[Federal Register Volume 64, Number 142 (Monday, July 26, 1999)]
[Proposed Rules]
[Pages 40321-40323]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-18926]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 514

[Docket No. 99N-2151]
RIN 0910-AB69


New Animal Drug Applications; Sheep as a Minor Species

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations to reclassify sheep as a minor species for all data 
collection purposes. This would allow sponsors of supplemental new 
animal drug applications (NADA's) to extrapolate human food safety data 
from a major species such as cattle to sheep. In particular, this will 
allow the extrapolation of the tolerances for residues of new animal 
drugs in cattle to sheep.

DATES: Written comments must be submitted by October 25, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Meg Oeller, Center For Veterinary 
Medicine (HFV-130), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-7581.
SUPPLEMENTARY INFORMATION:

I. Minor Use and Minor Species

    Since 1983 (48 FR 1922, January 14, 1983 (hereinafter referred to 
as the January 1983 final rule)), FDA has permitted some flexibility in 
the means to meet the data requirements to support the approval of new 
animal drugs intended for ``minor uses'' and ``minor species.'' 
Specifically, these classifications permit data extrapolation from a 
major use or major species to support the safety and effectiveness of a 
new animal drug for a minor use or minor species. The requirements were 
codified in Sec. 514.1(d) (21 CFR 514.1(d)) by the January 1983 final 
rule (effective February 14, 1983).
    ``Minor use'' is defined as use of new animal drugs in a minor 
animal species, or use of new animal drugs in any animal species for 
control of a disease that occurs infrequently or in limited geographic 
areas. ``Minor species'' are defined by exclusion as any species other 
than horses, cattle, swine, dogs, cats, chickens, and turkeys. Sheep 
are classified as a minor species for the purposes of target animal 
safety and effectiveness studies. However, they are considered a major 
species for the purpose of determining the human food safety of edible 
products.

II. The Minor Species Designation and Safety and Effectiveness

    The current minor use regulations (Sec. 514.1(d)) do not negate or 
alter the legal requirement that sponsors must provide data from 
``adequate and well-controlled investigations'' to show effectiveness 
and ``adequate tests by all methods reasonably applicable'' to 
demonstrate safety. The agency has guidance that lays out its 
interpretation of what data for minor use/minor species drugs will be 
sufficient to meet these legal standards (Ref. 1). The regulations 
permit data provided in support of a drug approved for use in a major 
species to be used in support of an approval for the same drug for use 
in a minor species where scientifically appropriate.

III. The Minor Species Designation and Human food safety

    The preamble of the January 1983 final rule (48 FR 1922 at 1923) 
described the toxicology, residue evaluation, and analytical 
methodology standards that are components of the human food safety 
evaluation for minor use drugs. For minor species, sufficient 
toxicology and metabolism data must be available within the residue 
evaluation data package in the application, or by reference, to 
establish a tolerance for new animal drug residues in animal-derived 
food. The tolerance is a limit on the amount of drug residue in edible 
tissue, as measured by the approved analytical method, that will not 
render the edible tissue adulterated under section 402(a)(2)(D) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 342(a)(2)(D)).
    The agency may require the residue evaluation data package to 
contain additional information on metabolism beyond that used for the 
approval in major species, if available information raises human food 
safety concerns about the level or toxicity of metabolic transformation 
products in edible tissues of the minor target species. In addition, if 
the conditions of safe use of the product require withholding of 
animals from slaughter for a prescribed period of time following 
treatment, a regulatory analytical method will be necessary. The 
sponsor of the minor use application must then demonstrate that the 
approved analytical methodology is suitable for monitoring compliance 
with the approved conditions of use.

IV. The Status of Sheep

    In the preamble of the January 1983 final rule, the agency set out 
the justification for the determination that sheep are a major species 
for human food safety purposes. The agency's concern centered on 
consumers in the United States who eat a large proportion of lamb and 
mutton in their diets. In its evaluations, FDA used data from consumers 
who had reported eating sheep products during the previous 2 weeks. 
Using these values, FDA calculated that those consumers eat 24 percent 
as much lamb as beef. The agency determined that this was enough to 
categorize sheep as a major species for human food safety purposes. The 
agency stated in the preamble that it would be willing to reevaluate 
this conclusion if new data became available.

[[Page 40322]]

V. The Evidence to Support a Change in the Designation of Sheep

    New data have become available since publication of the January 
1983 final rule. These data allow the agency to conclude that sheep 
should be a minor species with respect to all data requirements. The 
new data concern the similarity of drug metabolism between sheep and 
cattle rather than consumption levels. The agency now believes that the 
body of evidence concerning drug metabolism is more significant in 
determining the major/minor status of species than consumption data 
because it demonstrates the reliability of data extrapolated from a 
major species. C. R. Short (Ref. 2) reviewed a collection of studies 
demonstrating that cattle and sheep metabolize drugs similarly. He 
documented the similarity in both major and minor pathways of drug 
metabolism between cattle and sheep, and found no differences of a 
qualitative nature.
    These findings are further supported by a comparison of products 
that have been approved for use in both cattle and sheep under the 
current regulations. If sheep were considered a minor species for human 
food safety, the tolerance approved in cattle would be applied to 
sheep. A tissue residue depletion study would be conducted in sheep to 
establish the withdrawal period. To evaluate the impact of such an 
extrapolation, the agency reviewed the codified tolerances for cattle 
and sheep for those products with existing approvals in both species.
    In most cases, the codified tolerances for cattle and sheep already 
are the same (e.g., ceftiofur, 21 CFR 556.113; chlortetracycline, 21 
CFR 556.150; levamisole hydrochloride, 21 CFR 556.350; neomycin, 21 CFR 
556.430; oxytetracycline, 21 CFR 556.500; tetracycline, 21 CFR 556.720; 
and thiabendazole, 21 CFR 556.730).
    In two instances, the codified tolerances for cattle and sheep are 
different: Albendazole, 21 CFR 556.34 and ivermectin, 21 CFR 556.344. 
In the case of albendazole, the tolerance in cattle is lower than the 
tolerance in sheep (i.e., 200 parts per billion (ppb) for cattle and 
250 ppb in sheep). In this case, application of the cattle tolerance to 
sheep would result in a longer withdrawal time than the application of 
the approved sheep tolerance. For ivermectin, the currently approved 
cattle tolerance of 100 ppb is higher than the approved sheep tolerance 
of 30 ppb. However, the original tolerance for cattle was 15 ppb (51 FR 
27021, July 29, 1986). Following the original approvals in cattle and 
sheep, a revised acceptable daily intake (ADI) was calculated for 
ivermectin based on additional toxicological data (59 FR 50829, October 
6, 1994). However, the revised ADI was used only to support a revision 
in the cattle tolerance to 100 ppb. The sheep tolerance was not 
similarly revised and remained at 30 ppb. Thus, the sheep tolerance of 
30 ppb should be compared to the cattle tolerance of 15 ppb. In this 
circumstance, application of the cattle tolerance to sheep would also 
result in a longer withdrawal time. Thus, codified tolerances for 
existing approvals for cattle and sheep demonstrate that extrapolation 
of the tolerance is scientifically justified.

VI. Proposed Action

    The proposed rule would amend Sec. 514.1(d)(1)(ii) to designate 
sheep as a minor species with respect to all data collection purposes 
under NADA's. The effect of the change would be to permit the 
extrapolation of the tolerance from other closely related species, such 
as cattle, to sheep.

VII. Environmental Impact

    The designation of sheep as a minor species means that most new 
animal drugs to be used in sheep fall within a category of actions 
which FDA considers to not individually or cumulatively have a 
significant effect on the human environment and for which neither an 
environmental assessment nor an environmental impact statement is 
required (40 CFR 1508.4). The categorical exclusion is in 
Sec. 25.33(d)(4) (21 CFR 25.33(d)(4)) of FDA's environmental 
regulations. Categorical exclusion under Sec. 25.33(d)(4) for drugs for 
minor species applies to those new animal drugs that have been 
previously approved for use in another or the same species when similar 
animal management practices are used in the minor species.

VIII. Analysis of Economic Impacts

    FDA has examined the impact of the proposed rule under Executive 
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), 
and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory 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 Regulatory 
Flexibility Act requires agencies to examine regulatory alternatives 
for small entities, if the rule may have a significant impact on a 
substantial number of small entities. The Unfunded Mandates Reform Act 
requires agencies to prepare an assessment of anticipated costs and 
benefits before enacting 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 (adjusted annually for inflation) in 
any one year.
    FDA concludes that this proposed rule is consistent with the 
principles set forth in the Executive Order and in these two statutes. 
FDA estimates that the proposed rule will not impose any compliance 
costs on the animal drug industry, but rather expects it to provide a 
small cost savings for any company submitting an NADA for an animal 
drug to be used on sheep. As a result, 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 has further 
determined, as described in the following paragraph, that the proposed 
rule will not have a significant economic impact on a substantial 
number of small entities. Further, since this proposed rule makes no 
mandates on other government entities and is not expected to result in 
expenditures of $100 million in any one year, FDA need not prepare 
additional analyses under the Unfunded Mandates Reform Act.
    FDA is proposing to amend the new animal drug regulations to 
reclassify sheep as a minor species for all data collection purposes, 
thereby allowing extrapolation from major species data to be used in 
conjunction with a total residue depletion study in sheep to meet the 
human food safety data standard for NADA's. Currently, FDA considers 
sheep a minor species for the purpose of the data necessary to 
demonstrate animal safety and effectiveness only. It considers sheep a 
major species for the purpose of human food safety requirements. This 
division in the classifications for sheep was originally based on 
expectations of consumption levels of sheep, especially among certain 
consumer groups. Since the original classification was made, new data 
demonstrating the similarity of drug metabolism between ruminant 
species has become available. Since there are not significant 
differences in the metabolism of most drugs between ruminant species, 
FDA believes most data packages supporting an NADA for use in sheep 
should be able to rely on the tolerance calculated for cattle.
    The benefit of this proposed rule would be to permit the tolerance 
calculated for major species, including cattle, to be used with a 
tissue residue study in sheep to determine a

[[Page 40323]]

withdrawal time for new animal drugs to be used in sheep. The proposed 
rule is therefore expected to lower research expenses and provide an 
impetus for sponsors to submit supplemental NADA's for sheep. More 
specifically, it would eliminate the need for a total residue 
metabolism study that can be costly and prohibitive for sponsors of new 
animal drugs for small markets such as sheep. FDA believes this study 
is unnecessary in this instance due to the similarities in the 
metabolism of most drugs in cattle and sheep. Adopting the approach 
that allows for interspecies data extrapolation, along with the tissue 
residue depletion studies, would encourage NADA submissions by 
decreasing research costs while continuing to protect human food 
safety. Apart from these cost savings, FDA does not expect this 
proposal to impose any other compliance burdens on sponsors of new 
animal drugs.

IX. Regulatory Flexibility Analysis

    The proposed rule is intended to reduce research costs for sponsors 
of NADA's for animal drugs used in sheep while maintaining the 
necessary safeguards concerning animal drug residues in human food. FDA 
estimates that this rule will not result in any compliance costs on the 
affected industry, regardless of the size of the companies involved. 
Further, FDA estimates that the rule will result in cost savings to 
sponsors of NADA's for animal drugs for use in sheep. In addition, most 
NADA sponsors would not be considered small businesses according to the 
standards of the Small Business Administration. Thus, in accordance 
with the Regulatory Flexibility Act, FDA certifies that this proposed 
rule would not have a significant economic effect on a substantial 
number of small entities.

X. Unfunded Mandates Reform Act of 1995

    Section 202 of the Unfunded Mandates Reform Act requires that 
agencies prepare an assessment of anticipated costs and benefits before 
proposing any expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector of $100 million (adjusted 
annually for inflation) in any one year. The publication of the 
proposal to reclassify sheep as a minor species for all data collection 
purposes is not expected to result in expenditures of funds by State, 
local, and tribal governments or the private sector in excess of $100 
million in any one year. Because the agency estimates no compliance 
costs and modest cost savings due to the proposed rule, FDA is not 
required to perform a cost/benefit analysis according to the Unfunded 
Mandates Reform Act.

XI. The 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.

XII. Comments

    Interested persons may, on or before October 25, 1999, submit to 
the Dockets Management Branch (address above), written comments 
regarding this proposed rule. 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 above 
between 9 a.m. and 4 p.m., Monday through Friday.

XIII. References

    The following references have 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. U.S. Food and Drug Administration, ``Guidance for Industry: 
FDA Approval of New Animal Drugs for Minor Uses and for Minor 
Species,'' Guidance No. 61, January 1999.
    2. Short, C. R., ``Consideration of Sheep as a Minor Species: 
Comparison of Drug Metabolism and Disposition with Other Domestic 
Ruminants,'' Veterinary and Human Toxicology, vol. 36, No. 1, pp. 
24-40, February 1994.

List of Subjects in 21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.
    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 part 514 be amended as follows:

PART 514--NEW ANIMAL DRUG APPLICATIONS

    1. The authority citation for 21 CFR part 514 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 360b, 371, 379e, 381.
    2. Revise Sec. 514.1 in paragraph (d)(1)(ii) to read as follows:


Sec. 514.1  Applications.

* * * * *
    (d) * * *
    (1) * * *
    (ii) Minor species means animals other than cattle, horses, swine, 
chickens, turkeys, dogs, and cats.
* * * * *

    Dated: July 15, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-18926 Filed 7-23-99; 8:45 am]
BILLING CODE 4160-01-F