[Federal Register: September 20, 2007 (Volume 72, Number 182)]
[Proposed Rules]               
[Page 53711-53733]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20se07-20]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. 2007N-0262]
RIN 0910-AF92

 
Use of Ozone-Depleting Substances; Removal of Essential-Use 
Designation (Epinephrine)

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 designation for 
epinephrine used in oral pressurized metered-dose inhalers (MDIs). FDA 
has tentatively concluded that there are no substantial technical 
barriers to formulating epinephrine as a product that does not release 
ODSs, and therefore epinephrine would no longer be an essential use of 
ODSs. If the essential-use designation is removed, epinephrine MDIs 
containing an ODS could not be marketed after a suitable transition 
period. We will hold an open public meeting on the essential use of 
epinephrine on a date to be announced later.

DATES: Submit written or electronic comments by November 19, 2007.

[[Page 53712]]


ADDRESSES: You may submit comments, identified by Docket No. 2007N-0262 
and/or RIN number 0910-AF92, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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 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 previously in 
the ADDRESSES portion of this document under Electronic Submissions.
    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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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 joint 
meeting of the Nonprescription Drugs and Pulmonary-Allergy Drugs 
Advisory Committee held on January 24, 2006, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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. 2006 NDAC/PADAC Meeting
V. Epinephrine
    A. Do Substantial Technical Barriers Exist to Formulating 
Epinephrine Products Without ODSs?
    B. Do OTC Epinephrine MDIs Provide an Otherwise Unavailable 
Public Health Benefit?
    1. Does Epinephrine Provide a Greater Therapeutic Benefit Than 
Similar Adrenergic Bronchodilators?
    2. Does OTC Marketing of Epinephrine MDIs Provide an Important 
Public Health Benefit?
    3. Conclusions on the Public Health Benefits of OTC Epinephrine 
MDIs
    C. Does Use of OTC Epinephrine MDIs Release Cumulatively 
Significant Amounts of ODSs Into the Atmosphere or is the Release 
Warranted in View of the Otherwise Unavailable Important Public 
Health Benefit?
    D. Conclusions
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 Asthma
    5. Current U.S. Market for OTC Epinephrine MDIs
    D. Benefits and Costs of the Proposed Rule
    1. Baseline Conditions
    2. Benefits of the Proposed Rule
    3. Costs of the Proposed Rule and Alternatives
    4. Effects 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 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 exempt 
from the ban. The third listed essential use was for ``[m]etered-dose 
adrenergic bronchodilator human

[[Page 53713]]

drugs for oral inhalation.'' This use describes epinephrine MDIs.
    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 I.B.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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.unep.org/ozone/pdfs/Montreal-Protocol2000.pdf.\1\ The United 

States played a leading role in the negotiation of the Montreal 
Protocol, believing that internationally coordinated control of ODSs 
would best protect both the U.S. and global public health and the 
environment from potential adverse effects of depletion of 
stratospheric ozone. Currently, there are 191 Parties to this 
treaty.\2\ When it joined the treaty, the United States committed to 
reducing production and consumption of certain CFCs to 50 percent of 
1986 levels by 1998 (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).\3\ 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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    \1\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.
    \2\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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://ozone.unep.org/Meeting_Documents/mop/index.shtml
.

    \3\Production of CFCs in economically less-developed countries 
is being phased out and is scheduled to end by January 1, 2010. See 
Article 2A of the Montreal Protocol.
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    One of the most important essential uses of CFCs under the Montreal 
Protocol is their use in MDIs for the treatment of asthma and 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 health, safety, or is 
critical for the functioning of society (encompassing cultural and 
intellectual aspects) and (2) there are no available technically and 
economically feasible alternatives or substitutes that are acceptable 
from the standpoint of environment and health'' (Decision IV/25).
    Each request and any subsequent exemption is for only 1 year's 
duration (Decision V/18). Since 1994, the United States and some other 
Parties to the Montreal Protocol have annually requested, and been 
granted, essential-use exemptions for the production or importation of 
CFCs for their use in MDIs for the treatment of asthma and COPD (see, 
among others, Decisions VI/9 and VII/28). The exemptions have been 
consistent with the criteria established by the Parties, which make the 
grant of an exemption contingent on a finding that the use for which 
the exemption is being requested is essential for health, safety, or 
the functioning of society, and that there are no available technically 
and economically feasible alternatives or substitutes that are 
acceptable from the standpoint of health or the environment (Decision 
IV/25).
    Phasing out the use of CFCs in MDIs for the treatment of asthma and 
COPD has been an issue of particular interest to the Parties to the 
Montreal Protocol. Several decisions of the Parties have dealt with the 
transition to CFC-free MDIs, including the following decisions:
     Decision VIII/10 stated that the Parties that are 
developed countries would take various actions to promote industry's 
participation in a smooth and efficient transition away from CFC-based 
MDIs (San Jose, Costa Rica, 1996).
     Decision IX/19 required 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 stated 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\4\ 
(Nairobi, Kenya, 2003).
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    \4\Our obligation under XV/5 was met by our final rule 
eliminating the essential use status of albuterol (70 FR 17168, 
April 4, 2005).
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     Decision XVII/5 stated that Parties that are developed 
counties should provide a date to the Ozone Secretariat\5\

[[Page 53714]]

before the 18th Meeting of the Parties (October 30 to November 3, 2006) 
by which time a regulation or regulations will have been proposed to 
determine whether MDIs, other than those that have albuterol as the 
only active ingredient, are nonessential (Dakar, Senegal, 2005).
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    \5\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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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 the following:
     Arranging for and servicing the Conference of the 
Parties, Meetings of the Parties, their Committees, the Bureaux, 
Working Groups, and Assessment Panels;
     Arranging for the implementation of decisions resulting 
from these meetings;
     Monitoring the implementation of the Vienna Convention 
and the Montreal Protocol;
     Reporting to the Meetings of the Parties and to the 
Implementation Committee;
     Representing the Convention and the Protocol; and
     Receiving and analyzing data and information from the 
Parties on the production and consumption of ODSs.
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3. The 1990 Amendments to the Clean Air Act
    In 1990, Congress amended the Clean Air Act to, among other things, 
better protect stratospheric ozone (Public Law No. 101-549, November 
15, 1990) (the 1990 amendments). The 1990 amendments were drafted to 
complement, and be consistent with, our obligations under the Montreal 
Protocol (see section 614 of the Clean Air Act (42 U.S.C. 7671m)). 
Section 614(b) of the Clean Air Act provides that, in the case of a 
conflict between any provision of the Clean Air Act and any provision 
of the Montreal Protocol, the more stringent provision will govern. 
Section 604 of the Clean Air Act requires the phase-out of the 
production of CFCs by 2000 (42 U.S.C. 7671c),\6\ 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:
    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].
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    \6\In conformance with Decision IV/2, EPA issued regulations 
accelerating the complete phase-out of CFCs, with exceptions for 
essential uses, to January 1, 1996 (58 FR 65018, December 10, 1993).
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4. EPA's Implementing Regulations
    EPA regulations implementing the Montreal Protocol and the 
stratospheric ozone protection provisions of the 1990 amendments are 
codified in part 82 of title 40 of the Code of Federal Regulations (40 
CFR part 82). (See 40 CFR 82.1 for a statement of intent.) Like the 
1990 amendments, EPA's implementing regulations contain two separate 
prohibitions, one on the production and import of CFCs (subpart A of 40 
CFR part 82) and the other on the sale or distribution of products 
containing CFCs (40 CFR 82.66).
    The prohibition on production and import of CFCs contains an 
exception for essential uses and, more specifically, for essential 
MDIs. The definition of essential MDI at 40 CFR 82.3 requires that the 
MDI be intended for the treatment of asthma or COPD, be essential under 
the Montreal Protocol, and if the MDI is for sale in the United States, 
be approved by FDA and listed as essential in FDA's regulations at 
Sec.  2.125 (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 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\7\ 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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    \7\Section 314.108(a) (21 CFR 314.108(a)) defines ``active 
moiety'' as the molecule or ion, excluding those appended portions 
of the molecule that cause the drug to be an ester, salt (including 
a salt with hydrogen or coordination bonds), or other noncovalent 
derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological 
action of the drug substance. When describing the various essential 
uses, we will generally refer to the active moiety, for example, 
albuterol, as opposed to the active ingredient, which, using the 
same example, would be albuterol sulfate. 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 PROVENTIL HFA (among others). 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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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 for which there is no acceptable non-ODS alternative with the same 
active moiety. The process for removing the essential-use designation 
for such a drug must include 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) are: ``(i) 
Substantial technical barriers exist to formulating the product without 
ODSs; (ii) The product will provide an unavailable important public 
health benefit; and (iii) Use of the product does not release 
cumulatively significant amounts of ODSs into the atmosphere or the 
release is warranted in view of the unavailable important public health 
benefit.''
    The three criteria in Sec.  2.25(f)(1) are linked by the word 
``and''. Because the three criteria are linked by ``and'' (as

[[Page 53715]]

opposed to ``or''), failure to meet any single criterion satisfies the 
threshold under the regulation for determining 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 unusable to 
demonstrate that substantial technical barriers exist (1999 proposed 
rule at 47721).
    In applying the ``technical barriers'' criterion, we will be 
looking at the results of reformulation efforts for similar products, 
as well as statements made about the manufacturer's particular efforts 
to reformulate their product or products.
    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).
    In determining whether a drug product provides an otherwise 
unavailable important public health benefit, our primary focus is on 
the availability of non-ODS products that provide equivalent 
therapeutic benefits for patients who are currently using the CFC MDIs. 
If therapeutic alternatives exist for everyone using the CFC MDI, we 
would then determine that the CFC MDI does not provide an otherwise 
unavailable important public health benefit. In the case of epinephrine 
MDIs, the fact that they are marketed over-the-counter (OTC), while the 
therapeutic alternatives for epinephrine MDIs are prescription drugs, 
makes the analysis of whether everyone is adequately served by the 
therapeutic alternatives more complicated.
    Under the third criterion, the threshold for removing the essential 
use designation is satisfied unless we find either: (1) The use of the 
product does not release cumulatively significant amounts of ODSs into 
the atmosphere; or (2) 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 an MDI would result 
in the product 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, the release of CFCs from epinephrine MDIs is 
currently significant and as the phase-out of ODSs continues throughout 
the world, the significance of the quantities of CFCs released by 
epinephrine MDIs will increase.
    In applying the first part of the third criterion, we are guided by 
previous policy statements. 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, March 17, 
1978). As part of that evaluation, FDA concluded that the continued use 
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 that take 
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 for newly produced or imported CFCs (see 71 FR 
58504 (October 4, 2006)). Although it may appear to some that the CFCs 
released from MDIs represent insignificant quantities of ODSs, and 
therefore should be exempt, 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 
epinephrine MDIs is cumulatively significant.
    Given this proposed finding that the first part of the third 
criterion is not satisfied, the threshold for the removal of the 
essential-use designation for epinephrine under Sec.  2.125(f)(1)(iii) 
is met if we also find that the second part of the third criterion is 
not satisfied: it provides an otherwise unavailable important public 
health benefit which warrants the cumulatively significant release of 
the ODS.
    As noted previously, because the three criteria in Sec.  
2.125(f)(1) are linked by the word ``and,'' failure to meet any single 
criterion may result in a determination that the use is not essential. 
Accordingly, if we find that the product fails to provide an otherwise 
unavailable important health benefit (criterion two), this would meet 
the threshold under the regulation for a finding that the use of the 
product is not essential, and we would not necessarily need to reach 
the last step under the third criterion (balancing the important health 
benefit against the release of the ODS to determine if the release is 
warranted). Assuming, however that we do analyze the third criterion, 
then, because of our tentative conclusion that the release of ODSs from 
epinephrine MDIs is cumulatively significant, we would need to conduct 
the balancing inquiry under the second part of the third criterion. We 
will discuss our tentative conclusions on how the second part of the 
third criterion applies to OTC epinephrine MDIs in section V.C of this 
document.
    The criteria in Sec.  2.125(g)(2) (which refers to those found in 
Sec.  2.125(f)(1)) that we are using in this rulemaking are different 
from those in Sec.  2.125(g)(3) and (g)(4). Section 2.125(g)(2) 
specifically addresses the situation where there is no marketed non-ODS 
product containing the active moiety listed as an essential use, while 
Sec.  2.125(g)(3) and (g)(4) apply to situations where there is at 
least one marketed non-ODS product with the listed active moiety. 
Section 2.125(g)(2) permits FDA to remove an essential use even if a 
current essential-use active moiety is not reformulated, provided that 
sufficient alternative products exist to meet the needs of patients, 
because the essential use would no longer provide an otherwise 
unavailable important health benefit. Therefore, the analysis we use 
here is not identical to the analysis we used under Sec.  2.125(g)(4) 
in the recent rulemaking to remove the essential use for albuterol (70 
FR 17168, April 4, 2005). However, the basic concern of protecting the 
public health underlies all of the criteria. Therefore, our analyses 
are similar, and we have found it useful to borrow concepts from the

[[Page 53716]]

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).

III. Effective Date

    We are proposing that any rule finalizing the removal of the 
essential use for OTC epinephrine MDIs have an effective date of 
December 31, 2010. Because there are therapeutic alternatives which are 
marketed as prescription drugs, in determining the appropriate 
effective date for this rulemaking, we will consider both: (1) Whether 
adequate time exists to provide patient education for users of OTC 
epinephrine MDIs, particularly those who do not consult doctors, 
pharmacists, and other health care professionals; and (2) whether 
adequate production capacity and supplies are available to meet the 
new, presumably increased, demand for the therapeutic alternatives once 
OTC epinephrine MDIs are no longer sold.
    Patient education for any transition away from OTC epinephrine MDIs 
presents unique concerns. Much of the thinking about patient education 
on the transition from CFC MDIs has focused on the dissemination of 
information through physicians, pharmacists, and other health care 
professionals. This information could be given orally by health care 
professionals, or the information could be available in the 
professionals' offices or pharmacies for patients to read. Because 
epinephrine MDIs are sold OTC, many purchasers will not interact with a 
health care provider. New avenues of communication will have to be 
opened to reach all OTC epinephrine MDI users. Many OTC epinephrine MDI 
users may need to be provided information to help them select a 
physician. Some OTC epinephrine MDI users who face economic barriers to 
appropriate health care may need even more time to find and avail 
themselves of free or low-cost health care and prescription drug 
programs (see section V.B.2.b of this document). These factors have led 
us to believe that a transition away from OTC epinephrine MDIs may be 
more difficult than transitions in which patients change from one 
prescription drug to another prescription drug, and accordingly that 
any effective date for such a rulemaking should provide for a longer 
transition period than the transition period for the recently published 
proposed rule to eliminate the essential-use designation for MDIs 
containing flunisolide, triamcinolone, metaproterenol, pirbuterol, 
albuterol and ipratropium in combination, cromolyn, and nedocromil (72 
FR 32030, June 11, 2007). We have, therefore, tentatively concluded 
that the December 31, 2010, effective date would be appropriate for a 
final rule removing the essential-use designation for OTC epinephrine 
MDIs. We invite comment on the proposed effective date of December 31, 
2010, as well as possible alternative effective dates, such as December 
31, 2011 or 2012.
    In determining an appropriate effective date, we have kept in mind 
that albuterol MDIs that use the hydrofluoroalkane HFA-134a (HFA) as a 
propellant are a primary therapeutic alternative to OTC epinephrine 
MDIs, because both drugs are in the same therapeutic class (short-
acting inhaled beta-agonist bronchodilators), albuterol is the only 
member of the class available in an HFA MDI, and no members of the 
class are available as a DPI.\8\ Sales of OTC epinephrine MDIs have 
totaled approximately 4.5 million MDIs a year. We are confident that 
there will be adequate supplies of albuterol HFA MDIs to meet the needs 
of all users of albuterol CFC MDIs by December 31, 2008 (the date on 
which albuterol MDIs will no longer be designated an essential use).\9\ 
Although we have limited data on production increases above current 
demand for 2009, 2010, and later, we believe that by December 31, 2010, 
albuterol HFA production will be able to meet any increased demand 
caused by this rulemaking. This proposed effective date is 1 year later 
than the effective date that we proposed in the recently published 
proposed rule to eliminate the essential-use designation for MDIs 
containing flunisolide, triamcinolone, metaproterenol, pirbuterol, 
albuterol and ipratropium in combination, cromolyn, and nedocromil (72 
FR 32030, June 11, 2007). As we said in that proposed rule, many of the 
patients using some of those drugs would switch to albuterol HFA 
inhalers. We believe that the additional time required for the needed 
patient education on alternatives to OTC epinephrine MDIs will also 
provide additional time to scale up production of albuterol HFA MDIs. 
This additional time should provide greater assurance that there will 
be adequate supplies of albuterol HFA MDIs for all patients who use 
them. We specifically invite comments from manufacturers of albuterol 
HFA MDIs on this issue.
---------------------------------------------------------------------------

    \8\Neither HFA MDIs nor DPIs release ODSs. HFA MDIs and DPIs are 
generally considered to be the non-ODS drug products that are most 
comparable to CFC MDIs in terms of portability and ease of use.
    \9\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.
---------------------------------------------------------------------------

    In proposing a December 31, 2010, effective date, we expect that 
2010 would be a transition year characterized by declining production 
of OTC epinephrine MDIs. If a December 31, 2010, effective date is 
established by this rulemaking, we anticipate that other administrative 
actions taken by EPA and FDA would reflect the concept of 2010 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, 17179, April 4, 2005). We 
believe that this consideration is appropriate for this rulemaking 
also. In evaluating the period of time needed to sell remaining stocks 
of OTC epinephrine MDIs, a factor that must be considered is the 
expiration dating for the relevant products. Both PRIMATENE MIST and 
the OTC epinephrine MDIs made by Armstrong Pharmaceuticals, Inc. 
(Armstrong) have expiration dates set at 24 months after manufacture. 
Drug products are not generally sold right up to the expiration date. 
Drugs are generally sold well before the expiration date, allowing the 
purchasers a significant amount of time to use the drug before it 
reaches its expiration date; therefore, we believe that all OTC 
epinephrine MDIs manufactured prior to publication of a final rule 
based on this proposal should be sold by December 31, 2010.
    We are tentatively proposing a December 31, 2010, effective date 
based on our preliminary assumption that there will not be an inhaled 
epinephrine OTC drug product that does not contain ODSs on the market 
in the foreseeable future. We strongly urge interested individuals to 
submit detailed information on whether inhaled-epinephrine will be 
available in a non-ODS formulation and when a non-ODS inhaled 
epinephrine product can reasonably be expected to be on the market. We 
also specifically request comment on whether publishing a final rule or 
the effective date of any such rule should be affected by the 
additional information that we receive concerning the availability of 
an inhaled epinephrine OTC drug product that does not contain ODSs.

IV. 2006 NDAC/PADAC Meeting

    Section 2.125(g)(2) requires that we consult an advisory committee 
before we remove an essential-use designation when there is no non-ODS 
product with the same active moiety. We consulted the Nonprescription 
Drug Advisory

[[Page 53717]]

Committee (NDAC) and the Pulmonary-Allergy Drugs Advisory Committee 
(PADAC) on the essential-use status of OTC MDIs containing epinephrine 
at a joint committee meeting held on January 24, 2006 (NDAC/PADAC 
meeting).\10\ Presentations were made by representatives of Wyeth 
Consumer Health (Wyeth), two patient advocacy and public policy groups, 
and physician organizations. Seven of the joint committee members 
recommended that epinephrine be retained as an essential use, while 
eleven members recommended that the essential-use designation be 
removed. The opinions expressed by the NDAC and PADAC (NDAC/PADAC) 
members and other participants in the NDAC/PADAC meeting will be 
discussed below.
---------------------------------------------------------------------------

    \10\The transcript of the NCPAC/PADAC meeting, slides used in 
presentations made at the joint meeting, and written material 
presented to the committees for the meeting may be found at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/ac/cder06.html
.

---------------------------------------------------------------------------

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

V. Epinephrine

    Epinephrine is a short-acting adrenergic bronchodilator used in the 
treatment of asthma. A new drug application (NDA) for OTC epinephrine 
MDIs was approved in 1956. Epinephrine was included in the 1978 rule 
under the provision designating ``[m]etered-dose adrenergic 
bronchodilator human drugs for oral inhalation'' as an essential use. 
Approved NDAs for OTC epinephrine MDIs are currently held by Wyeth and 
Armstrong, (a subsidiary of Amphastar Pharmaceuticals, Inc.). Wyeth 
markets their OTC epinephrine MDIs as PRIMATENE MIST, while Armstrong 
labels their product as ``house brands'' for certain retail pharmacies. 
Epinephrine MDIs are the only MDIs for treatment of asthma (or any 
other disease) that are approved for OTC use.\11\ Customers do not need 
a prescription from a health care provider to purchase OTC epinephrine 
MDIs. Wyeth presented data at the NDAC/PADAC meeting estimating that 2 
to 3 million people with asthma use OTC epinephrine MDIs (meeting 
transcript p. 51, Wyeth slide 19). Based on the 2005 National Health 
Interview Survey (NHIS), the Centers for Disease Control and 
Prevention's National Center for Health Statistics (NCHS) has estimated 
that 7.7 percent of the U.S. population currently has asthma (Ref. 1). 
Using an estimate of the U.S. population of 300 million,\12\ we can 
estimate that approximately 23 million people in the United States 
currently have asthma.
---------------------------------------------------------------------------

    \11\The OTC monograph for Cold, Cough, Allergy, Bronchodilator, 
and Antiasthmatic Drug Products permits OTC marketing of epinephrine 
in a hand-held rubber nebulizer for use in the treatment of asthma 
(21 CFR part 341). While this product did not use CFCs, all of the 
information available to us shows that such products are no longer 
marketed. The OTC monograph for Cold, Cough, Allergy, 
Bronchodilator, and Antiashtmatic Drug Products permits OTC 
marketing of oral dosage forms of ephedrine. Ephedrine is not 
available in an MDI. In addition, OTC ephedrine products have a 
slower onset of action than epinephrine MDIs, and therefore they 
cannot be considered a suitable alternative to OTC epinephrine MDIs.
    \12\The U.S. Census' estimate of the U.S. Population was 
299,948,296 as of October 10, 2006, 1804 GMT, with an estimated net 
increase in the population of 1 person every 11 seconds. See http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.census.gov/population/www/popclockus.html
.

---------------------------------------------------------------------------

    Epinephrine is also an active ingredient in many other drug 
products. It is used in a self-injectable dosage form for treatment of 
severe allergic reactions. EPIPEN is an example of epinephrine in this 
dosage form. Epinephrine is also available OTC as a solution for use in 
an electrically powered nebulizer for the treatment of asthma. This 
rulemaking will not affect the availability of these non-MDI drug 
products.

A. Do Substantial Technical Barriers Exist to Formulating Epinephrine 
Products Without ODSs?

    As we said in the 2002 final rule, we intend the term ``technical 
barriers'' to refer to difficulties encountered in chemistry and 
manufacturing. To demonstrate that substantial technical barriers 
exist, it will have to be established that all available alternative 
technologies have been evaluated and why each alternative is unusable 
(2002 final rule at 48373). Wyeth did not present any significant data 
on technical barriers to formulating an inhaled epinephrine product 
without ODSs at the NDAC/PADAC meeting. At the NDAC/PADAC meeting, 
Wyeth said that they had been trying to reformulate or outsource their 
product for over a decade and mentioned unacceptable prototypes, but 
they mentioned that a significant difficulty in reformulation was 
avoiding designs that would infringe patents held by 3M Co. (3M) and 
GlaxoSmithKline (GSK) (meeting transcript, pp. 86-88). It should be 
kept in mind that patent licenses and contract manufacturing by patent 
holders have been very frequently used during the current transition 
away from CFC MDIs. An example of this is 3M's manufacture of, and 
patent licensing for, albuterol HFA MDIs. 3M holds patents on HFA MDI 
technology and it also manufactures PROVENTIL HFA (albuterol) MDIs for 
sale by Schering Corporation (Schering). Ivax Corp. has licensed HFA 
MDI technology patents from 3M and manufactures PROAIR HFA (albuterol) 
MDIs. We have not been presented with any evidence that Wyeth could not 
obtain patent licenses or arrange for contract manufacturing by a 
patent holder.
    At least nine different active moieties have been formulated as HFA 
MDIs for the treatment of asthma and COPD in the United States and 
abroad.\13\ HFA MDIs have been formulated with both suspensions and 
solutions. Albuterol and levalbuterol are close chemical analogs of 
epinephrine. Given the chemical similarity between them and the success 
with reformulating albuterol (as albuterol sulfate in PROAIR HFA, 
PROVENTIL HFA, and VENTOLIN HFA) and levalbuterol (as levalbuterol 
tartrate in XOPENEX), there appears to be no technical reason why 
epinephrine cannot be successfully reformulated into an HFA MDI. Wyeth 
said at the NDAC/PADAC meeting that early attempts to formulate an 
epinephrine HFA MDI were characterized by higher pressures and 
quantities of alcohol that provided unacceptable sensations to users of 
the product, including an unpleasant taste of alcohol\14\ (Wyeth 
briefing material, p. 1-7; meeting transcript, p. 87). These do not 
seem to represent technical barriers; rather they seem to be the type 
of problems routinely encountered in the development of a new product 
that require prototypes to be reengineered. Indeed, Wyeth did not seem 
to truly believe that there were technical barriers to development of 
an epinephrine HFA MDI, predicting that they would have a product 
developed and clinically tested by 2011, and attributing their earlier 
difficulties to a lack of in-house expertise (Wyeth briefing material, 
p. 1-7). FDA has had experience with several firms reformulating 
products from ODS containing MDIs to non-ODS products. Based on our 
experience with those reformulation efforts, it seems highly unlikely 
that a non-ODS inhaled epinephrine drug product will be

[[Page 53718]]

developed and clinically tested until well after 2011. As we mentioned 
before, we are particularly interested in receiving comment on current 
efforts on developing non-ODS inhaled epinephrine drug products that 
would be suitable for OTC sale, including any discernible impediments 
to such efforts.
---------------------------------------------------------------------------

    \13\The nine moieties formulated as HFA MDIs are albuterol, 
beclomethasone, budesonide, fenoterol, fluticasone, flunisolide, 
formoterol, ipratropium, and salmeterol. While a salmeterol DPI 
(SEREVENT) has been approved in the United States, salmeterol HFA 
MDIs have only been approved overseas. There are no approved 
fenoterol or formoterol products in the United States, but fenoterol 
HFA MDIs and formoterol HFA MDIs have been approved in several 
foreign countries.
    \14\PRIMATENE MIST contains 35 percent alcohol and other MDIs 
also contain alcohol. Wyeth did not reveal the amount of alcohol in 
their prototype or explain why the amount of alcohol could not be 
reduced or the taste otherwise minimized.
---------------------------------------------------------------------------

    Wyeth said that an epinephrine DPI was not a viable alternative to 
the epinephrine MDI, but without any elaboration (Wyeth briefing 
material, p. 1-7). The DPI has proven to be a very successful dosage 
form. At least nine different moieties have been formulated as DPIs for 
treatment of asthma and COPD in the United States or overseas.\15\ 
Alkermes, Inc., developed a large dose epinephrine DPI for 
investigations into using an epinephrine DPI for treatment of 
anaphylaxis. While this product has not been approved by FDA and it is 
not intended for the treatment of asthma, it does show that epinephrine 
can be formulated into a DPI (Refs. 2 and 3).
---------------------------------------------------------------------------

    \15\The nine moieties formulated as DPIs are albuterol, 
beclomethasone, budesonide, fluticasone, formoterol, mometasone, 
salmeterol, terbutaline, and tiotropium. While albuterol HFA MDIs 
have been approved in the United States, albuterol DPIs are not 
currently marketed in the United States, but are approved overseas. 
A terbutaline CFC MDI and other terbutaline products have been 
approved in the United States, but terbutaline DPIs have only been 
approved overseas. There are no approved formoterol products in the 
United States, but formoterol DPIs have been approved in several 
foreign countries.
---------------------------------------------------------------------------

    Thus, all of the evidence before us indicates that epinephrine can 
be formulated into a drug product that does not release ODSs. The facts 
presented by Wyeth at the NDAC/PADAC meeting did not indicate that 
there are technical barriers to the development of a non-ODS 
epinephrine product, despite the conclusions that Wyeth presented at 
the meeting. However, as noted previously, we are especially interested 
in receiving public comment concerning any such technical barriers that 
may exist.

B. Do OTC Epinephrine MDIs Provide an Otherwise Unavailable Important 
Public Health Benefit?

    Because we have reached a tentative conclusion that there are no 
substantial technical barriers to formulating epinephrine into a non-
ODS product, we do not believe it is necessary at this time to reach a 
conclusion on the public health benefits of OTC epinephrine MDIs. 
However, this issue was discussed at length at the NDAC/PADAC meeting 
and we are keenly interested in the potential public health benefits of 
having epinephrine MDIs available OTC. We will evaluate and weigh those 
public health benefits before issuing any final rule on the essential-
use designation for epinephrine. Accordingly, we will discuss some of 
the questions on which we would be particularly interested in receiving 
comments that would be relevant in reaching a conclusion on the public 
health benefits of OTC epinephrine MDIs.
1. Does Epinephrine Provide a Greater Therapeutic Benefit Than Similar 
Adrenergic Bronchodilators?
    During the last several years, four prescription HFA MDIs with two 
different forms of albuterol have come onto the market:
     Albuterol sulfate MDI (PROAIR HFA);
     Albuterol sulfate MDI (PROVENTIL HFA);
     Albuterol sulfate MDI (VENTOLIN HFA); and
     Levalbuterol tartrate MDI (XOPENEX HFA).
    These products use HFA as a replacement for ODSs, which does not 
affect stratospheric ozone. Albuterol and epinephrine are both 
adrenergic bronchodilators. Albuterol MDIs are therapeutic alternatives 
to OTC epinephrine MDIs and are, by far, the most widely prescribed 
short-acting bronchodilators. To determine whether epinephrine provides 
an otherwise unavailable important public health benefit, we should 
compare OTC epinephrine MDIs to albuterol HFA MDIs. The labeled 
indication for the OTC epinephrine MDIs is ``for temporary relief of 
occasional symptoms of mild asthma.'' The comparable labeled indication 
for the albuterol HFA MDIs is ``for treatment or prevention of 
bronchospasm with reversible obstructive airway disease.'' OTC 
epinephrine MDIs and three of the albuterol HFA MDIs are indicated for 
adults and children 4 years of age and older.\16\ The labeled 
indications for the albuterol HFA MDIs cover all patients described in 
the labeled indication for OTC epinephrine MDIs.
---------------------------------------------------------------------------

    \16\PROAIR HFA is indicated for adults and children 12 years of 
age and older.
---------------------------------------------------------------------------

    Clinical data presented by a representative of Wyeth at the NDAC/
PADAC meeting indicated that OTC epinephrine MDIs may be slightly 
quicker to onset of action than albuterol MDIs, but they have a 
significantly shorter duration of action (Wyeth briefing statement at 
p. 1-9). The slightly quicker onset of action may explain why some 
people with asthma describe OTC epinephrine MDI as working better than 
prescription drugs. The slightly quicker onset of action is a 
pharmacodynamic assessment, but there are no clinical data to support a 
conclusion that this perceived quicker relief provided by epinephrine 
leads to better outcomes. Therefore, we do not believe that this 
represents a ``otherwise unavailable important public health benefit.''
    Wyeth presented another study of the treatment of nocturnal asthma 
that concluded that OTC epinephrine MDIs can ``achieve the same benefit 
as albuterol'' MDIs (Ref. 4, p. 533).\17\ However, as pointed out by 
NDAC/PADAC members, the frequency of doses of epinephrine used in this 
study were several times the amount approved in labeling (this was also 
true, but to a smaller degree, for albuterol in this study).\18\ 
Further, this was a limited study with only eight subjects completing 
the evaluations. These elements made the utility of this study for 
purposes of this rulemaking very questionable, and even if these 
questions were ignored, the study shows, at best, that epinephrine is 
roughly as effective as, but not more effective than, albuterol.
---------------------------------------------------------------------------

    \17\The author of the study report did not appear to view the 
study as supporting the OTC use of epinephrine MDIs, stating that 
the results of the study do not imply that it is safe for people 
with asthma to self-medicate without physician intervention and that 
results of the study indicate that nonprescription epinephrine 
presents the same risk of delaying patients from seeking medical 
care as other beta-agonists. The report concluded with a statement 
that a larger study is required before epinephrine can be 
recommended as rescue therapy when a prescription beta2-
agonist MDI is not accessible (Ref. 3).
    \18\The author of the study report recognized that the large 
number of actuations might be impractical (Ref. 43).
---------------------------------------------------------------------------

    In the United States, the generally recognized standard of care for 
asthma is set forth in the National Heart, Lung, and Blood Institute's 
Expert Panel Report 2: Guidelines for the Diagnosis and Management of 
Asthma (EPR-2) (Ref. 5).\19\ The National Heart, Lung, and Blood 
Institute is one of the National Institutes of Health. In the 2002 
update to EPR-2 (Ref. 6), we find the latest updates to the standard.
---------------------------------------------------------------------------

    \19\The Guidelines represent best practices and are recognized 
as the clinical standard of care for treatment of asthma. See, e.g., 
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.asthmanow.net/care.html; http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.colorado.gov/bestpractices/index.html; http://www.doh.wa.gov/CFH/asthma/
thma/
publications/plan/health-care.pdf.
---------------------------------------------------------------------------

    In several points in Wyeth's written, oral, and visual presentation 
for the NDAC/PADAC meeting, it was stated that use of epinephrine was 
consistent with the National Heart, Lung and Blood Institute's asthma 
treatment guidelines (Ref. 5) (frequently called the second Expert 
Panel Report or EPR-2), issued as part of the National Asthma

[[Page 53719]]

Education and Prevention Program.\20\ The EPR-2, as updated, is widely 
seen as representing the generally recognized standard of care for 
asthma in the United States.\21\ Wyeth stated in its written materials 
that epinephrine is not mentioned specifically in the EPR-2 (Wyeth 
briefing material, p. 1-8; meeting transcript, pp. 50-51; Wyeth slide 
18). FDA disagrees with these statements. The 2002 update to the EPR-2 
states that ``[n]onselective agents (i.e., epinephrine, isoproterenol, 
metaproterenol) are not recommended due to their potential for 
excessive cardiac stimulation, especially in high doses'' (Ref. 6, p. 
120). While recognizing the possibility that the concerns expressed in 
the EPR-2 about cardiovascular risk may be overstated (see Refs. 4 and 
9), we do not need to reach a conclusion on the relative cardiovascular 
risk of the use of epinephrine compared to the use of albuterol. FDA is 
unaware of any evidence comparing epinephrine and albuterol at 
recommended doses indicating that the cardiovascular safety of 
epinephrine is better than that of albuterol.
---------------------------------------------------------------------------

    \20\EPR-2 was updated in 2002 (Ref. 6) (EPR--Update 2002). 
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 FDA 
regulations (21 CFR part 314).
    \21\The EPR-2 is very similar to other published standards of 
care (See the Australian Asthma Management Handbook: 2002 (Ref. 7) 
and the ``Canadian Asthma Consensus Report, 1999'' (Ref. 8).
---------------------------------------------------------------------------

    A voting consultant with NDAC characterized the OTC epinephrine MDI 
as an ``inferior medicine'' (meeting transcript, p. 181). She admitted 
there was an absence of good data on the safety and efficacy of OTC 
epinephrine MDIs. Her opinions were shared by many members of the 
committees. NDAC/PADAC members who recommended that the essential use 
for OTC epinephrine MDIs be retained did not state that epinephrine was 
safer or more effective than albuterol. The evidence before us 
indicates that epinephrine is not safer or more effective than 
albuterol. The EPR-2 recommends against epinephrine's use. The 
consensus opinion at the NDAC/PADAC meeting was that OTC epinephrine 
MDIs presented no significant therapeutic advantage over albuterol 
MDIs. This leads us to tentatively conclude that OTC epinephrine MDIs 
do not provide a clinical benefit that is otherwise unavailable. If we 
intended to draw a conclusion about the public health benefits of OTC 
epinephrine MDIs, and if OTC epinephrine MDIs were prescription drugs, 
as albuterol HFA MDIs are, our analysis would be nearly complete. 
However, the epinephrine MDIs, PRIMATENE MIST and the Armstrong 
products, are the only MDIs for treatment of asthma that are marketed 
OTC. We, therefore, have to examine more questions on the possible 
public health benefits of the continued OTC marketing of epinephrine 
CFC MDIs.
2. Does OTC Marketing of Epinephrine MDIs Provide an Important Public 
Health Benefit?
    Our discussion on the public health benefit of OTC marketing of 
epinephrine is largely informed by the data presented and the opinions 
expressed at the NDAC/PADAC meeting.
    a. Is patient convenience an important public health benefit? Wyeth 
asserted at the NDAC/PADAC meeting that the convenience of patients 
having an OTC MDI for asthma provides an ``important public health 
benefit'' (meeting transcript, p. 66). Having this OTC product 
available would allow patients who run out of their prescribed 
medication and cannot get a refill authorization from their physician 
to go to the local store and purchase OTC epinephrine MDI. Wyeth 
presented data from a survey they had conducted indicating that one-
third of OTC epinephrine MDI users use it as their sole asthma 
medication, while two-thirds use it in addition to prescription drugs. 
The survey indicated that 55 percent of people with asthma who solely 
use OTC epinephrine MDIs for their asthma said that the OTC product is 
``easier and quicker to obtain.'' Fifty-eight percent of asthma 
patients who use both prescription drugs and OTC epinephrine MDIs say 
they purchase the OTC MDI when they either ``run out of my prescription 
medication'' or ``have an asthma attack and I don't have my 
prescription with me'' (Wyeth slide 36).
    Maintaining current valid prescriptions and supplies of prescribed 
drugs is a regular and sometimes onerous, but necessary, task for many 
patients with chronic diseases. It would certainly be more convenient 
for all of these patients if some sort of therapeutic alternative were 
available OTC. However, there are no OTC remedies for most serious 
diseases. Of note, patients with anaphylaxis to bee stings or peanuts 
can face sudden, life-threatening attacks if exposed to their relevant 
triggers. Yet epinephrine autoinjectors, such as EPIPEN, are not OTC 
products because of considerations that include the proper evaluation 
and treatment of such patients. No evidence has been presented to us, 
in the course of this rulemaking, to indicate how asthma differs from 
other serious diseases in a way that warrants having an OTC treatment 
available.
    These facts would support a conclusion that any added convenience 
of OTC availability of epinephrine for patients who have been 
prescribed drugs for the treatment of asthma, such as albuterol MDIs, 
does not provide an ``important public health benefit.''
    b. Do OTC epinephrine MDIs provide an important health benefit for 
people who have poor access to adequate health care? Wyeth and several 
members of NDAC and PADAC have stated that a significant number of 
people with asthma do not have adequate access to health care, and a 
significant number of these people with asthma use OTC epinephrine 
MDIs. To examine the public health benefit of OTC marketing of 
epinephrine MDIs we must examine (1) The number of people with asthma 
who use epinephrine because of inadequate access to health care 
providers able to diagnose asthma and prescribe treatments other than 
epinephrine, and (2) the extent that OTC epinephrine benefits these 
people. We are particularly interested in the public health benefits 
that may be provided to this population by having epinephrine MDIs 
available OTC. Any final conclusion we reach on the essential-use 
designation of epinephrine could be affected by data on the public-
health benefit contained in comments submitted in response to this 
proposed rule.
    Wyeth presented information at the NDAC/PADAC meeting from their 
2005 survey indicating that 22 percent of people with asthma did not 
have health insurance (Wyeth slide 31). Statistics from NCHS (Ref. 10) 
indicate that slightly less than 14.1 percent of the general population 
does not have health insurance. While the difference between 14.1 
percent and 22 percent is not significant for purposes of this 
document,\22\ it may be true that the percentage of people with asthma 
who are uninsured is higher than that of the general population. Wyeth 
also presented data indicating that 27 percent of people with asthma do 
not have health insurance that provides prescription drug benefits 
(Wyeth slide

[[Page 53720]]

31). However, lack of insurance does not necessarily equate to poverty 
and financial barriers to adequate health care. Approximately 18 
percent of uninsured Americans have household incomes of $75,000 or 
more, and another 17 percent have household incomes of $50,000 to 
$74,999 (Ref. 11).
---------------------------------------------------------------------------

    \22\The reason we say that the difference is not significant for 
purposes of this document is that so many of the numbers discussed 
represent such broad estimates that the difference between 14 
percent and 22 percent would not affect any conclusion. We are 
acutely aware that for the individuals and families involved, 
absence of health insurance is very significant.
---------------------------------------------------------------------------

    Other barriers to health care exist, such as lack of sick leave, 
transportation, and child care. However, we do not have any data that 
would be useful in determining how these barriers affect people with 
asthma and their use of OTC epinephrine MDIs.
    There is very little data about how barriers to health care affect 
use of OTC epinephrine MDIs. According to data provided by Wyeth, 
roughly two-thirds of OTC epinephrine MDI users use the MDIs in 
addition to prescription drugs, while one-third solely use OTC 
epinephrine MDIs (Wyeth slide 32). As discussed in section V.B.2.b of 
this document, a majority of the two-thirds of OTC epinephrine MDI 
users who also use prescription drugs do so for reasons of convenience. 
However, because the two-thirds of OTC epinephrine MDI users who also 
use prescription drugs apparently have adequate access to health care, 
we will focus, for this part of the document, on the one-third of OTC 
epinephrine MDI users who solely use OTC epinephrine MDIs. We have very 
little data on why patients use OTC epinephrine MDIs instead of 
prescribed drugs. At the NDAC/PADAC meeting Wyeth presented data from 
their 2005 Internet survey of people with asthma (Wyeth slide 35). The 
data are summarized in table 1 as follows:

 Table 1.--Most Frequent Reasons Cited by Sole OTC Epinephrine MDI Users
``Easier and quicker to obtain''                         55 percent
------------------------------------------------------------------------
``More reasonably priced''                               41 percent
------------------------------------------------------------------------
``I don't have health insurance''                        25 percent
------------------------------------------------------------------------
``I don't want to go to a doctor''                       25 percent
------------------------------------------------------------------------
``I don't have a doctor''                                21 percent
------------------------------------------------------------------------
``OTC drugs work better for me''                         11 percent
------------------------------------------------------------------------

    The basis for the ``more reasonably priced'' response in the survey 
is unclear. While the perception of a percentage of the survey 
participants may have been that OTC epinephrine was less costly, an 
accurate determination of the relative price of the OTC product 
compared to the prescription substitutes would require a complex 
analysis which could not be embodied in an informal Internet opinion 
survey. For example, it is not clear how respondents calculated the 
retail price of the prescription drug products that they compared to 
OTC epinephrine, if they were comparing comparable drug products, or 
the degree to which they factored health insurance co-payments or the 
availability of patient assistance programs into their price 
comparison. It is also unclear if the respondents viewed the cost of a 
visit to a physician to obtain a prescription as a part of the price of 
a prescription drug. Because it is not clear what this response 
actually means, it contributes little to our analysis of the possible 
public health benefits of epinephrine.
    As discussed at length at the NDAC/PADAC meeting, the response in 
the survey that ``OTC drugs work better for my asthma'' is not 
supported by adequate and well-controlled studies.
    The responses that may best inform an attempt to reach a low-end 
estimate of the percentage of people who solely use OTC epinephrine 
MDIs who do so because of barriers to health care are ``I don't have 
health insurance'' (25 percent), ``I don't want to go to a doctor'' (25 
percent), and ``I don't have a doctor'' (21 percent). Those stating 
absence of health insurance are describing a potential barrier to 
health care. The other two statements are more ambiguous. ``I don't 
want to go to a doctor'' may be an expression of a general aversion to 
going to doctors, it may be a manifestation of a desire not to confront 
a potentially serious illness, or it also may reflect that an asthmatic 
may not wish to go to a doctor because of lack of insurance or other 
barriers to health care. ``I don't have a doctor,'' may be similar to 
``I don't want to go to a doctor,'' or it may reflect a person who has 
not yet chosen a doctor, because of a recent arrival in a locality or 
because the person has stopped seeing a previous doctor.
    The survey participants were permitted to select more than one 
reason for solely using an OTC epinephrine MDI. While we know that 
participants gave more than one answer (the sum of the answers is 178 
percent), we do not know how the responses overlapped with each other. 
We will assume, for now, that the 25 percent responding ``I don't have 
health insurance'' represents users of OTC epinephrine who do so 
because of barriers to health care. We realize that this may 
underrepresent those people with asthma whose responses of ``I don't 
want to go to a doctor,'' and ``I don't have a doctor'' also reflected 
a barrier to health care. However, any underestimation may be 
counterbalanced by other factors, such as:
     Approximately 18 percent of uninsured Americans have 
household incomes of $75,000 or more, and another 17 percent have 
household incomes of $50,000 to $74,999 (Ref. 11). While uninsured, 
these people would not necessarily face barriers to health care.
     According to Wyeth's 2005 Internet survey, 28 percent of 
people with asthma who solely use OTC epinephrine MDIs have visited a 
doctor in the previous year for treatment of asthma; these patients 
presumably have access to health care.
    We do not know how these two points relate to the numbers from 
Wyeth's 2005 Internet survey giving the reasons that people with asthma 
purchase OTC epinephrine MDIs. As was frequently noted at the NDAC/
PADAC meeting, the debate over the essential-use status of epinephrine 
is hobbled by a paucity of data, and we note here that we are 
especially interested in receiving public comments and any available 
data concerning this issue. The fact that this is an Internet survey, 
and that we know little about how the survey was conducted, raises 
questions about its reliability. However, in the absence of better 
data, we estimate that 25 percent of people with asthma who solely use 
OTC epinephrine MDIs for treatment of asthma do so because of barriers 
to

[[Page 53721]]

health care. Since two-thirds of people who use OTC epinephrine MDIs 
also use prescription drugs to treat their asthma, somewhat less than 9 
percent of all people with asthma using OTC epinephrine MDIs do so 
because of barriers to health care. These figures appear to be the best 
low-end estimate we can derive from the limited data we have before us. 
Referring to their 2005 Internet survey, Wyeth stated that 60 percent 
of people with asthma solely using OTC epinephrine MDIs replied that 
they had a ``prescription medication coverage plan'' (Wyeth slide 33). 
This figure is lower than the 66 percent who replied that they had 
insurance covering physicians visits. This means that approximately 40 
percent of OTC epinephrine MDI users who solely use the product did not 
have prescription drug coverage. This seems a reasonable high-end 
estimate of the percentage of people with asthma solely using OTC 
epinephrine MDIs who do so because of barriers to health care. This 
estimate is over-inclusive because it includes people with asthma whose 
income would mean that absence of insurance does not present a barrier 
to health care and patients with asthma that have access to free or 
low-priced drugs through doctor's samples or free and low-priced drug 
programs. The fact that lack of insurance coverage for prescription 
drugs does not perfectly reflect barriers to health care is shown by 
the fact, according to Wyeth's 2005 survey, that 19 percent of asthma 
patients who solely use prescription drugs do not have insurance 
coverage for prescription drugs. While it is over-inclusive for some 
groups, the higher figure may do a better job of capturing people who 
face other poorly quantified barriers to health care, such as lack of 
sick leave, transportation, or child care.
    We have arrived at an estimate that between 25 percent and 40 
percent of people with asthma who solely use OTC epinephrine MDIs, and 
therefore between 9 percent and 14 percent of all people with asthma 
that use OTC epinephrine MDIs, do so because of barriers to health 
care. We have also estimated that 1.7 to 2.3 million people with asthma 
use OTC epinephrine MDIs. This estimate is based on data provided by 
Wyeth at the NDAC/PADAC meeting, although Wyeth reached a different 
conclusion based on the same numbers.\23\ Applying our estimate that 
between 9 percent and 14 percent of all people with asthma who use OTC 
epinephrine MDIs do so because of barriers to health care to our 
estimate that 1.7 to 2.3 million people with asthma use OTC epinephrine 
MDIs, we arrive at an estimate that between 150,000 and 320,000 people 
with asthma who use OTC epinephrine MDIs do so because of barriers to 
health care. At the NDAC/PADAC meeting, a representative for several 
Hispanic-American health policy organizations presented information 
about the high incidence of asthma among Hispanic-Americans and 
African-Americans (meeting transcript, pp. 162 to 169). The 
representative opposed removing epinephrine's essential-use 
designation, stating that it would have a serious adverse impact on 
people with asthma who face barriers to health care, and that this 
impact would be disproportionately felt by Hispanic-Americans.
---------------------------------------------------------------------------

    \23\At the NDAC/PADAC meeting Wyeth presented estimates that 15 
to 20 percent of adults with asthma use OTC epinephrine (Wyeth slide 
32). Applying these percentages to the number of adults who have 
asthma, they estimated that 2 to 3 million people use OTC 
epinephrine MDIs at any given time. Wyeth appears to have made a 
mistake. If we look at the 1993 ACNielsen study (Wyeth slide 29) 
where the study population was adults, it appears that Wyeth 
compared the number of respondents who reported using an OTC asthma 
drug (557) to the number of respondents who reported having an 
asthma incident in the previous 12 months (2,713). If we divide 557 
by 2,713, we get 0.205 or 20 percent. The number of adults who have 
asthma is substantially higher than the number who have had an 
asthma incident in the previous 12 months; for 2004 the numbers are 
14.4 million and 7.7 million respectively (Ref. 35). Applying 15 to 
20 percent to the number of adults with asthma would result in a 
significant inflation of the number of OTC epinephrine MDI users. 
Applying 15 to 20 percent to the number of adults who have had an 
asthma incident in the previous 12 months gives us an estimate of 
1.7 to 2.3 million people using OTC epinephrine MDIs. We believe 
that this estimate is more accurate than the 2 to 3 million 
estimate.
---------------------------------------------------------------------------

    According to the 2002 NHIS (Ref. 12), 7.2 percent of Non-Hispanic 
Whites in the United States had asthma, while the prevalence of asthma 
in Non-Hispanic Blacks was 9.5 percent and the corresponding figure for 
Non-Hispanic American Indians was 9.9 percent. The incidence of asthma 
among all Hispanics in the United States (4.9 percent) was lower than 
the incidence for the general population (7.2 percent), but the rate 
for Puerto Ricans was markedly higher at 13.1 percent.
    The National Health Care Disparities Report (Ref. 13) (2005 NHCDR) 
(which was mentioned by the speaker), indicates that Hispanic-Americans 
have significantly worse access to health care in terms of numbers of 
uninsured persons (Ref. 13, p. 92) having a usual source of care (a 
facility where one regularly receives care) (Ref. 13, p. 94), and 
having a usual primary care provider (a doctor or nurse from whom one 
regularly receives care) (Ref. 13, p. 95). Other portions of the 2005 
NHCDR provide information about asthma counseling in community health 
centers (Ref. 13, p. 135) and hospital admissions for pediatric asthma 
(Ref. 13, p. 150). None of the data in the 2005 NHDCR refer directly to 
the use of OTC epinephrine MDIs, so drawing specific conclusions from 
the 2005 NHCDR is difficult and subjective.
    Results from the National Cooperative Inner City Asthma Study 
(NCICAS) were referred to at the NDAC/PADAC meeting. NCICAS was 
sponsored by the National Institute of Allergy and Infectious Diseases 
(NIAID). NCICAS studied a treatment strategy for children with asthma 
living in inner-city census tracts where at least 20 percent of the 
population was below federal poverty guidelines. The study was 
conducted in eight study units located in seven cities across the 
United States. Wyeth presented information from a report from NCICAS, 
showing that 53 percent of the participants in the study reported 
difficulties in obtaining short term care for their children's asthma 
(Ref. 14). Ninety-three percent of the families studied in NCICAS were 
insured, largely by Medicaid, and while 50 percent of the families 
studied had to pay for health care (presumably a co-payment for most of 
the families), only 8 percent reported ``care costs too much'' as a 
barrier to health care. The intervention studied in the NCICAS was 
described as effective by one of the lead investigators (Ref. 15). 
Failure to refill prescriptions for asthma drugs was mentioned by Wyeth 
at the NDAC/PADAC meeting (meeting transcript, p. 113). Another report 
from NCICAS shows that 16 percent of caregivers reported not having a 
prescription filled for the child with asthma for whom they were caring 
(Ref. 16). This number compares favorably with compliance rates found 
in the general population.\24\ People do not always have prescriptions 
filled or take their medicine, regardless of income or health 
insurance.
---------------------------------------------------------------------------

    \24\See Refs. 17 and 18. The various studies used different 
methods of measuring non-compliance, so direct numeric comparisons 
are not possible.
---------------------------------------------------------------------------

    Dr. Carolyn Kercsmar, who participated in the NCICAS and is a 
member of PADAC, responded to Wyeth's description of the data from the 
NCICAS by saying, ``* * *[the children with asthma and the caregiver's] 
access were problems and didn't prevent them, it just hindered their 
care, and it was not just for acute care. It was for problems in 
accessing chronic care. Also, in that study, the vast majority of the 
patients had medication prescribed including albuterol as part of that 
study.* * *'' (meeting transcript, p. 141).

[[Page 53722]]

    The NCICAS data do not show that the availability of OTC 
epinephrine is needed for adequate treatment of asthma in poor inner-
city areas. While recognizing that the patient population studied was 
largely insured, we believe that comparable health care access options 
for low-income, non-insured patients are widely available. Programs 
that offer free or low-cost drugs, such as Schering's ``SP Cares 
program'' (see http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.schering-plough.com/schering_plough/corp/sp_cares.jsp
), and organizations that provide more comprehensive health 

care free or at low-cost, such as Communicare in South Carolina or the 
Puget Sound Neighborhood Health Centers in Washington, should be able 
to help lower economic barriers to access for people with asthma who 
use OTC epinephrine MDIs. Although we do not believe that all of the 
people currently using OTC epinephrine MDIs due to economic barriers to 
health care can or will avail themselves of these programs, we do 
believe that these programs are widely available, and that they can 
provide adequate alternatives to OTC epinephrine MDIs for many people 
with asthma. This should minimize some of the adverse impacts that may 
result from the absence of OTC epinephrine MDIs.
    In looking at the issue of OTC epinephrine MDIs as an alternative 
for people with asthma who face barriers to health care, it should be 
kept in mind that the retail price of OTC epinephrine MDIs is also a 
barrier to health care. In comparing the price of OTC epinephrine to 
that of its alternatives, we must keep in mind that OTC epinephrine 
MDIs, which cost approximately $13 per inhaler (meeting transcript, p. 
127), are not available through any low-cost drug plans. Prescription 
drugs obtained through these programs can be substantially less 
expensive than OTC epinephrine MDIs. To give one example, an eligible 
person obtaining VENTOLIN HFA (albuterol MDI) through GSK's ``Bridges 
to Access'' program would make a $10 co-payment for a 60-day supply of 
the drug; after 60 days no further co-payment is required (see http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://bridgestoaccess.gsk.com/index.html
). OTC epinephrine MDIs are more 

expensive than prescription drugs for people who can and do avail 
themselves of low-cost drug programs such as ``SP Cares'' and ``Bridges 
to Access.''
    A public speaker representing an asthma education and advocacy 
organization before the NDAC/PADAC meeting said that the longer 
duration of effect of albuterol and levalbuterol (and other newer 
prescription drugs that do not release ODSs) means that, while these 
drug are more expensive per MDI and per dose, they may be cheaper than 
OTC epinephrine MDIs when the price is calculated for each hour of 
relief (meeting transcript, pp. 159-160). While a drug's duration of 
action can affect the cost to a patient (or other payor) for therapy 
with the drug, we do not have the comparative clinical data to confirm 
the assertion made by the speaker.
    We believe that a small population of people with asthma who face 
barriers to health care may derive some benefit from having epinephrine 
MDIs available OTC. We also believe that utilization of programs 
providing low-cost or free prescription drugs may reduce, but not 
eliminate, the number of people with asthma facing barriers to health 
care who depend on OTC epinephrine MDIs. We are keenly interested in, 
and request comments on, the public health effect and costs that may 
result from the removal of OTC epinephrine MDIs from the market and how 
these programs may reduce any adverse impact on the public health. We 
will take under consideration and weigh carefully the potential 
consequences identified in public comments before issuing any final 
rule. In assessing the public health benefits of OTC epinephrine MDIs, 
the benefits of having the drug available OTC must be balanced against 
the potential risks, if any.
    c. Do risks of self-treatment of asthma outweigh the public health 
benefits that OTC epinephrine MDIs may provide? Much of the discussion 
at the NDAC/PADAC meeting focused on the issue of whether the risks of 
self-treatment of asthma outweigh the public health benefits that OTC 
epinephrine MDIs may provide. This issue could affect any decision we 
make on the essential-use status of OTC epinephrine MDIs. Accordingly, 
we will discuss some of the points raised at the NDAC/PADAC meeting and 
other information we feel may be relevant, and request comment on these 
issues to the extent that they apply to OTC epinephrine MDIs as an 
essential use of ODSs.
    i. Misdiagnosis of asthma. OTC epinephrine MDIs are only indicated 
for mild intermittent asthma. The approved labeling for OTC epinephrine 
MDIs states that the drug should only be used after a doctor has 
diagnosed asthma. This is because asthma can be a difficult disease to 
diagnose, even for physicians (Ref. 19). COPD, vocal chord dysfunction, 
heart disease, and many other illnesses can be misdiagnosed as asthma 
(see Ref. 5, p. 22).
    The results of a study presented by Wyeth at the NDAC/PADAC meeting 
indicated that 92 percent of those surveyed who solely use OTC 
epinephrine MDI stated that they had been diagnosed with asthma by a 
doctor (Wyeth slide 23, citing Ref. 20). We do not have data on how 
recently the diagnoses were made or on the current accuracy of the 
diagnoses. The study did state that only 47 percent of those who solely 
use OTC epinephrine MDIs currently had a primary caregiver for 
management of asthma (Ref. 20, p. 989), which would seem to indicate 
that at least some of the diagnoses were not particularly recent. The 
Internet survey presented by Wyeth at the NDAC/PADAC meeting indicates 
that 8 percent of purchasers of OTC epinephrine MDIs have not been 
diagnosed with asthma by a physician, and 28 percent of those who 
solely use OTC epinephrine MDI reported that they visited a doctor's 
office in the past year for treatment of their asthma (Wyeth slide 33). 
This would imply that 72 percent of people who solely use OTC 
epinephrine MDI had not seen a doctor in the past year for diagnosis 
and treatment of their asthma.
    Asthma is a variable disease that can either lessen or worsen in 
severity over time. A person previously diagnosed with asthma may be 
asymptomatic for long periods of time. A diagnosis of asthma and, more 
important, an evaluation of its severity made at some point in the past 
may no longer be accurate. Currently, follow-up visits are recommended 
at 1- to 6-month intervals after an initial diagnosis of asthma (EPR-2, 
Ref. 5, p. 87). A previous diagnosis of asthma does not necessarily 
mean that an individual's current asthma-like symptoms are caused by 
asthma, or that the individual's asthma is of the same severity as 
originally diagnosed. The likelihood of the previous diagnosis 
accurately reflecting the patient's current status would seemingly have 
to decrease the older the diagnosis and evaluation is. A study referred 
to by Wyeth at the NDAC/PADAC meeting said that ``self assessment of 
asthma severity may not be `on target,' especially among individuals 
who self-medicate their illness with nonprescription bronchodilators'' 
(Ref. 20, p. 992). It should be kept in mind that this was said about a 
group in which 92 percent had reported having been diagnosed by a 
physician as having asthma. This study was relatively small and, while 
potentially informative, it cannot be viewed as conclusive at this 
time.
    There are some additional data available on the potential 
misdiagnosis of the severity of asthma by purchasers of OTC epinephrine 
MDIs. Wyeth presented data at the NDAC/PADAC

[[Page 53723]]

meeting that 76 percent of OTC epinephrine MDI purchasers bought one or 
two OTC epinephrine MDIs a year. This indicates that 24 percent of 
purchasers bought three or more OTC epinephrine MDIs each year. A Wyeth 
web page (http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.primatene.com/faq/answers.asp#puffs) says that 

each 15 milliliters (mL) vial should deliver 270 puffs and the 22.5 mL 
of PRIMATENE MIST vial should deliver 405 puffs. The 15 ml vial is the 
most popular size of PRIMATENE MIST (meeting transcript, p. 127). The 
15 mL size is also the size manufactured for sale as house brands by 
Armstrong. If we look at three 15 mL MDIs used over a year-long period, 
we see that they would provide 16 puffs a week, a level of use that 
would indicate asthma incidents that are so frequent or severe that it 
no longer should be characterized mild intermittent asthma. We realize 
that some of the 24 percent of people who solely use OTC epinephrine 
MDIs and purchase three or more MDIs in a year may not be using all of 
the contents of the OTC epinephrine MDIs they purchase. They may be 
replacing lost MDIs or purchasing extra MDIs to keep at work or in a 
gym bag. It also should be noted that the use of two 22.5 mL vials a 
year also provides 16 puffs a week, again indicating a level of use 
that would not be associated with mild intermittent asthma.
    There is other evidence that purchasers of OTC bronchodilators were 
unable to correctly diagnose the severity of their asthma. A study was 
conducted in Australia of purchasers of albuterol (or salbutamol, as it 
is known in Australia and most of the rest of the world), a 
bronchodilator that was available both with and without a prescription 
in the State of New South Wales (Ref. 21). In that study, 95 percent of 
the surveyed purchasers who usually or always purchased albuterol 
without a prescription were undertreated for their asthma according to 
a relevant standard of care. We have not formed an opinion on the 
applicability of the study to the questions involved in this 
rulemaking. We realize that the study involved a different drug 
(albuterol), in a different country (Australia), and that the study is 
over 13 years old. However, we also recognize that the study may 
represent some of the better data currently available on the question 
of self-diagnosis of asthma by the purchasers of OTC bronchodilators.
    The evidence seems to suggest that many OTC epinephrine MDI 
purchasers are buying the drug based either on self-diagnosis or on an 
out-of-date physician's diagnosis.
    The issue of the accuracy of the diagnosis of asthma upon which a 
purchase of an OTC epinephrine MDI is made is very important in 
reaching a determination on the public health benefits of having the 
drug available OTC. While some evidence suggests that many purchasers 
of OTC epinephrine MDIs are doing so based on an inaccurate diagnosis 
of the severity of their asthma, we have not reached a conclusion on 
that evidence's weight and significance.
    ii. Undertreatment of asthma. Undertreatment of asthma can cause 
more frequent symptoms and attacks, missed work and school, activity 
limitations, a decline in lung health and function and, possibly, death 
(Ref. 9).
    As mentioned earlier, in the United States, the generally 
recognized standard of care for asthma is set forth in the EPR-2 (Ref. 
5). In the 2002 update to EPR-2 (Ref. 6) we find the latest updates to 
the standard. Asthma is divided into four classes of severity, which 
correspond to treatment ``steps.'' More severe classes of asthma are 
defined by greater frequency of symptoms during the day and night, 
lower peak expiratory flow (PEF) and forced expiratory volume in 1 
second (FEV1) (both are measurements of how well a patient can exhale 
using the greatest effort), and higher variability in PEF measurements 
over the course of a day.
    As the severity of a patient's asthma increases, treatment becomes 
more aggressive: For mild persistent asthma, daily use of an inhaled 
corticosteroid (available only by prescription) is recommended; if the 
patient has moderate persistent asthma, higher doses of inhaled 
corticosteroids and/or inhaled corticosteroids with a long-acting beta-
agonist are recommended; and for severe persistent asthma, still higher 
doses of inhaled corticosteroids are recommended in conjunction with a 
long-acting bronchodilator (available only by prescription).
    If a patient's asthma becomes more severe, treatment should become 
more aggressive, and if the asthma is well controlled, a physician 
should generally try to reduce the quantity of drugs being taken in 
order to provide good control with the minimum quantity of drugs. This 
approach is characterized as a ``stepwise approach for managing 
asthma'' (EPR 2002 Update, Ref. 6, Appendix A-1).
    No daily medication is recommended for mild intermittent asthma, 
but the EPR-2 recommends the use of a short-acting inhaled 
beta2-agonist bronchodilator, as needed to treat the 
occasional bronchospasm. Albuterol is a short-acting inhaled 
beta2-agonist bronchodilator and albuterol MDIs are the most 
widely prescribed ``rescue inhalers'' in the United States. The EPR-2 
does not recommend nonselective short-acting beta-agonist 
bronchodilators as rescue inhalers, but rather they recommend use of an 
inhaled short-acting beta2 selective agonist. Beta-receptors 
are adrenergic sites in the autonomic nervous system in which 
physiological responses occur when agents, in this case beta-agonists, 
are bound to the receptor. Activation of beta-receptors causes various 
reactions, including relaxation of the bronchial muscles and an 
increase in the rate and force of cardiac contraction. The beta-
receptors are subdivided into beta1, located primarily in 
the heart and intestinal smooth muscle, and beta2, more 
localized to bronchial, vascular, and uterine smooth muscles. 
Epinephrine is a non-selective beta-agonist which affects both the 
beta1 and beta2-receptors so that it affects both 
heart and bronchial smooth muscles (as well as the intestinal, 
vascular, and uterine smooth muscles). Beta2 selective 
agonists, such as albuterol, have less of an effect on the heart than 
beta1 and non-selective beta-agonists have. Epinephrine's 
lack of selectivity has caused concerns about its effect on the heart, 
but the limited data we have before us do not indicate that use of OTC 
epinephrine MDIs is associated with a greater risk of significant 
adverse cardiovascular events.
    The question of undertreatment of asthma for purchasers of OTC 
epinephrine MDIs is not confined to people with asthma who solely or 
primarily use OTC epinephrine MDIs. The level of usage of short-acting 
beta2-agonists is a factor that should be monitored by 
physicians treating asthma patients (EPR-2, Ref. 6, p. 35). Increased 
usage may often indicate the need for treatment being stepped up, while 
decreased usage may indicate that treatment could be stepped down. The 
availability of OTC epinephrine MDIs allows patients to purchase a 
short-acting beta-agonist without a prescription. It seems possible 
that this may deny important information to the health care provider as 
to the accurate assessment of a patient's use of rescue inhalers. We 
are unaware of any data that directly address this issue.
    iii. Patient education. Patient education is generally regarded as 
a key component to successful asthma treatment. The EPR-2 says, 
``[E]ducation for an active partnership with patients remains the 
cornerstone of asthma management and should be carried out by health 
care providers delivering

[[Page 53724]]

asthma care. Education should start at the time of asthma diagnosis and 
be integrated into every step of clinical asthma care'' (Ref. 5, p. 5).
    Elements of patient education can include providing information 
about how asthma affects the lungs, the difference between short-acting 
rescue medications and control medications, the importance of using 
control medication as prescribed, important environmental control 
measures that may need to be considered, such as removing asthma 
triggers from the patient's home, the tracking of severity of the 
patient's asthma, and proper use of an MDI.
    The proper use of an MDI is an important factor in proper treatment 
of asthma. This issue was mentioned but not discussed at the NDAC/PADAC 
meeting (meeting transcript, p. 139). Improper use of an MDI can result 
in a reduction of the dose delivery by 50 percent or more (Ref. 22). A 
study in children and adolescents showed less than 25 percent used 
their MDIs correctly (Ref. 23), and a study in adults showed similar 
results (Ref. 24). Further, the last study showed that inadequate 
English language literacy is associated with poor use of MDIs.
    The importance of patient education may be a significant issue in 
any discussion of the risks and benefits of self-treatment of asthma.
    iv. Effects of undertreatment. While the cost of treatment for poor 
and medically underserved populations was frequently mentioned at the 
NDAC/PADAC meeting, much less was said about the effects and costs of 
undertreatment. A recent study of urban pediatric patients, who were 
predominantly from poor and minority households, showed that an 
increased use of corticosteroids in pediatric patients (in accordance 
with the guidelines in EPR-2) resulted in fewer hospitalizations, 
emergency department visits, and outpatient visits (Ref. 25).
    The importance of prompt appropriate treatment of asthma is 
reinforced by studies suggesting that delaying treatment with inhaled 
corticosteroids decreases the effectiveness of the inhaled 
corticosteroids once treatment begins (Refs. 26 and 27).
    Studies also indicate that regular use of beta-agonist 
bronchodilators may reduce the person with asthma's response to 
subsequent beta-agonist administration (Ref. 28). This tolerance could 
mean that patients who regularly use OTC epinephrine MDIs may be placed 
in a position where their occasional use of a beta2-agonist, 
as part of a course of treatment using inhaled corticosteroids as a 
control medication, may not be as effective for these patients as might 
otherwise be possible. The effects of undertreatment of asthma may be a 
key issue in any discussion of the risks and benefits of self-treatment 
of asthma.
    One public speaker did say that ``a delay in the early introduction 
of prescription anti-inflammatory asthma therapy could lead to the 
development of irreversible lung damage'' (meeting transcript, p. 171). 
We do not find his statement to be persuasive. The use of inhaled 
steroids was not shown to prevent damage to the lungs in several 
studies (Refs. 29, 30, and 31), and the evidence supporting the 
speaker's statement about ``irreversible lung damage'' is limited and 
not conclusive (Ref. 32). Any disagreement on the issue of permanent 
lung damage should not be allowed to obscure the fact that proper use 
of inhaled steroids significantly reduces asthma morbidity.
3. Conclusions on the Public Health Benefits of OTC Epinephrine MDIs
    We believe that epinephrine does not have any clinical advantages 
over albuterol HFA MDIs and that patient convenience for patients that 
have not kept their asthma drugs prescriptions current or do not have 
the prescribed drug product with them is not an important public health 
benefit. We have not reached a conclusion on the risks and benefits of 
continuing to have epinephrine available OTC for people with asthma who 
face barriers to obtaining appropriate health care, and therefore we 
cannot reach a conclusion on whether the use of OTC epinephrine MDIs 
provides an important health benefit. We specifically request comments 
on the expected costs and public health effects to individuals with 
asthma if OTC epinephrine MDIs were removed from the market without a 
similar product being available OTC. While our tentative conclusion 
that epinephrine is no longer an essential use is based primarily on 
the conclusion we have drawn regarding technical barriers to producing 
the epinephrine in a non-ODS formulation, we will evaluate the public-
health effects of removal of OTC epinephrine from the market, and any 
final conclusions we reach on the essential-use designation of 
epinephrine may be significantly influenced by data received in 
comments on the public-health issues raised by this proposal.

C. Does Use of OTC Epinephrine MDIs Release Cumulatively Significant 
Amounts of ODSs Into the Atmosphere or is the Release Warranted in View 
Of The Otherwise Unavailable Important Public Health Benefit?

    The use of CFCs in MDIs for the treatment of asthma and COPD is the 
only legal use in the United States of newly manufactured CFCs. The 
quantity of CFCs used in OTC epinephrine MDIs is a significant portion 
of the total quantity of newly manufactured CFCs used, and therefore 
eventually released, in the United States. The size of the portion will 
increase as other MDIs containing CFCs are removed from the market. As 
we discussed in part II of this document, the release of CFCs from MDIs 
is cumulatively significant. Because we have not reached a conclusion 
on the public health benefits of OTC epinephrine MDIs, we cannot reach 
a conclusion on whether the release of CFC ODSs is warranted in view of 
the public health benefits.

D. Conclusions

    We have tentatively concluded the following:
     The pharmaceutical industry has had success in formulating 
similar moieties without ODSs. In particular, HFA MDIs containing 
albuterol, a close chemical analog of epinephrine, have been approved 
by FDA. We have no evidence to suggest that formulating epinephrine in 
a product that does not release ODSs poses unique technical challenges. 
Therefore, we tentatively conclude that no substantial technical 
barriers exist to formulating an epinephrine inhaler without ODSs.
     The release of ODSs into the atmosphere from OTC 
epinephrine MDIs is cumulatively significant.
    We have not reached a conclusion on whether the use of OTC 
epinephrine MDIs provides an unavailable important public health 
benefit or whether the release of ODSs from OTC epinephrine MDIs is 
warranted in view of the otherwise unavailable public health benefit. 
However, as we discussed in part II of this document, if a use fails to 
meet any one of the three criteria in Sec.  2.125(f), FDA may elect to 
go through rulemaking to remove its essential-use designation.
    We have therefore tentatively concluded that oral pressurized MDIs 
containing epinephrine are no longer an essential use of ODSs and 
should be removed from the list of essential uses in Sec.  2.125(e). As 
noted throughout the preamble, we are keenly interested in receiving 
public comments and any available data concerning technical

[[Page 53725]]

barriers to developing an epinephrine inhaler without ODSs, the status 
of any ongoing efforts to develop such a product, and the public health 
effects and costs of removing epinephrine MDIs from the market prior to 
a similar product being available OTC. Any final conclusions that we 
reach on the essential-use designation of epinephrine may be 
significantly influenced by such comments.

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 No. 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 the 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 $122 million, using the most current (2005) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule may 
result in a 1-year expenditure that would meet or exceed this amount.
    The Congressional Review Act requires that regulations that have 
been identified as being major must be submitted to Congress before 
taking effect. This rule is major under the Congressional Review Act.
    This proposed rule would prohibit sales of OTC epinephrine CFC MDIs 
in interstate commerce after December 31, 2010, forcing users to either 
self-medicate with less effective therapies (see section VII.D.3.a), or 
to visit a physician and get a prescription for an alternative drug 
product such as albuterol. Because OTC epinephrine CFC MDIs are widely 
regarded by physicians and people with asthma as the most effective 
relief medication for asthma available OTC, if users of these MDIs 
choose to self-medicate, they will be more likely to require 
hospitalization or an emergency department visit. Alternatively, if 
they choose to see a physician to obtain a prescription for albuterol, 
the OTC epinephrine CFC MDI users, or their insurers, will have to pay 
more, not only for visits to the physician, but also for more expensive 
drugs. More physician visits, however, may lead current OTC epinephrine 
MDI users to increase their use of prescription control medication, 
such as inhaled corticosteroids, which should decrease their likelihood 
of both asthma attacks and hospital visits. We have no data suggesting 
whether current OTC epinephrine MDI users are more likely to self-
medicate or to visit a physician and get an albuterol MDI prescription 
once OTC epinephrine MDIs are no longer available. We therefore focus 
on scenarios where, if OTC epinephrine MDIs are no longer available, 
all current OTC epinephrine MDI users either self-medicate with other 
products such as herbal supplements, caffeine, and OTC ephedrine or 
visit a physician to obtain, and fill, prescriptions for albuterol 
MDIs. These extreme scenarios offer plausible bounds for estimating the 
costs and benefits resulting from this proposed rule and regulatory 
alternatives.
    CFCs available for production of OTC epinephrine MDIs may be 
exhausted prior to the effective date of this proposed rule if the 
United States was unable to obtain an essential-use allocation for CFCs 
under the Montreal Protocol for use in OTC epinephrine MDIs for 2010 
(see Ref. 33, p. 59). If so, this proposed rule may not have any 
significant impacts. To the extent that CFCs for production of OTC 
epinephrine MDIs remain available, we estimate this proposed rule will 
have the impacts summarized in the following table.

   Table 2.--Summary of Annual Quantifiable Effects of the Proposed Rule, Assuming CFCs for Production of OTC
                                        Epinephrine MDIs Remain Available
----------------------------------------------------------------------------------------------------------------
                                                                 Increased
                                              Increased Health   Emergency        Increased         Reduced CFC
                                             care Expenditure,   Department  Hospitalizationsfor  Emissions from
                                              in 2006 Dollars    Visits for         Asthma           Phase-Out
                                                                   Asthma                            (tonnes)
----------------------------------------------------------------------------------------------------------------
If current OTC epinephrine MDI users self-     $360 million to         0 to   40,000 to 120,000               70
 medicate                                         $1.0 billion      440,000
----------------------------------------------------------------------------------------------------------------
If current OTC epinephrine MDI users visit     $170 million to  ...........  ...................              70
 their physician for prescription albuterol       $340 million
 (excluding controller medication)
----------------------------------------------------------------------------------------------------------------

    We are unable to estimate quantitatively the reductions in skin 
cancers, cataracts, and environmental harm that may result from the 
reduction in CFC emissions by roughly 70 tonnes during these years. 
Although we cannot

[[Page 53726]]

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 OTC epinephrine MDI market, and the health conditions 
that epinephrine 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 VIII of this document. We 
discuss our conclusions in section VII.H of this document.

B. Need for Regulation and the Objective of This Rule

    This proposed regulation responds to U.S. obligations under the 
Montreal Protocol, as well as the requirements of the Clean Air Act. 
The Montreal Protocol itself recognizes that the regulation of ODSs is 
necessary because private markets are very unlikely to preserve levels 
of stratospheric ozone sufficient to protect the public health. In 
private markets, 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 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 an unregulated private market would be the 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.
    One of the objectives of this proposed rule is to respond to the 
obligations under the Montreal Protocol requiring the United States to 
reduce atmospheric emissions of ODSs, specifically CFCs. CFCs and other 
ODSs deplete the stratospheric ozone that protects the Earth from 
ultraviolet solar radiation. We are proposing to end the essential-use 
designation for ODSs used in MDIs containing epinephrine because we 
have tentatively concluded that no substantial technical barriers exist 
to formulating epinephrine in a product that does not release ODSs (see 
section V.A of this document). Removing this essential-use designation 
will reduce 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 ninety-one 
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, and by 2004, 
total annual production had been reduced to 70,000 tonnes (Ref. 34). 
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. 34).
    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 for that use.
    Each year, each Party nominates the amount of CFCs needed for each 
essential use and provides the reason such use is essential. Agreement 
on both the essentiality and the amount of CFCs needed for each 
nominated use has been reached by consensus at the annual Meeting of 
the Parties.
3. Benefits of the Montreal Protocol
    EPA has generated a series of estimates of the environmental and 
public health benefits of the Montreal Protocol (Ref. 35). 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 Asthma
    OTC epinephrine MDIs are 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, cough, or a combination of symptoms. Many factors, including 
allergens, exercise, and viral infections may trigger an asthma attack.
    Early release data from the first 6 months of the 2006 NHIS 
indicate that 8.0 percent of people in the United States have asthma 
(Ref. 36, fig. 15.5). The prevalence of asthma decreases with age, with 
the prevalence being 9.5 percent for children ages 0 to 14, compared to 
7.8 percent for persons ages 15 to 34, and 7.4 percent for adults ages 
35 and over (Ref. 36, fig. 15.5).
    The early release data from the first 6 months of the 2006 NHIS 
also indicate 4.2 percent of Americans had an asthma episode in the 
previous 12 months, with 5.5 percent of children under age 14, 3.6 
percent of persons ages 15 to 34, and 4.0 percent of adults over age 35 
reporting episodes (Ref. 36, fig. 15.2).

[[Page 53727]]

    According to data from the National Ambulatory Medical Care Survey, 
in 2004 there were about 15 million outpatient asthma visits to 
physician offices and hospital clinics and 1.8 million emergency 
department visits (Ref. 37, table 19). According to data from the 
National Center for Health Statistics: National Hospital Discharge 
Survey, there were 497,000 hospital admissions for asthma in 2004 (Ref. 
37, table 12) and 4,099 mortalities in 2003 (Ref. 37, table 1). The 
estimated direct medical cost of asthma (hospital services, physician 
care, and medications) was $11.5 billion in 2004 (Ref. 37, table 20).
    We estimate that OTC epinephrine MDI users make roughly 280,000 to 
370,000 visits to emergency departments and require roughly 75,000 to 
100,000 hospitalizations annually. We know of no data or study 
suggesting OTC epinephrine MDI users differ from other people with 
asthma in their risk of requiring emergency department visits or 
hospitalizations. In a published study of 601 people with asthma (Ref. 
38), the authors did not find any evidence that epinephrine users are 
more likely to visit emergency departments or to require 
hospitalization than people with asthma who do not use epinephrine. On 
the other hand, we know of no data suggesting that OTC epinephrine MDI 
users are less likely to visit emergency departments or require 
hospitalization. As described in section V.B.2.b of this document, we 
estimate that 1.7 to 2.3 million people with asthma use OTC epinephrine 
MDIs. Assuming 1.7 to 2.3 million people with asthma are OTC 
epinephrine MDI users, and that they require emergency department 
visits and hospitalization in proportion to their share of the 
population, OTC epinephrine MDI users account for roughly 280,000 to 
370,000 emergency department visits annually [15 percent of 1.8 million 
= 280,000; 20 percent of 1.8 million = 370,000] and 75,000 to 100,000 
hospitalizations annually [15 percent of 497,000 = 75,000; 20 percent 
of 497,000 = 100,000].\25\
---------------------------------------------------------------------------

    \25\The 15 to 20 percent figures were derived, in part, from 
comparing the number of purchasers of OTC epinephrine MDIs to the 
number of adults suffering an asthma incident in the previous 12 
months.
---------------------------------------------------------------------------

    While the prevalence of asthma (the percent of the population 
diagnosed with asthma) has been increasing in recent years, CDC reports 
that the incidence of asthma (the rate of new diagnoses) has remained 
fairly constant since 1997 (Ref. 39). Non-Hispanic Blacks, children 
under 17 years old, and females have higher incidence rates than the 
general population and also are more likely to have had an attack of 
asthma in the previous 12 months. The CDC notes that although increases 
have occurred in the numbers and rates of physician office visits, 
hospital outpatient visits, and emergency department visits, these 
increases are accounted for by the increase in prevalence. The CDC also 
notes that asthma mortality and asthma hospitalization rates were 
declining and stated that these downward trends might indicate early 
successes by asthma intervention programs.
5. Current U.S. Market for OTC Epinephrine MDIs
    We estimate that 1.7 million to 2.3 million consumers purchase 
roughly 4.5 million OTC epinephrine MDIs in the United States each 
year, at an average price of $13.29 per MDI.
    Based on data from ACNielsen for the 52 weeks ending September 9, 
2006 (Ref. 40), we estimate 3.5 million OTC epinephrine MDIs are sold 
in the United States annually, excluding sales through Wal-Mart Stores, 
Inc. (Wal-Mart).\26\ Wyeth estimates roughly 25 percent of OTC 
medications such as PRIMATENE MIST, a branded OTC epinephrine MDI 
product, are sold through Wal-Mart annually (Wyeth slide 32), implying 
a total market of roughly 4.5 million OTC epinephrine MDIs sold 
annually. This is equivalent to 1.3 billion inhalations per year, or 
146 million days of therapy (at 9 inhalations per day, the highest 
recommended long-term dose).
---------------------------------------------------------------------------

    \26\Retail sales data from drug stores and supermarkets provided 
by ACNielsen do not include retail sales data from Wal-Mart because 
Wal-Mart does not participate in ACNielsen surveys.
---------------------------------------------------------------------------

    Based on ACNielsen data (Ref. 40) for the 52 weeks ending September 
9, 2006, adjusted for sales through Wal-Mart, we estimate OTC 
epinephrine MDI sales amount to roughly $60 million in the United 
States annually and the average U.S. retail price of OTC epinephrine 
MDIs is $13.29, equivalent to roughly $0.41 per day of therapy.
    According to American Lung Association reports derived from the 
National Center for Health Statistics' 2004 NHIS (Ref. 37, table 10), 
11.6 million individuals reported having had an asthma attack in the 
last 12 months. According to Wyeth Pharmaceuticals (Wyeth slide 32), 15 
to 20 percent of adults with asthma that have had an asthma attack in 
the previous 12 months use OTC epinephrine MDIs. As we discussed in 
section V.B.2.b of this document, we estimate that 1.7 to 2.3 million 
people with asthma use OTC epinephrine MDIs. Each of these users, on 
average, purchases roughly 1.9 to 2.6 OTC epinephrine MDIs each year 
[4.5 million MDIs / 1.7 million users = 2.6 MDIs per user per year; 4.5 
million MDIs / 2.3 million users = 1.9 MDIs per user per year].
    We estimate 600,000 to 1.3 million OTC epinephrine MDI users do not 
regularly use prescription asthma products. According to Wyeth 
Pharmaceuticals, somewhere between 43 percent (Wyeth slide 33) and two-
thirds (Wyeth slide 32) of OTC epinephrine MDI users also use 
prescription drugs for treatment of their asthma. This implies that 
600,000 to 1.3 million OTC epinephrine MDI users do not use 
prescription asthma medicine [1,752,653 x .33 = 578,375; 2,336,871 x 
.57 = 1,332,016].

D. Benefits and Costs of the Proposed Rule

    We estimate the benefits and costs of government action relative to 
a baseline scenario that, in this case, is a description of the 
production, use, and access to OTC epinephrine MDIs in the absence of a 
final rule based on this proposed rule. In this section we first 
describe such a baseline, and then present our analysis of the benefits 
of the rulemaking. We also present an analysis of the most plausible 
regulatory alternatives, given the Montreal Protocol. Next, we turn to 
the costs of the rulemaking 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 OTC epinephrine MDIs after 
December 31, 2010. It is standard practice to use, as a baseline, the 
state of the world without the rulemaking in question, or where the 
rulemaking implements a legislative requirement, the world without the 
statute. For this proposed rule, we make the baseline assumption that 
it is questionable if the United States would be able to obtain an 
essential-use allocation for CFCs for the manufacture of OTC 
epinephrine MDIs under the Montreal Protocol for 2010.\27\ To the 
extent that new CFCs for production of OTC epinephrine MDIs remain 
available past that date, we estimate this rulemaking will have 
quantifiable impacts as summarized in table 2. If CFCs for the 
production of OTC epinephrine MDIs are no longer

[[Page 53728]]

available by the end of 2010, this rule will have no impact.
---------------------------------------------------------------------------

    \27\Even if there is no essential-use allocation under the 
Montreal Protocol for the year 2010, production of epinephrine CFC 
MDIs would likely continue well into the year with manufacturers 
using preexisting stocks of CFCs.
---------------------------------------------------------------------------

2. Benefits of the Proposed Rule
    The benefits of a final rule based on this proposed rule include 
environmental and public health improvements from protecting 
stratospheric ozone by reducing CFC emissions by roughly 70 tonnes 
annually. Benefits also include expectations of increased returns on 
investments in environmentally friendly technology, reduced risk of 
unexpected disruption of supply of OTC epinephrine MDIs, and continued 
international cooperation to comply with the spirit of the Montreal 
Protocol, thereby potentially reducing future emissions of ODSs 
throughout the world.
    Failure to finalize this proposed rule may lead the Parties to the 
Montreal Protocol to consider restrictions on access to the CFCs 
required to manufacture these OTC epinephrine MDIs products, which 
could create the risk of removal of these products from the market.
    a. Reduced CFC emissions. Withdrawal of OTC epinephrine MDIs from 
the market will reduce CFC emissions by approximately 70 tonnes 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 
OTC epinephrine CFC MDIs after December 31, 2010. There is some 
uncertainty with respect to the amount of inventory that will be 
available in the future, but the United States' ability to obtain an 
essential-use allocation for CFCs for the manufacture of OTC 
epinephrine MDIs in 2010 is questionable.
    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.
    The reduction of CFC emissions associated with removing OTC 
epinephrine CFC MDIs from the U.S. market represents only a fraction of 
1 percent of total global CFC emissions. Current allocations of CFCs 
for OTC epinephrine MDIs account for less than 0.1 percent of the total 
1986 global production of CFCs (Ref. 41). 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.
    If a final rule removing the essential-use designation of OTC 
epinephrine MDIs takes effect before CFCs cease to be available, the 
proposed rule may 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 the 
reduced emissions that might be associated with this proposed rule or 
the regulatory alternatives.
    b. Returns on investment in environmentally-friendly technology. 
Establishing a phase-out date prior to the expiration of patents on HFA 
MDI technology and other aerosolized drug technology that does not use 
ODSs rewards the developers of the ozone-safe technologies. In 
particular, such a phase-out date would validate expectations that the 
government will protect 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 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. 42).
    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 the Montreal Protocol's 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 of developed 
nations, such as the United States. If we had adopted a later phase-out 
date, other Parties could attempt to delay their own control measures.
3. Costs of the Proposed Rule and Alternatives
    The costs of removing OTC epinephrine MDIs from the market include 
the costs of increased physician visits, increased use of more 
expensive reliever MDIs, and potential increases in the use of 
controller medications, visits to emergency departments, and 
hospitalizations. Because we cannot predict whether OTC epinephrine MDI 
users will self-medicate or go to a physician for a prescription 
reliever once OTC epinephrine MDIs are removed from the market, we 
quantify the costs for two extreme cases. In the first case, OTC 
epinephrine MDI users not already seeing a physician self-medicate, 
while those who already see a physician switch from OTC epinephrine 
MDIs to albuterol HFA MDIs. In the second case, all OTC epinephrine MDI 
users visit their physician and switch to albuterol HFA MDIs. We 
propose these two cases as reasonable bounds for the expected cost of 
removing OTC epinephrine MDIs from the market.
    a. Self-medication. If all OTC epinephrine MDI users who do not 
already see a physician for asthma were to self-medicate once OTC 
epinephrine MDIs were no longer available, and those who do see a 
physician were to increase their albuterol use, we estimate this 
rulemaking would result in $360 million to $1.0 billion in increased 
spending annually. This spending includes $280 million to $1.0 billion 
resulting from increased hospitalizations and emergency department 
visits, and roughly $30 million to $80 million in increased spending on 
more expensive medicines. Under the assumption of self-medication, we 
estimate that removing OTC epinephrine MDIs from the market would 
result in 40,000 to 120,000 more hospitalizations for asthma annually, 
and up to 440,000 more asthma-related emergency department visits each 
year. These estimates, based on calculations throughout this section, 
do not capture the decreased quality of life of OTC

[[Page 53729]]

epinephrine MDI users, lost productivity, or the cost of alternative 
therapies, such as herbal remedies, caffeine and OTC ephedrine.
    The authors of a published study found that people with asthma who 
self-medicate with herbal products and caffeine, the most common forms 
of self medication, are at increased risk of requiring an emergency 
department visit or hospitalization (Ref. 38). They found that those 
using herbal treatments are 2.5 times as likely to require 
hospitalization, and that those who use caffeine to treat asthma are 
3.1 times as likely as other people with asthma to require both an 
emergency department visit and hospitalization.
    We estimate that OTC epinephrine MDI users who do not use 
prescription medicine for their asthma make roughly 100,000 to 200,000 
emergency department visits and require roughly 25,000 to 50,000 
hospitalizations. We estimate OTC epinephrine MDI users make roughly 
280,000 to 370,000 emergency department visits and require about 75,000 
to 100,000 hospitalizations annually, as described in section VII.C.4 
of this document. We estimate somewhere between 43 percent and two-
thirds of OTC epinephrine MDI users do not use prescription medicine 
for their asthma, as discussed in section 6. Assuming that OTC 
epinephrine MDI users who do not use prescription medicine for asthma 
do not differ in their rates of hospitalization and emergency 
department visits from those who do use prescription medicine for 
asthma, we estimate that OTC epinephrine MDI users who do not use 
prescription medicine for asthma make 100,000 to 200,000 emergency 
department visits and require 25,000 to 55,000 hospitalizations 
annually [275,700 emergency department visits x 1/3 = 91,900 emergency 
department visits; 367,600 emergency department visits x (1 - .43) = 
209,532 emergency department visits; 74,550 hospitalizations x 1/3 = 
24,850 hospitalizations; 99,400 hospitalizations x (1 - .43) = 56,658 
hospitalizations].
    If current OTC epinephrine MDI users who do not use prescription 
medicine for asthma were to self-medicate with herbal treatments, and 
those self-medicating with herbal treatments face 2.5 times the risk of 
a hospitalization, this would imply a lower bound increase of roughly 
40,000 hospitalizations [24,850 hospitalizations x (2.5 - 1) = 37,275]. 
As an upper bound, if all OTC epinephrine MDI users were to self-
medicate with caffeine, emergency department visits would increase by 
roughly 440,000 [209,532 emergency department visits x (3.1 - 1) = 
440,017] and hospitalizations would increase by roughly 120,000 [56,658 
hospitalizations x (3.1 - 1) = 118,983]. We do not have data that will 
allow us to estimate increases in hospitalizations and emergency 
department visits for patients using other forms of self-medication, 
such as OTC ephedrine. We request comments that would provide 
information allowing us to address this issue.
    We estimate the 2006 cost of an emergency department visit for 
asthma at roughly $300 and the cost of hospitalization for asthma at 
roughly $7500. Based on data from the 2004 National Hospital Discharge 
Survey, the American Lung Association estimates the 497,000 
hospitalizations for asthma cost roughly $3.6 billion in inpatient care 
and physician services, equivalent to roughly $7,300 per 
hospitalization (Ref. 37). The 1.8 million emergency department visits 
for asthma cost about $518 million, equivalent to roughly $280 per 
visit. Adjusting these figures for inflation according to the CPI for 
medical care, we estimate that the average hospitalization for asthma 
would cost roughly $7,500 and the average emergency department visit 
for asthma would cost roughly $300 in 2006.
    Based on these estimates, if current OTC epinephrine MDI users who 
do not currently use prescription medicine were to self-medicate, the 
result would be costs of roughly $280 million [37,275 hospitalizations 
x $7,565.84 = $282,016,770] to $1.0 billion annually [(118,982 
hospitalizations x $7,565.84) + (440,017 emergency department visits x 
$294.17) = $1,029,639,003].
    Assuming current OTC epinephrine MDI users who do use prescription 
medicine for asthma increase their use of albuterol HFA MDIs without 
requiring more frequent physician visits, we estimate that they will 
pay roughly $30 million to $80 million more for medicine each year. As 
discussed in section 6, somewhere between 43 percent and two-thirds of 
OTC epinephrine MDI users also use prescription medicine for their 
asthma. Assuming current OTC epinephrine MDI users who also use 
prescription medicines for their asthma use roughly the same number of 
OTC epinephrine MDIs per year as those who do not, we estimate dual 
users use roughly 2 million to 3 million OTC epinephrine MDIs annually 
[4,486,104 MDIs x 0.43 = 1,929,025; 4,486,104 MDIs x 2/3 = 2,990,736 
MDIs]. As discussed in the following section, we estimate an albuterol 
HFA MDI will cost between $16 and $25 more than an OTC epinephrine MDI, 
and that one albuterol MDI is roughly equivalent to one OTC epinephrine 
MDI. The lower priced albuterol MDIs are currently being withdrawn from 
the market, and will not be available at the time of the proposed 
effective date of this rule (see 70 FR 71685). The higher price for 
albuterol HFA MDIs implies that if OTC epinephrine MDI users who also 
use prescription medicine for their asthma were to increase their use 
of albuterol HFA MDIs when OTC epinephrine MDIs are no longer 
available, they and their insurers would spend roughly $30 million to 
$80 million more per year for medicine [1,929,025 MDIs x $16.08 per MDI 
= $31,022,023; 2,990,736 MDIs x $25.15 per MDI = $76,418,426].
    In total, self-medication by OTC epinephrine-only MDI users and 
increased albuterol use by those already using prescription medicine 
would result in increased spending of $360 million to $1.0 billion 
annually [$282,016,770 + $76,418,426 = $358,435,196; $1,029,639,003 + 
$31,022,023 = $1,060,661,026].
    b. Increased physician visits and albuterol use. If, as a result of 
the removal of OTC epinephrine MDIs from the market, all current OTC 
epinephrine MDI users were to seek out prescription albuterol HFA MDIs 
through increasing the frequency of physician visits, we estimate that 
this scenario would result in roughly $170 million to $340 million in 
increased health care spending, including $100 million to $225 million 
in economic costs through an increase in visits to physicians and $72 
million to $114 million in increased spending on prescription 
albuterol.
    We estimate that if current epinephrine users who do not use 
prescription medicine for their asthma make one additional physician 
visit per year to enable them to switch from OTC epinephrine MDIs to 
albuterol MDIs, the result would be roughly 600,000 to 1.3 million 
additional physician visits annually. This estimate stems directly from 
the estimate presented in section 6 that there are roughly 600,000 to 
1.3 million epinephrine users who do not use prescription medicine for 
their asthma. These estimates assume that OTC epinephrine MDI users who 
do use prescription medicine for their asthma, and therefore already 
make regular physician visits, are able to increase their albuterol use 
without increasing the frequency of those visits.
    We estimate the 2006 cost of a physician visit for asthma to be 
roughly $170. Based on 2004 data from the National Ambulatory Medical 
Care Survey, the American Lung Association estimates that 1.5 million 
physician visits and non-emergency outpatient

[[Page 53730]]

hospital visits for asthma cost roughly $2.4 billion, equivalent to 
roughly $160 per physician visit. Adjusting these figures for inflation 
according to the CPI for medical care, we estimate that a physician 
visit for asthma would cost roughly $170 per visit in 2006. An increase 
of 600,000 to 1.3 million physician visits each year would therefore 
cost roughly $100 million to $225 million annually [584,217.75 visits x 
$168.966 per visit = $98,712,936; 1,332,016.47 visits x $168.966 per 
visit = $225,065,495]. These estimates do not take into account the 
value of the time patients spend visiting their physicians.
    If all current OTC epinephrine MDI users were to switch to 
prescription albuterol HFA MDIs, we estimate the result to be roughly 
$70 million to $115 million in increased spending on medicine. We 
estimate that it will take roughly one albuterol HFA MDI to replace 
each OTC epinephrine MDI removed from the market. OTC epinephrine MDIs 
contain roughly 270, 405, or 540 inhalations, depending on the size of 
the MDI. Based on ACNielsen data for the 52 weeks ending September 9, 
2006 (Ref. 40), we estimate that the average OTC epinephrine MDI 
contained 293 inhalations, equivalent to 32.6 days of therapy, assuming 
OTC epinephrine MDI users use, but do not exceed, the long term maximum 
recommended dose of 9 inhalations per day. The usual dosage of 
albuterol HFA MDIs is 8 to 12 inhalations per day, and albuterol HFA 
MDIs contain 200 inhalations, implying that each MDI contains 17 to 25 
days of therapy per MDI. Allowing for the greater therapeutic 
effectiveness of albuterol compared to epinephrine, we estimate it will 
take roughly one albuterol HFA MDI to replace each OTC epinephrine MDI 
removed from the market.
    Based on ACNielsen data from the 52 weeks ending September 9, 2006 
(Ref. 40), we estimate the average retail price of an OTC epinephrine 
MDI to be $13.29. Based on average retail sales prices across all payer 
types for the first half of 2004, the average albuterol HFA MDI cost 
$39.42 (Ref. 43). This estimate does not reflect less expensive 
albuterol HFA MDIs introduced to the market since that time. Some 
market analysts also predict that albuterol HFA MDI prices will decline 
up to 20 percent as the market switches away from albuterol CFC MDIs 
and large payers use their market power to drive down prices (Ref. 44). 
Taking these factors into consideration, we estimate the average retail 
price of an albuterol HFA MDI is $30 or more, a price increase of 
roughly $16 to $25 per MDI. If current OTC epinephrine MDI users must 
purchase one albuterol MDI for each OTC epinephrine MDI they currently 
purchase, total expenditures by current OTC epinephrine MDI users and 
their insurers would increase roughly $70 million to $115 million 
[4,486,104 MDIs x $16.08 per MDI = $72,134,239; 4,486,104 MDIs x 
$25.55per MDI = $114,627,640].
    If, instead of self-medicating, OTC epinephrine MDI users go to the 
physician and increase their use of albuterol HFA MDIs, we estimate 
increased spending of roughly $170 million to $340 million dollars 
annually [$98,712,936 for physician visits + $72,134,239 for medicine 
(albuterol) = $170,857,175; $225,065,495 in physician visits + 
$114,627,640 in medicines = $339,693,135].
    These estimated expenditures would decrease dramatically if generic 
albuterol HFA MDIs were to be introduced 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 the Federal Government 
and State governments, to pharmaceutical manufacturers, patent holders, 
and other residual claimants. However, to some extent, these increased 
expenditures represent purchases of products that are more costly to 
manufacture and bring to market, and, therefore, would be social costs. 
We are unable to estimate the fraction of those increased expenditures 
on drugs that constitute social costs.
    c. Controller medication. We estimate that the cost to current OTC 
epinephrine MDI users of filling additional prescriptions for 
controller medications would, on average, exceed the potential direct 
cost savings from reducing hospitalizations and emergency department 
visits by more than $280 per current OTC epinephrine MDI user.
    In a study of almost 50,000 asthma patients (Ref. 45), the authors 
found that patients with low adherence to controller medication have 
significantly higher risk (odds ratio of 1.72) of emergency department 
visits or of hospitalization relative to patients with moderate or high 
adherence. The study found that patients receiving high daily doses of 
controller medication had the lowest risk (odds ratio of .37) of 
emergency department visits or of hospitalization. As discussed in 
section VII.D.3.a of this document, we estimate OTC epinephrine MDI 
users who do not use prescription medicines make roughly 100,000 to 
200,000 emergency department visits and require about 25,000 to 55,000 
hospitalizations annually. If they all were to visit their physicians, 
receive prescriptions for a controller medication, fill them, and use 
the medication, based on the results of the study of almost 50,000 
asthma patients, we estimate 20 to 40 percent of these emergency 
department visits and hospitalizations could be avoided, equivalent to 
roughly 20,000 to 80,000 fewer emergency department visits [20 percent 
of 91,900 is 18,380; 40 percent of 209,532 is 83,813] and 5,000 to 
10,000 fewer hospitalizations [20 percent of 24,850 is 4,970; 40 
percent of 56,658 is 11,332]. Assuming the average cost for an 
emergency department visit for asthma is about $300 and the average 
cost of a hospitalization for asthma is roughly $7,500, as discussed in 
section D.3.a of this document, this would reduce health care costs by 
roughly $40 million to $100 million annually [($294.17 per visit x 
18,380) + ($7565.84 per hospitalization x 4,970) = $41,236,000; 
($294.14 per visit x 83,813) + ($7565.84 per hospitalization x 11,332) 
= $105,837,600]. This cost is roughly $70 to $80 per current OTC 
epinephrine MDI user per year [$41,236,000 / 584,218 OTC epinephrine 
only MDI users = $70.58; $105,837,600 / 1,332,016 OTC epinephrine only 
MDI users = $79.46].
    We looked at a range of CFC-free controller medications such as 
FLOVENT HFA, ASMANEX TWISTHALER, PULMICORT TURBOHALER, and QVAR, and 
found the wholesale price of the smallest dose of the least expensive 
medication to be roughly $1.00 per day of therapy,\28\ equivalent to 
roughly $370 per patient year of therapy. On average, the cost of 
increasing the use of controller medication among current OTC 
epinephrine MDI users who do not currently use prescription medicine 
would exceed the benefits, in terms of decreased emergency department 
visits and hospitalizations, by over $280 per person per year. This 
number would be lower if a greater fraction of people with asthma at 
high risk of emergency department visits were to begin using controller 
medication on a regular basis, and higher if a greater fraction of low 
risk people with asthma were to begin using controller medication on a 
regular

[[Page 53731]]

basis. These estimates do not take into account the impact of asthma 
attacks on individuals' quality of life and productivity.
---------------------------------------------------------------------------

    \28\Analysis completed by FDA based on information provided by 
IMS Health, IMS National Sales Perspective (TM), 2005, extracted 
March 2006.
---------------------------------------------------------------------------

4. Effects on Medicaid and Medicare
    As a result of the removal of OTC epinephrine CFC MDIs from the 
market, we estimate State and Federal Medicaid spending will increase 
$35 million to $250 million annually and that Federal Medicare 
spending, together with private spending by Medicare beneficiaries, 
will increase $20 million to $250 million annually. Some OTC 
epinephrine MDI users may be eligible for both Medicare and Medicaid. 
To the extent this population is large, these estimates overstate 
potential spending increases from this proposed rule by counting these 
individuals twice: once in Medicaid estimates and once in Medicare 
estimates. We are unable to estimate the size of the population of OTC 
epinephrine MDI users eligible for both programs.
    a. Medicaid. We estimate that 20 to 25 percent of the costs of the 
removal of OTC epinephrine MDIs from the market will be born by State 
and Federal Medicaid programs, equivalent to $70 million to $250 
million annually if Medicaid-eligible OTC epinephrine MDI users who do 
not use prescription medicine for their asthma were to self-medicate 
upon implementation of this proposed rule, and equivalent to $35 
million to $85 million annually if Medicaid-eligible OTC epinephrine 
MDI users were to visit their physicians to obtain and fill 
prescriptions to enable them to switch to albuterol. Assuming 
epinephrine users with insurance, including Medicaid, are more likely 
to visit a doctor, and less likely to self-medicate, the costs of this 
proposed rule are more likely to fall in the $35 million to $85 million 
range.
    According to proprietary surveys conducted by or for Wyeth between 
1993 and 1994 (Wyeth slide 31), 27 percent to 33 percent of OTC 
epinephrine MDI users had incomes of less than $20,000 at the time the 
surveys were conducted. A 2005 Internet survey conducted by Wyeth found 
that 20 percent of OTC epinephrine MDI users had incomes of less than 
$25,000. Eligibility for Medicaid varies by State but is generally tied 
to the Federal poverty guidelines (Ref. 46). The 2006 Federal poverty 
guidelines establish a poverty threshold of $20,000 in annual income 
for a family of four (Ref. 47). Accordingly, if we assume 20 percent to 
25 percent of OTC epinephrine MDI users are eligible for Medicaid, if 
Medicaid-eligible OTC epinephrine MDI users who do not use prescription 
medicine were to self-medicate, and if those who do self-medicate were 
to switch to albuterol, Federal Medicaid spending would increase 
roughly $70 million to $250 million annually [20 percent of $360 
million = $72 million; 25 percent of 1 billion = $250 million]. If all 
current epinephrine users eligible for Medicaid were to instead visit 
their physicians and use prescription albuterol, we estimate that 
Federal Medicaid spending would increase by $35 million to $85 million 
dollars annually [20 percent of $170,857,175 = $34,171,435; 25 percent 
of $339,693,135 = $84,923,284]. These estimates exclude costs that may 
result from increased prescribing of controller medications, and do not 
take into account the impact of asthma attacks on individuals' quality 
of life and productivity.
    b. Medicare. We estimate 10 percent to 25 percent of the costs of 
the removal of OTC epinephrine MDIs from the market will be paid by 
Federal Medicare spending and by Medicare beneficiaries. If all 
Medicare-eligible OTC epinephrine MDI users were to self-medicate upon 
implementation of this proposed rule, Federal Medicare spending and 
spending by Medicare beneficiaries would increase roughly $40 million 
to $250 million dollars annually. Alternatively, if all Medicare-
eligible OTC epinephrine MDI users were to visit their doctors to 
obtain and fill prescriptions for albuterol, Federal Medicare spending 
and spending by Medicare beneficiaries would increase roughly $20 to 
$85 million annually. Assuming epinephrine users with insurance, 
including Medicare, are more likely to visit a doctor, and less likely 
to self-medicate, the costs of this proposed rule are more likely to 
fall in the $20 million to $85 million range.
    According to proprietary surveys conducted by or for Wyeth between 
1993 and 2005 (Wyeth slide 31), 16 percent to 33 percent of OTC 
epinephrine MDI users are over the age of 55, implying the percentage 
of epinephrine users over the age of 65, and therefore eligible for 
Medicare, must be lower. Accordingly, if we assume 10 percent to 25 
percent of OTC epinephrine MDI users are over the age of 65, Medicare 
spending and private spending by Medicare beneficiaries would increase 
$40 million to $250 million annually if all Medicare-eligible OTC 
epinephrine MDI users were to self-medicate [10 percent of $360 million 
= $36 million; 25 percent of $1.0 billion = $250 million], and by $20 
million to $85 million annually if they were all to visit their 
physicians for prescription albuterol [10 percent of $170,857,125 = $17 
million; 25 percent of $339,693,135 = 84,923,284]. These estimates 
exclude costs that may result from increased prescribing of controller 
medications, and do not take into account the impact of asthma attacks 
on individuals' quality of life and productivity.

E. Alternative Phase-Out Dates

    The alternatives we considered included the following phase-out 
dates:
    1. December 31, 2008;
    2. December 31, 2009;
    3. December 31, 2010 (the proposed rule).
    Spending per year does not differ among the regulatory 
alternatives. The only difference among the alternatives is how long 
the estimated costs shown in table 2 of this document would accrue. At 
some time in the near future, the unavailability of CFCs--not the 
proposed rule or an alternative--may lead to removal of OTC epinephrine 
from the marketplace. Our current belief is that bulk CFCs are likely 
to be unavailable in 2010 (see section VII.A), so the costs for the 
first alternative would be the present value of the annual costs for 2 
years, 2008-2009, and the cost for the second alternative would be the 
present value of the costs for 1 year, 2009. The third alternative, 
which is the proposed rule, would have no quantifiable costs or 
benefits. We invite comments on these projections and on the costs and 
benefits of any other possible alternative effective dates, such as 
December 31, 2011 or 2012.

F. Sensitivity Analyses

    The estimated costs summarized in table 2 incorporate a range of 
estimates about the price increases consumers and other payers will 
face, the size of the affected market, and the consequences of 
consumers' response to the removal of OTC epinephrine MDIs from the 
market. This represents the full range of uncertainty 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, taking into account the possibility that 
in response to the removal of OTC epinephrine MDIs from the market, OTC 
epinephrine MDI users who do not currently use prescription medicines 
will either self-medicate or visit a physician to get an albuterol 
prescription. The estimated increases in emergency department visits 
and hospitalizations depend upon a range of estimates of the percentage 
of people with asthma that use OTC

[[Page 53732]]

epinephrine MDIs (15 to 20 percent) and the fraction of OTC epinephrine 
MDI users that do not use prescription medicines and are therefore more 
likely to self-medicate (somewhere between 33 and 57 percent), as well 
as the rate we estimate hospitalizations and emergency department 
visits will increase among this population (2.5 to 3.1 times).
    Similarly, estimates of the impact of the removal of OTC 
epinephrine MDIs from the market on public and private spending depends 
on whether or not OTC epinephrine MDI users self-medicate, the above 
estimates on increased hospitalizations and emergency department 
visits, and the cost of those visits. A range of estimates of the 
percentage of adults with asthma that use OTC epinephrine MDIs (15 to 
20 percent) and the fraction of OTC epinephrine MDI users that do not 
use prescription medicine for their asthma (somewhere between 33 and 57 
percent), in addition to the overall size of the OTC epinephrine MDI 
market, determines the number of additional physician visits these 
users will require to switch from OTC epinephrine MDIs to albuterol 
MDIs. Estimated increases in spending on medicine depend on the size of 
the OTC epinephrine MDI market, and the price premium current OTC 
epinephrine MDI users can expect to pay for their medicine, roughly $16 
to $25 per MDI.

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 ODS emissions are 
potentially enormous but difficult to attribute to any of the small 
steps, such as this rulemaking, that make such cooperation effective. 
As discussed above in detail, the benefits of the removal of OTC 
epinephrine MDIs from the market 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. The removal of OTC epinephrine MDIs from the 
market could potentially cost public and private consumers of OTC 
epinephrine MDIs hundreds of millions of dollars annually, and increase 
hospitalizations and emergency department visits for asthma 
significantly. If CFCs cease to be available for OTC epinephrine MDIs 
before the effective date of a final rule removing the essential-use 
designation of OTC epinephrine MDIs, however, this proposed rule would 
have no benefits or costs. We specifically request comments on the 
costs and benefits of this proposed rule.

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. Because known current producers are not small 
entities and the likelihood that the proposed rule will not impose 
compliance costs, the agency does not believe that this proposed rule 
would have a significant economic impact on a substantial number of 
small entities. FDA requests comment on this issue.

IX. The Paperwork Reduction Act of 1995

    We have tentatively concluded that this proposed rule contains no 
collection 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 tentatively 
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. 
Consequently, we do not currently plan to prepare a federalism summary 
impact statement for this rulemaking procedure. We invite comments on 
the federalism implications of this proposed rule.

XI. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written comments regarding this proposal. Submit a 
single copy of electronic comments or two 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 OTC MDIs 
containing epinephrine 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 Web site addresses, 
but we are not responsible for subsequent changes to the Web site after 
this document publishes in the Federal Register.\29\
---------------------------------------------------------------------------

    \29\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.
---------------------------------------------------------------------------

    1. National Center for Health Statistics, ``Early Release of 
Selected Estimates Based on Data From the 2005 National Health 
Interview Survey,'' figure 15.4, available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/nchs/data/nhis/earlyrelease/200606_15.pdf
.

    2. Alkermes, Inc., press release, dated March 22, 2004, 
available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.alkermes.com/newsroom/showArticle.aspx?id=267
.

    3. Fu, K. et al., ``Air[reg]-Epinephrine: Inhalation Therapy for 
the Emergency Self-Treatment of Anaphylaxis,'' Journal of Aerosol 
Medicine, Vol. 16(2):190, June 2003.
    4. Hendeles, L. et al., ``Response to Nonprescription 
Epinephrine Inhaler During Nocturnal Asthma,'' Annals of Allergy, 
Asthma, and Immunology, 95:530, December 2005.
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Report 2: Guidelines for the Diagnosis and Management of Asthma,'' 
NIH publication No. 97-4051, July 1997.
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Report: Update on Selected Topics 2002: Guidelines for the Diagnosis 
and Management of Asthma,'' NIH publication No. 02-5074, June 2003.
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Handbook: 2002,'' Melbourne:2002.
    8. Boulet, J. P. et al., ``Canadian Asthma Consensus Report, 
1999,'' Canadian Medical Association Journal, 161(11 Supp.):S1, 
November 30, 1999.
    9. Dickinson, B. D. et al., ``Safety of Over-the-Counter 
Inhalers for Asthma: Report of the Council on Scientific Affairs,'' 
Chest, 118(2):522, August 2000.
    10. Cohen, R. A. and M. E. Martinez, ``Health Insurance 
Coverage: Estimates from the National Health Interview Survey, 
2005,'' National Center for Health Statistics, June 2006, available 
at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/nchs/data/nhis/earlyrelease/insur200606.pdf.

    11. U.S. Census Bureau, ``Table HI01. Health Insurance Coverage 
Status and Type of Coverage by Selected Characteristics: 2004: All 
Races,'' available at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://pubdb3.census.gov/macro/032005/health/h01_001.htm
.


[[Page 53733]]

    12. National Center for Health Statistics, ``Asthma Prevalence, 
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.

    13. Agency for Health Quality and Research, 2005 National 
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List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Devices, Drugs, 
Foods.cc
    Therefore, under the Federal Food, Drug, and Cosmetic Act, 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. In Sec.  2.125, remove and reserve paragraph (e)(2)(v).

    Dated: February 5, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.

    Editorial note: This document was received at the Office of the 
Federal Register on September 17, 2007.
[FR Doc. 07-4663 Filed 9-17-07; 12:01 pm]

BILLING CODE 4160-01-S