New Animal Drug Applications; Sheep as a Minor Species

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.

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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]

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