[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]
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