Viruses, Serums, Toxins, and Analogous Products; Rabies Vaccine, Killed Virus and Rabies Vaccine, Live Virus

Federal RegisterJun 21, 1996

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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 113

[Docket No. 95-012-2]

Viruses, Serums, Toxins, and Analogous Products; Rabies Vaccine,

Killed Virus and Rabies Vaccine, Live Virus

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Final rule.

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SUMMARY: We are amending the standard requirements for establishing the

immunogenicity of Rabies Vaccine, Killed Virus and Rabies Vaccine, Live

Virus. The amendment changes and clarifies alternate test procedures

which may be used in animals other than carnivores. Under the rule,

when a reduced number of challenge animals is used in a rabies

immunogenicity test, all vaccinates must survive challenge. If one or

more of the challenged vaccinates die of rabies, all of the remainder

of the vaccinates will have to be challenged or the test will be deemed

unsatisfactory and terminated.

This action corrects a problem associated with rabies

immunogenicity tests in the regulations and makes other changes deemed

necessary for clarity and consistency.

EFFECTIVE DATE: July 22, 1996.

FOR FURTHER INFORMATION CONTACT:

Dr. David A. Espeseth, Deputy Director, Veterinary Biologics, BBEP,

APHIS, USDA, 4700 River Road Unit 148, Riverdale, MD 20737-1237, (301)

734-8245.

SUPPLEMENTARY INFORMATION:

Background

The regulations in 9 CFR part 113 pertain to standard requirements

for the preparation of veterinary biological products. A standard

requirement consists of test methods, procedures, and criteria

established by the Animal and Plant Health Inspection Service (APHIS)

to determine that a veterinary biological product is pure, safe,

potent, and efficacious and not worthless, dangerous, contaminated, or

harmful.

The standard requirements for Rabies Vaccine, Killed Virus, and for

Rabies Vaccine, Live Virus, appear in Secs. 113.209 and 113.312,

respectively. Sections 113.209(b)(4) and 113.312(b)(4) provide for an

alternative immunogenicity test, for domestic species other than dogs

and cats, that reduces the number of animals that must be challenged.

On November 16, 1995, we published in the Federal Register (60 FR

57549-57550, Docket No. 95-012-1) a proposed rule to amend the standard

requirements for Rabies Vaccine, Killed Virus and Rabies Vaccine, Live

Virus. The amendments specify: (1) that for an immunogenicity study in

non-carnivores to be satisfactory, all animals must survive challenge

when less than 25 vaccinates are challenged, and (2) that a reduced

number of challenge animals may only be used for non-carnivores. The

rule more clearly

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defines which animals must be challenged when a reduced number of

vaccinates is used.

We solicited comments for a 60-day comment period ending January

16, 1996. One comment was received by that date. The comment was from a

licensed manufacturer of veterinary biological products. The comment

addressed which animals should be challenged and the percent survival

required for a reduced challenge. The commenter recommended that less

than 100 percent survival be acceptable for a reduced challenge. The

commenter requested that this be accomplished through a wording change

to the rule.

In response to the commenter, APHIS believes that when the number

of challenged animals is reduced, survival of less than 100 percent of

the animals of the lowest titer would not provide adequate assurance

that animals of higher titer would be protected against challenge.

Because of this, no change to the regulations is made in response to

this comment.

Therefore, based on the rationale set forth in the proposed rule

and in this document, we are adopting the provisions of the proposal as

a final rule without change.

Executive Order 12866 and Regulatory Flexibility Act

This rule has been reviewed under Executive Order 12866. The rule

has been determined to be not significant for the purposes of Executive

Order 12866 and, therefore, has not been reviewed by the Office of

Management and Budget.

This rule amending Secs. 113.209 and 113.312 is necessary to

clarify the regulations regarding the rabies immunogenicity test. The

amendment clarifies which animals are to be challenged in a reduced

immunogenicity study and the procedures to follow when one or more of

the vaccinates die of rabies. The amendment requires that additional

vaccinates be challenged if one of the low titer vaccinates succumbs to

rabies. In 7 of the last 10 rabies challenge tests of non-carnivores,

firms elected to challenge 25 or more animals. In the remaining three

cases in which a reduced number of animals were challenged in

accordance with current Sec. 113.209 or Sec. 113.312, paragraph (b)(4),

no additional animals were challenged and no additional animals would

have been challenged under the amendment. The amendment, therefore,

will have minimal economic effect.

Under these circumstances, the Administrator of the Animal and

Plant Health Inspection Service has determined that this action will

not have a significant economic impact on a substantial number of small

entities.

Executive Order 12372

This program/activity is listed in the Catalog of Federal Domestic

Assistance under No. 10.025 and is subject to Executive Order 12372,

which requires intergovernmental consultation with State and local

officials. (See 7 CFR part 3015, subpart V.)

Executive Order 12778

This rule has been reviewed under Executive Order 12778, Civil

Justice Reform. It is not intended to have retroactive effect. This

rule would not preempt any State or local laws, regulations, or

policies, unless they present an irreconcilable conflict with this

rule. There are no administrative procedures which must be exhausted

prior to a judicial challenge to the provisions of this rule.

Paperwork Reduction Act

This rule contains no new information collection or record keeping

requirements under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501

et seq.).

List of Subjects in 9 CFR Part 113

Animal biologics, Exports, Imports, Reporting and recordkeeping

requirements.

Accordingly, 9 CFR part 113 is amended as follows:

PART 113--STANDARD REQUIREMENTS

1. The authority citation for part 113 continues to read as

follows:

Authority: 21 U.S.C. 151-159; 7 CFR 2.22, 2.80, and 371.2(d).

2. Section 113.209 is amended by revising paragraph (b)(4) to read

as follows:

Sec. 113.209 Rabies Vaccine, Killed Virus.

* * * * *

(b) * * *

(4) An alternative to challenging all surviving test animals in

accordance with paragraph (b)(3)(iv) of this section may be used when

the test animals are of species other than carnivores. Vaccinates shall

be challenged at 1 year postvaccination. These shall include five

vaccinates with the lowest SN titers at the 270th-day bleeding, five

vaccinates with the lowest SN titers at the 365th-day bleeding, and all

vaccinates with SN titers below 1:10 by the mouse SN test or below 1:16

by the rapid-fluorescent-focus-inhibition test at any bleeding. At

least five SN-negative controls of each species shall be challenged at

the same time as the vaccinates. All SN titers shall be titrated to an

endpoint. All of the challenged vaccinates must remain well for a

period of 90 days, and at least 80 percent of the controls must die of

rabies for a satisfactory test without further challenge. If one or

more of the vaccinates die from rabies, all the remaining vaccines,

regardless of titer, along with the five controls shall be challenged.

The cumulative results from the two challenges shall be evaluated for

acceptance as specified in paragraph (b)(3)(v) of this section.

* * * * *

3. Section 113.312 is amended by revising the section heading and

paragraph (b)(4) to read as follows:

Sec. 113.312 Rabies Vaccine, Live Virus.

* * * * *

(b) * * *

(4) an alternative to challenging all surviving test animals in