[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