Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Epinephrine), 69532-69552 [E8-27436]

Agencies

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

[Federal Register Volume 73, Number 224 (Wednesday, November 19, 2008)]
[Rules and Regulations]
[Pages 69532-69552]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-27436]


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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.

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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 https://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 
https://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.
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    \1\ FDA has verified all Web site addresses cited in this 
document, but FDA is not responsible for any subsequent changes to 
the Web sites after this document has published in the Federal 
Register.
    \2\ The summary descriptions of the Montreal Protocol and 
decisions of Parties to the Montreal Protocol contained in this 
document are presented here to help you understand the background of 
the action we are taking. These descriptions are not intended to be 
formal statements of policy regarding the Montreal Protocol. 
Decisions by the Parties to the Montreal Protocol are cited in this 
document in the conventional format of ``Decision IV/2,'' which 
refers to the second decision recorded in the Report of the Fourth 
Meeting of the Parties to the Montreal Protocol on Substances That 
Deplete the Ozone Layer. Reports of Meetings of the Parties to the 
Montreal Protocol may be found on the United Nations Environment 
Programme's Web site at https://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.
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    To produce or import CFCs for an essential use under the Montreal 
Protocol, a Party must request and obtain approval for an exemption at 
a Meeting of the Parties. One of the most important essential uses of 
CFCs under the Montreal Protocol is their use in MDIs for the treatment 
of asthma and chronic obstructive pulmonary disease (COPD). The 
decision on whether the use of CFCs in MDIs is ``essential'' for 
purposes of the Montreal Protocol turns on whether ``(1) It is 
necessary for the 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).
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    \4\ Our obligation under XV/5 was met by our final rule 
eliminating the essential use status of albuterol (70 FR 17168, 
April 4, 2005).
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     Decision XVII/5 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).
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    \5\ The Ozone Secretariat is the Secretariat for the Montreal 
Protocol and the Vienna Convention for the Protection of the Ozone 
Layer (the Vienna Convention) (March 22, 1985, 26 I.L.M. 1529 
(1985)), available at https://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.
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3. The 1990 Amendments to the Clean Air Act
    In 1990, Congress amended the Clean Air Act to, among other things, 
better protect stratospheric ozone (Public Law No. 101-549, November 
15, 1990) (the 1990 amendments). The 1990 amendments were drafted to 
complement, and be consistent with, our obligations under the Montreal 
Protocol (see section 614 of the Clean Air Act (42 U.S.C. 7671m)). 
Section 614(b) of the Clean Air Act provides that, in the case of a 
conflict between any provision of the Clean Air Act and any provision 
of the Montreal Protocol, the more stringent provision will govern. 
Section 604 of the Clean Air Act requires the phase-out of the 
production of CFCs by 2000 (42 U.S.C. 7671c),\6\ while section 610 of 
the Clean Air Act (42 U.S.C. 7671i) required EPA to issue regulations 
banning the sale or distribution in interstate commerce of nonessential 
products containing CFCs. Sections 604 and 610 provide

[[Page 69535]]

exceptions for ``medical devices.'' Section 601(8) (42 U.S.C. 7671(8)) 
of the Clean Air Act defines ``medical device'' as:
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    \6\ In conformance with Decision IV/2, EPA issued regulations 
accelerating the complete phase-out of CFCs, with exceptions for 
essential uses, to January 1, 1996 (58 FR 65018, December 10, 1993).
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``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.
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    \7\ Section 314.108(a) (21 CFR 314.108(a)) defines ``active 
moiety'' as the molecule or ion, excluding those appended portions 
of the molecule that cause the drug to be an ester, salt (including 
a salt with hydrogen or coordination bonds), or other noncovalent 
derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological 
action of the drug substance. When describing the various essential 
uses, we will generally refer to the active moiety, for example, 
albuterol, as opposed to the active ingredient, which, using the 
same example, would be albuterol sulfate. When discussing particular 
indications and other material from the approved labeling of a drug 
product, we will generally use the brand name of the product, which, 
using the same example would be PROVENTIL HFA (among others). In 
describing material from treatises, journals, and other non-FDA 
approved publications, we will generally follow the usage in the 
original publication.
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    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.
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    \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 https://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 https://
www.census.gov/population/www/popclockus.html.
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    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 https://
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 https://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., https://
www.asthmanow.net/care.html; https://www.colorado.gov/bestpractices/
index.html; https://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 b