[Federal Register Volume 80, Number 127 (Thursday, July 2, 2015)]
[Rules and Regulations]
[Pages 37971-37974]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-16366]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 601, 610, and 680
[Docket No. FDA-2014-N-1110]
Revocation of General Safety Test Regulations That Are
Duplicative of Requirements in Biologics License Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
biologics regulations by removing the general safety test (GST)
requirements for biological products. FDA is finalizing this action
because the existing codified GST regulations are duplicative of
requirements that are also specified in biologics license applications
(BLAs), or are no longer necessary or appropriate to help ensure the
safety, purity, and potency of licensed biological products. FDA is
taking this action as part of its retrospective review of its
regulations to promote improvement and innovation, in response to the
Executive order.
DATES: This rule is effective August 3, 2015.
FOR FURTHER INFORMATION CONTACT: Lori J. Churchyard, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911.
SUPPLEMENTARY INFORMATION:
Executive Summary
Purpose and Coverage of the Final Rule
The final rule removes the codified GST \1\ regulations for
biological products which will update outdated requirements and
accommodate new and evolving technology and testing capabilities
without diminishing public health protections. FDA is finalizing
[[Page 37972]]
this action because the existing codified GST regulations are
duplicative of requirements that are also specified in BLAs, or are no
longer necessary or appropriate to help ensure the safety, purity, and
potency of licensed biological products. FDA is taking this action as
part of its retrospective review of its regulations to promote
improvement and innovation, in response to Executive Order (E.O.) 13563
of January 18, 2011.
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\1\ For purposes of this final rule, the terms ``general safety
test'' or ``GST'' refer to the requirements found under Title 21 of
the Code of Federal Regulations (CFR), subchapter F, parts 600
through 680 (21 CFR parts 600 through 680), specifically 21 CFR
610.11, 610.11a, and 680.3(b).
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Summary of the Major Provisions of the Final Rule
The final rule removes the requirements contained in Sec. Sec.
610.11, 610.11a, and 680.3(b) (21 CFR 610.11, 610.11a, and 680.3(b))
from the regulations. Section 610.11 requires a GST for the detection
of extraneous toxic contaminants in certain biological products
intended for administration to humans. Section 610.11a concerns the GST
requirements for inactivated influenza vaccine. Section 680.3(b)
concerns GST requirements for allergenic products. Removal of these
regulations, however, would not remove GST requirements specified in
individual BLAs. A biological product manufacturer would continue to be
required to follow the GST requirements specified in its BLA unless the
manufacturer advised FDA of its elimination or modification of the test
by a submission filed in accordance with Sec. 601.12 (21 CFR 601.12).
FDA would review proposed changes to a manufacturer's approved
biologics license on a case-by-case basis so that FDA can ensure that
any such action is appropriate.
Costs and Benefits
FDA is finalizing this action because the existing codified GST
regulations are duplicative of requirements that are also specified in
BLAs, or are no longer necessary or appropriate to help ensure the
safety, purity, and potency of licensed biological products. Because
this final rule would impose no additional regulatory burdens, this
rule is not anticipated to result in any compliance costs and the
economic impact is expected to be minimal.
I. Background
As part of FDA's retrospective review of its regulations to promote
improvement and innovation under Executive Order 13563, FDA is removing
the codified GST requirements as specified in this rule. We believe
this action is appropriate because in many instances, the GST
regulations duplicate requirements that are also specified in the BLA
requirements for biological products intended for human use under
section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262),
or they are outmoded or otherwise unnecessary to help ensure the
continued safety, purity, and potency of biological products. FDA
published the proposed rule ``Revocation of General Safety Test
Regulations That Are Duplicative of Requirements in Biological License
Applications'' in the Federal Register of August 22, 2014 (79 FR
49727). FDA corrected the title of that proposed rule to ``Revocation
of General Safety Test Regulations That Are Duplicative of Requirements
in Biologics License Applications'' in the Federal Register of
September 10, 2014 (79 FR 53670).
For a number of years, FDA has not codified specific test methods
as standards for licensed biological products, in part because
codifying specific test methods as standards can diminish the ability
of the Agency and industry to respond to technological developments.
Instead the Agency has required manufacturers to provide a full
description of manufacturing methods, including test methods, in
manufacturers' BLAs (Sec. 601.2(a) (21 CFR 601.2(a))). Since FDA
issued the March 2003 final rule ``Revision to the General Safety
Requirements for Biological Products'' in the Federal Register of March
4, 2003 (68 FR 10157), it has become increasingly clear that the
codified GST regulations are too restrictive for certain biological
products because alternatives may be available which provide the same
or greater level of assurance of safety as the GST. Thus, the Agency
believes that the GST regulations may not always reflect the scientific
community's assessment of the best current testing procedures, although
in certain circumstances the GST may still be appropriate. The Agency
believes that a more efficient way of prescribing testing requirements
for particular products would be to allow such requirements to be
specified in the BLA, which will enhance flexibility to make
appropriate changes to testing methods.
II. Summary of the Final Rule
FDA is adopting as final, without material change, the proposed
revocation of general safety test requirements that are duplicative of
requirements in BLAs.
The final rule is removing Sec. Sec. 610.11, 610.11a, and
680.3(b), the regulations that require that manufacturers of biological
products perform a specified test for general safety of biological
products. FDA is taking this action because the existing codified GST
regulations are duplicative, outmoded, or are otherwise unnecessary to
help ensure the continued safety, purity, and potency of licensed
biological products.
As set forth in an approved BLA or BLA supplement, for
products that present specific safety concerns, manufacturers will be
required to perform appropriate safety test(s) to address those
concerns. For example, the BLA may require testing for a specific
toxicity.
The appropriate tests will be specified in the
manufacturer's BLA or BLA supplement rather than codified as
regulations.
Elimination of the codified GST regulations would
encourage the implementation of the principles of the ``3Rs,'' to
reduce, refine, and replace animal use in testing. This addresses the
need to minimize the use of animals in such testing and promotes more
humane, appropriate and specific test methods for assuring the safety
of biological products.\2\
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\2\ Interagency Coordinating Committee on the Validation of
Alternative Methods (ICCVAM) Authorization Act of 2000 (42 U.S.C.
285l-3). Additional information on the Federal Government's
implementation of the principles of the 3Rs may be found at the
ICCVAM Web site at http://ntp.niehs.nih.gov/go/iccvam.
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The finalization of this rule does not automatically
revise a manufacturer's BLA or BLA supplement.
Manufacturers would continue to be required to perform the
GST unless the manufacturer's BLA were revised through a supplement to
eliminate or modify the test in accordance with Sec. 601.12.
The requirements for a licensed biological product
manufacturer to report changes in its product, product labeling,
production process, quality controls, equipment, facilities or
responsible personnel, as established in its approved BLA, are detailed
in Sec. 601.12.
Under Sec. 601.12, manufacturers must report each change
to the Agency in one of several different types of submissions. The
applicable submission category depends on the potential for the
change(s) at issue to have an adverse effect on the identity, strength,
quality, purity, or potency of the particular biological product as it
may relate to the safety or effectiveness of the product.
FDA anticipates that changes involving the discontinuance
of the GST or the reliance on a test other than the GST would have a
moderate potential to have an adverse effect on the identity, strength,
quality, purity, or potency of the product as it may relate to the
safety
[[Page 37973]]
or effectiveness of the product. Such changes must be identified in a
supplement submitted under Sec. 601.12(c) (changes requiring
supplement submission at least 30 days prior to distribution of the
product made using the change).
III. Legal Authority
FDA is issuing this regulation under the biological products and
communicable disease provisions of the PHS Act (42 U.S.C. 262 and 264),
and the provisions of the Federal Food, Drug, and Cosmetic Act (the
FD&C Act) (21 U.S.C. 321 et seq.) applicable to drugs. Under these
provisions of the PHS Act and the FD&C Act, we have the authority to
issue and enforce regulations designed to ensure, among other things,
that biological products are safe, pure, and potent and manufactured in
accordance with current Good Manufacturing Practice, and to prevent the
introduction, transmission, or spread of communicable disease.
IV. Comments on the Proposed Rule and FDA Response
The Agency received two letters of comments on the proposed rule.
Comments were received from a trade association, and an animal welfare
organization.
To make it easier to identify the comments and our responses, the
word ``Comment'' and a comment number appear in parentheses before each
comment's description, and the word ``Response'' in parentheses
precedes each response. We have also numbered each comment to help
distinguish between different comments. The number assigned to each
comment is purely for organizational purposes and does not signify the
comment's value or importance or the order in which it was received.
Certain comments were grouped together because the subject matter of
the comments was similar.
A. General Comments
(Comment 1) Both letters of comments support the proposed rule.
(Response) FDA acknowledges and appreciates that the comments we
received agree with the need for this rulemaking. As stated previously,
the rule removes the requirements contained in Sec. Sec. 610.11,
610.11a, and 680.3(b) from the regulations because the existing
codified GST regulations are duplicative of requirements that are also
specified in BLAs, or are no longer necessary or appropriate to help
ensure the safety, purity, and potency of licensed biological products.
Removal of these regulations provides a more efficient way of
prescribing testing requirements and enhances flexibility to make
appropriate changes to testing methods.
B. Comments on Specific Topics
(Comment 2) One comment requests that FDA encourage manufacturers
who have a GST described in their BLAs for their licensed products to
submit supplements to their BLAs to eliminate or modify the test and
that FDA take additional steps to ensure that the final rule will have
the intended effect of eliminating the use of animals in safety
testing.
(Response) As stated in the preamble of the proposed rule (79 FR
49727 at 49729), we anticipate that the elimination of the codified GST
regulations will encourage the implementation of the principles of the
``3Rs,'' to reduce, refine, and replace animal use in testing.
Moreover, on our own initiative, as discussed elsewhere in this
document, we have determined that the effective date of the final rule
will be 30 days after the date of its publication in the Federal
Register to give manufacturers the flexibility to submit supplements to
their BLAs for their licensed products as soon as possible.
(Comment 3) One comment requests that we add language to Sec.
601.2 or other relevant biologics regulation to clarify our intent to
encourage the implementation of the principles of the 3Rs.
(Response) FDA declines to adopt this recommended change because
the request to add language to Sec. 601.2 or other relevant biologics
regulations is outside the scope of this rulemaking.
(Comment 4) One comment requests that FDA establish user fees with
respect to the continued use of the GST after the effective date of
this final rule, or that FDA establish other clear policies that will
provide economic incentives to discontinue the use of the GST. Further,
the comment refers to Executive Order 13563, which encourages Federal
Agencies to ``. . . assess available alternatives to direct regulation,
including providing economic incentives to encourage the desired
behavior, such as user fees . . . .''
(Response) We decline to adopt these suggested changes because they
are beyond the scope of this rule. The proposed rule did not address
user fees or economic incentives. This rule allows, but does not
require, current BLA holders to submit to FDA supplements to their BLAs
to eliminate or modify the GST.
(Comment 5) One comment states that a manufacturer who submits a
supplement to eliminate or modify a GST in its BLA will not be able to
stop conducting the GST until FDA determines that the manufacturer has
appropriately reported this change.
(Response) We disagree in part. As stated in the preamble to the
proposed rule (79 FR 49727 at 49730), a manufacturer who desires to
discontinue the GST in its approved BLA or utilize an alternative
method other than the GST approved in its BLA must submit a BLA
supplement reporting the change in accordance with Sec. 601.12. Should
a manufacturer wish to discontinue the GST described in the approved
BLA, or to utilize an alternative method other than the GST approved in
its BLA, FDA anticipates that the change would have a moderate
potential to have an adverse effect on the identity, strength, quality,
purity, or potency of the product as it may relate to the safety or
effectiveness of the product. Accordingly, a manufacturer who desires
to make such a change must submit a BLA supplement reporting the change
in accordance with Sec. 601.12(c). Within 30 days of the date FDA
receives the submission, FDA will determine if the change has been
reported in the proper category and if any of the required information
is missing, and will inform the applicant accordingly. If FDA does not
so notify the applicant, distribution of the product made using the
change may begin not less than 30 days after receipt of the supplement
by FDA.
V. Conforming Amendments
As part of this final rule, we need to make conforming changes when
the removed provisions are referenced elsewhere in the CFR. The final
rule removes ``Sec. 610.11'' from Sec. 601.2(c)(1) and 21 CFR 601.22.
VI. Effective Date
We are making this rule effective 30 days after the date of
publication in the Federal Register. We are making this change in the
interest of reducing unnecessary regulatory burden to give
manufacturers the flexibility to submit supplements right away, should
they wish to do so.
VII. Economic Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select
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regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Agency believes that
this final rule is not a significant regulatory action as defined under
Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this final rule generally increases
flexibility for safety testing and would result in the reduction of
certain regulatory burdens and does not add any new regulatory
responsibilities, the Agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``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 $144 million, using the most current (2014) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
This final rule amends the biologics regulations by removing the
GST requirements for biological products found in Sec. Sec. 610.11,
610.11a and 680.3(b). FDA is finalizing this action because the current
codified GST regulations are duplicative of requirements that are also
specified in biologics licenses, or are no longer necessary or
appropriate to help ensure the safety, purity, and potency of licensed
biological products. The removal of the GST regulations for biological
products, however, would not remove GST requirements specified in
individual BLAs. All manufacturers that currently conduct a GST are
already required, as part of the standards specified in their BLAs, to
perform the GST and would thus continue to be required to perform the
GST unless the BLA were revised to eliminate or modify the test through
a supplement in accordance with Sec. 601.12. Because this rule would
impose no additional regulatory burdens, this regulation is not
anticipated to result in any compliance costs and the economic impact
is expected to be minimal.
VIII. The Paperwork Reduction Act of 1995
This final rule refers to previously approved collections of
information that are subject to review by the Office of Management and
Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C.
3501-3520). The collections of information in Sec. 601.12 have been
approved under OMB control number 0910-0338. Therefore, FDA tentatively
concludes that the requirements in this document are not subject to
review by OMB because they do not constitute a ``new collection of
information'' under the PRA.
IX. Environmental Impact
The Agency has 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.
X. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that would 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, the Agency has concluded
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.
List of Subjects
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 680
Biologics, Blood, Reporting and recordkeeping requirements.
Therefore under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 601, 610, and 680 are
amended as follows:
PART 601--LICENSING
0
1. The authority citation for 21 CFR part 601 continues to read as
follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note).
Sec. 601.2 [Amended]
0
2. Section 601.2 is amended in paragraph (c)(1) by removing
``610.11,''.
Sec. 601.22 [Amended]
0
3. Section 601.22 is amended in the third sentence by removing
``610.11,''.
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
0
4. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,
264.
Sec. 610.11 [Removed and Reserved]
0
5. Remove and reserve Sec. 610.11.
Sec. 610.11a [Removed and Reserved]
0
6. Remove and reserve Sec. 610.11a.
PART 680--ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS
0
7. The authority citation for 21 CFR part 680 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
Sec. 680.3 [Amended]
0
8. In Sec. 680.3, remove and reserve paragraph (b).
Dated: June 26, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-16366 Filed 7-1-15; 8:45 am]
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