[Federal Register: May 22, 1997 (Volume 62, Number 99)]
[Rules and Regulations]
[Page 27944-27947]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22my97-8]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 530
[Docket No. 97N-0172]
Extralabel Animal Drug Use; Fluoroquinolones and Glycopeptides;
Order of Prohibition
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule; order of prohibition.
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SUMMARY: The Food and Drug Administration (FDA) is issuing an order
prohibiting the extralabel use of fluoroquinolones and glycopeptides.
The agency is issuing this order because it believes that some
extralabel uses of fluoroquinolones and glycopeptides in food-producing
animals are capable of increasing the level of drug resistant zoonotic
pathogens (pathogens that are infective to humans) in treated animals
at the time of slaughter. FDA finds that some extralabel uses of
fluoroquinolone and glycopeptide drugs in food-producing animals likely
will cause an adverse event, which constitutes a finding under the
Animal Medicinal
[[Page 27945]]
Drug Use Clarification Act of 1994 (the AMDUCA) that extralabel use of
these drugs in food animals presents a risk to the public health.
Therefore, the agency is issuing this order of prohibition.
DATES: The order of prohibition is effective August 20, 1997. Submit
written comments by July 21, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Richard L. Arkin, Center for
Veterinary Medicine (HFV-238), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1737.
SUPPLEMENTARY INFORMATION:
I. Background
On October 22, 1994, the President signed the AMDUCA into law (Pub.
L. 103-396). The AMDUCA which amended the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 301 et seq.) to allow licensed
veterinarians to prescribe extralabel uses of approved animal drugs and
human drugs in animals. Section 2(a)(4)(D) of the AMDUCA (21 U.S.C.
360b(a)(4)(D)) provides that the agency may prohibit an extralabel drug
use in animals if, after affording an opportunity for public comment,
the agency finds that such use presents a risk to the public health.
In the Federal Register of November 7, 1996 (61 FR 57732), FDA
published the implementing regulations for the AMDUCA. The regulations
will be codified in part 530 (21 CFR part 530). Sections 530.21 and
530.25 describe the basis for issuing an order prohibiting an
extralabel drug use in food-producing animals. The procedure to be
followed in issuing an order of prohibition is set out in Sec. 530.25.
The list of drugs prohibited from extralabel use is set forth in
Sec. 530.41.
The AMDUCA requires that opportunity be given for public comment
before a prohibition becomes effective. The regulation provides, at
Sec. 530.25, for a public comment period of not less than 60 days. It
also provides that the order of prohibition will become effective 90
days after the date of publication, unless FDA revokes the order,
modifies it or extends the period of public comment. The regulation
also states that reasons for the prohibition will be specified.
In the November 7, 1996 final rule, FDA responded to comments from
the public on the proposed rule to implement the AMDUCA (61 FR 25106,
May 17, 1996) that expressed concerns about the implications of
extralabel use for the development and transfer of antimicrobial
resistance. FDA's response to these comments noted that the agency
believes that the selection of resistant human pathogens could be a
basis for restricting extralabel drug use provided that the statutory
standards for restriction can be met for particular drugs or classes of
drugs (61 FR 57732 at 57736 and 57737). The agency is aware that an
association between use of antimicrobial drugs and antimicrobial
resistance has been documented (Refs. 1, 2, 3, 4, and 5). Antimicrobial
resistant zoonotic enteric microorganisms can be transmitted to humans
through consumption of animal products, and certain resistant
microorganisms can be transmitted through contact with farm animals and
through the environment.
In response to comments suggesting that the agency prohibit
extralabel use of approved fluoroquinolones and glycopeptides in food-
producing animals, the agency stated that it had decided to initiate
the process specified by the AMDUCA to implement such prohibition (61
FR 57732 at 57737). The agency's Center for Veterinary Medicine (CVM)
has, since the time it first approved a fluoroquinolone for use in food
animals (August 1995), informally asked veterinarians to voluntarily
refrain from extralabel use of these drugs in food animals.
Veterinarians' professional associations have actively encouraged their
members to refrain from indiscriminate extralabel use of
fluoroquinolones.
FDA intends to prohibit by order the extralabel use of
fluoroquinolones and glycopeptides in food-producing animals because,
as discussed in sections II and III of this document, the agency has
determined that use of these drugs other than for the approved label
indications in food-producing animals meets the criteria for
prohibition in the AMDUCA. These drugs are added to the list of drugs
prohibited for extralabel use at Sec. 530.41.
Sixty days from the date of this publication are provided for
comment. The order will become effective 90 days from the date of this
publication, unless the agency before that time revokes or modifies the
order, or extends the period for public comment.
In passing the AMDUCA, Congress granted FDA broad authority to
protect the public health by allowing the agency to restrict or
prohibit extralabel uses. A prohibition may be based on a finding that
an extralabel use ``presents a risk to the public health,'' which FDA
has defined in Sec. 530.3(e) as ``likely will cause an adverse event.''
The statutory scheme clearly establishes that prohibiting an extralabel
use does not jeopardize an underlying approval or the future
approvability of the same active ingredient or class of drug. A total
prohibition against extralabel use is an action by the agency which
restricts use of the drug to conditions of use established through
approval of a new animal drug application. A finding of ``likely will
cause an adverse event'' is not a determination regarding the safety of
the drug for its approved uses. That determination is made in the
approval process, i.e., an approved drug has been determined to be safe
for use under labeled conditions.
II. Fluoroquinolones
FDA has approved sarafloxacin and enrofloxacin, both of which are
fluoroquinolones, for therapeutic use in poultry. The approvals, the
first of which was granted in August 1995, are for sarafloxacin
hydrochloride for use in drinking water and sarafloxacin and
enrofloxacin injectable products. The agency had previously approved
enrofloxacin for use in nonfood animals.
All of these approvals are conditioned on use under a
veterinarian's supervision. This restriction for the food-producing
animal approvals was established, among other reasons, to reduce the
rate of emergence of sarafloxacin-resistant organisms. Public health
concerns associated with potential increases in antimicrobial
resistance were satisfactorily addressed in the poultry approvals by
establishing conditions of use intended to minimize inappropriate use
of the products and to minimize excretion of the drug and drug-
resistant zoonotic pathogens into the environment. Essentially, the
agency was assured that under the conditions of use stated in the
approval, any increase in the level of resistant zoonotic pathogens
present in the animals at time of slaughter would be insignificant. The
sponsors agreed to provide baseline susceptibility information on
target animal pathogens and to conduct ongoing monitoring of the target
animal pathogens as a postmarketing surveillance program. Also, FDA
implemented with the Centers for Disease Control and Prevention and the
U.S. Department of Agriculture a national antibiotic resistance
monitoring program in zoonotic enteric pathogens in order to detect
emerging resistance to these pathogens and contain their development.
Thus, the agency concluded that resistance development under the
conditions of approval could be monitored and adequately contained.
Before granting the food animal approvals for fluoroquinolones, CVM
[[Page 27946]]
sought advice from its Veterinary Medicine Advisory Committee, and the
Center for Drug Evaluation and Research's Anti-Infective Drugs Advisory
Committee (the joint committee), in a joint meeting held May 11 and 12,
1994. The joint committee agreed that there is a need for
fluoroquinolones in food animal medicine and did not object to the
approval of fluoroquinolones for such use. However, the joint committee
members generally supported restrictions on the use of the drugs in
order to maximize benefits and minimize risks related to the
development of resistant organisms. Use restrictions that were
suggested included prohibiting extralabel use, as well as requiring a
veterinarian's supervision and monitoring resistance levels.
The data and information presented to the joint committee, and
otherwise available to the agency, support the agency's conclusion that
some extralabel uses of fluoroquinolones in food animals meet the
AMDUCA regulation's standard of ``likely will cause an adverse event''
(Ref. 6). Recent reports from the United Kingdom (U.K.) of the
occurrence of human cases and epizootic spread of a multiple-drug
resistant strain of Salmonella typhimurium, Definitive Type 104 (DT
104) are also of concern, (Refs. 7, 8, and 9). Epidemiological surveys
have found an increase in the percentage of DT 104 isolates in the U.K.
to be resistant to ciprofloxacin, a fluoroquinolone which is used for
the treatment of invasive salmonellosis in humans including
salmonellosis caused by DT 104. The spread of DT 104 in the U.K. from
animals to man has been associated with exposure via food and direct
contact is supported by data from the U.K. An association between
veterinary use of enrofloxacin and the development of fluoroquinolone
resistance in DT 104 has been suggested by several scientists (Ref. 7).
Additionally, studies in the U.K. and Europe document the development
of Campylobacter and Salmonella resistant to fluoroquinolones following
introduction of fluoroquinolone use in both humans and food animals
(Refs. 10, 11, 12, 13, 14, and 15).
Expert opinion expressed during the joint committee meeting and
opinions in comments to the proposed AMDUCA implementing regulations
support the view that increased selective pressure on bacteria
resulting from some of the many potential extralabel uses of
fluoroquinolones likely will lead to resistance development and to the
maintenance of the resistance levels until slaughter, thereby
increasing the risk of transfer of resistant organisms to humans and
the compromise of human therapy. The data and information necessary to
determine, in particular situations, whether the resistance level at
time of slaughter would be increased above normal as a result of
extralabel use is not generally available to practicing veterinarians,
who must make the extralabel use decisions. Thus, while the agency
cannot know the effect of each and every potential extralabel use on
the development of resistant pathogens and on their presence on or in
animals at the time of slaughter, it can reasonably conclude, based on
available information, that such development likely will occur, and
that such resistant pathogens likely will be present at slaughter as a
result of some extralabel uses. Because some extralabel uses likely
would cause an adverse public health event, the agency is acting in the
interest of the public health by prohibiting extralabel use of
fluoroquinolones in food-producing animals. The agency is thereby
restricting such drugs to conditions of use that are established
through the new animal drug approval process.
As explained previously, this conclusion does not undermine the new
animal drug approvals that have been granted for fluoroquinolones
because the necessary assurances of safety to the public were provided
for the approved conditions of use during the approval process.
The AMDUCA does not require the agency to prohibit an extralabel
use when the use meets the statutory standard for prohibition. The act
states that the agency ``may'' do so. The agency believes that this is
an appropriate case for the use of the prohibition authority Congress
provided. In addition to the reasons previously stated, the agency
notes that fluoroquinolones are used extensively in human medicine to
treat many infectious diseases, and they are the only antimicrobial
agents that are effective for treatment of certain diseases. Also,
extralabel use of fluoroquinolones in food-producing animals would
interfere with CVM's ability to interpret the monitoring and
surveillance data that will be obtained through the National
Antimicrobial Susceptibility Monitoring Program (see 61 FR 57732 at
57736 and 57737) and the postapproval monitoring program for the
approved fluoroquinolones. These data are critical because early
detection of emerging resistance, identified through the monitoring
program, will allow the agency to contain any resistance that does
occur, thereby limiting its spread.
III. Glycopeptides
One glycopeptide, vancomycin, is approved for use in human
medicine. No glycopeptides are approved for animal use. Thus, as a
practical matter, the agency's prohibition against extralabel use in
animals of glycopeptides applies only to this one human drug product.
However, the prohibition will apply to any future animal drug approvals
of glycopeptides unless the circumstances at the time of such approval
cause the agency to reevaluate any part of the prohibition.
A number of scientific organizations and individual experts who
commented on the proposed AMDUCA regulations recommended that the
agency prohibit extralabel use of glycopeptides (Ref. 16). Those
comments are supported by the following data and information.
Glycopeptide-resistant Enterococci have become a very serious concern
in human medicine, because a lack of effective alternative drugs for
treatment have resulted in increased morbidity and mortality (Ref. 4).
Vancomycin is a major agent used for treating serious methicillin-
resistant Staphylococcus aureus infections.
One study in the U.K. has shown that vancomycin resistant bacteria
may be acquired from animals (Ref. 17). Another study, done in Denmark,
has established a connection between feed use of avoparcin, a
glycopeptide, and vancomycin-resistant Enterococcus faecium (E.
Faecium) (Ref. 18). The resistant organisms were found in food products
from both poultry and swine that had been fed avoparcin. Further,
vancomycin-resistant E. faecium of the same type were found in both
pigs and humans, leading the authors to conclude that vancomycin
resistant E. faecium can be transmitted to humans through food.
The ``adverse event'' associated with extralabel use of
glycopeptides in food-producing animals is therefore the same as that
discussed earlier with regard to extralabel use of fluoroquinolones.
The agency's basis for prohibiting extralabel uses in food-producing
animals of glycopeptides is also the same as that for fluoroquinolones.
That is, the extralabel use of glycopeptides in food-producing animals
likely will lead to increased risk of transfer of resistant organisms
to humans and compromise human therapy. Therefore, the agency is acting
in the interest of the public health and prohibiting the extralabel use
of glycopeptides in food-producing animals.
[[Page 27947]]
IV. References
The following information has been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Report of the ASM Task Force on Antibiotic Resistance, The
American Society for Microbiology Public and Scientific Affairs
Board, Washington, March 16, 1995.
2. Lederberg, J., R. E. Shope, and S. C. Oaks, eds., Emerging
Infections; Microbial Threats to Health in the United States,
Institute of Medicine Committee on Emerging Microbial Threats to
Health, pp. 159-160, National Academy Press, 15, Washington, 1992.
3. Letter from Kenneth I. Berns and Gail Cassell, American
Society of Microbiology, p. 1, to Dockets Management Branch (HFA-
305), Food and Drug Administration, dated July 31, 1996.
4. U.S. Congress, Office of Technology Assessment, Impacts of
Antibiotic-Resistant Bacteria, OTA-H-629 p. 72, U.S. Government
Printing Office, Washington, DC, September 1995.
5. Piddock, L. J. V., ``Does the Use of Antimicrobial Agents in
16 Veterinary Medicine and Animal Husbandry Select Antibiotic-
Resistant Bacteria That Infect Man and Compromise Antimicrobial
Chemotherapy?'' Journal of Antimicrobial Chemotherapy, Vol. 38, pp.
1-3, 1996.
6. Joint Meeting of the Veterinary Medicine Advisory Committee
and Anti-Infective Drugs Advisory Committee, Food and Drug
Administration, Gaithersburg, MD, Associated Reporters of
Washington, pp. 144-195 (transcript), Washington, May 12, 1994.
7. Threlfall, E. J., et al., ``Increasing Spectrum of Resistance
in Multiresistant Salmonella typhimurium,'' Lancet, Vol. 327, pp.
1053-1054, 1996.
8. Threlfall, E. J., et al., ``Epidemic in Cattle of Salmonella
Typhimurium DT104 with Chromosomally Integrated Multiple Drug
Resistance,'' Veterinary Record, Vol. 134, p. 577, 1994.
9. Wall, P. G., et al., ``A Case Control Study of Infection with
an Epidemic Strain of Multi-resistant Salmonella Typhimurium DT104
in England and Wales,'' Communicable Disease Report, Vol. 4, pp.
R130-135, 1995.
10. Endtz, et al., ``Quinolone Resistance in Campylobacter
Isolated from Man and Poultry Following the Introduction of
Fluoroquinolones in Veterinary Medicine,'' Journal of Antimicrobial
Chemotherapy, Vol. 27, pp. 199-208, 1991.
11. Endtz, H. P., et al., ``Fluoroquinolone Resistance in
Campylobacter Spp. Isolated from Human Stools and Poultry
Products,'' Lancet, Vol. 335, p. 787, 1990.
12. Piddock, L. J. V., et al., ``Quinolone Resistance in
Salmonella Spp: Veterinary Pointers,'' Lancet, Vol. 336, p. 125,
1990.
13. Piddock, L. J. V., ``Quinolone Resistance and Campylobacter
Spp.'' (review), Journal of Antimicrobial Chemotherapy, Vol. 36, pp.
891-898, 1995.
14. Griggs, D. J., et al., ``Quinolone Resistance in Veterinary
Isolates of Salmonella,'' Journal of Antimicrobial Chemotherapy,
Vol. 33, pp. 1173-1189, 1994.
15. Velazquez, J. B., et al., ``Incidence and Transmission of
Antibiotic Resistance in Campylobacter Jejuni and Campylobacter
Coli,'' Journal of Antimicrobial Chemotherapy, Vol. 35, pp. 173-178,
1995.
16. Letter from William A. Craig, Professor of Medicine and
Pharmaceutics, University of Wisconsin, to Dockets Management Branch
(HFA-305), Food and Drug Administration, July 31, 1996.
17. Bates, J., J. Z. Jordens, and D. T. Griffiths, ``Farm
Animals as a Putative Reservoir for Vancomycin-resistant
Enterococcal Infection in Man,'' Journal of Antimicrobial
Chemotherapy, Vol. 34, pp. 507-516, 1994.
18. ``Report from the Danish Veterinary Laboratory: The Effect
of Avoparcin Used as a Feed Additive on the Occurrence of Vancomycin
Resistant Enterococcus Faecium in Pig and Poultry Production,''
Danish Veterinary Laboratory, Copenhagen, July 1995.
V. Request for Comments
Interested persons may, on or before July 21, 1997, submit to the
Dockets Management Branch (address above) written comments regarding
this document. Two copies of any comments are to be submitted, except
that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this
document. Received comments may be seen in the office between 9 a.m.
and 4 p.m., Monday through Friday.
VI. Order of Prohibition
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under the authority delegated to the Commissioner of Food and Drugs, I
hereby issue the following order under section 2(a)(4)(D) of the
AMDUCA, Pub. L. 1-3-396 (21 U.S.C. 360b(a)(4)(D)) and Secs. 530.21 and
530.25. FDA finds that some extralabel uses of fluoroquinolone and
glycopeptide drugs in food-producing animals likely will cause an
adverse event, which constitutes a finding under the AMDUCA that
extralabel use of these drugs in food animals presents a risk to the
public health. Therefore, fluoroquinolone and glycopeptide drugs are
prohibited for extralabel use in food-producing animals.
List of Subjects in 21 CFR Part 530
Administrative practice and procedure, Advertising, Animal drugs,
Animal feeds, Drugs, Labeling, Prescription drugs, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs and
redelegated to the Center for Veterinary Medicine, 21 CFR part 530 is
amended to read as follows:
PART 530--EXTRALABEL DRUG USE IN ANIMALS
1. The authority citation for 21 CFR part 530 continues to read as
follows:
Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 501, 502, 503, 505,
507, 512, 701, and 721 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b, 371, 379e).
2. Section 530.41 is revised to read as follows:
Sec. 530.41 Drugs prohibited for extralabel use in animals.
(a) The following drugs, families of drugs, and substances are
prohibited for extralabel animal and human drug uses in food-producing
animals.
(1) Chloramphenicol;
(2) Clenbuterol;
(3) Diethylstilbestrol (DES);
(4) Dimetridazole;
(5) Ipronidazole;
(6) Other nitroimidazoles;
(7) Furazolidone (except for approved topical use);
(8) Nitrofurazone (except for approved topical use);
(9) Sulfonamide drugs in lactating dairy cattle (except approved
use of sulfadimethoxine, sulfabromomethazine, and
sulfaethoxypyridazine);
(10) Fluoroquinolones; and
(11) Glycopeptides.
(b) The following drugs, families of drugs, and substances are
prohibited for extralabel animal and human drug uses in nonfood-
producing animals: [Reserved.]
Dated: May 19, 1997.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 97-13677 Filed 5-20-97; 2:50 pm]
BILLING CODE 4160-01-F