[Federal Register Volume 67, Number 94 (Wednesday, May 15, 2002)]
[Proposed Rules]
[Pages 34630-34633]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-12134]


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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Parts 112 and 113

[Docket No. 93-129-1]


Viruses, Serums, Toxins, and Analogous Products; Equine Influenza 
Vaccine, Killed Virus

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule.

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SUMMARY: We are proposing to amend the Virus-Serum-Toxin Act 
regulations concerning Standard Requirements for veterinary biologics 
by adding a Standard Requirement for Equine Influenza Vaccine, Killed 
Virus. This proposed rule would require that such vaccines be shown to 
protect vaccinates for at least 60 days based on a vaccination-
challenge study conducted in horses. In addition, we would establish a 
serum hemagglutination inhibition test in guinea pigs as the serial 
release potency test for the vaccine; establish procedures for adding 
and removing strains of virus based on evidence of changes in the 
antigenic character of the equine influenza viruses in current 
circulation; and add labeling requirements to the regulations. The 
effect of these proposed changes would be to standardize purity, 
safety, potency, and efficacy requirements for equine influenza vaccine 
to ensure that such products will provide a minimum level of protection 
to vaccinated horses.

DATES: We will consider all comments we receive that are postmarked, 
delivered, or e-mailed by July 15, 2002.

ADDRESSES: You may submit comments by postal mail/commercial delivery 
or by e-mail. If you use postal mail/commercial delivery, please send 
four copies of your comment (an original and three copies) to: Docket 
No. 93-129-1, Regulatory Analysis and Development, PPD, APHIS, Station 
3C71, 4700 River Road Unit 118, Riverdale, MD 20737-1238. Please state 
that your comment refers to Docket No. 93-129-1. If you use e-mail, 
address your comment to [email protected]. Your comment must 
be contained in the body of your message; do not send attached files. 
Please include your name and address in your message and ``Docket No. 
93-129-1'' on the subject line.
    You may read any comments that we receive on this docket in our 
reading room. The reading room is located in room 1141 of the USDA 
South Building, 14th Street and Independence Avenue SW., Washington, 
DC. Normal reading room hours are 8 a.m. to 4:30 p.m., Monday through 
Friday, except holidays. To be sure someone is there to help you, 
please call (202) 690-2817 before coming.
    APHIS documents published in the Federal Register, and related 
information, including the names of organizations and individuals who 
have commented on APHIS dockets, are available on the Internet at 
http://www.aphis.usda.gov/ppd/rad/webrepor.html.

FOR FURTHER INFORMATION CONTACT: Dr. Albert P. Morgan, Chief of 
Operational Support, Center for Veterinary Biologics, Licensing and 
Policy Development, APHIS, USDA, 4700 River Road Unit 148, Riverdale, 
MD 20737-1231; (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

    The Virus-Serum-Toxin Act regulations in 9 CFR part 113 (referred 
to below as the regulations) prescribe Standard Requirements for the 
preparation and testing of veterinary biological products. A Standard 
Requirement consists of test methods, procedures, and criteria that 
define the standards of purity, safety, potency, and efficacy for a 
given type of veterinary biological product. When a Standard 
Requirement for a product type does not exist, test methods, 
procedures, and criteria for evaluating the purity, safety, potency, 
and efficacy are provided in an Outline of Production for the product 
filed with the Animal and Plant Health Inspection Service (APHIS). Once 
uniform standards for a type of product are established, they are 
codified in the regulations as a Standard Requirement.

[[Page 34631]]

    Because there is no Standard Requirement in 9 CFR part 113 for 
Equine Influenza Vaccine, each manufacturer of these products has 
devised its own procedures, which are a part of the Outline of 
Production, to meet the requirements of the Virus-Serum-Toxin Act that 
all veterinary biological products be pure, safe, potent, and 
efficacious. Although several equine influenza vaccines have been 
licensed, the lack of standardized procedures for updating such 
products to compensate for the short-lived antibody response in horses 
and the natural antigenic shift and drift that is characteristic of the 
influenza virus, has resulted in horse owners having to revaccinate 
their animals every 3 to 4 months in order to ensure protection. 
Therefore, we are proposing to add a new Sec. 113.217 to the standards 
that would require uniform criteria, test methods, and procedures that 
would provide vaccine manufacturers a method by which to update their 
products to compensate for the natural evolution of the virus and 
ensure that equine influenza vaccines remain pure, safe, potent, and 
efficacious.
    In the proposed Standard Requirement, equine influenza vaccine 
would be evaluated for immunogenicity by vaccinating susceptible horses 
at the minimum age recommended on the label and challenging those 
horses at least 60 days after the last vaccine dose using a relevant 
equine influenza challenge virus provided by or acceptable to APHIS. 
Protection would have to be demonstrated for at least one component 
strain of each equine influenza virus subtype present in the vaccine, 
and would be based on the demonstration of a statistically significant 
difference in the characteristic clinical signs of equine influenza 
virus infection in vaccinated horses as compared to non-vaccinated 
control horses. In addition, once host animal protection against 
challenge has been demonstrated for any strain of a particular equine 
influenza virus subtype, protection may be claimed for other strains of 
the same subtype contained in the same product by using 
hemagglutination titers to demonstrate an acceptable dose-response 
relationship between the challenge and non-challenge strain(s) in 
horses or guinea pigs. Hemagglutination inhibition titers (HI titers) 
could serve as a basis for adding or substituting strains of a 
particular subtype as long as at least one strain of each subtype 
present in the vaccine has been evaluated in a host animal challenge-
protection study.
    The proposed serial release potency test for equine influenza 
vaccine is a serum hemagglutination inhibition test performed in guinea 
pigs; other tests could be used if they were found by APHIS to be 
acceptable. We are proposing HI titers in guinea pigs as a serial 
release potency test based on our experience with such tests that 
indicates manufacturers should be able to develop the dose-response 
data and mean relative potency value needed to establish the required 
correlation between guinea pig titers and HI titers in horses.
    In addition, we are proposing to add a new paragraph to the 
regulations in Sec. 112.7 to require equine influenza vaccine labeling 
to list the subtype(s) and strain(s) of the virus used in the product.
    This proposed Standard Requirement was developed with the 
cooperation of licensees, researchers, and scientists at APHIS' Center 
for Veterinary Biologics-Laboratory. The proposed Standard Requirement 
would establish uniform immunogenicity and potency criteria for equine 
influenza vaccine and improve the protection such vaccine provides.

Immunogenicity

    We are proposing that equine influenza vaccine be evaluated for 
immunogenicity in horses. For at least one strain of each subtype of 
equine influenza virus contained in the vaccine, 15 equine influenza 
susceptible horses (10 vaccinates and 5 controls) of the minimum age 
recommended on the label would be vaccinated with equine influenza 
vaccine made with virus at the highest passage from Master Seed and at 
the minimum preinactivation titer provided in the filed Outline of 
Production.

Duration of Immunity

    This proposed rule would also require equine influenza vaccine to 
protect horses against the characteristic signs of equine influenza for 
a minimum of 60 days. To demonstrate protection and duration of 
immunity, horses used in the immunogenicity study would be challenged 
not less than 60 days after vaccination with a representative strain of 
each equine influenza virus subtype present in the vaccine.

Potency

    Under this proposed rule, the potency of each serial would have to 
be evaluated for potency in guinea pigs. Each strain of each subtype of 
equine influenza virus contained in the vaccine would be evaluated for 
potency using guinea pigs as test animals.

Safety

    For safety, we are proposing that the guinea pigs used in the 
potency test be observed each day during the post-vaccination 
observation period for unfavorable reactions attributable to the 
vaccine.

Currently Licensed Vaccines

    Veterinary biologics manufacturers that produce equine influenza 
vaccine under present standards described in their filed Outlines of 
Production would be allowed 2 years after the effective date of the 
final rule to come into compliance. In the interim, we would allow such 
manufacturers to continue to release serials of equine influenza 
vaccine using the standard described in their filed Outlines of 
Production, provided that such serials of product are shown to be 
effective and the labels for such products specify the demonstrated 
duration of immunity.

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 purposes of Executive 
Order 12866, and, therefore, has not been reviewed by the Office of 
Management and Budget.
    We are proposing to amend the Virus-Serum-Toxin Act regulations in 
9 CFR part 113 by adding a new Standard Requirement for Equine 
Influenza Vaccine, Killed Virus. This proposed rule would require 
equine influenza vaccines to protect against clinical signs of equine 
influenza virus infection for at least 60 days based on challenge 
protection studies performed in horses. In addition, this proposed rule 
would allow claims for protection to be made for other strains of the 
equine influenza virus of the same subtype contained in the same 
product provided that the manufacturer demonstrates an acceptable dose-
response relationship between the challenge and non-challenge strain(s) 
in host animals or guinea pigs. This proposed Standard Requirement 
would affect all licensed manufacturers of veterinary biologics 
producing any new equine influenza vaccine by requiring manufacturers 
of equine influenza vaccine to incur the expense associated with 
demonstrating protection of horses against the characteristic signs of 
equine influenza for at least 60 days.
    Currently, only 8 of the approximately 135 licensed veterinary 
biologics manufacturers produce equine influenza vaccine and would be 
affected by this proposal. According to the standards of the Small 
Business Administration,

[[Page 34632]]

most veterinary biologics establishments would be classified as small 
entities.
    Veterinary biologics manufacturers that produce equine influenza 
vaccine that does not meet this proposed standard would be allowed 2 
years from the effective date of the final rule to come into 
compliance. In the interim, we would allow such manufacturers to 
continue to release serials of equine influenza vaccine using the 
current standard described in their filed Outlines of Production.
    We do not have an alternative option to this proposed rule in light 
of the ever-changing antigenic profile of the equine influenza virus, 
which has created a demand for equine influenza vaccine that provides 
better protection than the currently available products. This proposed 
rule, if adopted, would aid firms manufacturing equine influenza 
vaccines. The proposal contains a Standard Requirement for 
immunogenicity testing that would provide uniformity among firms 
instead of each firm having to meet APHIS' requirements by methods of 
its own design. This would reduce a firm's cost of research and 
development needed to design a method to test immunogenicity. In 
addition, once host animal protection has been demonstrated for any 
strain of a particular equine influenza virus subtype, non-host animal 
methods may be used to claim protection for other strains of the same 
subtype.
    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 is listed in the category 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 12988

    This proposed rule has been reviewed under Executive Order 12988, 
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. 
The Virus-Serum-Toxin Act does not provide administrative procedures 
which must be exhausted prior to a judicial challenge to the provisions 
of this rule.

Paperwork Reduction Act

    This proposed rule contains no new information collection or 
recordkeeping requirements under the Paperwork Reduction Act of 1995 
(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, we propose to amend 9 CFR parts 112 and 113 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 2.22, 2.80, and 371.4.

    2. Section 112.7 would be amended by adding new paragraph (n) to 
read as follows:


Sec. 112.7  Special additional requirements.

* * * * *
    (n) In the case of biological products containing equine influenza 
virus, all labels shall specify the subtype(s) and strain(s) of the 
virus used in the product and the revaccination recommendation as 
determined from the results of duration of immunity studies acceptable 
to the Animal and Plant Health Inspection Service.

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 2.22, 2.80, and 371.4.

    4. Section 113.217 would be added to read as set forth below.


Sec. 113.217  Equine Influenza Vaccine, Killed Virus.

    Equine Influenza Vaccine, Killed Virus, shall be prepared from 
virus-bearing cell culture fluids or embryonated chicken eggs. Only 
Master Seed that has been established as pure, safe, and immunogenic 
may be used for vaccine production. All serials of vaccine shall be 
prepared from the first through the fifth passage from the Master Seed. 
Firms currently producing equine influenza vaccine that does not 
satisfy this requirement have until [Insert date 2 years from effective 
date of final rule] to comply with this requirement unless granted an 
extension by the Administrator based on a showing by the firm seeking 
the extension that they have made a good faith effort with due 
diligence to achieve compliance.
    (a) The Master Seed shall meet the applicable general requirements 
prescribed in Sec. 113.200.
    (b) The immunogenicity of vaccine prepared from the Master Seed in 
accordance with the Outline of Production must be established by the 
method prescribed in this paragraph or other method acceptable to the 
Animal and Plant Health Inspection Service (APHIS). The vaccine used 
for this test must be at the highest passage from the Master Seed and 
at the minimum preinactivation titer provided in the Outline of 
Production. The test must establish that the vaccine when used as 
recommended on the label is capable of inducing an immune response that 
protects horses for at least 60 days following completion of the 
immunization regimen specified on the labeling.
    (1) For at least one strain of each subtype of equine influenza 
virus contained in the vaccine, at least 15 susceptible horses of the 
minimum age recommended on the label shall be used as test animals. 
Horses are considered susceptible if the HI titer of individual serum 
samples taken from each animal is less than 1:10 using a constant 
virus, decreasing serum HI assay against 4 HA units of each strain of 
virus tested. The virus (antigen) may not be treated prior to the 
assay.
    (2) At least 10 horses shall be vaccinated in accordance with the 
label recommendation, and at least 5 additional horses shall be held as 
unvaccinated controls. To demonstrate continued susceptibility, 
vaccinates must be negative for an anamnestic serologic response at 7 
days after the first vaccination.
    (3) Not less than 60 days after completion of the immunization 
regimen, the immunity of each of the vaccinates and the controls shall 
be challenged. At least 10 vaccinates and 5 controls must be challenged 
with a representative strain of each equine influenza virus subtype 
present in the vaccine in a manner acceptable to APHIS, and observed 
each day for 7 days for clinical signs of disease. Test animals must be 
bled immediately prior to challenge, and serum samples obtained for 
testing. If the controls are not seronegative at the time of challenge, 
the test is inconclusive and may be repeated.

[[Page 34633]]

    (4) If a statistically significant (p0.05) difference in clinical 
signs and temperature cannot be demonstrated between the vaccinates and 
controls using a scoring system acceptable to APHIS, the Master Seed is 
unsatisfactory.
    (5) If the Master Seed immunogenicity test is satisfactory, other 
strains of equine influenza virus of the same subtype(s) may be added 
to the vaccine at any time by demonstrating that the added strain(s) 
elicits a serum HI titer either in horses or in guinea pigs that is 
equal to or greater than the titer elicited by the strain of the virus 
used in the challenge study. Provided, That:
    (i) For each virus subtype claimed on the label for the product, 
the vaccine will at all times contain at least one strain of equine 
influenza virus whose immunogenicity has been determined in a host 
animal vaccination-challenge study.
    (ii) Guinea pig HI titers may be used only if a satisfactory dose-
response relationship correlated to host animal protection and a mean 
relative potency value of the vaccine in guinea pigs based on a minimum 
of 3 replicate tests conducted at the time of the efficacy study has 
been established or can be shown.
    (c) Test requirements for release. Each serial must meet the 
applicable general requirements prescribed in Sec. 113.200 and the 
special requirements for safety and potency provided in this section. 
Any serial or subserial found unsatisfactory by a prescribed test shall 
not be released.
    (1) Safety test. The vaccinates used in the potency test in 
paragraph (c)(2) of this section shall be observed each day during the 
post vaccination observation period. If unfavorable reactions occur 
which are attributable to the vaccine, the serial is unsatisfactory. If 
unfavorable reactions occur that are not attributable to the vaccine, 
the test is inconclusive and may be repeated: Provided, That, if the 
test is not repeated, the serial is unsatisfactory.
    (2) Potency test. Bulk or final container samples of completed 
product from each serial shall be tested for potency as provided in 
this paragraph. For each fraction of each subtype contained in the 
product--subtype A1 or subtype A2--the serological interpretations 
required in this test shall be made independently.
    (i) At least 12 guinea pigs, each weighing between 300 and 500 
grams, shall be used as test animals.
    (ii) A dose of product equivalent to one-half the recommended horse 
dose shall be administered by the recommended horse route to at least 
10 animals. A second dose shall be administered by the same route 14 to 
21 days later. At least two animals shall be held as unvaccinated 
controls.
    (iii) Fourteen to 21 days after the second vaccination, the animals 
shall be bled and serum samples obtained. The samples from each animal 
shall be tested in an HI assay consistent with that described in the 
following paragraph or by an alternative method acceptable to APHIS.
    (iv) The serum samples shall be treated with kaolin and chicken red 
blood cells prior to initiation of the assay. A constant-virus, 
decreasing-serum HI assay against four hemagglutination units of each 
virus fraction shall be employed. The antigens may not be treated prior 
to performance of the assay.
    (v) Test interpretation. If the controls for a given test fraction 
have not remained seronegative at the lowest test dilution (1:10), the 
test is inconclusive and may be repeated. If the geometric mean titer 
(GMT) of vaccinates in a valid test is less than the guinea pig GMT 
correlated with protection of horses against the applicable virus 
subtype, the serial is unsatisfactory unless the test is repeated. If 
the second test meets the requirements for validity and the GMT of 
vaccinates from both tests is less than the guinea pig GMT correlated 
with protection of horses for that subtype, then the serial is 
unsatisfactory without further testing.
    (d) If more than 60 days' duration of immunity is to be claimed for 
any fraction, it may be shown by vaccinating at least 10 horses as 
recommended on the label and demonstrating an HI titer that is equal to 
or greater than the titer achieved in the Master Seed immunogenicity 
study for the period of time claimed. Labels must specify revaccination 
every 60 days if longer duration of immunity is not shown. Although not 
required, horses used to establish the duration of immunity beyond the 
required minimum of 60 days may also be challenged.

    Done in Washington, DC, this 9th day of May, 2002.
Peter Fernandez,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 02-12134 Filed 5-14-02; 8:45 am]
BILLING CODE 3410-34-P