Definition of the Term “Biological Product”, 10057-10063 [2020-03505]
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Federal Register / Vol. 85, No. 35 / Friday, February 21, 2020 / Rules and Regulations
Issued in Washington, DC, on February 12,
2020.
Mark Gauch,
Acting Manager, Rules and Regulations
Group.
[FR Doc. 2020–03283 Filed 2–20–20; 8:45 am]
BILLING CODE 4910–13–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 600
[Docket No. FDA–2018–N–2732]
RIN 0910–AH57
Definition of the Term ‘‘Biological
Product’’
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
I. Executive Summary
The Food and Drug
Administration (FDA, the Agency, or
we) is issuing a final rule to amend its
regulation that defines ‘‘biological
product’’ to incorporate changes made
by the Biologics Price Competition and
Innovation Act of 2009 (BPCI Act) and
the Further Consolidated
Appropriations Act, 2020 (FCA Act),
and to provide its interpretation of the
statutory term ‘‘protein.’’ Under this
final rule, the term protein means any
alpha amino acid polymer with a
specific, defined sequence that is greater
than 40 amino acids in size. This final
rule is intended to clarify the statutory
framework under which such products
are regulated.
DATES: This rule is effective March 23,
2020.
ADDRESSES: For access to the docket to
read background documents or
comments received, go to https://
www.regulations.gov and insert the
docket number found in brackets in the
heading of this final rule into the
‘‘Search’’ box and follow the prompts,
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Daniel Gottlieb, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6208,
Silver Spring, MD 20993, 301–796–
6650, daniel.gottlieb@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
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SUMMARY:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
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B. Summary of the Major Provisions of the
Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used
Acronyms in This Document
III. Background
A. History of this Rulemaking
B. Summary of Comments on the Proposed
Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA
Response
A. Introduction
B. Specific Comments and FDA Response
VI. Effective Date
VII. Economic Analysis of Impacts
A. Introduction
B. Summary of Costs and Benefits
C. Summary of Regulatory Flexibility
Analysis
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With
Indian Tribal Governments
XII. References
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A. Purpose of the Final Rule
This final rule amends FDA’s
regulation that defines ‘‘biological
product’’ by making a technical revision
and conforming to the statutory
definition enacted in the BPCI Act, as
further amended by section 605 of the
FCA Act (Pub. L. 116–94). The BPCI Act
amended the definition of ‘‘biological
product’’ in section 351(i) of the Public
Health Service Act (PHS Act) (42 U.S.C.
262(i)) to include a ‘‘protein (except any
chemically synthesized polypeptide).’’
After publication of the proposed rule,
section 605 of the FCA Act further
amended the definition of ‘‘biological
product’’ in section 351(i) of the PHS
Act to remove the parenthetical ‘‘(except
any chemically synthesized
polypeptide)’’ from the statutory
category of ‘‘protein.’’ The final rule
makes conforming changes to § 600.3
(21 CFR 600.3) to add FDA’s
interpretation of the statutory term
‘‘protein.’’
B. Summary of the Major Provisions of
the Final Rule
Under the final rule, the term protein
means any alpha amino acid polymer
with a specific defined sequence that is
greater than 40 amino acids in size. This
is consistent with the interpretation of
this term that FDA previously described
in the notice of proposed rulemaking
published in the Federal Register on
December 12, 2018 (83 FR 63817) and
in a final guidance document issued on
April 30, 2015 (see 80 FR 24259
(announcing the availability of a
guidance for industry entitled
‘‘Biosimilars: Questions and Answers
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Regarding Implementation of the
Biologics Price Competition and
Innovation Act of 2009,’’ available at
https://www.regulations.gov (Docket No.
FDA–2011–D–0611) (2015 Biosimilars
Q&A Guidance); see also ‘‘New and
Revised Draft Q&As on Biosimilar
Development and the Biologics Price
Competition and Innovation Act
(Revision 2)’’ (December 2018; 83 FR
63898)).
C. Legal Authority
This final rule amends FDA’s
regulations to implement certain aspects
of the BPCI Act and the FCA Act. FDA’s
authority for this rule derives from the
biological product provisions in section
351 of the PHS Act and the provisions
of the Federal Food, Drug, and Cosmetic
Act (FD&C Act) (21 U.S.C. 321, et seq.)
applicable to drugs, as well as section
701 of the FD&C Act (21 U.S.C. 371).
The rule is necessary to clarify the
statutory authority under which
biological products are regulated, to
prevent inconsistent regulation of such
products, and for the efficient
enforcement of the FD&C Act.
D. Costs and Benefits
This final rule codifies FDA’s
interpretation of the statutory term
‘‘protein’’ in a manner that is consistent
with the interpretation of this term that
FDA previously described in guidance
(see 2015 Biosimilars Q&A Guidance)
and the proposed rule. Formalizing this
interpretation will reduce regulatory
uncertainty over whether certain
products are regulated as drugs or
biological products. This reduced
uncertainty, under the ‘‘bright-line’’
approach described in the proposed
rule, will allow both FDA and private
industry to avoid spending time and
resources on case-by-case
determinations for each product. The
primary estimate of the benefits in 2018
dollars annualized over 10 years is
$394,562 using a 7 percent discount rate
and $348,436 using a 3 percent discount
rate. We also calculate ranges of benefits
of $356,775 to $411,345 and $316,116 to
$362,792, respectively. The estimated
annualized costs range from $13,511 to
$16,889, with a primary estimate of
$15,012 using a 7 percent discount rate
over a 10-year horizon. For a 3 percent
discount rate, we estimate a range of
$12,471 to $15,589, with a primary
estimate of $13,857.
II. Table of Abbreviations/Commonly
Used Acronyms in This Document
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Abbreviation/acronym
What it means
BPCI Act ...................................................................................................
CFR ..........................................................................................................
EO .............................................................................................................
FCA Act ....................................................................................................
FD&C Act ..................................................................................................
FDA ...........................................................................................................
PHS Act ....................................................................................................
U.S. ...........................................................................................................
U.S.C. .......................................................................................................
III. Background
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A. History of This Rulemaking
The BPCI Act amended the definition
of ‘‘biological product’’ in section 351(i)
of the PHS Act to include a ‘‘protein
(except any chemically synthesized
polypeptide).’’ After publication of the
proposed rule, section 605 of the FCA
Act further amended the definition of
‘‘biological product’’ in section 351(i) of
the PHS Act to remove the parenthetical
‘‘(except any chemically synthesized
polypeptide)’’ from the statutory
category of ‘‘protein.’’ As amended by
the BPCI Act and the FCA Act, a
‘‘biological product’’ is defined as ‘‘a
virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood
component or derivative, allergenic
product, protein, or analogous product,
or arsphenamine or derivative of
arsphenamine (or any other trivalent
organic arsenic compound), applicable
to the prevention, treatment, or cure of
a disease or condition of human beings’’
(see section 351(i)(1) of the PHS Act).
The BPCI Act clarified the statutory
authority under which certain protein
products are to be regulated. Although
the majority of therapeutic biological
products have been licensed under
section 351 of the PHS Act, some
protein products historically have been
approved under section 505 of the FD&C
Act (21 U.S.C. 355). The BPCI Act
requires that a marketing application for
a ‘‘biological product’’ (that previously
would have been submitted under
section 505 of the FD&C Act) must be
submitted under section 351 of the PHS
Act, subject to certain exceptions during
a 10-year transition period ending on
March 23, 2020 (see section 7002(e)(1)
through (3) and (e)(5) of the BPCI Act).
FDA is adding its interpretation of the
term ‘‘protein’’ to the regulations to
clarify the statutory framework under
which such products are regulated.
The proposed rule includes a history
of this rulemaking and cites several
scientific resources, including textbooks
and dictionaries, to illustrate the aspects
of the meanings of the terms ‘‘protein,’’
‘‘polypeptide,’’ and ‘‘peptide’’ on which
there is or is not scientific consensus
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Biologics Price Competition and Innovation Act of 2009.
Code of Federal Regulations.
Executive Order.
Further Consolidated Appropriations Act, 2020.
Federal Food, Drug, and Cosmetic Act.
U.S. Food and Drug Administration.
Public Health Service Act.
United States.
United States Code.
(see 83 FR 63817 at 63819–63820). As
discussed in the proposed rule, despite
the lack of precise, agreed-upon
definitions, most, if not all, sources
agree about certain aspects of the
meanings of these terms. First, all of the
terms (‘‘protein,’’ ‘‘polypeptide,’’ and
‘‘peptide’’) refer to amino acid polymers
(also referred to as ‘‘amino acid chains’’)
made up of alpha amino acids that are
linked by peptide bonds. Second,
‘‘protein’’ refers to chains containing a
specific, defined sequence of amino
acids, generally provided by a
corresponding DNA or RNA sequence.
Finally, the term ‘‘protein’’ is distinct
from and excludes the term ‘‘peptide’’
(i.e., amino acid chains that are
generally shorter and simpler than a
protein).
In the proposed rule, FDA described
its proposed interpretation of the
statutory terms ‘‘protein’’ and
‘‘chemically synthesized polypeptide,’’
which appeared in the definition of
‘‘biological product’’ in section 351(i) of
the PHS Act prior to the enactment of
the FCA Act. FDA is now finalizing its
interpretation of the statutory term
‘‘protein’’ without change. However, in
light of the recently enacted FCA Act,
which removed the parenthetical
exception for ‘‘any chemically
synthesized polypeptide’’ from the
category of ‘‘protein’’ in the statutory
definition of ‘‘biological product,’’ FDA
is not finalizing its interpretation of
‘‘chemically synthesized polypeptide’’
because it is no longer necessary.
B. Summary of Comments on the
Proposed Rule
We received four comments on the
proposed rule. Two of the comments
were general comments supporting
FDA’s proposed interpretations; one of
these comments specifically supports
FDA’s proposal because the commenter
stated that it enables insulin to be
brought into the regulatory pathway for
biological products, including
biosimilar and interchangeable
products. Two of the comments
substantively addressed specific aspects
of the proposed interpretations of
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‘‘protein’’ and ‘‘chemically synthesized
polypeptide.’’
IV. Legal Authority
We are issuing this final rule under
the biological product provisions in
section 351 of the PHS Act and the
provisions of the FD&C Act (21 U.S.C.
321, et seq.) applicable to drugs. See
section 351(j) of the PHS Act. Under
these provisions, FDA has the authority
to issue regulations designed to ensure,
among other things, that biological
products are safe, pure, and potent and
are manufactured in accordance with
current good manufacturing practices.
FDA also has general authority to issue
regulations for the efficient enforcement
of the FD&C Act and the PHS Act under
section 701 of the FD&C Act and section
351(j) of the PHS Act.
V. Comments on the Proposed Rule and
FDA Response
A. Introduction
We received four comments on the
proposed rule by the close of the
comment period, two of which
contained one or more substantive
comments on one or more issues. We
received comments from trade
organizations, a patient advocacy group,
and a State bar association.
We describe and respond to the
comments in section B of this rule. We
have numbered each comment to help
distinguish between different
comments. We have grouped similar
comments together under the same
number, and in some cases, we have
separated different issues discussed in
the same comment and designated them
as distinct comments for purposes of
our responses. The number assigned to
each comment or comment topic is
purely for organizational purposes and
does not signify the comment’s value or
importance or the order in which
comments were received.
B. Specific Comments and FDA
Response
We proposed to amend § 600.3(h) to
revise the definition of ‘‘biological
product’’ in § 600.3(h) by replacing the
phrase ‘‘means any’’ with the phrase
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‘‘means a’’ to conform to the text of
section 351(i)(1) of the PHS Act. This
proposed technical revision to the
definition of ‘‘biological product’’ was
not intended to alter our interpretation
of section 351(i) of the PHS Act. We also
proposed to revise the definition of a
‘‘biological product’’ in § 600.3(h) to
include a ‘‘protein (except any
chemically synthesized polypeptide).’’
We received no comments regarding
these proposed revisions. However, after
publication of the proposed rule, section
605 of the FCA Act further amended the
definition of ‘‘biological product’’ in
section 351(i) of the PHS Act to remove
the parenthetical ‘‘(except any
chemically synthesized polypeptide)’’
from the statutory category of ‘‘protein.’’
Therefore, we are finalizing these
revisions to the definition of ‘‘biological
product’’ in § 600.3(h) with the
following change: We are defining
‘‘biological product’’ in § 600.3(h) to
include a ‘‘protein’’ instead of defining
‘‘biological product’’ in § 600.3(h) to
include a ‘‘protein (except any
chemically synthesized polypeptide).’’
We also proposed to amend § 600.3(h)
to add FDA’s interpretation of the
statutory terms ‘‘protein’’ and
‘‘chemically synthesized polypeptide.’’
We proposed to interpret the term
‘‘protein’’ to mean any alpha amino acid
polymer with a specific, defined
sequence that is greater than 40 amino
acids in size. We proposed to interpret
the term ‘‘chemically synthesized
polypeptide’’ to mean any alpha amino
acid polymer that is made entirely by
chemical synthesis and is greater than
40 amino acids but less than 100 amino
acids in size. We explained that when
two or more amino acid chains in an
amino acid polymer are associated with
each other in a manner that occurs in
nature, the size of the amino acid
polymer for purposes of our
interpretations of the terms ‘‘protein’’
and ‘‘chemically synthesized
polypeptide’’ will be based on the total
number of amino acids in those chains,
and will not be limited to the number
of amino acids in a contiguous
sequence.
In the following paragraphs, we
discuss comments on these proposed
interpretations. After considering these
comments, we are finalizing our
interpretation of ‘‘protein’’ without
change. We are not finalizing our
interpretation of ‘‘chemically
synthesized polypeptide’’ as it is no
longer necessary because of the change
to the statutory definition of ‘‘biological
product.’’
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1. Scientific Support for Interpretations
of ‘‘Protein’’ and ‘‘Chemically
Synthesized Polypeptide’’
(Comment 1) One comment asserts
that FDA’s interpretations of the
statutory terms ‘‘protein’’ and
‘‘chemically synthesized polypeptide’’
do not reflect current science and
maintains that there is more recent
evidence that amino acid polymers
composed of 40 or fewer amino acids
are capable of assuming secondary and
tertiary structural conformations
indicative of proteins. For these reasons,
the commenter requested that we revise
and reissue the proposed rule.
(Response 1) We disagree with the
comment’s suggestion that FDA’s
interpretation of the term ‘‘protein’’ as
set forth in the proposed rule and the
textbooks we cited in the proposed rule
no longer reflects current science. The
textbooks cited in the proposed rule
have been in use for decades and
continue to be in use (e.g., in college
biochemistry classes). Moreover, the
definitions and descriptions in these
textbooks and dictionaries illustrate the
point that there is not a scientific
consensus on certain aspects of the
definitions of the terms ‘‘peptide’’ and
‘‘protein,’’ an observation that is not
refuted by more recent editions of these
textbooks.
This lack of consensus is also
reflected in several of the articles cited
by the comment. For example, the
comment cites two articles to support its
claim of the existence of ‘‘proteins’’
composed of as few as 11 amino acids.
However, these two articles describe the
11-amino acid polymer differently. One
describes it as an 11-amino-acid
‘‘protein’’ (see Ref. 1) and the other
describes it as an 11-amino-acid
‘‘peptide’’ (see Ref. 2).
Given the lack of a clear scientific
consensus that FDA could consider for
adoption, the Agency is applying its
scientific expertise to interpret the
statutory term ‘‘protein’’ in a manner
that establishes a scientifically
reasonable, bright-line rule that
provides regulatory clarity and
facilitates the implementation of the
BPCI Act, as further amended by the
FCA Act. A clear rule facilitates efficient
use of time and resources by both FDA
and applicants and reduces regulatory
uncertainty. In deciding where to draw
this bright-line rule, one of the factors
that FDA considered is the number of
amino acids understood to be generally
necessary for an amino acid polymer to
exhibit characteristics that are generally
associated with ‘‘proteins,’’ lending a
higher level of complexity to these
products.
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FDA considered whether to include
structural or functional attributes (e.g.,
folding, provides structural support to
cellular macrostructures, catalyzes a
biochemical reaction, transports other
molecules, aids in the folding of other
proteins) in its interpretation of the term
‘‘protein,’’ but determined that this
would not serve to make the line
between peptides and proteins any
brighter. Among other things, relying on
a factor such as ‘‘folding’’ would not
provide regulatory certainty because it
would raise questions about how much
folding is sufficient to differentiate
between ‘‘peptides’’ and ‘‘proteins,’’ as
many peptides can arguably be said to
exhibit some folding. Therefore,
adopting this approach would not
provide for a bright-line rule and would
result in regulatory uncertainty and
inefficiency.
(Comment 2) One comment asserts
that ‘‘proteins’’ are a subset of
‘‘polypeptides,’’ yet FDA’s
interpretation of ‘‘chemically
synthesized polypeptide’’ presumes that
‘‘polypeptides’’ are a subset of
‘‘proteins.’’
(Response 2) With the FCA Act’s
removal of the parenthetical exception
for ‘‘any chemically synthesized
polypeptide’’ from the category of
‘‘protein’’ in the statutory definition of
‘‘biological product’’ in section 351(i) of
the PHS Act, all amino acid polymers
that meet FDA’s interpretation of the
term ‘‘protein’’ (including an amino acid
polymer that previously would have
fallen within the term ‘‘chemically
synthesized polypeptide’’ as interpreted
by FDA) will be considered to fall
within the statutory definition of
‘‘biological product.’’
(Comment 3) Two comments assert
that the proposed interpretations that
we have chosen were not supported by
a scientific consensus and that there is
a lack of scientific consensus for
distinguishing between ‘‘protein,’’
‘‘polypeptide,’’ and ‘‘peptide’’ based on
a particular number of amino acids.
(Response 3) While we agree that
there may not be clear scientific
consensus for a particular number of
amino acids to use when distinguishing
between the terms ‘‘protein’’ and
‘‘peptide,’’ there is strong support in
scientific literature for distinguishing
between types of amino acid polymers
based on the number of amino acids
they contain. Specifically, the
definitions cited in the preamble to the
proposed rule are clear that ‘‘peptides’’
are distinct from ‘‘proteins’’ and that the
term ‘‘peptide’’ generally refers to
smaller, simpler chains of amino acids,
while the term ‘‘protein’’ is used to refer
to longer, more complex chains (83 FR
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63817 at 63819–63820). Moreover, there
is scientific support for the fact that
amino acid polymers greater than 40
amino acids in size exhibit at least some
of the characteristics that are generally
associated with proteins (83 FR 63817 at
63820).
The removal of the parenthetical
exception for ‘‘any chemically
synthesized polypeptide’’ from the
category of ‘‘protein’’ in the statutory
definition of ‘‘biological product’’ has
eliminated any need to distinguish
between these terms.
(Comment 4) One comment asserts
that FDA’s example of insulin does not
support the number of amino acids in
FDA’s interpretation of ‘‘chemically
synthesized polypeptide’’ because
insulin is composed of 2 polypeptide
chain subunits, one containing 21
amino acids and the other containing 30
amino acids.
(Response 4) We disagree with the
comment because it confuses the terms
‘‘polypeptide’’ and ‘‘polypeptide
chain.’’ Even though the need to avoid
confusion between the terms
‘‘polypeptide’’ and ‘‘polypeptide chain’’
has been eliminated by the removal of
the parenthetical exception for ‘‘any
chemically synthesized polypeptide’’
from the category of ‘‘protein’’ in the
statutory definition of ‘‘biological
product’’ in section 351(i) of the PHS
Act, we note in passing that our
interpretation of ‘‘protein’’ uses the
phrase ‘‘amino acid chain’’ instead of
the phrase ‘‘polypeptide chain.’’ In
other words, instead of describing the
two subunits of the insulin protein as
polypeptides or polypeptide chains like
the comment, we describe them as
amino acid chains. It therefore follows
that insulin clearly is a ‘‘protein’’ as
interpreted in the final rule, because the
total number of amino acids exceeds 40.
In particular, insulin is an alpha amino
acid polymer with a specific, defined
sequence consisting of 2 amino acid
chain subunits with 21 amino acids and
30 amino acids, respectively. As these
amino acid chain subunits are
associated with each other in a manner
that occurs in nature, we add the
number of amino acids in each amino
acid chain together to determine
whether insulin is an alpha amino acid
polymer with a specific, defined
sequence that is greater than 40 amino
acids in size. Specifically, by adding
together the number of amino acids in
each of the two amino acid chain
subunits that comprise insulin, we
conclude that insulin is an alpha amino
acid polymer with a specific, defined
sequence of 51 amino acids. Therefore,
according to the interpretation we are
finalizing, insulin is a protein because it
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is an alpha amino acid polymer with a
specific, defined sequence that is greater
than 40 amino acids in size.
2. Alternate Proposals
(Comment 5) One comment requests
that FDA adopt functional definitions
for ‘‘protein’’ and ‘‘chemically
synthesized polypeptides’’ that are
principally focused on the method of
manufacture as well as the conformation
of the amino acid polymer rather than
the size of the amino acid polymer,
reflecting the comment’s view that the
method of manufacture, not size, should
be the determining factor.
(Response 5) We are not finalizing our
interpretation of the term ‘‘chemically
synthesized polypeptide’’ because of the
removal, by section 605 of the FCA Act,
of the parenthetical ‘‘(except any
chemically synthesized polypeptide)’’
from the category of ‘‘protein’’ in the
statutory definition of ‘‘biological
product.’’ Also, we do not agree that we
should adopt an interpretation of the
statutory term ‘‘protein’’ that is
principally focused on the method of
manufacture for the following reasons.
First, we disagree with the comment’s
premise that the statutory definition of
‘‘biological product,’’ which included
‘‘protein (except any chemically
synthesized polypeptide)’’ prior to the
enactment of the FCA Act, was
principally focused on the method of
manufacture. We need not address
whether the fact that the earlier version
of the statute described the method of
manufacture in the parenthetical clause
(excluding chemically synthesized
polypeptides from the scope of the term
‘‘protein’’) has any bearing on our
current interpretation. However, we
note in passing that, according to basic
rules of statutory construction, if
Congress wanted the term ‘‘protein’’ not
to include any ‘‘chemically synthesized
proteins,’’ then it seems unlikely that
the statute would employ two different
terms (‘‘protein’’ and ‘‘polypeptide’’).
Accordingly, we had described the term
‘‘polypeptide’’ as it appeared in section
351(i) of the PHS Act prior to the
enactment of the FCA Act as referring to
a subset of ‘‘protein.’’
Second, as noted in the response to
Comment 1, FDA considered whether to
include structural or functional
attributes in its interpretation of the
term ‘‘protein,’’ but determined that
doing so would not be appropriate as it
would lead to regulatory uncertainty
due to the lack of a bright-line rule.
Third, adopting an interpretation that
focused on the method of manufacture
could improperly incentivize product
developers to choose a suboptimal
method of manufacturing a product that
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may be less efficient and/or more costly,
based on a perceived regulatory
advantage under a particular regulatory
scheme.
It is FDA’s view that the optimal
policy for determining which products
are subject to regulation under the PHS
Act is to apply a bright-line rule that
provides regulatory certainty. Thus, in
order to provide regulatory certainty
and provide a bright-line interpretation
of the term ‘‘protein,’’ we are focusing
on the number of amino acids in the
amino acid polymer (irrespective of the
method of manufacture).
(Comment 6) One comment urges the
Agency to abandon the proposed caseby-case approach for determining
whether a proposed product composed
of amino acid chains that are associated
with each other in a manner not found
in nature constitutes a ‘‘biological
product.’’
(Response 6) FDA is not persuaded by
this comment because there are a
number of ways in which amino acid
chains could be associated with each
other in a novel manner that is not
found in naturally occurring proteins
and we cannot predict all of these
iterations. Although some of these
combinations may result in amino acid
polymers that exhibit characteristics
generally associated with proteins, some
may not.
We recognize that the application of
the fact-specific, case-by-case analysis
for proposed products composed of
amino acid chains that are associated
with each other in a manner not found
in nature does not provide the same
level of certainty that is provided by the
other criteria in § 600.3(h)(6) (see 83 FR
63817 at 63821), but it appears that
case-by-case analysis is currently the
best means of addressing such cases. We
encourage sponsors of these proposed
products to reach out to FDA early in
their development program to discuss
issues related to product classification
and the appropriate pathway for a
marketing application.
3. Relationship to Other Regulatory
Provisions
(Comment 7) One comment asserts
that FDA’s proposed definitions are
inconsistent with § 601.2(a)(4) and (c)
(21 CFR 601.2(a)(4) and (c)).
(Response 7) We disagree with the
comment’s assertion that our proposed
interpretations are inconsistent with our
current regulations in § 601.2(a)(4) and
(c). The comment appears to interpret
§ 601.2(a)(4) and (c) to mean that if a
product is a therapeutic recombinant
DNA-derived product, then, regardless
of size, the product is a biological
product subject to licensure and should
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Federal Register / Vol. 85, No. 35 / Friday, February 21, 2020 / Rules and Regulations
be regulated in accordance with
§ 601.2(c). However, that conclusion
seems to be based on a misreading of
these provisions. We interpret our
regulation at § 601.2(a)(4) and (c) to
mean that if the product meets the
definition of ‘‘biological product’’ under
§ 600.3(h), and also is a therapeutic
recombinant DNA-derived product, then
the application would be regulated in
accordance with § 601.2(c).
(Comment 8) One comment requests
that FDA propose a regulatory definition
of products that are ‘‘analogous’’ to a
protein and therefore are biological
products.
(Response 8) We appreciate the
comment. A definition of products that
are ‘‘analogous’’ to a ‘‘protein’’ for
purposes of section 351(i)(1) of the PHS
Act is outside the scope of this
rulemaking. We note, however, that it
would not be appropriate for the
statutory term ‘‘analogous product’’ to
be interpreted in a way that would
include products that are specifically
excluded by this final rule.
(Comment 9) One comment requests
that FDA clarify its approach to
assessing the appropriate application
type for combination products,
including peptide-protein combination
products.
(Response 9) We appreciate the
comment. The Agency’s approach for
determining the appropriate type of
marketing application for certain
combination products is outside the
scope of this rulemaking. If a sponsor is
unsure of the appropriate marketing
application for its combination product
containing a biological constituent part,
we encourage the sponsor to reach out
to FDA at an appropriate time in its
development program to discuss issues
related to product classification and the
appropriate pathway for a marketing
application.
VI. Effective Date
This final rule will become effective
March 23, 2020.
VII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the
final rule under Executive Order (E.O.)
12866, E.O. 13563, E.O. 13771, the
Regulatory Flexibility Act (5 U.S.C.
601–612), and the Unfunded Mandates
Reform Act of 1995 (Pub. L. 104–4).
E.O.s 12866 and 13563 direct us to
assess all costs and benefits of available
regulatory alternatives and, when
regulation is necessary, to select
regulatory approaches that maximize
net benefits (including potential
economic, environmental, public health
and safety, and other advantages;
distributive impacts; and equity). E.O.
13771 requires that the costs associated
with significant new regulations ‘‘shall,
to the extent permitted by law, be offset
by the elimination of existing costs
associated with at least two prior
regulations.’’ This final rule is a
significant regulatory action under sec.
3(f) of E.O. 12866. Based on the cost
savings summarized below and
discussed further in the regulatory
impact analysis, this final rule is
considered a deregulatory action under
E.O. 13771.
Pursuant to the Congressional Review
Act (5 U.S.C. 801 et seq.), the Office of
Information and Regulatory Affairs
designated this rule as not a ‘‘major
rule,’’ as defined by 5 U.S.C. 804(2).
The Regulatory Flexibility Act
requires us to analyze regulatory options
that will minimize any significant
impact of a rule on small entities.
Because this rule does not impose new
regulatory burden on small entities
other than administrative costs of
reading and understanding the rule, we
certify that the final rule will not have
a significant economic impact on a
substantial number of small entities.
The Unfunded Mandates Reform Act
of 1995 (section 202(a)) requires us to
prepare a written statement, which
includes an assessment of anticipated
costs and benefits, before issuing ‘‘any
rule that includes any Federal mandate
that may result in the expenditure by
State, local, and tribal governments, in
the aggregate, or by the private sector, of
$100,000,000 or more (adjusted
annually for inflation) in any one year.’’
The current threshold after adjustment
for inflation is $154 million, using the
most current (2018) Implicit Price
Deflator for the Gross Domestic Product.
This final rule will not result in an
10061
expenditure in any year that meets or
exceeds this amount.
B. Summary of Costs and Benefits
This final rule codifies FDA’s
interpretation of the statutory term
‘‘protein’’ that the Agency previously
described in guidance (see 2015
Biosimilars Q&A Guidance). This final
rule does not codify the FDA’s
interpretation of the statutory term
‘‘chemically synthesized polypeptide’’
because section 605 of the FCA Act
removed the parenthetical ‘‘(except any
chemically synthesized polypeptide)’’
from the category of ‘‘protein’’ in the
definition of ‘‘biological product’’ in
section 351(i) of the PHS Act.
Formalizing this interpretation will
reduce regulatory uncertainty
introduced by the BPCI Act and section
605 of the FCA Act. Specifically, the
rule clarifies the criteria for whether
certain products will be regulated as
drugs or biological products. The
‘‘bright-line’’ approach under the rule
will reduce the amount of time spent by
FDA staff and industry in support of
making such determinations.
In this regulatory impact analysis, we
identify the products most likely to
require a case-by-case determination
under the baseline scenario. Under the
rule, these determinations will be made
by FDA according to the bright-line
standard outlined in the final rule. We
calculate the cost savings from the
amount of time saved by both the FDA
and industry by avoiding a case-by-case
determination. We also calculate the
incremental costs to industry that are
the result of reading and understanding
the rule.
The primary estimate of the benefits
in 2018 dollars annualized over 10 years
is $394,562 using a 7 percent discount
rate and $348,436 using a 3 percent
discount rate. We also calculate ranges
of benefits of $356,775 to $411,345 and
$316,116 to $362,792, respectively. The
estimated annualized costs range from
$13,511 to $16,889, with a primary
estimate of $15,012 using a 7 percent
discount rate over a 10-year horizon. For
a 3 percent discount rate, we estimate a
range of $12,471 to $15,589, with a
primary estimate of $13,857. These
figures are shown in table 1.
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TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF RULE
Units
Category
Benefits:
Annualized Monetized $/year .....
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estimate
$394,562
$348,436
Jkt 250001
Low
estimate
High
estimate
$356,775
$316,116
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$411,345
$362,792
Fmt 4700
Year dollars
2018
2018
Sfmt 4700
Discount
rate
Period
covered
7%
3
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10
21FER1
Notes
Cost savings to FDA and industry to
avoid case-by-case review of applications.
10062
Federal Register / Vol. 85, No. 35 / Friday, February 21, 2020 / Rules and Regulations
TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF RULE—Continued
Units
Category
Annualized Quantified ................
Qualitative.
Costs:
Annualized Monetized $/year .....
Annualized Quantified ................
Qualitative.
Transfers:
Federal Annualized Monetized $/
year.
Primary
estimate
Low
estimate
High
estimate
Year dollars
....................
....................
....................
....................
7
3
....................
$15,012
$13,857
....................
$13,511
$12,471
....................
$16,889
$15,589
....................
2018
2018
....................
7
3
7
3
10
10
....................
....................
....................
....................
7
3
....................
....................
....................
....................
From/To ......................................
Other Annualized Monetized $/
year.
From:
From/To ......................................
Discount
rate
Notes
Period
covered
Costs of reading the rule.
To:
From:
7
3
To:
Effects:
State, Local, or Tribal Government:.
Small Business:.
Wages:.
Growth:.
In line with E.O. 13771, in table 2 we
estimate present and annualized values
of costs and cost savings over an infinite
time horizon. With a 7 percent discount
rate, the estimated annualized net costsavings equal $170,903 in 2016 dollars
over an infinite horizon. Based on these
cost savings, this final rule is considered
a deregulatory action under E.O. 13771.
TABLE 2—E.O. 13771 SUMMARY
TABLE
[In 2016 dollars, over an infinite time horizon]
Primary
estimate
(7%)
VIII. Analysis of Environmental Impact
We have determined under 21 CFR
25.30(h) that this action is of a type that
does not individually or cumulatively
$2,533,439
($2,441,468) have a significant effect on the human
$6,438 environment. Therefore, neither an
$177,341 environmental assessment nor an
($170,903) environmental impact statement is
required.
C. Summary of Regulatory Flexibility
IX. Paperwork Reduction Act of 1995
Analysis
This final rule has an influence on
To determine the impact of the final
previously approved collections of
rule on small entities, we first
information found in FDA regulations.
determined how many firms would be
These collections of information are
affected. We estimate that at least 1,615
subject to review by the Office of
firms classified in the Pharmaceutical
Management and Budget (OMB) under
and Medicine Manufacturing industry
the Paperwork Reduction Act of 1995
employ fewer than 1,250 employees and (44 U.S.C. 3501–3521). The collections
are therefore also classified as small
of information in 21 CFR parts 601 and
businesses. Although a large number of
610 for submission of BLAs and general
small businesses will face costs under
biological standards have been
the final rule, the costs to these firms
approved under OMB control number
would be limited to the time burden of
0910–0338; the collections of
Present Value of Costs ........
Present Value of Cost Savings ....................................
Present Value of Net Costs ..
Annualized Costs ..................
Annualized Cost Savings .....
Annualized Net Costs ...........
khammond on DSKJM1Z7X2PROD with RULES
reading the final rule. We estimate that
the time burden of reading the rule
would be about $79 per firm, with a
lower bound of $71 and upper bound of
$89. This range of costs is unlikely to
have a significant adverse impact on a
substantial number of small entities. We
have developed a comprehensive
Economic Analysis of Impacts that
assesses the impacts of the final rule.
The full analysis of economic impacts is
available in the docket for this final rule
(Ref. 3) and at https://www.fda.gov/
AboutFDA/ReportsManualsForms/
Reports/EconomicAnalyses/default.htm.
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$91,971
Jkt 250001
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Fmt 4700
Sfmt 4700
information in 21 CFR 600.80 through
600.90 for reporting of adverse
experiences have been approved under
OMB control number 0910–0308; and
the collections of information in 21 CFR
201.56, 201.57, and 201.80 for labeling
requirements of biological products
have been approved under OMB control
number 0910–0572.
X. Federalism
We have analyzed this final rule in
accordance with the principles set forth
in E.O. 13132. We have determined that
the rule does not contain policies that
have substantial direct effects on the
States, on the relationship between the
National Government and the States, or
on the distribution of power and
responsibilities among the various
levels of government. Accordingly, we
conclude that the rule does not contain
policies that have federalism
implications as defined in the Executive
order and, consequently, a federalism
summary impact statement is not
required.
XI. Consultation and Coordination With
Indian Tribal Governments
We have analyzed this rule in
accordance with the principles set forth
in E.O. 13175. We have determined that
the rule does not contain policies that
have substantial direct effects on one or
more Indian Tribes, on the relationship
between the Federal Government and
Indian Tribes, or on the distribution of
power and responsibilities between the
Federal Government and Indian Tribes.
E:\FR\FM\21FER1.SGM
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Federal Register / Vol. 85, No. 35 / Friday, February 21, 2020 / Rules and Regulations
Accordingly, we conclude that the rule
does not contain policies that have
tribal implications as defined in the E.O.
and, consequently, a tribal summary
impact statement is not required.
XII. References
The following references marked with
an asterisk (*) are on display at the
Dockets Management Staff (see
ADDRESSES) and are available for
viewing by interested persons between
9 a.m. and 4 p.m., Monday through
Friday; they also are available
electronically at https://
www.regulations.gov. References
without asterisks are not on public
display at https://www.regulations.gov
because they have copyright restriction.
Some may be available at the website
address, if listed. References without
asterisks are available for viewing only
at the Dockets Management Staff. FDA
has verified the website addresses, as of
the date this document publishes in the
Federal Register, but websites are
subject to change over time.
Dated: February 18, 2020.
Stephen M. Hahn,
Commissioner of Food and Drugs.
[FR Doc. 2020–03505 Filed 2–20–20; 8:45 am]
1. Su, M., Y. Ling, J. Yu, et al. ‘‘Small
Proteins: Untapped Area of Potential
Biological Importance,’’ Frontiers in
Genetics, vol. 4, p.286, 2013.
2. Galindo, M. I., J. I. Pueyo, S. Foux, et
al.’’Peptides Encoded by Short ORFs Control
Development and Define a New Eukaryotic
Gene Family’’ PLoS Biology, vol. 5, p. e106,
2007.
3. *FDA, Regulatory Impact Analysis,
‘‘Definition of the Term ‘Biological Product,’’’
available at https://www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/Economic
Analyses/default.htm.
BILLING CODE 4164–01–P
List of Subjects in 21 CFR Part 600
SUMMARY:
Biologics, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 600 is
amended as follows:
PART 600—BIOLOGICAL PRODUCTS:
GENERAL
1. The authority citation for part 600
continues to read as follows:
■
Authority: 21 U.S.C. 321, 351, 352, 353,
355, 356c, 356e, 360, 360i, 371, 374, 379k–
1; 42 U.S.C. 216, 262, 263, 263a, 264.
2. Amend § 600.3 by revising
paragraph (h) introductory text and
adding paragraph (h)(6) to read as
follows:
■
khammond on DSKJM1Z7X2PROD with RULES
derivative, allergenic product, protein,
or analogous product, or arsphenamine
or derivative of arsphenamine (or any
other trivalent organic arsenic
compound), applicable to the
prevention, treatment, or cure of a
disease or condition of human beings.
*
*
*
*
*
(6) A protein is any alpha amino acid
polymer with a specific, defined
sequence that is greater than 40 amino
acids in size. When two or more amino
acid chains in an amino acid polymer
are associated with each other in a
manner that occurs in nature, the size of
the amino acid polymer for purposes of
this paragraph (h)(6) will be based on
the total number of amino acids in those
chains, and will not be limited to the
number of amino acids in a contiguous
sequence.
*
*
*
*
*
§ 600.3
Definitions.
*
*
*
*
*
(h) Biological product means a virus,
therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or
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Jkt 250001
DEPARTMENT OF THE TREASURY
Office of the Secretary of the Treasury
31 CFR Parts 27 and 50
Inflation Adjustment of Civil Monetary
Penalties
Departmental Offices Treasury.
Final rule.
AGENCY:
ACTION:
The Department of the
Treasury (‘‘Department’’ or ‘‘Treasury’’)
publishes this final rule to adjust its
civil monetary penalties (‘‘CMPs’’) for
inflation as mandated by the Federal
Civil Penalties Inflation Adjustment Act
of 1990, as amended by the Federal
Civil Penalties Inflation Adjustment Act
Improvements Act of 2015 (collectively
referred to herein as ‘‘the Act’’). This
rule adjusts CMPs within the
jurisdiction of two components of the
Department to the maximum amount
required by the Act.
DATES: The adjustments to the CMPs set
forth in 31 CFR part 27 and 31 CFR part
50 are effective February 21, 2020.
FOR FURTHER INFORMATION CONTACT: For
information regarding the Terrorism
Risk Insurance Program’s CMPs, contact
Richard Ifft, Senior Insurance
Regulatory Policy Analyst, Federal
Insurance Office, Room 1410 MT,
Department of the Treasury, 1500
Pennsylvania Avenue NW, Washington,
DC 20220, at (202) 622–2922 (not a tollfree number), or Lindsey Baldwin,
PO 00000
Frm 00029
Fmt 4700
Sfmt 4700
10063
Senior Policy Analyst, Federal
Insurance Office, at (202) 622–3220 (not
a toll free number). Persons who have
difficulty hearing or speaking may
access these numbers via TTY by calling
the toll-free Federal Relay Service at
(800) 877–8339.
For information regarding the
Treasury-wide CMP, contact Richard
Dodson, Senior Counsel, General Law,
Ethics, and Regulation, 202–622–9949.
SUPPLEMENTARY INFORMATION:
I. Background
In order to improve the effectiveness
of CMPs and to maintain their deterrent
effect, the Federal Civil Penalties
Inflation Adjustment Act of 1990, 28
U.S.C. 2461 note (‘‘the Inflation
Adjustment Act’’), as amended by the
Federal Civil Penalties Inflation
Adjustment Act Improvements Act of
2015 (Pub. L. 114–74) (‘‘the 2015 Act’’),
requires Federal agencies to adjust each
CMP provided by law within the
jurisdiction of the agency. The 2015 Act
requires agencies to adjust the level of
CMPs with an initial ‘‘catch-up’’
adjustment through an interim final
rulemaking and to make subsequent
annual adjustments for inflation,
without needing to provide notice and
the opportunity for public comment
required by 5 U.S.C. 553. The
Department’s initial catch-up
adjustment interim final rules were
published on December 7, 2016
(Departmental Offices) (81 FR 88600),
and for 31 CFR part 27, on February 11,
2019 (84 FR 3105). The Department’s
2018 annual adjustment was published
on March 19, 2018 (83 FR 11876), and
the Department’s 2019 annual
adjustment was published on April 17,
2019 (84 FR 15955). The 2015 Act
provides that any increase in a CMP
shall apply to CMPs that are assessed
after the date the increase takes effect,
regardless of whether the underlying
violation predated such increase.1
II. Method of Calculation
The method of calculating CMP
adjustments applied in this final rule is
required by the 2015 Act. Under the
2015 Act and the Office of Management
and Budget guidance required by the
2015 Act, annual inflation adjustments
subsequent to the initial catch-up
adjustment are to be based on the
percent change between the Consumer
Price Index for all Urban Consumers
(‘‘CPI–U’’) for the October preceding the
date of the adjustment and the prior
1 However, the increased CMPs apply only with
respect to underlying violations occurring after the
date of enactment of the 2015 Act, i.e., after
November 2, 2015.
E:\FR\FM\21FER1.SGM
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]]>Agencies
[Federal Register Volume 85, Number 35 (Friday, February 21, 2020)]
[Rules and Regulations]
[Pages 10057-10063]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-03505]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 600
[Docket No. FDA-2018-N-2732]
RIN 0910-AH57
Definition of the Term ``Biological Product''
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule to amend its regulation that defines ``biological
product'' to incorporate changes made by the Biologics Price
Competition and Innovation Act of 2009 (BPCI Act) and the Further
Consolidated Appropriations Act, 2020 (FCA Act), and to provide its
interpretation of the statutory term ``protein.'' Under this final
rule, the term protein means any alpha amino acid polymer with a
specific, defined sequence that is greater than 40 amino acids in size.
This final rule is intended to clarify the statutory framework under
which such products are regulated.
DATES: This rule is effective March 23, 2020.
ADDRESSES: For access to the docket to read background documents or
comments received, go to https://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Daniel Gottlieb, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6208, Silver Spring, MD 20993, 301-796-
6650, [email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
B. Summary of the Major Provisions of the Final Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. History of this Rulemaking
B. Summary of Comments on the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
A. Introduction
B. Specific Comments and FDA Response
VI. Effective Date
VII. Economic Analysis of Impacts
A. Introduction
B. Summary of Costs and Benefits
C. Summary of Regulatory Flexibility Analysis
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Final Rule
This final rule amends FDA's regulation that defines ``biological
product'' by making a technical revision and conforming to the
statutory definition enacted in the BPCI Act, as further amended by
section 605 of the FCA Act (Pub. L. 116-94). The BPCI Act amended the
definition of ``biological product'' in section 351(i) of the Public
Health Service Act (PHS Act) (42 U.S.C. 262(i)) to include a ``protein
(except any chemically synthesized polypeptide).'' After publication of
the proposed rule, section 605 of the FCA Act further amended the
definition of ``biological product'' in section 351(i) of the PHS Act
to remove the parenthetical ``(except any chemically synthesized
polypeptide)'' from the statutory category of ``protein.'' The final
rule makes conforming changes to Sec. 600.3 (21 CFR 600.3) to add
FDA's interpretation of the statutory term ``protein.''
B. Summary of the Major Provisions of the Final Rule
Under the final rule, the term protein means any alpha amino acid
polymer with a specific defined sequence that is greater than 40 amino
acids in size. This is consistent with the interpretation of this term
that FDA previously described in the notice of proposed rulemaking
published in the Federal Register on December 12, 2018 (83 FR 63817)
and in a final guidance document issued on April 30, 2015 (see 80 FR
24259 (announcing the availability of a guidance for industry entitled
``Biosimilars: Questions and Answers Regarding Implementation of the
Biologics Price Competition and Innovation Act of 2009,'' available at
https://www.regulations.gov (Docket No. FDA-2011-D-0611) (2015
Biosimilars Q&A Guidance); see also ``New and Revised Draft Q&As on
Biosimilar Development and the Biologics Price Competition and
Innovation Act (Revision 2)'' (December 2018; 83 FR 63898)).
C. Legal Authority
This final rule amends FDA's regulations to implement certain
aspects of the BPCI Act and the FCA Act. FDA's authority for this rule
derives from the biological product provisions in section 351 of the
PHS Act and the provisions of the Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 321, et seq.) applicable to drugs, as well as
section 701 of the FD&C Act (21 U.S.C. 371). The rule is necessary to
clarify the statutory authority under which biological products are
regulated, to prevent inconsistent regulation of such products, and for
the efficient enforcement of the FD&C Act.
D. Costs and Benefits
This final rule codifies FDA's interpretation of the statutory term
``protein'' in a manner that is consistent with the interpretation of
this term that FDA previously described in guidance (see 2015
Biosimilars Q&A Guidance) and the proposed rule. Formalizing this
interpretation will reduce regulatory uncertainty over whether certain
products are regulated as drugs or biological products. This reduced
uncertainty, under the ``bright-line'' approach described in the
proposed rule, will allow both FDA and private industry to avoid
spending time and resources on case-by-case determinations for each
product. The primary estimate of the benefits in 2018 dollars
annualized over 10 years is $394,562 using a 7 percent discount rate
and $348,436 using a 3 percent discount rate. We also calculate ranges
of benefits of $356,775 to $411,345 and $316,116 to $362,792,
respectively. The estimated annualized costs range from $13,511 to
$16,889, with a primary estimate of $15,012 using a 7 percent discount
rate over a 10-year horizon. For a 3 percent discount rate, we estimate
a range of $12,471 to $15,589, with a primary estimate of $13,857.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
[[Page 10058]]
------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
BPCI Act............................... Biologics Price Competition and
Innovation Act of 2009.
CFR.................................... Code of Federal Regulations.
EO..................................... Executive Order.
FCA Act................................ Further Consolidated
Appropriations Act, 2020.
FD&C Act............................... Federal Food, Drug, and
Cosmetic Act.
FDA.................................... U.S. Food and Drug
Administration.
PHS Act................................ Public Health Service Act.
U.S.................................... United States.
U.S.C.................................. United States Code.
------------------------------------------------------------------------
III. Background
A. History of This Rulemaking
The BPCI Act amended the definition of ``biological product'' in
section 351(i) of the PHS Act to include a ``protein (except any
chemically synthesized polypeptide).'' After publication of the
proposed rule, section 605 of the FCA Act further amended the
definition of ``biological product'' in section 351(i) of the PHS Act
to remove the parenthetical ``(except any chemically synthesized
polypeptide)'' from the statutory category of ``protein.'' As amended
by the BPCI Act and the FCA Act, a ``biological product'' is defined as
``a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, protein, or analogous
product, or arsphenamine or derivative of arsphenamine (or any other
trivalent organic arsenic compound), applicable to the prevention,
treatment, or cure of a disease or condition of human beings'' (see
section 351(i)(1) of the PHS Act).
The BPCI Act clarified the statutory authority under which certain
protein products are to be regulated. Although the majority of
therapeutic biological products have been licensed under section 351 of
the PHS Act, some protein products historically have been approved
under section 505 of the FD&C Act (21 U.S.C. 355). The BPCI Act
requires that a marketing application for a ``biological product''
(that previously would have been submitted under section 505 of the
FD&C Act) must be submitted under section 351 of the PHS Act, subject
to certain exceptions during a 10-year transition period ending on
March 23, 2020 (see section 7002(e)(1) through (3) and (e)(5) of the
BPCI Act). FDA is adding its interpretation of the term ``protein'' to
the regulations to clarify the statutory framework under which such
products are regulated.
The proposed rule includes a history of this rulemaking and cites
several scientific resources, including textbooks and dictionaries, to
illustrate the aspects of the meanings of the terms ``protein,''
``polypeptide,'' and ``peptide'' on which there is or is not scientific
consensus (see 83 FR 63817 at 63819-63820). As discussed in the
proposed rule, despite the lack of precise, agreed-upon definitions,
most, if not all, sources agree about certain aspects of the meanings
of these terms. First, all of the terms (``protein,'' ``polypeptide,''
and ``peptide'') refer to amino acid polymers (also referred to as
``amino acid chains'') made up of alpha amino acids that are linked by
peptide bonds. Second, ``protein'' refers to chains containing a
specific, defined sequence of amino acids, generally provided by a
corresponding DNA or RNA sequence. Finally, the term ``protein'' is
distinct from and excludes the term ``peptide'' (i.e., amino acid
chains that are generally shorter and simpler than a protein).
In the proposed rule, FDA described its proposed interpretation of
the statutory terms ``protein'' and ``chemically synthesized
polypeptide,'' which appeared in the definition of ``biological
product'' in section 351(i) of the PHS Act prior to the enactment of
the FCA Act. FDA is now finalizing its interpretation of the statutory
term ``protein'' without change. However, in light of the recently
enacted FCA Act, which removed the parenthetical exception for ``any
chemically synthesized polypeptide'' from the category of ``protein''
in the statutory definition of ``biological product,'' FDA is not
finalizing its interpretation of ``chemically synthesized polypeptide''
because it is no longer necessary.
B. Summary of Comments on the Proposed Rule
We received four comments on the proposed rule. Two of the comments
were general comments supporting FDA's proposed interpretations; one of
these comments specifically supports FDA's proposal because the
commenter stated that it enables insulin to be brought into the
regulatory pathway for biological products, including biosimilar and
interchangeable products. Two of the comments substantively addressed
specific aspects of the proposed interpretations of ``protein'' and
``chemically synthesized polypeptide.''
IV. Legal Authority
We are issuing this final rule under the biological product
provisions in section 351 of the PHS Act and the provisions of the FD&C
Act (21 U.S.C. 321, et seq.) applicable to drugs. See section 351(j) of
the PHS Act. Under these provisions, FDA has the authority to issue
regulations designed to ensure, among other things, that biological
products are safe, pure, and potent and are manufactured in accordance
with current good manufacturing practices. FDA also has general
authority to issue regulations for the efficient enforcement of the
FD&C Act and the PHS Act under section 701 of the FD&C Act and section
351(j) of the PHS Act.
V. Comments on the Proposed Rule and FDA Response
A. Introduction
We received four comments on the proposed rule by the close of the
comment period, two of which contained one or more substantive comments
on one or more issues. We received comments from trade organizations, a
patient advocacy group, and a State bar association.
We describe and respond to the comments in section B of this rule.
We have numbered each comment to help distinguish between different
comments. We have grouped similar comments together under the same
number, and in some cases, we have separated different issues discussed
in the same comment and designated them as distinct comments for
purposes of our responses. The number assigned to each comment or
comment topic is purely for organizational purposes and does not
signify the comment's value or importance or the order in which
comments were received.
B. Specific Comments and FDA Response
We proposed to amend Sec. 600.3(h) to revise the definition of
``biological product'' in Sec. 600.3(h) by replacing the phrase
``means any'' with the phrase
[[Page 10059]]
``means a'' to conform to the text of section 351(i)(1) of the PHS Act.
This proposed technical revision to the definition of ``biological
product'' was not intended to alter our interpretation of section
351(i) of the PHS Act. We also proposed to revise the definition of a
``biological product'' in Sec. 600.3(h) to include a ``protein (except
any chemically synthesized polypeptide).''
We received no comments regarding these proposed revisions.
However, after publication of the proposed rule, section 605 of the FCA
Act further amended the definition of ``biological product'' in section
351(i) of the PHS Act to remove the parenthetical ``(except any
chemically synthesized polypeptide)'' from the statutory category of
``protein.'' Therefore, we are finalizing these revisions to the
definition of ``biological product'' in Sec. 600.3(h) with the
following change: We are defining ``biological product'' in Sec.
600.3(h) to include a ``protein'' instead of defining ``biological
product'' in Sec. 600.3(h) to include a ``protein (except any
chemically synthesized polypeptide).''
We also proposed to amend Sec. 600.3(h) to add FDA's
interpretation of the statutory terms ``protein'' and ``chemically
synthesized polypeptide.'' We proposed to interpret the term
``protein'' to mean any alpha amino acid polymer with a specific,
defined sequence that is greater than 40 amino acids in size. We
proposed to interpret the term ``chemically synthesized polypeptide''
to mean any alpha amino acid polymer that is made entirely by chemical
synthesis and is greater than 40 amino acids but less than 100 amino
acids in size. We explained that when two or more amino acid chains in
an amino acid polymer are associated with each other in a manner that
occurs in nature, the size of the amino acid polymer for purposes of
our interpretations of the terms ``protein'' and ``chemically
synthesized polypeptide'' will be based on the total number of amino
acids in those chains, and will not be limited to the number of amino
acids in a contiguous sequence.
In the following paragraphs, we discuss comments on these proposed
interpretations. After considering these comments, we are finalizing
our interpretation of ``protein'' without change. We are not finalizing
our interpretation of ``chemically synthesized polypeptide'' as it is
no longer necessary because of the change to the statutory definition
of ``biological product.''
1. Scientific Support for Interpretations of ``Protein'' and
``Chemically Synthesized Polypeptide''
(Comment 1) One comment asserts that FDA's interpretations of the
statutory terms ``protein'' and ``chemically synthesized polypeptide''
do not reflect current science and maintains that there is more recent
evidence that amino acid polymers composed of 40 or fewer amino acids
are capable of assuming secondary and tertiary structural conformations
indicative of proteins. For these reasons, the commenter requested that
we revise and reissue the proposed rule.
(Response 1) We disagree with the comment's suggestion that FDA's
interpretation of the term ``protein'' as set forth in the proposed
rule and the textbooks we cited in the proposed rule no longer reflects
current science. The textbooks cited in the proposed rule have been in
use for decades and continue to be in use (e.g., in college
biochemistry classes). Moreover, the definitions and descriptions in
these textbooks and dictionaries illustrate the point that there is not
a scientific consensus on certain aspects of the definitions of the
terms ``peptide'' and ``protein,'' an observation that is not refuted
by more recent editions of these textbooks.
This lack of consensus is also reflected in several of the articles
cited by the comment. For example, the comment cites two articles to
support its claim of the existence of ``proteins'' composed of as few
as 11 amino acids. However, these two articles describe the 11-amino
acid polymer differently. One describes it as an 11-amino-acid
``protein'' (see Ref. 1) and the other describes it as an 11-amino-acid
``peptide'' (see Ref. 2).
Given the lack of a clear scientific consensus that FDA could
consider for adoption, the Agency is applying its scientific expertise
to interpret the statutory term ``protein'' in a manner that
establishes a scientifically reasonable, bright-line rule that provides
regulatory clarity and facilitates the implementation of the BPCI Act,
as further amended by the FCA Act. A clear rule facilitates efficient
use of time and resources by both FDA and applicants and reduces
regulatory uncertainty. In deciding where to draw this bright-line
rule, one of the factors that FDA considered is the number of amino
acids understood to be generally necessary for an amino acid polymer to
exhibit characteristics that are generally associated with
``proteins,'' lending a higher level of complexity to these products.
FDA considered whether to include structural or functional
attributes (e.g., folding, provides structural support to cellular
macrostructures, catalyzes a biochemical reaction, transports other
molecules, aids in the folding of other proteins) in its interpretation
of the term ``protein,'' but determined that this would not serve to
make the line between peptides and proteins any brighter. Among other
things, relying on a factor such as ``folding'' would not provide
regulatory certainty because it would raise questions about how much
folding is sufficient to differentiate between ``peptides'' and
``proteins,'' as many peptides can arguably be said to exhibit some
folding. Therefore, adopting this approach would not provide for a
bright-line rule and would result in regulatory uncertainty and
inefficiency.
(Comment 2) One comment asserts that ``proteins'' are a subset of
``polypeptides,'' yet FDA's interpretation of ``chemically synthesized
polypeptide'' presumes that ``polypeptides'' are a subset of
``proteins.''
(Response 2) With the FCA Act's removal of the parenthetical
exception for ``any chemically synthesized polypeptide'' from the
category of ``protein'' in the statutory definition of ``biological
product'' in section 351(i) of the PHS Act, all amino acid polymers
that meet FDA's interpretation of the term ``protein'' (including an
amino acid polymer that previously would have fallen within the term
``chemically synthesized polypeptide'' as interpreted by FDA) will be
considered to fall within the statutory definition of ``biological
product.''
(Comment 3) Two comments assert that the proposed interpretations
that we have chosen were not supported by a scientific consensus and
that there is a lack of scientific consensus for distinguishing between
``protein,'' ``polypeptide,'' and ``peptide'' based on a particular
number of amino acids.
(Response 3) While we agree that there may not be clear scientific
consensus for a particular number of amino acids to use when
distinguishing between the terms ``protein'' and ``peptide,'' there is
strong support in scientific literature for distinguishing between
types of amino acid polymers based on the number of amino acids they
contain. Specifically, the definitions cited in the preamble to the
proposed rule are clear that ``peptides'' are distinct from
``proteins'' and that the term ``peptide'' generally refers to smaller,
simpler chains of amino acids, while the term ``protein'' is used to
refer to longer, more complex chains (83 FR
[[Page 10060]]
63817 at 63819-63820). Moreover, there is scientific support for the
fact that amino acid polymers greater than 40 amino acids in size
exhibit at least some of the characteristics that are generally
associated with proteins (83 FR 63817 at 63820).
The removal of the parenthetical exception for ``any chemically
synthesized polypeptide'' from the category of ``protein'' in the
statutory definition of ``biological product'' has eliminated any need
to distinguish between these terms.
(Comment 4) One comment asserts that FDA's example of insulin does
not support the number of amino acids in FDA's interpretation of
``chemically synthesized polypeptide'' because insulin is composed of 2
polypeptide chain subunits, one containing 21 amino acids and the other
containing 30 amino acids.
(Response 4) We disagree with the comment because it confuses the
terms ``polypeptide'' and ``polypeptide chain.'' Even though the need
to avoid confusion between the terms ``polypeptide'' and ``polypeptide
chain'' has been eliminated by the removal of the parenthetical
exception for ``any chemically synthesized polypeptide'' from the
category of ``protein'' in the statutory definition of ``biological
product'' in section 351(i) of the PHS Act, we note in passing that our
interpretation of ``protein'' uses the phrase ``amino acid chain''
instead of the phrase ``polypeptide chain.'' In other words, instead of
describing the two subunits of the insulin protein as polypeptides or
polypeptide chains like the comment, we describe them as amino acid
chains. It therefore follows that insulin clearly is a ``protein'' as
interpreted in the final rule, because the total number of amino acids
exceeds 40. In particular, insulin is an alpha amino acid polymer with
a specific, defined sequence consisting of 2 amino acid chain subunits
with 21 amino acids and 30 amino acids, respectively. As these amino
acid chain subunits are associated with each other in a manner that
occurs in nature, we add the number of amino acids in each amino acid
chain together to determine whether insulin is an alpha amino acid
polymer with a specific, defined sequence that is greater than 40 amino
acids in size. Specifically, by adding together the number of amino
acids in each of the two amino acid chain subunits that comprise
insulin, we conclude that insulin is an alpha amino acid polymer with a
specific, defined sequence of 51 amino acids. Therefore, according to
the interpretation we are finalizing, insulin is a protein because it
is an alpha amino acid polymer with a specific, defined sequence that
is greater than 40 amino acids in size.
2. Alternate Proposals
(Comment 5) One comment requests that FDA adopt functional
definitions for ``protein'' and ``chemically synthesized polypeptides''
that are principally focused on the method of manufacture as well as
the conformation of the amino acid polymer rather than the size of the
amino acid polymer, reflecting the comment's view that the method of
manufacture, not size, should be the determining factor.
(Response 5) We are not finalizing our interpretation of the term
``chemically synthesized polypeptide'' because of the removal, by
section 605 of the FCA Act, of the parenthetical ``(except any
chemically synthesized polypeptide)'' from the category of ``protein''
in the statutory definition of ``biological product.'' Also, we do not
agree that we should adopt an interpretation of the statutory term
``protein'' that is principally focused on the method of manufacture
for the following reasons.
First, we disagree with the comment's premise that the statutory
definition of ``biological product,'' which included ``protein (except
any chemically synthesized polypeptide)'' prior to the enactment of the
FCA Act, was principally focused on the method of manufacture. We need
not address whether the fact that the earlier version of the statute
described the method of manufacture in the parenthetical clause
(excluding chemically synthesized polypeptides from the scope of the
term ``protein'') has any bearing on our current interpretation.
However, we note in passing that, according to basic rules of statutory
construction, if Congress wanted the term ``protein'' not to include
any ``chemically synthesized proteins,'' then it seems unlikely that
the statute would employ two different terms (``protein'' and
``polypeptide''). Accordingly, we had described the term
``polypeptide'' as it appeared in section 351(i) of the PHS Act prior
to the enactment of the FCA Act as referring to a subset of
``protein.''
Second, as noted in the response to Comment 1, FDA considered
whether to include structural or functional attributes in its
interpretation of the term ``protein,'' but determined that doing so
would not be appropriate as it would lead to regulatory uncertainty due
to the lack of a bright-line rule.
Third, adopting an interpretation that focused on the method of
manufacture could improperly incentivize product developers to choose a
suboptimal method of manufacturing a product that may be less efficient
and/or more costly, based on a perceived regulatory advantage under a
particular regulatory scheme.
It is FDA's view that the optimal policy for determining which
products are subject to regulation under the PHS Act is to apply a
bright-line rule that provides regulatory certainty. Thus, in order to
provide regulatory certainty and provide a bright-line interpretation
of the term ``protein,'' we are focusing on the number of amino acids
in the amino acid polymer (irrespective of the method of manufacture).
(Comment 6) One comment urges the Agency to abandon the proposed
case-by-case approach for determining whether a proposed product
composed of amino acid chains that are associated with each other in a
manner not found in nature constitutes a ``biological product.''
(Response 6) FDA is not persuaded by this comment because there are
a number of ways in which amino acid chains could be associated with
each other in a novel manner that is not found in naturally occurring
proteins and we cannot predict all of these iterations. Although some
of these combinations may result in amino acid polymers that exhibit
characteristics generally associated with proteins, some may not.
We recognize that the application of the fact-specific, case-by-
case analysis for proposed products composed of amino acid chains that
are associated with each other in a manner not found in nature does not
provide the same level of certainty that is provided by the other
criteria in Sec. 600.3(h)(6) (see 83 FR 63817 at 63821), but it
appears that case-by-case analysis is currently the best means of
addressing such cases. We encourage sponsors of these proposed products
to reach out to FDA early in their development program to discuss
issues related to product classification and the appropriate pathway
for a marketing application.
3. Relationship to Other Regulatory Provisions
(Comment 7) One comment asserts that FDA's proposed definitions are
inconsistent with Sec. 601.2(a)(4) and (c) (21 CFR 601.2(a)(4) and
(c)).
(Response 7) We disagree with the comment's assertion that our
proposed interpretations are inconsistent with our current regulations
in Sec. 601.2(a)(4) and (c). The comment appears to interpret Sec.
601.2(a)(4) and (c) to mean that if a product is a therapeutic
recombinant DNA-derived product, then, regardless of size, the product
is a biological product subject to licensure and should
[[Page 10061]]
be regulated in accordance with Sec. 601.2(c). However, that
conclusion seems to be based on a misreading of these provisions. We
interpret our regulation at Sec. 601.2(a)(4) and (c) to mean that if
the product meets the definition of ``biological product'' under Sec.
600.3(h), and also is a therapeutic recombinant DNA-derived product,
then the application would be regulated in accordance with Sec.
601.2(c).
(Comment 8) One comment requests that FDA propose a regulatory
definition of products that are ``analogous'' to a protein and
therefore are biological products.
(Response 8) We appreciate the comment. A definition of products
that are ``analogous'' to a ``protein'' for purposes of section
351(i)(1) of the PHS Act is outside the scope of this rulemaking. We
note, however, that it would not be appropriate for the statutory term
``analogous product'' to be interpreted in a way that would include
products that are specifically excluded by this final rule.
(Comment 9) One comment requests that FDA clarify its approach to
assessing the appropriate application type for combination products,
including peptide-protein combination products.
(Response 9) We appreciate the comment. The Agency's approach for
determining the appropriate type of marketing application for certain
combination products is outside the scope of this rulemaking. If a
sponsor is unsure of the appropriate marketing application for its
combination product containing a biological constituent part, we
encourage the sponsor to reach out to FDA at an appropriate time in its
development program to discuss issues related to product classification
and the appropriate pathway for a marketing application.
VI. Effective Date
This final rule will become effective March 23, 2020.
VII. Economic Analysis of Impacts
A. Introduction
We have examined the impacts of the final rule under Executive
Order (E.O.) 12866, E.O. 13563, E.O. 13771, the Regulatory Flexibility
Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995
(Pub. L. 104-4). E.O.s 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity).
E.O. 13771 requires that the costs associated with significant new
regulations ``shall, to the extent permitted by law, be offset by the
elimination of existing costs associated with at least two prior
regulations.'' This final rule is a significant regulatory action under
sec. 3(f) of E.O. 12866. Based on the cost savings summarized below and
discussed further in the regulatory impact analysis, this final rule is
considered a deregulatory action under E.O. 13771.
Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.),
the Office of Information and Regulatory Affairs designated this rule
as not a ``major rule,'' as defined by 5 U.S.C. 804(2).
The Regulatory Flexibility Act requires us to analyze regulatory
options that will minimize any significant impact of a rule on small
entities. Because this rule does not impose new regulatory burden on
small entities other than administrative costs of reading and
understanding the rule, we certify that the final rule will not have a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $154
million, using the most current (2018) Implicit Price Deflator for the
Gross Domestic Product. This final rule will not result in an
expenditure in any year that meets or exceeds this amount.
B. Summary of Costs and Benefits
This final rule codifies FDA's interpretation of the statutory term
``protein'' that the Agency previously described in guidance (see 2015
Biosimilars Q&A Guidance). This final rule does not codify the FDA's
interpretation of the statutory term ``chemically synthesized
polypeptide'' because section 605 of the FCA Act removed the
parenthetical ``(except any chemically synthesized polypeptide)'' from
the category of ``protein'' in the definition of ``biological product''
in section 351(i) of the PHS Act. Formalizing this interpretation will
reduce regulatory uncertainty introduced by the BPCI Act and section
605 of the FCA Act. Specifically, the rule clarifies the criteria for
whether certain products will be regulated as drugs or biological
products. The ``bright-line'' approach under the rule will reduce the
amount of time spent by FDA staff and industry in support of making
such determinations.
In this regulatory impact analysis, we identify the products most
likely to require a case-by-case determination under the baseline
scenario. Under the rule, these determinations will be made by FDA
according to the bright-line standard outlined in the final rule. We
calculate the cost savings from the amount of time saved by both the
FDA and industry by avoiding a case-by-case determination. We also
calculate the incremental costs to industry that are the result of
reading and understanding the rule.
The primary estimate of the benefits in 2018 dollars annualized
over 10 years is $394,562 using a 7 percent discount rate and $348,436
using a 3 percent discount rate. We also calculate ranges of benefits
of $356,775 to $411,345 and $316,116 to $362,792, respectively. The
estimated annualized costs range from $13,511 to $16,889, with a
primary estimate of $15,012 using a 7 percent discount rate over a 10-
year horizon. For a 3 percent discount rate, we estimate a range of
$12,471 to $15,589, with a primary estimate of $13,857. These figures
are shown in table 1.
Table 1--Summary of Benefits, Costs and Distributional Effects of Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary Low High ---------------------------------------
Category estimate estimate estimate Year Discount Period Notes
dollars rate covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $/year............ $394,562 $356,775 $411,345 2018 7% 10 Cost savings to FDA and
$348,436 $316,116 $362,792 2018 3 10 industry to avoid case-by-
case review of applications.
[[Page 10062]]
Annualized Quantified.................. ........... ........... ........... ........... 7 ........... .............................
3
Qualitative............................
Costs:
Annualized Monetized $/year............ $15,012 $13,511 $16,889 2018 7 10 Costs of reading the rule.
$13,857 $12,471 $15,589 2018 3 10
Annualized Quantified.................. ........... ........... ........... ........... 7
3
Qualitative............................
Transfers:
Federal Annualized Monetized $/year.... ........... ........... ........... ........... 7
3
------------------------------------------------------------------------------------------------------------
From/To................................ From:
To:
------------------------------------------------------------------------------------------------------------
Other Annualized Monetized $/year...... ........... ........... ........... ........... 7
3
------------------------------------------------------------------------------------------------------------
From/To................................ From:
To:
------------------------------------------------------------------------------------------------------------
Effects:
State, Local, or Tribal Government:....
Small Business:........................
Wages:.................................
Growth:................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
In line with E.O. 13771, in table 2 we estimate present and
annualized values of costs and cost savings over an infinite time
horizon. With a 7 percent discount rate, the estimated annualized net
cost-savings equal $170,903 in 2016 dollars over an infinite horizon.
Based on these cost savings, this final rule is considered a
deregulatory action under E.O. 13771.
Table 2--E.O. 13771 Summary Table
[In 2016 dollars, over an infinite time horizon]
------------------------------------------------------------------------
Primary
estimate (7%)
------------------------------------------------------------------------
Present Value of Costs.................................. $91,971
Present Value of Cost Savings........................... $2,533,439
Present Value of Net Costs.............................. ($2,441,468)
Annualized Costs........................................ $6,438
Annualized Cost Savings................................. $177,341
Annualized Net Costs.................................... ($170,903)
------------------------------------------------------------------------
C. Summary of Regulatory Flexibility Analysis
To determine the impact of the final rule on small entities, we
first determined how many firms would be affected. We estimate that at
least 1,615 firms classified in the Pharmaceutical and Medicine
Manufacturing industry employ fewer than 1,250 employees and are
therefore also classified as small businesses. Although a large number
of small businesses will face costs under the final rule, the costs to
these firms would be limited to the time burden of reading the final
rule. We estimate that the time burden of reading the rule would be
about $79 per firm, with a lower bound of $71 and upper bound of $89.
This range of costs is unlikely to have a significant adverse impact on
a substantial number of small entities. We have developed a
comprehensive Economic Analysis of Impacts that assesses the impacts of
the final rule. The full analysis of economic impacts is available in
the docket for this final rule (Ref. 3) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
This final rule has an influence on previously approved collections
of information found in FDA regulations. These collections of
information are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3521). The collections of information in 21 CFR parts 601 and 610 for
submission of BLAs and general biological standards have been approved
under OMB control number 0910-0338; the collections of information in
21 CFR 600.80 through 600.90 for reporting of adverse experiences have
been approved under OMB control number 0910-0308; and the collections
of information in 21 CFR 201.56, 201.57, and 201.80 for labeling
requirements of biological products have been approved under OMB
control number 0910-0572.
X. Federalism
We have analyzed this final rule in accordance with the principles
set forth in E.O. 13132. We have determined that the rule does not
contain policies that have substantial direct effects on the States, on
the relationship between the National Government and the States, or on
the distribution of power and responsibilities among the various levels
of government. Accordingly, we conclude that the rule does not contain
policies that have federalism implications as defined in the Executive
order and, consequently, a federalism summary impact statement is not
required.
XI. Consultation and Coordination With Indian Tribal Governments
We have analyzed this rule in accordance with the principles set
forth in E.O. 13175. We have determined that the rule does not contain
policies that have substantial direct effects on one or more Indian
Tribes, on the relationship between the Federal Government and Indian
Tribes, or on the distribution of power and responsibilities between
the Federal Government and Indian Tribes.
[[Page 10063]]
Accordingly, we conclude that the rule does not contain policies that
have tribal implications as defined in the E.O. and, consequently, a
tribal summary impact statement is not required.
XII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
1. Su, M., Y. Ling, J. Yu, et al. ``Small Proteins: Untapped
Area of Potential Biological Importance,'' Frontiers in Genetics,
vol. 4, p.286, 2013.
2. Galindo, M. I., J. I. Pueyo, S. Foux, et al.''Peptides
Encoded by Short ORFs Control Development and Define a New
Eukaryotic Gene Family'' PLoS Biology, vol. 5, p. e106, 2007.
3. *FDA, Regulatory Impact Analysis, ``Definition of the Term
`Biological Product,''' available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
List of Subjects in 21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
600 is amended as follows:
PART 600--BIOLOGICAL PRODUCTS: GENERAL
0
1. The authority citation for part 600 continues to read as follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356c, 356e, 360,
360i, 371, 374, 379k-1; 42 U.S.C. 216, 262, 263, 263a, 264.
0
2. Amend Sec. 600.3 by revising paragraph (h) introductory text and
adding paragraph (h)(6) to read as follows:
Sec. 600.3 Definitions.
* * * * *
(h) Biological product means a virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood component or derivative, allergenic
product, protein, or analogous product, or arsphenamine or derivative
of arsphenamine (or any other trivalent organic arsenic compound),
applicable to the prevention, treatment, or cure of a disease or
condition of human beings.
* * * * *
(6) A protein is any alpha amino acid polymer with a specific,
defined sequence that is greater than 40 amino acids in size. When two
or more amino acid chains in an amino acid polymer are associated with
each other in a manner that occurs in nature, the size of the amino
acid polymer for purposes of this paragraph (h)(6) will be based on the
total number of amino acids in those chains, and will not be limited to
the number of amino acids in a contiguous sequence.
* * * * *
Dated: February 18, 2020.
Stephen M. Hahn,
Commissioner of Food and Drugs.
[FR Doc. 2020-03505 Filed 2-20-20; 8:45 am]
BILLING CODE 4164-01-P
