[Federal Register Volume 61, Number 165 (Friday, August 23, 1996)]
[Proposed Rules]
[Pages 43483-43486]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-21556]


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DEPARTMENT OF AGRICULTURE
Animal and Plant Health Inspection Service

9 CFR Part 101

[Docket No. 93-152-1]
RIN 0579-AA65


Viruses, Serums, Toxins, and Analogous Products; Definition of 
Biological Products and Guidelines

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Proposed rule.

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SUMMARY: We are proposing to amend the regulations by revising the 
definition of ``biological products.'' The amendment is necessary in 
order to reflect current usage and advances in scientific knowledge, 
and to clarify certain parts of the definition.
    We are also proposing to add a definition of ``guidelines'' to the 
regulations. Guidelines are used to assist manufacturers of veterinary 
biologics and other interested persons regarding test procedures, 
methods, and other considerations that would be acceptable to the 
agency in support of licensure of a veterinary biological product. This 
action would clarify in the regulations the purpose and intent of 
guidelines.

DATES: Consideration will be given only to comments received on or 
before October 22, 1996.

ADDRESSES: Please send an original and three copies of your comments to 
Docket No. 93-152-1, 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. 93-152-1. 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 A. Espeseth, Deputy 
Director, Veterinary Biologics, BBEP, APHIS, 4700 River Road Unit 148, 
Riverdale, MD 20737-1237, (301) 734-8245.

SUPPLEMENTARY INFORMATION:

Background

    Veterinary biological products are licensed under the Virus-Serum-
Toxin Act (hereinafter referred to as the VSTA) on the basis of their 
purity, safety, potency, and efficacy. Any ``virus, serum, toxin, or 
analogous product'' intended for use in the treatment of animals is 
subject to regulation under the VSTA. Such substances are commonly 
referred to as biologics or biological products. The definitions of 
terms related to veterinary biological products appear in 9 CFR 101.
    The Food and Drug Administration (FDA) regulates drugs for use in 
animals. The Federal Food, Drug, and Cosmetic Act (FFDCA) defines 
``drugs'' to include, among other things, articles intended for use in 
the diagnosis, cure, mitigation, treatment, or prevention of diseases 
in man or other animals; and articles (other than food) intended to 
affect the structure or any function of the body of man or other 
animals. Articles that are used to improve animal performance, such as 
increased rate of gain and enhanced feed efficiency, are ``drugs'' 
under the FFDCA. Section 902(c) of the FFDCA states that nothing in the 
FFDCA shall affect, modify, repeal, or supersede the provisions of the 
VSTA. FDA regulations under 21 U.S.C. 510.4 provide that an animal drug 
produced in full conformance with the VSTA will not be subject to the 
new animal drug approval requirements of the FFDCA.

Definition of Biological Product

    The definition of ``biological products'' in 9 CFR 101.2 was last 
amended on April 2, 1973 (See 38 FR 8426-8428). Since that time, the 
VSTA

[[Page 43484]]

has been amended by the 1985 Food Security Act (Pub. L. 99-198) and 
scientific advances have improved our understanding of how veterinary 
biologics work.
    The 1985 Food Security Act provided for additional enforcement 
authorities under the VSTA. These authorities include detention, 
seizure, and condemnation and injunctive procedures. In addition, 
unless otherwise exempted, all veterinary biological products shipped 
in or from the United States must meet Federal standards for licensure 
related to purity, safety, potency, and efficacy. Products manufactured 
in foreign countries may not be imported without a permit issued under 
the Act and regulations. The main purpose of the VSTA is to protect 
those who use veterinary biologics from products which are worthless, 
contaminated, dangerous, or harmful. In this regard, products which are 
represented to be biological products also fall under the jurisdiction 
of the VSTA.
    Since 1973, our understanding of how veterinary biologics work has 
advanced substantially. It is now recognized in the scientific 
literature that the generation or stimulation of an immune response 
involves both antigens and certain protein regulatory factors referred 
to as cytokines. Some cytokines (e.g. interleukins) serve as essential 
components in the generation and expression of an immune response, 
without which the vaccine would be worthless. These cytokines may be 
elicited through stimulation with antigens or certain 
``immunomodulators''.
    Cytokines are also produced in many body tissues and act on cell 
types other than those of the immune system. Cytokines of natural or 
synthetic origin can be prepared as products for administration to 
animals. Because of the diverse biological activity of the cytokines, 
not all products consisting of these substances would be regulated 
under the VSTA. Many of these cytokines intended to be used as drugs 
would fall under the jurisdiction of the Food and Drug Administration. 
In such instances, the VSTA would not apply.
    Both cytokines and immunomodulators are analogous to biological 
products when they are used to stimulate, supplement, enhance, or 
modulate the immunity of animals in the treatment of disease. Products 
consisting of these substances that work through these immune 
mechanisms in the treatment of specific disease appropriately fall 
within the definition of ``biological products''. Certain 
immunomodulators (e.g., cell wall extracts and products derived from 
the aloe vera plant) that are used in the treatment of specific 
diseases of animals have been regulated by the Animal and Plant Health 
Inspection Service (APHIS) since 1980.
    APHIS received a citizen's petition dated September 14, 1993, from 
the Animal Health Institute, a national trade association, requesting 
that the definition of ``biological products'' be amended as set forth 
below:

    The term ``animal biological product'' means any virus, serum, 
toxin, or analogous product represented as an animal biological 
product intended for use in the diagnosis, prevention, treatment and 
cure of disease in animals, including any vaccine, bacterin, toxoid, 
whole blood, plasma, serum, antiserum, antitoxin, other blood 
components involved in passive and active immunization, allergen, 
diagnostic component, or analogous product, whether any of these 
products is of natural or synthetic origin, or results from 
synthesizing or altering antigen or antibody components or similar 
technologies.
    1. A virus is interpreted to be not only a product containing 
the infective agent known as a virus, but also a product containing 
any live or killed microorganism and the antigenic or immunizing 
components of microorganisms.
    2. A serum product is whole blood or any product derived 
therefrom.
    3. A toxin product is a component or product of an organism 
(excluding substances that are selectively toxic to microorganisms, 
e.g., antibiotics) which is poisonous to other living organisms and 
which stimulates antibodies to itself when administered at sublethal 
doses.
    4. A product is analogous to a vaccine, bacterin, toxoid, whole 
blood, plasma, serum, antiserum, antitoxin, other blood components 
involved in passive and active immunization, allergen, or diagnostic 
components, and includes, but is not limited to filterable viruses, 
bacteria, rickettsia, fungi, mycoplasma and parasites, if it is 
intended to have a similar effect in the stimulation, enhancement, 
supplementation, or modulation of immunity of animals or in the 
detection or measurement of antigens, antibodies, nucleic acids or 
immunity of animals.

    In drafting the proposed definition, APHIS has considered the 
citizen's petition. APHIS has also reviewed its own definition of 
``biological products'' in 9 CFR 101.2. Such review has been ongoing 
because it has become apparent that some clarification and updating of 
the definition is necessary. In response to the citizen's petition and 
to reflect its own efforts to update the definition, APHIS is proposing 
this rule to amend the definition of ``biological products'' in 
Sec. 101.2.
    The proposed APHIS definition of ``biological products'' in 
Sec. 101.2 would refer to all viruses, serums, toxins (excluding 
antibiotics), or analogous products at any stage of production, 
shipment, distribution, or sale.
    Under the VSTA, a ``virus'' is not only a product containing the 
infective agent known as a virus, but also a product containing any 
live or killed microorganism and the antigenic or immunizing components 
of microorganisms.
    In addition, the proposed APHIS definition would:
    1. Recognize multiple components that interact in the functioning 
of the immune system.
    Such biological products would be used in the treatment of specific 
diseases of animals through the stimulation, supplementation, 
enhancement, or modulation of the immune system or immune response.
    The use of a biological product would be determined, among other 
things, by the approved label claim in the filed Outline of Production. 
The approved label claim would define the purpose and condition for use 
of the biological product.
    For purposes of this rule, the terms ``stimulation,'' 
``supplementation,'' ``enhancement,'' and ``modulation'' of the immune 
system would have the following meanings. ``Stimulation'' would refer 
to ``active immunization'' and ``supplementation'' of the immune system 
would refer to ``passive immunization'' (by blood or other components). 
``Enhancement'' or ``modulation'' of the immune system would refer to 
the ``up regulation'' or ``fine tuning,'' respectively, of the immune 
system in the generation of an effective immune response.
    2. Recognize as biological products certain immunomodulators used 
in the treatment of specific diseases of animals.
    Biological products would include, but not be limited to vaccines, 
bacterins, allergens, antibodies, antitoxins, toxoids, 
immunostimulants, certain cytokines, antigenic or immunizing components 
of live organisms, and diagnostic components, whether they are of 
natural or synthetic origin, or products which result from synthesizing 
or altering various substances.
    3. Recognize genetically engineered products.
    These substances would include microorganisms and their antigenic 
or immunizing components, genes or genetic sequences, carbohydrates, 
proteins, allergens, and antibodies.
    4. Define analogous products.
    The term ``analogous products'' in the proposed definition of 
``biological products'' would include substances, at any stage of 
production, shipment,

[[Page 43485]]

distribution, or sale, which are intended for use in the treatment of 
animals and which are similar in function to biological products in 
that they act, or are intended to act, by stimulating, supplementing, 
enhancing, or modulating the immune system or immune response. This 
term would also apply to substances, at any stage of production, 
shipment, distribution, or sale, which do not act or are not intended 
to act by stimulating, supplementing, enhancing, or modulating the 
immune system or immune response, but which resemble or are represented 
as biological products through appearance, packaging, labeling, claims 
(either oral or written), representations, or through any other means. 
For example, a substance consisting of water and coloring which appears 
to be a biological product or which is packaged or labeled or 
represented as a biological product would be considered an analogous 
product intended for use in the treatment of animals. The intended use 
would be determined using an objective standard and not a subjective 
one, and would be based on factors such as representations, claims, 
packaging, labeling, or appearance.
    5. Clarify coverage of diagnostic products and components.
    The proposed term ``analogous products'' would also include 
products intended for use in the treatment of diseases of animals by 
detecting or measuring antigens, antibodies, nucleic acids, or immunity 
of animals.
    6. Recognize blood or other components involved in passive or 
active immunization.
    Terms such as whole blood and plasma are not specifically included 
since whole blood intended for replacement of blood volume only would 
not be deemed a biological product. Whole blood, plasma, and other 
substances which meet the definition of analogous product would be 
covered under the definition.
    The proposed APHIS definition of ``biological products'' is 
somewhat similar to that proposed by the citizen's petition, but 
differs in some respects. For example, in the first paragraph of the 
definition in the citizen's petition, the term ``represented'' has been 
moved to paragraph (1)(a) in the APHIS definition. Other concepts and 
terms proposed in the petition have been adopted, but may be included 
in the definition in a different manner.
    7. Define the term ``treatment''.
    The term ``treatment'' in the definition of ``biological products'' 
would mean the prevention, diagnosis, management, or cure of diseases 
of animals.
    For the reasons discussed, APHIS proposes to amend the regulations 
by revising the definition of the term ``biological products'' to 
address advances in scientific knowledge, the recommendations in the 
citizen's petition submitted by the Animal Health Institute, and to 
clarify certain questions which have arisen.

Definition of Guidelines

    We are also proposing to add a definition of ``guidelines'' to the 
administrative terminology section of Sec. 101.2. ``Guidelines'' 
establish principles or practices related to test procedures, 
manufacturing practices, product standards, scientific protocols, 
labeling, or other technical or policy considerations. ``Guidelines'' 
that are issued by the agency include Veterinary Biologics Licensing 
Considerations, Memoranda, Notices, and Supplemental Assay Methods.
    The purpose of ``guidelines'' is to assist licensees and applicants 
in matters related to procedures, methods, and other considerations 
that would be acceptable to the agency. ``Guidelines'' also clarify and 
explain agency practice and requirements.

Executive Order 12866 and Regulatory Flexibility Act

    This proposed rule has been reviewed under Executive Order 12866. 
The rule has been determined to be significant for purposes of 
Executive Order 12866, and, therefore, has been reviewed by the Office 
of Management and Budget.
    APHIS is proposing to amend the definition of the term ``biological 
products'' in its regulations under the Virus-Serum-Toxin Act, based on 
a petition that APHIS received from the Animal Health Institute, a 
national trade association, requesting that the definition be updated 
to reflect current scientific usage. The agency is also proposing to 
amend the definition based on its own efforts to update the definition.
    Regulatory actions that are likely to result in a rule that may 
create a serious inconsistency or otherwise interfere with the actions 
taken or planned by another agency are considered ``significant'' under 
the Executive Order. Because of potential overlap between the 
definition of ``animal drugs'', that are regulated by the Food and Drug 
Administration (FDA), and the definition of ``veterinary biological 
products'', that are regulated by APHIS, the proposed rule was 
designated as ``significant'' under Executive Order 12866.
    In efforts to reduce inconsistency and to coordinate regulatory 
efforts between the two agencies, APHIS requested on July 1, 1994, 
specific comment from the Food and Drug Administration (FDA) regarding 
the proposed definition prior to its publication. In addition, meetings 
were held between representatives of the two agencies on October 25, 
November 8, November 22, 1994, and January 20, 1995, to clarify 
specific points in the proposed definition. In December 1994 and 
January 1995, APHIS revised its proposed definition in response to the 
comments received and the discussions at the meetings held with the 
FDA.
    Based on progress made during several meetings between APHIS and 
the FDA to discuss the proposed definition, and the specific changes 
made to the proposed definition in response to FDA comments, APHIS 
believes that the proposed rule on the definition of ``biological 
products'' should not lead to serious inconsistency or otherwise 
interfere with actions taken or planned by another agency.
    The primary effect of the proposed rule would be to update the 
definition of ``biological products'' and add a definition of the term 
``guidelines.'' This amendment to the regulations should have no 
adverse economic impact on firms and may even provide a benefit since 
the issuance of ``guidance'' documents may help to reduce the amount of 
time or resources required to complete licensure or testing of a 
biological product. It is anticipated that the amendment would benefit 
manufacturers of veterinary biologics by providing definitions that 
reflect current usage and accommodate advances in scientific knowledge.
    The proposed rule is also anticipated to provide guidance to 
manufacturers of veterinary biologics as to the scope of the term 
``biological products.'' Biologics manufacturers should thus be aided 
in their decisionmaking related to the choice of submissions to APHIS 
for licensure of veterinary biological products or to the Food and Drug 
Administration for the approval of veterinary drugs.
    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

[[Page 43486]]

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. There are no administrative procedures which must be exhausted 
prior to a judicial challenge to the provisions of this rule.

Paperwork Reduction Act

    This document contains no information collection or recordkeeping 
requirements under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.).

Regulatory Reform

    This action is part of the President's Regulatory Reform 
Initiative, which, among other things, directs agencies to remove 
obsolete and unnecessary regulations and to find less burdensome ways 
to achieve regulatory goals.

List of Subjects in 9 CFR Part 101

    Animal biologics.

    Accordingly, 9 CFR part 101 would be amended as follows:

PART 101--DEFINITIONS

    1. The authority citation for part 101 would be revised to read as 
follows:

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

    2. Section 101.2 would be amended by revising the term ``biological 
products'' to read as follows:


Sec. 101.2  Administrative terminology.

* * * * *
    Biological products. The term ``biological products,'' also 
referred to in this subchapter as biologics, biologicals, or products, 
shall mean all viruses, serums, toxins (excluding substances that are 
selectively toxic to microorganisms, e.g., antibiotics), or analogous 
products at any stage of production, shipment, distribution, or sale, 
which are intended for use in the treatment of animals and which act 
primarily through the direct stimulation, supplementation, enhancement, 
or modulation of the immune system or immune response. The term 
``biological products'' includes but is not limited to vaccines, 
bacterins, allergens, antibodies, antitoxins, toxoids, 
immunostimulants, certain cytokines, antigenic or immunizing components 
of live organisms, and diagnostic components, that are of natural or 
synthetic origin, or that are derived from synthesizing or altering 
various substances or components of substances such as microorganisms, 
genes or genetic sequences, carbohydrates, proteins, antigens, 
allergens, or antibodies.
    (1) The term analogous products shall include:
    (a) Substances, at any stage of production, shipment, distribution, 
or sale, which are intended for use in the treatment of animals and 
which are similar in function to biological products in that they act, 
or are intended to act, through the stimulation, supplemention, 
enhancement, or modulation of the immune system or immune response, or
    (b) Substances, at any stage of production, shipment, distribution, 
or sale, which are intended for use in the treatment of animals through 
the detection or measurement of antigens, antibodies, nucleic acids, or 
immunity, or
    (c) Substances, at any stage of production, shipment, distribution, 
or sale, which resemble or are represented as biological products 
through appearance, packaging, labeling, claims (either oral or 
written), representations, or through any other means.
    (2) The term ``treatment'' shall mean the prevention, diagnosis, 
management, or cure of diseases of animals.
* * * * *


Sec. 101.2  [Amended]

    3. In Sec. 101.2, the term ``Guidelines'' would be added in 
alphabetical order to read as follows:
* * * * *
    Guidelines. Guidelines establish principles or practices related to 
test procedures, manufacturing practices, product standards, scientific 
protocols, labeling, and other technical or policy considerations. 
Guidelines contain procedures or standards of general applicability 
that are usually not regulatory in nature, but that are related to 
matters that fall under the Virus-Serum-Toxin Act. Guidelines issued by 
the agency include Veterinary Biologics Licensing Considerations, 
Memoranda, Notices, and Supplemental Assay Methods.
* * * * *
    Done in Washington, DC, this 20th day of August 1996.
A. Strating,
Acting Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 96-21556 Filed 8-22-96; 8:45 am]
BILLING CODE 3410-34-P