[Federal Register Volume 60, Number 221 (Thursday, November 16, 1995)]
[Proposed Rules]
[Pages 57549-57550]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-28325]



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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service

9 CFR Part 113

[Docket No. 95-012-1]


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

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule.

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SUMMARY: We are proposing to amend the standard requirements for 
establishing the immunogenicity of Rabies Vaccine, Killed Virus and 
Rabies Vaccine, Live Virus. The amendment would change and clarify 
alternate test procedures which may be used in animals other than 
carnivores. Under the proposed 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 would have to be 
challenged or the test would be deemed unsatisfactory and terminated.
    This proposed action would correct a problem associated with rabies 
immunogenicity tests in the regulations and make other changes deemed 
necessary for clarity and consistency.

DATES: Consideration will be given only to comments received on or 
before January 16, 1996.

ADDRESSES: Please send an original and three copies of your comments to 
Docket No. 95-012-1, Regulatory Analysis and Development, PPD, APHIS, 
Suite 3C03, 4700 River Road Unit 118, Riverdale, MD 20737-1238. Please 
state that your comments refer to Docket No. 95-012-1. Comments 
received may be inspected at USDA, room 1141, South Building, 14th 
Street and Independence Avenue SW., Washington, DC, between 8 a.m. and 
4:30 p.m., Monday through Friday, except holidays. Persons wishing to 
inspect comments are requested to call ahead (202) 690-2817 to 
facilitate entry into the comment reading room.

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 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 to 
a minimum of five vaccinates and five unvaccinated control animals. The 
regulations require that a minimum of 25 animals be vaccinated and 
blood be taken for serology at prescribed intervals postvaccination. 
All surviving test animals must be challenged 1 year after vaccination 
unless the alternative test is used. In the case of the alternative 
test for domestic species other than dogs or cats, the five vaccinates 
with the lowest rabies antibody titers at each of the last two 
bleedings, and all vaccinates with titers below 1:10, as determined by 
the mouse serum neutralization (SN) test or below 1:16 by the rapid-
fluorescent-focus-inhibition test at any bleeding, must be challenged 
at 1 year after vaccination.
    The following example illustrates how the current regulations can 
lead to different interpretations for the rabies immunogenicity test 
for species other than dogs and cats. The regulations in 
Secs. 113.209(b)(3)(v) and 113.312(b)(3)(v) (applicable to all animal 
species) require that the statistical equivalent of 22 out of 25 or 26 
out of 30 vaccinates remain well for 90 days after challenge. If only 
five vaccinates are challenged and three die of rabies, the test would 
be deemed unsatisfactory under Secs. 113.209(b)(3)(v) and 
113.312(b)(3)(v). The results would be considered unsatisfactory 
because survival of 2 of 5 animals is not statistically equivalent to 
survival of 22 of 25 or 26 of 30 animals.
    Sections 113.209(b)(4) and 113.312(b)(4) (which apply to animals 
other than dogs and cats), however, state that all unchallenged 
vaccinates shall be considered protected for purposes of the test when 
evaluated for acceptance. The previous test would be considered 
satisfactory under Secs. 113.209(b)(4) and 113.312(b)(4), since the 
unchallenged vaccinates would be deemed protected, meeting the 
requirement that 22 of the 25 vaccinates be protected for a 
satisfactory test. For this reason, the 

[[Page 57550]]
regulations in Secs. 113.209(b)(4) and 113.312(b)(4) need to be 
amended.
    Sections 113.209(b)(4) and 113.312(b)(4) also need to be amended 
because serologic titer is not sufficiently correlated with efficacy to 
ensure that all of the unchallenged vaccinates in a reduced 
immunogenicity test would be protected after a real challenge.
    The amendment would clarify which of the vaccinates should be 
challenged under Secs. 113.209(b)(4) and 113.312(b)(4), and would 
require that all challenged vaccinates remain well for 90 days in order 
for the test to be satisfactory. The amendment would specify that the 
reduced immunogenicity test described in Secs. 113.209(b)(4) and 
113.312(b)(4) may not be used for carnivores (e.g., dogs, cats, and 
ferrets). The amendment would therefore exclude from a reduced 
challenge test species of animals that have a high potential for 
transmitting rabies.

Executive Order 12866 and Regulatory Flexibility Act

    This proposed 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 proposed rule amending Secs. 113.209 and 113.312 is necessary 
to clarify the regulations regarding the rabies immunogenicity test. 
The amendment would clarify 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 proposed amendment would 
require 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 proposed 
rule. The proposed amendment, therefore, would have minimal economic 
effect.
    Under these circumstances, the Administrator of the Animal and 
Plant Health Inspection Service has determined that this action would 
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 proposed rule has been reviewed under Executive Order 12778, 
Civil Justice Reform. If this proposed rule is adopted: (1) All State 
and local laws and regulations that are in conflict with this rule will 
be preempted; (2) no retroactive effect will be given to this rule; and 
(3) administrative proceedings will not be required before parties may 
file suit in court challenging this rule.

Paperwork Reduction Act

    This proposed rule contains no new information collection or record 
keeping requirements under the Paperwork Reduction Act of 1980 (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 would be amended as follows:

PART 113--STANDARD REQUIREMENTS

    1. The authority citation for part 113 would continue to read as 
follows:

    Authority: 21 U.S.C. 151-159; 7 CFR 2.17, 2.51, and 371.2(d).

    2. Section 113.209 would be 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 vaccinates, 
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 would be 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 
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 vaccinates, 
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.
* * * * *
    Done in Washington, DC, this 8th day of November 1995.
Terry L. Medley,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 95-28325 Filed 11-15-95; 8:45 am]
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