[Federal Register Volume 75, Number 192 (Tuesday, October 5, 2010)]
[Notices]
[Pages 61497-61501]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-24853]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

 [Docket No. FDA-2010-N-0477]


Approval Pathway for Biosimilar and Interchangeable Biological 
Products; Public Hearing; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public hearing; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a 2-day 
public hearing to obtain input on specific issues and challenges 
associated with the implementation of the Biologics Price Competition 
and Innovation Act of 2009 (BPCI Act). The BPCI Act establishes an 
abbreviated approval pathway for biological products that are 
demonstrated to be ``highly similar'' (biosimilar) to, or 
``interchangeable'' with, an FDA-licensed biological product. The 
purpose of this public hearing is to create a forum for interested 
stakeholders to provide input regarding the agency's implementation of 
the statute. FDA will take the information it obtains from the public 
hearing into account in its implementation of the BPCI Act.

DATES: The public hearing will be held November 2 and 3, 2010, from 
8:30 a.m. to 4:30 p.m. Individuals who wish to present at the public 
hearing must register on or before October 11, 2010. Section III of 
this document provides attendance and registration information. 
Electronic or written comments will be accepted after the public 
hearing until December 31, 2010.

ADDRESSES: The public hearing will be held at FDA's White Oak Campus, 
10903 New Hampshire Ave., Building 31, Rm. 1503, Silver Spring, MD 
20993.
    Submit electronic comments to http://www.regulations.gov. Submit 
written comments to the Division of Dockets Management (HFA-305), Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 
20852. Identify comments with the corresponding docket number found in 
brackets in the heading of this document.
    Transcripts of the public hearing will be available for review at 
the Division of Dockets Management and on the Internet at http://www.regulations.gov approximately 30 days after the public hearing (see 
Section VI of this document).
    A live webcast of this public hearing will be viewable at the 
following Web addresses on the days of the public hearing: http://www.fda.gov/Drugs/NewsEvents/ucm221688.htm. A video record of the 
public hearing will be available at the same Web addresses for 1 year.

FOR FURTHER INFORMATION CONTACT: Sandra J. Benton, Food and Drug 
Administration, Center for Drug Evaluation and Research, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6340, Silver Spring, MD 20993, 301-796-
1042, FAX: 301-847-3529, E-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    On March 23, 2010, President Obama 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) that amends the 
Public Health Service Act (PHS Act) and other statutes to create an 
abbreviated approval pathway for biological products shown to be 
biosimilar to, or interchangeable with, an FDA-licensed reference 
biological product (see sections 7001 through 7003 of the BPCI Act).
    The objectives of the BPCI Act are conceptually similar to those of 
the Drug Price Competition and Patent Term Restoration Act of 1984 
(Pub. L. 98-417) (commonly referred to as the ``Hatch-Waxman Act''), 
which established abbreviated pathways for the approval of drug 
products under the Federal Food, Drug, and Cosmetic Act (FD&C Act). The 
BPCI Act aligns with FDA's longstanding policy of permitting 
appropriate reliance on what is already known about a drug, thereby 
saving time and resources and avoiding unnecessary duplication of human 
or animal testing. The implementation of an abbreviated approval 
pathway for biological products can present challenges given the 
scientific and technical complexities that may be associated with the 
larger and often more complex structure of biological products, as well 
as the processes by which such products are manufactured. Most 
biological products are produced in a living system such as a 
microorganism, or plant or animal cells, whereas small molecule drugs 
are typically manufactured through chemical synthesis.
    Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI 
Act, describes the general requirements for an application for a 
proposed biosimilar biological product and an application or a 
supplement for a proposed interchangeable biological product.
    A biological product may be demonstrated to be ``biosimilar'' to a 
biological reference product based upon data derived from analytical 
studies, animal studies, and a clinical study or studies if the product 
is shown to be highly similar to the reference product, notwithstanding 
minor differences in clinically inactive components, and if there are 
no clinically meaningful differences between the biological product and 
the reference product in terms of safety, purity and potency.

[[Page 61498]]

    To meet the higher standard of ``interchangeability,'' a product 
must demonstrate that it can be expected to produce the same clinical 
result as the reference product in any given patient and, if the 
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 biological product and the reference 
product is not greater than the risk of using the reference product 
without such alternation or switch. Interchangeable products may be 
substituted for the reference product by a pharmacist without the 
intervention of the prescribing health care provider.
    The BPCI Act also includes, among other provisions: A 12-year 
period of marketing exclusivity from the date of first licensure of the 
reference product, during which approval of a 351(k) application 
referencing that product cannot be made effective; an exclusivity 
period for the first biological product submitted in a 351(k) 
application that has been determined to be interchangeable with the 
reference product for any condition of use, during which a second or 
subsequent biological product may not be determined interchangeable to 
that reference product; and a transition provision for protein products 
that have been or will be approved under section 505 of the FD&C Act 
(21 U.S.C. 355) prior to March 23, 2020.
    The BPCI Act also requires that FDA develop recommendations to 
present to Congress with respect to a user fee program for biosimilar 
and interchangeable biological products. Such recommendations must 
address the goals for the process of reviewing 351(k) applications, and 
plans for meeting those goals, for fiscal years (FY) 2013 to 2017. In 
developing such recommendations, FDA is required to consult with the 
Committee on Health, Education, Labor, and Pensions of the Senate; the 
Committee on Energy and Commerce of the House of Representatives; 
scientific and academic experts; healthcare professionals; 
representatives of patient and consumer advocacy groups; and regulated 
industry.
    The BPCI Act also establishes procedures for identifying and 
resolving patent disputes involving applications submitted under 
section 351(k) of the PHS Act; these procedures do not involve FDA and 
are not within the scope of this public hearing.

II. Purpose and Scope of the Public Hearing

    The purpose of this part 15 hearing is to receive information and 
comments from a broad group of stakeholders, such as healthcare 
professionals, healthcare institutions, manufacturers of biomedical 
products, interested industry and professional associations, patients 
and patient associations, third party payers, current and prospective 
biological license application (BLA) and new drug application (NDA) 
holders, and the public, regarding implementation of the BPCI Act.
    To prepare to begin negotiations with regulated industry regarding 
a user fee program, FDA must identify which companies and trade 
associations would be affected by a user fee program for biosimilar and 
interchangeable biological products (i.e., a company likely to submit 
an application for approval of a biosimilar or interchangeable 
biological product).
    The purpose of this public hearing is to create a forum for 
interested stakeholders to provide input regarding the agency's 
implementation of the statute concerning the following issues, among 
others: Scientific and technical factors related to a determination of 
biosimilarity or interchangeability; the type of information that may 
be used to support a determination of biosimilarity or 
interchangeability; development of a framework for optimal 
pharmacovigilance for biosimilar and interchangeable biological 
products; scope of the revised definition of a ``biological product''; 
priorities for guidance development; scientific and technical factors 
related to reference product exclusivity; scientific and technical 
factors that may inform the agency's interpretation of ``product 
class'' as it relates to available regulatory pathways for certain 
protein products during the 10-year transition period following 
enactment of the BPCI Act; and the establishment of a user fee program 
for biosimilar and interchangeable biological products.
    FDA is particularly interested in obtaining information and public 
comment on the following issues, although any comments on any issues 
related to biosimilar or interchangeable biological products are 
welcome.

A. Biosimilarity

    Section 351(k) of the PHS Act as set forth in the BPCI Act 
requires, among other things, that an application for a proposed 
biosimilar product include information demonstrating that the proposed 
product is biosimilar to a reference product based upon data derived 
from:
     Analytical studies that demonstrate that the biological 
product is highly similar to the reference product notwithstanding 
minor differences in clinically inactive components;
     Animal studies (including the assessment of toxicity); and
     A clinical study or studies (including the assessment of 
immunogenicity and pharmacokinetics or pharmacodynamics) that are 
sufficient to demonstrate safety, purity, and potency in one or more 
appropriate conditions of use for which the reference product is 
licensed.

The BPCI Act provides that FDA may determine, at its discretion, that 
an element described previously is unnecessary in a 351(k) application.

    FDA seeks comments on the following issues:
    1. What scientific and technical factors should the agency consider 
in determining whether the biological product is highly similar to the 
reference product notwithstanding minor differences in clinically 
inactive components?
    2. What scientific and technical factors should the agency consider 
in determining the appropriate analytical, animal, and clinical study 
or studies to assess the nature and impact of actual or potential 
structural differences between the proposed biosimilar product and the 
reference product?
    3. What range of structural differences between a proposed 
biosimilar product and the reference product is consistent with the 
standard ``highly similar'' and may be acceptable in a 351(k) 
application if the applicant can demonstrate the absence of any 
clinically meaningful differences between the proposed biosimilar 
product and the reference product?
    4. Under what circumstances should the agency consider finding that 
animal studies or a clinical study or studies are ``unnecessary'' for 
submission of a 351(k) application?

B. Interchangeability

    Section 351(k)(4) of the PHS Act requires that an application for a 
proposed interchangeable product contain information sufficient to 
demonstrate:
     The biological product is biosimilar to the reference 
product; and
     The biological product can be expected to produce the same 
clinical result as the reference product in any given patient; and
     For a biological product that is administered more than 
once to an

[[Page 61499]]

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.
    FDA seeks input on the following issues related to 
interchangeability:
    1. What factors should the agency consider in determining whether a 
proposed interchangeable biological product can be ``expected to 
produce the same clinical result as the reference product in any given 
patient?''
    2. What factors should the agency consider in evaluating the 
potential risk related to alternating or switching between use of the 
proposed interchangeable biological product and the reference product 
or among interchangeable biological products?

C. Patient Safety and Pharmacovigilance

    The agency considers the safety of patients who are taking any 
medical products to be of paramount importance. To that end and to 
protect each individual patient, the agency is developing a framework 
for optimal pharmacovigilance for biosimilar and interchangeable 
products that is informed by our current experience and industry best 
practices. In the interest of patient safety and for the purpose of 
pharmacovigilance, the agency must be able to distinguish between a 
reference product, a related biological product that has not been 
demonstrated to be biosimilar, a biosimilar product, and an 
interchangeable product.
    FDA seeks comments on the following issues:
    1. What factors unique to proposed biosimilar or interchangeable 
biological products and their use should the agency consider in 
developing its pharmacovigilance program for such products?
    2. What approaches can be undertaken by the agency, industry, or 
health care community to ensure appropriate pharmacovigilance for 
biosimilar and interchangeable products?
    3. If each product were given a unique nonproprietary name, should 
a distinguishing prefix or suffix be added to the nonproprietary name 
for a related biological product that has not been demonstrated to be 
biosimilar, a biosimilar product, or an interchangeable product to 
facilitate pharmacovigilance? What factors should be considered to 
reduce any negative impact on the healthcare delivery system related to 
unique nonproprietary names for highly similar biological products?
    4. What safeguards should the agency consider to assist the 
healthcare community when prescribing, administering, and dispensing 
biological products to prevent unsafe substitution of biological 
products?
    5. What are some mechanisms that FDA may consider to communicate 
findings that a particular product is or is not biosimilar to or 
interchangeable with a given reference product?

D. The Use of Supportive Data and Information

    The BPCI Act provides that an application for the licensure of a 
biosimilar or interchangeable product: Shall include publicly available 
information regarding the Secretary's (Department of Health and Human 
Services) previous determination that the reference product is safe, 
pure, and potent; and may include any additional information in support 
of the application, including publicly available information with 
respect to the reference product or another biological product (section 
351(k)(2)(A)(iii) of the PHS Act).
    The BPCI Act defines the term ``reference product'' to mean ``the 
single biological product licensed under [section 351(a)] against which 
a biological product is evaluated in an application submitted under 
[section 351(k)].'' Accordingly, section 351(k) requires that an 
applicant demonstrate biosimilarity to and or interchangeability with a 
reference product licensed by FDA (as distinguished from a biological 
product licensed by a foreign regulatory authority).
    The agency is aware that some prospective biosimilar sponsors have 
conducted animal and/or clinical studies to support regulatory approval 
in another jurisdiction using a non-U.S.-licensed biological product as 
a comparator. To avoid duplicative animal and human testing, sponsors 
may wish, to the extent permissible, to rely on these studies to 
support a 351(k) application.
    FDA seeks comments on the following issue: From a scientific 
perspective, to what extent, if any, should animal or clinical data 
comparing a proposed biosimilar product with a non-U.S.-licensed 
comparator product be used to support a demonstration of biosimilarity 
to a U.S.-licensed reference product? What type of bridging data or 
information would be needed to scientifically justify the relevance of 
the comparative data?

E. Definition of a Biological Product

    The BPCI Act changes the statutory authority under which certain 
protein products will be regulated by amending the definition of 
``biological product'' in section 351(i) of the PHS Act to include a 
protein (except any chemically synthesized polypeptide) before the 
phrase ``or analogous product.'' In light of the absence of scientific 
consensus on the distinction between the categories of ``protein'' and 
``polypeptide'' or ``peptide,'' FDA may establish a regulatory 
definition of ``protein'' and ``any chemically synthesized 
polypeptide'' to clarify the authority under which such products will 
be licensed and regulated and, to the extent possible, avoid the 
conflicting regulation of certain products (i.e., those that are 
manufactured through either synthetic and recombinant technology) under 
different authorities.
    FDA seeks comments on the following issues:
    1. What scientific and technical factors should FDA consider if it 
develops a regulatory definition for the category of ``protein'' (as 
distinguished from peptide or polypeptide)?
    2. What scientific and technical factors should FDA consider if it 
develops a regulatory definition for the category of ``any chemically 
synthesized polypeptide''?

F. Guidances

    Although the issuance or nonissuance of guidance does not preclude 
submission or agency review of, or action on, a 351(k) application, we 
are interested in obtaining public input regarding priorities for 
issuing guidance documents for industry (see section 351(k)(8) of the 
PHS Act).
    FDA seeks comments on the following issues:
    1. What types of guidance documents for industry should be a 
priority for the agency during the early period of implementation?
    2. Section 351(k)(8)(E) of the PHS Act permits the agency to 
indicate in a guidance document that the science and experience, as of 
the date of the guidance document, with respect to a product or product 
class (not including any recombinant protein) does not allow approval 
of a 351(k) application for such a product or product class. What 
scientific and technical factors should the agency consider in 
determining if the existing science and experience are sufficient to 
allow approval for a product or product class under section 351(k) of 
the PHS Act?

[[Page 61500]]

G. Exclusivity

    The BPCI Act provides for a 12-year period of marketing exclusivity 
from the date of first licensure of the reference biological product, 
during which approval of a 351(k) application cannot be made effective 
(see section 351(k)(7) of the PHS Act). The date of first licensure 
does not apply to a license for or approval of:
     A supplement for the biological product that is the 
reference product; or
     A subsequent application filed by the same sponsor or 
manufacturer of the biological product that is the reference product 
(or a related entity) for a change (not including a modification to the 
structure of the biological product) that results in a new indication, 
route of administration, dosing schedule, dosage form, delivery system, 
delivery device, or strength; or
     A subsequent application filed by the same sponsor or 
manufacturer of the biological product that is the reference product 
(or a related entity) for a modification to the structure of the 
biological product that does not result in a change in safety, purity, 
or potency (see section 351(k)(7)(C) of the PHS Act).
    FDA seeks comments on the following issues:
    1. In light of the potential transfer of BLAs from one corporate 
entity to another and the complexities of corporate and business 
relationships, what factors should the agency consider in determining 
the types of related entities that may be ineligible for a period of 
12-year exclusivity for a subsequent BLA?
    2. What factors should the agency consider in determining whether a 
modification to the structure of the licensed reference biological 
product results in a change in safety, purity, or potency, such that a 
subsequent BLA may be eligible for a second 12-year period of marketing 
exclusivity?

H. Transition Provisions

    The BPCI Act requires that an application for a biological product, 
which now includes the category of ``protein (except any chemically 
synthesized polypeptide),'' must be submitted under section 351 of the 
PHS Act, rather than under section 505 of the FD&C Act. However, the 
BPCI Act provides an exception for certain biological products that are 
in a ``product class'' for which an application has been approved under 
section 505 of the FD&C Act prior to March 23, 2010. An application for 
a biological product in these product classes may be submitted under 
section 505 of the FD&C Act until March 23, 2020, unless there is 
another biological product licensed under section 351(a) of the PHS Act 
that could serve as the reference product for the application, if the 
application were submitted under section 351(k) of the PHS Act (see 
section 7002(e) of the BPCI Act).
    FDA seeks comments on the following issues:
    1. What scientific factors should FDA consider in defining and 
applying ``product class'' for purposes of determining which 
applications for biological products may be submitted under the FD&C 
Act during the 10-year transition period?
    2. What scientific factors should FDA consider in determining 
whether another biological product approved under section 351(a) of the 
PHS Act could serve as the reference product for an application 
submitted under section 351(k) of the PHS Act?

I. User Fees

    The BPCI Act amends section 735 of the FD&C Act (21 U.S.C. 379g) to 
include 351(k) applications in the definition of a ``human drug 
application'' for the purposes of the prescription drug user fee 
provisions (see section 7002(f)(3) of the BPCI Act). The BPCI Act 
requires FDA to develop recommendations to present to Congress by 
January 15, 2012, for goals for the process of reviewing 351(k) 
applications, and plans for meeting those goals, for the first five 
fiscal years after FY 2012 (see section 7002(f)(3) of the BPCI Act).
    FDA seeks comments on the following issues:
    1. If the existing fee structure under the Prescription Drug User 
Fee Act (PDUFA) were to be considered as a model in establishing a user 
fee structure for applications and supplements for proposed biosimilar 
and interchangeable biological products, what factors and changes 
should FDA take into consideration, and why?
    2. What factors should FDA take into account when considering 
whether to recommend that user fees for biosimilar and interchangeable 
biological products should also be used to monitor safety after 
approval?
    In addition, FDA seeks to identify potential participants in any 
negotiations of user fee programs for biosimilar and interchangeable 
biological products, specifically companies that would be affected by 
such a user fee program and industry associations representing such 
companies. FDA requests that commenters identify these potential 
participants by sending to [email protected] the 
following information regarding any company that may be subject to a 
user fee program for biosimilar and interchangeable biological 
products, or any industry association representing such companies: The 
name of the entity; contact person; e-mail address; and a phone number.

III. Attendance and Registration

    The FDA Conference Center at the White Oak location is a Federal 
facility with security procedures and limited seating. Attendance is 
free and will be on a first-come, first-served basis. Individuals who 
wish to present at the public hearing must register by sending an e-
mail to [email protected] on or before October 11, 2010, 
and provide complete contact information, including name, title, 
affiliation, address, e-mail, and phone number. Those without e-mail 
access may register by contacting Sandra Benton (see FOR FURTHER 
INFORMATION CONTACT). FDA has included questions for comment in section 
II of this document. You should identify the section and the number of 
each question you wish to address in your presentation, so that FDA can 
consider that in organizing the presentations. Individuals and 
organizations with common interests should consolidate or coordinate 
their presentations and request time for a joint presentation. FDA will 
do its best to accommodate requests to speak and will determine the 
amount of time allotted for each oral presentation, and the approximate 
time that each oral presentation is scheduled to begin. FDA will notify 
registered presenters of their scheduled times, and make available an 
agenda at http://www.fda.gov/Drugs/NewsEvents/ucm221688.htm 
approximately 2 weeks prior to the public hearing. Once FDA notifies 
registered presenters of their scheduled times, presenters should 
submit to FDA an electronic copy of their presentation to 
[email protected] on or before October 27, 2010.
    If you need special accommodations because of disability, please 
contact Sandra Benton, (see FOR FURTHER INFORMATION CONTACT) at least 7 
days before the meeting.
    A live Webcast of this public hearing will be viewable at the 
following Web addresses on the days of the public hearing: http://www.fda.gov/Drugs/NewsEvents/ucm221688.htm. A video record of the 
public hearing will be available at the same Web addresses for one 
year.

[[Page 61501]]

IV. Notice of Hearing Under 21 CFR Part 15

    The Commissioner of Food and Drugs is announcing that the public 
hearing will be held in accordance with part 15 (21 CFR part 15). The 
hearing will be conducted by a presiding officer, who will be 
accompanied by FDA senior management from the Office of the 
Commissioner and the Center for Drug Evaluation and Research.
    Under Sec.  15.30(f), the hearing is informal and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer and panel members may 
question any person during or at the conclusion of each presentation. 
Public hearings under part 15 are subject to FDA's policy and 
procedures for electronic media coverage of FDA's public administrative 
proceedings (part 10, subpart C (21 CFR part 10, subpart C)). Under 
Sec.  10.205, representatives of the electronic media may be permitted, 
subject to certain limitations, to videotape, film, or otherwise record 
FDA's public administrative proceedings, including presentations by 
participants. The hearing will be transcribed as stipulated in Sec.  
15.30(b) (see section VI of this document). To the extent that the 
conditions for the hearing, as described in this notice, conflict with 
any provisions set out in part 15, this notice acts as a waiver of 
those provisions as specified in Sec.  15.30(h).

V. Request for Comments

    Regardless of attendance at the public hearing, interested persons 
may submit either electronic or written comments to the Division of 
Dockets Management (see ADDRESSES). It is only necessary to send one 
set of comments. It is no longer necessary to send two copies of mailed 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

VI. Transcripts

    Transcripts of the public hearing will be available for review at 
the Division of Dockets Management (see ADDRESSES) and on the Internet 
at http://www.regulations.gov approximately 30 days after the public 
hearing. A transcript will also be made available in either hard copy 
or on CD-ROM, upon submission of a Freedom of Information request. 
Written requests are to be sent to Division of Freedom of Information 
(HFI-35), Office of Management Programs, Food and Drug Administration, 
5600 Fishers Lane, Room 6-30, Rockville, MD 20857.

    Dated: September 29, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-24853 Filed 10-4-10; 8:45 am]
BILLING CODE 4160-01-P