
[Federal Register Volume 80, Number 126 (Wednesday, July 1, 2015)]
[Notices]
[Pages 37635-37637]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-16128]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0129]


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 July 
31, 2015.

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 0910-0719. 
Also include the FDA docket number found in brackets in the heading of 
this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, 8455 Colesville Rd., COLE-14526, Silver 
Spring, MD 20993-0002, PRAStaff@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 0910-0719--Extension

    The Patient Protection and Affordable Care Act (Affordable Care 
Act) (Pub. L. 111-148) 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 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.)
    In estimating the information collection burden for 351(k) 
applications, we reviewed the number of 351(k) applications FDA has 
received through fiscal year (FY) 2014, as well as the collection of 
information regarding the general licensing provisions for biologics 
license applications under section 351(a) of the PHS Act submitted 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, are 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.
    To submit an application seeking licensure of a proposed biosimilar 
product under section 351(k)(2)(A)(i) and (k)(2)(A)(iii) of the PHS 
Act, 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

[[Page 37636]]

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 as complex and 
technically demanding as a proposed 351(a) application. FDA may 
determine, in its discretion, 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 information collection 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; and
     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 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 section 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 section 351(l)(6)(C)(i).
    In the Federal Register of February 3, 2015 (80 FR 5761), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. FDA received three comments.
    (Comment) One comment requested FDA provide clarity and 
interpretation regarding the standards for interchangeability (sections 
351(k)(2)(B) and (k)(4) of the PHS Act). The comment also sought 
clarification regarding the timelines and the chosen mode of 
communication for FDA to convey to the stakeholders any details on an 
unnecessary element under a 351(k) application.
    (Response) FDA expects to issue a draft guidance, ``Considerations 
in Demonstrating Interchangeability to a Reference Product,'' in 2015. 
FDA issued a draft guidance, ``Formal Meetings Between the FDA and 
Biosimilar Biological Product Sponsors or Applicants,'' in 2013, which 
provides recommendations to industry on formal meetings between FDA and 
biosimilar biological product sponsors or applicants.
    (Comment) Another comment requested FDA provide clarity on the 
factors for consideration in assessing whether a proposed biosimilar is 
highly similar to a reference product to support a demonstration of 
biosimilarity--specifically, which product quality attributes are 
considered critical to match (and how much difference is allowed).
    (Response) FDA issued the final guidance, ``Quality Considerations 
in Demonstrating Biosimilarity of a Therapeutic Protein Product to a 
Reference Product,'' in April 2015. This final guidance provides 
further clarification on factors for consideration in assessing whether 
products are highly similar, including expression system, manufacturing 
process, impurities, reference product, and reference standards.
    (Comment) A third comment supported approval and post-market 
policies that would allow healthcare practitioners to make informative 
decisions when treating patients.
    (Response) FDA issued the final guidance, ``Scientific 
Considerations in Demonstrating Biosimilarity to a Reference Product,'' 
in April 2015. This guidance discusses a stepwise approach to 
demonstrating biosimilarity, the totality-of-the-evidence approach that 
FDA will use to review applications for biosimilar products, as well as 
general scientific principles in conducting comparative structural and 
functional analyses, animal testing, and clinical studies (including 
human pharmacokinetic and pharmacodynamic studies, clinical 
immunogenicity assessment, and comparative clinical studies). The 
guidance also provides information on postmarketing safety monitoring 
considerations.
    The comment also requested FDA consider adding as part of a 
biosimilar or interchangeable product's labeling instruction guidance 
on third party substitution of biosimilars without the knowledge of the 
healthcare provider. As noted by the comment, these issues

[[Page 37637]]

are also subject to state laws and regulations. Under the BPCI Act, a 
biological product that has been approved as an ``interchangeable'' may 
be substituted for the reference product without the intervention of 
the health care provider who prescribed the reference product.
    Based on the number of 351(k) applications FDA received through FY 
2014, we estimate that we will receive approximately five 351(k) 
applications annually. The number of respondents submitting 351(k) 
applications is based on the number of sponsors submitting 351(k) 
applications through FY 2014. In making these estimates, 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.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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                                                     Number of
 351(k) Applications (42 U.S.C.      Number of     responses per   Total annual   Average burden    Total hours
             262(k))                respondents     respondent       responses     per response
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351(k)(2)(A)(i) and                            5               1               5             860           4,300
 351(k)(2)(A)(iii) Biosimilar
 Product Applications...........
351(k)(2)(B) and (k)(4)                        2               1               2             860           1,720
 Interchangeable Product
 Applications or Supplements....
351(l)(6)(C) Patent Infringement               5               1               5               2              10
 Notifications..................
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    Total.......................  ..............  ..............  ..............  ..............           6,030
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


    Dated: June 25, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-16128 Filed 6-30-15; 8:45 am]
BILLING CODE 4164-01-P


