Agency Information Collection Activities; Proposed Collection; Comment Request; General Licensing Provisions; Section 351(k) Biosimilar Applications, 8880-8883 [2012-3548]
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Federal Register / Vol. 77, No. 31 / Wednesday, February 15, 2012 / Notices
the special control for the automated
blood cell separator device operating on
a filtration separation principle
intended for the routine collection of
blood and blood components
reclassified as class II (§ 864.9245 (21
CFR 864.9245)).
For currently marketed products not
approved under the premarket approval
process, the manufacturer should file
with FDA for 3 consecutive years an
annual report on the anniversary date of
the device reclassification from class III
to class II or, on the anniversary date of
the 510(k) of the Federal Food, Drug,
and Cosmetic Act (the FD&C Act) (21
U.S.C. 360) clearance. Any subsequent
change to the device requiring the
submission of a premarket notification
in accordance with section 510(k) of the
FD&C Act should be included in the
annual report. Also, a manufacturer of a
device determined to be substantially
equivalent to the centrifugal or
filtration-based automated cell separator
device intended for the routine
collection of blood and blood
components, should comply with the
same general and special controls.
The annual report should include, at
a minimum, a summary of anticipated
and unanticipated adverse events that
have occurred and that are not required
to be reported by manufacturers under
Medical Device Reporting (MDR) (part
803 (21 CFR part 803)). The reporting of
adverse device events summarized in an
annual report will alert FDA to trends
or clusters of events that might be a
safety issue otherwise unreported under
the MDR regulation.
Reclassification of this device from
class III to class II for the intended use
of routine collection of blood and blood
components relieves manufacturers of
the burden of complying with the
premarket approval requirements of
section 515 of the FD&C Act (21 U.S.C.
360e), and may permit small potential
competitors to enter the marketplace by
reducing the burden. Although the
special control guidance recommends
that manufacturers of these devices file
with FDA an annual report for 3
consecutive years, this would be less
burdensome than the current
postapproval requirements under part
814, subpart E (21 CFR part 814, subpart
E), including the submission of periodic
reports under § 814.84.
Collecting or transfusing facilities,
and manufacturers have certain
responsibilities under the Federal
regulations. For example, collecting or
transfusing facilities are required to
maintain records of any reports of
complaints of adverse reactions (21 CFR
606.170), while the manufacturer is
responsible for conducting an
investigation of each event that is
reasonably known to the manufacturer
and evaluating the cause of the event
(§ 803.50(b)). In addition, manufacturers
of medical devices are required to
submit to FDA individual adverse event
reports of death, serious injury, and
malfunctions (§ 803.50).
In the special control guidance
document, FDA recommends that
manufacturers include in their three
annual reports a summary of adverse
reactions maintained by the collecting
or transfusing facility or similar reports
of adverse events collected in addition
to those required under the MDR
regulation. The MedWatch medical
device reporting code instructions
(https://www.fda.gov/cdrh/mdr/
373.html) contains a comprehensive list
of adverse events associated with device
use, including most of those events that
we recommend summarizing in the
annual report.
FDA estimates the burden of this
collection of information as follows:
TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1
Reporting activity
Number of
respondents
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Annual Report .....................................................................................
4
1
4
5
1 There
20
are no capital costs or operating and maintenance costs associated with this collection of information.
Based on FDA records, there are
approximately four manufactures of
automated blood cell separator devices.
We estimate that the manufacturers will
spend approximately 5 hours preparing
and submitting the annual report.
Other burden hours required for
§ 864.9245 are reported and approved
under OMB control number 0910–0120
(premarket notification submission
501(k), 21 CFR part 807, subpart E), and
OMB control number 0910–0437 (MDR,
21 CFR part 803).
Dated: February 9, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012–3551 Filed 2–14–12; 8:45 am]
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Total
hours
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2012–N–1029]
Agency Information Collection
Activities; Proposed Collection;
Comment Request; General Licensing
Provisions; Section 351(k) Biosimilar
Applications
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing an
opportunity for public comment on the
proposed collection of certain
information by the Agency. Under the
Paperwork Reduction Act of 1995 (the
PRA), Federal Agencies are required to
publish notice in the concerning each
proposed collection of information, and
to allow 60 days for public comment in
response to the notice. This notice
SUMMARY:
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solicits comments on the information
collection for the requirements for an
application for a proposed biosimilar
product and an application for a
supplement for a proposed
interchangeable product.
Submit either electronic or
written comments on the collection of
information by April 16, 2012.
DATES:
Submit electronic
comments on the collection of
information to https://
www.regulations.gov. Submit written
comments on the collection of
information to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane., Rm.
1061, Rockville, MD 20852. All
comments should be identified with the
docket number found in brackets in the
heading of this document.
ADDRESSES:
FOR FURTHER INFORMATION CONTACT:
Juanmanuel Vilela, Office of
Information Management, Food and
Drug Administration, 1350 Piccard Dr.,
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PI50–400B, Rockville, MD 20850, 301–
796–7651.
SUPPLEMENTARY INFORMATION: Under the
PRA (44 U.S.C. 3501–3520), Federal
Agencies must obtain approval from the
Office of Management and Budget
(OMB) for each collection of
information they conduct or sponsor.
‘‘Collection of information’’ is defined
in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests
or requirements that members of the
public submit reports, keep records, or
provide information to a third party.
Section 3506(c)(2)(A) of the PRA (44
U.S.C. 3506(c)(2)(A)) requires Federal
Agencies to provide a 60-day notice in
the Federal Register concerning each
proposed collection of information
before submitting the collection to OMB
for approval. To comply with this
requirement, FDA is publishing notice
of the proposed collection of
information set forth in this document.
With respect to the following
collection of information, FDA invites
comments on these topics: (1) Whether
the proposed collection of information
is necessary for the proper performance
of FDA’s functions, including whether
the information will have practical
utility; (2) the accuracy of FDA’s
estimate of the burden of the proposed
collection of information, including the
validity of the methodology and
assumptions used; (3) ways to enhance
the quality, utility, and clarity of the
information to be collected; and (4)
ways to minimize the burden of the
collection of information on
respondents, including through the use
of automated collection techniques,
when appropriate, and other forms of
information technology.
General Licensing Provisions; Section
351(K) Biosimilar Applications
On March 23, 2010, the President
signed into law the Patient Protection
and Affordable Care Act (Affordable
Care Act) (Pub. L. 111–148). The
Affordable Care Act contains a subtitle
called the Biologics Price Competition
and Innovation Act of 2009 (BPCI Act)
which amends the Public Health Service
Act (PHS Act) and establishes an
abbreviated licensure pathway for
biological products shown to be
biosimilar to, or interchangeable with,
an FDA-licensed biological reference
product. (See sections 7001 through
7003 of the Affordable Care Act.)
Section 351(k) of the PHS Act (42
U.S.C. 262(k)), added by the BPCI Act,
sets forth the requirements for an
application for a proposed biosimilar
product and an application for a
supplement for a proposed
interchangeable product. Section 351(k)
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defines biosimilarity to mean ‘‘that the
biological product is highly similar to
the reference product notwithstanding
minor differences in clinically inactive
components’’ and that ‘‘there are no
clinically meaningful differences
between the biological product and the
reference product in terms of the safety,
purity, and potency of the product’’.
(See section 351(i)(2) of the PHS Act.) A
351(k) application must contain, among
other things, information demonstrating
that the biological product is biosimilar
to a reference product based upon data
derived from analytical studies, animal
studies, and clinical studies, unless
FDA determines, in its discretion, that
certain studies are unnecessary in a
351(k) application. (See section
351(k)(2).) To demonstrate
interchangeability, an applicant must
provide sufficient information to
demonstrate biosimilarity, and that the
biosimilar biological product can be
expected to produce the same clinical
result as the reference product in any
given patient and, if the biosimilar
biological product is administered more
than once to an individual, the risk in
terms of safety or diminished efficacy of
alternating or switching between the use
of the biosimilar biological product and
the reference product is not greater than
the risk of using the reference product
without such alternation or switch. (See
section 351(k)(4) of the PHS Act.)
Interchangeable products may be
substituted for the reference product
without the intervention of the
prescribing healthcare provider. (See
section 351(i)(3) of the PHS Act.) This
Federal Register information collection
document begins the process of
requesting public comment and
obtaining OMB approval for the
information collection regarding the
burden on the submission of a 351(k)
application not otherwise covered by
existing OMB approvals.
In estimating the information
collection burden for 351(k)
applications, FDA has reviewed the
collection of information regarding the
general licensing provisions for
biologics license applications (BLAs)
under section 351(a) of the PHS Act to
OMB (approved under OMB control
number 0910–0338). For the
information collection burden for 351(a)
applications, FDA described § 601.2(a)
(21 CFR 601.2(a)) as requiring a
manufacturer of a biological product to
submit an application on forms
prescribed for such purpose with
accompanying data and information
including certain labeling information
to FDA for approval to market a product
in interstate commerce. FDA also added
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in the burden estimate the container and
package labeling requirements provided
under §§ 610.60 through 610.65 (21 CFR
610.60 through 610.65). The estimated
hours per response for § 601.2, and
§§ 610.60 through 610.65, were 860
hours.
In addition, in submitting a 351(a)
application, an applicant completes the
Form FDA 356h ‘‘Application to Market
a New Drug, Biologic, or an Antibiotic
Drug for Human Use.’’ The application
form serves primarily as a checklist for
firms to gather and submit certain
information to FDA. The checklist helps
to ensure that the application is
complete and contains all the necessary
information, so that delays due to lack
of information may be eliminated. The
form provides key information to FDA
for efficient handling and distribution to
the appropriate staff for review. The
estimated burden hours for biological
product submissions using FDA Form
356h are included under the applicable
requirements approved under OMB
control number 0910–0338.
FDA intends for an applicant to
submit a 351(k) application following
Form FDA 356h, modifying the
information submitted to support the
information required under section
351(k) of the BPCI Act. To submit an
application seeking licensure of a
proposed biosimilar product under
section 351(k)(2)(A)(i) and (k)(2)(A)(iii),
FDA believes that the estimated burden
hours would be approximately the same
as noted under OMB control number
0910–0338 for a 351(a) application—860
hours. The burden estimates for seeking
licensure of a proposed biosimilar
product that meets the standards for
interchangeability under section
351(k)(2)(B) and (k)(4) would also be
860 hours. Until we gain more
experience with biosimilar applications,
FDA believes this estimate is
appropriate for 351(k) applications
because to determine biosimilarity or
interchangeability of a proposed 351(k)
product, the application and the
information submitted is expected to be
comparably complex and technically
demanding as a proposed 351(a)
application. FDA may determine, in its
discretion, that an element required
under a 351(k) application to be
unnecessary to support licensure of a
biosimilar or interchangeable product.
In those cases, the number of hours per
response may be less than the hours
estimated.
A summary of the collection of
information requirements in the
submission of a 351(k) application as
described under the BPCI Act follows:
Section 351(k)(2)(A)(i) requires
manufactures of 351(k) products to
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submit an application for FDA review
and licensure before marketing a
biosimilar product. An application
submitted under this section shall
include information demonstrating that:
• The biological product is biosimilar
to a reference product based upon data
derived from analytical studies, animal
studies (including toxicity) and a
clinical study or studies (including
immunogenicity and pharmacokinetics
or pharmacodynamics). The Secretary of
Health and Human Services (the
Secretary) may determine that any of
these elements is unnecessary.
• The biological product and
reference product utilize the same
mechanism or mechanisms of action for
the condition or conditions of use
prescribed, recommended, or suggested
in the proposed labeling, but only to the
extent the mechanism or mechanisms of
action are known for the reference
product.
• The condition or conditions of use
prescribed, recommended, or suggested
in the labeling proposed for the
biological product have been previously
approved for the reference product.
• The route of administration, the
dosage form, and the strength of the
biological product are the same as those
of the reference product.
• The facility in which the biological
product is manufactured, processed,
packed, or held meets standards
designed to assure that the biological
product continues to be safe, pure, and
potent.
Section 351(k)(2)(A)(iii) requires the
application to include publiclyavailable information regarding the
Secretary’s previous determination that
the reference product is safe, pure, and
potent. The application may include
any additional information in support of
the application, including publiclyavailable information with respect to the
reference product or another biological
product.
Under section 351(k)(2)(B) and (k)(4),
a manufacturer may include information
demonstrating that the biological
product meets the standards for
interchangeability either in the
application described above to show
biosimilarity, or in a supplement to
such an application. The information
submitted to meet the standard for
interchangeability must show that: (1)
The biological product is biosimilar to
the reference product and can be
expected to produce the same clinical
result as the reference product in any
given patient and (2) for a biological
product that is administered more than
once to an individual, the risk in terms
of safety or diminished efficacy of
alternating or switching between use of
the biological product and the reference
product is not greater than the risk of
using the reference product without
such alternation or switch.
In addition to the collection of
information regarding the submission of
a 351(k) application for a proposed
biosimilar or interchangeable biological
product, section 351(l) of the BPCI Act
establishes procedures for identifying
and resolving patent disputes involving
applications submitted under section
351(k) of the PHS Act. The burden
estimates for the patent provisions
under section 351(l)(6)(C) of the BPCI
Act are included in table 1 of this
document and are based on the
estimated number of 351(k) biosimilar
respondents. Based on similar reporting
requirements, FDA estimates this
notification will take 2 hours. A
summary of the collection of
information requirements under
351(l)(6)(C) follows:
Not later than 30 days after a
complaint from the reference product
sponsor is served to a 351(k) applicant
in an action for patent infringement
described under 351(l)(6), section
351(l)(6)(C) requires that the 351(k)
applicant provide the Secretary with
notice and a copy of such complaint.
The Secretary shall publish in the
Federal Register notice any complaint
received under 351(l)(6)(C)(i).
FDA has not received any 351(k)
applications to date. Under table 1 of
this document, the estimated number of
respondents submitting 351(k)
applications is based on the estimated
annual number of manufacturers that
would submit the required information
to FDA and the estimated annual
number of 351(k) submissions FDA
would receive. In making this estimate,
FDA has taken into account, among
other things, the expiration dates of
patents that relate to potential reference
products, and general market interest in
biological products that could be
candidates for 351(k) applications.
On November 2 and 3, 2010, FDA
held a public hearing and established a
public docket to obtain input on specific
issues and challenges associated with
the implementation of the BPCI Act.
(See Docket No. FDA–2010–N–0477.)
Based in part on this input, FDA is
announcing elsewhere in this issue of
the Federal Register, the availability of
three draft guidances describing FDA’s
current interpretation of certain
statutory requirements added by the
BPCI Act as well as quality and
analytical issues, demonstrating
biosimilarity, and implementation
policy issues. These draft guidances are:
‘‘Biosimilars: Questions and Answers
Regarding Implementation of the
Biologics Price Competition and
Innovation Act of 2009,’’ ‘‘Quality
Considerations in Demonstrating
Biosimilarity to a Reference Protein
Product,’’ and ‘‘Scientific
Considerations in Demonstrating
Biosimilarity to a Reference Product.’’
The Federal Register documents for
these guidances reference this Federal
Register information collection
document regarding the burden on the
submission of a 351(k) application not
otherwise covered by existing OMB
approvals. In addition, we note that the
draft guidance on ‘‘Scientific
Considerations in Demonstrating
Biosimilarity to a Reference Product’’
recommends that labeling for a product
subject to approval under section 351(k)
include statements that indicate that: (1)
The product is approved as biosimilar to
a reference product for stated
indication(s) and (2) the product (has or
has not) been determined to be
interchangeable with the reference
product. FDA has determined, under 5
CFR 1320.3(c)(2)), that these labeling
recommendations are not ‘‘collections of
information’’ for the purposes of the
PRA because the statements will
comprise solely information that FDA
will supply to the applicant for the
purpose of disclosing it to the public,
i.e. FDA’s determination upon review of
the application submitted under section
351(k), that the product is biosimilar
and/or interchangeable to its reference
product.
FDA estimates the burden of this
collection of information as follows:
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
351(k) Application for biosimilars (42 U.S.C. 262(k))
351(k)(2)(A)(i) and (k)(2)(A)(iii) ............................................
351(k)(2)(B) and (k)(4) .........................................................
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Number of
responses per
respondent
Number of
respondents
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2
1
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Average
burden per
response
Total annual
responses
1
1
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860
860
Total hours
1720
860
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TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued
351(k) Application for biosimilars (42 U.S.C. 262(k))
351(l)(6)(C) ...........................................................................
1 There
[FR Doc. 2012–3548 Filed 2–14–12; 8:45 am]
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2011–D–0605]
Draft Guidance for Industry on
Scientific Considerations in
Demonstrating Biosimilarity to a
Reference Product; Availability
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing the
availability of a draft guidance for
industry entitled ‘‘Scientific
Considerations in Demonstrating
Biosimilarity to a Reference Product.’’
This draft guidance is intended to assist
sponsors in demonstrating that a
proposed therapeutic protein product is
biosimilar to a reference product for the
purpose of submitting a marketing
application through an abbreviated
licensure pathway. This draft guidance
gives an overview of FDA’s approach to
determining biosimilarity.
DATES: Although you can comment on
any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the Agency
considers your comment on this draft
guidance before it begins work on the
final version of the guidance, submit
either electronic or written comments
on the draft guidance by April 16, 2012.
ADDRESSES: Submit written requests for
single copies of the draft guidance to the
Division of Drug Information, Center for
Drug Evaluation and Research, Food
and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2201,
Silver Spring, MD 20993–0002; or the
Office of Communication, Outreach and
Development (HFM–40), Center for
Biologics Evaluation and Research,
Food and Drug Administration, 1401
Rockville Pike, Suite 200N, Rockville,
MD 20852–1448. Send one selfaddressed adhesive label to assist that
SUMMARY:
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2
Average
burden per
response
Total annual
responses
1
2
Total hours
2
4
are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: February 9, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
AGENCY:
Number of
responses per
respondent
Number of
respondents
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office in processing your requests. See
the SUPPLEMENTARY INFORMATION section
for electronic access to the draft
guidance document.
Submit electronic comments on the
draft guidance to https://
www.regulations.gov. Submit written
comments to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Sandra Benton, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6340,
Silver Spring, MD 20993–0002, 301–
796–1042; or Stephen Ripley, Center for
Biologics Evaluation and Research
(HFM–17), Food and Drug
Administration, 1401 Rockville Pike,
Suite 200N, Rockville, MD 20852–1448,
301–827–6210.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of
a draft guidance for industry entitled
‘‘Scientific Considerations in
Demonstrating Biosimilarity to a
Reference Product.’’ This draft guidance
is intended to assist sponsors in
demonstrating that a proposed
therapeutic protein product is
‘‘biosimilar’’ 1 to a reference product for
the purpose of submitting a marketing
application through the abbreviated
licensure pathway under section 351(k)
of the Public Health Service Act (PHS
Act) (42 U.S.C. 262(k)).
The Biologics Price Competition and
Innovation Act of 2009, enacted as part
of the Affordable Care Act (Pub. L. 111–
148) on March 23, 2010, created an
abbreviated licensure pathway under
section 351(k) of the PHS Act for
biological products demonstrated to be
biosimilar to, or interchangeable with, a
reference product. Under this
1 In section 7002(b)(3) of the Patient Protection
and Affordable Care Act (Affordable Care Act),
Public Law 111–148, ‘‘biosimilar’’ or
‘‘biosimilarity’’ means ‘‘that the biological product
is highly similar to the reference product
notwithstanding minor differences in clinically
inactive components,’’ and that ‘‘there are no
clinically meaningful differences between the
biological product and the reference product in
terms of the safety, purity, and potency of the
product.’’
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abbreviated licensure pathway, FDA
will license a proposed biological
product submitted under section 351(k)
of the PHS Act if FDA ‘‘determines that
the information submitted in the
application * * * is sufficient to show
that the biological product is biosimilar
to the reference product * * *’’ and the
351(k) applicant (or other appropriate
person) consents to an inspection of the
facility that is the subject of the
application (i.e., a facility in which the
proposed biological product is
manufactured, processed, packed, or
held).2 The draft guidance gives an
overview of FDA’s approach to
determining biosimilarity. FDA intends
to consider the totality of the evidence
submitted in a 351(k) application and is
recommending that sponsors use a
stepwise approach in their development
of biosimilar products. The draft
guidance discusses important scientific
considerations in demonstrating
biosimilarity, including:
• A stepwise approach to
demonstrating biosimilarity, which can
include a comparison of the proposed
therapeutic protein product and the
reference product with respect to
structure, function, animal toxicity,
human pharmacokinetics and
pharmacodynamics, clinical
immunogenicity, and clinical safety and
effectiveness;
• The totality-of-the-evidence
approach that FDA will use to review
applications for biosimilar products;
and
• General scientific principles in
conducting comparative structural and
functional analysis, animal testing,
human pharmacokinetics and
pharmacodynamics studies, clinical
immunogenicity assessment, and
clinical safety and effectiveness studies
(including clinical study design issues).
This draft guidance is being issued
consistent with FDA’s good guidance
practices regulation (21 CFR 10.115).
The draft guidance, when finalized, will
represent the Agency’s current thinking
on scientific considerations in
demonstrating biosimilarity to a
reference product. It does not create or
confer any rights for or on any person
2 Section 7002(a)(2) of the Affordable Care Act,
adding section 351(k)(3) of the PHS Act (citing
section 351(a)(2)(C) of the PHS Act).
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]]>Agencies
[Federal Register Volume 77, Number 31 (Wednesday, February 15, 2012)]
[Notices]
[Pages 8880-8883]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-3548]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-N-1029]
Agency Information Collection Activities; Proposed Collection;
Comment Request; General Licensing Provisions; Section 351(k)
Biosimilar Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the Agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal Agencies are required to publish notice in the
concerning each proposed collection of information, and to allow 60
days for public comment in response to the notice. This notice solicits
comments on the information collection for the requirements for an
application for a proposed biosimilar product and an application for a
supplement for a proposed interchangeable product.
DATES: Submit either electronic or written comments on the collection
of information by April 16, 2012.
ADDRESSES: Submit electronic comments on the collection of information
to https://www.regulations.gov. Submit written comments on the
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane., Rm. 1061,
Rockville, MD 20852. All comments should be identified with the docket
number found in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Juanmanuel Vilela, Office of
Information Management, Food and Drug Administration, 1350 Piccard Dr.,
[[Page 8881]]
PI50-400B, Rockville, MD 20850, 301-796-7651.
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
Agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal Agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information before
submitting the collection to OMB for approval. To comply with this
requirement, FDA is publishing notice of the proposed collection of
information set forth in this document.
With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
General Licensing Provisions; Section 351(K) Biosimilar Applications
On March 23, 2010, the President signed into law the Patient
Protection and Affordable Care Act (Affordable Care Act) (Pub. L. 111-
148). The Affordable Care Act contains a subtitle called the Biologics
Price Competition and Innovation Act of 2009 (BPCI Act) which amends
the Public Health Service Act (PHS Act) and establishes an abbreviated
licensure pathway for biological products shown to be biosimilar to, or
interchangeable with, an FDA-licensed biological reference product.
(See sections 7001 through 7003 of the Affordable Care Act.)
Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI
Act, sets forth the requirements for an application for a proposed
biosimilar product and an application for a supplement for a proposed
interchangeable product. Section 351(k) defines biosimilarity to mean
``that the biological product is highly similar to the reference
product notwithstanding minor differences in clinically inactive
components'' and that ``there are no clinically meaningful differences
between the biological product and the reference product in terms of
the safety, purity, and potency of the product''. (See section
351(i)(2) of the PHS Act.) A 351(k) application must contain, among
other things, information demonstrating that the biological product is
biosimilar to a reference product based upon data derived from
analytical studies, animal studies, and clinical studies, unless FDA
determines, in its discretion, that certain studies are unnecessary in
a 351(k) application. (See section 351(k)(2).) To demonstrate
interchangeability, an applicant must provide sufficient information to
demonstrate biosimilarity, and that the biosimilar biological product
can be expected to produce the same clinical result as the reference
product in any given patient and, if the biosimilar biological product
is administered more than once to an individual, the risk in terms of
safety or diminished efficacy of alternating or switching between the
use of the biosimilar biological product and the reference product is
not greater than the risk of using the reference product without such
alternation or switch. (See section 351(k)(4) of the PHS Act.)
Interchangeable products may be substituted for the reference product
without the intervention of the prescribing healthcare provider. (See
section 351(i)(3) of the PHS Act.) This Federal Register information
collection document begins the process of requesting public comment and
obtaining OMB approval for the information collection regarding the
burden on the submission of a 351(k) application not otherwise covered
by existing OMB approvals.
In estimating the information collection burden for 351(k)
applications, FDA has reviewed the collection of information regarding
the general licensing provisions for biologics license applications
(BLAs) under section 351(a) of the PHS Act to OMB (approved under OMB
control number 0910-0338). For the information collection burden for
351(a) applications, FDA described Sec. 601.2(a) (21 CFR 601.2(a)) as
requiring a manufacturer of a biological product to submit an
application on forms prescribed for such purpose with accompanying data
and information including certain labeling information to FDA for
approval to market a product in interstate commerce. FDA also added in
the burden estimate the container and package labeling requirements
provided under Sec. Sec. 610.60 through 610.65 (21 CFR 610.60 through
610.65). The estimated hours per response for Sec. 601.2, and
Sec. Sec. 610.60 through 610.65, were 860 hours.
In addition, in submitting a 351(a) application, an applicant
completes the Form FDA 356h ``Application to Market a New Drug,
Biologic, or an Antibiotic Drug for Human Use.'' The application form
serves primarily as a checklist for firms to gather and submit certain
information to FDA. The checklist helps to ensure that the application
is complete and contains all the necessary information, so that delays
due to lack of information may be eliminated. The form provides key
information to FDA for efficient handling and distribution to the
appropriate staff for review. The estimated burden hours for biological
product submissions using FDA Form 356h are included under the
applicable requirements approved under OMB control number 0910-0338.
FDA intends for an applicant to submit a 351(k) application
following Form FDA 356h, modifying the information submitted to support
the information required under section 351(k) of the BPCI Act. To
submit an application seeking licensure of a proposed biosimilar
product under section 351(k)(2)(A)(i) and (k)(2)(A)(iii), FDA believes
that the estimated burden hours would be approximately the same as
noted under OMB control number 0910-0338 for a 351(a) application--860
hours. The burden estimates for seeking licensure of a proposed
biosimilar product that meets the standards for interchangeability
under section 351(k)(2)(B) and (k)(4) would also be 860 hours. Until we
gain more experience with biosimilar applications, FDA believes this
estimate is appropriate for 351(k) applications because to determine
biosimilarity or interchangeability of a proposed 351(k) product, the
application and the information submitted is expected to be comparably
complex and technically demanding as a proposed 351(a) application. FDA
may determine, in its discretion, that an element required under a
351(k) application to be unnecessary to support licensure of a
biosimilar or interchangeable product. In those cases, the number of
hours per response may be less than the hours estimated.
A summary of the collection of information requirements in the
submission of a 351(k) application as described under the BPCI Act
follows:
Section 351(k)(2)(A)(i) requires manufactures of 351(k) products to
[[Page 8882]]
submit an application for FDA review and licensure before marketing a
biosimilar product. An application submitted under this section shall
include information demonstrating that:
The biological product is biosimilar to a reference
product based upon data derived from analytical studies, animal studies
(including toxicity) and a clinical study or studies (including
immunogenicity and pharmacokinetics or pharmacodynamics). The Secretary
of Health and Human Services (the Secretary) may determine that any of
these elements is unnecessary.
The biological product and reference product utilize the
same mechanism or mechanisms of action for the condition or conditions
of use prescribed, recommended, or suggested in the proposed labeling,
but only to the extent the mechanism or mechanisms of action are known
for the reference product.
The condition or conditions of use prescribed,
recommended, or suggested in the labeling proposed for the biological
product have been previously approved for the reference product.
The route of administration, the dosage form, and the
strength of the biological product are the same as those of the
reference product.
The facility in which the biological product is
manufactured, processed, packed, or held meets standards designed to
assure that the biological product continues to be safe, pure, and
potent.
Section 351(k)(2)(A)(iii) requires the application to include
publicly-available information regarding the Secretary's previous
determination that the reference product is safe, pure, and potent. The
application may include any additional information in support of the
application, including publicly-available information with respect to
the reference product or another biological product.
Under section 351(k)(2)(B) and (k)(4), a manufacturer may include
information demonstrating that the biological product meets the
standards for interchangeability either in the application described
above to show biosimilarity, or in a supplement to such an application.
The information submitted to meet the standard for interchangeability
must show that: (1) The biological product is biosimilar to the
reference product and can be expected to produce the same clinical
result as the reference product in any given patient and (2) for a
biological product that is administered more than once to an
individual, the risk in terms of safety or diminished efficacy of
alternating or switching between use of the biological product and the
reference product is not greater than the risk of using the reference
product without such alternation or switch.
In addition to the collection of information regarding the
submission of a 351(k) application for a proposed biosimilar or
interchangeable biological product, section 351(l) of the BPCI Act
establishes procedures for identifying and resolving patent disputes
involving applications submitted under section 351(k) of the PHS Act.
The burden estimates for the patent provisions under section
351(l)(6)(C) of the BPCI Act are included in table 1 of this document
and are based on the estimated number of 351(k) biosimilar respondents.
Based on similar reporting requirements, FDA estimates this
notification will take 2 hours. A summary of the collection of
information requirements under 351(l)(6)(C) follows:
Not later than 30 days after a complaint from the reference product
sponsor is served to a 351(k) applicant in an action for patent
infringement described under 351(l)(6), section 351(l)(6)(C) requires
that the 351(k) applicant provide the Secretary with notice and a copy
of such complaint. The Secretary shall publish in the Federal Register
notice any complaint received under 351(l)(6)(C)(i).
FDA has not received any 351(k) applications to date. Under table 1
of this document, the estimated number of respondents submitting 351(k)
applications is based on the estimated annual number of manufacturers
that would submit the required information to FDA and the estimated
annual number of 351(k) submissions FDA would receive. In making this
estimate, FDA has taken into account, among other things, the
expiration dates of patents that relate to potential reference
products, and general market interest in biological products that could
be candidates for 351(k) applications.
On November 2 and 3, 2010, FDA held a public hearing and
established a public docket to obtain input on specific issues and
challenges associated with the implementation of the BPCI Act. (See
Docket No. FDA-2010-N-0477.) Based in part on this input, FDA is
announcing elsewhere in this issue of the Federal Register, the
availability of three draft guidances describing FDA's current
interpretation of certain statutory requirements added by the BPCI Act
as well as quality and analytical issues, demonstrating biosimilarity,
and implementation policy issues. These draft guidances are:
``Biosimilars: Questions and Answers Regarding Implementation of the
Biologics Price Competition and Innovation Act of 2009,'' ``Quality
Considerations in Demonstrating Biosimilarity to a Reference Protein
Product,'' and ``Scientific Considerations in Demonstrating
Biosimilarity to a Reference Product.'' The Federal Register documents
for these guidances reference this Federal Register information
collection document regarding the burden on the submission of a 351(k)
application not otherwise covered by existing OMB approvals. In
addition, we note that the draft guidance on ``Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product''
recommends that labeling for a product subject to approval under
section 351(k) include statements that indicate that: (1) The product
is approved as biosimilar to a reference product for stated
indication(s) and (2) the product (has or has not) been determined to
be interchangeable with the reference product. FDA has determined,
under 5 CFR 1320.3(c)(2)), that these labeling recommendations are not
``collections of information'' for the purposes of the PRA because the
statements will comprise solely information that FDA will supply to the
applicant for the purpose of disclosing it to the public, i.e. FDA's
determination upon review of the application submitted under section
351(k), that the product is biosimilar and/or interchangeable to its
reference product.
FDA estimates the burden of this collection of information as
follows:
Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
351(k) Application for Number of responses per Total annual burden per Total hours
biosimilars (42 U.S.C. 262(k)) respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
351(k)(2)(A)(i) and 2 1 2 860 1720
(k)(2)(A)(iii).................
351(k)(2)(B) and (k)(4)......... 1 1 1 860 860
[[Page 8883]]
351(l)(6)(C).................... 2 1 2 2 4
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Dated: February 9, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-3548 Filed 2-14-12; 8:45 am]
BILLING CODE 4160-01-P
