Federal Register, Volume 80 Issue 167 (Friday, August 28, 2015)

[Federal Register Volume 80, Number 167 (Friday, August 28, 2015)]
[Proposed Rules]
[Pages 52224-52231]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-21382]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 299

[Docket No. FDA-2015-N-0648]
RIN 0910-AH25

Designation of Official Names and Proper Names for Certain
Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing a
regulation to designate official names and proper names for certain
biological products. These products are filgrastim-sndz (Biologics
License Application (BLA) 125553), filgrastim (BLA 103353), tbo-
filgrastim (BLA 125294), pegfilgrastim (BLA 125031), epoetin alfa (BLA
103234), and infliximab (BLA 103772). The official names and proper
names of these products would include distinguishing suffixes composed
of four lowercase letters and would be designated as filgrastim-bflm
(BLA 125553), filgrastim-jcwp (BLA 103353), filgrastim-vkzt (BLA
125294), pegfilgrastim-ljfd (BLA 125031), epoetin alfa-cgkn (BLA
103234), and infliximab-hjmt (BLA 103772). Although FDA is continuing
to consider the appropriate naming convention for biological products,
including how such a convention would be applied retrospectively to
currently licensed products, FDA is proposing to take action with
respect to these six products because of the need to encourage routine
usage of designated suffixes in ordering, prescribing, dispensing,
recordkeeping, and pharmacovigilance practices for the biological
products subject to this rulemaking, and to avoid inaccurate
perceptions of the safety and effectiveness of biological products
based on their licensure pathway.

DATES: Submit either electronic or written comments on the proposed
rule by November 12, 2015. See section IV of this document for the
proposed effective date of any final rule that may publish based on
this proposal.

ADDRESSES: You may submit comments by any of the following methods.

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Docket No.
FDA-2015-N-0648 for this rulemaking. All comments received may be
posted without change to http://www.regulations.gov, including any
personal information provided. For additional information on submitting
comments, see the ``Comments'' heading in section VIII of the
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 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-
796-2500.

SUPPLEMENTARY INFORMATION:

[[Page 52225]]

I. Background

With the passage of the Biologics Price Competition and Innovation
Act of 2009 (BPCI Act), which established an abbreviated licensure
pathway for products demonstrated to be biosimilar to or
interchangeable with an FDA-licensed reference product, a growing
number of biological products will be entering the marketplace.
Section 351(k) of the Public Health Service Act (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(i) of
the PHS Act 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 (section 351(i)(2) of the PHS Act). To meet the additional
standard of interchangeability, an applicant must provide sufficient
information to demonstrate biosimilarity and also to demonstrate that
the biological product 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 (section 351(k)(4) of the PHS Act).
Interchangeable products may be substituted for the reference product
by a pharmacist without the intervention of the prescribing health care
provider (section 351(i)(3) of the PHS Act).
During FDA's implementation of the BPCI Act, the Agency has opened
several dockets to solicit comments on issues related to the naming of
biological products licensed under section 351(k) of the PHS Act.\1\
---------------------------------------------------------------------------

\1\ See, e.g., notices that published in the Federal Register
``Approval Pathway for Biosimilar and Interchangeable Biological
Products; Public Hearing; Request for Comments'' (75 FR 61497,
October 5, 2010) and ``Draft Guidances Relating to the Development
of Biosimilar Products; Public Hearing; Request for Comments'' (77
FR 12853, March 2, 2012) and other public dockets established by
FDA.
---------------------------------------------------------------------------

FDA also has received several citizen petitions directed to the
nonproprietary naming of biosimilar products. The citizen petition
submitted by Johnson & Johnson requests that FDA require biosimilar
products to bear nonproprietary names that are similar to, but not the
same as, those of their reference products or of other biosimilars (see
Docket No. FDA-2014-P-0077, available at http://www.regulations.gov).
The citizen petitions submitted by the Generic Pharmaceutical
Association and Novartis request that FDA require biosimilar products
to be identified by the same nonproprietary name as their reference
products (see Docket Nos. FDA-2013-P-1153 and FDA-2013-P-1398,
respectively, available at http://www.regulations.gov). Novartis
supplemented its petition to propose a unique name for all biologics
and biosimilars, such that if a biosimilar sponsor elected not to use a
unique proprietary name for its product, FDA should assign a unique
nonproprietary name composed of the reference product nonproprietary
name supplemented with a distinguishable suffix linked to the
biosimilar sponsor so that it can be differentiated from the reference
product. While FDA is proposing to designate distinguishable
nonproprietary names for the six biological products that are the
subject of this rulemaking for the reasons discussed in this document,
FDA is continuing to consider the issues raised by these citizen
petitions and the comments submitted to the corresponding public
dockets with respect to establishing a general naming convention for
biological products.
In a separate notice published elsewhere in this issue of the
Federal Register, FDA announced the availability of a draft guidance
document entitled ``Nonproprietary Naming of Biological Products''
(draft guidance). The draft guidance describes FDA's current thinking
and requests additional public comment on the Agency's proposal to
implement a naming convention of a proper name that will include a core
name and a designated suffix for all biological products within the
scope of the guidance. For originator products, FDA intends to use a
core name that is the name adopted by the United States Adopted Names
(USAN) Council for the drug substance when available. If the biological
product is a related biological product,\2\ a biosimilar product, or an
interchangeable product, the core name will be the name of the drug
substance contained in the relevant previously licensed product. As
described in the draft guidance, a designated suffix composed of four
lowercase letters will be added to the core name of each product and
will be attached with a hyphen. Importantly, use of a shared core name
would indicate a relationship among products. The placement of the
identifier as a suffix should result in biological products with the
same core name being grouped together in electronic databases to help
health care providers identify these products. The draft guidance
states that FDA intends to apply the naming convention described in the
guidance to interchangeable products and is considering comment on two
alternative approaches: A unique suffix that distinguishes an
interchangeable product from other products sharing the same core name,
or a suffix shared with the reference product.
---------------------------------------------------------------------------

\2\ A ``related biological product'' is described in the
guidance as a biological product submitted in a BLA under section
351(a) of the PHS Act (i.e., a ``stand-alone'' BLA) for which there
is a previously licensed biological product submitted in a different
section 351(a) BLA that contains a drug substance for which certain
nomenclature conventions (e.g., USAN Guiding Principles) would be
expected to provide for use of the same drug substance name. An
``originator biological product'' is defined as a biological product
submitted in a BLA under section 351(a) of the PHS Act (i.e., a
``stand-alone'' BLA) for which there is no previously licensed
biological product submitted under section 351(a) that is a related
biological product. FDA uses these definitions for purposes of this
notice.
---------------------------------------------------------------------------

While the draft guidance describes a naming convention in which the
designated suffixes would be devoid of meaning, the notice of
availability for the draft guidance invites comment not only on that
naming convention but also on the benefits and challenges of alternate
approaches, including meaningful suffixes such as a suffix derived from
the name of the license holder.
The draft guidance describes FDA's rationale for the proposed
naming convention and requests public comment on FDA's intention to
apply this convention to biological products previously licensed and
newly licensed under section 351(a) or section 351(k) of the PHS Act.
The draft guidance explains that FDA is continuing to consider the most
effective regulatory approach to implement the naming convention for
previously licensed biological products, and FDA encourages interested
parties to submit comments on biological product naming issues to the
public docket established for the draft guidance (Docket No. FDA-2013-
D-1543, available at http://www.regulations.gov).
For the reasons described in the following section, FDA believes it
is necessary at this time to designate official names and proper names
for the

[[Page 52226]]

six biological products described in this proposed rule.

II. Description of the Proposed Rule

This proposed rule would designate the official names and the
proper names of six biological products that fall under one of the
following categories: (1) A reference product for an approved or
publicly disclosed section 351(k) application (i.e., filgrastim (BLA
103353), pegfilgrastim (BLA 125031), infliximab (BLA 103772), and
epoetin alfa (BLA 103234)); (2) a related biological product to one of
these reference products (i.e., tbo-filgrastim (BLA 125294)); or (3) a
biosimilar product (i.e., filgrastim-sndz (BLA 125553)).\3\
---------------------------------------------------------------------------

\3\ FDA recognizes that a limited number of previously licensed
biological products share the same proper name. As described in the
draft guidance, FDA intends to apply the naming convention to
biological products previously licensed under section 351(a) of the
PHS Act, and is continuing to consider the most effective regulatory
approach. In the meantime, FDA is proposing to assign distinguishing
identifiers to biological products that are referenced by approved
or publicly disclosed section 351(k) applications and any related
biological products to those reference products.
---------------------------------------------------------------------------

Section 508 of the Federal Food, Drug, and Cosmetic Act (the FD&C
Act) (21 U.S.C. 358), which applies to biological products pursuant to
section 351(j) of the PHS Act, provides FDA with authority to designate
official names for drugs if it determines that such action is necessary
or desirable in the interest of usefulness and simplicity. Section 508
further specifies that any official name designated under that section
shall be the only official name of that drug used in any official
compendium published after such name has been prescribed or for any
other purpose of this chapter. Under Sec. 299.4(e) (21 CFR 299.4(e)),
FDA will publish official names under the provisions of section 508 of
the FD&C Act when the Agency determines, among other bases, that the
USAN or other official or common or usual name is unduly complex or is
not useful for any other reason.
For biological products licensed under the PHS Act, FDA designates
the proper name in the license for use upon each package of the
biological product (see section 351(a)(1)(B)(i) of the PHS Act and 21
CFR 600.3(k)). The proper name of a biological product reflects certain
scientific characteristics of the product, such as chemical structure
and pharmacological properties. Among other things, the proper name of
a biological product helps health care providers identify the product's
drug substance and distinguish biological products from one another.
Although FDA typically designates the proper name of a product upon its
licensure, FDA also has the authority to designate proper names for
biological products through regulation (see, e.g., designation of
proper names for various products in 21 CFR part 640).

A. Basis for the Designation of Distinguishable Names for Certain
Biological Products

1. Safe Use
Biological products generally consist of large, complex molecules
and can raise unique safety concerns related to immunogenicity. FDA
believes that the nonproprietary naming convention for the biological
products described in this proposed rule should help prevent
inadvertent substitution, which may lead to unintended switching or
alternating of biological products that have not been determined by FDA
to be interchangeable with each other. FDA believes this naming
convention will help to facilitate safe use and protect the safety of
patients.
Inadvertent switching between biological products that have not
been shown to be interchangeable may affect immune response. For
example, in some instances, immune responses to therapeutic proteins
may pose safety and efficacy issues (Ref. 1). For example, immune
responses can lead to significant clinical consequences, such as pure
red cell aplasia; inhibition of the efficacy of therapeutics; and
reactions, including serum sickness and anaphylaxis (Ref. 1).
Individual patients can vary in their immune responses to protein
products, and these differences can be caused by the same genetic
components that have an impact on sensitivity to small changes in
structure (Ref. 2). Thus, switching or alternating of biological
products not determined by FDA to be interchangeable may raise unique
safety concerns related to immunogenicity.
If originator biological products, related biological products, and
biosimilar products share the same proper name, a patient could receive
a product different from what was intended to be prescribed, leading to
medication errors. For example, this could occur if a biosimilar
product were licensed for fewer than all of the indications and routes
of administration for which its reference product is licensed, or is
packaged in a different delivery system (e.g., a pre-filled syringe
instead of a vial) than approved for its reference product, which may
lead to confusion and dosing errors. A related biological product also
may be licensed for different indications than an originator biological
product and may have different dosage forms or strengths than an
originator biological product. Confusion may also arise among health
care providers who, based on their experience with small-molecule drugs
and generic versions of those drugs, may incorrectly assume the use of
the same proper name to mean that the biological products are
interchangeable.
Thus, FDA has determined that designation of a proper name
containing a distinguishing identifier for these six biological
products is the best mechanism to facilitate their safe use. FDA
believes that incorporating a distinguishing suffix into the
nonproprietary names of these six biological products will increase the
likelihood that the intended biological product will be prescribed and
will not be inadvertently substituted at the dispensing or product
administration level. Specifically, FDA believes that incorporation of
these suffixes into the nonproprietary product names listed in
prescribing, ordering, and dispensing systems will assist prescribers
in selecting the specific intended product, pharmacists in dispensing
the correct product, and health care providers in administering the
correct product.
Health care providers and information technology specialists who
program electronic databases can consult the Purple Book (Lists of
Licensed Biological Products with Reference Product Exclusivity and
Biosimilarity or Interchangeability Evaluations), an online resource
that lists all FDA-licensed biological products by their nonproprietary
name and clearly identifies products that have been approved as
biosimilar to or interchangeable with a particular reference product.
2. Pharmacovigilance
The Agency considers appropriate pharmacovigilance fundamentally
important for all biological products. Although safety of drug and
biological products is rigorously assessed prior to approval, safety
issues that are specific to a manufacturer may arise after approval
with any marketed product. Therefore, a robust pharmacovigilance
program is essential to help ensure patient safety. To ensure continued
safety of a biological product, appropriate pharmacovigilance
necessitates that FDA be able to track adverse events to a specific
manufacturer (and, as appropriate, site or lot for a particular
biological product), and that surveillance systems be able to detect
safety signals throughout the lifecycle of a product, so that the
Agency and the manufacturer

[[Page 52227]]

can act swiftly and in a targeted manner to identify and address a
problem.
Pharmacovigilance systems, both active and passive, vary in their
use of identifiers to differentiate among biological products; these
identifiers may include the brand (proprietary) name, proper
(nonproprietary) name, manufacturer, national drug code (NDC) number,
lot number, and billing codes. Successful use of active
pharmacovigilance systems (such as FDA's Sentinel system) for adverse
event tracking relies on the standardized coding systems for capturing
drug information in administrative and health care claims and billing
records. These coding systems may vary based on the setting in which a
drug is dispensed. Many therapeutic biological products are
administered in settings, such as physician offices, clinics, or
hospitals, where the administrative and billing data do not routinely
include product identifiers such as brand name, manufacturer, NDC
number, or lot number (Refs. 3 and 4). Thus, active pharmacovigilance
systems that use administrative and billing data currently have limited
ability to track biological products that share the same nonproprietary
name to the manufacturer.
Similarly, in many passive pharmacovigilance systems, proprietary
names and NDC numbers are often not included in adverse event reports
(Refs. 5 and 6). FDA uses the FDA Adverse Event Reporting System, a
``passive'' surveillance system that compiles mandatory adverse event
reports from manufacturers and voluntary reports submitted directly to
FDA by health care professionals and patients. FDA requires
manufacturers and others with mandatory reporting obligations to submit
an adverse event report to FDA when a minimum of four elements
(identifiable patient, identifiable reporter, suspect product, and an
event or fatal outcome) are present, even if other required elements,
such as NDC numbers, are not available. It is well known that many
reports lack key information and that the information identifying
products in spontaneous reports can be unreliable (Ref. 6). Proprietary
names, even when included, may not reliably identify products in
spontaneous adverse event reports since misattribution can occur with
adverse event reporting. Furthermore, because national health care
systems, health care professional organizations, and patient safety
organizations recommend the use of nonproprietary names for prescribing
and listing of drug products, the nonproprietary name may be the name
used by some reporters to identify the drug products in the adverse
event reports (Refs. 7 and 8). In addition, although NDC numbers can be
used to identify manufacturer-specific information about a product,
they are infrequently provided in spontaneous adverse event reports,
and may not be available to the reporter at the time of reporting, or
during followup with the reporter. As a result, the use of distinct
proprietary names or NDC numbers is currently insufficient to address
all concerns regarding pharmacovigilance. Distinguishable
nonproprietary names for the biological products in this rulemaking
would provide another critical tool in uniquely identifying these
biological products. Use of such names for the biological products in
this rulemaking would preserve the ability to detect both product-
specific safety signals and class effects, and would facilitate prompt
evaluation of safety signals in passive and active postmarketing
surveillance systems.
Although FDA believes the use of distinguishable nonproprietary
names for originator biological products, related biological products,
and biosimilar products could improve pharmacovigilance, FDA is
interested in comments addressing whether any potential alternative
approaches such as increased use of NDC numbers and/or other tracking
information would also improve pharmacovigilance of these products.
3. Additional Benefits of Consistent Naming Convention for These
Biological Products
FDA believes that it is important to initiate and encourage routine
usage of designated suffixes in ordering, prescribing, dispensing,
recordkeeping, and pharmacovigilance practices for these six biological
products. The designated suffix would provide a consistent, readily
available, and recognizable mechanism for health care professionals
(including providers and pharmacists) and patients to correctly
identify these biological products, regardless of their licensure
pathway. The consistent use of a designated suffix for these biological
products would remove ambiguity about the identity of the intended
biological product. If a core name was used without such identifier, it
may be unclear whether the originator product, a related biological
product, or a biosimilar product was intended to be ordered,
prescribed, dispensed, administered, or reported.
This naming convention would have the added benefit of avoiding
inaccurate perceptions of the safety and effectiveness of biological
products based on their licensure pathway. The safety and effectiveness
of biological products is rigorously assessed before approval. A number
of comments have expressed concern that requiring distinguishable
proper names only for biosimilar products would adversely affect health
care provider and patient use of these new products (Ref. 9). FDA
shares the concern that such an approach could lead to inaccurate and
scientifically unfounded assertions of inferiority or clinically
meaningful differences of an approved biosimilar product for its
approved indications. FDA anticipates that use of proper names with
designated suffixes for these originator biological products, related
biological products, and biosimilar products, irrespective of their
licensure pathway, would help avoid any inaccurate perceptions of the
safety and effectiveness of biological products based on licensure
pathway and thus address concerns raised by the comments.

B. Designation of Official Names and Proper Names for Certain
Biological Products

We are proposing to add subpart B on Designated Names and proposed
Sec. 299.20 (21 CFR 299.20) to designate the official names and proper
names of certain biological products. The six biological products
included in proposed Sec. 299.20 have been selected because they fall
under one of the following categories: (1) Reference product for an
approved or publicly disclosed section 351(k) application (i.e.,
filgrastim (BLA 103353), epoetin alfa (BLA 103234), infliximab (BLA
103772), and pegfilgrastim (BLA 125031)); (2) related biological
product to one of these reference products (i.e., tbo-filgrastim (BLA
125294)); or (3) biosimilar product (i.e., filgrastim-sndz (BLA
125553)).
We are proposing to designate the official name of ``filgrastim-
jcwp'' for the biological product licensed under BLA 103353, held by
Amgen, Inc. (Amgen) and to change the proper name designated in the
license from ``filgrastim'' to ``filgrastim-jcwp.'' Filgrastim,
marketed as NEUPOGEN, is the reference product for ZARXIO (filgrastim-
sndz), a biosimilar product recently licensed under section 351(k) of
the PHS Act.
We also are proposing to designate the official name of
``filgrastim-vkzt'' for the biological product licensed under BLA
125294, held by Sicor Biotech, UAB, and to change the proper name
designated in the license from ``tbo-filgrastim'' to ``filgrastim-
vkzt.'' Tbo-filgrastim, marketed as GRANIX, is a related biological
product. FDA has

[[Page 52228]]

determined that the current names of filgrastim and tbo-filgrastim are
not useful within the meaning of section 508 of the FD&C Act. Although
these products are distinguished from each other and from filgrastim-
sndz, FDA believes that the addition of a distinguishing suffix to both
names, and the elimination of the prefix from tbo-filgrastim, would
avoid confusion regarding these products' relationships to one another
and to filgrastim-sndz. The placement of the identifier as a suffix
should result in an originator product, a related biological product,
and a biosimilar product being grouped together in electronic
databases, yet remaining distinguishable, which should help health care
providers identify these products. Also, assignment of suffixes to all
filgrastim products would help avoid a potential inaccurate perception
that filgrastim-sndz, or any other biosimilar product that may be
licensed in the future, differs in a clinically meaningful way from its
reference product or is inferior for its approved conditions of use.
In addition, we are proposing to designate the official name of
``filgrastim-bflm'' for the biological product licensed under BLA
125553, held by Sandoz, Inc., and to change the proper name designated
in the license from ``filgrastim-sndz'' to ``filgrastim-bflm.''
Filgrastim-sndz, marketed as ZARXIO, is a biosimilar product recently
licensed under section 351(k) of the PHS Act, and the distinguishing
suffix designated at the time of licensure was derived from the name of
the license holder. In light of FDA's current proposal to designate
official names and proper names for five other biological products that
would include distinguishing suffixes devoid of meaning, in the
interest of usefulness and simplicity the name ``filgrastim-bflm''
should be designated as the official name and the proper name and
codified with the names designated for filgrastim and tbo-filgrastim in
proposed Sec. 299.20.
We are proposing to designate the official names and change the
proper names for three other reference products for section 351(k)
applications that have been publicly disclosed. These reference
products are epoetin alfa (BLA 103234), infliximab (BLA 103772), and
pegfilgrastim (BLA 125031). We are proposing to designate the official
name of ``epoetin alfa-cgkn'' for the biological product licensed under
BLA 103234, held by Amgen and marketed as EPOGEN and PROCRIT, and to
change the proper name designated in the license from ``epoetin alfa''
to ``epoetin alfa-cgkn.'' We also are proposing to designate the
official name of ``infliximab-hjmt'' for the biological product
licensed under BLA 103772, held by Janssen Biotech, Inc. and marketed
as REMICADE, and to change the proper name designated in the license
from ``infliximab'' to ``infliximab-hjmt.'' Finally, we are proposing
to designate the official name of ``pegfilgrastim-ljfd'' for the
biological product licensed under BLA 125031, held by Amgen and
marketed as NEULASTA, and to change the proper name designated in the
license from ``pegfilgrastim'' to ``pegfilgrastim-ljfd.''
FDA has determined that the current names of ``epoetin alfa,''
``infliximab,'' and ``pegfilgrastim'' are not useful within the meaning
of section 508 of the FD&C Act. Considerations similar to those
described for filgrastim and tbo-filgrastim warrant the designation of
official names and proper names that include distinguishing suffixes
for pegfilgrastim, epoetin alfa, and infliximab. These products are the
reference products for publicly disclosed applications under section
351(k) of the PHS Act (Ref. 10). FDA believes that it is important to
initiate and encourage routine usage of designated suffixes in
ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance
practices for these products. Also, in the event that a biosimilar
product is approved that relies upon one of these products as a
reference product, assignment of designated suffixes to the reference
products would help avoid potential inaccurate perceptions that any
biosimilar product with a proper name that features a distinguishing
suffix differs in a clinically meaningful way or is inferior for its
approved conditions of use. Accordingly, in the interest of usefulness
and simplicity, FDA is proposing to designate official names with
designated suffixes that would also be designated as the proper names
for these products.
The official names and proper names in proposed Sec. 299.20
include designated suffixes composed of four lowercase letters. The
official names and proper names, if finalized, will appear on all
labeling and marketing materials for these products where the product's
proper name or drug substance name is provided.
In addition, FDA also has determined that the following alternative
names that include distinguishing suffixes devoid of meaning may be
acceptable for these products: epoetin alfa-mkdv, filgrastim-gknh,
filgrastim-kbhj, filgrastim-zbdt, infliximab-djfg, and pegfilgrastim-
vjbk.
FDA is also considering an alternative nonproprietary naming format
for biological products in which the suffix attached to the core name
would be derived from the name of the license holder listed on the
license. Under this alternative naming format, the official names and
proper names for the six products that are the subject of this proposed
rule could be as follows:

----------------------------------------------------------------------------------------------------------------
BLA Number and holder Official name and proper name
----------------------------------------------------------------------------------------------------------------
103234, Amgen, Inc............................. epoetin alfa-amgn.
103353, Amgen, Inc............................. filgrastim-amgn.
125553, Sandoz, Inc............................ filgrastim-sndz.
125294, Sicor Biotech UAB...................... filgrastim-srbt.
103772, Janssen Biotech, Inc................... infliximab-jnsn.
125031, Amgen, Inc............................. pegfilgrastim-amgn.
----------------------------------------------------------------------------------------------------------------

Each of the official names and proper names in proposed Sec.
299.20 and each the alternative official names and proper names
discussed previously was rigorously evaluated and determined unlikely
to be a source of errors. Each of these official names and proper names
(core name-suffix) would be sufficiently distinct from the
nonproprietary names of other products. The designated suffixes are
distinct from other drug substance names, do not look similar to the
names of other currently marketed products, are sufficiently distinct
from other suffix designations, and do not include any abbreviations
commonly used in clinical practice in a manner that may lead the suffix
to be misinterpreted as another element on the prescription or order.
While alternative official names and proper names are described in
this preamble to the proposed rule, the final rule would designate a
single official name that also would be designated as the proper name
for each product.

[[Page 52229]]

FDA invites comment on the proposed official names and proper names
for these products, including the alternative names listed previously
and any other proposed names containing suffixes composed of four
lowercase letters that would accomplish the objectives stated in this
document. In particular, FDA invites comment on the benefits and
challenges of designating a distinguishing suffix that is unique to
each of these six biological products versus designating a
distinguishing suffix that is shared by each product manufactured by a
single license holder (i.e., the three biological products manufactured
by Amgen). FDA also invites comment on whether meaningful suffixes
(e.g., suffixes derived from the names of the license holders) would be
expected to be more memorable or useful to health care providers or
patients than suffixes devoid of meaning, and therefore be more useful
for facilitating the safe use and appropriate pharmacovigilance of
these products. FDA further requests comment on whether meaningful
suffixes derived from the name of the license holder might create
inappropriate market advantages that would impede biosimilar products'
acceptance in the market.
Following approval of a BLA supplement to update product labeling
with the official name and proper name designated in any final rule,
FDA would take steps to ensure that its drug listings that interface
with other databases and systems reflect the newly designated
nonproprietary name. FDA also would work with other governmental
organizations and external stakeholders that play a role in national
drug naming or listings to help ensure that the official name and
proper name for the product is displayed accurately in drug listing
systems. We invite comment on the best means of coordinating with
external stakeholders that play a role in drug naming and listing to
achieve this objective considering, among other things, any transition
period before market availability of products labeled with the newly
designated nonproprietary names.

III. Legal Authority

Section 508 of the FD&C Act and section 351 of the PHS Act serve as
the principal legal authorities for this proposed rule. Section 508 of
the FD&C Act, which applies to biological products pursuant to section
351(j) of the PHS Act, provides FDA with authority to designate
official names for drugs if it determines that such action is necessary
or desirable in the interest of usefulness and simplicity. For the
reasons described previously, FDA has determined that the interest of
usefulness and simplicity warrants the designation of official names
for the products included in this rulemaking. FDA also has authority
under section 351(a) of the PHS Act to designate the proper name of a
biological product and may do so through rulemaking. FDA is exercising
this authority to designate matching proper names for these products.
Thus, section 508 of FD&C Act and section 351 of the PHS Act, in
conjunction with FDA's general rulemaking authority in section 701(a)
of the FD&C Act (21 U.S.C. 371(a)), provide legal authority for this
proposed rule.

IV. Effective Date

FDA proposes that any final rule that may be issued based on this
proposal become effective 90 days after the date of its publication in
the Federal Register. During the 90-day period after publication of any
final rule, FDA expects that BLA holders for these six products would
submit a prior approval supplement to their BLA to update the labeling
of their product. After approval of the supplement, FDA intends to work
with sponsors to minimize any manufacturing and distribution
disruptions related to the implementation of new labeling and any
related marketing materials. FDA expects that manufacturers will
implement the new labeling at the time of their next manufacturing run
and does not intend to object to manufacturers exhausting existing
inventories of finished product that is not labeled with the official
names and proper names designated by this rule.

V. Environmental Impact

The Agency has determined under 21 CFR 25.30(h) and (k) and
25.31(a) that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.

VI. Economic Analysis of Impacts: Summary

FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Office of Management and Budget (OMB) has determined that
this proposed rule is a significant regulatory action as defined by
Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the proposed rule imposes one-time
relabeling costs on one small business, the Agency proposes to certify
that the final rule will not have a significant economic impact on a
substantial number of small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $144 million, using the most current (2014) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.
We estimate the one-time costs of learning about the rule;
submitting labeling supplements, forms, and revised marketing materials
to FDA; changing labeling on affected products; FDA review of labeling
supplements, forms, and revised marketing materials; and activities to
educate practitioners about name changes. The one-time costs range from
$0.78 million to $3.04 million. Over 10 years, the annualized costs
range from $0.10 million to $0.40 million with a 7 percent discount
rate, and from $0.09 million to $0.35 million with a 3 percent discount
rate.
We expect the rule would have other costs that are not yet included
in these estimated costs. Additional costs to industry may include
costs updating prescribing and reimbursement systems to reflect the new
names and changing marketing materials to reflect the new names.
We lack data to quantify the benefits of the proposed rule. In the
event of biosimilar entry, the name changes for certain products that
would be required by this proposed rule may help mitigate a potential
competitive disadvantage for

[[Page 52230]]

biosimilar products that receive a nonproprietary name that includes a
distinguishing suffix. More competition between the biosimilar product
and the reference product may reduce the price and increase the usage
of those products. The proposed rule may also encourage the routine use
of suffixes for these six biological products, which may facilitate
more accurate prescribing and monitoring of these six biological
products if biosimilar products enter the market.

Table 1--Summary of Costs \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
One-time costs ($ mil) Total annualized costs over 10 Total annualized costs over 10
---------------------------------- years with 3 percent discount years with 7 percent discount
Total benefits rate ($ mil) rate ($ mil)
Low estimate High estimate -------------------------------------------------------------------
Low estimate High estimate Low estimate High estimate
--------------------------------------------------------------------------------------------------------------------------------------------------------
Not estimated..................................... 0.78 3.04 0.09 0.35 0.10 0.40
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Note: Costs are rounded.

The Economic Analysis of Impacts of the proposed rule performed in
accordance with Executive Order 12866, Executive Order 13563, the
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act is
available at http://www.regulations.gov under Docket No. FDA-2015-N-
0648 and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 11).

VII. Paperwork Reduction Act of 1995

FDA tentatively concludes that this proposed rule contains no new
collection of information. The official names and proper names of each
of these biological products, as designated by the proposed rule, would
be information originally supplied by the Federal government to the
recipient for the purpose of disclosure to the public, and the public
disclosure of such information is not a ``collection of information''
within the meaning of the Paperwork Reduction Act of 1995 (the PRA).
See 5 CFR 1320.3(c)(2). Therefore, clearance by the OMB under the PRA
(44 U.S.C. 3501-3520) is not required.
The discussion of effective date in the preamble (section IV) to
this proposed rule references certain actions that would be taken by
manufacturers and applicants for the specific approved biological
products for which this proposed rule would designate official names
and proper names, in order to comply with existing FDA regulations that
contain collections of information that are subject to review by OMB
under the PRA.
Specifically, prior to the effective date of any final rule based
on this proposal, a prior approval supplement would be submitted in
accordance with Sec. 601.12 (21 CFR 601.12) for each of six specific
BLAs referenced in this rule, to update the labeling of the product
(which includes the immediate container label and outer container or
package) with the designated official name and proper name. The
submission of supplements to approved license applications under Sec.
601.12 is approved under OMB control number 0910-0338. We estimate that
this rulemaking would result in the one-time submission of six
supplements. In conjunction with our previously approved collection of
information under Sec. 601.12, we estimated that each such supplement
would incur a burden of 40 hours.
The discussion of effective date also acknowledges that these
applicants would revise their labeling, which includes the immediate
container label and outer container or package, to reflect the newly
designated official names and proper names. (As noted, disclosing the
official names and proper names of each of these biological products to
the public is not a ``collection of information'' within the meaning of
the PRA. See 5 CFR 1320.3(c)(2).) The design and testing of
prescription drug labeling required under Sec. Sec. 201.56 and 201.57
(21 CFR 201.56 and 201.57) (including Sec. 201.56(a)(2)) is approved
under OMB control number 0910-0572. Concerning the immediate container
label and outer container or package, in the Federal Register of
December 18, 2014 (79 FR 75506), we published a proposed rule on the
electronic distribution of prescribing information for human
prescription drugs, including biological products. In section VII,
``Paperwork Reduction Act of 1995,'' we estimated the burden to design
(including revisions), test, and produce the label for a drug's
immediate container and outer container or package, as set forth in 21
CFR part 201 and other sections in subpart A and subpart B.

VIII. Comments

Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov or written comments to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of 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, and will be posted to the docket at http://www.regulations.gov.

IX. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

X. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified all the Web site addresses in this reference section,
but FDA is not responsible for any subsequent changes to the Web sites
after this document publishes in the Federal Register.)

1. FDA, Guidance for Industry, ``Immunogenicity Assessment for
Therapeutic Protein Products,'' August 2014, available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf.
2. Buck D., S. Cepok, S. Hoffmann, et al., ``Influence of the HLA-
DRB1 Genotype on Antibody Development to Interferon Beta in Multiple
Sclerosis.'' Archives of Neurology, 68(4):480-487, 2011.

[[Page 52231]]

3. Nease, R., S. Miller, and S. G. Frazee, ``2010 Specialty Drug
Trend Report.'' Express Scripts Specialty Benefit Services (June
2011).
4. Vora, J. B., ``Evaluation of Medical Specialty Medications:
Utilization and Management Opportunities,'' Commissioned by CVS
Caremark (April 8, 2014), available at http://info.cvscaremark.com/insights2014/Singh06-Medical-Specialty-Utilization-and-Management-Opportunities.pdf.
5. Dal Pan, G. J., M. Lindquist, and K. Gelperin, ``Postmarketing
Spontaneous Pharmacovigilance Reporting Systems,'' Chapter 10, in
Pharmacoepidemiology, 5th ed., edited by B. L. Strom and S.
Hennessy. Etobicoke (Canada): John Wiley & Sons; 2012.
6. Getz, K. A., S. Stergiopoulos, and K. I. Kaitin, ``Evaluating the
Completeness and Accuracy of MedWatch Data,'' American Journal of
Therapeutics, 21(6):442-446, 2014.
7. American Society of Health-System Pharmacists (ASHP), ``ASHP
Guidelines on Preventing Medication Errors With Chemotherapy and
Biotherapy,'' 2014, available at http://www.ashp.org/DocLibrary/BestPractices/MedMisGdlAntineo.aspx.
8. Institute for Safe Medication Practices (ISMP), ``ISMP's
Guidelines for Standard Order Sets,'' available at http://ismp.org/tools/guidelines/StandardOrderSets.asp.
9. See, e.g., Comments from AARP to Docket Nos. FDA-2011-D-0605,
FDA-2011-D-0602, and FDA-2011-D-0611 on ``Draft Guidance Documents
on Biosimilar Product Development,'' available at http://www.regulations.gov.
10. ``Apotex Announces FDA Has Accepted for Filing Its Biosimilar
Application for Pegfilgrastim'' (December 17, 2014), available at
http://www.apotex.com/global/about/press/20141217.asp; ``Hospira
Submits New Biologics License Application to U.S. FDA for Proposed
Epoetin Alfa Biosimilar,'' PR Newswire (January 12, 2015), available
at http://www.prnewswire.com/news-releases/hospira-submits-new-biologics-license-application-to-us-fda-for-proposed-epoetin-alfa-biosimilar-300018991.html; ``Celltrion Files for US FDA Approval of
Remsima[supreg],'' (August 11, 2014), available at http://www.celltrion.com/en/COMPANY/notice_view.asp?idx=456&code=ennews&intNowPage=1&menu_num=&align_year=all.
11. ``Preliminary Regulatory Impact Analysis, Initial Regulatory
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for
Designation of Official Names and Proper Names for Certain
Biological Products; Proposed Rule,'' available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects in 21 CFR Part 299

Drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, FDA proposes to amend 21 CFR part 299
as follows:

PART 299--DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES

0
1. The authority citation for 21 CFR part 299 is revised to read as
follows:

Authority: 21 U.S.C. 331, 351, 352, 355, 358, 360b, 371; 42
U.S.C. 262.

0
2. Add subpart B to Part 299 to read as follows:

Subpart B--Designated Names

Sec. 299.20 Official names and proper names of certain biological
products.

(a) The Food and Drug Administration has designated official names
under section 508 of the Federal Food, Drug, and Cosmetic Act for the
biological products licensed under section 351 of the Public Health
Service Act in the biologics license applications provided in the
following list. The official name shall be the proper name designated
in the license for use upon each package of the product.

----------------------------------------------------------------------------------------------------------------
Biologics license application (BLA) number Official name and proper name
----------------------------------------------------------------------------------------------------------------
BLA 103234..................................... epoetin alfa-cgkn.
BLA 103353..................................... filgrastim-jcwp.
BLA 125553..................................... filgrastim-bflm.
BLA 125294..................................... filgrastim-vkzt.
BLA 103772..................................... infliximab-hjmt.
BLA 125031..................................... pegfilgrastim-ljfd.
----------------------------------------------------------------------------------------------------------------

(b) [Reserved]

Dated: August 25, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-21382 Filed 8-27-15; 8:45 am]
BILLING CODE 4164-01-P