[Federal Register: April 14, 2010 (Volume 75, Number 71)]
[Rules and Regulations]
[Page 19213-19241]
[DOCID:fr14ap10-10]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. FDA-2006-N-0304] (formerly Docket No. 2006N-0262)
RIN 0910-AF92

Use of Ozone-Depleting Substances; Removal of Essential-Use
Designation (Flunisolide, etc.)

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY:  The Food and Drug Administration (FDA), after consultation
with the Environmental Protection Agency (EPA), is amending FDA's
regulation on the use of ozone-depleting substances (ODSs) in self-
pressurized containers to remove the essential-use designations for
flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and
ipratropium in combination, cromolyn, and nedocromil used in oral
pressurized metered-dose inhalers (MDIs). The Clean Air Act requires
FDA, in consultation with the EPA, to determine whether an FDA-
regulated product that releases an ODS is an essential use of the ODS.
FDA has concluded that there are no substantial technical barriers to
formulating flunisolide, triamcinolone, metaproterenol, pirbuterol,
albuterol and ipratropium in combination, cromolyn, and nedocromil as
products that do not release ODSs, and therefore they will no longer be
essential uses of ODSs as of the effective dates of this rule. MDIs for
these active moieties containing an ODS may not be marketed after the
relevant effective date.

DATES:  Removal of Sec.  2.125(e)(2)(iii) and Sec.  2.125(e)(4)(vii) is
effective June 14, 2010. Removal of Sec.  2.125(e)(1)(v) and Sec.
2.125(e)(4)(iv) is effective December 31, 2010. Removal of Sec.
2.125(e)(1)(iii) is effective June 30, 2011. Removal of Sec.
2.125(e)(2)(iv) and Sec.  2.125(e)(4)(viii) is effective December 31,
2013.

ADDRESSES:  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:  Martha Nguyen, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 6352, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction and Highlights of the Rule
II. Background
    A. CFCs
    B. Regulation of ODSs
    1. The 1978 Rules
    2. The Montreal Protocol
    3. The 1990 Amendments to the Clean Air Act
    4. EPA's Implementing Regulations
    5. FDA's 2002 Regulation
III. Criteria
IV. Comments on the 2007 Proposed Rule
    A. Flunisolide, Triamcinolone, Metaproterenol
    B. Cromolyn and Nedocromil
    C. Pirbuterol
    1. Do Substantial Technical Barriers To Formulating Pirbuterol
Products Without ODSs Exist?
    2. Do Pirbuterol MDIs Provide an Otherwise Unavailable Important
Public Health Benefit?
    a. Does Pirbuterol Provide a Greater Therapeutic Benefit Than
Similar Adrenergic Bronchodilators?
    b. Does the Breath-Actuated Device Associated With Pirbuterol MDIs
Provide an Important Public Health Benefit?
    3. Does Use of Pirbuterol MDIs Release Cumulatively Significant
Amounts of ODSs Into the Atmosphere and Is the Release Warranted
Because These MDIs Provide an Otherwise Unavailable Important Public
Health Benefit?
    4. Additional Comments on Miscellaneous Issues
    a. Sufficiency of Advisory Committee and Open Public Meetings
    b. Sufficiency of Proposed Rule
    c. Regulatory Flexibility Act
    d. National Environmental Policy Act
    D. Albuterol and Ipratropium in Combination
    1. Do Substantial Technical Barriers To Formulating Products
Containing Albuterol and Ipratropium in Combination Without ODSs Exist?
    2. Do MDIs Containing Albuterol and Ipratropium in Combination
Provide an Otherwise Unavailable Important Public Health Benefit?
    3. Does Use of MDIs Containing Albuterol and Ipratropium in
Combination Release Cumulatively Significant Amounts of ODSs Into the
Atmosphere and Is the Release Warranted Because These MDIs Provide an
Otherwise Unavailable Important Public Health Benefit?
    4. Additional Comments on Miscellaneous Issues
    a. Criteria Used in Rulemaking
    b. Intent to Reformulate
    c. Deadline for Overall CFC Phase-Out
    d. Sufficiency of Advisory Committee Meeting
    E. Effective dates
    F. Conclusions
V. Environmental Impact
VI. Analysis of Impacts
    A. Introduction
    B. Need for Regulation and the Objective of this Rule
    C. Background
    1. CFCs and Stratospheric Ozone
    2. The Montreal Protocol
    3. Benefits of the Montreal Protocol
    4. Characteristics of COPD
    5. Characteristics of Asthma
    6. Current U.S. Market for CFC MDIs
    D. Benefits and Costs of the Final Rule
    1. Baseline Conditions
    2. Benefits of the Final Rule
    a. Reduced CFC Emissions
    b. Returns on Investment in Environmentally-Friendly Technology
    c. International Cooperation
    3. Costs of the Final Rule
    4. Effects on Medicare and Medicaid
    a. Medicaid
    b. Medicare
    E. Alternative Phase-Out Dates
    F. Sensitivity Analyses
    G. Conclusion
VII. Regulatory Flexibility Analysis
VIII. The Paperwork Reduction Act of 1995
IX. Federalism
X. References

I. Introduction and Highlights of the Rule

    With this rule, FDA removes the last remaining essential-use
designations for chlorofluorocarbons (CFCs) used in MDIs for the
treatment of asthma and chronic obstructive pulmonary disease (COPD).
This regulatory action is the culmination of many years of efforts to
protect the environment by limiting the production and use of ODSs. It
began with a rulemaking in 1978 and involved an international treaty,
legislation, and rulemakings as described in the background section.
After the effective date of this rule, there will remain only three
essential uses of ODSs: (1) Anesthetic drugs for topical use on
accessible mucous membranes of humans where a cannula is used for
application; (2) metered-dose atropine sulfate aerosol human drugs
administered by oral inhalation; and (3) sterile aerosol talc
administered intrapleurally by thoracoscopy for human use (21 CFR
2.125(e)(4)(iii), (vi), and (ix)).
    On June 11, 2007, FDA published a proposed rule in the Federal
Register (72 FR 32030) (the proposed rule), proposing to remove the
essential-use designations for oral pressurized MDIs containing
flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and
ipratropium in combination, cromolyn, and nedocromil. These MDIs
containing chlorofluorocarbons (CFCs) or other ODSs may not be marketed
without an essential-use designation. There are three criteria that
must all be met for each of these MDIs to retain their essential-use
designation. For each of these MDIs to retain its essential-use
designation, we must find that:
    1. Substantial technical barriers exist to formulating the product
without ODSs;
    2. The product will provide an unavailable important public health
benefit; and
    3. Use of the product does not release cumulatively significant
amounts of ODSs into the atmosphere or the release is warranted in view
of the unavailable important public health benefit.
    With respect to MDIs containing flunisolide, triamcinolone,
metaproterenol, pirbuterol, cromolyn, and nedocromil, we tentatively
found in the proposed rule that no substantial technical barriers exist
to formulating them without ODSs, they do not provide an otherwise
unavailable important public health benefit because of the availability
of therapeutic alternatives, and the release of ODSs into the
atmosphere from these MDIs is cumulatively significant and is not
warranted because they do not provide an otherwise unavailable
important public health benefit. In addition, we had proposed an
effective date for this rule of December 31, 2009.
    After considering the information received at the August 2, 2007,
public meeting and written comments submitted in response to the
proposal, FDA has concluded that there are no

substantial technical barriers to formulating flunisolide,
triamcinolone, metaproterenol, pirbuterol, cromolyn, and nedocromil as
products that do not release ODSs, and therefore flunisolide,
triamcinolone, metaproterenol, pirbuterol, cromolyn, and nedocromil no
longer meet the criteria to be an essential use of ODSs. We have also
determined that the appropriate effective date for the removal of the
essential-use designation for metaproterenol and nedocromil MDIs is
June 14, 2010, the appropriate effective date for the removal of the
essential-use designation for triamcinolone and cromolyn MDIs is
December 31, 2010, and the appropriate effective date for the removal
of the essential-use designation for flunisolide is June 30, 2011. In
addition, we have determined that the appropriate effective date for
pirbuterol is December 31, 2013, because this date provides over 3
years for Maxair Autohaler (pirbuterol acetate inhalation aerosol)
users who are accustomed to a breath-actuated device to consult with
their health care providers, evaluate options, and transition to
appropriate therapeutic alternatives. We will discuss our
determinations on the criteria and the effective date in section IV of
this document, ``Comments on the 2007 Proposed Rule.''
    With respect to MDIs containing albuterol and ipratropium in
combination, we were unable to determine initially whether substantial
technical barriers exist to formulating them without ODSs. In the
proposed rule, we tentatively found that these MDIs do not provide an
otherwise unavailable important public health benefit and the release
of ODSs into the atmosphere from these MDIs is cumulatively significant
and is not warranted because they do not provide an otherwise
unavailable important public health benefit. Again, we proposed an
effective date for this rule of December 31, 2009.
    After considering the information received at the August 2, 2007,
public meeting and written comments submitted in response to the
proposal, FDA has concluded that there are no substantial technical
barriers to formulating albuterol and ipratropium bromide in
combination as a product that does not release ODSs, and therefore
albuterol and ipratropium bromide in combination no longer meets the
criteria to be an essential use of ODSs. We have determined that the
appropriate effective date for the removal of the essential-use
designation for albuterol and ipratropium bromide in combination is
December 31, 2013, because this date provides over 3 years to
disseminate information about the transition to Combivent Inhalation
Aerosol users who may have multiple health conditions that may make the
transition to therapeutic alternatives more difficult. The transition
period allows these individuals time to consult with their health care
providers, evaluate options, and transition to appropriate therapeutic
alternatives. We will discuss our determinations on the criteria and
the effective date in section IV of this document ``Comments on the
2007 Proposed Rule.''

II. Background

A. CFCs

    Chlorofluorocarbons (CFCs) are organic compounds that contain
carbon, chlorine, and fluorine atoms. CFCs were first used commercially
in the early 1930s as a replacement for hazardous materials then used
in refrigeration, such as sulfur dioxide and ammonia. Subsequently,
CFCs were found to have a large number of uses, including as solvents
and as propellants in self-pressurized aerosol products, such as MDIs.
    CFCs are very stable in the troposphere, the lowest part of the
atmosphere. They move to the stratosphere, a region that begins about
10 to 16 kilometers (km) (6 to 10 miles) above the Earth's surface and
extends up to about 50 km (31 miles) altitude. Within the stratosphere,
there is a zone about 15 to 40 km (10 to 25 miles) above the Earth's
surface in which ozone is relatively highly concentrated. This zone in
the stratosphere is generally called the stratospheric ozone layer.
Once in the stratosphere, CFCs are gradually broken down by strong
ultraviolet light, releasing chlorine atoms that then deplete
stratospheric ozone. Depletion of stratospheric ozone by CFCs and other
ODSs allows more ultraviolet-B (UV-B) radiation to reach the Earth's
surface, where it increases skin cancers and cataracts, and damages
some marine organisms, plants, and plastics.

B. Regulation of ODSs

    The link between CFCs and the depletion of stratospheric ozone was
discovered in the mid-1970s. Since 1978, the U.S. Government has
pursued a vigorous and consistent policy, through the enactment of laws
and regulations, of limiting the production, use, and importation of
ODSs, including CFCs.
1. The 1978 Rules
    In the Federal Register of March 17, 1978 (43 FR 11301), FDA and
EPA published rules banning, with a few exceptions, the use of CFCs as
propellants in aerosol containers. These rules were issued under
authority of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 321 et seq.) and the Toxic Substances Control Act (15 U.S.C.
2601 et seq.), respectively. FDA's rule (the 1978 rule) was codified as
Sec.  2.125 (21 CFR 2.125). These rules issued by FDA and EPA had been
preceded by rules issued by FDA and the Consumer Product Safety
Commission requiring products that contain CFC propellants to bear
environmental warning statements on their labeling (42 FR 22018, April
29, 1977; 42 FR 42780, August 24, 1977).
    The 1978 rule prohibited the use of CFCs as propellants in self-
pressurized containers in any food, drug, medical device, or cosmetic.
As originally published, the rule listed five essential uses exempt
from the ban. The second listed essential use was for ``[m]etered-dose
steroid bronchodilator human drugs for oral inhalation.'' This use
describes flunisolide MDIs and triamcinolone MDIs. The third listed
essential use was for ``[m]etered-dose adrenergic bronchodilator human
drugs for oral inhalation.'' This use describes metaproterenol MDIs and
pirbuterol MDIs.\1\
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    \1\ The essential-use designation for ``[m]etered-dose cromolyn
sodium human drugs administered by oral inhalation'' was added to
Sec.  2.125(e) on February 6, 1986 (51 FR 5190). The essential-use
designation for ``[m]etered-dose nedocromil sodium human drugs
administered by oral inhalation'' was added to Sec.  2.125(e) on
January 26, 1993 (58 FR 6086). The essential-use designation for
``[m]etered-dose ipratropium bromide and albuterol sulfate, in
combination, administered by oral inhalation'' was added on April 9,
1996 (61 FR 15700).
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    The 1978 rule provided criteria for adding new essential uses, and
several uses were added to the list using these criteria, the last one
in 1996. The 1978 rule did not provide any mechanism for removing
essential uses from the list as alternative products were developed or
CFC-containing products were removed from the market. The absence of a
removal procedure came to be viewed as a deficiency in the 1978 rule,
and was addressed in a later rulemaking, discussed in section II.B.5 of
this document.
2. The Montreal Protocol
    On April 21, 1989, the United States became a Party to the Montreal
Protocol on Substances that Deplete the Ozone Layer (Montreal Protocol)
(September 16, 1987, 26 I.L.M. 1541 (1987)),

available at http://www.unep.org/ozone/pdfs/Montreal-
Protocol2000.pdf.\2\ The United States played a leading role in the
negotiation of the Montreal Protocol, believing that internationally
coordinated control of ODSs would best protect both the U.S. and global
public health and the environment from potential adverse effects of
depletion of stratospheric ozone. Currently, there are 196 Parties to
this treaty.\3\ When it joined the treaty, the United States committed
to reducing production and consumption of certain CFCs to 50 percent of
1986 levels by 1998-99 (Article 2(4) of the Montreal Protocol). It also
agreed to accept an ``adjustment'' procedure, by which, following
assessment of the existing control measures, the Parties could adjust
the scope, amount, and timing of those control measures for substances
already subject to the Montreal Protocol. As the evidence regarding the
impact of ODSs on the ozone layer became stronger, the Parties used
this adjustment procedure to accelerate the phase-out of ODSs. At the
fourth Meeting of the Parties to the Montreal Protocol, held at
Copenhagen in November 1992, the Parties adjusted Article 2 of the
Montreal Protocol to eliminate the production and importation of CFCs
by January 1, 1996, by Parties that are developed countries (Decision
IV/2).\4\ The adjustment also indicated that it would apply, ``save to
the extent that the Parties decide to permit the level of production or
consumption that is necessary to satisfy uses agreed by them to be
essential'' (Article 2A(4)). Under the treaty's rules of procedure, an
essential-use decision requires a two-thirds majority vote by the
Parties to the treaty, although, to date, all such decisions have been
made by consensus. To produce or import CFCs for an essential use under
the Montreal Protocol, a Party must request and obtain approval for an
exemption at a Meeting of the Parties.
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    \2\ FDA has verified all Web site addresses cited in this
document, but FDA is not responsible for any subsequent changes to
the Web sites after this document has published in the Federal
Register.
    \3\ The summary descriptions of the Montreal Protocol and
decisions of Parties to the Montreal Protocol contained in this
document are presented here to help you understand the background of
the action we are taking. These descriptions are not intended to be
formal statements of policy regarding the Montreal Protocol.
Decisions by the Parties to the Montreal Protocol are cited in this
document in the conventional format of ``Decision IV/2,'' which
refers to the second decision recorded in the Report of the Fourth
Meeting of the Parties to the Montreal Protocol on Substances That
Deplete the Ozone Layer. Reports of Meetings of the Parties to the
Montreal Protocol may be found on the United Nations Environment
Programme's Web site at http://ozone.unep.org/Meeting_Documents/
mop.
    \4\ Production of CFCs in economically less-developed countries
is being phased out and is scheduled to end by January 1, 2010. See
Article 2A of the Montreal Protocol.
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    One of the most important essential uses of CFCs under the Montreal
Protocol is their use in MDIs for the treatment of asthma and COPD. The
decision on whether the use of CFCs in MDIs is ``essential'' for
purposes of the Montreal Protocol turns on whether ``(1) It is
necessary for the health, safety, or is critical for the functioning of
society (encompassing cultural and intellectual aspects) and (2) there
are no available technically and economically feasible alternatives or
substitutes that are acceptable from the standpoint of environment and
health'' (Decision IV/25).
    Each request and any subsequent exemption is for only 1 year's
duration (Decision V/18). Since 1994, the United States and some other
Parties to the Montreal Protocol have annually requested, and been
granted, essential-use exemptions for the production or importation of
CFCs for their use in MDIs for the treatment of asthma and COPD (see,
among others, Decisions VI/9 and VII/28). The exemptions have been
consistent with the criteria established by the Parties, which make the
grant of an exemption contingent on a finding that the use for which
the exemption is being requested is essential for health, safety, or
the functioning of society, and that there are no available technically
and economically feasible alternatives or substitutes that are
acceptable from the standpoint of health or the environment (Decision
IV/25).
    Phasing out the use of CFCs in MDIs for the treatment of asthma and
COPD has been an issue of particular interest to the Parties to the
Montreal Protocol. Several decisions of the Parties have dealt with the
transition to CFC-free MDIs, including the following decisions:
     Decision VIII/10 stated that the Parties that are
developed countries would take various actions to promote industry's
participation in a smooth and efficient transition away from CFC-based
MDIs (San Jose, Costa Rica, 1996).
     Decision IX/19 required developed country Parties that
submitted essential-use nominations for CFC-propelled MDIs to present
an initial national or regional transition strategy by January 31, 1999
(Montreal, Canada, 1997).
     Decision XII/2 elaborated on the content of national or
regional transition strategies required under Decision IX/19 and
indicated that any MDI for the treatment of asthma or COPD approved for
marketing after 2000 would not be an ``essential use'' unless it met
the criteria laid out by the Parties for essential uses (Ouagadougou,
Burkina Faso, 2000).
     Decision XIV/5 requested that each Party report annually
the quantities of CFC and non-CFC MDIs and dry-powder inhalers (DPIs)
sold or distributed within its borders and the approval and marketing
status of non-CFC MDIs and DPIs. Decision XIV/5 also noted ``with
concern the slow transition to CFC-free metered-dose inhalers in some
Parties'' (Rome, Italy, 2002).
     Decision XV/5 states that, at the 17th Meeting of the
Parties (in December 2005) or thereafter, no essential uses of CFCs
will be authorized for Parties that are developed countries, unless the
Party requesting the essential-use allocation has submitted an action
plan. Among other items, the action plan should include a specific date
by which the Party plans to cease requesting essential-use allocations
of CFCs for albuterol MDIs to be sold or distributed in developed
countries\5\ (Nairobi, Kenya, 2003).
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    \5\ Our obligation under XV/5 was met by our final rule
eliminating the essential-use status of albuterol (70 FR 17168,
April 4, 2005).
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     Decision XVII/5 states that Parties that are developed
counties should provide a date to the Ozone Secretariat\6\ before the
18th Meeting of the Parties (October 30 to November 3, 2006) by which
time a regulation or regulations will have been proposed to determine
whether MDIs, other than those that have albuterol as the only active
ingredient, are nonessential (Dakar, Senegal, 2005).
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    \6\ The Ozone Secretariat is the Secretariat for the Montreal
Protocol and the Vienna Convention for the Protection of the Ozone
Layer (the Vienna Convention) (March 22, 1985, 26 I.L.M. 1529
(1985)), available at http://ozone.unep.org/pdfs/
viennaconvention2002.pdf. Based at the United Nations Environment
Programme (UNEP) offices in Nairobi, Kenya, the Secretariat
functions in accordance with Article 7 of the Vienna Convention and
Article 12 of the Montreal Protocol.
    The main duties of the Secretariat include the following:
     Arranging for and servicing the Conference of the
Parties, Meetings of the Parties, their Committees, the Bureaux,
Working Groups, and Assessment Panels;
     Arranging for the implementation of decisions resulting
from these meetings;
     Monitoring the implementation of the Vienna Convention
and the Montreal Protocol;
     Reporting to the Meetings of the Parties and to the
Implementation Committee;
     Representing the Convention and the Protocol; and
     Receiving and analyzing data and information from the
Parties on the production and consumption of ODSs.
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3. The 1990 Amendments to the Clean Air Act
    In 1990, Congress amended the Clean Air Act to, among other things,
better protect stratospheric ozone (Public Law

No. 101-549, November 15, 1990) (the 1990 amendments). The 1990
amendments were drafted to complement, and be consistent with, our
obligations under the Montreal Protocol (see section 614 of the Clean
Air Act (42 U.S.C. 7671m)). Section 614(b) of the Clean Air Act
provides that, in the case of a conflict between any provision of the
Clean Air Act and any provision of the Montreal Protocol, the more
stringent provision will govern. Section 604 of the Clean Air Act
requires the phase-out of the production of CFCs by 2000 (42 U.S.C.
7671c),\7\ while section 610 of the Clean Air Act (42 U.S.C. 7671i)
required EPA to issue regulations banning the sale or distribution in
interstate commerce of nonessential products containing CFCs. Sections
604 and 610 provide exceptions for ``medical devices.'' Section 601(8)
(42 U.S.C. 7671(8)) of the Clean Air Act defines ``medical device'' as:
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    \7\ In conformance with Decision IV/2, EPA issued regulations
accelerating the complete phase-out of CFCs, with exceptions for
essential uses, to January 1, 1996 (58 FR 65018, December 10, 1993).
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``any device (as defined in the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 321)), diagnostic product, drug (as defined in the Federal
Food, Drug, and Cosmetic Act), or drug delivery system-
    (A) if such device, product, drug, or drug delivery system utilizes
a class I or class II substance for which no safe and effective
alternative has been developed, and where necessary, approved by the
Commissioner [of Food and Drugs]; and (B) if such device, product,
drug, or drug delivery system, has, after notice and opportunity for
public comment, been approved and determined to be essential by the
Commissioner [of Food and Drugs] in consultation with the Administrator
[of EPA].''
4. EPA's Implementing Regulations
    EPA regulations implementing the Montreal Protocol and the
stratospheric ozone protection provisions of the 1990 amendments are
codified in part 82 of title 40 of the Code of Federal Regulations (40
CFR part 82). (See 40 CFR 82.1 for a statement of intent.) Like the
1990 amendments, EPA's implementing regulations contain two separate
prohibitions, one on the production and import of CFCs (subpart A of 40
CFR part 82) and the other on the sale or distribution of products
containing CFCs (40 CFR 82.66).
    The prohibition on production and import of CFCs contains an
exception for essential uses and, more specifically, for essential
MDIs. The definition of essential MDI at 40 CFR 82.3 requires that the
MDI be intended for the treatment of asthma or COPD, be essential under
the Montreal Protocol, and if the MDI is for sale in the United States,
be approved by FDA and listed as essential in FDA's regulations at
Sec.  2.125.
    The prohibition on the sale of products containing CFCs includes a
specific prohibition on aerosol products and other pressurized
dispensers. The aerosol product ban contains an exception for medical
devices listed in Sec.  2.125(e). The term ``medical device'' is used
with the same meaning it was given in the 1990 amendments and FDA
regulations have interpreted the term ``medical device'' to refer to
any product that contains an active moiety that appears on the
essential-use list found in Sec.  2.125.
5. FDA's 2002 Regulation
    In the 1990s, we decided that Sec.  2.125 required revision to
better reflect our obligations under the Montreal Protocol, the 1990
amendments, and EPA's regulations, and to encourage the development of
ozone-friendly alternatives to medical products containing CFCs. In
particular, as acceptable alternatives that did not contain CFCs or
other ODSs came on the market, there was a need to provide a mechanism
for removing essential uses from the list in Sec.  2.125(e). In the
Federal Register of March 6, 1997 (62 FR 10242), we published an
advance notice of proposed rulemaking (the 1997 ANPRM) in which we
outlined our then-current thinking on the content of an appropriate
rule regarding ODSs in products FDA regulates. We received almost
10,000 comments on the 1997 ANPRM. In response to the comments, we
revised our approach and drafted a proposed rule published in the
Federal Register of September 1, 1999 (64 FR 47719) (the 1999 proposed
rule). We received 22 comments on the 1999 proposed rule. After minor
revisions in response to these comments, we published a final rule in
the Federal Register of July 24, 2002 (67 FR 48370) (the 2002 final
rule) (corrected in 67 FR 49396, July 30, 2002, and 67 FR 58678,
September 17, 2002). The 2002 final rule listed as a separate essential
use each active moiety\8\ marketed under the 1978 rule as essential
uses for metered-dose steroid human drugs for oral inhalation and
metered-dose adrenergic bronchodilator human drugs for oral inhalation;
eliminated the essential-use designations in Sec.  2.125(e) for
metered-dose steroid human drugs for nasal inhalation and for products
that were no longer marketed; set new standards to determine when a new
essential-use designation should be added to Sec.  2.125; and set
standards to determine whether the use of an ODS in a medical product
remains essential.
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    \8\ Section 314.108(a) (21 CFR 314.108(a)) defines ``active
moiety'' as 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. When describing the various essential
uses, we will generally refer to the active moiety, for example,
pirbuterol, as opposed to the active ingredient, which, using the
same example, would be pirbuterol acetate. When discussing
particular indications and other material from the approved labeling
of a drug product, we will generally use the brand name of the
product, which, using the same example would be Maxair. In
describing material from treatises, journals, and other non-FDA
approved publications, we will generally follow the usage in the
original publication.
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    This rulemaking fulfills our obligation under Sec.  2.125, as well
as the Clean Air Act, the Montreal Protocol, and our general duty to
protect the public health, by removing ODS products from the
marketplace when those products are no longer essential.

III. Criteria

    The 2002 final rule revised 21 CFR Sec.  2.125(g)(2) to establish a
standard for removing an essential-use designation after January 1,
2005, for any drug for which there is no acceptable non-ODS alternative
with the same active moiety. As explained in the proposed rule, we have
reviewed the essential-use designation for flunisolide, triamcinolone,
metaproterenol, pirbuterol, albuterol and ipratropium in combination,
cromolyn, and nedocromil under that authority. The process for removing
the essential-use designation under Sec.  2.125(g)(2) includes
consultation with a relevant advisory committee and an open public
meeting, in addition to a proposed rule and a final rule. The criterion
established for removing the essential use in such circumstances is
that the use no longer meets the criteria specified in revised Sec.
2.125(f) for adding a new essential use (21 CFR Sec.  2.125(g)(2)). The
criteria in Sec.  2.125(f) are: ``(i) Substantial technical barriers
exist to formulating the product without ODSs; (ii) The product will
provide an unavailable important public health benefit; and (iii) Use
of the product does not release cumulatively significant amounts of
ODSs into the atmosphere or the release is warranted in view of the
unavailable important public health benefit.''
    The three criteria in Sec.  2.25(f)(1) are linked by the word
``and.'' Because the three criteria are linked by ``and'' (as

opposed to ``or''), failure to meet any single criterion results in a
determination that the use is not essential.
    As noted in the 2002 proposed rule, we intend the term ``technical
barriers'' to refer to difficulties encountered in chemistry and
manufacturing. To demonstrate that substantial technical barriers
exist, it would have to be established that all available alternative
technologies have been evaluated and that each alternative is unusable
(67 FR 48370 at 48373). In applying the ``technical barriers''
criterion, we look at the results of reformulation efforts for similar
products, as well as statements made about the manufacturer's
particular efforts to reformulate its product or products.
    In discussing what is ``an unavailable important public health
benefit,'' we have said: The agency intends to give the phrase
``unavailable important public health benefit'' a markedly different
construction from the [phrase used in the 1978 rule] ``substantial
health benefit.'' One key point to note here is that the 2002 final
rule (67 FR 48370) raised the hurdle for the public health benefit that
needs to be shown. A use that was shown to have a ``substantial health
benefit'' under the 1978 rule (all essential uses were established
under the 1978 rule), will not necessarily be able to clear the higher
hurdle of the 2002 final rule's ``unavailable important public health
benefit.'' A petitioner seeking to add an essential-use designation
should show that the use of an ODS-containing MDI would save lives,
significantly reduce or prevent an important morbidity, or
significantly increase patient quality of life to support a claim of
important public health benefit (64 FR 47719 at 47722).
    In determining whether a drug product provides an otherwise
unavailable important public health benefit, our primary focus is on
the availability of non-ODS products that provide similar therapeutic
benefits for patients who are currently using the CFC MDIs. If
therapeutic alternatives to the CFC MDI exist, we can determine that
the CFC MDI does not provide an otherwise unavailable important public
health benefit.
    The third criterion in Sec.  2.125(f)(1) provides that the
essential use must be eliminated unless we find either: (a) The use of
the product does not release cumulatively significant amounts of ODSs
into the atmosphere; or (b) the release, although cumulatively
significant, is warranted in view of the otherwise unavailable
important public health benefit that the use of the drug product
provides.
    Based on an extensive record dating back to the 1970s, we reached a
tentative conclusion in the proposed rule that the release of ODSs into
the atmosphere from the MDIs that are the subject of this rulemaking is
cumulatively significant. We noted that the use of CFCs in MDIs for the
treatment of asthma and COPD is the only legal use in the United States
of newly produced or imported CFCs; all other uses of newly produced or
imported CFCs are prohibited by the Montreal Protocol. We noted that
the environmental impact of individual uses of nonessential CFCs must
not be evaluated independently, but rather must be evaluated in the
context of the overall use of CFCs. Cumulative impacts can result from
individually minor, but collectively significant, actions that take
place over a period of time (40 CFR 1508.7).
    The criteria in Sec.  2.125(g)(2) (which refers to those found in
Sec.  2.125(f)(1)) that we are using in this rulemaking are different
from those in Sec.  2.125(g)(3) and (g)(4)). Section 2.125(g)(2)
specifically addresses the situation where there is no marketed non-ODS
product containing the active moiety listed as an essential use, while
Sec.  2.125(g)(3) and (g)(4) apply to situations where there is at
least one marketed non-ODS product with the listed active moiety.
Section 2.125(g)(2) permits FDA to remove an essential use even if a
current essential-use active moiety is not reformulated, provided that
sufficient alternative products exist to meet the needs of patients,
because the essential use would no longer provide an otherwise
unavailable important health benefit. As we explained in the proposed
rule, the analysis we use here is different from the analysis we used
under Sec.  2.125(g)(4) in the rulemaking to remove the essential use
for albuterol (70 FR 17168, April 4, 2005). However, the basic concern
of protecting the public health underlies all of the criteria.
Therefore, our analyses are similar, and we have found it useful to
borrow concepts from the more specific provisions of Sec.  2.125(g)(3)
and (g)(4) to help give more structure to our analysis under the
broader language of Sec.  2.125(f)(1).
    Section 2.125(g)(2) requires that we consult an advisory committee
and hold an open public meeting before we remove an essential-use
designation when there is no non-ODS product with the same active
moiety. Prior to publishing the proposed rule, on July 14, 2005, we
consulted with FDA's Pulmonary and Allergy Drugs Advisory Committee
(PADAC) on the essential-use status of MDIs containing flunisolide,
triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in
combination, cromolyn, and nedocromil (PADAC meeting) (see 70 FR 24605,
May 10, 2005).\9\
---------------------------------------------------------------------------

    \9\ A transcript of the meeting and other meeting material is
available on the Internet at http://www.fda.gov/ohrms/dockets/ac/
cder05.html#PulmonaryAllergy.
---------------------------------------------------------------------------

    On August 2, 2007, following publication of the proposed rule, we
held the required open public meeting to discuss the issues involved in
removing the essential-use designations for flunisolide, triamcinolone,
metaproterenol, pirbuterol, albuterol and ipratropium in combination,
cromolyn, and nedocromil MDIs (see the Federal Register of July 9, 2007
(72 FR 37137)). Input from the open public meeting is considered and
discussed in section IV of this document together with the written
comments that were submitted in response to the proposed rule.

IV. Comments on the 2007 Proposed Rule

    We received over 4,000 comments in response to the proposed rule.
They were submitted by consumers, health care providers, patient
advocacy groups, professional groups, manufacturers, a Congressional
caucus, and industry organizations. The speakers who participated in
the open public meeting on August 2, 2007, also submitted written
comments. In the discussion that follows, we address the oral
presentations and written comments submitted at or following the open
public meeting, and the written and electronic comments submitted to
the docket in response to the 2007 proposed rule.
    To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same comment
number. The number assigned to each comment is purely for
organizational purposes and does not signify the comment's value or
importance or the order in which it was received.
    In reviewing these comments we are particularly focused on our
proposed findings relating to the criteria in Sec.  2.125(f) of our
regulations. As discussed above, we must remove the

essential-use designation for a CFC-containing drug product unless we
find that all of the following are met: (1) Substantial technical
barriers exist to formulating the product without ODSs; (2) the product
provides an unavailable important public health benefit; and (3) use of
the product does not release cumulatively significant amounts of ODSs
into the atmosphere or, if the release is significant, it is warranted
in view of the unavailable important public health benefit. As
discussed in the proposed rule, the failure to meet any one of these
criteria results in our determination that the use is not essential.

A. Flunisolide, Triamcinolone, Metaproterenol

    We are removing the essential-use designations for MDIs containing
flunisolide (Aerobid Inhaler System) and triamcinolone (Azmacort
Inhalation Aerosol). Aerobid and Azmacort are orally inhaled
corticosteroids. Azmacort is the only currently marketed drug product
that provides orally inhaled triamcinolone. Both Aerobid and Aerospan
Inhalation Aerosol provide orally inhaled flunisolide, but Aerobid is
the only currently marketed flunisolide drug product that contains
ODSs. Aerobid and Azmacort are the only two orally inhaled
corticosteroids marketed that contain ODSs. Both drugs are indicated
for the maintenance treatment and prophylaxis of asthma in patients 6
years of age and older, and both are prescription drugs. Flunisolide
and triamcinolone, as well as other corticosteroids, are not indicated
for relief of acute bronchospasm. Inflammation is an important
component in the development of asthma. The anti-inflammatory actions
of corticosteroids contribute to their efficacy in asthma. Though
effective for the treatment of asthma, corticosteroids do not
appreciably affect asthma symptoms immediately. Individual patients
experience a variable time to onset and degree of symptom relief.
Maximum benefit may not be achieved for 1 to 2 weeks or longer after
starting treatment. Aerobid was approved on April 23, 1982, and
Azmacort was approved on August 17, 1984. Their use was considered
essential under the 1978 rule, which stated that ``[m]etered-dose
steroid human drugs for oral inhalation'' were essential. Flunisolide
and triamcinolone were designated as essential as different active
moieties in the 2002 rule. In addition to the ODS-containing Aerobid,
Aerospan Inhalation Aerosol, a new drug application (NDA) for a
flunisolide HFA MDI, was approved January 27, 2006 (NDA 21-247), but
has not yet been introduced onto the market.
    We are also removing the essential-use designation for MDIs
containing metaproterenol (Alupent Inhalation Aerosol). Metaproterenol
is a short-acting beta2-adrenergic agonist used in the
treatment of bronchospasm associated with asthma and COPD. It acts as a
bronchodilator. Metaproterenol is also available as a syrup, as
tablets, and as an inhalation solution for use in nebulizers. This
rulemaking will not affect any dosage form of metaproterenol other than
the Alupent Inhalation Aerosol which contains CFCs. Alupent Inhalation
Aerosol is a prescription drug. Alupent Inhalation Aerosol's use was
considered essential under the 1978 rule, which stated that
``[m]etered-dose adrenergic bronchodilator human drugs for oral
inhalation'' were essential. Metaproterenol was designated as essential
as an active moiety in the 2002 rule. Alupent Inhalation Aerosol was
approved on July 31, 1973. Boehringer Ingelheim Pharmaceuticals, Inc.,
the manufacturer of Alupent Inhalation Aerosols, has informed us that
they discontinued U.S. distribution of Alupent Inhalation Aerosols as
of November 14, 2008.
    In the proposed rule, we tentatively concluded that there are no
technical barriers to formulating flunisolide, triamcinolone, and
metaproterenol MDIs without ODSs (72 FR 32030 at 32036-37). We did not
receive any substantive comments disagreeing with our tentative
conclusion. Therefore, we conclude that that there are no technical
barriers to formulating flunisolide, triamcinolone, and metaproterenol
MDIs without ODSs. As stated earlier, flunisolide has been reformulated
in an HFA MDI, but the product is not yet marketed. We also did not
receive any substantive comments on the second and third criteria in
Sec.  2.125(f)(1).\10\ As explained in section III of this document,
because the three criteria are linked by the word ``and,'' failure to
meet any single criterion results in a determination that the use is
not essential. Accordingly, because we have found in this rule that
there are no substantial barriers to reformulating these products, we
are required to find that the use of the products is not essential, and
we do not need to reach a decision on the second or third criteria in
Sec.  2.125(f)(1).
---------------------------------------------------------------------------

    \10\ Abbott Laboratories, the NDA holder for Azmacort Inhalation
Aerosol, submitted and later withdrew its comment. Therefore, we do
not address the comment submitted by Abbot in response to the
proposed rule.
---------------------------------------------------------------------------

B. Cromolyn and Nedocromil

    Cromolyn sodium and nedocromil sodium are members of the class of
drugs called ``cromones.'' Although it is not entirely clear how
cromones exert their clinical effect, cromones are thought to inhibit
antigen-induced bronchospasm as well as the release of histamine and
other autacoids from sensitized mast cells. Cromolyn is also available
for use in treating asthma as an inhalation solution for use in a
nebulizer. Both cromolyn and nedocromil are also used in ophthalmic
products, and cromolyn is available for oral administration for
treatment of symptoms associated with mastocytosis. Only MDI
formulations are affected by this rulemaking.
    The only cromolyn MDI (Intal Inhaler) was approved for marketing on
December 5, 1985. The essential-use designation for ``[m]etered-dose
cromolyn sodium human drugs administered by oral inhalation'' was added
to Sec.  2.125(e) on February 6, 1986 (51 FR 5190). The only nedocromil
MDI (Tilade Inhaler) was approved for marketing on December 30, 1992.
The essential-use designation for ``[m]etered-dose nedocromil sodium
human drugs administered by oral inhalation'' was added to Sec.
2.125(e) on January 26, 1993 (58 FR 6086). Intal Inhaler and Tilade
Inhaler are indicated for the management of asthma in patients 5 years
and older and 6 years and older, respectively. Both are prescription
drugs. Neither drug is indicated for the relief of acute bronchospasm.
On November 21, 2008, King Pharmaceuticals, Inc., the manufacturer of
Tilade Inhaler, informed us that they had discontinued manufacturing of
Tilade Inhaler in July 2008.
    In the proposed rule, we tentatively concluded that there are no
technical barriers to formulating cromolyn and nedocromil MDIs without
ODSs (72 FR 32030 at 32038). We did not receive any substantive
comments disagreeing with our tentative conclusion. Therefore, we
conclude that there are no technical barriers to formulating cromolyn
and nedocromil MDIs without ODSs. As explained in section III of this
document, because the three criteria in Sec.  2.125(f)(1) are linked by
the word ``and,'' failure to meet any single criterion results in a
determination that the use is not essential. Accordingly, because we
have found in this rule that there are no substantial barriers to
reformulating these products, we are required to find that the use of
the products is not essential, and we do not need to reach a decision
on the second or third criteria in Sec.  2.125(f)(1).

However, we received several comments addressing the second and third
criteria with respect to cromolyn and nedocromil, and we respond to
these comments below.
    (Comment 1) We received one comment arguing that there are no
acceptable treatment alternatives for cromolyn and nedocromil.
    (Response) In the proposed rule, we identified several orally
inhaled corticosteroids that do not contain CFCs as therapeutic
alternatives to Intal Inhalers and Tilade Inhalers, including
beclomethasone dipropionate inhalers, budesonide inhalers, fluticasone
propionate inhalers, and mometasone furoate inhalers (72 FR 32030 at
32037). We believe that most patients using Intal Inhalers and Tilade
Inhalers as a controller medication should be adequately served by at
least one of these currently marketed formulations. The comment did not
provide explanation as to why the proposed alternatives are
insufficient, so it is difficult to address this comment more fully. In
addition to the active moieties described in the proposed rule, oral
montelukast may be an appropriate therapeutic alternative. Also,
cromolyn is available in a solution for use in nebulizers. For patients
who use Intal Inhalers to treat exercise-induced bronchospasm, inhaled
beta2-agonists such as albuterol, salmeterol, and formoterol
are considered suitable therapeutic alternates.
    (Comment 2) One comment notes that Intal inhalers are safe for
pregnant women and protect against pet allergen exposure.
    (Response) Current FDA regulations on labeling for use during
pregnancy require the classification of each drug product under one of
five pregnancy categories (A, B, C, D, or X) on the basis of risk of
reproductive and developmental adverse effects or, for certain
categories, on the basis of such risk weighed against potential
benefit. 21 CFR Sec.  201.57(c)(9)(i)(A)(2). Intal Inhalers are
classified as a Pregnancy Category B drug. Pregnancy Category B
indicates that animal reproduction studies have failed to demonstrate a
risk to the fetus, and there are no adequate and well-controlled
studies in pregnant women. In the proposed rule, we identified several
non-CFC orally inhaled corticosteroids as therapeutic alternatives to
cromolyn and nedocromil MDIs. One of these orally inhaled
corticosteroids, budesonide inhalers (marketed as Pulmicort Turbuhaler
and Pulmicort Flexhaler), is also classified as a Pregnancy Category B
drug. We believe that budesonide inhalers are an appropriate non-CFC
therapeutic alternative for pregnant women who are currently using
Intal Inhalers.
    We have no data to suggest that Intal is more effective than the
therapeutic alternatives at preventing asthma symptoms triggered by pet
allergens. Although we believe that current Intal and Tilade users will
be adequately served by the inhaled corticosteroids identified above,
we also note the availability of cromolyn sodium in a nebulized
solution, which may provide a therapeutic alternative for situations
involving planned and known exposures to allergens.
    (Comment 3) One comment suggested that the amount of CFCs released
from Intal and Tilade Inhalers is inconsequential.
    (Response) As we have noted in previous rulemakings, the
environmental impact of CFCs used in MDIs, including Intal and Tilade
MDIs, must not be evaluated independently, but rather must be evaluated
in the context of the overall use of CFCs. Cumulative impacts can
result from individually minor but collectively significant actions
taking place over a period of time (40 CFR 1508.7). Significance cannot
be avoided by breaking an action down into small components (40 CFR
1508.27(b)(7)). Currently, MDIs for the treatment of asthma and COPD,
including Intal and Tilade, are the only legal use of newly produced or
imported CFCs (see EPA 2006 Allocation rule).
    Although it may appear to some that the CFCs released from Intal
and Tilade MDIs represent insignificant quantities of ODSs, and
therefore should be exempted, the elimination of CFC use in MDIs is one
of the final steps in the overall phase-out of CFC use. The release of
ODSs from some of the MDIs, including Intal and Tilade, may be
relatively small compared to total quantities that were released 2 or 3
decades ago, but if each use that resulted in the release of relatively
small quantities of ODSs were provided an exemption, the cumulative
effect would be to prevent the elimination of ODS releasing products.
This would prevent the full phase-out envisioned by the Clean Air Act
and the Montreal Protocol.

C. Pirbuterol

    We are removing the essential-use designations for MDIs containing
pirbuterol (Maxair Autohaler). Pirbuterol is a short-acting
beta2-adrenergic agonist used in the treatment of
bronchospasm associated with asthma and COPD. Pirbuterol acts as a
bronchodilator. Pirbuterol is only available in a CFC MDI. Maxair
Autohaler is one of two beta2-adrenergic agonist MDIs
currently marketed as a prescription drug which contains CFCs. The
other product, Alupent Inhalation Aerosol, is addressed in section IV.A
of this document. Albuterol is also a beta2-adrenergic
agonist, but it is no longer marketed as a CFC MDI. Albuterol was
addressed in a separate rulemaking, which removed its essential-use
designation effective December 31, 2008. Maxair Autohaler is a
prescription drug that was approved on November 30, 1992. Maxair
Autohaler's use was considered essential under the 1978 rule, which
stated that ``[m]etered-dose adrenergic bronchodilator human drugs for
oral inhalation'' were essential. Pirbuterol was designated as
essential as an active moiety in the 2002 rule. Maxair Autohaler has a
breath-actuated delivery system.
1. Do Substantial Technical Barriers To Formulating Pirbuterol Products
Without ODSs Exist?
    We proposed a finding that there are no technical barriers to
formulating pirbuterol MDIs without ODSs (72 FR 32030 at 32037).
    (Comment 4) One comment, Graceway Pharmaceuticals, LLC (Graceway),
the manufacturer of Maxair Autohaler, states that there are substantial
barriers (chemistry, manufacturing, and engineering) to reformulating
Maxair Autohaler without ODSs. Graceway also states these barriers are
complicated by the breath-actuated system, which is more sensitive with
respect to particle size and energy force.
    (Response) When determining whether technical barriers to
formulating pirbuterol MDIs without ODSs exist, we consider whether all
available alternative technologies have been evaluated and whether each
alternative is unusable (64 FR 47719 at 47721, September 1, 1999). In
addition, we look at results of reformulation efforts for similar
products, as well as statements made about the manufacturer's
particular efforts to reformulate their product or products. Graceway
has not demonstrated that the breath-actuated system is more sensitive
with respect to particle size and energy force or explained how any
such sensitivity poses a barrier to reformulating Maxair without ODSs.
As noted in the proposed rule, the pharmaceutical industry has had
success in formulating other orally inhaled beta2-adrenergic
bronchodilators without ODSs. At least nine different active moieties
have been

formulated as HFA MDIs for the treatment of asthma and COPD in the
United States and abroad.\11\ HFA MDIs have been formulated with both
suspensions and solutions. Pirbuterol is a close chemical analog to
albuterol and levalbuterol. Given the chemical similarity between them
and the success with reformulating albuterol (as albuterol sulfate in
ProAir HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and
Ventolin HFA Inhalation Aerosol) and levalbuterol (as levalbuterol
tartrate in Xopenex HFA Inhalation Aerosol), there appears to be no
technical reason why pirbuterol cannot be successfully reformulated
into an HFA MDI.
---------------------------------------------------------------------------

    \11\ The nine moieties formulated as HFA MDIs are albuterol,
beclomethasone, budesonide, fenoterol, fluticasone, flunisolide,
formoterol, ipratropium, and salmeterol. While a salmeterol DPI
(SEREVENT) has been approved in the United States, salmeterol HFA
MDIs have only been approved overseas. There are no approved
fenoterol or formoterol HFA products in the United States, but
fenoterol HFA MDIs and formoterol HFA MDIs have been approved in
several foreign countries.
---------------------------------------------------------------------------

    Furthermore, Graceway has not demonstrated that it evaluated all
available alternative technologies and found each alternative
unusable--the standard described in section III of this document (64 FR
47719 at 47721, September 1, 1999). At the time the proposed rule
published, we had no evidence to suggest that the ODS containing
pirbuterol oral inhalation drug product posed unique technical
challenges to formulation without ODSs. Since the time the proposed
rule published, no data have been submitted to change that conclusion.
Therefore, after consideration of the public comments on the issue, we
conclude that there are no technical barriers to the development of a
non-ODS pirbuterol product.
2. Do Pirbuterol MDIs Provide an Otherwise Unavailable Important Public
Health Benefit?
    In the proposed rule we tentatively found that pirbuterol MDIs do
not provide an otherwise unavailable important public health benefit
(72 FR 32030 at 32037). Because we have reached a conclusion that there
are no substantial technical barriers to formulating pirbuterol into a
non-ODS product, we do not believe it is necessary to reach a
conclusion on the public health benefits of pirbuterol MDIs. However,
we received a large number of comments in response to the proposed rule
addressing the public health benefits of pirbuterol MDIs, and we
believe it is appropriate to address the public health benefits in
light of these comments.
    a. Does Pirbuterol provide a greater therapeutic benefit than
similar adrenergic bronchodilators? (Comment 5) In its comment in
response to the proposed rule, Graceway claims that Maxair Autohaler
provides important public health benefits that would otherwise be
unavailable to substantial numbers of patients who have asthma or COPD.
Graceway states that Maxair Autohaler is an alternative for those who
do not tolerate or respond to albuterol and levalbuterol. Graceway
bases this conclusion in part on the distinct chemical structure of
pirbuterol, which Graceway claims is different from albuterol and
levalbuterol, and also on variation among patients. In its comment,
Graceway presents statements from physicians and patients claiming that
many patients experience intolerance or allergic reaction to albuterol,
but succeed on pirbuterol. In addition, we received many comments from
pirbuterol users and physicians who prescribe pirbuterol, detailing
experiences with pirbuterol and alternative MDIs, such as albuterol.
The comments describe reactions to and intolerance experienced with
albuterol and success with pirbuterol. Furthermore, many of the
comments from the physicians and pirbuterol users claim that experience
indicates that pirbuterol MDIs are more effective than albuterol MDIs.
    (Response) Albuterol and pirbuterol are both short-acting
beta2-adrenergic bronchodilators. Bronchodilation occurs
primarily through stimulation of the beta2-adrenergic
receptor. Albuterol MDIs are therapeutic alternatives to pirbuterol
MDIs and are, by far, the most widely prescribed short-acting
bronchodilators. We are not aware of any studies that support the
comments' contentions that albuterol inhalers are not an appropriate
alternative for pirbuterol inhalers. Moreover, we disagree with the
contention that the pirbuterol MDIs provide any unique therapeutic or
other advantage over the available alternatives. The labeling for
Maxair Autohaler does not contain any superiority claims based on
controlled clinical trials and we do not believe that anecdotal
evidence is adequate to support such a conclusion.
    Four prescription HFA MDIs with two different forms of albuterol
are approved and currently available:
     ProAir HFA (albuterol sulfate) Inhalation Aerosol;
     Proventil HFA (albuterol sulfate) Inhalation Aerosol;
     Ventolin HFA (albuterol sulfate) Inhalation Aerosol; and
     Xopenex HFA (levalbuterol tartrate) Inhalation Aerosol.
These products use HFA, which does not affect stratospheric ozone as a
replacement for ODSs. Maxair Autohaler and the therapeutic alternatives
are all very similar drugs. They are all indicated for the relief of
bronchospasms associated with asthma and COPD (although the labeled
indications may be worded differently), have very similar safety
profiles, and have similar dosing regimens. At least one of the
currently available albuterol drug products should be an adequate
therapeutic alternative for patients currently using Maxair Autohaler.
    We are not aware of any adequate and well-controlled studies which
support the comments' views that individuals who do not respond to or
tolerate albuterol and levalbuterol would find pirbuterol MDIs more
effective or better tolerate pirbuterol, or that pirbuterol MDIs are
more effective than other asthma MDIs, including albuterol HFA MDIs.
The National Asthma Education and Prevention Program, Expert Panel
Report 3 (NAEPP EPR-3) recommends that short-acting beta2-
adrenergic bronchodilators, in particular albuterol, levalbuterol, and
pirbuterol, are the most effective medications for relieving acute
bronchospasm. (Ref. 1) The NAEPP EPR-3 does not distinguish pirbuterol
as providing any unique therapeutic or other advantage over the
available alternatives.\12\ Furthermore, the opinion of all PADAC
members who voted on the issue was that pirbuterol is no longer an
essential use of ODSs (72 FR 32030 at 32037). The studies and
literature cited by Graceway in its comment provide cases of non-
response or inadequate response to albuterol and levalbuterol. Graceway
did not present studies comparing pirbuterol to albuterol or showing
that pirbuterol would be more effective for those users who do not
respond to or inadequately responded to albuterol. In fact, in its
comment (Comment No. 4), Graceway stated that clinical studies have not
been conducted to establish whether patients may respond differently to
pirbuterol.
---------------------------------------------------------------------------

    \12\ In the United States, the generally recognized standard of
care for asthma is set forth in the National Heart, Lung, and Blood
Institute's National Asthma Education and Prevention Program, Expert
Panel Report 3: Guidelines for the Diagnosis and Management of
Asthma (EPR-3) (Ref. 2). The National Heart, Lung, and Blood
Institute is one of the National Institutes of Health. In the 2007
update, we find the latest updates to the standard. The Guidelines
represent best practices and are recognized as the clinical standard
of care for treatment of asthma. See, e.g., http://
www.asthmanow.net/care.html; http://www.colorado.gov/bestpractices/
index.html; http://www.doh.wa.gov/CFH/asthma/publications/plan/
health-care.pdf.

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

    As stated previously, if therapeutic alternatives exist for users
of the CFC MDI, we can determine that the CFC MDI does not provide an
otherwise unavailable important public health benefit. We have
carefully considered these comments asserting that Maxair Autohaler is
a more effective alternative to other asthma MDIs. However, no data
were submitted to the agency as part of this rulemaking, and the agency
is not aware of any data that allow us to reach the conclusion that
pirbuterol provides a greater therapeutic benefit than similar
adrenergic bronchodilators. Thus, we believe that patients will be
adequately served by alternative MDIs.
    (Comment 6) Graceway also argues that pirbuterol is more likely
than albuterol to select beta2 receptors, which presents
less risk of cardiac side effects.
    (Response) As stated in response to the previous comment, albuterol
and pirbuterol are both short-acting selective beta2-
adrenergic bronchodilators that achieve bronchodilation primarily
through the beta2-adrenergic receptor. Therefore, they both
bind to the same receptor that causes bronchodilation. The studies
Graceway submitted to support the conclusion that pirbuterol is more
likely than albuterol to select beta2-adrenergic receptors
do not demonstrate that there is any difference in clinical efficacy or
safety between the two drugs. Moreover, the Maxair Autohaler label
warns of the same cardiovascular effects as other inhaled beta
adrenergic agonists. The NAEPP EPR-3 states that albuterol,
levalbuterol, and pirbuterol are all effective agonists and have few
negative cardiovascular effects. Accordingly, we disagree that there is
less risk of cardiac side effects with use of pirbuterol MDIs than with
use of albuterol MDIs.
    b. Does the breath-actuated device associated with pirbuterol MDIs
provide an important public health benefit? (Comment 7) Graceway, as
well as many other comments, stresses the importance of Maxair
Autohaler's breath-actuated device in providing an otherwise
unavailable important public health benefit. Many people claim they
cannot operate traditional press-and-breathe MDIs. They further claim
that it is extremely inconvenient and more challenging to use a
traditional press-and-breathe MDI with a spacer device to assist with
coordination problems. Because spacers are bulky and less portable,
people are less likely to carry them, and because they require
additional maintenance, people are less likely to use them. The
comments argue that Maxair Autohaler's ease of use, convenience, and
portability allow for increased compliance. Graceway argues that the
compliance obstacles will lead to an increase in morbidity, as well as
an increase in missed school/work days and physician, hospital, and
emergency department visits.
    (Response) While some individuals or groups of people may have
difficulty operating the alternative MDIs that use traditional press-
and-breathe devices, and Maxair Autohaler's Autohaler device may be
convenient, there are other options for these individuals and groups to
treat their asthma or COPD. We understand the difficulties for certain
groups of people, such as young children, older adults, and the
physically or mentally disabled, of coordinating inhalation with MDI
activation. Learning how to properly maintain medical devices and
administer medication is a sometimes difficult, but necessary task for
many patients with chronic diseases. It would certainly be more
convenient to have available many different devices to meet the
individual and distinct needs of every patient group. However, we do
not believe that this type of patient convenience provides a basis to
conclude that a product provides an otherwise unavailable health
benefit. Because therapeutic alternatives exist, use of pirbuterol MDIs
is not absolutely necessary to save lives, to reduce or prevent asthma
morbidity, or to significantly increase patient quality of life.
    The use of spacer devices with alternative products provides
options for patient groups who have difficulties coordinating
inhalation with MDI operation, allowing them to more satisfactorily use
MDIs that do not have a breath-actuated delivery mechanism. A spacer is
a device that adds space between the mouthpiece of an MDI and the
patient's mouth and is used to increase the effectiveness of an MDI.
Some have valves that result in the aerosol from the MDI being briefly
held in a reservoir from which the patient subsequently inhales the
aerosolized medication. Nebulizers provide another option for
individuals or patient groups with coordination problems. Systematic
reviews and meta-analyses have suggested that each of the aerosol
delivery devices can work equally well in patients who can use them
correctly. (Ref. 2) The availability of alternatives for those
individuals or patient groups who are unable to operate traditional
press-and-breathe devices supports a conclusion that any added
convenience of a breath-actuated device for patients who have been
prescribed drugs for the treatment of asthma or COPD does not provide
an unavailable important public health benefit within the meaning of 21
CFR 2.125(f)(1)(ii).
    Furthermore, we are not removing the breath-actuated delivery
mechanism from the market; rather, as a result of this rule, the CFC-
propelled pirbuterol may no longer be marketed. Graceway, or another
company, may develop a breath-actuated delivery system with pirbuterol
or other drugs of the class that do not use CFCs.
    (Comment 8) Graceway also claims that it will be more costly to
switch to one of the proposed alternatives. Increased costs include
higher copayments for branded HFA MDIs, extra visits to health care
providers to adjust treatment, purchase of spacers, and the cost of
failing to adequately manage asthma or COPD. Graceway contends that the
use of alternative MDIs is more costly because Maxair Autohaler
contains 400 inhalations per MDI, twice the number of inhalations of
alternative MDIs.
    (Response) The bases Graceway identifies in support of its argument
that it will be more costly to switch from Maxair Autohaler to an
alternative MDI are largely invalid. First, Maxair Autohaler, the only
marketed pirbuterol drug product, is a branded, rather than a generic,
product. The therapeutic alternatives for Maxair Autohaler are also
branded products. Therefore the purchase of an alternate branded HFA
(hydrofluoroalkane HFA-134a) inhaler would require no greater
copayment. Second, for most patients with asthma or COPD who use
inhalers, regular doctor visits to adjust treatment plans are routine.
There is no reason to believe that patients who use alternative HFA
inhalers require any more adjustment in treatment than patients who use
pirbuterol inhalers with a CFC propellant. Finally, no data have been
presented to demonstrate that the cost of failing to adequately manage
asthma or COPD is greater for individuals who use alternative HFA
inhalers than for those who use Maxair Autohaler. As discussed in
section VI of this rule, we anticipate the price per day of therapy to
decrease after patients transition from Maxair to alternative
therapies. Nevertheless, some individual patients might face higher
costs, perhaps related to the costs of additional copayments associated
with fewer numbers of inhalations provided by an alternative MDI.
    We recognize that the pirbuterol breath-actuated MDIs may provide
some public health benefits; however, nothing in this rulemaking
suggests that continued use of these MDIs provides an unavailable
important health benefit as previously defined. We do not

believe that we can conclude on the basis of the record in this
rulemaking that continued use of Maxair Autohaler is necessary to save
lives, to reduce or prevent asthma morbidity, or to significantly
increase patient quality of life, particularly given the availability
of albuterol MDIs as therapeutic alternatives, and the availability of
spacers and nebulizers for use in lieu of breath-actuated MDIs.
    In any case, given that we have already found no technical barriers
to reformulation of pirbuterol MDIs under Sec.  2.125(g)(2), a finding
on the public health benefit issue is not necessary to this rulemaking,
and we decline to make a specific finding on that issue in this final
rule.
3. Does Use of Pirbuterol MDIs Release Cumulatively Significant Amounts
of ODSs Into the Atmosphere and Is the Release Warranted Because These
MDIs Provide an Otherwise Unavailable Important Public Health Benefit?
    As explained in the proposed rule and above, because we have found
in this rule that there are no substantial technical barriers to
reformulating pirbuterol, we are required to find that the use of the
product is not essential, and we do not need to reach a decision on the
third criterion in Sec.  2.125(f)(1). Nonetheless, based on the
criteria described above and in the proposed rule, the quantity of CFCs
used in pirbuterol MDIs is a significant portion of the total quantity
of newly manufactured CFCs used, and therefore eventually released, in
the United States. Accordingly, we tentatively concluded that any
release of CFCs from pirbuterol MDIs is cumulatively significant (72 FR
32030 at 32033, 32034, and 32037). We received comments on the amount
of CFCs released into the atmosphere from pirbuterol MDI use.
    (Comment 9) Graceway asserts that the use of Maxair Autohaler does
not release cumulatively significant amounts of ODSs into the
atmosphere, and its de minimis release is warranted in view of the
essential health benefits provided by the product. Graceway claims that
Maxair Autohaler releases fewer CFCs than other MDIs because it
releases fewer CFCs per puff than other MDIs and has a smaller market
share. Graceway argues that without calculating the quantity of CFCs
released from use of Maxair Autohaler alone, the agency admitted the
quantity would, in any event, be minor. Graceway further argues that
the agency has not shown how aggregate release of CFCs from all seven
moieties has a significant impact on the environment.
    (Response) Although we based our tentative conclusion that
pirbuterol MDIs release cumulatively significant amounts of ODSs on
previous policy statements about the environmental impact of CFCs, the
basis for removing the essential-use designation for pirbuterol in this
rulemaking is no significant barriers exist to reformulating pirbuterol
MDIs without ODSs. We need not reach a conclusion that pirbuterol MDIs
release cumulatively significant amounts of ODSs. Furthermore, as
discussed previously, it is not necessary for us to reach a conclusion
on the public health benefits of Maxair Autohaler, or to conduct the
balancing test to reach a determination as to whether the release of
CFC ODSs is warranted in view of the public health benefits. Regardless
of outcome, the balancing test would not affect the ultimate finding in
this rulemaking that, because there are no significant technical
barriers to reformulation of the product, pirbuterol is no longer an
essential use of ODSs and should be removed from the list of essential
uses in Sec.  2.125(e).
4. Additional Comments on Miscellaneous Issues
    a. Sufficiency of advisory committee and open public meetings.
(Comment 10) Graceway submitted a number of comments claiming
insufficiencies of the two meetings held concerning the proposed rule
to remove the essential-use designations of the seven moieties that are
the subject of this final rule. Graceway asserts that the Pulmonary and
Allergy Drugs Advisory Committee (PADAC) meeting held on July 14, 2005,
did not fulfill the 21 CFR 2.125(g)(2) requirement for consultation
with an advisory committee because the notice of the meeting did not
identify the products and moieties at issue, state that the meeting was
intended to fulfill requirements of 21 CFR 2.125(g)(2), or discuss the
purpose and scope of the meeting. Therefore, informed views from
independent experts could not be obtained because interested persons/
companies either had no knowledge of the meeting or had insufficient
time to adequately prepare for the meeting. Graceway also asserts that
the background memorandum provided to the PADAC was inadequate and that
committee members were confused. In addition, Graceway asserts that the
agency did not properly consult with the committee members as to the
health benefits of the moieties at issue and failed to consider the
committee's advice or recognize issues raised by the committee members.
    (Response) FDA may remove an essential-use designation under
section 2.125(g)(2) if it no longer meets certain criteria after
consultation with a relevant advisory committee and after holding an
open public meeting. FDA made clear in the 1999 rule proposing criteria
for removing essential-use designations that, before removing any
essential-use designation, it would consult with an advisory committee
and provide opportunity for public comment (64 FR 47719 at 47722). FDA
published a notice in the Federal Register on May 10, 2005 (70 FR
24605), that the PADAC would be convening on July 14, 2005, to discuss
the continued need for the essential-use designations of prescription
drugs for the treatment of asthma and COPD. The notice further stated
that interested persons could present data, information, or views,
orally or in writing, on the issues pending before the committee. This
notice provided sufficient time for those persons or companies with an
interest in the essential-use designations of any moieties used in
drugs that treat asthma or COPD to provide the committee members with
any information they believed would be pertinent to the decision to
remove a designation.
    It was noted at the meeting that the committee was convened to
determine whether changes in medical practice and the availability of
alternatives render the products listed as essential no longer
essential. The background memorandum provided to the PADAC described
the regulatory criteria for removing essential uses and advised the
committee to focus attention on the criterion related to the important
public health benefits of the moieties. The background memorandum also
listed those products containing CFCs that were still marketed and for
which there were no current reformulations or direct alternative
products, and products currently approved or marketed that do not
contain CFCs. These lists were provided to assist the committee when
considering whether adequate alternative therapy is available. The
opportunity to ask clarifying questions was provided at the meeting,
and presentations were made by an association representing
manufacturers of MDIs, particular MDI manufacturers, and an interested
person. Therefore, we disagree with the assertion that informed views
from independent experts could not be or were not obtained.
    After the presentations, the committee discussed the individual
moieties, including pirbuterol, with regard to their essentiality. A
majority of the members agreed that pirbuterol is

nonessential. The transcript of the meeting, available at http://
www.fda.gov/ohrms/dockets/ac/cder05.html#PulmonaryAllergy, does not
reveal any confusion on the part of the committee members. In the
proposed rule, we stated that we consulted with the PADAC at their July
14, 2005, meeting on the essential-use status of MDIs containing, among
other moieties, pirbuterol, and that the PADAC members gave their
opinions, without dissent, that pirbuterol was no longer an essential
use of ODSs (72 FR 32030 at 32035, 32037). Thus, FDA has taken full
consideration of the opinions of the committee members.
    (Comment 11) Graceway asserts that the agency failed to meet the
spirit of the 21 CFR 2.125(g)(2) public meeting requirement to enrich
notice-and-comment rulemaking. Graceway stated that scheduling the
meeting with less than 3 weeks' notice, the lack of publicity, and the
decision to hold a single meeting in one location were barriers to
participation by patients, clinicians, and outside experts. Graceway
also stated that the agency failed to solicit feedback on patients'
experience with HFA alternatives and thus limited the scope of the
administrative record.
    (Response) FDA published a notice in the Federal Register on July
9, 2007 (72 FR 37137), that the public meeting would be held on August
2, 2007, at FDA's Center for Drug Evaluation and Research Advisory
Committee conference room in Rockville, MD. The notice stated that the
meeting was to solicit comments on the proposed rule amending the
regulation on the use of ODSs to remove the essential-use designations
for certain MDIs, and invited written or electronic comments for
consideration at the meeting, as well as requests to speak at the
meeting. We believe we provided sufficient notice of the meeting to
allow for widespread participation and did not create barriers to
participation by patients, clinicians, and outside experts.
Accordingly, we disagree with Graceway's implication that the agency
did not comply with the regulatory requirement for an open public
meeting. Furthermore, in the proposed rule, we solicited any comments
related to the removal of the essential-use designations for MDIs
containing pirbuterol and other moieties, and in the notice of the
public meeting we invited discussion of issues on which we asked for
comments in the proposed rule. In fact, we received thousands of
comments on patients' experiences with HFA alternatives to pirbuterol
in particular. Therefore, we strongly disagree that the scope of the
administrative record was limited in any way.
    b. Sufficiency of proposed rule. (Comment 12) Graceway argues that
FDA failed to publicize the proposed rule through a press release,
public announcement, or on the Internet, and inhibited public
participation in the rulemaking process.
    (Response) Interested persons have had ample notice that FDA was
considering removing the essential-use designation for pirbuterol and
the six other drugs that are the subject of this rulemaking. This issue
was first considered at the July 14, 2005, PADAC meeting (see 70 FR
24605). The trade press reported on this meeting, and minutes and a
transcript of the meeting were placed on the Internet and are available
at http://www.fda.gov/OHRMS/DOCKETS/ac/cder05.html#PulmonaryAllergy. We
also announced our intention to publish a proposed rule in the unified
agendas published in the Federal Register on December 11, 2006 (71 FR
73195 at 73223), and April 30, 2007 (72 FR 22489 at 22516). As stated
previously, we published the proposed rule in the Federal Register on
June 11, 2007 (72 FR 32030). These publications put the public on
notice of our intent to remove the essential-use designations, and
invited comments on our proposal. In addition, we held an open public
meeting, as discussed previously, for which we solicited input from
interested parties. Several companies, including Graceway, gave
presentations at the open public meeting. Furthermore, our MDI Web
site, http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/
ucm063054.htm, discusses the phase-out of all essential use
designations and contains copies of all relevant documents, including
the June 11, 2007, proposed rule. Our receipt of thousands of comments
on the proposed rule further shows that the public was well aware of
our intent to remove the essential-use designations and that public
participation was not inhibited.
    (Comment 13) Graceway also argues that FDA must give weight to the
quality and quantity of comments submitted in response to the proposed
rule because the number of comments is material where the degree of
public interest is a legitimate factor for consideration. Graceway
states that with regard to this rule, input from patients, physicians,
and pharmacists is crucial because the decision-making involves
weighing important and competing public policy considerations.
    (Response) We have given due weight and full consideration to all
comments submitted in response to the proposed rule. We have read each
comment individually and provided responses to all unique comments
submitted. When comments were duplicative in substance, we provided one
response to all like comments. We fully understand the concern with
removal of the essential-use designations and have weighed the public
policy considerations, as discussed previously. After weighing the
important and competing public policy considerations, and considering
the nature and number of comments, we have concluded that the public is
best served by the decision to remove the essential-use designations
that are the subject of this rule.
    (Comment 14) Graceway asserts that FDA's failure to create a
confidential docket prevented companies from commenting on issues
related to development of non-ODS formulations of pirbuterol.
    (Response) There is no provision in our regulations for creating a
confidential docket. As we commented previously with regard to
technical barriers, the pharmaceutical industry has had success in
formulating other orally inhaled beta2-adrenergic
bronchodilators without ODSs. Given the chemical similarity between the
moieties used in these other bronchodilators and pirbuterol, and the
success with reformulating albuterol and levalbuterol, there appears to
be no technical reason why pirbuterol cannot be successfully
reformulated into an HFA MDI or other non-ODS inhalation delivery
system. Moreover, Graceway could have readily provided general comments
related to development of a non-ODS delivery system.
    (Comment 15) Graceway stated that FDA's concerns over the
availability of CFCs beyond 2009 are more properly addressed through
negotiation at Montreal Protocol meetings, rather than through removal
of essential-use designations.
    (Response) As a Party to the Montreal Protocol, the United States
Government committed to eliminating all non-essential uses and reducing
essential uses of CFCs. The Preamble to the Protocol states that the
Parties are: ``Determined to protect the ozone layer by taking
precautionary measures to control equitably total global emissions of
substances that deplete it, with the ultimate objective of their
elimination'' (Preamble to the Montreal Protocol (emphasis added.)).
FDA's actions in this rulemaking are consistent with the United States'
position in meetings regarding the Montreal Protocol. Discussion of the
United States' position with regard to the Montreal Protocol is more
appropriately directed to the

Department of State, which heads the United States delegation to
meetings regarding the Montreal Protocol. If any company wants the
United States to alter any of the positions taken with the Parties to
the Protocol, it should present its views to appropriate officials in
the State Department.
    c. Regulatory Flexibility Act. (Comment 16) Graceway asserts that
FDA erroneously concluded that none of the firms that manufacture the
seven CFC MDIs is a small entity under the Regulatory Flexibility Act
because none employs fewer than 750 people, and therefore the proposed
rule would not have a significant economic impact on a substantial
number of small entities. Graceway states that it is a small entity
because it employs fewer than 750 people. It also claims that it
constitutes a significant number of small entities because Graceway
makes up more than 5 percent of the total number of affected entities
(the five NDA holders for prescription CFC MDI products) and 100
percent of the affected small entities. Graceway also states that the
rule would have a significant economic impact on it because Maxair
comprises 15 percent of Graceway's U.S. revenues.
    (Response) As explained in our Regulatory Flexibility Analysis (see
section VII), for purposes of determining whether a substantial number
of small entities are affected by this rule, the affected industry
sector includes all manufacturers of pharmaceutical products in the
United States. The effects of this final rule are not limited to the
five NDA holders who are marketing the seven ODS drug products. Thus,
the industry sector which will be directly affected by this rule
includes all U.S. ``pharmaceutical preparation manufacturers.'' The
same industry sector was considered to be affected by the Albuterol
final rule (70 FR 17191, April 4, 2005).
    According to the U.S. Department of Commerce, the industry of
``pharmaceutical preparation manufacturers'' includes 901
establishments controlled by 723 companies (Ref. 3). Of these
establishments, 822 have fewer than 500 employees. Only one of these
companies, Graceway, has claimed that it is a small business and that
the rule will cause it substantial economic harm. We do not need to
determine if Graceway is in fact a small business, because even if it
is, one single small affected entity among an industry of hundreds does
not constitute a ``substantial number'' under the Regulatory
Flexibility Act. Department of Health and Human Services Guidance\13\
defines ``substantial number'' as 5 percent or more of the affected
small entities within an identified industry. Graceway does not
constitute 5 percent of the small entities in the ``pharmaceutical
preparation manufacturers'' sector.
---------------------------------------------------------------------------

    \13\ Guidance on Proper Consideration of Small Entities in
Rulemakings of the U.S. Department of Health and Human Services (May
2003).
---------------------------------------------------------------------------

    Because this rule would not affect a substantial number of small
entities, we do not need to determine whether it would have a
significant economic impact upon Graceway. Thus, we continue to believe
that this rule would not have a significant economic impact on a
substantial number of small entities and decline to reverse our
previous determination under the Regulatory Flexibility Act.
    d. National Environmental Policy Act. (Comment 17) Graceway asserts
that FDA erroneously concluded that the rule would not have a
significant adverse impact on the human environment. Graceway states
that HFA alternatives to Maxair Autohaler and the overall shift of the
market to HFA products have a significant global warming impact.
Consequently, Graceway claims that FDA must provide evidence and
analysis in support of its determination not to prepare an
environmental impact statement. In particular, it maintains that FDA
must discuss the impact of the proposed action and alternative
approaches.
    (Response) Therapeutic alternatives that do not use an ODS are
currently marketed and appear to provide all of the important public
health benefits of the listed drugs. These alternatives generally use
HFC-134a (CH2FCF3), or, to a lesser degree, HFC-
227ea (C3HF7) as a propellant. While HFC-134a and
HFC-227ea are greenhouse gases (the global warming potentials (GWPs)
are around 1300 GWP\14\ and 2600 GWP, respectively),\15\ the CFCs that
were previously used are ozone disrupting compounds that have much
higher global warming potentials of 5000 to 11,000.\16\ In addition,
considering the density of the HFC propellant is about 30 percent lower
than for the CFC propellant, on a mass basis, the quantities emitted
are reduced by 30 percent (Ref. 4).
---------------------------------------------------------------------------

    \14\ GWP: Global warming potential; represents how much a given
mass of chemical contributes to global warming over a given time
period compared with the same mass of carbon dioxide (GWP =1). It is
defined as the ratio of the time-integrative radiative forcing from
the instantaneous release of 1 kg of a trace substance relative to
that of 1 kg of a reference gas (in most cases CO2). All
GWP values represent global warming potential over a 100-year time
horizon.
    \15\ U.S. Environmental Protection Agency, Global Warming
Potentials of ODS Substitutes: http://www.epa.gov/Ozone/geninfo/
gwps.html. Accessed 5/21/2009.
    \16\ U.S. Environmental Protection Agency. Class I Ozone-
depleting Substances: http://www.epa.gov/Ozone/science/ods/
classone.html. Accessed 5/21/2009.
---------------------------------------------------------------------------

    Considering this data, we concluded that there will be an overall
improvement in the levels of potent greenhouse gases released annually
from the use of oral pressurized MDIs as a result of this action.
Therefore, the removal of the essential-use designations results in a
net improvement on the environmental effects of the use of these
devices. Because there is no net negative environmental impact of this
action, alternative actions will not be addressed. We encourage the
development of new forms of propellants with even lower GWPs, as well
as other delivery possibilities, but in the absence of such
alternatives we reaffirm the removal of the essential-use designations
for CFC-propelled MDIs as an environmentally sound action.

D. Albuterol and Ipratropium in Combination

    We are removing the essential-use designations for MDIs containing
albuterol sulfate and ipratropium bromide in combination (Combivent
Inhalation Aerosol).\17\ Combivent Inhalation Aerosol is a prescription
drug. Albuterol is a beta2-adrenergic bronchodilator and
ipratropium is an anticholinergic bronchodilator. Both are used in the
treatment of bronchospasm associated with COPD. The primary advantage
of using the two drugs in combination is that by using two distinctly
different mechanisms of action, the two drugs in combination should
produce greater bronchodilator effect than using either drug alone. The
essential use for MDIs containing albuterol sulfate and ipratropium
bromide in combination was added to Sec.  2.125(e) in the Federal
Register of April 9, 1996 (61 FR 15700). Albuterol and ipratropium, in
combination, are also sold as an inhalation solution (DuoNeb Inhalation
Solution) for use in a nebulizer. Nebulizers do not use CFCs. This
current rulemaking will not affect the regulatory status of DuoNeb
Inhalation Solution.
---------------------------------------------------------------------------

    \17\ As noted in the proposed rule, we have received a citizen
petition from Boehringer Ingelheim Pharmaceuticals, Inc. (BI)
(Docket No. 2006P-0428/CP1). The petition asks us to refrain from
taking any action to remove the essential-use designation for
Combivent Inhalation Aerosol. We have treated the petition as a
comment on this proposal.

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

1. Do Substantial Technical Barriers to Formulating Products Containing
Albuterol and Ipratropium in Combination Without ODSs Exist?
    In the proposed rule, we noted that we had not been supplied with
any information to support a conclusion that substantial technical
barriers exist and could not make an initial determination on whether
such barriers exist. We received several comments about technical
barriers to reformulating Combivent Inhalation Aerosol without CFCs,
one of which provided additional information about Combivent Inhalation
Aerosol's reformulation efforts.
    (Comment 18) In its comment in response to the proposed rule,
Boehringer Ingelheim Pharmaceuticals, Inc. (BI), argues that
substantial technical barriers have hampered the development of a CFC-
free Combivent Inhalation Aerosol. Specifically, BI notes that
Combivent Inhalation Aerosol's combination of two active ingredients
with different physico-chemical properties presents unique challenges
for formulating a Combivent HFA Inhalation Aerosol, including the
development of different valves and materials for the HFA product.
According to BI, significant problems arose during the clinical trial
phase, including clogging and valve sticking. In addition, multiple
formulations have been developed. BI also provides more detailed
information on its current progress in developing a non-HFA CFC-free
Combivent. Specifically, BI stated that it anticipated filing an NDA
for Combivent Respimat at the end of 2008, permitting FDA review and
approval to be completed by 2010 or 2011.
    (Response) We have carefully reviewed the information provided by
BI on its reformulation efforts. We have considered whether all
available alternative technologies have been evaluated and whether each
alternative is unusable. The information available to the agency
suggests that viable alternatives exist or are in development. BI
representatives stated at the Public Meeting in August 2007 and BI
stated in its comment to the proposed rule that it is in the process of
developing Combivent Respimat. BI's comments suggest that they
anticipate being ready to commercially produce and legally distribute,
and have the capacity to meet current market demand for, a non-CFC
alternative Combivent product by 2011. In addition, BI's actions to
date indicate that it has overcome difficulties in chemistry and
manufacturing as it has developed and tested a Combivent Respimat
product (see clinicaltrials.gov at Respimat Combivent Trial in Chronic
Obstructive Pulmonary Disease (COPD), ClinicalTrials.gov identifier
NCT00400153 (completed April 2008)). We also note that both
albuterol and ipratropium bromide have been successfully reformulated
as non-CFC products. We believe that the success of BI's reformulation
efforts to date demonstrates that although difficulties may have been
encountered, they do not pose a substantial barrier to reformulating as
described in section III of this document. Therefore, we conclude that
substantial technical barriers to the development of a non-CFC
combination albuterol and ipratropium product do not exist.
2. Do MDIs Containing Albuterol and Ipratropium in Combination Provide
an Otherwise Unavailable Important Public Health Benefit?
    In the proposed rule, we solicited comments on the public health
benefits of Combivent Inhalation Aerosols (72 FR 32039). We tentatively
concluded that Combivent Inhalation Aerosol does not provide an
otherwise unavailable public health benefit and based this tentative
conclusion on our tentative determination that an ipratropium bromide
HFA MDI used with an albuterol sulfate HFA MDI would provide an
acceptable therapeutic alternative to Combivent Inhalation Aerosol.
Because we have reached a conclusion that there are no substantial
technical barriers to formulating Combivent Inhalation Aerosol into a
non-ODS product, we do not believe it is necessary to reach a
conclusion on the public health benefits of Combivent Inhalation
Aerosol. However, we sought and received multiple comments in response
to the proposed rule addressing the public health benefits of Combivent
Inhalation Aerosol, and we believe it is appropriate to address the
public health benefits in light of these comments.
    (Comment 19) For a number of reasons, BI disagrees with our
tentative conclusion that Combivent Inhalation Aerosol does not provide
an otherwise unavailable important public health benefit. BI claims
that Combivent Inhalation Aerosol users are elderly and have COPD and
co-morbid conditions, making them an especially vulnerable population.
BI asserts that noncompliance is a significant problem among this
population because many users have multiple medical conditions
requiring multiple medications. According to BI, switching Combivent
Inhalation Aerosol users to two separate inhalers would decrease
compliance, increase medication errors due to incorrect administration,
and increase treatment delays due to patient confusion over which
inhaler to use. BI explains that compliance might decrease because
ipratropium bromide has a longer onset of action, and patients may
perceive a lack of efficacy if ipratropium bromide is administered
separately from albuterol, which would lead patients to either overuse
the product or not use it at all. BI also argues that some patients
with COPD suffer from hyperinflation of the lungs, which makes it more
difficult to take the deep breaths required for optimal dosing of
medications, and doubling the number of inhalations to approximate the
same therapeutic effect of Combivent Inhalation Aerosol would
significantly increase the burden on the patient. We also received
comments from patients who claim that using two inhalers would be too
bulky. Several other comments raise similar concerns about compliance,
and one comment raises these concerns with respect to patients with
cystic fibrosis. Our response below addresses all such comments.
    (Response) We believe that the ipratropium bromide HFA MDI and the
albuterol sulfate HFA MDI, when used together, provide similar
therapeutic benefits to Combivent Inhalation Aerosol. Using the two
MDIs together will deliver the same dose of ipratropium (18 micrograms
(mcg) per inhalation) and essentially the same dose of albuterol (108
mcg versus 103 mcg per inhalation) as the dose delivered by Combivent
Inhalation Aerosol. As we noted in the proposed rule, the primary
advantage of using the two drugs in combination is that by using two
distinctly different mechanisms of action (albuterol is a
beta2-adrenergic bronchodilator while ipratropium bromide is
an anticholinergic bronchodilator), the two drugs in combination should
produce greater bronchodilator effect than using either drug alone.
Combivent Inhalation Aerosol is a combination of convenience that is
intended to facilitate patient use of the two drug products together.
    Although it is not necessary for this rulemaking to evaluate
whether the non-CFC therapeutic alternative has approximately the same
level of convenience as the product it replaces, the analysis may be
useful in light of the comments. As we stated in the 2002 rule, ``in
evaluating whether an alternative has approximately the same level of
convenience of use compared to the ODS product containing the same
active moiety, FDA will consider whether: (1) The product has
approximately the same or better portability; (2) the product requires

approximately the same amount of or less preparation before use; and
(3) the product does not require significantly greater physical effort
or dexterity'' (67 FR 48370 at 48374).
    The proposed non-CFC alternatives to Combivent Inhalation Aerosol,
an ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI,
are MDIs like Combivent Inhalation Aerosol and are similarly portable.
Both the CFC product and the HFA products require priming if they have
not been used for a period of time, and therefore both products require
approximately the same amount of preparation. We note that priming is
only required when the product has not been used for a period of time.
Because these inhalers are intended for daily use, we do not anticipate
that regular priming would be necessary. And although twice as many
puffs are required to deliver the dose of separate albuterol and
ipratropium bromide into the lungs, the additional puffs do not require
significantly greater physical effort or dexterity. In addition, we
have not found any data to suggest that administering twice the number
of puffs would be a significant burden for patients with
hyperinflation. We acknowledge that carrying two inhalers is twice as
bulky as carrying one, and some patients may find Combivent Inhalation
Aerosol more convenient to use, but we believe that the therapeutic
alternatives are only marginally less convenient, and any convenience
provided by the availability of Combivent Inhalation Aerosol does not
reach the level of essentiality.
    We also acknowledge that some patients, particularly those with co-
morbid conditions who are taking multiple medications, may be more
compliant when using a Combivent Inhalation Aerosol than when using an
ipratropium bromide HFA MDI with an albuterol sulfate HFA MDI. We
believe that concerns about patient compliance can be appropriately
addressed with patient outreach campaigns that provide education on how
to use HFA MDIs correctly and the benefits of using both MDIs together.
As we have stated elsewhere in this document, learning how to properly
maintain and administer medications is a sometimes difficult, but
necessary, task for many patients with chronic diseases. During the
transition period, we intend to conduct this type of patient outreach
campaign, and we encourage other stakeholders to work with us in
educating Combivent Inhalation Aerosol users on the therapeutic
alternatives. Because patient compliance may be greater with
combination products such as Combivent Inhalation Aerosol, we intend to
closely monitor the availability of any reformulated combination MDI
product and the transition to the therapeutic alternatives identified
in this rule, including albuterol and ipratropium delivered in single-
ingredient MDIs, and modify the patient outreach efforts as
appropriate.
    (Comment 20) BI and other comments also argue that a decrease in
compliance would lead to increased exacerbations and an increase in
overall health care costs.
    (Response) In one nonrandomized retrospective study comparing use
of two separate inhalers to use of Combivent Inhalation Aerosol,
Chrischilles et al. concluded that Combivent Inhalation Aerosol users
were more compliant and had significantly lower average monthly health
care costs compared to users of two separate inhalers (Ref. 5).
Although the validity of the results depends on the authors' ability to
control for important differences in the patient populations, we do not
disagree with the conclusion that using two inhalers may be more
expensive than using one combination inhaler, and we have identified
and assessed those costs in our Analysis of Impacts.
    (Comment 21) BI further argues that the proposed CFC-free
therapeutic alternatives to Combivent Inhalation Aerosol (an
ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI)
have not been shown to provide similar therapeutic benefits. One
comment claims that clinical studies have shown that a single inhaler
of Combivent Inhalation Aerosol is more effective for the treatment of
COPD than two separate inhalers. Several comments oppose the market
removal of Combivent Inhalation Aerosol, arguing the combination of two
medications that must be taken separately is not a substitute for the
single product, Combivent Inhalation Aerosol.
    (Response) As stated earlier, using the two MDIs together will
deliver the same dose of ipratropium (18 mcg per inhalation) and
essentially the same dose of albuterol (108 mcg versus 103 mcg per
inhalation) as the dose delivered by Combivent Inhalation Aerosol. We
are not aware of any data demonstrating that Combivent Inhalation
Aerosol is clinically superior to an ipratropium bromide HFA MDI used
with an albuterol sulfate HFA MDI. Other than the study by Chrischilles
discussed earlier, most of the data cited by BI refers to older studies
that did not study albuterol and ipratropium in combination inhalers.
And as discussed earlier, we acknowledge that use of a combination
inhaler may increase compliance, but we believe compliance can be
increased with proper patient education, and we do not consider this
factor to be determinative of public health benefit.
    Neither the Chrischilles study nor any other study available to us
or cited by BI demonstrates that Combivent Inhalation Aerosol is
clinically superior to the two inhalers used together. We believe that
the ipratropium bromide HFA MDI and the albuterol sulfate HFA MDI used
together provide similar therapeutic benefits to the Combivent
Inhalation Aerosol. We also note that albuterol and ipratropium bromide
in combination are also available as an inhalation solution for use in
a nebulizer (marketed as DuoNeb Inhalation Solution). DuoNeb Inhalation
Solution is an option for patients who prefer a combination drug
product. The availability of these therapeutic alternatives supports a
conclusion that Combivent Inhalation Aerosol does not provide an
otherwise unavailable important public health benefit.
3. Does Use of MDIs Containing Albuterol and Ipratropium in Combination
Release Cumulatively Significant Amounts of ODSs Into the Atmosphere
and Is the Release Warranted Because These MDIs Provide an Otherwise
Unavailable Important Public Health Benefit?
    As explained in the criteria in section III of this document,
because we have found in this rule that there are no substantial
technical barriers to reformulating Combivent Inhalation Aerosol, we
are required to find that the use of Combivent Inhalation Aerosol is
not essential, and we do not need to reach a decision on the third
criterion in Sec.  2.125(f)(1). However, we received several comments
about this criterion, which we address below.
    (Comment 22) BI argues that removing Combivent Inhalation Aerosol
from the market would not significantly decrease the cumulative release
of CFCs into the atmosphere and would have a negligible effect on the
recovery of the stratospheric ozone layer. They also argue that any
effect would not outweigh treatment disruption, health risks, and costs
to Combivent Inhalation Aerosol users as a result of the market
removal. According to BI, Combivent Inhalation Aerosol usage is
expected to account for approximately 175 to 200 metric tons of annual
CFC emissions in the coming years. Several comments assert that the
amount of ODSs released from Combivent Inhalation Aerosol is
insignificant, and eliminating their use would not provide a
significant environmental benefit.

    (Response) As we stated in the proposed rule and elsewhere in this
document, the environmental impact of individual uses of nonessential
CFCs must be evaluated in the context of the overall use of CFCs. The
quantity of CFCs released from Combivent Inhalation Aerosol represents
a significant portion of the total quantity of CFCs released from MDIs
in the United States. FDA has not been assigned the task of determining
what amount of environmental benefit would result from the removal of
CFC-containing medical devices, diagnostic products, drugs, and drug
delivery systems from the market. FDA is required to determine whether
such products are essential uses of ODSs, and this rulemaking fulfills
that obligation with respect to Combivent Inhalation Aerosol.
    (Comment 23) BI argues that the proposed rule did not provide data
or analysis demonstrating the amount of CFCs which constitutes a
significant release. BI also comments that the criterion under the
essential-use regulation was established to determine an individual
product's release and its effect on the ozone layer, not whether it is
significant relative to the release from other products. BI argues that
our standard for determining whether a product releases significant
amounts of ODSs into the atmosphere is not supported by science and
should be developed in accordance with notice-and-comment rulemaking
procedures.
    (Response) We do not agree that the proposed rule did not provide
data or analysis demonstrating the amount of CFCs which constitutes a
significant release. We also disagree that our standard is not science-
based or was developed without the opportunity for public comment. In
reaching our tentative conclusion in the proposed rule that any release
of CFCs from Combivent Inhalation Aerosol is cumulatively significant,
we discussed our reasoning at length and cited multiple policy
statements and other sources in support of our conclusion. We also
solicited and received comments on our tentative conclusion. Through
previous legislative and administrative actions, the United States has
evaluated the environmental effect of eliminating the use of all CFCs
and has made a decision to fully phase out the use of CFCs over time.
Our conclusion that any release is cumulative is based on these
legislative and administrative actions and reflects environmental
science policies that have been developed over time through a public
process.
    (Comment 24) A few comments claim that CFCs used in Combivent
Inhalation Aerosol do not have an adverse impact on the environment
because the CFCs are inhaled rather than released into the environment.
    (Response) As we have noted in previous rulemakings, nearly all of
the CFCs inhaled into the lungs from an MDI are almost immediately
exhaled into the environment (70 FR 17168 at 17179, April 4, 2005; 73
FR 69532 at 69540, November 19, 2008). The small amounts of CFCs
absorbed into the body are later excreted and exhaled without being
broken down. Essentially all of the CFCs released from an MDI end up in
the atmosphere with resulting harm to the stratospheric ozone layer.
    (Comment 25) One comment argues that the CFCs released from
Combivent Inhalation Aerosol are less damaging to the ozone layer than
the fumes from one diesel truck.
    (Response) This comment appears to confuse CFCs with other
greenhouse gases such as carbon dioxide and nitrous oxide. FDA's
regulations at 21 CFR 2.125 reflect an international effort to reduce
the production, importation, and use of substances that deplete the
ozone layer. We are publishing this rule because the criteria in Sec.
2.125 have been met, rather than because of any contribution CFCs may
be making towards global warming.
    (Comment 26) Another comment suggests FDA retain the essential-use
designation for Combivent Inhalation Aerosol and instead remove other
inhalants, such as aerosol hair sprays, spray paint, and perfumes.
    (Response) The use of CFCs in cosmetics such as aerosol hair
sprays, deodorant, shaving cream, and perfume was banned in 1978, along
with the use of CFCs in spray paint, and household, food and automotive
products.
4. Additional Comments on Miscellaneous Issues
    a. Criteria used in rulemaking. (Comment 27) BI argues that the
criteria in 21 CFR 2.125(g)(3)(ii), (g)(3)(iii), (g)(3)(iv), and
(g)(4)(ii)\18\ should be applied to any proposed CFC-free replacement.
According to its comment, ignoring or failing to fully consider these
criteria could result in patients being switched to ``therapeutically
inferior'' alternatives. At a minimum, BI argues that this rulemaking
should incorporate the analysis used in the albuterol rulemaking.
---------------------------------------------------------------------------

    \18\ Included in 21 CFR 2.125(g)(3)(ii), (g)(3)(iii), and
(g)(3)(iv) are some of the criteria for removing an essential-use
designation for individual active moieties marketed as ODS products
and represented by one new drug application. They require, among
other criteria, that supplies and product capacity for the non-ODS
product(s) exist or will exist at levels sufficient to meet patient
need; adequate U.S. postmarketing data are available for the non-ODS
product; and patients who medically require the ODS product are
adequately served by the non-ODS product(s) containing that active
moiety and other available products. Section 2.125(g)(4)(ii)
incorporates these criteria by cross-reference and requires that
they be met prior to removing the essential-use designation for
individual active moieties marketed as ODS products that are
represented by two or more NDAs.
---------------------------------------------------------------------------

    (Response) The criteria in Sec.  2.125(f)(1) we are using in this
rulemaking, as cross-referenced in Sec.  2.125(g)(2), are different
from those in the albuterol rulemaking. Although the analysis used here
is not identical to that used under Sec.  2.125(g)(4) in the albuterol
rulemaking, in both the albuterol rulemaking and this rulemaking, the
primary focus is on determining whether acceptable alternatives exist
for the products that are marketed under the essential use. Section
2.125(g)(2) permits FDA to remove an essential use even if there are no
alternatives available with the same active moiety provided that
sufficient alternative products with different active moieties exist to
meet the needs of patients, because the essential use would then no
longer provide an otherwise unavailable important health benefit. In
the case of Combivent Inhalation Aerosol, both active moieties have
been reformulated without CFCs, and FDA disagrees that the albuterol
HFA MDI and the ipratropium bromide HFA MDI are therapeutically
inferior to Combivent Inhalation Aerosol. As stated earlier, we find
them to be therapeutically equivalent, and we believe the two MDIs used
together will meet the needs of current Combivent Inhalation Aerosol
users.
    b. Intent to reformulate. (Comment 28) BI argues that removing
Combivent Inhalation Aerosol's essential-use designation before a
replacement can be developed preempts BI's good faith efforts to
reformulate (a requirement under the Montreal Protocol).
    (Response) Nothing about this decision precludes BI from
reformulating. A reformulated product can be approved at any time after
FDA has determined an NDA meets approval standards. Based on BI's
assertions, it is possible a replacement will be available prior to the
effective date of this rule for Combivent Inhalation Aerosol.
    c. Deadline for overall CFC phase-out. (Comment 29) BI comments
that the Montreal Protocol and the Clean Air Act do not set a firm
deadline for the phase-out of CFC usage in MDIs, and FDA should
exercise greater flexibility in its essential-use rulemakings.

    (Response) As stated in the 2002 final rule, we reviewed the text
of the Clean Air Act, its legislative history, the text of the Montreal
Protocol, and decisions by the Parties to the Protocol. FDA also
further discussed its understanding of the Clean Air Act and the
Protocol with the EPA. The Clean Air Act does not state specifically
whether such essential-use exemptions may continue indefinitely or must
terminate at some future time. However, the legislative history for
section 604(d)(2) of the Clean Air Act makes clear that the exemption
is only permitted for a limited time. Specifically, the Senate
Conference Report for this section of the Clean Air Act states: The
centerpiece of the stratospheric ozone protection program established
by this title is the phase-out of production and consumption of all
ODSs (136 Cong. Rec. S16895 at 16946 and 16947 (daily ed. Oct. 27,
1990)). These statements are consistent with the Montreal Protocol. The
Preamble to the Protocol states that the Parties are: Determined to
protect the ozone layer by taking precautionary measures to control
equitably total global emissions of substances that deplete it, with
the ultimate objective of their elimination (Preamble to the Montreal
Protocol (emphasis added)). Decision IV/25 of the Parties to the
Protocol also indicates that essential-use exemptions are temporary.
This decision asks the Technology and Economic Assessment Panel to
determine an estimated duration for each essential use, the steps
necessary to ensure alternatives are available as soon as possible, and
whether previously qualified essential uses should no longer qualify as
essential. Thus, although it is true that there is no set date for
termination of essential-use exemptions, it is also clear that the
exemptions were intended to be limited in number and duration and were
not intended to exist forever.
    d. Sufficiency of advisory committee meeting. (Comment 30) BI
argues that little public notice was provided for the 2005 PADAC
meeting and the notice contained little guidance on public
participation and did not seek specific public input. BI also argues
that the straw poll conducted at the PADAC meeting did not take into
account the status of BI's CFC-free Combivent development programs. BI
claims that had the PADAC members been provided a more complete record
upon which to base their opinions, a majority would have recommended
continuation of Combivent Inhalation Aerosol's essentiality and
rejected the proposed therapeutic alternatives.
    (Response) As stated earlier in this document, FDA, after
consultation with a relevant advisory committee and after holding an
open public meeting, may remove an essential-use designation under
section 2.125(g)(2) if it no longer meets certain criteria. FDA made
clear in the 1999 rule proposing criteria for removing essential-use
designations that before removing any essential-use designation, it
would consult with an advisory committee and provide opportunity for
public comment (64 FR 47719 at 47722). FDA published a notice in the
Federal Register on May 10, 2005 (70 FR 24605), that the PADAC would be
convening on July 14, 2005, to discuss the continued need for the
essential-use designations of prescription drugs for the treatment of
asthma and COPD. The notice further stated that interested persons
could present data, information, or views, orally or in writing, on the
issues pending before the committee. This notice provided sufficient
time for those persons or companies with an interest in the essential-
use designations of any moieties used in drugs that treat asthma or
COPD to provide the committee members with any information they
believed would be pertinent to the decision to remove or continue a
designation. Therefore, we disagree with the assertion that little
public notice was provided for the 2005 PADAC meeting and the notice
contained little guidance on public participation and did not seek
specific public input.
    We also disagree with the assertion that PADAC members were not
provided a complete record upon which to base their opinions. At the
PADAC meeting, an FDA representative made a detailed presentation to
committee members on the Montreal Protocol and the essential-use
process and rulemakings, including identification and description of
the current essential uses and their therapeutic alternatives, as well
as the criteria for removing the essential-use designations. After the
FDA presentation, committee members had the opportunity to ask
clarifying questions, and additional presentations were made by an
association representing manufacturers of MDIs, specific MDI
manufacturers, and an interested person. Committee members had
additional time to discuss the individual moieties after these
presentations were made. We believe that the record demonstrates the
PADAC was provided ample information on which to render a vote.

E. Effective date

    In the proposed rule, we proposed an effective date for removal of
the essential-use designations for all seven moieties of December 31,
2009, and we solicited comments on this proposed effective date. We
noted in the proposed rule that, depending on the data presented to us
during the course of the rulemaking, we may determine that it is
appropriate to have different effective dates for different uses.
    We did not receive any substantive comments on the proposed
effective date for metaproterenol and nedocromil. Alupent Inhalation
Aerosol and Tilade Inhaler have been discontinued by BI and King
Pharmaceuticals, Inc., respectively. BI has informed us that any
Alupent Inhalation Aerosols that may be in retail or wholesale stocks
will have passed their expiration date by December 2009. Accordingly,
we have determined that the appropriate effective date for the removal
of the essential-use designations for metaproterenol and nedocromil is
June 14, 2010.
    We did not receive any substantive comments on the proposed
effective date for triamcinolone, and cromolyn. To allow an adequate
length of time for patients to transition to the therapeutic
alternatives identified in this rule, we have determined that December
31, 2010, is an appropriate effective date for removing the essential-
use designations for triamcinolone and cromolyn. The additional period
ensures more time to disseminate information about the phase-out to
patients to ensure an orderly transition that is protective of public
health.
    We received one comment regarding the effective date for
flunisolide from Forest Laboratories, Inc., the exclusive distributor
for Aerobid (flunisolide) Inhaler System via a licensing agreement with
Roche Palo Alto, the NDA holder for Aerobid. Forest requests an 18-
month delay in the effective date of the rule. In its comment, Forest
states that a June 30, 2011, effective date would allow time for Forest
to commercially produce and market its non-CFC flunisolide formulation,
Aerospan Inhalation Aerosol. We have considered this request and have
determined that a June 30, 2011, effective date is appropriate for
removing the essential-use designation for flunisolide. The June 30,
2011, effective date will provide sufficient time for current Aerobid
Inhaler System users to transition to the therapeutic alternatives
including Aerospan Inhalation Aerosol. We also note that the June 30,
2011, effective date provides sufficient time for Forest to prepare for
commercial distribution of Aerospan Inhalation Aerosol.
    We received several comments on the effective date for Combivent
Inhalation Aerosol and Maxair Autohaler. After

considering the comments, we were persuaded that December 31, 2013,
rather than December 31, 2009, as proposed, is a more appropriate
effective date for removing the essential-use designations for
Combivent Inhalation Aerosol and Maxair Autohaler. The December 31,
2013, date provides additional time to disseminate information about
the transition to Combivent Inhalation Aerosol and Maxair Autohaler
users who may have multiple health conditions that may make it more
difficult to transition, and allows these individuals more time to
transition to appropriate non-CFC alternatives. It also allows
sufficient time for manufacturers to increase production of albuterol
HFA MDIs and ipratropium bromide HFA MDIs to ensure adequate supplies
for patients. Finally, we believe a December 31, 2013, effective date
gives sufficient time for the development of a non-CFC formulation of a
combination product containing albuterol and ipratropium or a non-CFC
formulation of pirbuterol and processing of an application for new drug
approval. In our responses to the comments below, we further explain
the basis for our decision to extend the effective date from that
proposed for Combivent Inhalation Aerosol and Maxair Autohalers.
    (Comment 31) We received many comments requesting that the
effective date be delayed until a CFC-free Combivent Inhalation Aerosol
is available and to ensure patients will continue to have access to
Maxair Autohaler during the reformulation and regulatory review phases.
BI requests that FDA refrain from removing the essential-use
designation for Combivent Inhalation Aerosol and initiate a future
rulemaking addressing Combivent Inhalation Aerosol once a non-CFC
Combivent product has been developed and approved by the agency for
marketing. Another comment suggests that FDA condition the effective
date (and therefore the length of the transition period) on the
submission of an NDA and reconsider the appropriateness and length of
the date once the NDA has been submitted for review. Graceway
recommends that the agency revisit the essential-use status of
pirbuterol after December 2012 to ensure essential products are
available and requests an effective date of December 31, 2015.