[Federal Register Volume 72, Number 111 (Monday, June 11, 2007)]
[Proposed Rules]
[Pages 32030-32049]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-2883]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. 2006N-0454]
RIN 0910-AF93


Use of Ozone-Depleting Substances; Removal of Essential-Use 
Designations

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA), after consultation 
with the Environmental Protection Agency (EPA), is proposing to amend 
FDA's regulation on the use of ozone-depleting substances (ODSs) in 
self-pressurized containers to remove the essential-use designations 
for oral pressurized metered-dose inhalers (MDIs) containing 
flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and 
ipratropium in combination, cromolyn, and nedocromil. Under the Clean 
Air Act, FDA, in consultation with the EPA, is required to determine 
whether an FDA-regulated product that releases an ODS is an essential 
use of the ODS. 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. If the applicable essential-use 
designations are removed, flunisolide, triamcinolone, metaproterenol, 
pirbuterol, albuterol and ipratropium in combination, cromolyn, and 
nedocromil MDIs containing an ODS could not be marketed after a 
suitable transition period. We will hold an open public meeting on 
removing these essential-use designations in the near future.

DATES: Submit written or electronic comments by August 10, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2006N-
0454, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted directly to the agency by e-mail. FDA 
encourages you to continue to submit electronic comments by using the 
Federal eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents, 
comments, a transcript of, and material submitted for, the Pulmonary-
Allergy Advisory Committee meeting held on June 10, 2005, go to http://www.fda.gov/ohrms/dockets/default.htm and insert the docket number(s), 
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: Wayne H. Mitchell or Martha Nguyen, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. 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
II. Criteria
III. Effective Date
IV. 2005 PADAC Meeting
V. Drugs We Are Proposing as Nonessential
    A. Flunisolide and Triamcinolone
    B. Metaproterenol and Pirbuterol
    C. Cromolyn and Nedocromil
    D. Albuterol and Ipratropium in Combination
VI. Environmental Impact
VII. 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

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    6. Current U.S. Market for CFC MDIs
    D. Benefits and Costs of the Proposed Rule
    1. Baseline Conditions
    2. Benefits of the Proposed Rule
    3. Costs of the Proposed Rule
    4. Effect on Medicaid and Medicare
    E. Alternative Phase-out Dates
    F. Sensitivity Analyses
    G. Conclusion
VIII. Regulatory Flexibility Analysis
IX. The Paperwork Reduction Act of 1995
X. Federalism
XI. Request for Comments
XII. References

I. 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 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 at 11318), 
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 that were 
exempt from the ban. The second listed essential use was for 
``[m]etered-dose steroid human drugs for oral inhalation,'' and the 
third listed essential use was for ``[m]etered-dose adrenergic 
bronchodilator human drugs for oral inhalation.'' These provisions 
describe flunisolide, triamcinolone, and pirbuterol MDIs, so the list 
of essential uses did not have to be amended when these products were 
approved by FDA.\1\
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    \1\ A metaproterenol MDI (Alupent MDI) was approved July 31, 
1973, before the 1978 rule.
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    The 1978 rule provided criteria for adding new essential uses, and 
several uses were added to the list, 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.C.5 of this document.
2. The Montreal Protocol
    On January 1, 1989, the United States became a party to the 
Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal 
Protocol) (September 16, 1987, 26 I.L.M. 1541 (1987)), available at 
http://www.unep.org/ozone/pdfs/Montreal-Protocol2000.pdf.\2\ The United 
States played a leading role in the negotiation of the Montreal 
Protocol, believing that internationally coordinated control of ozone-
depleting substances 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 191 Parties to this 
treaty.\3\ When it joined the treaty, the United States committed to 
reducing its production and consumption of certain CFCs to 50 percent 
of 1986 levels by 1998 (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)).
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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/index.asp.
    \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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    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. One of the most important essential uses of 
CFCs under the Montreal Protocol is their use in MDIs for the treatment 
of asthma and chronic obstructive pulmonary disease (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

[[Page 32032]]

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).''
    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).
    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 the Parties that are developed 
countries 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 for MDIs for which the sole active ingredient is albuterol. 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, effective 
December 31, 2008 (70 FR 17168, April 4, 2005).
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     Decision XVII/5 states that Parties that are developed 
countries 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 non-essential (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://hq.unep.org/ozone/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: Arranging for 
and servicing the Conference of the Parties, meetings of the 
Parties, their committees, the bureaus, working groups, and 
assessment panels; Arranging for the implementation of decisions 
resulting from these meetings; Monitoring the implementation of the 
Vienna Convention and the Montreal Protocol; Reporting to the 
meetings of the Parties and to the Implementation Committee; 
Representing the Convention and the Protocol; and Receiving and 
analyzing data and information from the Parties on the production 
and consumption of ODSs.
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3. The 1990 Amendments to the Clean Air Act
    In 1990, Congress amended the Clean Air Act to, among other things, 
better protect stratospheric ozone (Public Law No. 101-549, November 
15, 1990) (the 1990 amendments). The 1990 amendments were drafted to 
complement, and be consistent with, our obligations under the Montreal 
Protocol (see section 614 of the Clean Air Act (42 U.S.C. 7671m)). 
Section 614(b) of the Clean Air Act provides that, in the case of a 
conflict between any provision of the Clean Air Act and any provision 
of the Montreal Protocol, the more stringent provision will govern. 
Section 604 of the Clean Air Act required 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 the adjustment contained in 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 21 
CFR 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 includes 
drugs as well as medical devices.
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

[[Page 32033]]

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) of the act (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, 
cromolyn, as opposed to the active ingredient, which, using the same 
example, would be cromolyn sodium. 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 INTAL MDI. 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.

II. Criteria

    Among other changes, the 2002 final rule, in revised Sec.  
2.125(g)(2), establishes a standard for removing an essential-use 
designation for any drug after January 1, 2005, that would apply to a 
drug where there are no acceptable non-ODS alternatives with the same 
active moiety. This standard provides an incentive for manufacturers to 
reformulate their products in a timely manner. There are no acceptable 
non-ODS alternatives available that have the same active moieties as 
the products marketed under the essential uses that are the subject of 
this proposed rule; therefore, we are proceeding with this rulemaking 
under the provisions of Sec.  2.125(g)(2). The process for removing the 
essential use designation under Sec.  2.125(g)(2) includes a 
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 it no longer meets the criteria specified in revised Sec.  
2.125(f) for adding a new essential use (Sec.  2.125(g)(2)). The 
criteria in Sec.  2.125(f) for adding an essential use 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.
    Because the three criteria in Sec.  2.125(f) are linked by the word 
``and,'' failure to meet any single criterion results in a 
determination that the use is not essential.
    We discussed these criteria in the preamble to the 1999 proposed 
rule. A key point in our discussion of technical barriers was: 
``Generally, FDA intends the term `technical barriers' to refer to 
difficulties encountered in chemistry and manufacturing. A petitioner 
would have to establish that it evaluated all available alternative 
technologies and explain in detail why each alternative was deemed to 
be unusable to demonstrate that substantial technical barriers exist.'' 
(1999 proposed rule at 47721.)
    In applying the ``technical barriers'' criteria, we look at the 
results of reformulation efforts for similar products as well as 
statements made about the manufacturer's particular efforts to 
reformulate their product.
    Similarly, in discussing what is ``an unavailable important public 
health benefit,'' we 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.' A petitioner should show that the use of an ODS 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.'' (1999 proposed rule at 47722.)
    One key point to note here is that we 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.''
    In determining if a drug product provides an otherwise unavailable 
important public health benefit, our primary focus is on the 
availability of non-ODS products that provide equivalent therapeutic 
benefits for patients who are currently using the CFC MDIs. If 
therapeutic alternatives exist for all patients using the CFC MDI, we 
would then determine that the CFC MDI does not provide an otherwise 
unavailable important public health benefit.
    Under the third criterion, the essential use must be eliminated 
unless we find that use of the product does not release cumulatively 
significant amounts of ODSs into the atmosphere, or that 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. In evaluating whether continuing the 
essential-use designation of these MDIs would result in the products 
releasing significant quantities of ODSs, in light of past policy 
statements (2002 final rule p. 48380) and the current state of the 
phase-out of ODSs, we tentatively conclude that the release of CFCs 
from MDIs containing flunisolide, triamcinolone, metaproterenol, 
pirbuterol, albuterol and ipratropium in combination, cromolyn, and 
nedocromil would be significant. The reasons for this tentative 
conclusion are discussed in the following paragraphs.
    The United States evaluated the environmental effect of eliminating 
the use of all CFCs in an environmental impact statement in the 1970s 
(see 43 FR 11301). As part of that evaluation, FDA concluded that the 
continued use

[[Page 32034]]

of CFCs in medical products posed an unreasonable risk of long-term 
biological and climatic impacts (see Docket No. 1996N-0057 (formerly 
96N-0057)). Congress later enacted provisions of the Clean Air Act that 
codified the decision to fully phase out the use of CFCs over time (see 
42 U.S.C. 7671 et seq. (enacted November 15, 1990)). We note 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 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 
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 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 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. 
Therefore, we tentatively conclude that the release of ODSs from these 
MDIs is cumulatively significant.
    Given this proposed finding, the essential use for each product 
must be eliminated under Sec.  2.25(f)(1)(iii) unless we also find that 
the product provides an otherwise unavailable important health benefit 
which warrants the cumulatively significant release of the ODS.
    As noted previously, because the three criteria in Sec.  2.25(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, 
if we find that any product fails to provide an otherwise unavailable 
important health benefit (criterion two), we would be required to find 
that the use of the product is not essential, and we would not need to 
reach the last step under the third criteria (balancing the important 
health benefit against the release of the ODS to determine if the 
release is warranted). Assuming, however that the first and second 
criteria in Sec.  2.125(f) are met, because of our tentative conclusion 
that the release of ODSs from these MDIs is cumulatively significant, 
we would then need to conduct the balancing inquiry under the third 
criterion for that product.
    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 
Sec.  2.125(g)(3) and (g)(4). Section 2.125(g)(2) specifically 
addresses the situation where there is no other marketed product 
containing the same active moiety in a non-ODS formulation, while Sec.  
2.125(g)(3) and (4)\9\ apply to situations where there is at least one 
other product marketed with the same active moiety in a non-ODS 
formulation. When we removed the essential-use designation for 
albuterol (70 FR 17168, April 4, 2005) we used the criteria found in 
Sec.  2.125(g)(4) because there were more than one albuterol CFC MDI 
being marketed and there were two acceptable alternatives containing 
albuterol (Proventil HFA and Ventolin HFA) to the albuterol CFC MDIs. 
This contrasts to Sec.  2.125(g)(2), which 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. Therefore, the analyses we use here are not 
identical to the analyses we 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, but with this rulemaking we are able to consider 
alternatives with different active moieties. 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). In general, as explained in the preamble to the 1999 
proposed rule, ``FDA is requiring the existence of feasible 
alternatives that are acceptable from a health standpoint before it 
will find any CFC-MDI no longer essential.'' (1999 proposed rule at 
47736.) Thus, we request comment on whether the available alternatives 
for each of the seven moieties are acceptable from a public health 
perspective.
---------------------------------------------------------------------------

    \9\ The text of Sec.  2.125(g)(3) and (4) is as follows:
    (3) For individual active moieties marketed as ODS products and 
represented by one new drug application (NDA):
    (i) At least one non-ODS product with the same active moiety is 
marketed with the same route of administration, for the same 
indication, and with approximately the same level of convenience of 
use as the ODS product containing that active moiety;
    (ii) Supplies and production capacity for the non-ODS product(s) 
exist or will exist at levels sufficient to meet patient need;
    (iii) Adequate U.S. postmarketing use data is available for the 
non-ODS product(s); and
    (iv) Patients who medically required the ODS product are 
adequately served by the non-ODS product(s) containing that active 
moiety and other available products; or
    (4) For individual active moieties marketed as ODS products and 
represented by two or more NDAs:
    (i) At least two non-ODS products that contain the same active 
moiety are being marketed with the same route of delivery, for the 
same indication, and with approximately the same level of 
convenience of use as the ODS products; and
    (ii) The requirements of paragraphs (g)(3)(ii), (g)(3)(iii), and 
(g)(3)(iv) of this section are met.
    There are noteworthy procedural differences between Sec.  
2.125(g)(2) and Sec.  2.125(g)(3) and (4). A rulemaking under Sec.  
2.125(g) (3) or (4) could have been started before January 1, 2005, 
and there is no requirement for either an advisory committee meeting 
or public meeting. The proposed rule for the removal of the 
essential-use designation for albuterol was published in the Federal 
Register of June 16, 2004 (69 FR 33602) and although the matter was 
discussed at a public meeting of the Pulmonary-Allergy Drug Advisory 
Committee on June 10, 2004, no separate public meeting on the matter 
was held.
---------------------------------------------------------------------------

III. Effective Date

    We are proposing that any rule finalizing the removal of an 
essential use proposed in this document have an effective date of 
December 31, 2009. In determining the appropriate effective date or 
dates for this rulemaking, we will consider not only whether 
therapeutic alternatives are on the market but also whether adequate 
production capacity and supplies are available to meet the new, 
presumably increased, demand for the therapeutic alternatives once 
products marketed under the old essential use are no longer sold. 
Depending on the data presented to us in the course of the rulemaking, 
we may determine that it is appropriate to have different effective 
dates for different uses.
    In determining an appropriate effective date, we have kept in mind 
that albuterol HFA\10\ MDIs are primary therapeutic alternatives to 
drugs produced under three of the essential uses described in this 
rule. Sales of the products marketed under those essential uses have 
totaled approximately 14

[[Page 32035]]

million MDIs a year. We are confident there will be adequate supplies 
of albuterol HFA MDIs to meet the needs of all current users of 
albuterol CFC MDIs by December 31, 2008 (the date on which albuterol 
MDIs will no longer be designated an essential use).\11\ Although we 
have limited data on production increases above current demand for 2009 
and later, we believe that, by December 31, 2009, albuterol HFA 
production will be able to meet any increased demand caused by this 
rulemaking. We specifically invite comments from manufacturers of 
albuterol HFA MDIs on this issue.
---------------------------------------------------------------------------

    \10\ These albuterol inhalers use the non-ozone-depleting 
hydrofluoroalkane HFA-134a (usually referred to as HFA) as a 
propellant.
    \11\ Current information indicates that production of albuterol 
HFA MDIs will be adequate to meet the current demand for albuterol 
MDIs much earlier than December 31, 2008.
---------------------------------------------------------------------------

    We also believe that a December 31, 2009 effective date is more 
than sufficient to allow patients to consult their health care 
providers and obtain prescriptions for therapeutic alternatives in an 
orderly fashion.
    In proposing a December 31, 2009, effective date, we expect that 
2009 would be a transition year characterized by declining production 
of the CFC MDIs that are the subject of this rule. If a December 31, 
2009 effective date is established by this rulemaking, we anticipate 
that other administrative actions taken by EPA and FDA would reflect 
the concept of 2009 being a transition year.
    The sale of remaining stocks of CFC MDIs by manufacturers, 
wholesalers, and retailers was a consideration in setting the effective 
date of the albuterol rule (70 FR 17168 and 17179). We believe that 
this consideration also is appropriate for this rulemaking. In 
evaluating the period of time that is needed to sell remaining stocks 
of the CFC MDIs that are the subject of this rulemaking, a factor that 
must be considered is the expiration dating for the relevant products. 
One product has an expiration date set at 18 months after manufacture, 
five products have dates set at 24 months, and three products' 
expiration dates are 30 months or more after production.\12\ 
Prescription drug products, particularly those for chronic diseases 
such as asthma and COPD, are generally dispensed well before the 
expiration date, allowing the patients a significant amount of time to 
use the drugs before they reach their expiration dates. Therefore, we 
believe that all of the products with 18-month and 24-month expiration 
dates manufactured prior to publication of a final rule based on this 
proposal will have passed their expiration dates and been dispensed or 
destroyed by December 31, 2009. We invite comments on the relationship 
between expiration dates and the distribution and dispensing of the 
products that are the subject of the rulemaking.
---------------------------------------------------------------------------

    \12\ Nine different products, including two sizes of COMBIVENT 
and two flavors (plain and menthol) of AEROBID, are produced under 
the seven essential uses that are the subject of this rule.
---------------------------------------------------------------------------

IV. 2005 PADAC Meeting

    As required by Sec.  2.125(g)(2), we consulted an advisory 
committee before drafting this proposed rule. We consulted with FDA's 
Pulmonary and Allergy Drugs Advisory Committee (PADAC) at their July 
14, 2005, meeting (2005 meeting) on the essential-use status of MDIs 
containing flunisolide, triamcinolone, metaproterenol, pirbuterol, 
albuterol and ipratropium in combination, cromolyn, and nedocromil. The 
opinions expressed by the PADAC members about each of these essential 
uses will be discussed below.\13\
---------------------------------------------------------------------------

    \13\ A transcript of the meeting and other meeting material is 
available on the Web at http://www.fda.gov/ohrms/dockets/ac/cder05.html#PulmonaryAllergy.
---------------------------------------------------------------------------

    This PADAC meeting should not be confused with the open public 
meeting that we will be holding in the near future on the essential-use 
status of these MDIs. We will publish a notice for the public meeting 
in the Federal Register shortly.

V. Drugs We Are Proposing as Nonessential

A. Flunisolide and Triamcinolone

    We are proposing to remove the essential-use designations for MDIs 
containing flunisolide (AEROBID) and triamcinolone (AZMACORT). AEROBID 
and AZMACORT are orally inhaled corticosteroids. AZMACORT is the only 
currently marketed drug product that provides orally inhaled 
triamcinolone. 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 as 
young as 6 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, a flunisolide HFA MDI, was approved January 27, 2006, but has 
not yet been introduced onto the market.
    We have tentatively concluded that the following orally inhaled 
corticosteroid drug products, which do not contain ODSs, collectively 
provide adequate therapeutic alternatives to AEROBID and AZMACORT:
     Beclomethasone dipropionate MDI (QVAR),
     Budesonide DPI (PULMICORT TURBUHALER),
     Fluticasone propionate MDI (FLOVENT HFA), and
     Mometasone furoate DPI (ASMANEX TWISTHALER).
    All of these drugs are indicated for the maintenance treatment and 
prophylaxis of asthma. All of the therapeutic alternatives have 
adequate safety profiles similar to those of AEROBID and AZMACORT. Our 
tentative conclusion that these four drugs collectively provide 
adequate therapeutic alternatives does not mean that each can be freely 
substituted for AEROBID and AZMACORT, or freely substituted one for 
another. Rather, we believe that at least one of those drugs should be 
an adequate therapeutic alternative for every patient currently using 
AEROBID or AZMACORT. There are significant differences among these 
drugs, for example FLOVENT HFA and ASMANEX TWISTHALER are both 
indicated for patients 12 and older, compared to AEROBID and AZMACORT, 
which are indicated for patients 6 and older. However, QVAR and 
PULMICORT TURBUHALER are indicated for patients as young as 5 and 6, 
respectively. With these two drugs, younger pediatric patients who used 
AEROBID and AZMACORT should be more than adequately served. There are 
other notable differences: ASMANEX TWISTHALER contains lactose; there 
is clinical data on the use of inhaled budesonide by pregnant women in 
labeling for PULMICORT TURBUHALER; QVAR and FLOVENT HFA are MDIs; 
ASMANEX TWISTHALER and PULMICORT TURBUHALER are different types of 
DPIs. All of these elements, and more, may factor into a decision on 
which drug product to substitute for AEROBID

[[Page 32036]]

and AZMACORT for any individual patient.
    A therapeutic alternative to AEROBID and AZMACORT, primarily for 
patients who are using both salmeterol and either AEROBID or AZMACORT, 
is the ADVAIR DPI which contains fluticasone propionate and another 
asthma drug salmeterol, in combination, which is available in various 
strengths. .
    FDA has recently approved SYMBICORT, an HFA MDI combining 
budesonide and formoterol, a long-acting beta-agonist. This drug 
product is expected to enter the U.S. market in mid-2007 and would be a 
logical first option for patients using both formoterol (FORADIL) and 
either AEROBID or AZMACORT. However, the lack of postmarketing data and 
the unavailability of information on future production capacity and 
supplies for SYMBICORT means that we cannot consider at this time the 
expected availability of SYMBICORT as grounds for eliminating the 
essential use of flunisolide under Sec.  2.125(g)(2). The expected 
availability of SYMBICORT was not considered a material issue in our 
tentative determination that flunisolide MDIs are not an essential use 
of ODSs: there are more than a sufficient number of therapeutic 
alternatives to AEROBID and AZMACORT without considering SYMBICORT.
    We realize that inhaled corticosteroids are widely considered the 
drugs of choice, used in conjunction with other drugs, for treatment of 
severe persistent, moderate persistent, and mild persistent asthma in 
adults and children (Ref. 1, app. A-1).\14\ However certain health care 
providers and patients, particularly in cases of mild persistent 
asthma, may decide to switch from AEROBID and AZMACORT to drugs other 
than inhaled corticosteroids. If these other drugs do not release ODSs, 
such as leukotriene modifiers and theophylline, then they also provide 
alternative therapies.
---------------------------------------------------------------------------

    \14\ References to outside publications or any other statements 
of fact or opinion in this document concerning a drug product are 
not intended to be equivalent to statements in labeling approved 
under section 505 of the act (21 U.S.C. 355) and part 314 of our 
regulations (21 CFR part 314).
---------------------------------------------------------------------------

    The recently approved AEROSPAN (flunisolide HFA MDI) may also be a 
therapeutic alternative to AEROBID and AZMACORT. However, as previously 
noted with SYMBICORT, the lack of postmarketing data and the 
unavailability of information on future production capacity and 
supplies for AEROSPAN mean that we cannot consider at this time the 
availability of AEROSPAN as grounds for eliminating the essential use 
of flunisolide under Sec.  2.125(g)(3). The availability of AEROSPAN 
was not considered a material issue in our tentative determination that 
flunisolide MDIs are not an essential use of ODSs: there are more than 
a sufficient number of therapeutic alternatives to AEROBID and AZMACORT 
without considering AEROSPAN. However, we do solicit comments on 
postmarketing data for AEROSPAN and its suitability as an alternative 
to AEROBID and AZMACORT.
    PADAC members expressed the opinion, without dissent, that 
flunisolide and triamcinolone were no longer essential uses of ODSs.
    We have tentatively come to the following conclusion:
     The pharmaceutical industry has had success in formulating 
other orally inhaled corticosteroids without ODSs. In particular, the 
AEROSPAN flunisolide HFA MDI was approved by FDA. We have no evidence 
to suggest that the ODS containing triamcionolone or flunisolide oral 
inhalation drug products pose unique technical challenges to 
formulation without ODSs. Therefore, we tentatively conclude that no 
substantial technical barriers exist to formulating triamcinolone or 
flunisolide oral inhalation drug products without ODSs.
     Flunisolide and triamcinolone MDIs do not provide an 
otherwise unavailable important public health benefit because of the 
available therapeutic alternatives.
     The release of ODSs into the atmosphere from flunisolide 
and triamcinolone MDIs is cumulatively significant and is not warranted 
because they do not provide an otherwise unavailable important public 
health benefit.
    We, therefore, tentatively conclude that oral pressurized MDIs 
containing flunisolide and triamcinolone are no longer essential uses 
of ODSs and should be removed from the list of essential uses in Sec.  
2.125(e).

B. Metaproterenol and Pirbuterol

    We are proposing to remove the essential-use designations for MDIs 
containing metaproterenol (ALUPENT MDI) and pirbuterol (MAXAIR). 
Metaproterenol and pirbuterol are short-acting beta2-
adrenergic agonists used in the treatment of bronchospasm associated 
with asthma and COPD. They act as bronchodilators. Pirbuterol is only 
available in a CFC MDI, while 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 MDI which contains CFCs. ALUPENT MDI and MAXAIR are 
the only beta2-adrenergic agonist MDIs currently marketed 
containing CFCs (other than albuterol, whose essential use status will 
end December 31, 2008). ALUPENT MDI and MAXAIR are prescription drugs. 
Their use was considered essential under the 1978 rule, which stated 
that ``[m]etered-dose adrenergic bronchodilator human drugs for oral 
inhalation'' were essential. Metaproterenol and pirbuterol were 
designated as essential as different active moieties in the 2002 rule. 
ALUPENT MDI was approved on July 31, 1973, and MAXAIR was approved on 
November 30, 1992.
    We have tentatively concluded that the following beta2-
adrenergic agonist MDIs, which use HFA-134a (1,1,1,2, 
tetrafluoroethane) as a propellant instead of ODSs, collectively 
provide adequate therapeutic alternatives to ALUPENT MDI and MAXAIR:
     Albuterol sulfate MDI (PROAIR HFA),
     Albuterol sulfate MDI (PROVENTIL HFA),
     Albuterol sulfate MDI (VENTOLIN HFA),
     Levalbuterol tartrate MDI (XOPONEX HFA).
    ALUPENT MDI, MAXAIR, 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,\15\ and have 
similar dosing regimens. When we say that these 4 drugs collectively 
provide adequate therapeutic alternatives, we are not saying that each 
can be freely substituted for ALUPENT MDI and MAXAIR, or freely 
substituted one for another. Rather, we are saying that one of those 
drugs should be an adequate therapeutic alternative for every patient 
currently using ALUPENT MDI or MAXAIR. ALUPENT MDI and MAXAIR are 
indicated for children as young as 12, while the therapeutic 
alternatives are indicated for children as young as 4. The albuterol 
sulfate products are indicated for prevention of exercise-induced 
asthma, while ALUPENT MDI, MAXAIR, and Xopenex are not. MAXAIR includes 
one product form that incorporates an ``autohaler'' device. This 
mechanism senses patient effort and delivers the dose in relationship 
to inhalation by the patient. While this

[[Page 32037]]

mechanism is believed to lessen issues with coordinating inhalation to 
actuation, there are no data to adequately document that this feature 
leads to improvements in therapy. However, the use of spacer devices 
with other alternative products may provide options for individuals who 
have difficulties in coordinating inhalation with MDI operation, 
allowing them to more satisfactorily use MDIs that do not have a 
breath-actuated mechanism.
---------------------------------------------------------------------------

    \15\ Metaproterenol, because it is less selective than 
pirputerol, albuterol, levalbuterol, and some other 
beta2-agonists, may present greater potential for 
excessive cardiac stimulation (Ref. 2, p. 64; Ref. 1, Appendix A-2).
---------------------------------------------------------------------------

    PADAC members gave their opinion, without dissent, that 
metaproterenol and pirbuterol were no longer essential uses of ODSs.
    We have tentatively come to the following conclusions:
     The pharmaceutical industry has had success in formulating 
other orally inhaled beta2-adrenergic bronchodilators 
without ODSs. We have no evidence to suggest that the ODS containing 
metaproterenol or pirbuterol oral inhalation drug products pose unique 
technical challenges to formulation without ODSs Therefore, we 
tentatively conclude that no substantial technical barriers exist to 
formulating metaproterenol and pirbuterol oral inhalation drug products 
without ODSs.
     Metaproterenol and pirbuterol MDIs do not provide an 
otherwise unavailable important public health benefit because of the 
available therapeutic alternatives.
     The release of ODSs into the atmosphere from 
metaproterenol and pirbuterol MDIs is cumulatively significant and is 
not warranted because they do not provide an otherwise unavailable 
important public health benefit.
    We, therefore, tentatively conclude that oral pressurized MDIs 
containing metaproterenol and pirbuterol are no longer essential uses 
of ODSs and should be removed from the list of essential uses in Sec.  
2.125(e).

C. 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 an 
enteric indication. None of these formulations would be affected by 
this proposed action.
    The only cromolyn MDI (INTAL MDI) 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) was approved for marketing 
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).
    No other cromone drug is marketed in an MDI or other dosage form.
    Both INTAL MDI and TILADE are indicated for the management of 
asthma in patients as young as 5 and 6, respectively. Both are 
prescription drugs. Neither drug is indicated for the relief of acute 
bronchospasm.
    We have tentatively concluded that the following orally inhaled 
corticosteroid drug products, which do not contain ODSs, collectively 
provide adequate therapeutic alternatives to INTAL MDI and TILADE:
     Beclomethasone dipropionate MDI (QVAR),
     Budesonide DPI (PULMICORT TURBUHALER),
     Fluticasone propionate MDI (FLOVENT HFA), and
     Mometasone furoate DPI (ASMANEX TWISTHALER).
    Inhaled corticosteroids are generally considered the preferred 
treatment for mild but persistent asthma, while cromolyn and nedocromil 
are considered to be alternative, or secondary, treatments (Ref. 1, 
appendix A-1, and p. 23). Cromolyn and nedocromil are generally 
regarded as having an excellent safety profile, but their clinical 
usefulness has been questioned, particularly when compared to inhaled 
corticosteroids (Ref. 1., p. 23; Ref. 2;). The clinical evidence of 
better effectiveness outweighs any minor concerns we may have about the 
slight differences that may exist between the safety profiles of the 
cromones (cromolyn and nedocromil) and the inhaled corticosteroids. 
QVAR, and PULMICORT TURBUHALER, as discussed in part V.A of this 
document, provide more than adequate therapeutic alternatives for 
younger pediatric patients. While low-dose inhaled corticosteroids are 
generally considered the drugs of choice for mild but persistent asthma 
in adults and children, health care providers and patients, 
particularly in cases of patients who do not tolerate corticosteroids, 
may decide to switch from INTAL MDI and TILADE to drugs other than 
inhaled corticosteroids. Also, there are non-inhaled asthma 
medications, such as leukotriene modifiers and theophylline, which also 
provide alternative therapies. Leukotriene modifiers and theophylline 
(as well as cromolyn and nedocromil) have been suggested as alternative 
medications for moderate but persistent asthma in children older than 5 
and in adults (Ref. 1, app. A-1)
    Although we believe that patients using INTAL MDIs and TILADE will 
be adequately served by the inhaled corticosteroids and other 
therapeutic alternatives described previously, another therapeutic 
alternative may be the use of cromolyn inhalation solution in a 
portable nebulizer. We bring up this issue here because of the absence 
of MDIs and DPIs containing a cromone, and the availability of cromolyn 
in an inhalation solution. In the past we have downplayed, but never 
categorically rejected, the suitability of portable nebulizers as 
therapeutic alternatives to ODS-containing MDIs (see the 1999 Proposed 
Rule at 47226, and the 2002 Final Rule at 48377). We invite comment on 
the suitability of portable nebulizers as therapeutic alternatives to 
INTAL MDIs and TILADE, and whether use of a portable nebulizer would be 
necessary to serve all patients who are currently using INTAL MDIs and 
TILADE.
    PADAC members were closely divided at the 2005 meeting on whether 
cromolyn is essential. Several members questioned the drug's 
effectiveness with some concluding that the drug was no longer 
essential, while others felt that the drug was preferable for treating 
some ``niche'' patient populations, even though inhaled corticosteroids 
were more generally effective. The two niche patient populations 
identified were patients who could not tolerate beta2-
adrenergic agonists who experience exercised-induced bronchospasm, and 
patients who need prophylaxis for a specific allergy-induced 
bronchospasm, such as might happen when an allergic patient visits a 
house with a cat in it. One member said that for the small group of 
patients that have no other alternative than to use cromolyn, 
nebulizers, while somewhat inconvenient, may provide a therapeutic 
alternative for situations involving planned and known exposures to 
allergens. Another member disagreed with this opinion, responding that 
nebulizers are too inconvenient to provide a therapeutic alternative to 
MDIs.
    A consensus quickly developed among the PADAC members at the 2005 
meeting that nedocromil was not essential. One member questioned

[[Page 32038]]

whether TILADE was still on the market and another stated that he had 
assumed it was off the market. One member said that his view on 
nedocromil, which he viewed as very comparable to cromolyn (a view well 
supported by available literature), was influenced by the supposition 
that a cromolyn product would still be on the market.
    The issue of exercise-induced bronchospasm in determining the 
essential-use status of cromolyn and nedocromil is a difficult subject 
to address. Beta2-adrenergic agonists are generally regarded 
as the treatment of choice for prophylaxis of exercise induced 
bronchospasm (Ref. 3, p. 100). The labeling for PROVENTIL HFA, VENTOLIN 
HFA, PROAIR HFA, formoterol fumarate inhalation powder (FORADIL), and 
SEREVENT DISKUS includes indications for exercise induced bronchospasm. 
As stated at the 2005 PADAC meeting, the primary issue then becomes one 
of prophylaxis of exercise induced bronchospasm in patients who do not 
tolerate beta2-adrenergic agonists. The size of this patient 
population is not well documented. Studies of albuterol in HFA MDIs 
show rates of adverse events that are not significantly different from 
the rates with a placebo, indicating that this is a very well-tolerated 
drug.\16\ If a patient population that cannot tolerate 
beta2-adrenergic agonists exists, it would seem to be very 
small. However, there appear to be therapeutic alternatives for INTAL 
MDIs and TILADE for this population. Long-term control therapy using 
corticosteroids may provide an appropriate therapeutic alternative for 
prophylaxis of exercise induced bronchospasm. Long-term control 
therapy, including corticosteroids and montelukasts (SINGULAIR), may 
decrease the bronchial hyperresponsiveness and therefore significantly 
lessen the need for immediate prophylaxis of exercise induced 
bronchospasm with a shorter-acting drug, such as cromolyn, nedocromil, 
or albuterol. (Ref. 3, p. 100; Ref. 4; Ref. 5; Ref. 6). Portable 
nebulizers using cromolyn may provide an attractive therapeutic 
alternative for this patient population as well. A nebulizer too large 
to carry in a pocket or purse might be easily carried in a gym bag. 
Larger nebulizers using cromolyn may also provide an acceptable 
therapeutic alternative for prophylaxis of exercise induced 
bronchospasm, because exercise can be scheduled so that access to a 
nebulizer is available before the exercise.
---------------------------------------------------------------------------

    \16\ Other beta2-adrenergic bronchodilators, 
particularly older, less selective beta2-adrenergic 
bronchodilators, may not be as well tolerated. Salmeterol has 
specific safety concerns (see the boxed warning on the approved 
labeling of Serevent Diskus). However, albuterol is the most widely 
used beta2-adrenergic bronchodilator, and it is indicated 
for prophylaxis of exercise induced bronchospasm, so we feel 
comfortable in focusing our discussion on this single member of the 
class.
---------------------------------------------------------------------------

    The issue of INTAL MDI and TILADE patients who needed prophylaxis 
for a specific allergy-induced bronchospasm, such as might occur when 
an allergic patient visits a house with a cat in it, is less well 
defined than the prophylaxis of exercise induced bronchospasm. We 
believe that our discussion of alternatives to INTAL MDIs and TILADE in 
regard to exercise induced bronchospasm would be equally relevant to 
this issue.
    We agree with the PADAC member that cromolyn and nedocromil are 
very comparable drugs (see Ref. 7 (cromolyn and nedocromil administered 
by MDI provide similar protection against exercise induced bronchospasm 
in children)). We request comment as to whether there is a medically 
sound rationale for treating them differently. It would seemingly make 
little sense to remove the essential use of one and retain the other 
without such a rationale. There would be no net decrease in the amount 
of ODSs released into the atmosphere if everyone currently using INTAL 
MDI switched to TILADE, or vice versa. Therefore, our analysis has 
treated the two drugs together.
    We have tentatively come to the following conclusion:
     The pharmaceutical industry has had success in formulating 
other orally inhaled drugs with similar physical properties to cromolyn 
and nedocromil without ODSs, including the development of cromolyn and 
nedocromil HFA MDIs overseas. We have no evidence to suggest that the 
ODS containing cromolyn or nedocromil oral inhalation drug products 
pose unique technical challenges to formulation without ODSs. 
Therefore, we tentatively conclude that no substantial technical 
barriers exist to formulating cromolyn and nedocromil oral inhalation 
drug products without ODSs.
     Cromolyn and nedocromil MDIs do not provide an otherwise 
unavailable important public health benefit because of the available 
therapeutic alternatives. However, given the issues raised during the 
discussion at the PADAC meeting, we request comment on our tentative 
conclusion.
     The release of ODSs into the atmosphere from cromolyn and 
nedocromil MDIs is cumulatively significant and is not warranted, 
because they do not provide an otherwise unavailable important public 
health benefit.
    We, therefore, tentatively conclude that oral pressurized MDIs 
containing cromolyn sodium and nedocromil sodium are no longer 
essential uses of ODSs and should be removed from the list of essential 
uses in Sec.  2.125(e).

D. Albuterol and Ipratropium in Combination

    We are proposing to remove the essential-use designations for MDIs 
containing albuterol sulfate and ipratropium bromide in combination 
(COMBIVENT).\17\ COMBIVENT 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. Albuterol is somewhat faster acting 
than ipratropium, while ipratropium is somewhat longer acting than 
albuterol. 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) for use in a nebulizer. Nebulizers do not 
use CFCs. This current rulemaking will not affect the regulatory status 
of DUONEB.
---------------------------------------------------------------------------

    \17\ 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. We have not had adequate 
time to evaluate this lengthy petition and its 52 references. We 
will treat the petition as a comment on this proposal. The contents 
of this petition do not need to be resubmitted, but BI is free to 
submit any additional information or analysis they feel is relevant.
---------------------------------------------------------------------------

    We have tentatively determined that an ipratropium bromide MDI 
(ATROVENT HFA) used with an albuterol sulfate HFA MDI (PROAIR HFA, 
PROVENTIL HFA, OR VENTOLIN HFA) will provide an acceptable therapeutic 
alternative to COMBIVENT. 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). While 
the acceptability as a therapeutic alternative of the same two drugs 
delivered by two separate MDIs rather than by one may seem obvious, 
this opinion is not universally shared. A Boehringer

[[Page 32039]]

Ingelheim Pharmaceuticals, Inc. (BI), employee commented at the 2005 
PADAC meeting that having patients use albuterol and ipratropium in a 
single combination MDI resulted in higher patient compliance with the 
prescribed regimen of medication than having the patient use two 
separate MDIs. Several PADAC members agreed with BI that higher 
compliance rates among patients was a significant factor that justified 
continuing the essential-use status of albuterol and ipratropium in 
combination. Other PADAC members stated that combining the two drugs 
was more of a convenience than an essentiality. One member noted that 
the hospital at which he practiced did not have COMBIVENT on its 
formulary, and albuterol and ipratropium are prescribed in separate 
MDIs. He concluded that providing the two drugs together in a 
combination MDI was not essential. One PADAC member pointed out that 
the increasing popularity of the tiotropium bromide DPI (SPIRIVA 
HANDIHALER) would decrease demand for COMBIVENT, because ipratropium 
cannot be used in conjunction with tiotropium. One PADAC member stated 
that the combination should remain essential for the time being because 
of the unnecessary anxiety that removing COMBIVENT from the market 
could cause. Opinion on whether the combination should retain its 
essential-use status was evenly divided.
    We are aware of one health economics survey suggesting that a 
single inhaler containing both albuterol and ipratropium might increase 
compliance and decrease risk of emergency department visits and mean 
length of hospital stays compared to the effects achieved with separate 
inhalers for these two moieties (Ref. 8). However, we have not fully 
evaluated this survey. A patient's failure to use albuterol and 
ipratropium as prescribed would be expected to lead to increased 
symptoms, but it would not affect the permanent underlying state of the 
patient's lungs (Ref. 9). When the patient resumes using albuterol and 
ipratropium as prescribed (which he or she would have a major incentive 
to do), the symptoms should be relieved, with no significant changes in 
the patient's health compared to the period before the patient stopped 
using the MDIs as prescribed. We welcome any reports of studies on 
these subjects. We request comment on whether increased compliance and 
increased quality of life would be compelling reasons for continuing 
the essential-use designation for albuterol and ipratropium in 
combination. We do not currently have sufficient information to say 
that continuing the essential use will significantly increase patient 
quality of life to support a claim of important public health benefit.
    Continuing the essential-use status of albuterol and ipratropium in 
combination is no longer supported by one of the rationales that BI 
proposed in their citizen petition requesting that MDIs containing 
albuterol sulfate and ipratropium bromide in combination be listed as 
essential in Sec.  2.125(e). BI said that use of the COMBIVENT MDI 
could reduce the release of CFCs into the atmosphere, because patients 
would be using one CFC MDI for both albuterol and ipratropium, instead 
of two separate CFC MDIs (neither albuterol nor ipratropium was 
available in a non-ODS MDI at the time) (Citizen Petition, dated 
October 19, 1992, Docket No. 1992P-0403/CP1 (formerly 92P-0403)). We 
adopted this rationale in our rulemaking to add the essential use to 
Sec.  2.125(e) (60 FR 53725, October 17, 1995; 61 FR 15699, April 9, 
1996). Now, however, with ATROVENT HFA and albuterol sulfate HFA MDIs 
on the market, this rationale is no longer valid.
    We have tentatively come to the following conclusion:
     Although a BI employee said at the 2005 PADAC meeting that 
there were substantial technical barriers to formulating albuterol and 
ipratropium in combination without ODSs, we have not been supplied with 
any information to support this conclusion and we cannot make an 
initial determination on whether substantial technical barriers exist.
     Albuterol and ipratropium in combination CFC MDIs do not 
provide an otherwise unavailable important public health benefit. 
However, given the issues raised during the discussion at the PADAC 
meeting, we request comment on our tentative conclusion.
     The release of ODSs into the atmosphere from albuterol and 
ipratropium in combination MDIs is cumulatively significant and is not 
warranted, because they do not provide an otherwise unavailable 
important public health benefit.
    We, therefore, tentatively conclude that metered-dose ipratropium 
bromide and albuterol sulfate, in combination, administered by oral 
inhalation for human use is no longer an essential use of ODSs and 
should be removed from the list of essential uses in Sec.  2.125(e). We 
would be able to reach this conclusion without reaching a conclusion 
about whether substantial technical barriers exist to formulating an 
ipratropium bromide and albuterol sulfate combination without ODSs 
because a CFC ODS product must meet all three criteria to remain 
designated as an essential use (see Sec.  2.125(g)(2)).

VI. Environmental Impact

    We have carefully considered the potential environmental effects of 
this action. We have tentatively concluded that the action will not 
have a significant adverse impact on the human environment, and that an 
environmental impact statement is not required. Our initial finding of 
no significant impact and the evidence supporting that finding, 
contained in a draft environmental assessment, may be seen in the 
Division of Dockets Management (see ADDRESSES) between 9 a.m. and 4 
p.m., Monday through Friday. We invite comments on the draft 
environmental assessment. Comments on the draft environmental 
assessment may be submitted in the same way as comments on this 
document (see DATES).

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, 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 proposed rule is a significant regulatory action as defined by the 
Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The agency does not believe that this proposed rule 
would have a significant economic impact on a substantial number of 
small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $118 million, using the most current (2004) Implicit 
Price Deflator for the Gross

[[Page 32040]]

Domestic Product. FDA does not expect this proposed rule to result in 
any 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 proposed 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) and MDIs delivering albuterol and 
ipratropium in combination (COMBIVENT) will face higher prices because 
available substitutes cost more. In contrast, users of triamcinilone 
MDIs (AZMACORT), metaproterenol MDIs (ALUPENT), pirbuterol MDIs 
(MAXAIR), cromolyn sodium MDIs (INTAL), and nedocromil sodium MDIs 
(TILADE) 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.
    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, when 
it occurs, the introduction of generic albuterol HFA MDIs to the market 
will eliminate price and spending increases resulting from this 
proposed 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 and goodwill 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 HFA 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 earlier rulemaking 
(70 FR 17168). These estimated spending increases may also be 
attributed to the withdrawal of albuterol CFC MDIs (including all of 
the less-expensive generic albuterol MDIs) from the market (see 70 FR 
17168). The rightmost column in table 1 of this document shows 
estimates of the amount of increased spending attributable to this 
proposed rule if COMBIVENT prices were to increase dramatically, as 
discussed in section VII.C.6 of this document, even in the absence of 
this proposed rule. These remaining costs would be attributable to this 
proposed rule until a mandatory phase-out of all CFCs under the 
Montreal Protocol.

  Table 1.--Summary of Annual Quantifiable Effects of the Proposed Rule
------------------------------------------------------------------------
                                                         Increased MDI
                               Possible                   Expenditures
  Patient     Increased MDI   Reduction   Reduced CFC   Attributable to
  Days of     Expenditures,   in Days of   Emissions     this Proposed
  Therapy        in 2005       Therapy    from Phase-     Rule Without
  Affected       dollars         Used         out         Increase in
                              (millions)    (tonnes)    Expenditures by
                                                        COMBIVENT Users
------------------------------------------------------------------------
440 million  $200-$400       0.7-11       310-365      -$70 to $70
              million                                   million
------------------------------------------------------------------------


    Table 2.--Summary of Increases in Impacts Relative to HFA Patent
                               Expiration
------------------------------------------------------------------------
                 Possible Decreases                      Increases in
  Date of HFA   in Use of Asthma and                 Expenditures on CFC-
    Patent          COPD Therapy      Discount Rate  based MDIS, Present
  Expiration      (million days of                      Value in 2006
                      therapy)                            (billions)
------------------------------------------------------------------------
2010            .68-11                3%             $.19-$.38
                                     -----------------------------------
                ....................  7%             $.17-$.35
------------------------------------------------------------------------
2017            5.4-88                3%             $1.3-$2.7
                                     -----------------------------------
                ....................  7%             $1.1-$2.2
------------------------------------------------------------------------

    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 
VII.B of this document. Section VII.C of this document provides 
background on CFC depletion of stratospheric ozone, the Montreal 
Protocol, the albuterol MDI market, and the health conditions that 
albuterol is used to treat. We analyze the benefits and costs of the 
rule, including effects on government outlays, in section VII.D of this 
document. We assess alternative dates in section VII.E of this 
document, and discuss sensitivity analysis in section VII.F of this 
document. We present an analysis of the effects on small business in a 
regulatory flexibility analysis in section VII.G of this document. We 
discuss our conclusions in section VII.H of this document.

[[Page 32041]]

B. Need for Regulation and the Objective of this Rule

    This proposed regulation responds to U.S. obligations under the 
Montreal Protocol and the Clean Air Act. The Montreal Protocol itself 
recognizes that the regulation of ozone-depleting substances is 
necessary because private markets are very unlikely to preserve levels 
of stratospheric ozone sufficient to protect the public health. 
Individual users of CFC MDIs have no significant private incentive to 
switch to non-ozone-depleting products because, under current 
regulations, the environmental and health costs of ozone-depleting 
products are external to end users. Moreover, should MDI users 
voluntarily internalize these costs by switching to alternative 
products, they would not receive the benefits of their actions. Each 
user would bear all of the costs and virtually none of the benefits of 
such a switch, as the environmental and health benefits would tend to 
be distributed globally and occur decades in the future. Thus, the 
outcome of a private market would likely be continued use of CFC MDIs, 
even if the social value of reducing emissions were clearly much 
greater than the price premium for non-ozone-depleting therapies and 
the possible adverse affects on some patients due to the decreased use 
of MDIs.
    The objective of this proposed rule is to respond to the Clean Air 
Act and the Montreal Protocol's requirements that the United States, 
and other nations, 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 proposing to end the 
essential-use designation for ODSs used in MDIs containing 
triamcinilone, metaproterenol, pibuterol, cromolyn sodium, nedocromil 
sodium, flunisolide, and albuterol and ipratropium in combination, 
because we tentatively conclude 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 I.B.2 of this document. One hundred and eighty-
eight countries have now ratified 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. 
10). 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. 10).
    A relevant aspect of the Montreal Protocol is that production of 
CFCs in any year by any country is generally 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 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. 11). 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 estimates 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 $6 trillion 
after adjusting for inflation between 1990 and 2004. 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 proposed 
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 Sates carried the diagnosis 
of COPD in 2000 (table 1 of Ref. 12). The underlying surveys depend on 
patient-reported diagnoses and many affected individuals have not been 
formally diagnosed. Data from the National Health and Nutrition 
Examination Survey (table 3 of Ref. 12), which was not based on patient 
self-reporting, suggests that as many as 24 million Americans may 
actually be affected by the illness. 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. Among smokers, 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 on top of 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,

[[Page 32042]]

viral infections, and others, may trigger an asthma attack.
    According to the NHIS, approximately 21 million patients in the 
United States reported they had asthma in 2004 (table 7 of Ref. 13). 
The prevalence of asthma decreases with age, with the prevalence being 
84.7 per 1,000 children ages 0-17 (6.2 million children) compared to 
63.9 per 1,000 among adults ages 18-44 (7.1 million), 69.4 per 1,000 
among adults ages 45-64 (4.9 million), and 70.2 per 1,000 among adults 
age 65 and over (2.4 million) (table 7 of Ref. 13).
    The NHIS reported that, during 2004, about 12 million patients 
reported experiencing an asthma attack in the course of the previous 
year (table 10 of Ref. 13). According to the National Ambulatory 
Medical Care Survey and National Hospital Ambulatory Medical Care 
Survey, in 2004 there were 14 million outpatient asthma visits to 
physician offices and hospital clinics and 1.8 million emergency room 
visits (table 19 of Ref. 13). According to the National Center for 
Health Statistics' National Hospital Discharge Survey, there were 
497,000 hospital admissions for asthma in 2004 (table 17 of Ref. 13) 
and 4,099 mortalities in 2003 (table 1 of Ref. 13). The direct medical 
cost of asthma (hospital services, physician care, and medications) was 
estimated as $11.5 billion for 2004 (table 20 of Ref. 13).
    While the prevalence of asthma has been increasing in recent years, 
the Centers for Disease Control and Prevention (CDC) reports that the 
patients reported experiencing an asthma attack in the course of the 
previous year has remained fairly constant since 1997 (Ref. 14). 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. CDC also reported declines in 
hospitalization for asthma and mortality. The declines may indicate 
early successes by asthma intervention programs that include access to 
medications.
6. Current U.S. Market for CFC MDIs
    In the 2005 calendar year, we estimate that sales of these seven 
CFC MDIs provided roughly 440 million days of therapy, sufficient to 
treat roughly 1.2 million COPD and asthma patients for a full year. We 
focus on 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. 
15).
    We calculate the average price per day of therapy for a CFC MDI as 
the total revenue derived from sales of that product in 2005, 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 the 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. 15)
------------------------------------------------------------------------
                                             Price Premium per Day of
                                                      Therapy
   CFC MDI       Non-ODS Alternatives    -------------------------------
                                              Maximum         Minimum
------------------------------------------------------------------------
AEROBID       QVAR                                 $1.63           $0.27
AEROBID-M     PULMICORT TURBOHALER
              FLOVENT HFA
              ASMANEX TWISTHALER
------------------------------------------------------------------------
AZMACORT      QVAR                                 $0.35          -$1.01
              PULMICORT TURBOHALER
              FLOVENT HFA
              ASMANEX TWISTHALER
------------------------------------------------------------------------
ALUPENT       PROAIR HFA                           $0.07          -$0.14
              PROVENTIL HFA
              VENTOLIN HFA
              XOPENEX HFA
------------------------------------------------------------------------
MAXAIR        PROAIR HFA                          -$0.23          -$0.53
              PROVENTIL HFA
              VENTOLIN HFA
              XOPENEX HFA
------------------------------------------------------------------------
INTAL         QVAR                                -$0.33          -$1.69
              PULMICORT TURBOHALER
              FLOVENT HFA
              ASMANEX TWISTHALER
------------------------------------------------------------------------

[[Page 32043]]

 
TILADE        QVAR                                -$2.34          -$5.12
              PULMICORT TURBOHALER
              FLOVENT HFA
              ASMANEX TWISTHALER
------------------------------------------------------------------------
COMBIVENT     ATROVENT HFA + one of the            $1.22           $0.92
               following:
              PROAIR HFA
              PROVENTIL HFA
              VENTOLIN HFA
              XOPENEX HFA
------------------------------------------------------------------------
Source: IMS Health, IMS National Sales Perspective (TM), 2005, extracted
  March 2006.

    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 TURBOHALER, FLOVENT HFA, or 
ASMANEX TWISTHALER. The most expensive of these alternatives would cost 
roughly 35 cents more per day of therapy, and the least would cost 
roughly $1 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, during the past year, changes in prices of CFC 
MDIs did not differ systematically from the changes in prices of the 
proposed alternatives.
    We estimate that, on average, users of these seven CFC MDIs will 
pay 20 percent to 50 percent more per day of 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 2005, would increase roughly 20 
percent; if all users switch to the most expensive alternative therapy, 
the average price per day of therapy would increase roughly 50 percent. 
These prices represent average ex-manufacturer prices across all 
distribution channels, and do not incorporate retail markups or off-
invoice discounts (Ref. 15).
    These estimated price increases may also be attributed to the 
withdrawal of albuterol CFC MDIs (including all generic albuterol MDIs) 
from the market (see 70 FR 17168). These estimated price increases are 
driven almost entirely by the large population of COMBIVENT users 
switching to both the ipratropium MDI (ATROVENT HFA) 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. 
Since 2003, the price of a day of COMBIVENT therapy has risen 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. One might predict that, 
with the withdrawal of albuterol CFC MDIs (including all generic 
albuterol MDIs) from the market (see 70 FR 17168), the price of a day 
COMBIVENT therapy would increase to the sum of a day of therapy with 
ATROVENT HFA and an albuterol HFA MDI. To the extent that this 
prediction is accurate, the price increases described previously, and 
the estimated spending increases derived from it, result not from this 
proposed rule, but from the earlier rule removing albuterol CFC MDIs 
from the market. Indeed, without the estimated increase in spending 
estimated for the price per day of COMBIVENT therapy, the expected 
average price per day of therapy would not increase; the midpoint of 
the range of spending changes shown in table 1 of this document, -$70 
million to $70 million, is zero.
    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. The CFC MDI manufacturers have requested roughly 365 tonnes 
of CFCs for production of the seven CFC MDIs in 2007, our high 
estimate.\18\
---------------------------------------------------------------------------

    \18\ CFC MDI manufacturers disclose the CFC content of their 
MDIs to EPA as part of the process of requesting essential-use 
allocations; however, the CFC content of any particular MDI is 
considered a trade secret and may not be disclosed without the 
manufacturer's consent.
---------------------------------------------------------------------------

D. Benefits and Costs of the Proposed 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 proposed 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 after 
December 31, 2009. 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 proposed 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 32044]]

    Throughout this analysis, we assume that sufficient inventories of 
CFCs are available to meet demand for these seven CFC MDIs through 
December 31, 2009, and that there will be sufficient therapeutic 
alternatives to meet demand after December 31, 2009.
    However, in the absence of this proposed rule, the parties to the 
Montreal Protocol are likely to consider restrictions on access to the 
CFCs needed to produce these seven CFC MDI products. These likely 
restrictions imply the costs detailed in section 3 of this document may 
very well accrue regardless of whether this proposed rule is made 
final. The cost-benefit analysis presented here would then reflect the 
withdrawal of the CFC-containing products from the market, rather than 
the specific effects of this rulemaking.
2. Benefits of the Proposed Rule
    The benefits of the proposed 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 and goodwill to comply with the spirit of the 
Montreal Protocol, thereby potentially reducing future emissions of 
ODSs throughout the world.
    Failure to promulgate the requirements proposed in this proposed 
rule would likely lead the parties to the Montreal Protocol to consider 
restricting access to the CFCs required to manufacture these seven CFC 
MDI products, leading to a risk of unexpected disruptions of supplies 
of drug products which are still being used by patients with asthma and 
COPD. These disruptions could potentially harm the public health of the 
United States by preventing a smooth transition from CFC MDIs to non-
CFC products.
    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 proposed rule would ban marketing of 
these seven CFC MDIs after December 31, 2009. 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 allocating any CFCs for 2009. 
Therefore, we estimate the proposed regulation will reduce CFC use by 
310 to 365 tonnes per year after the end of 2009, a benefit that will 
continue beyond the evaluation period.
    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 $6 trillion in 2004 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 
included in EPA's earlier estimate of benefits.
    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. 
10). 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 $6 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 proposed 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 serves as a signal to other potential developers of ozone-safe 
technologies. In particular, such a phase-out date would preserve 
expectations that the government protects incentives to research and 
develop ozone-safe technologies.
    Newly developed technologies to avoid ODS emissions have resulted 
in more environmentally ``friendly'' air conditioners, refrigerants, 
solvents, and propellants, but only after significant private-sector 
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. 16).
    These investments have resulted in several innovative products in 
addition to HFA MDIs. For example, breath-activated delivery systems, 
dose counters, DPIs, 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 propose to adopt a later phase-out date, other Parties could attempt 
to delay their own control measures.
3. Costs of the Proposed Rule
    The proposed rule would increase spending for needed medicines used 
to treat asthma and COPD. The social costs of the proposed rule include 
the 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 which consumers, and 
their doctors, can choose, but we note that these costs may be 
substantial. 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 440 million days 
of therapy of 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

[[Page 32045]]

COPD patients use the most or least expensive of alternatives, once 
this proposed rule becomes final and goes into effect, private, third-
party and public expenditures on inhaled medicines would increase by 
roughly $200 million to $400 million per year. These expenditure 
increases will be driven almost exclusively by COMBIVENT users changing 
to both ATROVENT HFA and one of four available albuterol HFA products. 
With most--perhaps all--of this increase coming from estimated 
increased spending on albuterol HFA MDIs, what happens to the prices of 
albuterol MDIs will largely determine the change in overall spending. 
As discussed in section VII.C.6, it is possible that, in response to 
earlier rulemaking removing generic CFC albuterol MDIs from the market, 
COMBIVENT prices would increase dramatically even in the absence of 
this proposed rule. If, even in the absence of this proposed rule, the 
cost of a day of COMBIVENT therapy were to increase to the sum of a day 
of albuterol HFA MDI and ATROVENT HFA therapy, this proposed rule would 
change private, third-party and public expenditures on inhaled 
medicines by roughly -$70 million to $70 million per year. This 
increased expenditure 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 prior rulemaking (70 FR 17168) will remove albuterol CFC 
MDIs, including generic albuterol CFC MDIs, from the market by December 
31, 2008. If these cheaper generic albuterol MDIs were somehow to 
remain on the market, the expected cost of switching from COMBIVENT to 
both ATROVENT HFA and an albuterol HFA MDI would be essentially 
eliminated. Because expenditure increases resulting from this proposed 
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. Patents listed in Approved 
Drug Products with Therapeutic Equivalence Evaluations (Orange Book) 
for albuterol HFA MDIs expire in 2010 and 2017, making those possible 
dates for generic entry. Of course, unforeseen introduction of 
alternative therapies could reduce these 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 expect that price increases resulting from market withdrawal of 
less expensive CFC MDIs could reduce use of inhaled therapy by 0.7 to 
11 million days annually, equivalent to roughly 2 to 30 thousand 
patient years of therapy. The impact of this reduction on health 
outcomes is too uncertain to quantify given available data, and we 
invite comments on this issue. We also invite comments on changes in 
copayments (resulting in higher out-of-pocket costs for insured 
consumers) and potential effect on therapy days.
    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. 17). 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. This evidence is insufficient to permit us to quantify any 
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 proposed 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 quantity of MDI and DPI therapy consumed may decline as a 
result of this rule. 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, researched 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 
antiasthmatic drugs) to -0.22 (for antiasthmatic 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. 17), 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. 17, p. 2348). Drugs included as antiasthmatics in this 
study include anticholinergics, 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.
    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. Based on IMS data, we 
estimate that asthma and COPD patients receive roughly 440 million days 
of therapy each year in the form of these seven CFC MDIs (Ref. 15). If 
users of these products are uninsured in proportion to the share of 
uninsured in the overall U.S. population (15.7 percent) (Ref. 18), then 
uninsured asthma and COPD patients receive roughly 69 million days of 
therapy [(440 million) x (15.7 percent)] in the form of these seven CFC 
MDIs, equivalent to roughly 188 thousand patient years. However, 
increases in the price of therapy will fall disproportionately on 
COMBIVENT users with COPD. In 1995, more than two-thirds of COPD 
patients were over the age of 65 (Ref. 19); these individuals would 
therefore be covered, at least in part, by Medicare. If the remaining, 
under-65 third of the COPD patients are uninsured in proportion to the 
uninsured share of the population, then only 23 million days of therapy 
[(440 million) x (15.7 percent) / 3] are used by uninsured COPD 
patients each year. We are unable to estimate the extent to which 
Medicare's Part D benefit will cover the increased costs to those 
patients over age 65. Because most

[[Page 32046]]

of those over age 65 have insurance, 15.7% likely understates the true 
percentage of individuals under 65 without insurance. To the extent 
this is true, these estimates will understate the true impact of this 
proposed rule. Finally we estimate that users of these seven CFC MDIs 
face an average price increases of between 20 and 50 percent per day of 
therapy, 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 in 2005. Excluding COMBIVENT, users of 
the other six CFC MDIs would face prices somewhere between 30 percent 
higher and 30 percent lower.
    We combine different measures of price elasticities (-0.15 to -
0.33), the size of the uninsured CFC MDI market (23 to 69 million days 
of therapy), and estimated price increases (20 percent to 50 percent) 
to estimate the impact of price increases on use. For example, assuming 
a price elasticity of -0.15 and 23 million days of therapy sold to the 
uninsured annually, a 20 percent price increase would reduce demand for 
inhaled therapy by the uninsured by roughly 700,000 days of therapy 
annually. By contrast, assuming a price elasticity of -0.33 and 69 
million days of therapy sold to the uninsured annually, a 50 percent 
price increase would reduce uninsured demand by roughly 11 million days 
of therapy [(69 million days) x (-0.33 elasticity) x (50 percent price 
increase) = 11 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.
    When we exclude COMBIVENT from the calculation, we get a much 
smaller effect. The expected price change of 30 percent higher to 30 
percent lower implies a -4.5 percent to 4.5 percent change in days of 
therapy if the price elasticity is -0.15 and a -10 percent to 10 
percent change in days of therapy if the price elasticity is -0.33. The 
expected change in days of therapy would be zero, the midpoint of the 
range.
4. Effects on Medicaid and Medicare
    Based on 2005 Medicaid utilization data, we estimate this proposed 
rule would reduce Federal Medicaid spending by $40 million to $60 
million annually. Based on Medicare Current Beneficiary Survey 
estimates of the Medicare population and estimates of the price 
difference between CFC MDIs and HFA MDIs, we estimate Federal spending 
on Medicare beneficiaries, as well as by Medicare beneficiaries 
themselves, will increase from $190 million to $450 million annually. 
We recognize these estimates of increased Medicare spending suggest a 
broader range of potential spending increases than estimates of the 
overall impact of the proposed rule introduced in table 1 of this 
document. We discuss data limitations that cause this in section 
VII.D.3.b of this document.
    a. Medicaid. Based on aggregated state Medicaid utilization data 
for 2005,\19\ we estimate this proposed rule will reduce Medicaid 
reimbursements by roughly $40 million annually, because Medicaid 
reimbursement rates for CFC MDI products are, on average, higher than 
reimbursement rates for the proposed HFA MDI alternatives. First, we 
estimate total days of therapy reimbursed by Medicaid in 2005 for each 
of the seven CFC MDIs and calculate the average reimbursement per day 
of therapy. Second, we estimate the average reimbursement per day of 
therapy for each alternative therapy. If all Medicaid beneficiaries 
using CFC MDIs switch to the most expensive of available alternatives 
and reimbursement rates remain unchanged, total reimbursements would 
decrease by approximately $40 million; if they all switch to the least 
expensive of available alternatives, total reimbursements would 
decrease by roughly $60 million. Because these estimates are based on 
2005 data, they do not take into account decreases in Medicaid 
reimbursements that will occur as those individuals eligible for both 
Medicaid and Medicare, and who were covered by Medicaid in 2005, 
receive their 2006 coverage through Medicare.
---------------------------------------------------------------------------

    \19\ Our estimate uses State drug utilization data for 
outpatient drugs paid for by State Medicaid agencies as part of the 
Medicaid Drug Rebate Program. The data is available at: http://www.cms.hhs.gov/MedicaidDrugRebateProgram/SDUD/list.asp#TopOfPage.

                                        Table 4.--Estimated Impact on Medicaid Reimbursements Based on 2005 Data
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                           Reimbursement       Expenditure Premium             Expenditure Change
                CFC MDIs                  Total Days of       Total         per Day of   ---------------------------------------------------------------
                                             Therapy       Expenditure        Therapy        Maximum        Minimum         Maximum          Minimum
--------------------------------------------------------------------------------------------------------------------------------------------------------
MAXAIR                                        7,248,876      $12,320,046           $1.70         -$0.36         -$0.36      -$2,581,185      -$2,581,185
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEROBID                                       1,513,499       $4,506,603           $2.98          $1.77         -$1.42       $2,679,966      -$2,149,445
--------------------------------------------------------------------------------------------------------------------------------------------------------
AZMACORT                                      6,519,580      $19,408,252           $2.98          $1.77         -$1.42      $11,548,769      -$9,254,506
--------------------------------------------------------------------------------------------------------------------------------------------------------
COMBIVENT                                    47,888,737     $138,485,222           $2.89         -$1.15         -$0.93     -$54,987,774     -$44,318,563
--------------------------------------------------------------------------------------------------------------------------------------------------------
INTAL                                           550,246       $1,801,310           $3.27          $1.47         -$1.72         $811,434        -$944,343
--------------------------------------------------------------------------------------------------------------------------------------------------------
TILADE                                           27,497         $151,039           $5.49         -$0.74         -$3.94         -$20,474        -$108,214
--------------------------------------------------------------------------------------------------------------------------------------------------------
ALUPENT                                               0               $0           $0             $0             $0                  $0               $0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                      -$42,549,264     -$59,356,256
--------------------------------------------------------------------------------------------------------------------------------------------------------

    b. Medicare. Based on 2003 data from the Medicare Current 
Beneficiary Survey and price estimates introduced in table 3 of this 
document, we estimate Federal Medicare spending, together with private 
expenditure by Medicare beneficiaries, will increase roughly $190 
million to $450 million. We estimate roughly 1.2 million beneficiaries 
used

[[Page 32047]]

these seven CFC MDIs in 2003. Excluding COMBIVENT, we estimate that 
this spending could increase by as much as $75 million or decrease by 
as much as $90 million.

                                                 Table 5.--Increased Spending on Medicare Beneficiaries
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                        Number of Full-     Price Premium                Cost Per day                          Cost Per Year
                                         year Medicare -------------------------------------------------------------------------------------------------
                                             users         Max        Min            Max               Min                Max                 Min
--------------------------------------------------------------------------------------------------------------------------------------------------------
Aerobid                                        112,259      $1.63      $0.27       $183,219.05        $30,151.89      $66,874,952.64      $11,005,440.65
--------------------------------------------------------------------------------------------------------------------------------------------------------
Azmacort                                       185,035      $0.35     -$1.01        $65,250.68      -$187,047.39      $23,816,497.79     -$68,272,296.85
--------------------------------------------------------------------------------------------------------------------------------------------------------
Alupent                                         10,415      $0.07     -$0.14           $752.26        -$1,505.96         $274,574.93        -$549,676.92
--------------------------------------------------------------------------------------------------------------------------------------------------------
Maxair                                          26,909     -$0.23     -$0.53        -$6,109.49       -$14,387.81      -$2,229,962.64      -$5,251,551.32
--------------------------------------------------------------------------------------------------------------------------------------------------------
Intal                                            9,950     -$0.33     -$1.69        -$3,273.69       -$16,840.06      -$1,194,895.82      -$6,146,620.75
--------------------------------------------------------------------------------------------------------------------------------------------------------
Tilade                                          15,108     -$2.34     -$3.70       -$35,296.79       -$55,896.24     -$12,883,326.74     -$20,402,126.86
--------------------------------------------------------------------------------------------------------------------------------------------------------
Combivent                                      833,103      $1.22      $0.92     $1,019,601.26       $763,304.20     $372,154,460.78     $278,606,034.58
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                        1,192,779  .........  .........  ................  ................     $446,812,300.95     $188,989,202.52
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The 1.2 million figure for the number of Medicare users presented 
previously includes people enrolled as of January 2002 who lived in a 
community setting during 2003 and who filled a prescription for at 
least one of these MDIs in 2003. It excludes an additional 102,000 
users of these MDIs who were enrolled as of January 2002, lived in a 
facility for some or all of 2003, and filled at least one prescription. 
This 1.2 million figure also counts each individual who used more than 
one of these MDI products one time for each kind of MDI used. An 
individual using more than one of these products will therefore be 
counted as a full year user of each product. These estimates exclude 
individuals who enrolled after January 2002.
    Based on the price per day of therapy of each of these products and 
of their alternatives, we estimate annual Federal spending on Medicare 
beneficiaries and private spending by Medicare beneficiaries will 
increase by $190 million to $450 million, depending on whether 
beneficiaries switch to the least, or most, expensive of available 
alternatives. This calculation assumes that full-year beneficiaries 
that use each of these products use a full 365 days of therapy per 
year, and therefore likely overestimates spending increases, 
particularly in the case where an individual switched from one to 
another MDI in the course of a year. These estimates also combine 
estimates of the Medicare population with price estimates (introduced 
in table 3 of this document) based on the entire market. Actual prices 
paid by Medicare beneficiaries are likely to differ systematically from 
the market as a whole, though it is not clear that the relevant price 
premiums do.
    We are unable to estimate the extent to which these price 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 plan they choose. Data from the Medicare Part D benefit, which 
would give us better estimates of prices paid and the public and 
private shares of the burden, are not yet available.

E. Alternative Phase-out Dates

    We consider the impacts of the alternative phase-out date of 
December 31, 2010, in table 6 of this document. A phase-out date set 
too far in the future would be incompatible with the timetable set by 
the Montreal Protocol. An earlier phase-out date 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. This leaves a narrow window for consideration.

 Table 6.--Summary of Impacts of a December 31, 2010 Phase-Out Relative
                        to HFA Patent Expiration
------------------------------------------------------------------------
               Possible Decreases                         Increases in
 Date of HFA    in Use of Asthma                        Expenditures on
    Patent      and COPD Therapy      Discount Rate     CFC-based MDIS,
  Expiration    (million days of                        Present Value in
                    therapy)                            2006 (billions)
------------------------------------------------------------------------
2010           0.................  3%................  $0
                                  --------------------------------------
               ..................  7%................  $0
------------------------------------------------------------------------
2017           4.9-77............  3%................  $1.2-$2.4
                                  --------------------------------------
               ..................  7%................  $0.9-$1.8
------------------------------------------------------------------------

    Table 6 of this document shows the effect of different expiration 
dates for HFA MDI patents on the impact of the proposed rule. Listed 
HFA MDI patents expire in 2010 and 2017. We assume albuterol HFA MDIs 
are not inherently more costly to produce than albuterol CFC MDIs. Once 
the relevant patents have expired, generic competition should drive the 
price of albuterol HFA MDIs down to the current level of generic 
albuterol CFC MDIs. If generic albuterol HFA MDIs become available in 
2010, we estimate COMBIVENT users would not pay more to switch to both

[[Page 32048]]

albuterol HFA MDIs and ATROVENT HFA, due to lower prices of generic 
albuterol HFA MDIs. Therefore, current CFC MDI users would not, on 
average, pay more for MDIs as a result of this proposed rule. If 
current CFC MDI users would not pay more on average, they would not 
reduce their use of these products solely in response to higher prices.
    If, however, relevant HFA MDI patents do not expire until 2017, 
this proposed rule will cause current CFC MDI users to pay more for 
their MDIs until then, and to reduce their use of these MDIs in 
response to higher prices.

F. Sensitivity Analyses

    The estimated impacts of this proposed rule summarized in table 1 
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 proposed 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 23 million to 69 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 20 to 50 percent per day of therapy, depending on whether they 
switch to the most expensive or least expensive of the 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 proposed 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 440 million days of therapy in the form of CFC MDIs annually, 
and that prices will increase 20 to 50 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 30 percent increase to a 30 percent 
decrease, depending on whether they switch to the most expensive or 
least expensive of available alternatives.

G. Conclusion

    Limits in available data prevent us from quantifying the costs and 
benefits of the proposed 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 proposed rule, that make such cooperation 
effective. As discussed previously in detail, the benefits of the 
proposed 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 proposed 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.

VIII. 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. FDA requests comment on this issue. This rule may 
have a significant impact on firms that manufacture the seven CFC MDIs, 
including firms that distribute CFC MDIs that are manufactured under 
contract for them. According to the U.S. Small Business Administration, 
``pharmaceutical preparation manufacturers'' (North American Industrial 
Classification System (NAICS) code 325412) are considered small 
entities if they employ fewer than 750 people, and ``drug and 
druggists' sundries merchant wholesalers'' (NAICS code 424210) are 
small entities if they employ fewer than 100 people. None of the firms 
that manufacture the seven CFC MDIs, including firms that distribute 
CFC MDIs that are manufactured under contract for them, employ fewer 
than 750 people and therefore none are small entities.
    We do not expect that premiums paid by small businesses or other 
small entities for employees' prescription drug benefit plans will 
increase significantly as a result of this rulemaking. Accordingly, the 
agency does not believe that this proposed rule would have a 
significant economic impact on a substantial number of small entities.

IX. The Paperwork Reduction Act of 1995

    This proposed 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.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have 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. While this rule may result in States 
increasing spending for albuterol MDIs in programs such as Medicaid, 
the increased spending is not a substantial direct compliance cost, as 
the term is used in Executive Order 13132. Accordingly, we have 
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.

XI. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this proposal. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
    An upcoming public meeting on the essential-use status of MDIs 
containing flunisolide, triamcinolone, metaproterenol, pirbuterol, 
albuterol and ipratropium in combination, cromolyn, and nedocromil will 
provide an additional opportunity for public comment. We will provide 
details on the meeting in a notice published in the Federal Register in 
the near future.

XII. 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. FDA has verified the

[[Page 32049]]

Web site addresses, but we are not responsible for subsequent changes 
to the Web site after this document publishes in the Federal Register.
    1. National Heart, Lung, and Blood Institute, Expert Panel 
Report: Update on Selected Topics 2002: Guidelines for the Diagnosis 
and Management of Asthma, NIH publication No. 02-5074, June 2003.
    2. Tasche, M. J. A. et al., ``Inhaled Disodium Cromoglycate 
(DSCG) as Maintenance Therapy in Children with Asthma: A Systematic 
Review,'' Thorax 55:913-920, 2000; P. J. Helms, ``Inhaled Disodium 
Cromoglycate as Maintenance Therapy for Childhood Asthma: Time to 
Consign to History?'' (editorial), Thorax 55:886, 2000; Letter from 
A. Edwards et al., and reply by Tasche et al., Thorax 56:331-2, 
2001; Letter from G. Laszlo, and separate replies by Helms and 
Tasche et al., Thorax 56:502-503, 2001; Letter from M. Silverman, 
and reply by Tasche, et al., Thorax 56:585, 2001; Letter from H. K. 
Reddel and C. R. Jenkins, Thorax 56:896, 2001; Letter from Edwards 
et al. Thorax 57:282, 2002; Letter from Tasche, et al., Thorax 
57:751-752, 2002.
    3. National Heart, Lung, and Blood Institute, Expert Panel 
Report 2: Guidelines for the Diagnosis and Management of Asthma, NIH 
publication No. 97-4051, July 1997.
    4. Hofstra, W. B. et al., ``Dose-Responses Over Time to Inhaled 
Fluticasone Propionate Treatment of Exercise-and Methacholine-
Induced Bronchoconstriction in Children with Asthma,'' Pediatric 
Pulmonology, 29:415-423, 2000.
    5. Jonasson, G. et al., ``Low-Dose Budesonide Improves Exercise-
Induced Bronchospasm in Schoolchildren,'' Pediatric Allergy and 
Immunology, 11:120-123, 2000.
    6. Blake, K.V., ``Montelukast: Data from Clinical Trials in the 
Management of Asthma,'' Annals of Pharmacotherapy, 33 (12):1299-314, 
December 1999 (errata, 34:541, April 2000).
    7. de Benedictis, F. M. et al., ``Cromolyn Versus Nedocromil: 
Duration of Action in Exercise-Induced Asthma in Children'' Journal 
of Allergy and Clinical Immunology, 96:510-4, 1995.
    8. Chrischilles, E. et al., ``Delivery of Ipratropium and 
Albuterol Combination Therapy for Chronic Obstructive Pulmonary 
Disease: Effectiveness of Two-in-one Inhaler Versus Separate 
Inhalers'' The American Journal of Managed Care, 8:902-911, 2002.
    9. Anthonisen, N. R. et al., ``Hospitalizations and Mortality in 
the Lung Health Study'' American Journal of Respiratory and Critical 
Care Medicine, 166:333-339, 2002.
    10. United Nations Environmental Programme, Production and 
Consumption of Ozone-Depleting Substances: 1986-2004, 2005.
    11. U.S. Environmental Protection Agency, ``The Benefits and 
Costs of the Clean Air Act: 1990-2010'' (http://www.epa.gov/air/sect812/copy99.html) (November 1999).
    12. Mannino, D. M. et al., ``Chronic Obstructive Pulmonary 
Disease Surveillance--United States, 1971-2000,'' Morbidity and 
Mortality Weekly Report, 51(SS06):1-16, August 2, 2002.
    13. American Lung Association, ``Trends in Asthma Morbidity and 
Mortality,'' Epidemiology & Statistics Unit, Research and Program 
Services, July 2006.
    14. Mannino, D. M. et al., ``Surveillance for Asthma--United 
States, 1980-1999,'' Morbidity and Mortality Weekly Report, 
51(SS01):1-13, March 29, 2002.
    15. Analysis completed by FDA based on information provided by 
IMS Health, IMS National Sales Perspective (TM), 2005, extracted 
March 2006. These data are available for purchase from IMS Health. 
Please send all inquiries to: IMS Health, Attn: Brian Palumbo, 
Account Manager, 660 West Germantown Pike, Plymouth Meeting, PA 
19462.
    16. Rozek, R. P., and E. R. Bishko, ``Economics 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).
    17. Goldman, D. P. et al., ``Pharmacy Benefits and the Use of 
Drugs by the Chronically Ill,'' JAMA: The Journal of the American 
Medical Association, 291:2344-2350, May 19, 2004.
    18. DeNavas-Walt, C., B.D. Proctor, and C. H. Lee, U.S. Census 
Bureau, Current Population Reports, P60-229, Income, Poverty, and 
Health Insurance Coverage in the United States: 2004, p. 18, 2005.
    19. Hurd, S., ``The Impact of COPD on Lung Health Worldwide: 
Epidemiology and Incidence,'' Chest, 117:2 (supplement):1S-4S, 
February 2000.

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Drugs, Foods.
    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, it is proposed that 21 CFR part 2 be 
amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

    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]

    2. Section 2.125 is amended by removing and reserving paragraphs 
(e)(1)(iii), (e)(1)(v), (e)(2)(iii), (e)(2)(iv), (e)(4)(iv), 
(e)(4)(vii), and (e)(4)(viii).

    Dated: June 4, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 07-2883 Filed 6-6-07; 1:35 pm]
BILLING CODE 4160-01-S