[Federal Register Volume 68, Number 153 (Friday, August 8, 2003)]
[Proposed Rules]
[Pages 47272-47277]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-20244]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 510 and 558

[Docket No. 2003N-0324]


New Animal Drugs; Removal of Obsolete and Redundant Regulations

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing removal of 
regulations that exempted certain new animal drugs administered in feed 
from batch certification requirements. FDA is also proposing removal of 
regulations that required sponsors to submit data regarding the 
subtherapeutic use of certain antibiotic, nitrofuran, and sulfonamide 
drugs administered in animal feed. The intended effect of this proposed 
rule is to remove regulations that are obsolete or redundant. Some of 
the products and combination uses subject to the listings in these 
regulations are subject to a notice of findings of effectiveness and an 
opportunity for hearing published elsewhere in this issue of the 
Federal Register. One approved product subject to the regulations 
proposed for removal is being codified elsewhere in this issue of the 
Federal Register.

DATES: Submit written comments on the proposed rule by November 6, 
2003.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to: http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Andrew J. Beaulieu, Center for 
Veterinary Medicine (HFV-1), 7519 Standish Pl., Rockville, MD 20855, 
301-827-2954, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Elsewhere in this issue of the Federal Register, the agency is 
announcing the effective conditions of use for some of the products or 
use combinations subject to the listings in parts 510 and 558 (21 CFR 
part 510 and 558), specifically, Sec. Sec.  510.515 and/or 558.15, and 
the agency is proposing to withdraw the new animal drug applications 
(NADAs) for those products or use combinations lacking substantial 
evidence of effectiveness following a 90-day opportunity to supplement 
the NADAs with labeling conforming to the relevant findings of 
effectiveness. One approved product subject to Sec.  558.15 is being 
codified in part 558, subpart B in a final rule published elsewhere in 
this issue of the Federal Register. Concurrent with that announcement 
and final rule, the agency is proposing to remove these two sections of 
the Code of Federal Regulations (Sec. Sec.  510.515 and 558.15) for the 
reasons described in sections II and III of this document.

II. Part 510, Subpart F Animal Use Exemptions From Certification and 
Labeling Requirements and Sec.  510.515 Animal Feeds Bearing or 
Containing New Animal Drugs Subject to the Provisions of Section 512(n) 
of the Act

A. History of Part 510, Subpart F and Sec.  510.515

    In 1945, Congress added section 507 to the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 357) requiring the agency to provide 
for the certification of batches of drugs composed wholly or partly of 
any kind of penicillin (Public Law 79-139, 59 Stat. 463). No 
distinction was made

[[Page 47273]]

between the use of the drugs in man or other animals. Section 507 of 
the act was subsequently amended several times to include streptomycin, 
chlortetracycline, bacitracin, chloramphenicol, and their derivatives. 
The law allowed the agency to issue regulations exempting drugs or 
classes of drugs from the batch certification requirements. Over the 
years, FDA issued exemption regulations for a number of antibiotics 
used in animal feeds, provided the involved products were in compliance 
with certain provisions. The exemptions are currently contained in 
Sec.  510.515.
    The Animal Drug Amendments of 1968 consolidated provisions of the 
act relating to new animal drugs (including antibiotics in section 507 
of the act) into new section 512 (21 U.S.C. 360b). The agency 
established procedural regulations under parts 510 and 514 (21 CFR part 
514) to implement this provision of the act.
    Subsequent to the establishment of the exemption provisions in 
Sec.  510.515, the agency came to the conclusion that batch-by-batch 
certification was no longer required under any circumstances to assure 
the safety of antibiotics. In the Federal Register of September 7, 1982 
(47 FR 39155), the agency published regulations exempting all classes 
of human and animal use antibiotics from batch certification 
requirements based upon a finding of extremely low rejection rates for 
the certifiable antibiotics.
    In 1988, Congress removed from the act all antibiotic certification 
provisions for animal drugs when it enacted the Generic Animal Drug and 
Patent Term Restoration Act (GADPTRA). Subsequently, the agency 
published a final rule on May 26, 1989 (54 FR 22741), which removed all 
of the certifiable antibiotic procedural regulations that then appeared 
in parts 510 and 514. That rule indicated that removal of the technical 
regulations concerning specific antibiotic drugs, such as Sec.  
510.515, which contained information about their conditions of use, 
would be the subject of future regulations.
    Since that time, FDA has removed many drug uses and use 
combinations from Sec.  510.515. The agency did this when it withdrew 
approval of products subject to the regulation, or when it published 
approval regulations for them, in part 558, subpart B, after completing 
their Drug Efficacy Study Implementation (DESI) finalization (see, 
e.g., 61 FR 35949, July 9, 1996). Consequently, a regulation that at 
one time contained dozens of batch certification exemption provisions 
now lists only a few products and use combinations.

B. Removal of Sec.  510.515

    The purpose of Sec.  510.515, which was to provide exemption from 
batch certification of certain drugs intended for use in animal feed, 
was rendered obsolete with the enactment of GADPTRA. Because the 
regulation is out dated relative to its intended purpose, the agency is 
proposing to remove it.
    This action is not intended to have a substantive effect on any 
approved new animal drugs. As noted in section II.A of this document, 
some of the drug uses and use combinations currently listed in Sec.  
510.515 have approvals that are codified in part 558 subpart B. 
Therefore, these uses will not be substantively affected by removal of 
listings in this regulation. Other drug use combinations currently 
listed in Sec.  510.515 are also listed in Sec.  558.15, but their 
approvals, if any, have not been codified in part 558 subpart B. As 
discussed in section II.B of this document, and in the notice appearing 
elsewhere in this issue of the Federal Register, the use combinations 
that have been approved will be codified in part 558 subpart B. In 
regard to the only other listed drug (para-aminobenzoic acid), the 
agency is unaware of any company that currently holds approval for it, 
or markets it, and believes it is no longer used in the practice of 
veterinary medicine. If a person wishes to market a drug or drug 
combination being removed under this proposal and believes that it 
holds a valid approval for it that is not already codified in part 558 
subpart B or subject to the final rule or notice published elsewhere in 
this issue of the Federal Register, the person should present evidence 
supporting approval to avoid facing potential regulatory action in the 
event of future marketing.

III. Section 558.15 Antibiotic, Nitrofuran, and Sulfonamide Drugs in 
the Feed of Animals

A. History of Sec.  558.15

    In the mid-1960s, FDA became concerned about the safety to man and 
animals of long-term antibiotic use in animals, and for several years 
the agency studied the effects of low-level feeding of antibiotics to 
animals. In April 1970, the Commissioner of Food and Drugs 
(Commissioner) established a task force of scientists from government, 
industry, and academia to comprehensively review the use of antibiotics 
in animal feed. In the Federal Register of February 1, 1972 (37 FR 
2444), the agency published the conclusions of that task force and 
proposed to require sponsors to submit specific data for antibacterial 
drugs intended for subtherapeutic or growth promotion use. The task 
force identified areas in which data were needed and established 
criteria for studies intended to show whether use of antimicrobials in 
animal feed presents a hazard to human or animal health. The criteria 
reflected four basic issues with respect to which data were needed: (1) 
The potential to increase the frequency of bacteria carrying 
transferable drug resistance; (2) the potential to increase the 
antibiotic resistance of, or the shedding of, Salmonella spp.; (3) the 
potential to enhance bacterial pathogenicity; and (4) the potential for 
drug residues to cause an increase in pathogenic bacteria resistant to 
human antibiotics drugs or to cause human hypersensitivity reactions. 
The 1972 proposal also stated that all then-approved subtherapeutic 
and/or growth promoting uses in animal feeds of antibiotics and 
sulfonamides that are also used in humans would be revoked unless data 
identified by the task force were submitted to FDA.
    In the Federal Register of April 20, 1973 (38 FR 9811), the agency 
published the final rule which established 21 CFR 135.109 Antibiotic 
and sulfonamide drugs in the feed of animals (redesignated as Sec.  
558.15 in 1974). The section was subsequently amended on September 5, 
1973, to include the nitrofurans (38 FR 23942). In the Federal Register 
of February 25, 1976 (41 FR 8282), the agency withdrew approvals for 
those antimicrobial drugs not in compliance with the data submission 
requirements of Sec.  558.15. The same document added paragraphs (g)(1) 
and (g)(2) to Sec.  558.15. These paragraphs listed the medicated 
premixes and drug combinations, respectively, which had submitted the 
required data for agency review. These are known as the interim 
marketing provisions.

B. Approval Status of Products and Use Combinations Subject to the 
Listings in Sec.  558.15

    The preamble to the final rule that added the Sec.  558.15 interim 
marketing provisions stated that all products and combination uses 
subject to the listings in the regulation were the subject of approved 
applications (41 FR 8282 and 8285, February 25, 1976). However, a 
number of years after this regulation was issued, it became apparent 
that the administrative record associated with 15 products was 
incomplete, calling into question their approval status.

[[Page 47274]]

    One cause of this problem relates to the Animal Drug Amendments of 
1968. Under Section 108 of this law, any product that had been approved 
before 1968 by a new drug application, food additive petition, 
certifiable antibiotic application, or master file would be considered 
to be the subject of an approved new animal drug application under the 
new section 512. Because Sec.  558.15 dealt with antimicrobials used in 
animal feed, the products listed in Sec.  558.15 were considered food 
additives before the 1968 animal drug amendments. In addition, a number 
of them contained certifiable antibiotics. The approval processes for 
these products before the 1968 amendments were complex, redundant, and 
involved the acceptance of secondary manufacturers/distributors, 
sometimes based on a demonstration of equivalence of their products to 
primary sponsor products and sometimes not. Unlike the current new 
animal drug application process under section 512 of the act, this was 
generally not an orderly process. As a result, the agency's and 
sponsors' ability to document the pre-1968 approvals has been hampered.
    Because their administrative records were incomplete, in 1998 the 
agency undertook to determine whether any of the 15 products were 
unapproved and, therefore, erroneously listed in Sec.  558.15. In this 
regard, the agency asked sponsors to identify the involved product, 
attach associated labeling, and certify its approval status. 
Certification was forthcoming for 10 of the 15 applications. The agency 
informed the involved parties by letter that their certifications would 
be used as part of the administrative record of approval and that it 
planned to codify these approvals as soon as possible, very likely in 
concert with the removal of Sec.  558.15. Because the agency was unable 
to verify that the remaining five products were approved, the agency 
believes they were erroneously listed in Sec.  558.15.

C. Reasons for Removal of Sec.  558.15

    The agency is proposing to remove Sec.  558.15 because it long ago 
fulfilled its stated purpose of requiring sponsors to submit data 
regarding the subtherapeutic use of antibiotics on the market at the 
time of its publication. The safety studies required to be conducted on 
the products listed at the time the section was issued were completed 
long ago. In addition, as discussed in section III.D of this document, 
the agency has a new strategy and concept for assessing the safety of 
antimicrobial new animal drugs, including subtherapeutic use of 
antimicrobials in animal feed, with regard to their microbiological 
effects on bacteria of human health concern. Therefore, the removal of 
Sec.  558.15 does not mean that studies will no longer be required to 
assess the consequences of the use of antimicrobials in food-producing 
animals.

D. The Antibiotic Resistance Issue After Publication of Sec.  558.15

    While, at the time of its publication, Sec.  558.15 accurately 
reflected FDA's basis for assessing the safety of subtherapeutic uses 
of antibiotics in feed, based on new information and considerable 
experience, over time FDA developed a new strategy and concept to deal 
with the issue of antimicrobial resistance. Accordingly, it is useful 
to review the history of the antimicrobial resistance issue from the 
time Sec.  558.15 was issued to the present relative to the 
significance of the removal of Sec.  558.15 on FDA's ability to deal 
with the issue.
    As discussed in section III.A of this document, under Sec.  558.15, 
FDA received data addressing the subtherapeutic use of antibiotics in 
animal feed. To assist FDA in assessing the data, the Commissioner 
asked the agency's National Advisory Food and Drug Committee (NAFDC) to 
review the data and issues involved and to make recommendations to him 
on the future use of subtherapeutic antibiotics in animal feeds.
    In 1977, the NAFDC made its findings known to FDA. The FDA 
carefully considered the recommendations made by the NAFDC. On August 
30, 1977 (42 FR 43770), the Director of the Center for Veterinary 
Medicine (Director) proposed to revoke all regulations providing for 
the subtherapeutic use of penicillin alone and in combination with 
other drugs in animal feeds. Because the National Academy of Sciences 
National Research Council (NAS/NRC) DESI review concluded that no 
therapeutic uses of penicillin in animal feed were supported by 
adequate evidence of effectiveness, he also proposed to revoke all 
regulations providing for the therapeutic use of penicillin in animal 
feed. Also, in the Federal Register of August 30, 1977 (42 FR 43772), 
the Director issued a notice of opportunity for hearing (NOOH) on a 
proposal to withdraw approval of NADAs for all penicillin-containing 
premixes intended for use in animal feeds. The NOOH was issued, under 
section 512(e) of the act (21 U.S.C. 360b(e)), on the grounds that 
evidence showed that such products have not been shown to be safe, that 
the applicants failed to establish and maintain records and make 
reports as required, and that there was a lack of substantial evidence 
that such products were effective for certain uses.
    Subsequently, in the Federal Register of October 21, 1977 (42 FR 
56254), the Director proposed to revoke regulations providing for the 
subtherapeutic use of tetracyclines in animal feed except for those 
specific conditions of use for which there were no safe and effective 
substitutes at that time. Also in the Federal Register of October 21, 
1977 (42 FR 56264), the Director issued an NOOH on a proposal to 
withdraw approval of NADAs for certain subtherapeutic uses of 
tetracyclines (chlortetracycline and oxytetracycline) in animal feeds.
    In 1978, after FDA proposed to withdraw approval of various uses of 
penicillin and tetracyclines in animal feeds, Congress directed FDA to 
conduct further studies related to the use of antibiotics in animal 
feed and to hold in abeyance implementation of its proposed withdrawal 
actions pending the outcome of the studies (see H.R. Rept. 95-1290 at 
p. 99 (June 13, 1978)). As directed, FDA spent $1.5 million of its 
appropriations for a study of the safety issues relating to the use of 
antibiotics in animal feeds. The study entitled ``The Effects on Human 
Health of Subtherapeutic Use of Antimicrobials in Animal Feeds,'' 
conducted by the NAS/NRC, was published in 1980 (Ref. 1). It concluded 
that existing data could neither prove nor disprove the postulated 
hazards to human health from subtherapeutic antimicrobial use in animal 
feeds.
    On November 20, 1984, the Natural Resources Defense Council, Inc. 
(NRDC), petitioned the Secretary of Health and Human Services 
(Secretary) to immediately suspend approval of the subtherapeutic use 
of penicillin and tetracyclines in animal feeds (Ref. 2). NRDC's 
petition requested that the Secretary invoke the imminent hazard 
provision of the act (21 U.S.C. 360b(e)(1)) which authorizes the 
Secretary to suspend approval of an application for the use of a new 
animal drug if an imminent hazard exists to the health of man or to the 
animals for which the drug is intended. Soon after the filing of the 
petition, there was a congressional hearing in December 1984 before the 
House of Representatives Committee on Science and Technology, 
Subcommittee on Investigations and Oversight, as well as an informal 
hearing before the Commissioner of FDA on January 25, 1985.
    On November 13, 1985, the Secretary denied the NRDC petition on the 
basis that an ``imminent hazard'' had not been demonstrated (Ref. 3). 
This decision was based on an analysis of the evidence cited by the 
NRDC as well as scientific

[[Page 47275]]

evidence, information, and opinions coming out of the January 25, 1985, 
public hearing and other relevant data collected and analyzed by FDA.
    Subsequently, the Commissioner directed the agency to contract with 
the NAS, Institute of Medicine (IOM), to conduct a risk assessment of 
the potential risk to human health associated with the practice of 
feeding subtherapeutic levels of penicillin and the tetracyclines to 
animals for growth promotion, feed efficiency, and disease prevention.
    In 1988, the NAS/IOM reviewed the information concerning the 
antibiotic resistance issue available at the time. An expert committee 
was convened to determine the human health risks associated with the 
practice of feeding subtherapeutic levels of penicillin and 
tetracyclines to animals for growth promotion, feed efficiency, and 
disease prevention. In the report entitled ``Human Health Risks with 
the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed'' 
the committee developed a risk-analysis model, using data only on 
Salmonella infections that resulted in human death (Ref. 4). The 
committee found a considerable amount of indirect evidence implicating 
both subtherapeutic and therapeutic use of antimicrobials as a 
potential human health hazard. The committee did not find data 
demonstrating that use of subtherapeutic penicillin or tetracycline 
directly caused humans to die from salmonellosis. The committee noted 
that it was not possible to separate the public health effects of 
therapeutic and subtherapeutic uses and strongly recommended further 
study of the issue.
    Based upon the report and other relevant information, the agency: 
(1) Concluded that the risks were neither proved nor disproved, (2) did 
not deny there was some degree of risk, and (3) did not conclude that 
the continued subtherapeutic use of penicillin and the tetracycylines 
in animal feed is safe. The notices of opportunity for hearing 
published in the Federal Registers of August 30 and October 21, 1977, 
remain pending.
    The American Society of Microbiology issued a report in 1995 that 
cited grave concerns about both human and animal antibiotic use and the 
rise in antimicrobial resistance (Ref. 5). The report advocated: A 
significant increase in resistance monitoring in the United States, 
more education about the use and risks of antimicrobials, and more 
basic research designed to develop new antimicrobials and vaccines and 
disease prevention measures. The report criticized overuse of 
antibacterials in human medicine, but also pointed out the extensive 
use of antibacterials in food production, which was partly attributed 
to the consolidation of farms to facilities with large numbers of 
confined animals. The report made it clear that the antibiotic 
resistance problem is global and was a precursor to involvement by the 
United Nation's World Health Organization (WHO). The meetings of the 
WHO in 1997 and 1998 led to the development of a number of 
recommendations regarding the use of antimicrobial drugs in food-
producing animals (Refs. 6 and 7).
    In 1999, FDA issued ``Guidance for Industry: Consideration of the 
Human Health Impact of the Microbial Effects of Antimicrobial New 
Animal Drugs Intended for Use in Food-Producing Animals'' ([numsign]78) 
(64 FR 70715, Dec. 17, 1999). In this guidance, FDA reaffirmed its 
statutory authority to evaluate the safety of new animal drugs with 
respect to their microbiological effects on bacteria of human health 
concern. FDA asserted that this consideration applies to all 
antimicrobial new animal drugs intended for use in food-producing 
animals including both therapeutic use and use at subtherapeutic levels 
for production purposes. Subsequently, the agency released a concept 
paper, which has come to be known as the Framework Document, which 
described a possible approach that the FDA could take in regulating 
antimicrobial new animal drugs intended for use in food-producing 
animals (Ref. 8).
    Since the publication of the Framework Document, FDA has held a 
number of public meetings as well as two meetings of its Veterinary 
Medical Advisory Committee to obtain input on the concepts outlined in 
the Framework Document. Based on this input, FDA drafted a guidance for 
industry (GFI) to implement several of the key strategies and concepts 
discussed in the Framework Document. The draft guidance for industry 
entitled ``Draft Guidance for Industry: Evaluating the Safety of 
Antimicrobial New Animal Drugs With Regard to Their Microbiological 
Effects on Bacteria of Human Health Concern'' ([numsign]152) (67 FR 
58058, Sept. 13, 2002) outlines a risk analysis process for evaluating 
the safety of antimicrobial new animal drugs. This guidance, subject to 
public comment, represents the Center for Veterinary Medicine's current 
best thinking on how to assure the safety of antimicrobial new animal 
drugs intended for use in food-producing animals.

E. Effect of the Removal of Sec.  558.15

    Based on the previous discussion, the removal of Sec.  558.15 will 
have no effect on FDA's ability to address the issue of antimicrobial 
resistance. Additionally, the removal of Sec.  558.15 is not intended 
to have a substantive effect on the products subject to the section's 
interim marketing provisions. Most of the products or use combinations 
subject to the listings have approvals that are already codified in 
part 558 subpart B. The agency's actions on the products and use 
combinations whose approval is not already codified in part 558 subpart 
B are described elsewhere in this issue of the Federal Register. One 
action consists of publishing the agency's findings of effectiveness 
for these products and use combinations, under DESI, and, where 
relevant, proposing to withdraw approval of applications for 
indications lacking substantial evidence of effectiveness and providing 
a notice of opportunity for hearing. The other action is the codifying 
of one approval in part 558 subpart B. This action is a final rule 
since the product is not subject to DESI. As noted in section III.B of 
this document, the agency believes that five products subject to the 
listings in Sec.  558.15 were erroneously listed there. Because the 
regulation could only permit the interim marketing of approved 
products, the removal of Sec.  558.15 will not have a substantive 
effect on the five unapproved products. Further, the agency is unaware 
of any company that currently markets any of these five products. If a 
company wishes to market one of these drug products and believes that 
it holds a valid approval for it that is not already subject to an 
approval reflected in part 558 subpart B, the company should present 
evidence supporting approval to avoid facing potential regulatory 
action in the event of future marketing.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory

[[Page 47276]]

alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). The agency believes that this 
proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
order and so is not subject to review under the Executive order.
    FDA is proposing to revoke Sec. Sec.  510.515 and 558.15 because 
they are obsolete. The purpose of Sec.  510.515 was to provide 
exemption from certification and labeling requirements of certain drugs 
used in animal feeds. FDA has discontinued the practice of certifying 
antibiotic animal drugs, thereby rendering the regulation obsolete 
relative to its intended purpose. The original purpose of Sec.  558.15, 
requiring the submission of the results of studies on the effects of 
long-term administration of then-marketed antimicrobial drugs in animal 
feed on the occurrence of multiple drug-resistant bacteria associated 
with these animals, is also obsolete as FDA has a new strategy and 
concept for assessing the safety of antimicrobial new animal drugs, 
including subtherapeutic use of antimicrobials in animal feed, with 
regard to their microbiological effects on bacteria of human health 
concern.
    Almost all of the drug product listings contained in Sec. Sec.  
510.515 and/or 558.15 are already reflected in approval regulations 
published elsewhere in part 558 subpart B. In two documents published 
in this issue of the Federal Register, the agency is addressing the 
drug product listings whose approvals are not currently reflected in 
the approval regulations in part 558 subpart B.

A. Benefits

    This proposal is expected to provide clarity and equity in the 
regulations for new animal drugs for use in animal feeds by deleting 
the obsolete provisions at Sec. Sec.  510.515 and 558.15. We do not 
expect this proposed rule to result in a direct human or animal health 
benefit. Rather, this proposal would remove unnecessary regulations 
that both provided exemptions for certifications that no longer occur, 
or required the submission of safety data for approved subtherapeutic 
uses of antibiotics, nitrofurans and sulfonamides in the 1970s.

B. Compliance Costs

    FDA expects this proposal to result in the loss of marketing 
ability for five combination uses listed in Sec.  558.15 as described 
in III.B of this document. In an attempt to certify the approval 
status, FDA contacted, or attempted to contact, the three sponsors of 
these five drug combinations. Attempts with one sponsor indicated that 
they did not wish to certify the transitional approvals, and no 
response was received from the other sponsors concerning these 
transitional approvals. Accordingly, we believe that these products 
were erroneously listed in Sec.  558.15 and that these sponsors no 
longer market these combination uses as provided for under Sec.  
558.15. The revocation of Sec.  558.15 is not expected to have a 
substantive effect on any approved new animal drugs, or to cause any 
approved new animal drug to lose its marketing ability. Therefore, we 
do not expect any loss of sales to result from this provision. We 
request public comment on the loss of sales or other effects to any 
products or drug combinations that will lose marketing ability due to 
this proposed rule.

C. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options to minimize any significant impact on a substantial 
number of small entities. FDA has determined in section V.B of this 
document that this proposed rule would not impose compliance costs on 
the sponsors of any products that are currently marketed. Further, it 
is not expected to cause any drugs that are currently marketed to lose 
their marketing ability. We therefore certify that the proposed rule 
would not have a significant economic effect on a substantial number of 
small entities. No further analysis is required under the Regulatory 
Flexibility Act (as amended).

D. Unfunded Mandates Reform Act

    Section 202(a) of the Unfunded Mandates Reform Act of 1995 (Public 
Law 104-4) requires that agencies prepare a written statement of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million or more in any 
one year (adjusted annually for inflation).
    The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for the proposed rule because the rule 
is not expected to result in any 1-year expenditure that would exceed 
$100 million adjusted for inflation. The current inflation-adjusted 
statutory threshold is about $110 million.

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no 
collections of information. Therefore, clearance by the Office of 
Management and Budget under the Paperwork Reduction Act of 1995 is not 
required.

VII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. National Academy of Sciences/National Research Council, ``The 
Effects on Human Health of Subtherapeutic Use of Antimicrobials in 
Animal Feeds,'' 1980.
    2. Petition of the Natural Resources Defense Council, Inc., to 
Secretary of Health and Human Services, New York, NY, November 20, 
1984.
    3. Decision of the Secretary Denying Petition, Docket No. 84P-
0399, November 13, 1985.
    4. National Academy of Sciences/Institute of Medicine, ``Human 
Health Risks With the Subtherapeutic Use of Penicillin or 
Tetracyclines in Animal Feed,'' 1989.
    5. Report of the American Society for Microbiology Task Force on 
Antibiotic Resistance; the American Society for Microbiology, Public 
and Scientific Affairs Board; Washington, DC, March 16, 1995.
    6. World Health Organization (WHO), ``The Medical Impact of the 
Use of Antimicrobials in Food Animals,'' Report of a WHO meeting, 
WHO/EMC/ZOO/97.4, Berlin, Germany, October 13 to 17, 1997.
    7. WHO, ``Use of Quinolones in Food Animals and Potential Impact 
on Human Health,'' Report of a WHO meeting, WHO/EMC/ZDI/98.12, 
Geneva, Switzerland, June 2 to 5, 1998.
    8. Discussion paper: ``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,'' 
Center for Veterinary Medicine, Food and Drug Administration, 1999; 
Docket 98D-1146 (http://www.fda.gov/cvm/antimicrobial/ar_framework.htm).

VIII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments or two paper copies of any written comments, except 
that individuals may submit one paper 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 Division

[[Page 47277]]

of Dockets Management between 9 a.m. and 4 p.m. Monday through Friday.

List of Subjects

21 CFR Part 510

    Administrative practice and procedure, Animal drugs, Labeling, 
Reporting and recordkeeping requirements.

21 CFR Part 558

    Animal drugs, Animal feeds.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 510 and 558 be amended as follows:

PART 510--NEW ANIMAL DRUGS

    1. The authority citation for 21 CFR part 510 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e.

Subpart F [Removed and Reserved]

    2. Subpart F, consisting of Sec.  510.515, is removed and reserved.

PART 558--NEW ANIMAL DRUGS FOR USE IN ANIMAL FEEDS

    3. The authority citation for 21 CFR part 558 continues to read as 
follows:

    Authority: 21 U.S.C. 360b, 371.


Sec.  558.4  [Amended]

    4. Section 558.4 Requirement of a medicated feed mill license is 
amended in paragraph (c) by removing ``and in Sec. Sec.  510.515 and 
558.15 of this chapter''.


Sec.  558.15  [Removed]

    5. Section 558.15 Antibiotic, nitrofuran, and sulfonamide drugs in 
the feed of animals is removed.

    Dated: August 1, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-20244 Filed 8-5-03; 4:09 pm]
BILLING CODE 4160-01-S