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

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