[Federal Register Volume 71, Number 235 (Thursday, December 7, 2006)]
[Rules and Regulations]
[Pages 70870-70873]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-20797]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 2
[Docket No. 2006N-0416]
RIN 0910-AF93
Use of Ozone-Depleting Substances; Removal of Essential Use
Designations
AGENCY: Food and Drug Administration, HHS.
ACTION: Direct final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulation on the use of ozone-depleting substances (ODSs) in
pressurized containers to remove the essential use designations for
beclomethasone, dexamethasone, fluticasone, bitolterol, salmeterol,
ergotamine tartrate, and ipratropium bromide used in oral pressurized
metered-dose inhalers (MDIs). Under the Clean Air Act, FDA, in
consultation with the Environmental Protection Agency (EPA), is
required to determine whether an FDA-regulated product that releases an
ODS is essential. None of these products is currently being marketed,
which provides grounds for removing their essential use designation. We
are using direct final rulemaking for this action because the agency
expects that there will be no significant adverse comment on the rule.
In the proposed rule section in this issue of the Federal Register, we
are concurrently proposing and soliciting comments on this rule. If
[[Page 70871]]
significant adverse comments are received, we will withdraw this final
rule and address the comments in a subsequent final rule. FDA will not
provide additional opportunity for comment.
DATES: The direct final rule is effective April 23, 2007, except for
Sec. 2.125(e)(4)(v) (21 CFR 2.125(e)(4)(v)), which is effective August
1, 2007. Submit written or electronic comments on or before February
20, 2007. If we receive no timely significant adverse comments, we will
publish a document in the Federal Register before March 22, 2007,
confirming the effective date of the direct final rule. If we receive
any timely significant adverse comments, we will publish a document of
significant adverse comment in the Federal Register withdrawing this
direct final rule before April 23, 2007.
ADDRESSES: You may submit comments, identified by Docket No. 2006N-0416
and RIN Number 0910-AF93, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and docket number and Regulatory Information Number (RIN) for this
rulemaking. All comments received will be posted without change to
http://www.fda.gov/ohrms/dockets/default.htm, including any personal
information provided. For additional information on submitting
comments, see the ``Request for Comments`` heading 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.fda.gov/ohrms/dockets/default.htm
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: Martha Nguyen or Wayne H. Mitchell,
Center for Drug Evaluation and Research (HFD-7), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
FDA, in consultation with EPA, determines whether a medical product
is essential for purposes of Title VI of the Clean Air Act (42 U.S.C.
7671 et seq.). If a medical product, including a drug, is determined to
be essential and meets the other elements of the definition found in
section 601 of the Clean Air Act, the product will be considered a
``medical device.'' ``Medical devices'' are exempt from the general
prohibition on nonessential uses of chlorofluorocarbons (CFCs) (a class
of ODSs) found in section 610 of the Clean Air Act. ODSs produced for
use in ``medical devices'' may also be exempt, if other conditions are
met, from the general prohibitions on production and consumption of
ODSs found in sections 604 and 605 of the Clean Air Act.
In 1978, we published a rule listing several essential uses of CFCs
and providing criteria for adding new essential uses (43 FR 11301 at
11316, March 17, 1978). The rule was codified as Sec. 2.125 (21 CFR
2.125) and Sec. 2.125 was amended at various times to add new
essential uses.
Over the years, alternatives were developed to ODS products whose
uses were listed in Sec. 2.125 as being essential, while other listed
ODS products were removed from the market. In light of these facts, and
in furtherance of our obligations under the Clean Air Act and the
Montreal Protocol on Substances that Deplete the Ozone Layer (September
16, 1987, 26 I.L.M. 1541 (1987)), we determined that it would be
appropriate to revise Sec. 2.125 to remove the essential use
designations of some products and provide criteria for the removal of
additional essential use designations in the future. Thus, the rule
revising Sec. 2.125 was published in the Federal Register of July 24,
2002 (67 FR 48370). Among other provisions, the rule removed the
essential use designations of various specific products that, at the
time the rule was being prepared, were no longer being marketed. The
rule went into effect on January 20, 2003. That rule also revised Sec.
2.125(g)(1) (21 CFR 2.125(g)(1)) to provide that if any product that
releases an ODS is no longer being marketed, the product may have its
essential use designation revoked through notice-and-comment
rulemaking.
II. Citizen Petition From Glaxosmithkline
In a citizen petition dated November 15, 2005, GlaxoSmithKline
(GSK) requested that MDIs containing the single active moieties
beclomethasone, fluticasone, and salmeterol be removed from the
essential use list of ODSs. GSK stated that because beclomethasone,
fluticasone, and salmeterol are no longer being marketed in MDIs that
release ODSs, all three active moieties meet the criterion under
revised Sec. 2.125(g) for being removed from the essential use list.
GSK requested that the essential use designation for beclomethasone,
fluticasone, and salmeterol be revoked through a direct final rule.
In addition, we have determined that dexamethasone, bitolterol,
ergotamine tartrate, and ipratropium bromide are no longer being
marketed in MDIs that release ODSs, which provides grounds for removing
their essential use designation.
III. Direct Final Rulemaking
We have determined that the subject of this rulemaking is suitable
for a direct final rule. The actions taken should be noncontroversial,
and the agency does not anticipate receiving any significant adverse
comments on this rule. However, in the even that significant adverse
comment is received, we are also publishing a companion proposed rule
to satisfy the requirement under Sec. 2.125(g) that essential uses be
removed through notice-and-comment rulemaking.
If we receive no significant adverse comment, we will publish a
document in the Federal Register, confirming the effective date of the
direct final rule. A significant adverse comment is one that explains
why the rule would be inappropriate, including challenges to the rule's
underlying premise or approach, or would be ineffective or unacceptable
without a change. A comment recommending a rule change in addition to
this rule will not be considered a significant adverse comment, unless
the comment states why this rule would be ineffective
[[Page 70872]]
without the additional change. If timely significant adverse comments
are received, we will publish a notice of significant adverse comment
in the Federal Register withdrawing this direct final rule within 30
days after the comment period ends.
Elsewhere in this issue of the Federal Register, we are publishing
a companion proposed rule, identical in substance to this direct final
rule, that provides a procedural framework from which to proceed with
standard notice and comment rulemaking in the event the direct final
rule is withdrawn because of significant adverse comment. The comment
period for the direct final rule runs concurrently with that of the
companion proposed rule. Any comments received under the companion
proposed rule will be treated as comments regarding the direct final
rule. Likewise, significant adverse comments submitted to the direct
final rule will be considered as comments to the companion proposed
rule, and we will consider those comments in developing a final rule.
We will not provide additional opportunity for comment on the companion
proposed rule.
If a significant adverse comment applies to part of this rule and
that part may be severed from the remainder of the rule, we may adopt
as final those parts of the rule that are not the subject of a
significant adverse comment. A full description of our policy on direct
final rule procedures may be found in a guidance document published in
the Federal Register of November 21, 1997 (62 FR 62466).
IV. Beclomethasone, Dexamethasone, Fluticasone, Bitolterol, Salmeterol,
Ergotamine Tartrate, and Ipratropium Bromide
The manufacturers of all approved beclomethasone, dexamethasone,
fluticasone, bitolterol, salmeterol, ergotamine tartrate, and
ipratropium bromide oral pressurized MDIs containing an ODS have
provided information that leads us to conclude that they have removed
these products from the market.\1\ Accordingly, we are amending our
regulation to remove beclomethasone, dexamethasone, fluticasone,
bitolterol, salmeterol, ergotamine tartrate, and ipratropium bromide
from the list of essential use drugs found in Sec. 2.125(e) (21 CFR
2.125(e)). Essential uses for metered-dose corticosteroid human drugs
for oral inhalation, metered-dose short-acting adrenergic
bronchodilator human drugs for oral inhalation, and metered-dose
salmeterol, ergotamine tartrate, and ipratropium bromide drug products
for oral inhalation, are listed in Sec. 2.125(e)(1), (e)(2), and
(e)(4) by active moiety. ``Active moiety'' is defined in 21 CFR
314.108(a) as follows: ``the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the physiological or pharmacological
action of the drug substance.''
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\1\ The drug products discussed in this direct final rule were
all approved for marketing under section 505 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355). We are unaware of any
unapproved beclomethasone, dexamethasone, fluticasone, bitolterol,
salmeterol, ergotamine tartrate, and ipratropium bromide oral
pressurized MDIs using an ODS as a propellant that are marketed in
the United States.
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MDIs that contain the active moieties beclomethasone,
dexamethasone, fluticasone, bitolterol, salmeterol, ergotamine
tartrate, and ipratropium bromide, use certain forms of these moieties.
Specifically, MDIs that have beclomethasone or fluticasone as their
active moieties use those moieties in the forms of beclomethasone
dipropionate and fluticasone propionate, respectively. Similarly, MDIs
that have dexamethasone, bitolterol, or salmeterol as their active
moieties use those moieties in the forms of dexamethasone sodium
phosphate, bitolterol mesylate, and salmeterol xinafoate, respectively.
Ergotamine tartrate is a salt of ergotamine, and it was used in oral
MDIs for the treatment of migraines. Its essential use designation is
for the ergotamine tartrate salt rather than the active moiety
ergotamine.
A. Beclomethasone
Oral pressurized MDIs that contain beclomethasone are listed in
Sec. 2.125(e)(1)(i) as an essential use. BECLOVENT and VANCERIL are
the only two oral pressurized MDIs that have been marketed and contain
beclomethasone with an ODS. On January 10, 2002, GSK, the manufacturer
of BECLOVENT, requested that we withdraw approval of their new drug
application (NDA) for BECLOVENT ODS MDIs (NDA 18-153) and informed us
that they had stopped marketing BECLOVENT ODS MDIs. On May 2, 2001,
Schering-Plough Corp. (Schering), the manufacturer of VANCERIL,
requested that we withdraw approval of NDA, for VANCERIL ODS MDIs, 84
micrograms per inhalation (microg/inh), and informed us that they had
stopped marketing VANCERIL 84 microg/inh MDIs in November 1999. Also,
on July 25, 2002, Schering informed us that they were removing VANCERIL
42 microg/inh from the market. On April 14, 2005, Schering requested
withdrawal of approval of NDA 17-573 for VANCERIL 42 microg/inh.
B. Dexamethasone
Oral pressurized MDIs that contain dexamethasone are listed in
Sec. 2.125(e)(1)(ii) as an essential use. DEXACORT ORAL MDI is the
only oral pressurized MDI that has been marketed and contains
dexamethasone with an ODS. On September 13, 2002, Celltech
Pharmaceuticals, Inc., the manufacturer of DEXACORT ORAL MDI, requested
that we withdraw approval of NDA 01-3413 for DEXACORT ORAL MDIs and
informed us that they had stopped marketing DEXACORT ORAL MDIs on
August 15, 1996.
C. Fluticasone
Oral pressurized MDIs that contain fluticasone are listed in Sec.
2.125(e)(1)(iv) as an essential use. FLOVENT CFC MDI is the only oral
pressurized MDI that has been marketed and contains fluticasone with an
ODS. GSK, the manufacturer of FLOVENT CFC MDIs, has informed us that
they stopped marketing FLOVENT CFC MDIs in November 2004.
D. Bitolterol
Oral pressurized MDIs that contain bitolterol are listed in Sec.
2.125(e)(2)(ii) as an essential use. TORNALATE MDI is the only oral
pressurized MDI that has been marketed and contains bitolterol with an
ODS. On January 28, 2003, Sanofi-Synthelabo, Inc., the manufacturer of
TORNALATE MDIs, informed us that they had stopped marketing TORNALATE
MDIs on October 1, 2000.
E. Salmeterol
Metered-dose salmeterol drug products are listed in Sec.
2.125(e)(4)(i) as an essential use. SEREVENT MDI is the only metered-
dose salmeterol drug product with an ODS that has been marketed. GSK,
the manufacturer of SEREVENT MDIs, has informed us that they stopped
marketing SEREVENT MDIs in January 2003.
F. Ergotamine Tartrate
Oral pressurized MDIs that contain ergotamine tartrate are listed
in Sec. 2.125(e)(4)(ii) as an essential use. MEDIHALER ERGOTAMINE is
the only oral pressurized MDI that has been marketed and contains
ergotamine tartrate with an ODS. 3M Pharmaceuticals, the manufacturer
of MEDIHALER ERGOTAMINE, has informed us that they stopped
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marketing MEDIHALER ERGOTAMINE in November 1991.
G. Ipratropium Bromide
Oral pressurized MDIs that contain ipratropium bromide are listed
in Sec. 2.125(e)(4)(v) as an essential use. ATROVENT CFC MDI is the
only oral pressurized MDI that has been marketed and contains
ipratropium bromide with an ODS. Boehringer Ingelheim Pharmaceuticals,
the manufacturer of ATROVENT CFC MDI, has informed us that they stopped
marketing ATROVENT CFC MDIs in January 2006. This direct final rule
does not affect MDIs containing ipratropium bromide and albuterol
sulfate in combination, marketed as COMBIVENT, which are listed in
Sec. 2.125(e)(4)(viii) as a separate essential use.
H. Wholesale and Retail Stocks
Based on information given to us by the manufacturers, we have
concluded that any beclomethasone, dexamethasone, fluticasone,
bitolterol, salmeterol, and ergotamine tartrate ODS MDIs that may be in
retail or wholesale stocks will have passed their expiration dates by
the effective date for removal of Sec. 2.125(e)(1)(i), (e)(1)(ii),
(e)(1)(iv), (e)(2)(ii), (e)(4)(i), and (e)(4)(ii). Boehringer Ingelheim
Pharmaceuticals, the manufacturer of ipratropium bromide, has informed
us that any ipratropium bromide that may be in retail or wholesale
stocks will have passed its expiration date by July 2007. Accordingly,
we have set the effective date for removal of Sec. 2.125(e)(4)(v) as
August 1, 2007.
V. Environmental Impact
We have carefully considered, under 21 CFR part 25, the potential
environmental effects of this action. We have concluded that the action
will not have a significant impact on the human environment and that an
environmental impact statement is not required. Our finding of no
significant impact and the evidence supporting that finding, contained
in an environmental assessment, may be seen in the Division of Dockets
Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday through
Friday.
VI. Analysis of Impacts
FDA has examined the impacts of the direct final rule under
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4).
Executive Order 12866 directs 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 agency believes that
this direct final rule is not a significant regulatory action as
defined by the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because we are removing the essential use
designations for certain drug products that are either no longer being
marketed or are no longer being marketed in a formulation containing
ODSs, the agency certifies that the direct 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 $118 million, using the most current (2004) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
direct final rule to result in any 1-year expenditure that would meet
or exceed this amount.
VII. The Paperwork Reduction Act of 1995
This direct final rule contains no collections of information.
Therefore, clearance by the Office of Management and Budget under the
Paperwork Reduction Act of 1995 is not required.
VIII. Federalism
FDA has analyzed this direct final rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that 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 has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, we do
not plan to prepare a federalism summary impact statement for this
rulemaking procedure. We invite comments on the federalism implications
of this direct final rule.
IX. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two copies of any
written comments are to be submitted, except that individuals may
submit one paper copy. Comments are to be identified 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.
List of Subjects in 21 CFR Part 2
Administrative practice and procedure, Cosmetics, Drugs, Foods.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Clean
Air Act, and under authority delegated to the Commissioner of Food and
Drugs, after consultation with the Administrator of the Environmental
Protection Agency, 21 CFR part 2 is amended as follows:
PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS
0
1. The authority citation for 21 CFR part 2 continues to read as
follows:
Authority: 15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342,
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42
U.S.C. 7671 et seq.
Sec. 2.125 [Amended]
0
2. Section 2.125 is amended by removing and reserving paragraphs
(e)(1)(i), (e)(1)(ii), (e)(1)(iv), (e)(2)(ii), (e)(4)(i), (e)(4)(ii),
and (e)(4)(v).
Dated: October 13, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-20797 Filed 12-6-06; 8:45 am]
BILLING CODE 4160-01-S