[Federal Register Volume 62, Number 99 (Thursday, May 22, 1997)]
[Rules and Regulations]
[Pages 27944-27947]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-13677]


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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