
[Federal Register Volume 77, Number 101 (Thursday, May 24, 2012)]
[Notices]
[Pages 31019-31022]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-12591]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-1029]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; General Licensing 
Provisions; Section 351(k) Biosimilar Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by June 
25, 2012.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
Fax: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All 
comments should be identified with the OMB control number 0910-New and 
title ``General Licensing Provisions; Section 351(k) Biosimilar 
Applications''. Also include the FDA 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., 
PI50-400B, Rockville, MD 20850, 301-796-7651, 
juanmanuel.vilela@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

General Licensing Provisions; Section 351(k) Biosimilar Applications--
(OMB Control Number 0910--New)

    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,

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sets forth the requirements for an application for a proposed 
biosimilar product and an application or 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) of the PHS Act.) 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 health 
care 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 
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 
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 in 
this document 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

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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 announced 
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.
    In the Federal Register of February 15, 2012 (77 FR 8880), FDA 
published a 60-day notice requesting comments on the information 
collection for the requirements for an application for a proposed 
biosimilar product and an application or a supplement for a proposed 
interchangeable product. In the Federal Register of February 23, 2012 
(77 FR 10752), FDA published a correction to the 60-day notice 
providing the correct docket number to submit comments. FDA received no 
comments that pertained to the information collection analysis.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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                                                     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
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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
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.



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    Dated: May 17, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-12591 Filed 5-23-12; 8:45 am]
BILLING CODE 4160-01-P


