Use of Ozone-Depleting Substances; Removal of Essential-Use Designations, 32030-32049 [07-2883]

Agencies

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

[Federal Register Volume 72, Number 111 (Monday, June 11, 2007)]
[Proposed Rules]
[Pages 32030-32049]
From the Federal Register Online via the Government Printing 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: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://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 https://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 https://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

[[Page 32031]]

    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 
https://www.unep.org/ozone/pdfs/Montreal-Protocol2000.pdf.\2\ The United 
States played a leading role in the negotiation of the Montreal 
Protocol, believing that internationally coordinated control of 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 https://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 https://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 https://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 nedocr