strategies developed since
the publication of the 1977 NOOHs with respect to addressing microbial
food safety issues; FDA would update the NOOHs to reflect current data,
information, and policies if, in the future, it decides to move forward
with withdrawal of the approved uses of the new animal drugs described
in the NOOHs; and FDA would need to prioritize any withdrawal
proceedings (for example, take into account which withdrawal(s) would
likely have the most significant impact on the public health) if, in
the future, it decides to seek withdrawal of the approved uses of any
new animal drug or class of drugs. FDA is also withdrawing the
companion proposed rules to these NOOHs. (Refs. 3 and 4)
---------------------------------------------------------------------------
\1\ FDA's approval to withdraw the approved uses of the drugs
was based on three statutory grounds: (1) The drugs are not shown to
be safe (21 U.S.C. 360b(e)(1)(B)); (2) lack of substantial evidence
of effectiveness (21 U.S.C. 360b(e)(1)(C)); and (3) failure to
submit required reports (21 U.S.C. 360b(e)(2)(A)).
---------------------------------------------------------------------------
DATES: This notice is effective December 22, 2011.
ADDRESSES: Submit electronic comments to https://www.regulations.gov.
Submit written comments to the Division of Dockets Management (HFV-
305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: William Flynn, Center for Veterinary
Medicine (HFV-1), Food and Drug Administration, 7519 Standish Pl.,
Rockville, MD 20855, (240) 276-9000, email: William.flynn@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
Questions regarding the use of antimicrobial drugs in food-
producing animals have been raised and debated for many years. (Ref. 5)
\2\ Following a report that was issued by the British government in
1969 on the use of antibiotics in veterinary medicine and animal
husbandry, known as the ``Swann Report,'' the Commissioner of Food and
Drugs established a task force to review the use of antibiotic drugs in
animal feeds. The task force, established in 1970, included specialists
on infectious diseases and animal science from FDA, the National
Institutes of Health, the U.S. Department of Agriculture, and the
Centers for Disease Control and Prevention, as well as representatives
from universities and industry. The task force identified three primary
areas of concern (human health hazard, animal health hazard, and
antibiotic effectiveness) and guidelines were established to show
whether the use of any antibiotic or antibacterial agent in animal feed
presents a hazard to human and animal health. (Refs. 1 and 6) The task
force also made certain recommendations concerning restrictions on the
use of antibiotic drugs in animal feeds at growth promotion and
subtherapeutic levels. (Ref. 6)
---------------------------------------------------------------------------
\2\ The term ``antimicrobial'' refers broadly to drugs with
activity against a variety of microorganisms including: Bacteria,
viruses, fungi, and parasites. Antimicrobial drugs that have
specific activity against bacteria are referred to as antibacterial
or antibiotic drugs. However, the broader term ``antimicrobial,''
commonly used in reference to drugs with activity against bacteria,
is used in this document interchangeably with the terms
antibacterial or antibiotic. Antimicrobial resistance is the ability
of bacteria or other microbes to resist the effects of a drug.
Antimicrobial resistance, as it relates to bacterial organisms,
occurs when bacteria change in some way that reduces or eliminates
the effectiveness of drugs, chemicals, or other agents designed to
treat bacterial infections. (Ref. 5)
---------------------------------------------------------------------------
In 1972, FDA published the conclusions and recommendations of that
task force and proposed to require sponsors to submit specific data for
antibiotic drugs in animal feeds intended for subtherapeutic or growth
promotion use when such drugs are also used in human clinical medicine.
(Ref. 6) In 1973, FDA finalized this proposal in 21 CFR 135.109 (re-
codified at 21 CFR 558.15 in 1974).\3\ (Refs. 7, 8, and 9) This section
provided that FDA would propose to revoke approved uses in animal feed
of antibiotic and sulfonamide drugs unless certain data were submitted
which satisfactorily addressed the outstanding safety and effectiveness
issues.
---------------------------------------------------------------------------
\3\ Since that time, portions of 21 CFR 558.15 have been removed
because those portions of the regulation were determined to be
redundant or obsolete. (See 75 FR 16001, March 31, 2010.)
---------------------------------------------------------------------------
By 1974, FDA had begun to review the data submitted by the sponsors
of the antibiotic products and requested that the National Advisory
Food and Drug Committee (NAFDC) review the data and make
recommendations on the subtherapeutic uses of penicillin and
tetracyclines. A subcommittee (the Antibiotics in Animal Feeds
subcommittee) was appointed to work in conjunction with expert
consultants to address these issues. With respect to the penicillin-
containing drugs, the subcommittee recommended FDA immediately withdraw
approval of the subtherapeutic uses of penicillin. The
[[Page 79698]]
NAFDC accepted the subcommittee's recommendation and recommended to FDA
that it ``immediately withdraw approval for the subtherapeutic uses of
penicillin, i.e., growth promotion/feed efficiency, and disease
control.'' \4\ (Ref. 1) FDA accepted these recommendations. (Ref. 1)
---------------------------------------------------------------------------
\4\ Generally, FDA no longer considers disease control or
prevention to be subtherapeutic uses.
---------------------------------------------------------------------------
With respect to the tetracycline-containing drugs, the subcommittee
recommended that FDA: (1) Discontinue use for growth promotion and/or
feed efficiency in all animal species for which effective substitutes
are available; (2) permit their use for disease control where effective
alternate drugs are unavailable; and (3) control the distribution of
the tetracyclines to restrict their use. NAFDC did not accept the
subcommittee's first two recommendations, and instead recommended that
FDA make no changes in the permitted use of chlortetracycline and
oxytetracycline in animal feed. (Ref. 2) The NAFDC did adopt the
subcommittee's third recommendation that the addition of the
tetracycline in feeds be restricted. (Ref. 2) FDA considered these
recommendations and decided to propose withdrawal of approval of
subtherapeutic uses of tetracyclines in animal feeds except for those
conditions of use for which there are no safe and effective
substitutes. (Ref. 2)
This process culminated in the 1977 publication of two NOOHs in the
Federal Register on proposals by the Bureau of Veterinary Medicine (now
Center for Veterinary Medicine) to withdraw all uses of penicillin in
animal feed, and all subtherapeutic uses of tetracycline in animal feed
except for: (1) Oxytetracyline, as an aid in the control of fowl
cholera caused by Pasteurella multocida in chickens and infectious
synovitis caused by Mycoplama synoviae in chickens and turkeys; and (2)
chlortetracycline (a) as an aid in the maintenance of weight gains in
the presence of respiratory diseases, such as shipping fever, in
combination with sulfamethazine in beef cattle, (b) as an aid in the
control of infectious synovitis caused by M. pasteurella in chickens
and turkeys, (c) for the control of active infections of anaplasmosis
in beef cattle, and (d) as an aid in reducing the incidence of
virbrionic abortion in breeding sheep. (Ref. 1 and 2) \5\ These NOOHs
were published on August 30, 1977 (penicillin) and October 21, 1977
(tetracycline).
---------------------------------------------------------------------------
\5\ These matters were assigned Docket Numbers 77N-0230 and 77N-
0316, respectively. Since the original dockets were opened, FDA
started using a different numbering convention. Docket Number 77N-
0230 is now Docket Number FDA-1977-N-0019, and Docket Number 77N-
0316 is now Docket Number FDA-1977-N-0022.
---------------------------------------------------------------------------
At the same time, FDA also published two companion proposed rules
proposing to amend the regulations to delete those provisions
referencing the approved penicillin and tetracycline uses that would be
affected by a withdrawal. (Refs. 3 and 4) FDA did not withdraw any
approved use of penicillin or tetracyclines intended for use in feeds
for food-producing animals as a result of these NOOHs, or finalize the
proposed companion rules, and some new animal drug approvals for the
use of these new animal drugs in feeds for food-producing animals
remain in effect.
Although FDA initially granted some hearing requests to provide
sponsors with the opportunity to present evidence on the safety of the
NOOH products, Congress intervened before any hearing was held,
directing FDA to hold in abeyance the implementation of its proposed
withdrawal actions pending the outcome of further research related to
the use of antibiotics in animal feed. (Refs. 10, 11, and 12)
II. Discussion
At this time, FDA is withdrawing the 1977 NOOHs because: (1) FDA is
engaging in other ongoing regulatory strategies developed since the
publication of the 1977 NOOHs with respect to addressing microbial food
safety issues; (2) FDA would update the NOOHs to reflect current data,
information, and policies if, in the future, it decides to move forward
with withdrawal of the approved uses of the new animal drugs described
in the NOOHs; and (3) FDA would need to prioritize any withdrawal
proceedings (for example, take into account which withdrawal(s) would
likely have the most significant impact on the public health) if, in
the future, it decides to seek withdrawal of the approved uses of any
new animal drug or class of drugs.
Although FDA is withdrawing the 1977 NOOHs, FDA remains concerned
about the issue of antimicrobial resistance. Today's action should not
be interpreted as a sign that FDA no longer has safety concerns or that
FDA will not consider re-proposing withdrawal proceedings in the
future, if necessary. FDA has not ruled out the prospect of future
regulatory action, either with respect to the antimicrobial new animal
drugs covered by the 1977 NOOHs or any others. However, as discussed
further in this document, FDA intends to focus its efforts for now on
the potential for voluntary reform and the promotion of the judicious
use of antimicrobials in the interest of public health. Importantly,
this strategy leaves open the possibility of pursuing withdrawal
proceedings at a later time if FDA's proposed strategy does not yield
satisfactory results.
1. FDA Is Engaging in Other Ongoing Regulatory Strategies Developed
Since the Publication of the 1977 NOOHs With Respect to Addressing
Microbial Food Safety Issues
Since the 1977 NOOHs published, FDA has continued to investigate
the safety concerns associated with subtherapeutic uses of antibiotics
intended for use in feeds for food-producing animals. As mentioned
previously, Congress directed FDA to hold proceedings with respect to
the 1977 NOOHs in abeyance and instead to conduct more research on the
issues in question. (Ref. 10, 11, and 12) In response, FDA contracted
with the National Academy of Sciences (NAS) to conduct a study of the
safety issues related to the use of antibiotics in animal feed. (Refs.
5 and 13) In particular, FDA asked the NAS to: (1) Study the human
health effects of the subtherapeutic use of penicillin and tetracycline
in animal feed; (2) review and analyze published and unpublished
epidemiological and other data necessary to assess human health
consequences of such use; (3) assess the scientific feasibility of
additional epidemiological studies; and (4) make recommendations about
additional research needed. (Refs. 5 and 9)
The NAS issued its report in 1980, concluding that a very limited
amount of epidemiological research had been completed on either the
subtherapeutic or therapeutic use of antimicrobials in animal feeds and
that existing data could neither prove nor disprove the postulated
hazards to human health from subtherapeutic antimicrobial use in animal
feed. (Refs. 5 and 9) The report stated that ``[t]he 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.'' (Refs. 5 and 13)
In 1984, FDA contracted with the Seattle-King County Health
Department to complete a study intended to provide additional
information regarding potential public health concerns regarding the
use of antimicrobial drugs in animal feed. The study focused on
[[Page 79699]]
the relationship between the occurrence of Salmonella spp. (Salmonella)
and Campylobacter jejuni (C. jejuni) in foods of animal origin and the
occurrence of human illness caused by those two organisms. The study
report indicated that the bacteria obtained from human cases and those
obtained from retail poultry had similar antibiotic susceptibility
patterns, including similar levels of resistance to tetracycline.
(Refs. 5 and 14)
In 1987, FDA asked the Institute of Medicine to conduct an
independent review of the human health risks associated with the
subtherapeutic uses of penicillin and tetracycline in animal feed.
(Refs. 5 and 15) The IOM established a committee which developed a
risk-analysis model using data on Salmonella infections that resulted
in human death. (Refs. 5 and 15) The Committee did not find a
substantial body of direct evidence establishing conclusively the
presence of a human health hazard resulting from the use of
subtherapeutic concentrations of penicillin and the tetracyclines in
animal feeds. (Refs. 5 and 15) Nonetheless, the Committee found a
considerable body of indirect evidence implicating both the
subtherapeutic and therapeutic use of antimicrobials as a potential
human health hazard, and made recommendations for further study of the
issue.\6\ (Refs. 5 and 15)
---------------------------------------------------------------------------
\6\ FDA's draft guidance titled ``The Judicious Use of Medically
Important Antimicrobial Drugs in Food-Producing Animals'' (Draft GFI
209) contains information on additional key studies
relevant to this issue. For example, in 1997, the World Health
Organization (WHO) issued a report which concluded that all uses of
antimicrobials lead to the selection of resistant forms of bacteria
and that ``low-level, long-term exposure to antimicrobials may have
greater selective potential than short-term, full-dose therapeutic
use.'' (Ref. 17) The WHO report contained several recommendations,
including a recommendation that the use of antimicrobial drugs for
growth promotion in animals be terminated if these drugs are also
prescribed for use as anti-infective agents in human medicine or if
they are known to induce cross-resistance to antimicrobials used for
human medical therapy. (Ref. 17) It also recommended that national
practices of antimicrobial use in animals be reviewed, and policies
be developed to reduce the risks of selection and dissemination of
antimicrobial resistance. (Ref. 17) Further, in 1999 the National
Research Council issued a report that, among other things,
recommended that further development and use of antibiotics in both
human and animal medicine have oversight by an interdisciplinary
panel of experts. (Ref. 18)
---------------------------------------------------------------------------
During the 1990's, FDA continued to investigate the potential risks
associated with the use of antibiotic drugs intended for use in feeds
for food-producing animals and how to mitigate risks associated with
such use. In 1999, FDA published a concept paper titled, ``Proposed
Framework For Evaluating and Assuring the Human Safety of the Microbial
Effects of Antimicrobial New Animal Drugs Intended for Use in Food-
Producing Animals'' (``Framework Document''). (Ref. 19) Among other
things, the Framework Document called for revisions to the pre-approval
safety assessment for antimicrobial new animal drugs, and the
categorization of antimicrobial drugs based on their importance to
human medicine. (Ref. 19)
In 2003, FDA published a final guidance for industry (GFI
152), outlining an approach for conducting a qualitative risk
assessment to evaluate human food safety with respect to the potential
microbiological effects of antimicrobial new animal drugs on food-borne
bacteria of human health concern. (Ref. 20) The importance of a drug
for human medical therapy is a key factor to be considered in the
evaluation. (Ref. 20) Since 2003, FDA has applied the principles
contained in GFI 152 when assessing antimicrobial resistance
risks for antimicrobial drugs as part of the new animal drug approval
process. In some cases, this has had the effect of limiting the claims
for which such drugs are approved while still protecting animal and
human health.
Recognizing that already-approved antimicrobial new animal drugs
also have antimicrobial resistance risks associated with their use, FDA
began to look at the safety of some of these already approved drugs.
However, because the process of reviewing safety information for
antimicrobial drugs approved before 2003 (and pursuing withdrawal
proceedings if appropriate in some cases) would take many years and
would impose significant resource demands on the Agency, FDA began
thinking about alternate approaches to address safety concerns. As a
result, in June 2010 FDA proposed a different strategy to promote the
judicious use of medically important antimicrobials in food-producing
animals in a draft guidance for industry titled ``The Judicious Use of
Medically Important Antimicrobial Drugs in Food-Producing Animals''
(draft GFI 209). (Ref. 5) Generally speaking, judicious uses
would be those uses that are appropriate and necessary to maintaining
the health of humans and animals.
Draft GFI 209 proposes two principles aimed at ensuring
the judicious use of medically important antimicrobials in food-
producing animals. The first principle described in the draft guidance
is that the use of medically important antimicrobial drugs in food-
producing animals should be limited to those uses that are considered
necessary for assuring animal health. (Ref. 5) As set out in the draft
guidance, FDA does not consider production uses of such drugs to be
necessary for assuring animal health because, unlike other uses,
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 (e.g., promoting
faster weight gain or improving feed efficiency). (Ref. 5) The second
principle set out in the draft guidance is that the use of medically
important antimicrobial drugs in food-producing animals should be
limited to those uses that include veterinary oversight or
consultation. (Ref. 5) This principle speaks to the need for the
scientific and clinical training of licensed veterinarians to assure
that medically important antimicrobials are used in a judicious manner.
Based on feedback the Agency received following the issuance of
draft GFI 209, FDA believes that the animal pharmaceutical
industry is generally responsive to the prospect of working
cooperatively with the Agency to accomplish the principles recommended
in draft GFI 209. FDA intends to work with sponsors who
approach FDA and are interested in working cooperatively with the
Agency to phase out production uses of medically important
antimicrobials, and to achieve an orderly transition of medically
important antimicrobials currently approved for over-the-counter use in
food-producing animals to a marketing status that involves veterinary
oversight (i.e., veterinary feed directive (VFD) status for feed use
drugs and prescription status for drugs approved for use through other
routes of administration).
As part of the proposed strategy, FDA issued an advance notice of
proposed rulemaking (ANPRM) on March 29, 2010 (75 FR 15387), to seek
public comment on whether and to what extent efficiency improvements
should be made to the current VFD process as set forth in FDA's
regulation at 21 CFR 558.6. (Ref. 21) FDA received numerous public
comments in response to the ANPRM and is taking those comments into
account in considering possible revisions to this regulation.
FDA believes that the strategy set out in draft GFI 209
represents another pathway to achieving the same goals contemplated by
the 1977 NOOHs, i.e., the judicious use of medically important
antimicrobial drugs. FDA believes that by implementing this strategy
and proceeding in part under the statutory authority provided under the
Animal
[[Page 79700]]
Drug Availability Act of 1996 (ADAA) \7\ to designate drugs as VFD
drugs (authority which was not available in 1977), it will achieve its
goal of promoting the judicious use of antimicrobial drugs in a more
timely and resource-efficient manner than could be accomplished
otherwise.\8\
---------------------------------------------------------------------------
\7\ ADAA (Pub. L. 104-250), which was signed into law on October
9, 1996, introduced several amendments to the Federal Food, Drug,
and Cosmetic Act that provided FDA with more flexibility in how it
regulates animal drugs and animal feeds. One such amendment made by
the law was to add a new ``veterinary feed directive'' category of
new animal drugs to allow the approval and use of drugs in animal
feed on a veterinarian's order while incorporating safeguards to
help ensure the safe use of the drug.
\8\ FDA's experience with contested, formal withdrawal
proceedings is that the process can consume extensive periods of
time and significant amounts of Agency resources. For example, when
FDA withdrew a class of animal drugs called nitrofurans in 1991, the
proceedings took nearly 20 years. In another proceeding, the
withdrawal of diethylstilbestrol (``DES'') in animals became final
in 1979, 7 years after issuance of an NOOH. More recently, the
withdrawal of enrofloxacin for use in poultry took almost 5 years
and cost FDA approximately $3.3 million.
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2. FDA Would Update the NOOHs To Reflect Current Data, Information and
Policies If, in the Future, it Decides To Move Forward With the
Withdrawal of the Approved Uses of the New Animal Drugs Described in
the NOOHs
Although FDA is optimistic that its proposed strategy to achieve
the judicious use of all medically important antimicrobials, as set out
in draft GFI 209, will be successful, it has not foreclosed
the possibility of using the withdrawal provisions in the Federal Food,
Drug, and Cosmetic Act, if necessary, in the future. This applies not
only to the classes of antimicrobial drugs covered by the 1977 NOOHs,
but also any other production use claims (i.e., growth promotion/feed
efficiency uses) for a medically important antimicrobial new animal
drug or class of drugs intended for use in food-producing animals.
However, if FDA were to pursue withdrawal of approval of any production
use claims, it would first publish a notice in the Federal Register
giving the sponsor(s) of the affected new animal drug(s) notice of the
proposed withdrawal(s) and an opportunity for a hearing.
If, at some future time, FDA decides to proceed with the withdrawal
of the production uses of penicillins and tetracyclines intended for
use in feeds for food-producing animals that were the subject of the
1977 NOOHs, it would publish a new Federal Register notice giving
sponsors an opportunity for a hearing on the matter. A new notice would
be appropriate for many reasons. First, more than three decades have
passed since the original notice appeared in the Federal Register. FDA
would publish a new Federal Register notice to ensure all current
sponsors of the approved new animal drugs are properly notified and
have an opportunity to request a hearing.
Second, not all uses proposed to be withdrawn in the 1977 NOOHs are
still approved. The 1977 NOOH which proposed withdrawal of all
penicillin-containing premixes intended for use in animal feed also
included the then-approved therapeutic uses of penicillin in feed. The
stated grounds for proposing to withdraw approval of the therapeutic
uses of the penicillin-containing premixes were that there was not
substantial evidence of effectiveness of these products for the claimed
therapeutic uses. However, there are no currently approved therapeutic
uses of penicillins in animal feed.
Third, the body of scientific information relevant to the use of
penicillins and tetracyclines in animal feeds has grown since 1977. If
the Agency were to pursue the NOOHs, FDA would need to provide notice
to the sponsors that the information available since 1977 would be used
to support the proposal to withdraw the approved uses of the drugs.
For example, in the early 1990's FDA began collaborating with other
government agencies to track antibiotic resistance in foodborne
bacteria through a national public health surveillance system, known as
the National Antimicrobial Resistance Monitoring System or ``NARMS,''
established to monitor antimicrobial susceptibility among enteric
bacteria from humans, retail meats, and food animals. (Ref. 22) Also,
since the 1977 NOOHs published, there have been numerous reports,
including those by the National Academy of Sciences (Ref. 13), the
Institute of Medicine (Ref. 15), the World Health Organization (Ref.
17), and the National Research Council (Ref. 18), that have reviewed
available information and made recommendations. In addition, there have
been advances in our understanding of the genetics of resistance (e.g.,
ways in which bacteria accumulate multiple resistance genes).
Fourth, FDA would need to provide notice regarding which approved
uses were the subject of the NOOH. In the past, FDA has referred to
``subtherapeutic'' uses at various times to include: (1) ``Increased
rate of gain, disease prevention, etc.'' (Ref. 7); (2) ``any use of an
antibacterial drug continuously in feed for longer than 14 days'' (Ref.
23); and (3) ``lower levels than therapeutic levels needed to cure
disease.'' (Refs. 1 and 2) FDA's thinking on this issue has evolved
over the last three decades, and FDA now generally considers disease
control and prevention claims to be judicious uses (in other words,
therapeutic uses), especially when the drug is administered at the
direction and under the oversight of a licensed veterinarian. (Ref. 5)
3. FDA Would Need To Prioritize Any Withdrawal Proceedings (for
Example, Take Into Account Which Withdrawal(s) Would Likely Have the
Most Significant Impact on the Public Health) if, in the Future, It
Decides To Seek Withdrawal of the Approved Uses of Any New Animal Drug
or Class of Drugs
To the extent that FDA decides to move forward with withdrawal
proceedings for any medically important antimicrobial drugs intended
for use in feeds for food-producing animals, it would need to
prioritize which withdrawal(s) to propose first based on various
considerations, including which withdrawal(s) would have the most
significant impact on the public health. It is possible that FDA would
conclude that its judicious use goals would better be achieved by first
pursuing withdrawals of drugs other than penicillins and tetracyclines.
FDA notes that it would need to conduct such an evaluation regardless
of the statutory grounds contemplated for the withdrawal action.
III. Conclusion
At this time, FDA is withdrawing the 1977 NOOHs because: (1) FDA is
engaging in other ongoing regulatory strategies developed since the
publication of the 1977 NOOHs with respect to addressing microbial food
safety issues; (2) FDA would update the NOOHs to reflect current data,
information, and policies if, in the future, it decides to move forward
with withdrawal of the approved uses of the new animal drugs described
in the NOOHs; and (3) FDA would need to prioritize any withdrawal
proceedings (for example, take into account which withdrawal(s) would
likely have the most significant impact on the public health) if, in
the future, it decides to seek withdrawal of the approved uses of any
new animal drug or class of drugs.
Although FDA is withdrawing the 1977 NOOHs, FDA continues to view
antimicrobial resistance as a significant public health issue. Today's
action should not be interpreted as a sign that FDA no longer has
safety concerns about the use of medically important antibiotics in
food producing animals or
[[Page 79701]]
that FDA will not consider re-proposing withdrawal proceedings in the
future, if necessary. FDA has not ruled out the prospect of future
regulatory action, either with respect to the antimicrobial new animal
drugs covered by the 1977 NOOHs or any others. However, for now, FDA's
efforts will focus on promoting voluntary reform and the judicious use
of antimicrobials in the interest of best using the agency's overall
resources to protect the public health. Importantly, this strategy
leaves open the possibility of pursuing withdrawal proceedings at a
later time if FDA's proposed strategy does not yield satisfactory
results.
As indicated previously, as part of the withdrawal of the two 1977
NOOHs, the Agency will close their corresponding dockets. However, we
encourage interested persons to submit comments to the docket
established in connection with draft GFI 209. The docket
number associated with draft GFI 209 is FDA-2010-D-0094.
IV. Penicillin and Tetracycline Uses in Animal Feed
FDA is withdrawing the 1977 NOOHs, and the related companion
proposed rules, because: (1) FDA is engaging in other ongoing
regulatory strategies developed since the publication of the 1977 NOOHs
with respect to addressing microbial food safety issues; (2) FDA would
update the NOOHs to reflect current data, information, and policies if,
in the future, it decides to move forward with withdrawal of the
approved uses of the new animal drugs described in the NOOHs; and (3)
FDA would need to prioritize any withdrawal proceedings (for example,
take into account which withdrawal(s) would likely have the most
significant impact on the public health) if, in the future, it decides
to seek withdrawal of the approved uses of any new animal drug or class
of drugs.
V. References
The following references are on display in the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20857, and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday (except on Federal
holidays). We have verified all Web site addresses, but we are not
responsible for any subsequent changes to the Web sites after this
document publishes in the Federal Register.
1. 42 FR 43772 (August 30, 1977).
2. 42 FR 56264 (October 21, 1977).
3. 42 FR 43770 (August 30, 1977).
4. 42 FR 56254 (October 21, 1977).
5. Draft GFI 209, ``The Judicious Use of Medically
Important Antimicrobial Drugs in Food-Producing Animals,'' June 28,
2010; https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM216936.pdf.
6. 37 FR 2444 (February 1, 1972).
7. 38 FR 9811 (April 20, 1973).
8. 21 CFR 135.109 (revised as of April 1, 1974).
9. 21 CFR 558.15 (revised as of April 1, 1975).
10. H. Rept. 95-1290, ``Agriculture, Rural Development and
Related Agencies Appropriation Bill, 1979,'' June 13, 1978.
11. H. Rept. 96-1095, ``Agriculture, Rural Development and
Related Agencies Appropriation Bill, 1981,'' June 17, 1980.
12. S. Rept. 97-248, ``Agriculture, Rural Development and
Related Agencies Appropriation Bill, 1982,'' October 23 (legislative
day, October 14), 1981.
13. National Academy of Sciences/National Research Council,
``The Effects on Human Health of Subtherapeutic Uses of
Antimicrobials in Animal Feeds,'' 1980, pp. 53-54.
14. 1984 Seattle-King County Study: ``Surveillance of the Flow
of Salmonella and Campylobacter in a Community.''
15. National Academy of Sciences/Institute of Medicine, ``Human
Health Risks With the Subtherapeutic Use of Penicillin or
Tetracyclines in Animal Feed,'' 1988.
16. 68 FR 47272, 47275 (August 8, 2003).
17. 1997 World Health Organization (WHO) Report, '' The Medical
Impact of Antimicrobial Use in Food Animals,'' https://whqlibdoc.who.int/hq/1997/WHO_EMC_ZOO_97.4.pdf
18. 1999 National Research Council (NRC) Report: ``The Use of
Drugs in Food Animals-Benefits and Risks.''
19. A Proposed Framework for Evaluating and Assuring the Human
Safety of the Microbial Effects of Antimicrobial New Animal Drugs
Intended for Use in Food-Producing Animals, https://www/fda/gov/
AdvisoryCommittees/CommitteesMeetingMaterials/
VeterinaryMedicineAdvisoryCommittee/ucm126607.htm.
20. Final Guidance for Industry 152, ``Evaluating the
Safety of Antimicrobial New Animal Drugs With Regard to Their
Microbiological Effects on Bacteria of Human Health Concern,''
October 23, 2003.
21. 75 FR 15387 (March 29, 2010).
22. https://www/fda/gov/AnimalVeterinarySafetyHealth/
AntimicrobialResistance/
NationalAntimmicrobialResistanceMonitoringSystem/default.htm.
23. 41 FR 8282 (February 25, 1976).
Dated: December 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-32775 Filed 12-21-11; 8:45 am]
BILLING CODE 4160-01-P
