[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