[Federal Register: June 11, 2007 (Volume 72, Number 111)]
[Proposed Rules]
[Page 32030-32049]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr11jn07-22]
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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
[[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
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.
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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