[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]
BILLING CODE 3410-34-P
