[Federal Register Volume 60, Number 89 (Tuesday, May 9, 1995)]
[Proposed Rules]
[Pages 24584-24587]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-11375]



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DEPARTMENT OF AGRICULTURE
9 CFR Parts 112 and 113

[Docket No. 94-046-1]


Viruses, Serums, Toxins, and Analogous Products; Marek's Disease 
Vaccines

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule.

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SUMMARY: This proposed rule would amend the standard requirements for 
Marek's disease vaccines by including vaccines prepared from any of the 
three Marek's disease virus serotypes, and by defining the identity, 
safety, and efficacy requirements for vaccines prepared from each 
serotype or combinations of serotypes. The proposed rule would also 
amend the requirements for labeling Marek's disease vaccines. These 
proposed amendments are necessary based on the evolution of the disease 
in the field, advances in the types of vaccines currently prepared to 
prevent the disease, and advances in the methods of evaluating such 
vaccines. The effect of the proposed rule would be to save licensees 
time during the application process by clarifying and codifying the 
guidelines developed for licensing these products over the past several 
years.

DATES: Consideration will be given only to comments received on or 
before July 10, 1995.

ADDRESSES: Please send an original and three copies of your comments to 
Docket 94-046-1, 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. 94-046-1. 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 on (202) 690-2817 to facilitate 
entry into the comment reading room.

FOR FURTHER INFORMATION CONTACT:
Dr. David Espeseth, Deputy Director, Veterinary Biologics, BBEP, APHIS, 
4700 River Road Unit 148, Riverdale, MD, 20737-1237, (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

    Veterinary biologics are regulated under the Virus-Serum-Toxin Act 
of 1913, as amended by the Food Security Act of 1985 (21 U.S.C. 151-
159, hereinafter referred to as the Act). In accordance with this Act, 
the Animal [[Page 24585]] and Plant Health Inspection Service (APHIS) 
promulgates standard requirements that establish the purity, safety, 
potency, and efficacy requirements for these products.
    The current standard requirements in Sec. 113.330 (hereinafter 
referred to as the regulations) for licensing Marek's disease vaccines 
were promulgated at a time when only Serotype 3 Marek's disease 
vaccines were prepared. Also, the standard requirements did not include 
a standard for evaluating vaccine efficacy. Since that time, vaccines 
for Serotypes 1 and 2 have been developed, very virulent forms of the 
field virus have emerged, and other advances in our understanding of 
this virus have occurred. In response to these changes, APHIS has 
developed guidelines over the past several years for licensing these 
products. APHIS now proposes to amend the standard requirement for 
Marek's disease vaccines to include Serotypes 1 and 2, and to codify 
appropriate efficacy standards and guidelines which license applicants 
currently utilize.
    Although all three Marek's disease virus serotypes have been used 
to prepare licensed vaccines, the current true names found on the 
labels of Marke's disease vaccines do not contain this information. 
Therefore, we propose to add new Sec. 112.7(m) which would require that 
the true names of all Marke's disease vaccines specify the virus 
serotypes contained in the product (e.g., ``Serotype(s) 1, 2, and/or 3, 
Live Virus''). Also, the true names currently found on labels of many 
of these products include the final form in which the product is 
prepared (e.g., ``Cell Associated'' or ``Cell Free''). The reference to 
final form in the current true name is not consistent with the labeling 
of other live virus vaccines. Therefore, APHIS would no longer include 
references to ``Cell Associated'' or ``Cell Free'' when assigning true 
names for Marek's disease vaccines.
    The current standard requirements limit the preparation of Marek's 
disease vaccines to five passages from the master seed virus (see 
Sec. 113.330, introductory paragraph). A number of exemptions from this 
requirement, however, have been granted to accommodate production 
problems, particularly in the propagation of Serotype 2 viruses. 
Therefore, we propose to remove the five-passage restriction from the 
introductory paragraph of Sec. 113.330. Licensees, however, would still 
be required to specify the highest passage, established by efficacy 
data, that may be contained in the final product for each master seed 
virus pursuant to Sec. 113.330(c) of the regulations.
    Due to the lack of an acceptable identity test at the time the 
current standard requirements were published, the current regulations 
provide in paragraph (a) and introductory paragraph (d) of Sec. 113.330 
an exemption from identity testing for Marek's disease master seed 
viruses and final products that is no longer appropriate. Current 
vaccines contain any of the three Marek's disease virus serotypes, and 
the reagents and techniques to identify the different serotypes are 
available. Therefore, the proposed rule would remove the identity test 
exemption in paragraph (a) and the introductory paragraph (d) of 
Sec. 113.330 and would require a serotype-specific identity test in 
proposed paragraph (a) and introductory paragraph (d) of Sec. 113.330.
    Sections 113.330 (a) and (d)(1) of the current standard 
requirements permit applicants to disregard lesions typical of turkey 
herpes virus when evaluating master seed viruses and final products for 
extraneous agents in the chicken embryo inoculation test prescribed in 
Sec. 113.37. Such lesions may arise when a vaccine virus override 
occurs during the performance of this test. This exemption for herpes 
virus lesions is inconsistent with the evaluation of other master seed 
viruses and products, which are typically evaluated in the chicken 
inoculation test prescribed in Sec. 113.36 when a vaccine virus 
override occurs. Therefore, APHIS would require in proposed paragraphs 
(a) and (d)(1) of Sec. 113.330 that the chicken inoculation test be 
conducted if a vaccine virus override occurs during the chicken embryo 
inoculation test for a Marek's disease virus master seed or vaccine 
serial.
    The current regulations do not contain an efficacy standard for 
Marek's disease vaccines. APHIS addressed the need for such standard by 
issuing Veterinary Biologics Memorandum No. 800.82 on January 19, 1993. 
This memorandum prescribed efficacy criteria on the basis that Serotype 
1 and 2 vaccines typically provide protection against a more (``very'') 
virulent challenge, while the Serotype 3 vaccines typically provide 
protection against a less (``standard'') virulent challenge. The 
proposed rule would codify the efficacy guidelines found in that 
memorandum in proposed Sec. 113.330(c)--Immunogenicity. Furthermore, 
because licensees have obtained approval for label claims for both 
subcutaneous and in ovo routes of administration for these products, 
the proposed efficacy standard has been written to include the 
requirements for either route.
    The master seed virus safety test found in Sec. 113.330(b) of the 
current standard requirements requires modification in order to 
adequately evaluate all three Marek's disease virus serotypes. As with 
the efficacy standard, the safety test is addressed in the Veterinary 
Biologics Memorandum No. 800.82. The memorandum describes the 
appropriate challenge virus for the positive control group and adds a 
contact control group for the evaluation of Serotype 1 viruses, which 
have an increased potential for horizontal spread. This proposed rule 
would codify these guidelines with some modifications. Also, this 
proposed rule would expand the safety test to cover the use of embryos 
as well as chickens as test subjects (See proposed Sec. 113.330(b).
    Because Marek's disease vaccines may include more than one serotype 
in each final container, the proposed rule would require that the 
potency test for the final product be serotype-specific for all 
products containing more than one serotype. Also, the acceptable virus 
titers for product release and expiration would be based on the titers 
used in the efficacy study for each serotype, with specified minimum 
titers (See proposed Sec. 113.330(d)(3)).

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 purposes of 
Executive Order 12866, and, therefore, has not been reviewed by the 
Office of Management and Budget.
    The proposed amendments to the standard requirements for Marek's 
disease vaccines would codify guidelines developed for licensing these 
products over the past several years. These amendments would affect all 
(currently a total of eight) manufacturers of Marek's disease vaccines, 
some of which may be small businesses. By clarifying licensing 
requirements for Marek's disease vaccines, the proposed rule would save 
time during the application process and would cause no adverse economic 
impact on the regulated industry.
    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. [[Page 24586]] 

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 inconsistent 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 
recordkeeping requirements under the Paperwork Reduction Act of 1980 
(44 U.S.C. 3501 et seq.).

List of Subjects

9 CFR part 112

    Animal biologics, Exports, Imports, Labeling, Packaging and 
containers, Reporting and recordkeeping requirements.

9 CFR part 113

    Animal biologics, Exports, Imports, Reporting and recordkeeping 
requirements.

    Accordingly, 9 CFR parts 112 and 113 would be amended as follows:

PART 112--PACKAGING AND LABELING

    1. The authority citation for part 112 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 112.7 would be amended by adding paragraph (m) to read 
as follows:


Sec. 112.7  Special additional requirements.

* * * * *
    (m) In the case of biological products containing Marek's disease 
virus, all labels shall specify the Marek's disease virus serotype(s) 
used in the product.

PART 113--STANDARD REQUIREMENTS

    3. 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).

    4. Section 113.330 would be revised to read as follows:


Sec. 113.330  Marek's Disease Vaccines.

    Marek's disease vaccine shall be prepared from virus-bearing tissue 
culture cells. Only Master Seed Virus which has been established as 
pure, safe, and immunogenic shall be used for preparing the production 
seed virus for vaccine production.
    (a) The Master Seed Virus shall meet the applicable requirements 
prescribed in Sec. 113.300, and the requirements prescribed in this 
section. The identity test required in Sec. 113.300(c) shall be 
conducted in a serotype-specific manner by a method acceptable to 
APHIS. Each lot of Master Seed Virus shall also be tested for pathogens 
by the chicken embryo inoculation test prescribed in Sec. 113.37, 
except that, if the test is inconclusive because of a vaccine virus 
override, the chicken inoculation test prescribed in Sec. 113.36 may be 
conducted and the virus judged accordingly.
    (b) Safety test. The Master Seed Virus shall be nonpathogenic for 
chickens as determined by the following procedure:
    (1) Specific pathogen free chickens or embryos, negative for 
Marek's disease virus antibodies, and from the same source, shall be 
isolated into the following groups:
    (i) Group 1. At least 50 test subjects shall be inoculated with 10 
times as much viable virus as will be contained in one dose of vaccine, 
by the route recommended for vaccination.
    (ii) Group 2. At least 50 test subjects shall be injected with a 
very virulent Marek's disease virus provided or approved by APHIS, at a 
dosage level that will cause gross lesions of Marek's disease in at 
least 80 percent of the chickens within 50 days.
    (iii) Group 3. Fifth uninoculated controls. For in ovo studies, 
this group should receive a sham inoculation of diluent.
    (iv) Group 4. For studies evaluating Serotype 1 Master Seed Viruses 
a group of 50 uninoculated control chickens shall be housed in contact 
with the group 1 vaccinated chickens.
    (2) At least 40 chickens in each group shall survive to 5 days of 
age. All chickens that die shall be necropsied an examined for lesions 
of Marek's disease and cause of death. The test shall be judged 
according to the following criteria:
    (i) At 50 days of age, the remaining chickens in group 2 shall be 
killed and examined for gross lesions of Marek's disease. If at least 
80 percent of this group do not develop Marek's disease, the test is 
inconclusive and may be repeated.
    (ii) At 120 days of age, the remaining chickens in groups 1, 3, and 
4 shall be weighed, killed, and necropsied. If less than 30 of the 
chickens in group 3 survive the 120 day period, or if any of the 
chickens in group 3 have gross lesions of Marek's disease at necropsy, 
the test is declared inconclusive. If less than 30 chickens in groups 1 
and 4 survive the 120 day period; or if any of the chickens in groups 1 
and 4 have gross lesions of Marek's disease at necropsy; of if the 
average body weight of the chickens in groups 1 or 4 is significantly 
(statistically) different from the average in group 3 at the end of the 
120 days, the lot of Master Seed Virus is unsatisfactory.
    (3) For tests involving in ovo innoculation, hatchability results 
shall also be reported for each group.
    (c) Immunogenicity. Each lot of Master Seed Virus used for vaccine 
production shall be tested for immunogenicity at the highest passage 
level allowed for the product, and the virus dose to be used shall be 
established as follows:
    (1) Specific pathogen free chickens or embryos, negative for 
Marek's disease antibodies, and from the same source, shall be isolated 
into the following groups:
    (i) Group 1. A minimum of 35 test subjects shall be inoculated with 
the vaccine, using the recommended route, at 1 day of age for chicks or 
18 days of embryonation for embryos. The dose used shall be established 
by 5 replicate virus titrations conducted by a cell culture system or 
other titration method acceptable to APHIS.
    (ii) Group 2. A minimum of 35 nonvaccinated test subjects shall be 
held as challenge controls.
    (iii) Group 3. A minimum of 25 nonvaccinated test subjects shall be 
held as nonchallenge controls.
    (iv) Group 4. Except for studies evaluating vaccines which contain 
only a Serotype 3 virus as the Marek's disease fraction, a minimum of 
35 chicks shall be vaccinated at 1 day of age with a licensed Serotype 
3 vaccine, in order to document the severity of the very virulent 
challenge.
    (2) At least 30 chickens in groups 1, 2, and 4, and at least 20 
chickens in group 3, shall survive to 5 days of age. All chickens in 
groups 1, 2, and 4 shall be challenged at 5 days of age in the 
following manner:
    (i) For studies evaluating vaccines which contain only a Serotype 3 
virus as the Marek's disease fraction, groups 1 and 2 shall be 
inoculated with a standard virulent challenge virus provided or 
approved by APHIS.
    (ii) For all other Marek's disease vaccines, groups 1, 2, and 4 
shall be inoculated with a very virulent [[Page 24587]] challenge virus 
provided or approved by APHIS.
    (3) All chickens shall be observed until 7 weeks of age, 
necropsied, and examined for grossly observable lesions consistent with 
Marek's disease. All chickens dying before the end of the 7 week 
observation period shall be necropsied and evaluated for gross lesions 
of Marek's disease. Any chickens not so examined shall be scored as 
positive for Marek's disease.
    (4) For a valid test, at least 80% of the chickens in group 2 must 
develop grossly observable lesions, none of the chickens in group 3 
shall develop grossly observable lesions, and (when included) at least 
20% of the chickens in group 4 must develop grossly observable lesions.
    (5) For a valid test to be considered satisfactory, at least 80% of 
the chickens in group 1 must remain free of grossly observable lesions. 
the appropriate product claim resulting from a satisfactory test would 
be to aid in the prevention of Marek's disease, for vaccines containing 
only a Serotype 3 virus as the Marek's disease fraction, or to aid in 
the prevention of very virulent Marek's disease, for all other 
vaccines.
    (d) Test requirements for release. Each serial and subserial shall 
meet the applicable requirements prescribed in Sec. 113.300. The 
identity test required in Sec. 113.300(c) shall be conducted in a 
serotype-specific manner by a method acceptable to APHIS. Final 
container samples of completed product shall also meet the requirements 
in paragraphs (d)(1), (2), and (3) of this section. Any serial or 
subserial found unsatisfactory by a prescribed test shall not be 
released.
    (1) Purity test. The chicken embryo inoculation test prescribed in 
Sec. 113.37 shall be conducted, except that, if the test is 
inconclusive because of a vaccine virus override, the chicken 
inoculation test prescribed in Sec. 113.36 may be conducted and the 
virus judged accordingly.
    (2) Safety test. At least 25 one-day-old, specific pathogen free 
chickens shall be injected, by the subcutaneous route, with the 
equivalent of 10 chicken doses of virus (vaccine concentrated 10X). The 
chickens shall be observed each day for 21 days. Chickens dying during 
the period shall be examined, cause of death determined, and the 
results recorded.
    (i) If at least 20 chickens do not survive the observation period, 
the test is inconclusive.
    (ii) If lesions of any disease or cause of death are directly 
attributable to the vaccine, the serial is unsatisfactory.
    (iii) If less than 20 chicks survive the observation period and 
there are no deaths or lesions attributable to the vaccine, the test 
may be repeated one time, Provided, that if the test is not repeated, 
the serial shall be declared unsatisfactory.
    (3) Potency test. The samples shall be titrated using a cell 
culture system or other titration method acceptable to APHIS. For 
vaccines composed of more than one Marek's disease virus serotype, each 
fraction shall be titrated in a serotype-specific manner.
    (i) Samples of desiccated vaccine shall be incubated at 37 deg.C 
for 3 days before preparation for use in the potency test. Samples of 
desiccated or frozen vaccine shall be reconstituted in diluent 
according to the label recommendations, and held in an ice bath at 
0 deg.C to 4 deg.C for 2 hours prior to use in the potency test.
    (ii) For a serial or subserial to be eligible for release, each 
serotype contained in the vaccine shall have a virus titer per dose 
which is at least 3 times greater than the number of plaque forming 
units (pfu) used in the immunogenicity test prescribed in paragraph (c) 
of this section, but not less than 1000 pfu per dose.
    (iii) When tested (without the pretest incubation of desiccated 
products) at any time within the expiration period, each serotype 
contained in the vaccine shall have a virus titer per dose which is at 
least 2 times the number of pfu used in the immunogenicity test, but 
not less than 750 pfu per dose.

    Done in Washington, DC, this 28th day of April 1995.
Lonnie J. King,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 95-11375 Filed 5-8-95; 8:45 am]
BILLING CODE 3410-34-M