Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Flunisolide, etc.), 19213-19241 [2010-8467]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 75, Number 71 (Wednesday, April 14, 2010)]
[Rules and Regulations]
[Pages 19213-19241]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2010-8467]


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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 https://

[[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 https://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 https://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 https://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 https://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., https://www.asthmanow.net/care.html; https://www.colorado.gov/bestpractices/; https://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 bron