[Federal Register Volume 62, Number 110 (Monday, June 9, 1997)]
[Rules and Regulations]
[Pages 31326-31329]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14997]


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DEPARTMENT OF AGRICULTURE

Animal and Plant Health Inspection Service

9 CFR Part 101

[Docket No. 93-152-2]
RIN 0579-AA65


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

AGENCY: Animal and Plant Health Inspection Service, USDA.

ACTION: Final rule.

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SUMMARY: We are amending 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 adding a definition of 
``guidelines'' to the regulations. Guidelines are issued to assist 
manufacturers of veterinary biological products and others in 
understanding test procedures, standards, and regulatory requirements 
pertaining to such products. This addition clarifies the purpose and 
intent of guidelines.

EFFECTIVE DATE: July 9, 1997.

FOR FURTHER INFORMATION CONTACT: Dr. David A. Espeseth, Director, 
Licensing and Policy Development, Center for Veterinary Biologics, VS, 
APHIS, 4700 River Road Unit 148, Riverdale, MD 20737-1231, (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 purity, 
safety, potency, and efficacy. A product which is a ``virus, serum, 
toxin, or analogous product'' and which is intended for use in the 
treatment of animals is subject to regulation under the VSTA. Such 
products are commonly referred to as biologics or biological products. 
The definitions of terms related to veterinary biological products 
appear in 9 CFR part 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.

[[Page 31327]]

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 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 VSTA 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 petition dated September 14, 1993, from the Animal 
Health Institute, a national trade association, requesting that the 
definition of ``biological products'' be amended.
    In drafting the amended definition, APHIS considered various points 
raised in the petition and reviewed the definition of ``biological 
products'' in 9 CFR 101.2. Such review has been ongoing for some time 
because it has been apparent that a clarification and an update of the 
definition is necessary. Therefore, in response to the petition and as 
a result of its own efforts to update the definition, APHIS issued a 
proposal amending the definition of ``biological products'' in 
Sec. 101.2. The definition proposed by APHIS is applicable to all 
viruses, serums, toxins (excluding antibiotics), or analogous products 
at any stage of production, shipment, distribution, or sale. APHIS also 
proposed to add a definition of guidelines to Sec. 101.2. The purpose 
of guidelines is to assist licensees and applicants in matters related 
to procedures, methods, and other considerations pertaining to the 
regulation and licensure of biological products. Guidelines also 
clarify and explain agency practice and requirements.
    The proposed rule was published in the Federal Register (61 FR 
43483-43486, Docket No. 93-152-1) on August 23, 1996.
    We solicited comments concerning our proposal for 60 days ending 
October 22, 1996. Three comments were received by that date. They were 
from a professional association and two trade associations. We 
carefully considered all of the comments we received. They are 
discussed below.
    One commenter supported the rule as proposed. The commenter agreed 
that the revised definition is necessary to reflect current usage and 
advances in science. In addition, the commenter commended the agency 
for clarifying matters covered under the VSTA.
    Another commenter believed that the rule would benefit biologics 
manufacturers and the animal health industry. The commenter supported 
the rule as proposed but requested clarification of several points 
related to the definition. The first point raised by the commenter 
related to the term ``treatment of specific diseases.'' The commenter 
inquired whether the term excluded products for the control of 
fertility from the definition of ``biological products.'' In response 
to the commenter, it is the position of APHIS that products intended 
for the control of fertility are not intended for the ``treatment of 
specific diseases'' and therefore fall outside of the definition of 
``biological products.''
    Two comments were received regarding section 4 of the preamble 
which deals with analogous products. There seemed to be some confusion 
about the reference to water and coloring and the statement concerning 
any stage of production. A question was also raised about the 
regulation of oral claims by APHIS. A careful reading of section 4 of 
the preamble will reveal that it merely meant to distinguish between 
the types of products which would be considered ``analogous.'' These 
are products having a legitimate use which are similar in function to 
biological products, and products which may resemble, or are 
represented as, biological products, but may consist of nothing but 
water and coloring. Both types fall under the definition of products 
regulated under the Act. Furthermore, products would not be exempted 
from regulation simply because they failed to reach some step in their 
manufacture or packaging. To further clarify the definition, an 
additional statement concerning the interpretation of the meaning of 
intended use, which appears in the discussion of analogous products in 
the proposal, has been added to Sec. 101.2.
    The same two commenters inquired whether ``guidelines'' would 
become requirements. In response to the commenters, the purpose of the 
guidelines is to assist manufacturers and others with questions 
concerning licensing, testing, regulatory requirements, and other areas 
dealing with biologics. Therefore, while ``guidelines'' clarify and 
explain agency

[[Page 31328]]

policy and regulatory requirements, ``guidelines'' themselves do not 
have the force and effect of regulations. No change to the regulations 
is made in response to these comments.
    One commenter recommended that the definition of ``biological 
products'' also include ``natural products'' and ``live or killed 
vector carrier systems.'' In response to this comment, APHIS believes 
that ``natural products'' that fit the definition of ``biological 
products'' are already included under the proposed definition under the 
phrase ``that are of natural or synthetic origin.'' In addition, ``live 
or killed vector systems'' that carry ``immune components of live 
organisms'' intended for the treatment of specific diseases already 
fall under the proposed definition. No change to the regulations is 
made in response to this comment.
    Therefore, based on the rationale set forth in the proposed rule 
and in this document, we are adopting the provisions of the proposal as 
a final rule, with the change discussed in this document.

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 the purposes of Executive 
Order 12866 and, therefore, has not been reviewed by the Office of 
Management and Budget.
    APHIS is amending 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 amending the 
definition based on its own efforts to update the definition.
    This action has been coordinated with the Food and Drug 
Administration.
    The primary effect of the rule is 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 will benefit 
manufacturers of veterinary biologics by providing definitions that 
reflect current usage and accommodate advances in scientific knowledge.
    The rule also provides 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.
    There are currently approximately 118 veterinary biologics 
establishments that may be affected by this rule. According to the 
Small Business Administration regulations, many of them would be 
classified as small entities.
    Three comments were received for the proposed rule on the 
definition of ``biological products'' and ``guidelines.'' All three 
comments supported the definition as proposed and believed that the 
definition would reflect current usage and advances in science and 
provide a benefit to manufacturers of veterinary biologics and the 
animal health industry.
    Under these circumstances, the Administrator of the Animal and 
Plant Health Inspection Service has determined that this action will 
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 12988

    This 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 is amended as follows:

PART 101--DEFINITIONS

    1. The authority citation for part 101 continues 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 is amended by revising the definition of 
Biological products and by adding a definition for Guidelines, in 
alphabetical order, 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) A product's intended use shall be determined through an 
objective standard and not a subjective one, and would be dependent on 
factors such as representations, claims (either oral or written), 
packaging, labeling, or appearance.
    (2) The term analogous products shall include:
    (i) 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, supplementation, 
enhancement, or modulation of the immune system or immune response; or
    (ii) Substances, at any stage of production, shipment, 
distribution, or

[[Page 31329]]

sale, which are intended for use in the treatment of animals through 
the detection or measurement of antigens, antibodies, nucleic acids, or 
immunity; or
    (iii) Substances, at any stage of production, shipment, 
distribution, or sale, which resemble or are represented as biological 
products intended for use in the treatment of animals through 
appearance, packaging, labeling, claims (either oral or written), 
representations, or through any other means.
    (3) The term ``treatment'' shall mean the prevention, diagnosis, 
management, or cure of diseases of animals.
* * * * *
    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 3rd day of June 1997.
Terry L. Medley,
Administrator, Animal and Plant Health Inspection Service.
[FR Doc. 97-14997 Filed 6-6-97; 8:45 am]
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