Document ID: FDA-2006-N-0304-0039
Agency: fda
Document Type: Rule
Title: Use of Ozone-Depleting Substances; Removal of Essential-Use Designation: Flunisolide, etc.
Posted Date: 2010-04-14T04:00Z

[Federal Register: April 14, 2010 (Volume 75, Number 71)]
[Rules and Regulations]               
[Page 19213-19241]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[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://

[[Page 19214]]

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

[[Page 19215]]

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)),

[[Page 19216]]

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

[[Page 19217]]

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

[[Page 19218]]

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

[[Page 19219]]

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).

[[Page 19220]]

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

[[Page 19221]]

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.

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[[Page 19222]]

    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

[[Page 19223]]

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

[[Page 19224]]

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

[[Page 19225]]

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.

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[[Page 19226]]

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

[[Page 19227]]

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.

[[Page 19228]]

    (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.

[[Page 19229]]

    (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

[[Page 19230]]

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.
    (Response) As stated above, we carefully evaluated the comments 
submitted in response to the proposed rule and have determined that an 
effective date of December 31, 2013, is appropriate for the removal of 
the essential-use designation for Combivent Inhalation Aerosol and 
Maxair Autohaler. We acknowledge that the presence of a non-CFC 
replacement for Combivent Inhalation Aerosol and Maxair Autohaler may 
be convenient for users. However, we note that a December 31, 2013, 
effective date allows a reasonable time to permit the development of a 
non-CFC replacement. Currently, we believe there are adequate non-CFC 
alternatives for Combivent Inhalation Aerosol available in the form of 
separate albuterol HFA MDIs and ipratropium bromide HFA MDIs. With 
respect to Maxair Autohaler, we believe adequate non-CFC alternatives 
exist in the form of Albuterol in HFA MDIs or in a nebulizer.
    The effective date we are establishing for the removal of the 
essential-use designations for Combivent Inhalation Aerosol and Maxair 
Autohaler provides over 3 additional years for manufacturers to scale 
up production of albuterol HFA MDIs and ipratropium bromide HFA MDIs 
and will help ensure that there will be adequate supplies of the MDIs 
for patients. The effective date also provides over 3 years for 
patients and their health care providers to consider the different 
formulations of albuterol HFA MDI and levalbuterol HFA MDI and select 
the most appropriate therapeutic alternative. We are also permitting 
additional time for patients to transition from using a combination 
product to using two separate MDIs, to choose and adapt to a 
traditional press-and-breathe MDI, or to switch to using a nebulized 
solution.
    We believe that educating patients and health care providers about 
the transition to other asthma treatments is very important to an 
orderly and safe transition of patients currently using Combivent 
Inhalation Aerosol and Maxair Autohaler, particularly for elderly 
patients, those with co-morbid conditions who are taking multiple 
medications, or those patients with coordination problems. The need to 
ensure that we have permitted sufficient time for patient education for 
transitioning from a Combivent Inhalation Aerosol or a Maxair Autohaler 
to an appropriate non-CFC substitute was an important factor in our 
decision to extend the proposed effective date in this final rule, to 
December 31, 2013. We will actively monitor the transition to CFC-free 
alternatives. Anyone who wishes to discuss a cooperative educational 
effort with DHHS and FDA should contact FDA or the Office of the 
Secretary of DHHS.
    With respect to a conditional effective date for Combivent 
Inhalation Aerosol, we believe it is important to specify a date 
certain when Combivent Inhalation Aerosol can no longer be marketed so 
patients and their health care providers may transition to therapeutic 
alternatives in a timely and orderly manner. We also note that the 
December 31, 2013, effective date allows a reasonable time to permit 
the development and approval of a non-CFC replacement for Combivent 
Inhalation Aerosol.
    We decline to exclude Combivent Inhalation Aerosol from the 
rulemaking, as requested by BI. As discussed elsewhere in this 
document, the United States is committed to phasing out the remaining 
essential-use designations in the context of the Montreal Protocol. We 
believe finalizing this rule now and setting an effective date for 
Combivent Inhalation Aerosol that provides over a 3-year transition 
affects the eventual transition in a manner that is consistent with our 
duty to protect the public health.

F. Conclusions

    We conclude 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. The evidence presented to the agency 
during this rulemaking does not meet the high threshold required by the 
first criterion on substantial technical barriers. We therefore 
conclude that oral pressurized MDIs containing flunisolide, 
triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in 
combination, cromolyn, and nedocromil are no longer essential uses of 
ODSs and will be removed from the list of essential uses in Sec.  
2.125(e) as of the effective dates specified in this rule.

V. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this action. FDA has concluded that the action will not have 
a significant impact on the human environment, and that an 
environmental impact statement is not required. The agency's finding of 
no significant impact and the evidence supporting that finding, 
contained in an environmental assessment, may be seen in the Division 
of Dockets Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday. Under FDA's regulations implementing the National 
Environmental Policy Act (21 CFR part 25), an action of this type would 
require an environmental assessment under 21 CFR 25.31(a).

[[Page 19231]]

VI. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is an economically significant regulatory action under 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because only one CFC MDI manufacturer may possibly 
be considered a small entity, and one single small entity among an 
industry of hundreds does not constitute a ``substantial number'' under 
the Regulatory Flexibility Act, the agency certifies that the final 
rule will not have a significant economic impact on a substantial 
number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $133 million, using the most current (2008) Implicit 
Price Deflator for the Gross Domestic Product. This final rule may 
result in a 1-year expenditure that would meet or exceed this amount.
    The Congressional Review Act requires that regulations that have 
been identified as being major must be submitted to Congress before 
taking effect. This rule is major under the Congressional Review Act.
    Limitations in the available data prevent us from estimating 
quantitatively the anticipated costs and benefits to society, so we 
focus instead on proxy measures. The costs of this final rule include 
the benefits lost by consumers who would have bought MDIs at current 
prices, but would not buy them at higher prices. Consumers of 
flunisolide MDIs (Aerobid Inhaler System) and MDIs delivering albuterol 
and ipratropium in combination (Combivent Inhalation Aerosol) will face 
higher prices because available substitutes cost more. In contrast, 
users of triamcinolone MDIs (Azmacort Inhalation Aerosol), 
metaproterenol MDIs (Alupent Inhalation Aerosol), pirbuterol MDIs 
(Maxair Autohaler), cromolyn sodium MDIs (Intal Inhaler), and 
nedocromil sodium MDIs (Tilade Inhaler) will be able to switch to less 
expensive alternatives. Consumers of these products may benefit as they 
are made aware of less expensive, therapeutically adequate alternatives 
to the MDIs they currently use. In the transition, these consumers may 
also be inconvenienced by the need to become accustomed to using an 
alternative product.
    Net spending by consumers and third-party payers, including Federal 
and State Governments, will increase as patients switch to more 
expensive therapeutic alternatives; the potential for spending 
reductions by users of Azmacort, Alupent, Maxair, Intal, and Tilade is 
not enough to offset expected increases in spending by users of Aerobid 
and Combivent. These spending increases, however, overstate social 
costs because, to some extent, they represent resources transferred 
from drug buyers (consumers and third-party payers) to drug sellers 
(drug manufacturers, wholesalers, pharmacies). We estimate that the 
introduction of generic albuterol HFA MDIs to the market will eliminate 
price and spending increases resulting from this final rule. The 
benefits of this rule include the value of improvements in the 
environment and public health that may result from reduced emissions of 
ODSs (for example, the reduced future incidence of skin cancers and 
cataracts). The benefits also include improved expected returns on 
investments in environmentally-friendly technologies and greater 
international cooperation to comply with the Montreal Protocol.
    Estimated spending increases (summarized in tables 1 and 2 of this 
document) cannot be attributed solely to this rule. These increases 
result from Combivent users switching to Atrovent Inhalation Aerosol 
and albuterol HFA MDIs. The increased spending from this switch, in 
turn, is driven by the switch from inexpensive generic albuterol CFC 
MDIs to more expensive albuterol HFA MDIs, which was mandated in an 
earlier rulemaking (70 FR 17168, April 4, 2005). The spending increases 
described here may therefore be viewed as costs of the larger 
transition away from CFC products, rather than costs resulting from 
this rule in particular. We cannot conclusively attribute these 
estimated spending increases to either the prior rule or this final 
rule. While table 1 provides the annual quantifiable effects after all 
moieties have been removed from the market, table 2 provides the total 
impacts, factoring in the staggered phase-out and using two different 
possibilities for the date of HFA patent expiration.

Table 1.--Summary of Annual Quantifiable Effects of the Final Rule After All Seven Moieties Are Removed From the
                                                     Market
----------------------------------------------------------------------------------------------------------------
    Patient Days of      Increased MDI Expenditures,   Possible Reduction in Days    Reduced CFC Emissions From
   Therapy Affected            in 2009 dollars         of Therapy Used (millions)        Phase-Out (tonnes)
----------------------------------------------------------------------------------------------------------------
300 million                         $90-$280 million                      0.20-4.2                       310-365
----------------------------------------------------------------------------------------------------------------

                  Table 2.--Summary of Impacts From Phase-Out to Date of HFA Patent Expiration
----------------------------------------------------------------------------------------------------------------
                          Possible Change in Use of                                 Increases in Expenditures on
  Date of HFA Patent       Asthma and COPD Therapy            Discount Rate            CFC-based MDIs, Present
      Expiration          (million days of therapy)                                   Value in 2010 (billions)
----------------------------------------------------------------------------------------------------------------
2012                                              NA                            3%               -$0.09 - -$0.04
                                                     -----------------------------------------------------------
                        ............................                            7%               -$0.09 - -$0.04
----------------------------------------------------------------------------------------------------------------

[[Page 19232]]

2017                                         0.33-14                            3%                   $0.16-$0.91
                                                     -----------------------------------------------------------
                        ............................                            7%                   $0.12-$0.73
----------------------------------------------------------------------------------------------------------------

    The decreased use of MDIs may adversely affect some patients, but 
we currently lack data that would allow us to characterize such effects 
quantitatively. We also are unable to estimate quantitatively the 
reductions in skin cancers, cataracts, and environmental harm that may 
result from the reduction in CFC emissions by 310 to 365 tonnes during 
these years. Although we cannot estimate quantitatively the public 
health effects of the phase-out, based on a qualitative assessment, the 
agency concludes that the benefits of this regulation justify its 
costs.
    We state the need for the regulation and its objective in section 
VI.B of this document. Section VI.C of the analysis provides background 
on CFC depletion of stratospheric ozone, the Montreal Protocol, the MDI 
market, and the health conditions that the seven moieties treat. We 
analyze the benefits and costs of the rule, including effects on 
government outlays, in section VI.D of this analysis. We assess 
alternative dates in section VI.E of this analysis, and discuss our 
sensitivity analysis in section VI.F. We discuss our conclusions in 
section VI.G of this analysis. We present an analysis of the effects on 
small business in a regulatory flexibility analysis in section VII of 
this document.

B. Need for Regulation and the Objective of this Rule

    The objective of this final rule is to respond to the treaty 
requiring the United States to reduce atmospheric emissions of ODSs, 
specifically CFCs. CFCs and other ODSs deplete the stratospheric ozone 
that protects the Earth from ultraviolet solar radiation. We are ending 
the essential-use designation for ODSs used in MDIs containing 
triamcinolone, metaproterenol, pirbuterol, cromolyn sodium, nedocromil 
sodium, flunisolide, and albuterol and ipratropium in combination, 
because we have concluded that adequate therapeutic alternatives are 
available. Removing this essential-use designation will comply with 
obligations under the Montreal Protocol and the Clean Air Act, thereby 
reducing emissions that deplete stratospheric ozone.

C. Background

1. CFCs and Stratospheric Ozone
    During the 1970s, scientists became aware of a relationship between 
the level of stratospheric ozone and industrial use of CFCs. Ozone 
(O3), which causes respiratory problems when it occurs in 
elevated concentrations near the ground, shields the Earth from 
potentially harmful solar radiation when it is in the stratosphere. 
Excessive exposure to solar radiation is associated with adverse health 
effects such as skin cancer and cataracts, as well as adverse 
environmental effects. Emissions of CFCs and other ODSs reduce 
stratospheric ozone concentrations through a catalytic reaction, 
thereby allowing more solar radiation to reach the Earth's surface. 
Because of this effect and its consequences, environmental scientists 
from the United States and other countries advocate ending all uses of 
these chemicals.
2. The Montreal Protocol
    The international effort to craft a coordinated response to the 
global environmental problem of stratospheric ozone depletion 
culminated in the Montreal Protocol, an international agreement to 
regulate and reduce production of ODSs. The Montreal Protocol is 
described in section II.B.2 of this document. One hundred and ninety-
six countries are now Parties to the Montreal Protocol, and the overall 
usage of CFCs has been dramatically reduced. In 1986, global 
consumption of CFCs totaled about 1.1 million tonnes annually, and by 
2004, total annual production had been reduced to 70,000 tonnes (Ref. 
6). This decline amounts to more than a 90-percent decrease in 
production and is a key measure of the success of the Montreal 
Protocol. Within the United States, use of ODSs, and CFCs in 
particular, has fallen sharply; production and importation of CFCs is 
less than 1 percent of 1989 production and importation (Ref. 6).
    A relevant aspect of the Montreal Protocol is that production of 
CFCs in any year by any country is banned after the phase-out date 
unless the Parties to the Montreal Protocol agree to designate the use 
for which the CFCs are produced as ``essential'' and approve a quantity 
of new production for that use.
    Each year, each Party nominates the amount of CFCs needed for each 
essential use and provides the reason why such use is essential. 
Agreement on both the essentiality and the amount of CFCs needed for 
each nominated use is reached by consensus at the annual Meeting of the 
Parties.
3. Benefits of the Montreal Protocol
    EPA has generated a series of estimates of the environmental and 
public health benefits of the Montreal Protocol (Ref. 7). The benefits 
include reductions of hundreds of millions of nonfatal skin cancers, 6 
million fewer fatalities due to skin cancer, and 27.5 million cataracts 
avoided between 1990 and 2165 if the Montreal Protocol were fully 
implemented. EPA estimated the value of these and related benefits to 
equal $4.3 trillion in present value when discounted at 2 percent over 
the period of 175 years. This amount is equivalent to about $7 trillion 
in 2008 prices after adjusting for inflation between 1990 and 2008. 
This estimate includes all benefits of total global ODS emission 
reductions expected from the Montreal Protocol and is based on 
reductions from a baseline scenario in which ODS emissions would 
continue to grow for decades but for the Montreal Protocol.
4. Characteristics of COPD
    The seven CFC MDI products that are the subject of this final rule, 
and Combivent in particular, may be used to treat COPD. While there is 
some overlap between asthma patients and COPD patients, COPD 
encompasses a group of diseases characterized by relatively fixed 
airway obstruction associated with breathing-related symptoms (for 
example, chronic coughing, expectoration, and wheezing). COPD is 
generally associated with cigarette smoking and is extremely rare in 
persons younger than 25.
    According to the National Health Interview Survey (NHIS), an 
estimated 10 million adults in the United States

[[Page 19233]]

carried the diagnosis of COPD in 2007 (Ref. 8). The proportion of the 
U.S. population with mild or moderate COPD has declined over the last 
quarter century, although the rate of COPD in females increased 
relative to males between 1980 and 2000. The most effective 
intervention in modifying the course of COPD is smoking cessation. 
Symptoms such as coughing, wheezing, and sputum production are treated 
with medication.
5. Characteristics of Asthma
    These seven CFC MDIs, with the exception of Combivent, may be used 
to treat asthma, a chronic respiratory disease characterized by 
episodes or attacks of bronchospasm in addition to chronic airway 
inflammation. These attacks can vary from mild to life-threatening and 
involve shortness of breath, wheezing, coughing, or a combination of 
symptoms. Many factors, including allergens, exercise, viral 
infections, and others, may trigger an asthma attack.
    According to the 2007 NHIS, approximately 23 million adult patients 
in the United States reported they had asthma (Ref. 9). The prevalence 
of asthma decreases then increases with age, with the prevalence being 
100 per 1,000 children ages 5-17 (5.3 million children) compared to 72 
per 1,000 among adults ages 18-44 (8.0 million), 72 per 1,000 among 
adults ages 45-64 (5.5 million), and 75 per 1,000 among adults age 65 
and over (2.7 million) (Ref. 9).
    The NHIS reported that during 2007, about 12 million patients 
reported experiencing an asthma attack in the course of the previous 
year (Ref. 9, table 10). According to the National Ambulatory Medical 
Care Survey, in 2006 there were 1.2 million outpatient asthma visits to 
physician offices and hospital clinics and 1.7 million emergency room 
visits (Ref. 9, table 19). According to the National Center for Health 
Statistics, there were 444,000 hospital admissions for asthma in 2006 
(Ref. 9, table 16) and 3,563 deaths (Ref. 9, table 1). The estimated 
direct medical cost of asthma (hospital services, physician care, and 
medications) was $14.7 billion (Ref. 9, table 20).
    While the prevalence of asthma has been increasing in recent years, 
the CDC reports that the incidence of asthma (or the rate of new 
diagnoses) has remained fairly constant since 1997 (Ref. 10). Non-
Hispanic Blacks, children under 17 years old, and females have higher 
incidence rates than the general population and also have higher attack 
prevalence. The CDC notes that although increases have occurred in the 
numbers and rates of physician office visits, hospital outpatient 
visits, and emergency room visits, these increases are accounted for by 
the increase in prevalence. This phenomenon might indicate early 
successes by asthma intervention programs that include access to 
medications.
6. Current U.S. Market for CFC MDIs
    For the 12-month period ending June 2009, we estimate that sales of 
these seven CFC MDIs provided roughly 300 million days of therapy, 
sufficient to treat roughly 800,000 COPD and asthma patients for a full 
year. We use days of therapy as a common metric because these MDIs vary 
in the number of inhalations provided, and the number of inhalations 
that the average user would use each day. We calculate the number of 
days of therapy provided by each MDI as equal to the number of MDIs 
sold, multiplied by the number of inhalations contained by the MDI, 
divided by the recommended, or usual, daily inhalations described in 
the MDI's physician labeling: [(Days of Therapy)=(MDIs)x(Inhalations/
MDI)/(Inhalations/day)]. We calculate MDI sales for each of the seven 
products using data from IMS Health's National Sales Perspective (Ref. 
11).
    We calculate the average price per day of therapy for a CFC MDI as 
the total revenue derived from sales of that product in the 12 months 
ending June 2009, as reported by IMS Health's National Sales 
Perspective, divided by the number of days of therapy for that product: 
[(Price/Day of Therapy)=(Total Sales)/(Total Days of Therapy)]. We use 
the same method to calculate the average price per day of therapy for 
the nine non-ozone depleting products we consider the most medically 
appropriate alternatives to these seven CFC MDIs. We then estimate the 
price premium (or savings) associated with alternatives as the 
difference between price per day of the CFC product and price per day 
of its most appropriate alternatives.

 Table 3.--Summary of CFC MDIs, Non-ODS Alternatives, and Expected Price
                  Changes per Day of Therapy (Ref. 11)
------------------------------------------------------------------------
                                      Price Premium per Day of Therapy
     CFC MDI           Non-ODS     -------------------------------------
                    Alternatives         Maximum            Minimum
------------------------------------------------------------------------
Aerobid           QVAR                          $1.06              $0.34
Aerobid-M         PULMICORT         .................  .................
                   TURBUHALER
                  FLOVENT HFA
                  ASMANEX
                   TWISTHALER
------------------------------------------------------------------------
Azmacort          QVAR                         -$1.10             -$1.82
                  PULMICORT
                   TURBUHALER
                  FLOVENT HFA
                  ASMANEX
                   TWISTHALER
------------------------------------------------------------------------
Alupent           PROAIR HFA                    $0.34             -$0.31
                  PROVENTIL HFA
                  VENTOLIN HFA
                  XOPENEX HFA
------------------------------------------------------------------------
Maxair            PROAIR HFA                   -$0.21             -$0.86
                  PROVENTIL HFA
                  VENTOLIN HFA
                  XOPENEX HFA
------------------------------------------------------------------------

[[Page 19234]]

Intal             QVAR                         -$1.34             -$2.06
                  PULMICORT
                   TURBUHALER
                  FLOVENT HFA
                  ASMANEX
                   TWISTHALER
------------------------------------------------------------------------
Tilade            QVAR                            N/A                N/A
                  PULMICORT
                   TURBUHALER
                  FLOVENT HFA
                  ASMANEX
                   TWISTHALER
------------------------------------------------------------------------
Combivent         ATROVENT HFA +                $1.30              $0.65
                   one of the
                   following:
                  PROAIR HFA
                  PROVENTIL HFA
                  VENTOLIN HFA
                  XOPENEX HFA
------------------------------------------------------------------------
Source: IMS Health, IMS National Sales Perspective (TM), 2009, extracted
  September 2009.

    Table 3 of this document shows each of the CFC MDIs that would no 
longer be marketed, the therapeutic alternatives that users of these 
CFC MDIs would be expected to purchase, and the range of differences in 
price per day of therapy. For example, an Azmacort user would be 
expected to switch to QVAR, PULMICORT TURBUHALER, FLOVENT HFA, or 
ASMANEX TWISTHALER. The most expensive of these alternatives would cost 
roughly $1.10 cents less per day of therapy, and the least expensive 
would cost roughly $1.80 less per day of therapy. Combivent users would 
be expected to switch to both ATROVENT HFA and one of four albuterol 
HFA MDIs currently marketed. We make no attempt to forecast future 
price changes, but note that recent changes in prices of CFC MDIs did 
not differ systematically from the changes in prices of the proposed 
alternatives. For our Maxair calculations, we have added the annual 
purchase of a $30 spacer to the cost of switching to an alternative 
therapy.
    If all users switched to the least expensive alternative therapy, 
the average price for users of these seven CFC MDIs, weighted by the 
number of days of therapy sold for each product in 2009, would increase 
9 percent; if all users switched to the most expensive alternative 
therapy, the average price per day of therapy would increase 28 
percent. These price differences represent differences in average ex-
manufacturer prices across all distribution channels and do not 
incorporate differences introduced by retail markups or off-invoice 
discounts (Ref. 11).
    It is not possible to attribute these estimated price increases 
exclusively to this final rule. These estimated price increases are 
driven almost entirely by the large population of Combivent users 
switching to both Atrovent Inhalation Aerosol and albuterol HFA MDIs, 
which, together, are more expensive. Through 2003, the price for a day 
of therapy with Combivent was roughly equal to the sum of a day of 
therapy with Atrovent (the ipratropium CFC MDI which has been withdrawn 
from the market) and a day of therapy with a generic albuterol CFC MDI. 
After 2003, the price of a day of Combivent therapy rose to be roughly 
equal to the sum of a day of therapy with Atrovent HFA and a day of 
therapy with a generic albuterol CFC MDI, likely in anticipation of the 
withdrawal of Atrovent from the market. The range of spending changes 
for Combivent therapy alone is $150 million to $300 million; excluding 
the effects of Combivent therapy, the range of spending changes is -$25 
million to -$65 million.
    We estimate that these seven CFC MDIs are responsible for roughly 
310 to 365 tonnes of CFC emissions annually. The CFC content of the 
seven CFC MDIs ranges from about 6 to 20.5 grams per MDI. Multiplying 
the total 2005 sales of each of the CFC MDIs by its CFC content, and 
allowing for an additional 10 percent loss in the production process, 
yields a total of 310 tonnes of CFC emissions annually, our low 
estimate. Our recent data shows a decline in the use of the seven 
moieties to be phased out, so our low estimate may overstate the 
reduction in CFCs attributable to this final rule. The CFC MDI 
manufacturers requested roughly 365 tonnes of CFCs for production of 
the seven CFC MDIs for 2007, which we use for our high estimate.

D. Benefits and Costs of the Final Rule

    We estimate the benefits and costs of a government action relative 
to a baseline scenario that in this case is a description of the 
production, use, and access to these seven CFC MDIs in the absence of 
this rule. In this section, we first describe such a baseline and then 
present our analysis of the benefits of the final rule. We also present 
an analysis of the most plausible regulatory alternative, given the 
Montreal Protocol. Next we turn to the costs of the rule and to an 
analysis of the effects on the Medicare and Medicaid programs.
1. Baseline Conditions
    We developed baseline estimates of future conditions to assess the 
economic effects of prohibiting marketing of these seven CFC MDIs. MDIs 
containing metaproterenol and nedocromil will be removed from the 
market June 14, 2010. MDIs containing triamcinolone and cromolyn will 
be removed from the market December 31, 2010. MDIs containing 
flunisolide will be removed from the market June 30, 2011. Those 
containing albuterol and ipratropium in combination and pirbuterol will 
be removed from the market December 31, 2013.
    It is standard practice to use, as a baseline, the state of the 
world without the rule in question, or where this implements a 
legislative requirement, the world without the statute. For this final 
rule, the Montreal Protocol makes the baseline assumption of indefinite 
availability infeasible, but we can nevertheless use it as a point of 
reference. In addition to the baseline of indefinite availability, we 
also assess alternative phase-out dates for the final disappearance of 
CFC products.

[[Page 19235]]

Throughout this baseline analysis, we assume that sufficient 
inventories of CFCs are available to meet demand for these seven CFC 
MDIs through the date they lose their essential-use designation and 
that there will be sufficient therapeutic alternatives to meet demand 
after they are removed from the market.
    However, in the absence of this final rule, the parties to the 
Montreal Protocol would still have the ability to restrict access to 
CFCs required for the manufacture of products using these seven 
moieties. This final rule, in establishing a timetable for phasing out 
these seven moieties, demonstrates a commitment to phasing out CFCs, 
which reduces the need for the parties to act on their own. In a sense, 
this final rule does not phase out these moieties, but attempts to 
establish a phase-out timetable preferable to the one that the parties 
to the Montreal Protocol might impose. The existence of a timetable 
imposed by the parties to the Montreal Protocol different from this 
final rule implies the costs detailed in the next section of this 
analysis will accrue, although perhaps at a different time, regardless 
of whether this final rule is enacted. The cost-benefit analysis 
presented here would then apply to the withdrawal of the CFC-containing 
products from the market rather than to the specific effects of the 
final rule.
2. Benefits of the Final Rule
    The benefits of the final rule include environmental and public 
health improvements from protecting stratospheric ozone by reducing CFC 
emissions. Benefits also include expectations of increased returns on 
investments in environmentally friendly technology, and continued 
international cooperation to comply with the spirit of the Montreal 
Protocol, thereby potentially reducing future emissions of ODSs 
throughout the world.
    Failure to enact this final rule would leave the timetable for 
phasing out these seven moieties in the hands of the parties to the 
Montreal Protocol. As the parties to the Montreal Protocol would see 
these drugs with therapeutic alternatives and no regulation in place to 
commit to their phase-out, their likely response would be to deny the 
provision of CFCs for their continued production and to do so in a way 
that did not provide for an adequate transition period.
    a. Reduced CFC emissions. Market withdrawal of these seven CFC MDIs 
will reduce emissions by approximately 310 to 365 tonnes of CFCs per 
year. Current CFC inventories are substantial. Nominations for new CFC 
production are generally approved by the Parties to the Montreal 
Protocol 2 years in advance. The final rule would ban marketing of two 
of the seven CFC MDIs after June 14, 2010, two more after December 31, 
2010, one after June 30, 2011, and the remaining two after December 31, 
2013.
    There is some uncertainty with respect to the amount of inventory 
that will be available in the future, but we anticipate that existing 
inventory will allow EPA, in consultation with FDA, to avoid nominating 
additional CFC production for 2010 through 2013. Therefore, we estimate 
the regulation will reduce CFC use by 310 to 365 tonnes per year after 
the end of 2013, a benefit that will continue indefinitely.
    In an evaluation of its program to administer the Clean Air Act, 
EPA has estimated that the benefits of controlling ODSs under the 
Montreal Protocol are the equivalent of $7 trillion in 2008 dollars. 
However, EPA's report provides no information on the total quantities 
of reduced emissions or the incremental value per tonne of reduced 
emissions. EPA derived its benefits estimates from a baseline that 
included continued increases in emissions in the absence of the 
Montreal Protocol. We have searched for authoritative scientific 
research that quantifies the marginal economic benefit of incremental 
emission reductions under the Montreal Protocol, but have found none 
conducted during the last 10 years. As a result, we are unable to 
quantify the environmental and human health benefits of reduced 
emissions from this regulation. Such benefits, in any event, were 
apparently included in EPA's earlier estimate of benefits of the Clean 
Air Act.
    As a share of total global emissions, the reduction associated with 
the elimination of the seven CFC MDIs represents only a fraction of 1 
percent. Current allocations of CFCs for the seven MDIs account for 
less than 0.1 percent of the total 1986 global production of CFCs (Ref. 
6). Furthermore, current U.S. CFC emissions from MDIs represent a much 
smaller, but unknown share of the total emissions reduction associated 
with EPA's estimate of $7 trillion in benefits because that estimate 
reflects future emissions growth that has not occurred.
    Although the direct benefits of this regulation are small relative 
to the overall benefits of the Montreal Protocol, the reduced exposure 
to UV-B radiation that will result from these reduced emissions will 
help protect public health. The final rule will account for some small 
part of the benefits estimated by EPA. However, we are unable to assess 
or quantify specific reductions in future skin cancers and cataracts 
associated with these reduced emissions.
    b. Returns on investment in environmentally-friendly technology. 
Establishing a phase-out date prior to the expiration of patents on HFA 
MDI technology not only rewards the developers of the HFA technology, 
but also encourages other potential developers of ozone-safe 
technologies. Furthermore, a phase-out date would preserve expectations 
that the government protects incentives to research and develop ozone-
safe and other new technologies.
    Newly developed technologies to avoid ODS emissions have resulted 
in more environmentally ``friendly'' air conditioners, refrigerants, 
solvents, and propellants, but only after significant investments. 
Several manufacturers have claimed development costs that total between 
$250 million and $400 million to develop HFA MDIs and new propellant-
free devices for the global market (Ref. 12).
    These investments have resulted in several innovative products in 
addition to HFA MDIs. For example, breath-activated delivery systems, 
dose counters, dry-powder inhalers, and mini-nebulizers have also been 
successfully marketed.
    c. International cooperation. The advantages of selecting a date 
that maintains international cooperation are substantial because the 
Montreal Protocol, like most international environmental treaties, 
relies primarily on a system of national self-enforcement, although it 
also includes a mechanism to address noncompliance. In addition, 
compliance with its directives is subject to differences in national 
implementation procedures. Economically less-developed nations, which 
have slower phase-out schedules than developed nations, have emphasized 
that progress in eliminating ODSs in developing nations is affected by 
observed progress by developed nations, such as the United States. If 
we had adopted a later phase-out date, other Parties could attempt to 
delay their own control measures.
3. Costs of the Final Rule
    The final rule would increase spending for needed medicines used to 
treat asthma and COPD. The social costs of the final rule include the 
health benefits lost through decreased use of medicines that may result 
from increased prices. We discuss the increased spending and then the 
social costs in turn. We are unable to quantify the economic costs of 
reducing the variety of marketed products from

[[Page 19236]]

which consumers, and their doctors, can choose. Because we lack data 
that would enable us to measure the effects of a decreased number of 
products from which to choose, in this analysis we only quantify the 
effects on spending.
    In the absence of this regulation, we would expect 300 million days 
of therapy with these seven CFC MDIs to be sold annually. With this 
regulation, patients who would have used any of these seven CFC MDIs 
are expected to switch to one of several other products as described in 
table 3 of this document. Depending on whether asthma and COPD patients 
use the most or least expensive of alternatives, private, third-party, 
and public expenditures on inhaled medicines would increase by roughly 
$90 million to $280 million per year. These expenditure increases will 
be driven almost exclusively by Combivent users changing to both 
Atrovent and one of four available albuterol HFA products. With most, 
perhaps all, of this increase coming from estimated increased spending 
on albuterol HFA products, what happens to the prices of albuterol 
products will largely determine the change in overall spending. To the 
extent that expenditures rise, these higher costs would continue until 
lower-priced non-ODS substitutes appear on the market. For many of 
these products it is difficult to predict when this might occur. With 
the exception of albuterol CFC MDIs, generic versions of prescription 
MDIs and DPIs for treatment of asthma and COPD have not been 
introduced, despite the expiration of the patents on many of the 
innovator products. However, the market for albuterol MDIs has a clear 
history of generic competition. A previous rulemaking (70 FR 17168, 
April 4, 2005) removed albuterol CFC MDIs, including generic albuterol 
CFC MDIs, from the market on December 31, 2008. If these cheaper 
generic albuterol MDIs had been able to remain on the market, the 
expected cost of switching from Combivent to both Atrovent and an 
albuterol HFA MDI would be essentially eliminated. Because expenditure 
increases resulting from this final rule stem almost exclusively from 
the transition away from Combivent, such increases would most likely be 
eliminated with the introduction of generic albuterol HFA MDIs to the 
market. There are multiple patents listed in ``Approved Drug Products 
with Therapeutic Equivalence Evaluations'' (Orange Book) for albuterol 
HFA MDIs, expiring from late 2009 to beyond 2020, creating a wide range 
of possible dates for generic entry. In the proposed rule, we assumed 
potential entry in 2010 and 2017. As moieties will not start to be 
removed from the market until June 14, 2010, generic entry in 2010 
would eliminate almost all of the estimated costs of the transition. 
For this final rule, we use 2012 and 2017 for assumed entry of generic 
substitutes for current branded albuterol MDI products. One recent 
study predicted the introduction of a generic albuterol HFA MDI in 2012 
(Ref. 13). For the year 2010, we include only the impact of Alupent and 
Tilade and for the years 2011 through 2013, we include in the analysis 
the impact of all moieties except Combivent and Maxair. Removing those 
five moieties from the market results in a change in annual private, 
third-party, and public expenditures of roughly -$20 million to -$50 
million. Of course, unforeseen introduction of alternative therapies 
could reduce any expected increases in expenditures.
    These increased expenditures represent, to some extent, transfers 
from consumers and third-party payers, including State and Federal 
Governments, to pharmaceutical manufacturers, patent holders, and other 
residual claimants. However, to some extent, increased expenditures 
represent purchases of products that are more costly to manufacture and 
bring to market. We are unable to estimate the fraction of the 
increased expenditures that constitute societal costs.
    We estimate that the average price increases resulting from market 
withdrawal of less expensive CFC MDIs could reduce use of inhaled 
therapy by a range of 0.20 to 4.2 million days annually, equivalent to 
roughly 0.5 to 12 thousand patient years of therapy. The impact of this 
reduction on health outcomes is too uncertain to quantify given 
available data. Some patients, however, respond to price increases for 
medications for chronic conditions in ways that may adversely affect 
their health.
    A recent article found that, ``copayment increases led to increased 
use of emergency department visits and hospital days for the sentinel 
conditions of diabetes, asthma, and gastric acid disorder: predicted 
annual emergency department visits increased by 17 percent and hospital 
days by 10 percent when copayments doubled'' (Ref. 14). However, the 
article proceeds to characterize these results as ``not definitive.'' 
This finding suggests that increased prices for medicines may lead to 
some adverse public health effects among the users of these seven CFC 
MDIs.
    Another article found that, ``a single inhaler containing both 
ipratropium and albuterol can increase compliance and decrease 
respiratory morbidity and charges over and above the effects achieved 
with separate inhalers for these 2 agents'' (Ref. 5). The article found 
that access to single inhaler therapy was associated with a 17 percent 
reduction in monthly costs. This finding suggests that some current 
users of Combivent may suffer adverse health consequences because of 
compliance issues associated with using multiple inhalers. This 
preliminary evidence is insufficient to permit us to quantify adverse 
public health effects. We use expected reductions in days of therapy 
purchased as a surrogate measure of the impact.
    Our approach to estimating the effects of this final rule assumes 
that the primary effect of an elimination of these seven CFC MDIs from 
the market would be an increase in the average price of MDI and DPI 
therapy. Given the price increase expected, we have projected how the 
overall quantity of MDI and DPI therapy consumed may decline as a 
result of the increase in price. We assume that the reduction in the 
use of MDI and DPI therapy attributable to this rule can be calculated 
as the product of the sensitivity of use with respect to the price 
increase, the baseline use of these seven CFC MDIs among price-
sensitive patients, and the price increase in percentage terms. We 
discuss these in turn.
    We have no information about how consumers react to increases in 
the price of these seven forms of CFC MDIs in particular, much less to 
what amounts to a compulsory switch to different, more expensive drugs. 
Economists have, however, estimated the response of consumers to higher 
insurance copayments for drugs in general. Goldman et al. estimate 
price elasticities in the range of -0.33 (for all anti-asthmatic drugs) 
to -0.22 (for anti-asthmatic drugs among patients with chronic asthma), 
implying that a 10 percent increase in insurance copayments apparently 
leads to a reduction in use of between 2.2 and 3.3 percent (Ref. 14), 
but the authors report that there is wide variance based on the 
availability of over-the-counter substitutes. For example, for drugs 
with no over-the-counter substitutes--a set that includes all seven of 
these CFC MDIs--the reported price elasticity was -0.15 (Ref. 14, p. 
2348). Drugs included as anti-asthmatics in this study include anti-
cholinergics, anti-inflammatory asthma agents, leukotriene modulators, 
oral steroids, steroid inhalers, sympathomimetics, and xanthines. We 
have used price elasticities of between -0.15 and -0.33 to estimate the 
potential effect of price increases on demand.

[[Page 19237]]

    To derive an estimate of the quantity of medicines not sold as a 
result of this rule, we need an estimate of the baseline use of these 
seven CFC MDIs by price-sensitive consumers. To do so, we distinguish 
between the insured and the insured the uninsured. Based on IMS data, 
we estimate that asthma and COPD patients receive roughly 300 million 
days of therapy each year in the form of these seven CFC MDIs (Ref. 
11). If users of these products are uninsured in proportion to the 
share of uninsured in the overall U.S. population (15.4 percent) (Ref. 
15), then uninsured asthma and COPD patients receive roughly 46 million 
days of therapy [(300 million)x(15.4 percent)] in the form of these 
seven CFC MDIs, equivalent to roughly 126 thousand patient years.
    Increases in the price of therapy, however, will mostly affect 
Combivent users with COPD. For Combivent users, we use the two major 
sources of decreased use, price increases for the uninsured and 
increased copayments for the insured, to calculate a very rough 
estimate of reduced patient days. According to the 2007 NHIS, 1.8 
million individuals over the age of 65 have bronchitis and 1.7 million 
have emphysema. Data from the 2007 NHIS also suggest that approximately 
31 percent of adults with emphysema also have chronic bronchitis (Ref. 
8, Figure 2). Assuming this ratio holds for those over 65, there are 
about 3.1 million individuals over the age of 65 with COPD (3.6 million 
with either diagnosis--500,000 with both). This number of patients 
represents approximately 30 percent of the 10 million adults with COPD. 
Assuming all of those over 65 with COPD and about 85 percent of those 
under 65 have some form of drug insurance means that about 9.1 million 
of those with COPD are covered by drug insurance and 1.1 million are 
not. The uninsured estimate represents 10 percent of the population 
with COPD, so there would be approximately 23.7 million days of 
uninsured therapy for Combivent annually.
    The midpoint of the high and low price increase estimates for 
Combivent is 27 percent. Assuming uninsured consumers face a 27 percent 
price increase and have an elasticity of 0.15, there would be among the 
uninsured an annual reduction in therapy of approximately 960,000 days 
after Combivent is removed from the market.
    We do not know the characteristics of the prescription drug 
insurance held by those with COPD, but recognize that many of the 9.1 
million insured face per-product copayments. These copayments will 
likely be a smaller fraction of income for the insured than are the 
price increases for the uninsured, so we assume the demand to be less 
elastic. Assuming 214 million annual days of insured therapy and an 
elasticity of 0.075, a 100 percent increase in the size of copayments 
would imply a 7.5 percent reduction in quantity demanded, or 16.0 
million annual days of therapy foregone. Thus, a very rough estimate of 
a change in quantity of Combivent demanded in response to a price 
increase would be 17 million days of therapy (960,000 + 16.0 million). 
The appearance of a reformulated non CFC product combining albuterol 
and ipratroprium would avert the 16 million lost days of therapy 
potentially associated with the co-payment effect.
    Finally, for an overall average estimate of the effects of the 
average price increases, we estimate that users of these seven CFC MDIs 
face an average price increase of between 9 and 28 percent per day of 
therapy after all seven moieties have been removed from the market, 
depending on whether asthma and COPD patients switch to the most or 
least expensive of the proposed alternatives detailed in table 3 of 
this document. We calculate the low and high estimates as the average 
percentage price change of the least and most expensive alternatives to 
each of the seven CFC MDIs, weighted by the number of days of therapy 
of CFC MDIs sold for the twelve months ending June 2009. Excluding 
Combivent, users of the other six CFC MDIs would face prices somewhere 
between 15 and 41 percent lower. Excluding Combivent and Maxair, the 
users of the other five CFC MDIs would face prices between 17 and 39 
percent lower.
    We combine different measures of price elasticities (-0.15 to -
0.33), the size of the uninsured CFC MDI market (15 to 46 million days 
of therapy), and estimated price increases (9 percent to 28 percent) to 
estimate the impact of average price increases on use. For example, 
assuming a price elasticity of -0.15 and 15 million days of therapy 
sold to the uninsured annually, a 9 percent price increase would reduce 
demand for inhaled therapy by the uninsured by roughly 200,000 days of 
therapy annually. By contrast, assuming a price elasticity of -0.33 and 
46 million days of therapy sold to the uninsured annually, a 28 percent 
price increase would reduce uninsured demand by roughly 4 million days 
of therapy [(46 million days) x (-0.33 elasticity) x (28 percent price 
increase) = 4 million days of therapy]. We recognize that because of 
varying measures of the size of the CFC MDI market for the uninsured, 
uncertainty about the magnitude of price increases, and consumer 
response, the true impact of the rule could fall outside this range.
    We recognize that as a result of this rulemaking, patients will 
lose access to products they prefer to use. This regulatory action will 
constrain consumption decisions, forcing patients to switch to 
substitute products they would not otherwise choose to consume, 
resulting in consumer welfare loss. We lack information to reliably 
estimate the social cost associated with the loss of preferred 
products, but we recognize such a cost exists.
4. Effects on Medicare and Medicaid
    According to the 2006 Medical Expenditure Panel Survey (MEPS), 
Medicaid pays for 13.8 of the expenses attributable to COPD and asthma. 
Medicare pays for 30.6 percent of these expenses. Assuming these MEPS 
payment estimates for Medicaid and Medicare apply to the incremental 
expenses from switching to HFA MDIs, this final rule will increase 
annual Federal Medicaid spending between $12 and $39 million. We 
estimate that total spending by Medicare and Medicare beneficiaries 
will increase between $27 million to $87 million annually. The 
estimated annual impacts would apply after 2013, after all seven 
moieties have been phased out, and continue until the HFA technology 
loses patent protection. Where the impact would occur within these 
broad ranges would depend on the alternative therapies chosen.
    For the year 2010, the change in Medicaid and Medicare spending 
would be associated with the costs of switching from Tilade and 
Alpuent. Medicaid spending would change somewhere between a decline of 
$50,000 and an increase of $60,000. The change in Medicare spending 
would be between a decline of $110,000 and an increase of $130,000. For 
the years 2011 through 2013, we include the impacts associated with all 
seven moieties except Maxair and Combivent. In those years, annual 
Medicaid spending would fall by an estimated $2.9 to $6.7 million. 
Medicare spending would decline between $6.3 and $15 million annually.
    The present discounted value of the impact of the regulation on 
Medicaid expenses, assuming HFA patent expiration at the end of 2017 is 
from $20 million to $100 million at a 7 percent discount rate and from 
$20 million to $130 million at 3 percent. For Medicare, the present 
disounted value is from $40 million to $220 million at a 7 percent 
discount rate and from $50 million to $280 million at 3 percent. 
Assuming the HFA technology loses patent protection

[[Page 19238]]

at the end of 2012, the change in Medicaid expenditures is a present 
discounted -$12 million to -$5 million at 7 percent and -$13 million to 
-$5 million at 3 percent. For Medicare, the change in expenditures is -
$30 million to -$10 million at a 7 percent discount rate and -$30 
million to -$10 million at a 3 percent rate.
    We are unable to estimate the extent to which Medicare cost 
increases will be paid by Medicare beneficiaries themselves or by the 
Federal Government. Whether individuals or the Federal Government will 
pay depends on beneficiaries' aggregate drug spending in a given year 
and the Medicare Part D plan they choose. Moreover, as we expect the 
characteristics of Medicare Part D and the types of plans chosen by 
beneficiaries to continue to evolve in coming years, past payment 
statistics may not reflect future conditions. These are rough 
estimates.

E. Alternative Phase-Out Dates

    We consider the impacts of the alternative phase-out date of 
December 31, 2010, for the five moieties not already phased out at the 
end of 2010. The expense information in table 4 shows such an earlier 
phase-out would increase expenditures and further decrease the use of 
asthma and COPD therapy. Moreover, an earlier phase-out data would be 
impractical due to the time necessary to complete the regulatory 
process and to the risk of MDI shortages if the market has insufficient 
time to switch from CFC to HFA MDIs. A phase-out date set too far in 
the future, however, would be incompatible with the timetable set by 
the Montreal Protocol. This leaves a narrow window for consideration.

         Table 4.--Summary of Impacts of a December 31, 2010 Phase-Out Relative to HFA Patent Expiration
----------------------------------------------------------------------------------------------------------------
                                                 Possible Decreases                             Increases in
                                                in Use of Asthma and                        Expenditures on CFC-
         Date of HFA Patent Expiration              COPD Therapy          Discount Rate      based MDIS, Present
                                                  (million days of                              Value in 2009
                                                      therapy)                                   (billions)
----------------------------------------------------------------------------------------------------------------
2012                                                        0.40-8.5                    3%           $0.17-$0.54
                                                                     -------------------------------------------
                                                ....................                    7%           $0.16-$0.51
----------------------------------------------------------------------------------------------------------------
2017                                                          1.4-30                    3%           $0.55-$1.77
                                                                     -------------------------------------------
                                                ....................                    7%           $0.48-$1.53
----------------------------------------------------------------------------------------------------------------

F. Sensitivity Analyses

    The estimated impacts of this final rule summarized in table 5 of 
this document incorporate a range of estimates about the price 
increases consumers and other payers will face, the size of the 
affected market and how consumers will respond to price increases. This 
range represents the full uncertainty range for the estimated effects 
of this final rule. The full range incorporates the ranges of estimates 
for the individual uncertain variables in the analysis.
    In each section of the document, we show the ranges associated with 
each major uncertain variable. To estimate reduced use of inhaled 
medications, we estimate 15 million to 46 million days of therapy are 
used by uninsured individuals annually. We estimate that these 
consumers will face price increases in switching from CFC to HFA MDIs 
from 9 to 28 percent per day of therapy, depending on whether they 
switch to the most expensive or least expensive of available 
alternatives. We use price elasticities ranging from -0.15 to -0.33 to 
estimate how consumers will reduce their MDI use in response to price 
increases.
    Similarly, estimates of the impact of the final rule on public and 
private spending depend on the overall size of the CFC MDI market and 
how much prices increase. We estimate the consumers purchase roughly 
300 million days of therapy in the form of CFC MDIs annually, and that 
prices will increase 9 to 28 percent depending on whether they switch 
to the most expensive or least expensive of available alternatives. If 
we exclude Combivent from the calculation, the expected price effects 
range from a 15 to 41 percent decrease, depending on whether they 
switch to the most expensive or least expensive of available 
alternatives. If we also exclude Maxair, expected price effects range 
from a 17 to 39 percent decrease.

G. Conclusion

    Limits in available data prevent us from quantifying the costs and 
benefits of the final rule and weighing them in comparable terms. The 
benefits of international cooperation to reduce ozone emissions are 
potentially enormous but difficult to attribute to any of the small 
steps, such as this final rule, that make such cooperation effective. 
As discussed above in detail, the benefits of the final rule include 
environmental and public health improvements from protecting 
stratospheric ozone by reducing CFC emissions. Benefits also include 
expectations of increased returns on investments in environmentally 
friendly technology, reduced risk of unexpected disruption of supply of 
CFC MDIs, and continued international cooperation to comply with the 
spirit of the Montreal Protocol, thereby potentially reducing future 
emissions of ODSs throughout the world. This final rule could 
potentially cost public and private consumers of CFC MDIs hundreds of 
millions of dollars annually, but it is difficult to link these costs 
to adverse public health outcomes.

                                                           Table 5.--Summary Accounting Table
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                 Units
                                Primary                                    ------------------------------------------------
         Category              Estimate      Low Estimate    High Estimate                                      Period                  Notes
                                                                             Year Dollars    Discount Rate      Covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 19239]]

Annualized Quantified       ..............  ..............  ..............  ..............              7%          Annual  Reduction of CFC emissions
                                                                                                                             by 310-365 tonnes.
                           ------------------------------------------------------------------------------------------------
                            ..............  ..............  ..............  ..............              3%          Annual  ............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative                                                                 ..............  ..............  ..............  Compliance with Montreal
                                                                                                                             Protocol. Increased
                                                                                                                             investment in
                                                                                                                             environmentally friendly
                                                                                                                             technologies. International
                                                                                                                             cooperation.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized        ..............  -$12 million- -   $16 million-            2010              7%          Annual  Consumers lose access to
 $millions/year                               $4.9 million     $98 million                                                   therapies that, but for
                                                                                                                             this action, would have
                                                                                                                             been their preferred
                                                                                                                             products. Uses 10-year
                                                                                                                             annualization. Range of
                                                                                                                             estimates captures
                                                                                                                             underlying uncertainty. Low
                                                                                                                             estimate assumes 2012 HFA
                                                                                                                             patent expiration. High
                                                                                                                             estimate assumes 2017 HFA
                                                                                                                             patent expiration. No
                                                                                                                             central tendency. These
                                                                                                                             costs are transfers from
                                                                                                                             payers to drug companies
                                                                                                                             and are largely
                                                                                                                             attributable to the
                                                                                                                             withdrawal of generic
                                                                                                                             albuterol which occurred
                                                                                                                             under another rulemaking.
                           ------------------------------------------------------------------------------------------------
                            ..............  -$11 million- -   $19 million-            2010              3%          Annual  ............................
                                              $4.5 million    $100 million
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative                                                                 ..............  ..............  ..............  Consumers may respond to
                                                                                                                             higher prices by forgoing
                                                                                                                             medication, which could
                                                                                                                             result in adverse health
                                                                                                                             outcomes.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 19240]]

Federal Annualized          ..............  -$5.2 million-   $6.9 million-            2010              7%          Annual  Medicare plus Medicaid, 10-
 Monetized $millions/year                    -$2.2 million     $43 million                                                   year annualization. Low
                                                                                                                             estimate assumes 2012 HFA
                                                                                                                             patent expiration. High
                                                                                                                             estimate assumes HFA patent
                                                                                                                             expires end of 2017. Rough
                                                                                                                             approximation.
                           ------------------------------------------------------------------------------------------------
                            ..............  -$4.7 million-   $8.3 million-            2010              3%          Annual  ............................
                                             -$2.0 million     $46 million
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To                                  From: U.S. Government
                                                To: Drug manufacturers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
Small Business                                                                                                              A single drug manufacturer
                                                                                                                             may meet threshold for
                                                                                                                             small business. Affected
                                                                                                                             entities are otherwise not
                                                                                                                             small.
--------------------------------------------------------------------------------------------------------------------------------------------------------

VII. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. For purposes of determining whether a substantial 
number of small entities are affected by this rule, the industry 
includes all manufacturers of pharmaceutical products in the United 
States. 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.
    This rule significantly affects firms that manufacture the seven 
CFC MDIs. Because there is, at most, a single small CFC MDI 
manufacturer that would be significantly affected by the rule, in an 
industry with hundreds of small entities, the agency certifies that the 
final rule will not have a significant economic impact on a substantial 
number of small entities. Additional discussion of our analysis can be 
found in section IV, Comments on the 2007 Proposed Rule, which responds 
to Comment 16 submitted by Graceway.

VIII. The Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

IX. Federalism

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

X. References

    The following references have been placed on display in the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852, and may be seen by interested persons between 9 a.m. and 4 
p.m., Monday through Friday.

    1. Expert Panel Report 3: Guidelines for the Diagnosis and 
Management of Asthma (EPR-3), NIH Publication No. 07-4051, Bethesda, 
MD, U.S. Department of Health and Human Services; National 
Institutes of Health; National Heart, Lung, and Blood Institute; 
National Asthma Education and Prevention Program, 2007, available at 
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
    2. Hess, Dean R., ``Aerosol Delivery Devices in the Treatment of 
Asthma,'' Respiratory Care, 53, 2008: 699-723.
    3. United States, Department of Commerce, Census Bureau; 
Economics and Statistics Administration, Pharmaceutical Preparation 
Manufacturing: 2002, Washington, D.C., U.S. Census Bureau, 2004.
    4. Envrios March, Study on the Use of HFCs for Metered Dose 
Inhalers In the European Union: Final report following submission to 
the ECCP (European Commission Climate Change Policy Group), Republic 
of Geneva: International Pharmaceutical Aerosol Consortium, December 
2000.
    5. Chrischilles, Elizabeth, Daniel Gilden, Joanna Kubisiak, 
Linda Rubenstein, and Hemal Shah, ``Delivery of Ipratropium and 
Albuterol Combination Therapy for Chronic Obstructive Pulmonary 
Disease: Effectiveness of a Two-in-one Inhaler Versus Separate 
Inhalers,'' The American Journal of Managed Care, 8 (2002): 902-11.
    6. United Nations Environmental Programme, Production and 
Consumption of Ozone-Depleting Substances: 1986-2004, 2005.
    7. U.S. Environmental Protection Agency, ``The Benefits and 
Costs of the Clean Air Act: 1990-2010'' (http://www.epa.gov/air/
sect812/1990-2010/fullrept.pdf, November 1999.
    8. American Lung Association, ``Trends in COPD (Chronic 
Bronchitis and Emphysema): Morbidity and Mortality,'' Epidemiology & 
Statistics Unit, Research and Scientific Affairs, February 2010.
    9. American Lung Association, ``Trends in Asthma Morbidity and 
Mortality,''

[[Page 19241]]

Epidemiology & Statistics Unit, Research and Scientific Affairs, 
January 2009.
    10. Mannino, D. M. et al., ``Surveillance for Asthma--United 
States, 1980-1999,'' Morbidity and Mortality Weekly Report, 
51(SS01):1-13, March 29, 2002.
    11. Analysis completed by FDA based on information provided by 
IMS Health, IMS National Sales Perspective (TM), 2009, extracted 
September 2009. These data can be purchased from IMS Health. Please 
send all inquiries to: IMS Health, Attn: Brian Palumbo, Account 
Manager, 660 West Germantown Pike, Plymouth Meeting, PA 19462.
    12. Rozek, R. P., and E. R. Bishko, ``Economic Issues Raised in 
the FDA's Proposed Rule on Removing the Essential-Use Designation 
for Albuterol MDIs,'' National Economic Research Associates, August 
13, 2004 (FDA Docket No. 2003P-0029/C25).
    13. Hendeles, L. G, L. Colice, and R. J. Meyer, ``Withdrawal of 
Albuterol Inhalers Containing Chlorofluorocarbon Propellants,'' New 
England Journal of Medicine, 356:1344-1351, March 29, 2007.
    14. Goldman, D. P. et al., ``Pharmacy Benefits and the Use of 
Drugs by the Chronically Ill,'' The Journal of the American Medical 
Association, 291:2344-2350, May 19, 2004.
    15. DeNavas-Walt, C., B. D. Proctor, and J. C. Smith, U.S. 
Census Bureau, Current Population Reports, P60-236(RV), Income, 
Poverty, and Health Insurance Coverage in the United States: 2008, 
Table 7, p. 21, 2009.

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Drugs, Foods.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and the Clean 
Air Act and under authority delegated to the Commissioner of Food and 
Drugs, after consultation with the Administrator of the Environmental 
Protection Agency, 21 CFR part 2 is amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

0
1. The authority citation for 21 CFR part 2 continues to read as 
follows:

    Authority:  15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342, 
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42 
U.S.C. 7671 et seq.

Sec.  2.125  [Amended]

0
2. Effective June 14, 2010, in Sec.  2.125, remove and reserve 
paragraphs (e)(2)(iii) and (e)(4)(vii).

Sec.  2.125  [Amended]

0
3. Effective December 31, 2010, in Sec.  2.125, remove and reserve 
paragraphs (e)(1)(v) and (e)(4)(iv).

Sec.  2.125  [Amended]

0
4. Effective June 30, 2011, in Sec.  2.125, remove and reserve 
paragraph (e)(1)(iii).

Sec.  2.125  [Amended]

0
5. Effective December 31, 2013, in Sec.  2.125, remove and reserve 
paragraphs (e)(2)(iv) and (e)(4)(viii).

    Dated: April 8, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-8467 Filed 4-13-10; 8:45 am]
BILLING CODE 4160-01-S