Document ID: FDA-2007-N-0314-0044
Agency: fda
Document Type: Rule
Title: Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Epinephrine) - Notice of Final Rule
Posted Date: 2008-11-19T05:00Z

[Federal Register: November 19, 2008 (Volume 73, Number 224)]
[Rules and Regulations]               
[Page 69532-69552]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19no08-4]                         

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. FDA-2007-N-0314] (formerly 2007N-0262)
RIN 0910-AF92

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

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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

SUMMARY:  The Food and Drug Administration (FDA), after consultation 
with the Environmental Protection Agency (EPA), is amending FDA's 
regulation on the use of ozone-depleting substances (ODSs) in self-
pressurized containers to remove the essential-use designation for 
epinephrine used in oral pressurized metered-dose inhalers (MDIs). The 
Clean Air Act requires FDA, in consultation with the EPA, to determine 
whether an FDA-regulated product that releases an ODS is an essential 
use of the ODS. FDA has concluded that there are no substantial 
technical barriers to formulating epinephrine as a product that does 
not release ODSs, and therefore epinephrine would no longer be an 
essential use of ODSs as of December 31, 2011. Epinephrine MDIs 
containing an ODS cannot be marketed after this date.

DATES:  This rule is effective December 31, 2011.

ADDRESSES:  For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov 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:  Martha Nguyen or Michelle Bernstein, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 51, rm. 6224, Silver Spring, MD 20993-
0002, 301-796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction and Highlights of the Rule
II. Background
    A. CFCs
    B. Regulation of ODSs
    1. The 1978 Rules
    2. The Montreal Protocol
    3. The 1990 Amendments to the Clean Air Act
    4. EPA's Implementing Regulations
    5. FDA's 2002 Regulation
III. Epinephrine
IV. Criteria
V. Comments on the 2007 Proposed Rule
    A. Do Substantial Technical Barriers To Formulating Epinephrine 
Products Without ODSs Exist?
    B. Do OTC Epinephrine MDIs Provide an Otherwise Unavailable 
Important Public Health Benefit?
    1. Does Epinephrine Provide a Greater Therapeutic Benefit Than 
Similar Adrenergic Bronchodilators?
    2. Does the OTC Marketing Status of Epinephrine MDIs Provide an 
Important Public Health Benefit?
    C. Does Use of OTC Epinephrine MDIs Release Cumulatively 
Significant Amounts of ODSs Into the Atmosphere and Is the Release 
Warranted Because OTC Epinephrine MDIs Provide an Otherwise Unavailable 
Important Public Health Benefit?
    D. Effective Date
    E. Additional Comments on Miscellaneous Issues
    F. 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

[[Page 69533]]

    4. Characteristics of Asthma
    5. Current U.S. Market for Epinephrine MDIs
    D. Benefits and Costs of the Final Rule
    1. Baseline Conditions
    2. Benefits of the Final Rule
    3. Costs of the Final 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. References

I. Introduction and Highlights of the Rule

    On September 20, 2007, FDA published a proposed rule in the Federal 
Register (72 FR 53711) (the proposed rule), proposing to remove the 
essential-use designation for epinephrine MDIs. Epinephrine MDIs 
containing chlorofluorocarbons (CFCs) or other ODSs cannot be marketed 
without an essential-use designation. There are three criteria that 
must all be met for epinephrine MDIs to retain their essential-use 
designation. For epinephrine MDIs to retain their essential-use 
designation, we must find that:
    1. Substantial technical barriers exist to formulating the product 
without ODSs;
    2. The product will provide an otherwise unavailable important 
public health benefit; and
    3. Use of the product does not release cumulatively significant 
amounts of ODSs into the atmosphere or the release is warranted in view 
of the otherwise unavailable important public health benefit.
    In the proposed rule, we tentatively found that no substantial 
technical barriers exist to formulating an epinephrine MDI without ODSs 
and that the release of ODSs into the atmosphere from over-the-counter 
(OTC) epinephrine MDIs is cumulatively significant. After considering 
the information received at a December 5, 2007, public meeting and 
written comments submitted in response to the proposal, FDA has 
concluded that there are no substantial technical barriers to 
formulating epinephrine as a product that does not release ODSs, and 
therefore epinephrine no longer meets the criteria to be an essential 
use of ODSs. In addition, we had proposed an effective date for this 
rule of December 31, 2010. However, in response to the public input 
received in this rulemaking, we have determined that the appropriate 
effective date for the removal of the essential-use designation for 
epinephrine MDIs is December 31, 2011. We will discuss our 
determinations on the criteria and the effective date in section V of 
this document ``Comments on the 2007 Proposed Rule.''

II. Background

A. CFCs

    Chlorofluorocarbons (CFCs) are organic compounds that contain 
carbon, chlorine, and fluorine atoms. CFCs were first used commercially 
in the early 1930s as a replacement for hazardous materials then used 
in refrigeration, such as sulfur dioxide and ammonia. Subsequently, 
CFCs were found to have a large number of uses, including as solvents 
and as propellants in self-pressurized aerosol products, such as MDIs.
    CFCs are very stable in the troposphere, the lowest part of the 
atmosphere. They move to the stratosphere, a region that begins about 
10 to 16 kilometers (km) (6 to 10 miles) above 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 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 II.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://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 192 Parties to this 
treaty.\2\ When it

[[Page 69534]]

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)). Under the treaty's rules of procedure, the Parties may make 
such an essential-use decision by a two-thirds majority vote, although, 
to date, all such decisions have been made by consensus.
---------------------------------------------------------------------------

    \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://ozone.unep.org/Meeting_Documents/
mop.
    \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.
---------------------------------------------------------------------------

    To produce or import CFCs for an essential use under the Montreal 
Protocol, a Party must request and obtain approval for an exemption at 
a Meeting of the Parties. One of the most important essential uses of 
CFCs under the Montreal Protocol is their use in MDIs for the treatment 
of asthma and chronic obstructive pulmonary disease (COPD). The 
decision on whether the use of CFCs in MDIs is ``essential'' for 
purposes of the Montreal Protocol turns on whether ``(1) It is 
necessary for the 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 states that, at the 17th Meeting of the 
Parties (in December 2005) or thereafter, no essential uses of CFCs 
will be authorized for Parties that are developed countries, unless the 
Party requesting the essential-use allocation has submitted an action 
plan. Among other items, the action plan should include a specific date 
by which the Party plans to cease requesting essential-use allocations 
of CFCs for albuterol MDIs to be sold or distributed in developed 
countries\4\ (Nairobi, Kenya, 2003).
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

     Decision XVII/5 states that Parties that are developed 
counties should provide a date to the Ozone Secretariat\5\ 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).
---------------------------------------------------------------------------

    \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://ozone.unep.org/pdfs/
viennaconvention2002.pdf. Based at the United Nations Environment 
Programme (UNEP) offices in Nairobi, Kenya, the Secretariat 
functions in accordance with Article 7 of the Vienna Convention and 
Article 12 of the Montreal Protocol.
    The main duties of the Secretariat include the following:
     Arranging for and servicing the Conference of the 
Parties, Meetings of the Parties, their Committees, the Bureaux, 
Working Groups, and Assessment Panels;
     Arranging for the implementation of decisions resulting 
from these meetings;
     Monitoring the implementation of the Vienna Convention 
and the Montreal Protocol;
     Reporting to the Meetings of the Parties and to the 
Implementation Committee;
     Representing the Convention and the Protocol; and
     Receiving and analyzing data and information from the 
Parties on the production and consumption of ODSs.
---------------------------------------------------------------------------

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

[[Page 69535]]

exceptions for ``medical devices.'' Section 601(8) (42 U.S.C. 7671(8)) 
of the Clean Air Act defines ``medical device'' as:
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

``any device (as defined in the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 321)), diagnostic product, drug (as defined in the 
Federal Food, Drug, and Cosmetic Act), or drug delivery system-
    (A) if such device, product, drug, or drug delivery system 
utilizes a class I or class II substance for which no safe and 
effective alternative has been developed, and where necessary, 
approved by the Commissioner [of Food and Drugs]; and (B) if such 
device, product, drug, or drug delivery system, has, after notice 
and opportunity for public comment, been approved and determined to 
be essential by the Commissioner [of Food and Drugs] in consultation 
with the Administrator [of EPA].''
4. EPA's Implementing Regulations
    EPA regulations implementing the Montreal Protocol and the 
stratospheric ozone protection provisions of the 1990 amendments are 
codified in part 82 of title 40 of the Code of Federal Regulations (40 
CFR part 82). (See 40 CFR 82.1 for a statement of intent.) Like the 
1990 amendments, EPA's implementing regulations contain two separate 
prohibitions, one on the production and import of CFCs (subpart A of 40 
CFR part 82) and the other on the sale or distribution of products 
containing CFCs (40 CFR 82.66).
    The prohibition on production and import of CFCs contains an 
exception for essential uses and, more specifically, for essential 
MDIs. The definition of essential MDI at 40 CFR 82.3 requires that the 
MDI be intended for the treatment of asthma or COPD, be essential under 
the Montreal Protocol, and if the MDI is for sale in the United States, 
be approved by FDA and listed as essential in FDA's regulations at 
Sec.  2.125 (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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    This rulemaking fulfills our obligation under Sec.  2.125, as well 
as the Clean Air Act, the Montreal Protocol, and our general duty to 
protect the public health, by removing ODS products from the 
marketplace when those products are no longer essential.

III. 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 
Consumer Healthcare (Wyeth) and Armstrong Pharmaceuticals, Inc. 
(Armstrong) (a subsidiary of Amphastar Pharmaceuticals, Inc.). Wyeth 
markets its 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.\8\ Customers do not need 
a prescription from a health care provider to purchase OTC epinephrine 
MDIs. Wyeth has estimated that 2 to 3 million people with asthma use 
OTC epinephrine MDIs.\9\ 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,\10\ we can estimate 
that approximately 23 million people in the United States currently 
have asthma.
---------------------------------------------------------------------------

    \8\ 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 Antiashthmatic 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.
    \9\ This information was presented at a joint committee meeting 
of the Nonprescription Drug Advisory Committee and Pulmonary-Allergy 
Drugs Advisory Committee (NDAC/PADAC) held on January 24, 2006 
(meeting transcript p. 51, Wyeth slide 19). The transcript of the 
NDAC/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://www.fda.gov/ohrms/dockets/ac/
cder06.html.
    \10\ 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://
www.census.gov/population/www/popclockus.html.
---------------------------------------------------------------------------

    Epinephrine is also an active ingredient in many other drug 
products. For example, it is used in a self-

[[Page 69536]]

injectable dosage form for treatment of severe allergic reactions. 
EPIPEN is a specific example of epinephrine in this dosage form. This 
rulemaking does not affect the availability of these drug products. It 
only affects OTC epinephrine MDIs, which contain CFCs.

IV. Criteria

    The 2002 final rule revised 21 CFR Sec.  2.125(g)(2) to establish a 
standard for removing an essential-use designation after January 1, 
2005, for any drug for which there is no acceptable non-ODS alternative 
with the same active moiety. As explained in the proposed rule, we are 
reviewing the essential-use designation for epinephrine under that 
authority. 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 (21 
CFR Sec.  2.125(g)(2)). The criteria in Sec.  2.125(f) are: ``(i) 
Substantial technical barriers exist to formulating the product without 
ODSs; (ii) The product will provide an unavailable important public 
health benefit; and (iii) Use of the product does not release 
cumulatively significant amounts of ODSs into the atmosphere or the 
release is warranted in view of the unavailable important public health 
benefit.''
    The three criteria in Sec.  2.25(f)(1) are linked by the word 
``and.'' Because the three criteria are linked by ``and'' (as opposed 
to ``or''), failure to meet any single criterion results in a 
determination that the use is not essential.
    The criteria in Sec.  2.125(g)(2) (which refers to those found in 
Sec.  2.125(f)(1)) that we are using in this rulemaking are different 
from those in Sec.  2.125(g)(3) and (g)(4). Section 2.125(g)(2) 
specifically addresses the situation where there is no marketed non-ODS 
product containing the active moiety listed as an essential use, while 
Sec.  2.125(g)(3) and (g)(4) apply to situations where there is at 
least one marketed non-ODS product with the listed active moiety. 
Section 2.125(g)(2) permits FDA to remove an essential use even if a 
current essential-use active moiety is not reformulated, provided that 
sufficient alternative products exist to meet the needs of patients, 
because the essential use would no longer provide an otherwise 
unavailable important health benefit. As we explained in the proposed 
rule, the analysis we use here is different than the analysis we used 
under Sec.  2.125(g)(4) in the rulemaking to remove the essential use 
for albuterol (70 FR 17168, April 4, 2005). However, the basic concern 
of protecting the public health underlies all of the criteria. 
Therefore, our analyses are similar, and we have found it useful to 
borrow concepts from the more specific provisions of Sec.  2.125(g)(3) 
and (g)(4) to help give more structure to our analysis under the 
broader language of Sec.  2.125(f)(1).
    Section 2.125(g)(2) requires that we consult an advisory committee 
and hold an open public meeting before we remove an essential-use 
designation when there is no non-ODS product with the same active 
moiety. Prior to publishing the proposed rule, on January 24, 2006, we 
convened a joint meeting of the Nonprescription Drug Advisory Committee 
(NDAC) and the Pulmonary and Allergy Drugs Advisory Committee (PADAC) 
on the essential-use status of OTC MDIs containing epinephrine. (NDAC/
PADAC meeting).\11\ Presentations were made by representatives of Wyeth 
Consumer Healthcare (Wyeth), two patient advocacy and public policy 
groups, and physician organizations. With regard to the criteria for 
removing the epinephrine essential-use designation, a presenter from 
Wyeth expressed concern about reformulating an epinephrine product 
without ODSs; however, no specific technical barriers to reformulation 
efforts were presented. In addition, some information on the 
therapeutic benefits of epinephrine CFC MDIs was presented and 
discussed at length by Wyeth, but many on the panel questioned the 
information presented, and the consensus opinion was that epinephrine 
CFC MDIs present no significant therapeutic benefit and no advantage 
over albuterol MDIs.
---------------------------------------------------------------------------

    \11\ 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://
www.fda.gov/ohrms/dockets/ac/cder06.html.
---------------------------------------------------------------------------

    Opinions concerning the public health benefits of having an OTC MDI 
were also expressed, such as the convenience of having an OTC MDI for 
asthma. Some participants believed 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. They asserted that many of these people with asthma who use OTC 
epinephrine MDIs do so because of barriers to obtaining health care. 
One speaker from a patient advocacy organization expressed the point 
that the longer duration of effect of albuterol and levalbuterol (and 
other newer prescription drugs that do not release ODSs) means that, 
while these drugs are more expensive per MDI and per dose, they may be 
cheaper than OTC epinephrine MDIs when the price is calculated for the 
number of inhalations needed per day. No data were provided, however, 
to support this assertion.
    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. Issues 
considered were whether asthma was being properly diagnosed and treated 
by purchasers of OTC epinephrine CFC MDIs. 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 proposed rule contains a more extensive discussion of the 
NDAC/PADAC meeting and the views that were expressed at the meeting.
    On December 5, 2007, following publication of the proposed rule, we 
held the required open public meeting to discuss the issues involved in 
removing the essential-use designation for epinephrine MDIs (see the 
Federal Register of November 8, 2007 (72 FR 63141)). Presentations were 
made by a representative of Amphastar Pharmaceuticals and Armstrong (a 
wholly owned subsidiary of Amphastar, which manufactures and 
distributes epinephrine CFC MDIs) and by a patient advocacy 
organization. The Armstrong representative stated that Armstrong did 
not oppose the proposal to eliminate the essential-use status for 
epinephrine, but requested postponing the effective date until December 
31, 2011, to allow sufficient time for development and approval of an 
HFA-propelled epinephrine MDI before the CFC-containing MDI is phased 
out. The representative further stated that Armstrong anticipates being 
able to successfully develop and receive approval for a non-ODS 
epinephrine product by the beginning of 2011 and begin marketing by the 
end of 2011. The representative stated that removing OTC epinephrine 
from the market and attempting to switch patients to prescription 
medications will, in Armstrong's view, have significant costs and 
health consequences, which can be avoided by extending the effective 
date to allow time for a non-ODS OTC epinephrine product to be 
developed before the current product is phased out.
    The patient advocacy organization presented results of two surveys, 
one directed to patients and the other

[[Page 69537]]

directed to medical professionals, on the essential-use status of OTC 
epinephrine. This organization found that the results demonstrated that 
CFC-propelled OTC epinephrine does not present a public health benefit 
worthy of continued essential-use exemption. In summary, medical 
professionals surveyed did not recommend the use of OTC epinephrine 
because it is an antiquated therapy, does not keep patients out of the 
emergency room or hospital, and asthma should be treated by a medical 
professional. According to the patient advocacy organization, the 
results of the patient survey showed that many patients do not have an 
appreciation for the seriousness of their condition and that the OTC 
drug is not keeping patients out of the emergency room or hospital. 
They also showed that patients and parents of pediatric patients 
overwhelmingly do not think removal of OTC epinephrine will seriously 
affect them. Input from the open public meeting is considered and 
discussed in section V together with the written comments that were 
submitted in response to the proposed rule.

V. Comments on the 2007 Proposed Rule

    We received 32 written and electronic comments in response to the 
proposed rule. They were submitted by consumers, health care providers, 
a patient advocacy group, professional groups, manufacturers, an 
international governmental organization, and industry organizations. 
The speakers who participated in the open public meeting on December 5, 
2007, also submitted written comments. In the discussion that follows, 
we address all the comments submitted in response to this rulemaking, 
the oral presentations and written comments submitted at or following 
the open public meeting, and the written and electronic comments 
submitted to the docket in response to the 2007 proposed rule.
    To make it easier to identify comments and our responses, the word 
``Comment,'' in parentheses, appears before the comment's description, 
and the word ``Response,'' in parentheses, appears before our response. 
We have numbered each comment to help distinguish between different 
comments. Similar comments are grouped together under the same comment 
number. The number assigned to each comment is purely for 
organizational purposes and does not signify the comment's value or 
importance or the order in which it was received.
    In reviewing these comments we are particularly focused on our 
proposed findings relating to the criteria in Sec.  2.125(f) of our 
regulations. As discussed above, we must remove the essential-use 
designation for the CFC-containing epinephrine drug product unless we 
find that all of the following are met: (1) Substantial technical 
barriers exist to formulating the product without ODSs; (2) the product 
provides an otherwise unavailable important public health benefit; and 
(3) use of the product does not release cumulatively significant 
amounts of ODSs into the atmosphere or, if the release is significant, 
it is warranted in view of the otherwise unavailable important public 
health benefit. As discussed in the proposed rule, the failure to meet 
any one of these criteria must result in our determination that the use 
is not essential.

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

    We proposed to find that there are no technical barriers to 
formulating epinephrine MDIs without ODSs (72 FR 53711 at 53718). As 
noted in the proposed rule, we intend the term ``technical barriers'' 
to refer to difficulties encountered in chemistry and manufacturing. To 
demonstrate that substantial technical barriers exist, it would have to 
be established that all available alternative technologies have been 
evaluated and that each alternative is unusable (67 FR 48370 at 48373). 
In applying the ``technical barriers'' criterion, we looked 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.
    We did not receive any comments disagreeing with this tentative 
conclusion or otherwise addressing the conclusion in any substantive 
way. Indeed, in the context of its request for an effective date of 
December 31, 2011, discussed elsewhere in this document, the 
manufacturer of OTC epinephrine MDIs submitted comments suggesting that 
it would be ready to commercially produce and legally distribute, and 
have the capacity to meet current market demand for, a non-CFC 
alternative epinephrine MDI by 2011.
    As noted in the proposed rule, as of this time, 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.\12\ 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 HFA), there appears to be no technical reason why epinephrine 
cannot be successfully reformulated into an HFA MDI. Therefore, after 
consideration of the public comments on the issue, we finalize our 
tentative conclusion that there are no technical barriers to the 
development of a non-ODS epinephrine product.
---------------------------------------------------------------------------

    \12\ 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.
---------------------------------------------------------------------------

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

    In the proposed rule, we solicited comments on the public health 
benefits of OTC epinephrine MDIs (72 FR 53711 at 53718). In discussing 
what is ``an unavailable important public health benefit,'' we have 
said: The agency intends to give the phrase ``unavailable important 
public health benefit'' a markedly different construction from the 
[phrase used in the 1978 rule] ``substantial health benefit.'' A 
petitioner should show that the use of an ODS-containing MDI would save 
lives, significantly reduce or prevent an important morbidity, or 
significantly increase patient quality of life to support a claim of 
important public health benefit (64 FR 47719 at 47722). One key point 
to note here is that the 2002 final rule (67 FR 48370) raised the 
hurdle for the public health benefit that needs to be shown. A use that 
was shown to have a ``substantial health benefit'' under the 1978 rule 
(all essential uses were established under the 1978 rule), will not 
necessarily be able to clear the higher hurdle of the 2002 final rule's 
``unavailable important public health benefit.''
    In determining whether a drug product provides an otherwise 
unavailable important public health benefit, our primary focus is on 
the availability of non-ODS products that provide similar therapeutic 
benefits for patients who are currently using the CFC MDIs. If 
therapeutic alternatives exist for everyone using the CFC MDI, we can 
determine that the CFC MDI does not provide an otherwise

[[Page 69538]]

unavailable important public health benefit. In determining whether 
everyone is adequately served by the therapeutic alternatives, in the 
case of epinephrine MDIs, we take into consideration the fact that they 
are marketed OTC, while the therapeutic alternatives for epinephrine 
MDIs are prescription drugs. Because we have reached a conclusion that 
there are no substantial technical barriers to formulating epinephrine 
into a non-ODS product, we do not believe it is necessary to reach a 
conclusion on the public health benefits of OTC epinephrine MDIs. 
However, we received several comments in response to the proposed rule 
addressing the public health benefits of OTC epinephrine MDIs, and we 
believe it is appropriate to address the public health benefits in 
light of these comments.
1. Does Epinephrine Provide a Greater Therapeutic Benefit Than Similar 
Adrenergic Bronchodilators?
    (Comment 1) Several comments from epinephrine users stated that 
their experience indicates that epinephrine CFC MDIs are more effective 
than other asthma MDIs, including HFA MDIs, and that there are no 
alternatives.
    (Response) Albuterol and epinephrine are both adrenergic 
bronchodilators. Epinephrine is a non-selective beta adrenergic 
bronchodilator. Other available bronchodilators, including albuterol, 
are selective beta-2 adrenergic bronchodilators. Bronchodilation occurs 
primarily through stimulation of the beta-2 adrenergic receptor. 
Albuterol MDIs are therapeutic alternatives to OTC epinephrine MDIs and 
are, by far, the most widely prescribed short-acting bronchodilators. 
We are not aware of any data that support the commenter's contention 
that albuterol inhalers are not an appropriate alternative for 
epinephrine inhalers.
    Four prescription HFA MDIs with two different forms of albuterol 
are approved and currently available:
     ProAir HFA (albuterol sulfate) Inhalation Aerosol;
     Proventil HFA (albuterol sulfate) Inhalation Aerosol;
     Ventolin HFA (albuterol sulfate) Inhalation Aerosol; and
     Xopenex HFA (levalbuterol tartrate) Inhalation Aerosol.
    These products use HFA as a replacement for ODSs, which does not 
affect stratospheric ozone. The consensus at the NDAC/PADAC meeting, 
held prior to publication of the proposed rule, was that OTC 
epinephrine MDIs presented no significant therapeutic advantage over 
albuterol MDIs (72 FR 53711 at 53719). In addition, we are not aware of 
any adequate and well-controlled studies which support the commenters' 
view that epinephrine CFC MDIs are more effective than other asthma 
MDIs, including HFA MDIs.
    (Comment 2) One comment stated that the OTC epinephrine CFC MDI is 
the fastest acting [asthma] inhaler.
    (Response) Prior to publishing the proposed rule, we were presented 
with clinical data indicating that OTC epinephrine MDIs may be slightly 
quicker to onset of action than albuterol MDIs, although they have a 
significantly shorter duration of action. This slightly quicker onset 
of action may explain why some people with asthma describe OTC 
epinephrine MDIs as working better than other prescription inhalers for 
asthma. In the proposed rule, we stated that there were no clinical 
data to support a conclusion that this perceived quicker relief 
provided by epinephrine leads to better outcomes or that epinephrine 
CFC MDIs are more effective than other asthma MDIs, including HFA MDIs. 
No new data were submitted in response to the proposed rule or at the 
public meeting that would support the conclusion that epinephrine leads 
to better outcomes than albuterol MDIs for asthma.
    In fact, at the open public meeting held after publication of the 
proposed rule, one organization presented results of a survey of 
medical professionals who overwhelmingly recommended against use of OTC 
epinephrine by asthma patients because they believe it is an antiquated 
therapy and does not work as well as prescription inhalers (December 5, 
2007, hearing transcript at 25-34, available at http://www.fda.gov/
cder/meeting/ozone-dec2007.htm). In addition, the NAEPP EPR-3 
recommends against epinephrine's use and recommends that short acting 
beta-2 adrenergic bronchodilators are the most effective medication for 
relieving acute bronchospasm.\13\
---------------------------------------------------------------------------

    \13\ In the United States, the generally recognized standard of 
care for asthma is set forth in the National Heart, Lung, and Blood 
Institute's National Asthma Education and Prevention Program, Expert 
Panel Report 3: Guidelines for the Diagnosis and Management of 
Asthma (EPR-3) (Ref. 2). The National Heart, Lung, and Blood 
Institute is one of the National Institutes of Health. In the 2007 
update, we find the latest updates to the standard. The Guidelines 
represent best practices and are recognized as the clinical standard 
of care for treatment of asthma. See, e.g., http://
www.asthmanow.net/care.html; http://www.colorado.gov/bestpractices/
index.html; http://www.doh.wa.gov/CFH/asthma/publications/plan/
health-care.pdf.
---------------------------------------------------------------------------

    (Comment 3) One comment stated that no other bronchodilators attach 
to the same receptors in the lungs as epinephrine, apparently 
suggesting that epinephrine has a unique mechanism of action and may 
therefore provide a unique therapeutic benefit.
    (Response) Epinephrine is a nonselective beta adrenergic 
bronchodilator. Other available bronchodilators, including albuterol, 
are selective beta-2 adrenergic bronchodilators. Both epinephrine and 
albuterol achieve bronchodilation primarily via the beta-2 adrenergic 
receptor; therefore, they both bind to the same receptor that causes 
bronchodilation. Accordingly, we disagree with the commenter's 
implication that the OTC epinephrine MDIs provide any unique 
therapeutic or other advantage over the available alternatives.
    We have carefully considered these comments asserting that 
epinephrine MDIs are more effective and/or faster acting than other 
asthma MDIs or provide some unique therapeutic benefit. However, no 
data were submitted to the Agency as part of this rulemaking and the 
Agency is not aware of any data that allow us to reach the conclusion 
that epinephrine provides a greater therapeutic benefit than similar 
adrenergic bronchodilators.
2. Does the OTC Marketing Status of Epinephrine MDIs Provide an 
Important Public Health Benefit?
    Our discussion on the public health benefit of OTC epinephrine CFC 
MDIs must take into consideration the fact that they are marketed OTC, 
while the therapeutic alternatives for epinephrine MDIs are 
prescription drugs.
    (Comment 4) We received several comments that expressed concern 
that removing the essential-use designation for epinephrine would 
eliminate an OTC asthma treatment option that should be available for 
low-income, elderly, and uninsured individuals. Several comments 
asserted that most individuals cannot afford private health insurance, 
and that physician visits and prescription medications are cost-
prohibitive. Another comment stated that prescription bronchodilators 
are very expensive when compared to epinephrine CFC MDIs, and removal 
of the essential-use designation would result in increased health care 
costs. Another comment questioned why we were removing a product that 
lowered health care costs. We also received three comments emphasizing 
the importance of access to an OTC rescue MDI available for 
emergencies. One comment further stated that ambulances and emergency 
room visits are more costly than epinephrine CFC MDIs.
    (Response) In the proposed rule, we recognized that a small 
population of

[[Page 69539]]

people with asthma who face barriers to health care may derive some 
benefit from having OTC epinephrine MDIs available OTC. However, we 
noted that use of programs providing low-cost or free prescription 
drugs and the availability of physician samples may reduce the number 
of people with asthma who face barriers to health care and depend on 
OTC epinephrine MDIs and minimize the adverse impact that may result 
from the absence of OTC epinephrine MDIs. In addition, OTC epinephrine 
MDIs are not available through low-cost drug plans. Prescription drugs 
obtained through these programs can be substantially less expensive 
than OTC epinephrine MDIs for people who can and do avail themselves of 
these programs. Finally, there are ways patients may modify their 
behavior in order to minimize the impact of elimination of OTC 
epinephrine MDIs, including buying fewer MDIs to keep in different 
locations. Considering the availability of programs providing low-cost 
or free prescription drugs that would allow low-income, elderly, and 
uninsured individuals to purchase alternative MDIs, and the 
availability of physician samples, we believe that patients will be 
adequately served by alternative MDIs.
    We understand that 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 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 so that 
appropriate treatment plans can be made. In the proposed rule, we noted 
that no evidence had been presented to indicate how asthma differs from 
other serious diseases in a way that necessitated having an OTC 
treatment available. We did not receive any additional information, 
either in written comments or testimony at the public meeting, that 
contradicted the view expressed in the proposed rule that asthma is a 
serious disease, comparable to other serious diseases that require 
evaluation and treatment by a health care professional, that would 
enable us to reach the conclusion that an OTC treatment option for 
asthma is absolutely essential to the public health.
    (Comment 5) One comment stated that epinephrine MDIs permit a user 
to visually determine how much medication is still in the MDI, 
presumably making it more convenient to use than other available 
substitute MDIs.
    (Response) OTC epinephrine MDIs, in fact, do not have a dose 
counter but do permit the user to see the amount of product remaining 
in the canister. An available therapeutic alternative, Ventolin HFA 
Inhalation Aerosol (Glaxo Smith Kline), contains a dose counter to 
track the number of doses remaining. Accordingly, this type of feature 
is not unique to OTC epinephrine MDIs. Moreover, we do not believe that 
this type of patient convenience would provide a basis to conclude that 
a product provides an otherwise unavailable health benefit.
    (Comment 6) We received comments from patient advocacy and health 
care provider associations stating that self-medication of any inhaled 
medication to treat respiratory conditions without any clinical input 
from health care professionals to instruct and train the user can, in 
fact, endanger the health of the patient. Some comments stated, in 
particular, that epinephrine CFC MDIs should be removed from the market 
because they are not recommended by the National Heart, Lung, and Blood 
Institute's asthma treatment guidelines (Guidelines for the Diagnosis 
and Management of Asthma) and their OTC availability makes it difficult 
for health care professionals to monitor asthmatics' conditions and 
provide appropriate care. A patient advocacy group, in a written 
comment and at the December 2007 public meeting, asserted that medical 
professionals generally recommend against use of OTC epinephrine 
because asthma is a potentially life-threatening condition that should 
not be self-diagnosed or treated and because OTC epinephrine does not 
work as well as other treatments and has more unwanted side effects.
    (Response) In the proposed rule, we evaluated the risks of self-
treatment of asthma against the public health benefits that OTC 
epinephrine MDIs may provide. We noted that OTC epinephrine MDIs are 
only indicated for mild intermittent asthma and acknowledged the 
importance of obtaining a physician's diagnosis of asthma before using 
an OTC epinephrine MDI, as specified in the approved OTC epinephrine 
labeling. In addition, we noted the importance of patient education on 
such issues as how asthma affects the lungs, the difference between 
medications, consideration of environmental control measures, and 
proper use of an MDI. We also noted the possible effects of 
undertreatment of asthma, such as more frequent symptoms and attacks, 
missed work and school, activity limitations, fewer hospitalizations, 
emergency department visits and outpatient visits, a decline in lung 
health and function, and possibly, death. Finally, we noted that 
purchasers of OTC epinephrine MDIs who are self-treating may not 
provide important information to a health care provider that would 
allow the health care provider to accurately assess and advise on the 
patient's use of asthma inhalers.
    In addition to providing proper diagnosis and instructions in the 
use of bronchodilators, health care professionals often prescribe 
additional or alternative prescription medications, such as inhaled 
steroids, to certain asthma patients who can benefit from this therapy. 
As described in the proposed rule, the treatment guidelines recommend 
use of an inhaled corticosteroid for treatment in most classes of 
asthma severity: 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 
adrenergic bronchodilators 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). Taken properly, these drugs can actually improve the 
patient's condition (i.e., do more than just treat symptoms). As noted 
in the proposed rule, proper prescribing and use of inhaled steroids 
significantly reduces asthma morbidity. Specifically, the proposed rule 
cited a study of urban pediatric patients in which increased use of 
corticosteroids in accordance with the treatment guidelines resulted in 
fewer hospitalizations, emergency department visits, and outpatient 
visits. However, only patients who are seen by a qualified health care 
provider can benefit from this additional therapy. Thus, patients who 
are self-treating with OTC remedies will be foregoing such additional 
beneficial treatment. While we do not dismiss the impact of increased 
costs of prescription drugs to the patient, as discussed above, we 
believe that the general improvement in respiratory health that will 
result through consultation with a healthcare provider in terms of 
proper diagnosis,

[[Page 69540]]

treatment, and patient training in the use of MDIs is an important 
consideration. Accordingly, we believe that there are clear public 
health benefits that might accrue if fewer asthma patients self-
diagnose and self treat with OTC drugs, including epinephrine.
    In the proposed rule, we specifically requested comments on the 
expected costs and public health effects if OTC epinephrine MDIs were 
removed from the market without a similar product being available OTC 
(72 FR 53711 at 53724). Other than the comments described above, we 
received no data or information in response to our request. Because we 
received no new data or information on this issue, and given the 
evidence of significant benefit to asthma patients who seek assessment 
and treatment by a professional, rather than self-treating, we 
therefore agree with the commenter that the public health benefits that 
would result from increased assessment and treatment of asthma patients 
by a health care professionals may be significant.
    We recognize that epinephrine MDIs may provide some public health 
benefits; however, nothing in this rulemaking suggests that continued 
use of OTC epinephrine MDIs provides an unavailable important health 
benefit as previously defined. We do not believe that we can conclude 
on the basis of the record in this rulemaking that continued use of OTC 
epinephrine MDIs is necessary to save lives, to reduce or prevent 
asthma morbidity, or to significantly increase patient quality of life, 
particularly given the availability of albuterol MDIs as therapeutic 
alternatives, and the possibility that, in the absence of the OTC drug 
product, additional patients may seek assessment and treatment for 
their asthma conditions from health care professionals and reduce their 
asthma morbidity as a result.
    Based on the record in this rulemaking, we therefore remain very 
doubtful that the OTC availability of epinephrine constitutes an 
otherwise unavailable public health benefit. Given that we have already 
found no technical barriers to reformulation of OTC epinephrine MDIs 
under Sec.  2.125(g)(2), a finding on the public health benefit issue 
is not necessary to this rulemaking, and we decline to make a specific 
finding on that issue in this final rule.

C. Does Use of OTC Epinephrine MDIs Release Cumulatively Significant 
Amounts of ODSs Into the Atmosphere and Is the Release Warranted 
Because OTC Epinephrine MDIs Provide an Otherwise Unavailable Important 
Public Health Benefit?

    As explained in the proposed rule, because the three criteria in 
Sec.  2.125(f)(1) are linked by the word ``and,'' failure to meet any 
single criterion results in a determination that the use is not 
essential. Accordingly, because we have found in this rule that there 
are no substantial barriers to reformulating the product, we are 
required to find that the use of the product is not essential, and we 
do not need to reach a decision on the third criterion in Sec.  
2.125(f)(1). The third criterion in Sec.  2.125(f)(1), provides that 
the essential use must be eliminated unless we find either: (a) The use 
of the product does not release cumulatively significant amounts of 
ODSs into the atmosphere; or (b) the release, although cumulatively 
significant, is warranted in view of the otherwise unavailable 
important public health benefit that the use of the drug product 
provides.
    Based on an extensive record dating back to the 1970's, we reached 
a tentative conclusion in the proposed rule that the release of ODSs 
into the atmosphere from OTC epinephrine is cumulatively significant. 
We noted that the use of CFCs in MDIs for the treatment of asthma and 
COPD is the only legal use in the United States of newly manufactured 
CFCs. We noted that the environmental impact of individual uses of 
nonessential CFCs must not be evaluated independently, but rather must 
be evaluated in the context of the overall use of CFCs. Cumulative 
impacts can result from individually minor, but collectively 
significant, actions that take place over a period of time (40 CFR 
1508.7). The 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. 
Accordingly, we tentatively concluded that any release of CFCs from OTC 
epinephrine MDIs is cumulatively significant. (72 FR 53711 at 53715 and 
53724).
    (Comment 7) Several comments asserted that CFCs used in epinephrine 
CFC MDIs do not have an adverse impact on the environment because the 
CFCs are inhaled rather than released into the environment.
    (Response) Nearly all of the CFCs inhaled into the lungs from an 
MDI are almost immediately exhaled into the environment. The small 
amounts of CFCs absorbed into the body are later excreted and exhaled 
without being broken down. Essentially all of the CFCs released from an 
MDI end up in the atmosphere with resulting harm to the stratospheric 
ozone layer.
    (Comment 8) A few comments asserted that the amount of ODSs 
released from epinephrine CFC MDIs is insignificant, and eliminating 
their use would not provide a significant environmental benefit. One 
comment also stated that the impact of CFCs on the ozone layer is much 
less than previously believed.
    (Response) The United States evaluated the environmental effect of 
eliminating the use of all CFCs in an environmental impact statement 
(EIS) in the 1970s (see 43 FR 11301, March 17, 1978) (the 1978 rule). 
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. 96N-0057). In 1990, 
Congress enacted Title VI of the Clean Air Act, which codified the 
decision to fully phase out the use of CFCs over time. Congress did not 
assign us the task of determining what amount of environmental benefit 
would result from the removal of CFC-containing medical devices, 
diagnostic products, drugs, and drug delivery systems from the market. 
Congress did instruct us to determine whether such products are 
essential. This rulemaking fulfills that obligation with respect to 
epinephrine CFC MDIs. Moreover, as we stated in the proposed rule, the 
release of CFCs from epinephrine MDIs is currently significant and as 
the phaseout continues throughout the world, the significance of the 
quantities of CFCs released by epinephrine MDIs will, actually, 
increase. (72 FR 53715).
    We received no additional comments disagreeing with our tentative 
conclusion in the proposed rule that any release of CFCs from OTC 
epinephrine MDIs is cumulatively significant, or addressing this 
conclusion in any substantive way. We therefore finalize our conclusion 
that any release of an ODS into the atmosphere from OTC epinephrine 
MDIs is cumulatively significant. However, because we have not reached 
a conclusion on the public health benefits of OTC epinephrine MDIs, we 
cannot conduct the balancing test to reach a determination as to 
whether the release of CFC ODSs is warranted in view of the public 
health benefits. This does not effect the ultimate finding in this 
rulemaking that, because there are no significant technical barriers to 
reformulation of the

[[Page 69541]]

product, OTC epinephrine MDIs are no longer an essential use of ODSs 
and should be removed from the list of essential uses in Sec.  
2.125(e).

D. Effective Date

    We proposed an effective date for removal of the essential-use 
designation for OTC epinephrine MDIs of December 31, 2010, and we 
solicited comments on this proposed effective date. We received a 
number of comments on the effective date and on the related issue of 
insuring adequate time to transition patients who use OTC epinephrine 
MDIs to non-CFC alternatives. After considering the comments, we were 
persuaded that December 31, 2011, rather than December 31, 2010, as 
proposed, is a more appropriate effective date for this rule. The 
December 31, 2011 date provides additional time to disseminate 
information about the transition to OTC epinephrine MDI users and 
allows these individuals more time to transition to appropriate non-CFC 
alternatives. It also allows sufficient time for manufacturers to 
increase production of albuterol HFA MDIs to ensure adequate supplies 
of albuterol HFA MDIs for all patients who need them, including current 
OTC epinephrine MDI users who transition to albuterol HFA MDIs. 
Finally, while the availability of a non-CFC OTC replacement product 
for the OTC epinephrine MDIs is not necessary for this rulemaking, we 
believe a December 31, 2011, effective date gives sufficient time for 
the development of a non-CFC formulation of epinephrine MDIs and 
processing of an application for new drug approval for a drug that was 
previously the subject of an approved application and is being 
submitted for approval with a new formulation. In our responses to the 
comments below, we further explain the basis for our decision to extend 
the effective date by one year from that proposed.
    (Comment 9) One comment urged an effective date of December 31, 
2008, because all essential uses that destroy the ozone layer, 
including epinephrine, should be totally banned.
    (Response) We disagree with this comment that a 2008 effective date 
would be appropriate. FDA has been committed to a vigorous and 
consistent policy of limiting the production, use, and importation of 
CFCs. In this regard, we have already removed, or proposed to remove, 
the essential-use designation for a number of drugs, including 
albuterol MDIs. See 70 FR 17168 (Apr. 4, 2005), 71 FR 70870 (Dec. 7, 
2006), as confirmed at 72 FR 20942 (Apr. 27, 2007), 72 FR 32030 (June 
11, 2007). We agree with the commenter that CFC-containing medical 
products should eventually be completely phased out. However, in 
addition to considering the environmental impact of CFCs, it is 
important to balance public health issues related to eliminating a 
treatment option for certain individuals with serious health concerns. 
In determining an appropriate effective date, we must provide 
sufficient time to permit an orderly transition for patients who rely 
on these drugs. Accordingly, we decline to follow the recommendation of 
this commenter that we adopt an earlier effective date of December 31, 
2008. We believe that the effective date (see the DATES section of this 
document) that we are establishing in this final rule appropriately 
balances our duty to protect the public health and our various legal 
obligations as described elsewhere in this rule.
    (Comment 10) We received a number of comments in support of the 
proposed December 31, 2010, effective date. One comment from a 
manufacturer of epinephrine CFC MDIs expressed disappointment in FDA's 
proposal to remove the essential-use designation for epinephrine but 
agreed that the proposed effective date of December 31, 2010, is 
required to provide consumers with sufficient time to transition to 
other asthma treatments. One comment from a patient advocacy 
organization supported our proposed effective date of December 31, 
2010, on the basis that epinephrine CFC MDIs do not provide a public 
health benefit, are not recommended by the National Guidelines for the 
Diagnosis and Management of Asthma, and do not meet the criteria for 
essential-use exemptions.
    (Comment 11) Several comments urged us to adopt a later 
implementation date than that proposed. One comment asked that we set 
an effective date that allows reasonable time to develop a non-CFC 
replacement for epinephrine CFC MDIs. One comment asked FDA to 
encourage pharmaceutical companies to develop a non-CFC formulation for 
epinephrine CFC MDIs. Two comments urged that we work with 
manufacturers to develop an inhaler that does not contain CFCs. A 
manufacturer of OTC epinephrine MDIs submitted two comments that both 
stated that it is in the process of transitioning to a new propellant 
and projects that it will not be ready to commercially produce and 
legally distribute a non-CFC alternative until 2011. This manufacturer 
believes that it will be able to meet current market demand for 
epinephrine MDIs and transition to a non-CFC formulation by December 
31, 2011, and therefore requested that FDA set an effective date of 
December 31, 2011.
    One comment was concerned that there would be inadequate time to 
transition patients to CFC-free MDIs. The comment urged FDA to begin 
proactive planning immediately to transition patients to available CFC-
free alternatives by collecting relevant data regarding production 
capacity and supply from manufacturers of CFC-free alternatives, 
actively exploring opportunities with the manufacturers of both CFC 
epinephrine drugs and of the CFC-free alternatives on possible means to 
promote timely and effective patient education, and by obtaining 
relevant information on patient assistance programs available from MDI 
manufacturers.
    (Response) As stated above, we carefully evaluated the comments 
submitted in response to the 2007 proposed rule and have determined 
that an effective date of December 31, 2011, is appropriate for the 
removal of the essential-use designation for epinephrine. While we 
believe that the presence of a non-CFC replacement for the epinephrine 
product may be convenient for users and a December 31, 2011 effective 
date allows a reasonable time to permit the development of a non-CFC 
replacement, we do not believe it is necessary for the purposes of this 
rulemaking. Currently, there are adequate non-CFC alternatives 
available in the form of HFA albuterol MDIs which are marketed as 
prescription drugs. Both albuterol and epinephrine MDIs are in the same 
therapeutic class (adrenergic bronchodilators), and albuterol MDIs are 
therapeutic alternatives to epinephrine. The effective date we are 
establishing for the removal of the essential-use designation for 
epinephrine provides an additional year for manufacturers to scale up 
production of albuterol HFA MDIs and will help ensure that there will 
be adequate supplies of albuterol HFA MDIs for all patients who need 
them, including those now using epinephrine MDIs. In choosing December 
31, 2011, rather than 2010, as the effective date of this rule, we are 
providing additional assurance that adequate supplies and production 
capacity of albuterol HFA MDIs will exist by that time.
    In addition, in the event a non-CFC formulation of epinephrine MDI 
is not developed, the December 31, 2011, date will allow adequate time 
to transition patients using epinephrine MDIs to albuterol MDIs. We 
believe that educating patients and health care providers about the 
transition to other asthma treatments is very important to an orderly 
and safe transition of patients

[[Page 69542]]

currently using OTC epinephrine. The need to ensure that we have 
permitted sufficient time for patient education for transitioning from 
OTC epinephrine CFC MDIs to an appropriate non-CFC substitute was an 
important factor in our decision to extend the proposed effective date 
by 1 year in this final rule, to December 31, 2011. Because epinephrine 
CFC MDIs are sold OTC, many purchasers do not interact with a doctor, 
pharmacist, or other health care provider who would normally 
disseminate information about the transition. Therefore, additional 
avenues of communication will be needed to communicate information to 
users about the transition away from OTC epinephrine CFC MDIs. For 
example, some OTC epinephrine CFC MDI users may need information to 
help them select a physician, and some may need time to find and avail 
themselves of free or low-cost health care and prescription drug 
programs. We realize that it will take some time to prepare and 
distribute educational materials before the final transition begins. 
The additional year from the proposed date of December 31, 2010, will 
provide for a longer transition period and ensure there is adequate 
time to disseminate transition information to OTC epinephrine CFC MDI 
users and sufficient time for these users to transition to an 
appropriate non-CFC substitute. Although we are cognizant of the 
environmental benefits and associated public health benefits of 
removing the essential-use designation of OTC epinephrine MDIs, as we 
discussed in reference to comments supporting such removal, we are 
equally cognizant of the treatment needs of asthma patients and the 
need to provide an adequate period of time for transition. In 
determining the appropriate length of the phase-out, we have also taken 
into account our recent experience with the on-going phase-out of CFC-
containing albuterol products. While we are confident that the 
albuterol phase-out remains on track, given the fact that patients here 
may have additional decisions to make, in that they may need to both 
find a health care provider and switch to a drug with a different 
active moiety, we believe the additional year from that proposed is 
necessary to permit an orderly transition with minimal disruptions to 
patients currently using OTC epinephrine MDIs.
    We will actively monitor the transition to CFC-free alternatives. 
Anyone who wishes to discuss a cooperative educational effort with the 
Department of Health and Human Services (HHS) and FDA should contact 
FDA or the Office of the Secretary of HHS.
    In sum, we believe the effective date (see the DATES section of 
this document), provides for the phase-out of OTC epinephrine CFC MDIs 
in a manner that is consistent with our duty to protect the public 
health while still meeting our obligations under the Clean Air Act and 
Montreal Protocol.

E. Additional Comments on Miscellaneous Issues

    (Comment 12) One comment from an international governmental 
organization asked that the final rule consider Decision VIII/10(1), 
regarding actions to promote industry's participation in a smooth and 
efficient transition away from CFC-based MDIs, including a request for 
companies to demonstrate research and development of alternatives to 
CFC MDIs, and Decision XIX/13(3), reached at the 19th Meeting of the 
Parties to the Montreal Protocol, regarding requests to companies for a 
commitment to reformulate products.
    (Response) In order to remove the essential-use designation for a 
particular moiety, we are obligated to follow the procedures and 
criteria in Sec.  2.125 of FDA regulations. The Decisions cited by the 
comment are not criteria listed in Sec.  2.125(f); however, we believe 
that our actions in this area, including this rulemaking, are 
consistent with the general principles expressed in the Decisions cited 
by the comment.
    (Comment 13) One comment from a nurse anesthetist supported the 
removal of the essential use for epinephrine CFC MDIs, but was 
concerned that albuterol MDIs remain necessary in the operating room.
    (Response) This rulemaking is limited to removing the essential-use 
designation for epinephrine MDIs, which are currently marketed OTC, as 
PRIMATENE MIST, and as private label generics. This rulemaking does not 
affect any albuterol MDIs, which were the subject of a separate 
rulemaking that was completed in 2005 (70 FR 17168).
    (Comment 14) One comment supported the phase-out of epinephrine CFC 
MDIs but recommended making albuterol HFA MDIs available without a 
prescription.
    (Response) We have noted several times throughout this document 
that, in general, asthma is a chronic inflammatory disease of the 
airways that should be managed under the care and supervision of a 
health care provider. Consistent with this, even current OTC labeling 
for epinephrine MDIs directs patients to use the product only after 
they have first consulted a physician and received an appropriate 
asthma diagnosis, which is somewhat unique labeling for an OTC drug and 
reflects the importance of using these products with appropriate 
professional supervision. If a sponsor of an albuterol HFA MDI were to 
submit an application to FDA to switch the marketing status of an 
albuterol MDI to OTC, as with all NDAs, FDA would review the supporting 
data submitted with the application and determine whether the switch to 
OTC marketing status was appropriate. United States and international 
committees have provided guidelines for the management of asthma (NAEPP 
EPR-3 (Ref.2) and Global Strategy for Asthma Management and Prevention, 
Global Initiative for Asthma (GINA), 2007 (Ref. 3)) which recognize the 
importance of health care providers in the management of asthma.

F. Conclusions

    We have 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 conclude that no substantial technical barriers exist to 
formulating an epinephrine inhaler without ODSs.
    We have therefore 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).

VI. Environmental Impact

    The agency has carefully considered the potential environmental 
effects of this action. FDA has concluded that the action will not have 
a significant impact on the human environment, and that an 
environmental impact statement is not required. The agency's finding of 
no significant impact and the evidence supporting that finding, 
contained in an environmental assessment, may be seen in the Division 
of Dockets Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday. Under FDA's regulations implementing the National 
Environmental Policy Act (21 CFR part 25), an action of this type would 
require an environmental assessment under 21 CFR 25.31a(a).

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866

[[Page 69543]]

and the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded 
Mandates Reform Act of 1995 (Public Law 104-4). Executive Order 12866 
directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is an economically significant regulatory action under 
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. Because known producers of OTC epinephrine CFC MDIs 
are not small entities and because of the likelihood that the final 
rule will not impose compliance costs, the agency certifies that the 
final rule will not 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 $130 million, using the most current (2007) Implicit 
Price Deflator for the Gross Domestic Product. This final 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 final rule will prohibit sales of OTC epinephrine CFC MDIs in 
interstate commerce after December 31, 2011. If a non-CFC alternative 
is not available OTC by that time, this would force users to either 
visit a physician and get a prescription for an alternative drug 
product such as albuterol or to self-medicate with less effective 
therapies. 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 final rule and regulatory 
alternatives assuming that no OTC non-CFC formulation of epinephrine 
MDIs is available.
    If an OTC non-CFC formulation of epinephrine MDIs were approved by 
FDA, the impacts of this final rule would largely depend on the 
difference in price of currently available CFC-based MDIs and the new 
non-CFC formulation. According to ACNielsen data (Ref. 10) for the 52 
weeks ending September 9, 2006, adjusted for sales through Wal-Mart, 
the average price of OTC epinephrine MDIs is $13.29 and annual retail 
sales of OTC epinephrine MDIs are roughly $60 million in the United 
States. We assume that a newly approved non-CFC epinephrine MDI would 
be branded with no generic alternatives. If we assume that the average 
price of the new branded non-CFC alternatives to be roughly the same as 
the current price of branded epinephrine MDIs of about $14.50, we 
estimate a 9 percent increase in annual expenditures on OTC 
epinephrine, or an increase of roughly $5 million.
    CFCs available for production of OTC epinephrine MDIs may be 
exhausted prior to the effective date of this final rule if the United 
States is unable to obtain an essential-use allocation for CFCs under 
the Montreal Protocol for use in OTC epinephrine MDIs through 2011. If 
so, this final rule may not have any significant impacts. To the extent 
that CFCs for production of OTC epinephrine MDIs remain available, we 
estimate this final rule will have the impacts summarized below. As the 
estimates do not include the positive public health effects of improved 
medical care for asthma and ignores the likelihood of an HFA-based 
substitute, they should be viewed as upper bounds on net costs. If FDA 
were to approve an OTC version of an HFA-based substitute, consumers 
would not need to choose between self-medication and visiting a 
physician and the estimated impacts, as illustrated in the example 
above, would be far smaller.

     Table 1.--Summary of Annual Quantifiable Effects of the Final Rule, Assuming CFCs for Production of OTC
                                        Epinephrine MDIs Remain Available
----------------------------------------------------------------------------------------------------------------
                                                         Increased                                 Reduced CFC
                                  Increased Health       Emergency             Increased         Emissions from
                                 Care Expenditure,   Department Visits   Hospitalizations for       Phase-Out
                                  in 2007 Dollars        for Asthma             Asthma              (tonnes)
----------------------------------------------------------------------------------------------------------------
If current OTC epinephrine MDI  $350 million to      0 to 440,000       40,000 to 120,000       70
 users self-medicate             $1.1 billion
----------------------------------------------------------------------------------------------------------------
If current OTC epinephrine MDI  $180 million to      .................  ......................  70
 users visit their physician     $355 million
 for prescription albuterol
 (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 69544]]

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 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.G of this document.

B. Need for Regulation and the Objective of This Rule

    This 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.
    An objective of this final 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 ending the essential-use 
designation for ODSs used in MDIs containing epinephrine because we 
have concluded that no substantial technical barriers exist to 
formulating epinephrine in a product that does not release ODSs. 
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-
three countries have now ratified the Montreal Protocol, and the 
overall usage of CFCs has been dramatically reduced. In 2007, global 
production of CFCs totaled about 11,000 tonnes, down from base year 
levels exceeding 1.1 million tonnes (Ref. 4). This decline amounts to 
more than a 99-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 in 2007 was less than 1 percent of 1986 production 
and importation (Ref. 4).
    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. 5). 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 9 months of the 2006 NHIS 
indicate that 8.0 percent of people in the United States have asthma 
(Ref. 6, 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. 6, 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. 6, fig. 15.2).
    According to data from the National Ambulatory Medical Care Survey, 
in 2004 there were about 15 million outpatient asthma visits to 
physician

[[Page 69545]]

offices and hospital clinics and 1.8 million emergency department 
visits (Ref. 7, 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. 7, table 16) and 
4,099 mortalities in 2003 (Ref. 7, table 1). The estimated direct 
medical cost of asthma (hospital services, physician care, and 
medications) was $11.5 billion in 2004 (Ref. 7, 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. 
8), 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 the proposed rule, 
we estimate that 1.7 to 2.3 million people with asthma use OTC 
epinephrine MDIs. This estimate is based on data provided by Wyeth, 
although Wyeth reached a different conclusion based on the same 
numbers.\14\ 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].\15\
---------------------------------------------------------------------------

    \14\ 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, Wyeth estimated that 2 to 3 million people used 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 numbers who have had an 
asthma incident in the previous 12 months; for 2004 the numbers are 
14.4 million and 7.7 million adults. 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 provides an estimate of 1.7 to 2.3 million 
people using OTC epinephrine MDIs. We believe that this estimate is 
more accurate than Wyeth's estimate of 2 to 3 million OTC 
epinephrine MDI users.
    \15\ 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. 9). 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. 10), we estimate 3.5 million OTC epinephrine MDIs are sold 
in the United States annually, excluding sales through Wal-Mart Stores, 
Inc. (Wal-Mart).\16\ 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).
---------------------------------------------------------------------------

    \16\ 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. 10) 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. 7, 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 who have had an asthma attack in 
the previous 12 months use OTC epinephrine MDIs. As we discussed in 
section V.B.2.b of the proposed rule, 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 Final 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 
this final rule. Our approach is the same as used in the proposed rule 
(see 72 FR 53711), except that we are using a phase-out date of 
December 31, 2011, and not December 31, 2010. 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,

[[Page 69546]]

2011. This date is 1 year later than what was used in the proposed 
rule. 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 final rule, we make the baseline assumption that it is 
questionable whether 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 2011.\17\ 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 1 of this document. If CFCs 
for the production of OTC epinephrine MDIs are no longer available by 
the end of 2011, this rule will have no impact.
---------------------------------------------------------------------------

    \17\ Even if there is no essential-use allocation under the 
Montreal Protocol for the year 2011, production of epinephrine CFC 
MDIs would likely continue well into the year with manufacturers 
using preexisting stocks of CFCs.
---------------------------------------------------------------------------

2. Benefits of the Final Rule
    The benefits of this final 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 promulgate this rule may lead the Parties to the 
Montreal Protocol to consider restrictions on access to the CFCs 
required to manufacture these OTC epinephrine MDI products, which could 
create the risk of removal of these products without adequate time for 
a deliberate and planned transition 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 final rule will ban marketing of OTC 
epinephrine CFC MDIs after December 31, 2011. 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 2011 
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. 11). 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 
final 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 final 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. 12).
    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, 
and we would be risking losing the goodwill that comes from fulfilling 
our treaty obligations.
3. Costs of the Final 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

[[Page 69547]]

reasonable bounds for the expected cost of removing OTC epinephrine 
MDIs from the market. Of course, if FDA were to approve an OTC non-CFC 
formulation of epinephrine MDIs, consumers would not need to choose 
between self-medication and visiting a physician and the estimated 
costs would be far lower. For illustrative purposes, we assume the 
current average price of all OTC epinephrine MDIs is $13.29 and a new 
formulation would cost the same as the current price of branded 
epinephrine MDIs, or about $14.50. As annual retail sales of OTC 
epinephrine MDIs are roughly $60 million, the 9 percent in increase in 
price would result of an increase in expenditures of about $5 million.
    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 $350 million to $1.1 billion in increased 
spending annually measured in 2007 dollars. This spending includes $300 
million to $1.1 billion resulting from increased hospitalizations and 
emergency department visits, and roughly $50 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 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. 8). 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 annually. 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 VII.C.5 
of this document. 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, calculated by netting out the baseline to get 
the incremental effect (2.5 - 1) or [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 would allow us to estimate increases in hospitalizations and 
emergency department visits for patients using other forms of self-
medication, such as OTC ephedrine, and do not include these factors in 
our analysis.
    We estimate the 2006 cost of an emergency department visit for 
asthma at roughly $300 and the cost of hospitalization for asthma at 
roughly $7,500. 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. 7). 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 Consumer 
Price Index 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 $300 million in 2007 dollars [37,275 
hospitalizations x $7,565.84 x 1.052 inflation = $296,681,642] to $1.1 
billion annually [(118,982 hospitalizations x $7,565.84 x 1.052 
inflation) + (440,017 emergency department visits x $294.17 x 1.052 
inflation) = $1,083,180,231].\18\
---------------------------------------------------------------------------

    \18\ To inflate our 2006 analysis to 2007 dollars we use the 
year-over-year change in the CPI-U for medical care, which was 5.2 
percent.
---------------------------------------------------------------------------

    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 $50 million to $80 million more for medicine each year. As 
discussed in section VII.C.5 of this document, 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 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 $50 million to $80 million more per year for

[[Page 69548]]

medicine in 2007 dollars [2,990,736 MDIs x $16.08 per MDI x 1.052 
inflation = $50,591,769; 2,990,736 MDIs x $25.15 per MDI x 1.052 
inflation = $80,392,184].
    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 $350 million to $1.1 billion 
annually in 2007 dollars [$296,681,642 + $50,591,769 = $347,273,411; 
$1,083,180,231 + $50,591,769 = $1,133,772,000].
    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 $180 million to $355 million in 
increased health care spending in 2007 dollars, including $105 million 
to $235 million in economic costs through an increase in visits to 
physicians and $75 million to $120 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 VII.C.5 of this document 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 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 
$105 million to $235 million annually in 2007 dollars [584,217.75 
visits x $168.966 per visit x 1.052 inflation = $103,846,009; 
1,332,016.47 visits x $168.966 per visit x 1.052 inflation = 
$236,768,901]. 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 
$75 million to $120 million in increased spending on medicine measured 
in 2007 dollars. 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. 10), 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. 10), 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. 13). 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. 14). 
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 $75 million to $120 million in 
2007 dollars [4,486,104 MDIs x $16.08 per MDI x 1.052 inflation = 
$75,885,219; 4,486,104 MDIs x $25.55per MDI x 1.052 inflation = 
$120,588,277].
    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 $180 million to $355 million annually in 
2007 dollars [$103,846,009 for physician visits + $75,885,219 for 
medicine (albuterol) = $179,731,228; $236,768,901 in physician visits + 
$120,588,277 in medicines = $357,357,178].
    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. 15), 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

[[Page 69549]]

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 
VII.D.3.a of this document, this would reduce health care costs by 
roughly $40 million to $110 million annually in 2007 dollars [($294.17 
per visit x 18,380 x 1.052 inflation) + ($7,565.84 per hospitalization 
x 4,970 x 1.052 inflation) = $43,380,000; ($294.14 per visit x 83,813 x 
1.052 inflation) + ($7,565.84 per hospitalization x 11,332 x 1.052 
inflation) = $111,341,155]. This cost is roughly $75 to $85 per current 
OTC epinephrine MDI user per year [$43,380,000/ 584,218 OTC epinephrine 
only MDI users = $74.25; $111,341,000 / 1,332,016 OTC epinephrine only 
MDI users = $83.59].
    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,\19\ 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 basis. These estimates do not take into account the impact of 
asthma attacks on individuals' quality of life and productivity.
---------------------------------------------------------------------------

    \19\ 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 $275 million annually and that Federal Medicare 
spending, together with private spending by Medicare beneficiaries, 
will increase $20 million to $275 million annually, all measured in 
2007 dollars. 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 final 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 borne by State 
and Federal Medicaid programs, equivalent to $70 million to $275 
million annually in 2007 dollars if Medicaid-eligible OTC epinephrine 
MDI users who do not use prescription medicine for their asthma were to 
self-medicate upon implementation of this final rule, and equivalent to 
$35 million to $90 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 
final rule are more likely to fall in the $35 million to $90 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. 16). The 2006 Federal poverty 
guidelines establish a poverty threshold of $20,000 in annual income 
for a family of four (Ref. 17). 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 measured in 2007 
dollars would increase roughly $70 million to $275 million annually [20 
percent of $350 million = $70 million; 25 percent of 1.1 billion = $275 
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 $90 million dollars annually [20 percent of $179,731,228 = 
$35,946,246; 25 percent of $357,357,178 = $89,339,294]. 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 final rule, Federal Medicare spending and 
spending by Medicare beneficiaries would increase roughly $35 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 final 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 measured in 
2007 dollars would increase $35 million to $275 million annually if all 
Medicare-eligible OTC epinephrine MDI users were to self-medicate [10 
percent of $350 million = $35 million; 25 percent of $1.1 billion = 
$275 million], and by $20 million to $90 million annually if they were 
all to visit their physicians for prescription

[[Page 69550]]

albuterol [10 percent of $179,731,228 = $18 million; 25 percent of 
$357,357,178 = $89,339,294]. 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);
    4. December 31, 2011 (the final 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 1 of this document would accrue. At 
some time in the near future, the unavailability of CFCs--not the final 
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 was 
presented in the proposed rule, would have no quantifiable costs or 
benefits. The fourth alternative, which is this final rule, would have 
no quantifiable costs or benefits even if bulk CFCs were available in 
2011, 1 year after we believe they will disappear from the marketplace.

F. Sensitivity Analyses

    The estimated costs summarized in table 1 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 final 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 who use OTC epinephrine MDIs (15 to 20 percent) 
and the fraction of OTC epinephrine MDI users who 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 who use OTC epinephrine MDIs (15 to 20 
percent) and the fraction of OTC epinephrine MDI users who 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 final 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 final rule will have 
no benefits or costs.

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 final rule will not impose 
compliance costs, the agency certifies that the final rule will not 
have a significant economic impact on a substantial number of small 
entities.

                                       Table 2.--Summary Accounting Table
----------------------------------------------------------------------------------------------------------------
                                                                          Units
                  Primary                         High     ----------------------------------
   Category       Estimate    Low  Estimate     Estimate       Year     Discount     Period          Notes
                                                             Dollars      Rate      Covered
----------------------------------------------------------------------------------------------------------------
Benefits
----------------------------------------------------------------------------------------------------------------
Annualized     .............  .............  .............  .........  7%          Annual     Reduction of CFC
 Quantified                                                                                    emissions by 70
                                                                                               tonnes
              -------------------------------------------------------------------------------
               .............  .............  .............  .........  3%          Annual     ..................
----------------------------------------------------------------------------------------------------------------

[[Page 69551]]

Qualitative                                                 .........  ..........  .........  Increased
                                                                                               investment in
                                                                                               environmentally
                                                                                               friendly
                                                                                               technologies.
                                                                                               International
                                                                                               cooperation.
----------------------------------------------------------------------------------------------------------------
Costs
----------------------------------------------------------------------------------------------------------------
Annualized     .............  $180 - $355    $350 million - 2007       7%          Annual     Range of estimates
 Monetized                     million         $1.1                                            capture
 $millions/                                   billion                                          underlying
 year                                                                                          uncertainty. No
                                                                                               central tendency.
              -------------------------------------------------------------------------------
               .............  $180 - $355    $350 million - 2007       3%          Annual     ..................
                               million         $1.1
                                              billion
----------------------------------------------------------------------------------------------------------------
Qualitative                                                 .........  ..........  .........  Depending on
                                                                                               consumer
                                                                                               willingness to
                                                                                               self-medicate,
                                                                                               potential
                                                                                               increase in
                                                                                               annual emergency
                                                                                               department visits
                                                                                               for asthma of 0
                                                                                               to 440,000 and
                                                                                               hospitalizations
                                                                                               for asthma of
                                                                                               40,000 to
                                                                                               120,000.
----------------------------------------------------------------------------------------------------------------
Transfers
----------------------------------------------------------------------------------------------------------------
Federal        .............  $55 million    $550 million   2007       7%          Annual     Medicare and
 Annualized                                                                                    Medicaid. Rough
 Monetized                                                                                     approximation.
 $millions/
 year
              -------------------------------------------------------------------------------
               .............  $55 million    $550 million   2007       3%          Annual     ..................
----------------------------------------------------------------------------------------------------------------
From/To                   From: U.S. Government
                   To: Healthcare providers and drug manufacturers
----------------------------------------------------------------------------------------------------------------
Effects
----------------------------------------------------------------------------------------------------------------
Small Business                                                                                None. Affected
                                                                                               entities are not
                                                                                               small.
----------------------------------------------------------------------------------------------------------------

IX. The Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

X. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has 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. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

XI. 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 sites 
after this document publishes 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://www.cdc.gov/
nchs/data/nhis/earlyrelease/200606_15.pdf.
    2. Expert Panel Report 3: Guidelines for the Diagnosis and 
Management of Asthma (EPR-3), NIH Publication No. 07-4051, Bethesda, 
MD, U.S. Department of Health and Human Services; National 
Institutes of Health; National Heart, Lung, and Blood Institute; 
National Asthma Education and Prevention Program, 2007, available at 
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
    3. Global Strategy for Asthma Management and Prevention, Global 
Initiative for Asthma (GINA), updated 2007, available at http://
www.ginasthma.org.
    4. United Nations Environmental Programme, Status of information 
provided by Parties in accordance with Article 7 of the Montreal 
Protocol on Substances that Deplete the Ozone Layer--Report by the 
Secretariat, 2008.
    5. U.S. Environmental Protection Agency, ``The Benefits and 
Costs of the Clean Air Act: 1990-2010,'' (http://www.epa.gov/air/
sect812/copy99.html) November 1999.
    6. National Center for Health Statistics, ``Early Release of 
Selected Estimates Based on Data From the January-September 2006 
National Health Interview Survey'' March, 28, 2007 (available at 
http://www.cdc.gov/nchs/about/major/nhis/released200703.htm#15).
    7. American Lung Association, ``Trends in Asthma Morbidity and 
Mortality,'' Epidemiology & Statistics Unit, Research and Scientific 
Affairs, July 2006.
    8. Blanc, P. D. et al., ``Use of Herbal Products, Coffee or 
Black Tea, and Over-the-

[[Page 69552]]

Counter Medications as Self-Treatments Among Adults with Asthma,'' 
Journal of Allergy and Clinical Immunology, 100:(6\1) 789, December 
1997.
    9. Mannino, D. M. et al., ``Surveillance for Asthma--United 
States, 1980-1999,'' Morbidity and Mortality Weekly Report, 
51(SS01):1-13, March 29, 2002.
    10. Analysis completed by FDA based on retail sales data from 
drug stores and supermarkets provided by ACNielsen for the 52 weeks 
ending September 9, 2006.
    11. U.S. Environmental Protection Agency, final rule, 
``Protection of Stratospheric Ozone: Allocation of Essential Use 
Allowances for Calendar Year 2006,'' 71 FR 58504, October 4, 2006.
    12. Rozek, R. P., and E. R. Bishko, ``Economics Issues Raised in 
the FDA's Proposed Rule on Removing the Essential-Use Designation 
for Albuterol MDIs,'' National Economic Research Associates, August 
13, 2004 (FDA Docket No. 2003P-0029/C25).
    13. Analysis completed by FDA based on prescription data 
provided by IMS Health, National Prescription Audit, 2004; IMS 
Health, IMS MIDAS (TM), Q1/2004-Q2/2004.
    14. Gal, A., and N. R. Chari, ``TEVA, SEPR: SGP to Phase Out CFC 
Albuterol Production by Early 2007; TEVA and SEPR Likely to 
Benefit,'' report prepared for Sanford C. Bernstein & Co., LLC (New 
York), October 17, 2006.
    15. Berger, W. E. et al., ``The Utility of the Health Plan 
Employer Data and Information Set (HEDIS) Asthma Measure to Predict 
Asthma-Related Outcomes,'' Annals of Allergy, Asthma and Immunology, 
93:538, December 2004.
    16. Centers for Medicare and Medicaid Services, Medicaid at-a-
Glance 2005: A Medicaid Information Source, available at http://
www.cms.hhs.gov/MedicaidEligibility/downloads/MedGlance05.pdf.
    17. Department of Health and Human Services, notice, ``Annual 
Update of the HHS Poverty Guidelines,'' 71 FR 3848, January 24, 
2006.

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Devices, Drugs, 
Foods.

0
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, 21 CFR part 2 is amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

0
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]

0
2. In Sec.  2.125, remove and reserve paragraph (e)(2)(v).

    Dated: November 13, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-27436 Filed 11-17-08; 11:15 am]

BILLING CODE 4160-01-S