Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Epinephrine), 53711-53733 [07-4663]

Agencies

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

[Federal Register Volume 72, Number 182 (Thursday, September 20, 2007)]
[Proposed Rules]
[Pages 53711-53733]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 07-4663]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

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


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA), after consultation 
with the Environmental Protection Agency (EPA), is proposing to amend 
FDA's regulation on the use of ozone-depleting substances (ODSs) in 
self-pressurized containers to remove the essential-use designation for 
epinephrine used in oral pressurized metered-dose inhalers (MDIs). FDA 
has tentatively concluded that there are no substantial technical 
barriers to formulating epinephrine as a product that does not release 
ODSs, and therefore epinephrine would no longer be an essential use of 
ODSs. If the essential-use designation is removed, epinephrine MDIs 
containing an ODS could not be marketed after a suitable transition 
period. We will hold an open public meeting on the essential use of 
epinephrine on a date to be announced later.

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

[[Page 53712]]


ADDRESSES: You may submit comments, identified by Docket No. 2007N-0262 
and/or RIN number 0910-AF92, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described previously in 
the ADDRESSES portion of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For 
additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents, 
comments, a transcript of, and material submitted for, the joint 
meeting of the Nonprescription Drugs and Pulmonary-Allergy Drugs 
Advisory Committee held on January 24, 2006, go to https://www.fda.gov/
ohrms/dockets/default.htm and insert the docket number(s), found in 
brackets in the heading of this document, into the ``Search'' box and 
follow the prompts and/or go to the Division of Dockets Management, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell or Martha Nguyen, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. CFCs
    B. Regulation of ODSs
    1. The 1978 Rules
    2. The Montreal Protocol
    3. The 1990 Amendments to the Clean Air Act
    4. EPA's Implementing Regulations
    5. FDA's 2002 Regulation
II. Criteria
III. Effective Date
IV. 2006 NDAC/PADAC Meeting
V. Epinephrine
    A. Do Substantial Technical Barriers Exist to Formulating 
Epinephrine Products Without ODSs?
    B. Do OTC Epinephrine MDIs Provide an Otherwise Unavailable 
Public Health Benefit?
    1. Does Epinephrine Provide a Greater Therapeutic Benefit Than 
Similar Adrenergic Bronchodilators?
    2. Does OTC Marketing of Epinephrine MDIs Provide an Important 
Public Health Benefit?
    3. Conclusions on the Public Health Benefits of OTC Epinephrine 
MDIs
    C. Does Use of OTC Epinephrine MDIs Release Cumulatively 
Significant Amounts of ODSs Into the Atmosphere or is the Release 
Warranted in View of the Otherwise Unavailable Important Public 
Health Benefit?
    D. Conclusions
VI. Environmental Impact
VII. Analysis of Impacts
    A. Introduction
    B. Need for Regulation and the Objective of This Rule
    C. Background
    1. CFCs and Stratospheric Ozone
    2. The Montreal Protocol
    3. Benefits of the Montreal Protocol
    4. Characteristics of Asthma
    5. Current U.S. Market for OTC Epinephrine MDIs
    D. Benefits and Costs of the Proposed Rule
    1. Baseline Conditions
    2. Benefits of the Proposed Rule
    3. Costs of the Proposed Rule and Alternatives
    4. Effects on Medicaid and Medicare
    E. Alternative Phase-Out Dates
    F. Sensitivity Analyses
    G. Conclusion
VIII. Regulatory Flexibility Analysis
IX. The Paperwork Reduction Act of 1995
X. Federalism
XI. Request for Comments
XII. References

I. Background

A. CFCs

    Chlorofluorocarbons (CFCs) are organic compounds that contain 
carbon, chlorine, and fluorine atoms. CFCs were first used commercially 
in the early 1930s as a replacement for hazardous materials then used 
in refrigeration, such as sulfur dioxide and ammonia. Subsequently, 
CFCs were found to have a large number of uses, including as solvents 
and as propellants in self-pressurized aerosol products, such as MDIs.
    CFCs are very stable in the troposphere, the lowest part of the 
atmosphere. They move to the stratosphere, a region that begins about 
10 to 16 kilometers (km) (6 to 10 miles) above Earth's surface and 
extends up to about 50 km (31 miles) altitude. Within the stratosphere, 
there is a zone about 15 to 40 km (10 to 25 miles) above the Earth's 
surface in which ozone is relatively highly concentrated. This zone in 
the stratosphere is generally called the ozone layer. Once in the 
stratosphere, CFCs are gradually broken down by strong ultraviolet 
light, releasing chlorine atoms that then deplete stratospheric ozone. 
Depletion of stratospheric ozone by CFCs and other ODSs allows more 
ultraviolet-B (UV-B) radiation to reach the Earth's surface, where it 
increases skin cancers and cataracts, and damages some marine 
organisms, plants, and plastics.

B. Regulation of ODSs

    The link between CFCs and the depletion of stratospheric ozone was 
discovered in the mid-1970s. Since 1978, the U.S. Government has 
pursued a vigorous and consistent policy, through the enactment of laws 
and regulations, of limiting the production, use, and importation of 
ODSs, including CFCs.
1. The 1978 Rules
    In the Federal Register of March 17, 1978 (43 FR 11301 at 11318), 
FDA and EPA published rules banning, with a few exceptions, the use of 
CFCs as propellants in aerosol containers. These rules were issued 
under authority of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 321 et seq.) and the Toxic Substances Control Act (15 U.S.C. 
2601 et seq.), respectively. FDA's rule (the 1978 rule) was codified as 
Sec.  2.125 (21 CFR 2.125). These rules issued by FDA and EPA had been 
preceded by rules issued by FDA and the Consumer Product Safety 
Commission requiring products that contain CFC propellants to bear 
environmental warning statements on their labeling (42 FR 22018, April 
29, 1977; 42 FR 42780, August 24, 1977).
    The 1978 rule prohibited the use of CFCs as propellants in self-
pressurized containers in any food, drug, medical device, or cosmetic. 
As originally published, the rule listed five essential uses exempt 
from the ban. The third listed essential use was for ``[m]etered-dose 
adrenergic bronchodilator human

[[Page 53713]]

drugs for oral inhalation.'' This use describes epinephrine MDIs.
    The 1978 rule provided criteria for adding new essential uses, and 
several uses were added to the list, the last one in 1996. The 1978 
rule did not provide any mechanism for removing essential uses from the 
list as alternative products were developed or CFC-containing products 
were removed from the market. The absence of a removal procedure came 
to be viewed as a deficiency in the 1978 rule, and was addressed in a 
later rulemaking, discussed in section I.B.5 of this document.
2. The Montreal Protocol
    On January 1, 1989, the United States became a Party to the 
Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal 
Protocol) (September 16, 1987, 26 I.L.M. 1541 (1987)), available at 
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 191 Parties to this 
treaty.\2\ When it joined the treaty, the United States committed to 
reducing production and consumption of certain CFCs to 50 percent of 
1986 levels by 1998 (Article 2(4) of the Montreal Protocol). It also 
agreed to accept an ``adjustment'' procedure, by which, following 
assessment of the existing control measures, the Parties could adjust 
the scope, amount, and timing of those control measures for substances 
already subject to the Montreal Protocol. As the evidence regarding the 
impact of ODSs on the ozone layer became stronger, the Parties used 
this adjustment procedure to accelerate the phase-out of ODSs. At the 
fourth Meeting of the Parties to the Montreal Protocol, held at 
Copenhagen in November 1992, the Parties adjusted Article 2 of the 
Montreal Protocol to eliminate the production and importation of CFCs 
by January 1, 1996, by Parties that are developed countries (Decision 
IV/2).\3\ The adjustment also indicated that it would apply, ``save to 
the extent that the Parties decide to permit the level of production or 
consumption that is necessary to satisfy uses agreed by them to be 
essential'' (Article 2A(4)).
---------------------------------------------------------------------------

    \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/index.shtml.
    \3\Production of CFCs in economically less-developed countries 
is being phased out and is scheduled to end by January 1, 2010. See 
Article 2A of the Montreal Protocol.
---------------------------------------------------------------------------

    One of the most important essential uses of CFCs under the Montreal 
Protocol is their use in MDIs for the treatment of asthma and chronic 
obstructive pulmonary disease (COPD). The decision on whether the use 
of CFCs in MDIs is ``essential'' for purposes of the Montreal Protocol 
turns on whether ``(1) It is necessary for the health, safety, or is 
critical for the functioning of society (encompassing cultural and 
intellectual aspects) and (2) there are no available technically and 
economically feasible alternatives or substitutes that are acceptable 
from the standpoint of environment and health'' (Decision IV/25).
    Each request and any subsequent exemption is for only 1 year's 
duration (Decision V/18). Since 1994, the United States and some other 
Parties to the Montreal Protocol have annually requested, and been 
granted, essential-use exemptions for the production or importation of 
CFCs for their use in MDIs for the treatment of asthma and COPD (see, 
among others, Decisions VI/9 and VII/28). The exemptions have been 
consistent with the criteria established by the Parties, which make the 
grant of an exemption contingent on a finding that the use for which 
the exemption is being requested is essential for health, safety, or 
the functioning of society, and that there are no available technically 
and economically feasible alternatives or substitutes that are 
acceptable from the standpoint of health or the environment (Decision 
IV/25).
    Phasing out the use of CFCs in MDIs for the treatment of asthma and 
COPD has been an issue of particular interest to the Parties to the 
Montreal Protocol. Several decisions of the Parties have dealt with the 
transition to CFC-free MDIs, including the following decisions:
     Decision VIII/10 stated that the Parties that are 
developed countries would take various actions to promote industry's 
participation in a smooth and efficient transition away from CFC-based 
MDIs (San Jose, Costa Rica, 1996).
     Decision IX/19 required the Parties that are developed 
countries to present an initial national or regional transition 
strategy by January 31, 1999 (Montreal, Canada, 1997).
     Decision XII/2 elaborated on the content of national or 
regional transition strategies required under Decision IX/19 and 
indicated that any MDI for the treatment of asthma or COPD approved for 
marketing after 2000 would not be an ``essential use'' unless it met 
the criteria laid out by the Parties for essential uses (Ouagadougou, 
Burkina Faso, 2000).
     Decision XIV/5 requested that each Party report annually 
the quantities of CFC and non-CFC MDIs and dry-powder inhalers (DPIs) 
sold or distributed within its borders and the approval and marketing 
status of non-CFC MDIs and DPIs. Decision XIV/5 also noted ``with 
concern the slow transition to CFC-free metered-dose inhalers in some 
Parties'' (Rome, Italy, 2002).
     Decision XV/5 stated that, at the 17th Meeting of the 
Parties (in December 2005) or thereafter, no essential uses of CFCs 
will be authorized for Parties that are developed countries, unless the 
Party requesting the essential-use allocation has submitted an action 
plan for MDIs for which the sole active ingredient is albuterol. Among 
other items, the action plan should include a specific date by which 
the Party plans to cease requesting essential-use allocations of CFCs 
for albuterol MDIs to be sold or distributed in developed countries\4\ 
(Nairobi, Kenya, 2003).
---------------------------------------------------------------------------

    \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 stated that Parties that are developed 
counties should provide a date to the Ozone Secretariat\5\

[[Page 53714]]

before the 18th Meeting of the Parties (October 30 to November 3, 2006) 
by which time a regulation or regulations will have been proposed to 
determine whether MDIs, other than those that have albuterol as the 
only active ingredient, are nonessential (Dakar, Senegal, 2005).
---------------------------------------------------------------------------

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

3. The 1990 Amendments to the Clean Air Act
    In 1990, Congress amended the Clean Air Act to, among other things, 
better protect stratospheric ozone (Public Law No. 101-549, November 
15, 1990) (the 1990 amendments). The 1990 amendments were drafted to 
complement, and be consistent with, our obligations under the Montreal 
Protocol (see section 614 of the Clean Air Act (42 U.S.C. 7671m)). 
Section 614(b) of the Clean Air Act provides that, in the case of a 
conflict between any provision of the Clean Air Act and any provision 
of the Montreal Protocol, the more stringent provision will govern. 
Section 604 of the Clean Air Act requires the phase-out of the 
production of CFCs by 2000 (42 U.S.C. 7671c),\6\ while section 610 of 
the Clean Air Act (42 U.S.C. 7671i) required EPA to issue regulations 
banning the sale or distribution in interstate commerce of nonessential 
products containing CFCs. Sections 604 and 610 provide exceptions for 
``medical devices.'' Section 601(8) (42 U.S.C. 7671(8)) of the Clean 
Air Act defines ``medical device'' as:
    any device (as defined in the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 321)), diagnostic product, drug (as defined in the Federal 
Food, Drug, and Cosmetic Act), or drug delivery system-
    (A) if such device, product, drug, or drug delivery system utilizes 
a class I or class II substance for which no safe and effective 
alternative has been developed, and where necessary, approved by the 
Commissioner [of Food and Drugs]; and
    (B) if such device, product, drug, or drug delivery system, has, 
after notice and opportunity for public comment, been approved and 
determined to be essential by the Commissioner [of Food and Drugs] in 
consultation with the Administrator [of EPA].
---------------------------------------------------------------------------

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

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.
---------------------------------------------------------------------------

II. Criteria

    Among other changes, the 2002 final rule, in revised Sec.  
2.125(g)(2), establishes a standard for removing an essential-use 
designation for any drug after January 1, 2005, that would apply to a 
drug for which there is no acceptable non-ODS alternative with the same 
active moiety. The process for removing the essential-use designation 
for such a drug must include a consultation with a relevant advisory 
committee and an open public meeting, in addition to a proposed rule 
and a final rule. The criterion established for removing the essential 
use in such circumstances is that it no longer meets the criteria 
specified in revised Sec.  2.125(f) for adding a new essential use 
(Sec.  2.125(g)(2)). The criteria in Sec.  2.125(f) are: ``(i) 
Substantial technical barriers exist to formulating the product without 
ODSs; (ii) The product will provide an unavailable important public 
health benefit; and (iii) Use of the product does not release 
cumulatively significant amounts of ODSs into the atmosphere or the 
release is warranted in view of the unavailable important public health 
benefit.''
    The three criteria in Sec.  2.25(f)(1) are linked by the word 
``and''. Because the three criteria are linked by ``and'' (as

[[Page 53715]]

opposed to ``or''), failure to meet any single criterion satisfies the 
threshold under the regulation for determining that the use is not 
essential.
    We discussed these criteria in the preamble to the 1999 proposed 
rule. A key point in our discussion of technical barriers was: 
Generally, FDA intends the term ``technical barriers'' to refer to 
difficulties encountered in chemistry and manufacturing. A petitioner 
would have to establish that it evaluated all available alternative 
technologies and explain in detail why each alternative was unusable to 
demonstrate that substantial technical barriers exist (1999 proposed 
rule at 47721).
    In applying the ``technical barriers'' criterion, we will be 
looking at the results of reformulation efforts for similar products, 
as well as statements made about the manufacturer's particular efforts 
to reformulate their product or products.
    Similarly, in discussing what is ``an unavailable important public 
health benefit,'' we said: The agency intends to give the phrase 
``unavailable important public health benefit'' a markedly different 
construction from the [phrase used in the 1978 rule] ``substantial 
health benefit.'' A petitioner should show that the use of an ODS would 
save lives, significantly reduce or prevent an important morbidity, or 
significantly increase patient quality of life to support a claim of 
important public health benefit (1999 proposed rule at 47722).
    In determining whether a drug product provides an otherwise 
unavailable important public health benefit, our primary focus is on 
the availability of non-ODS products that provide equivalent 
therapeutic benefits for patients who are currently using the CFC MDIs. 
If therapeutic alternatives exist for everyone using the CFC MDI, we 
would then determine that the CFC MDI does not provide an otherwise 
unavailable important public health benefit. In the case of epinephrine 
MDIs, the fact that they are marketed over-the-counter (OTC), while the 
therapeutic alternatives for epinephrine MDIs are prescription drugs, 
makes the analysis of whether everyone is adequately served by the 
therapeutic alternatives more complicated.
    Under the third criterion, the threshold for removing the essential 
use designation is satisfied unless we find either: (1) The use of the 
product does not release cumulatively significant amounts of ODSs into 
the atmosphere; or (2) the release, although cumulatively significant, 
is warranted in view of the otherwise unavailable important public 
health benefit that the use of the drug product provides. In evaluating 
whether continuing the essential-use designation of an MDI would result 
in the product releasing significant quantities of ODSs, in light of 
past policy statements (2002 final rule p. 48380) and the current state 
of the phase-out of ODSs, the release of CFCs from epinephrine MDIs is 
currently significant and as the phase-out of ODSs continues throughout 
the world, the significance of the quantities of CFCs released by 
epinephrine MDIs will increase.
    In applying the first part of the third criterion, we are guided by 
previous policy statements. The United States evaluated the 
environmental effect of eliminating the use of all CFCs in an 
environmental impact statement in the 1970s (see 43 FR 11301, March 17, 
1978). As part of that evaluation, FDA concluded that the continued use 
of CFCs in medical products posed an unreasonable risk of long-term 
biological and climatic impacts (see Docket No. 1996N-0057 formerly 
96N-0057). Congress later enacted provisions of the Clean Air Act that 
codified the decision to fully phase out the use of CFCs over time (see 
42 U.S.C. 7671 et seq. (enacted November 15, 1990)). We note that the 
environmental impact of individual uses of nonessential CFCs must not 
be evaluated independently, but rather must be evaluated in the context 
of the overall use of CFCs. Cumulative impacts can result from 
individually minor, but collectively significant, actions that take 
place over a period of time (40 CFR 1508.7). Significance cannot be 
avoided by breaking an action down into small components (40 CFR 
1508.27(b)(7)). Currently, MDIs for the treatment of asthma and COPD 
are the only legal use for newly produced or imported CFCs (see 71 FR 
58504 (October 4, 2006)). Although it may appear to some that the CFCs 
released from MDIs represent insignificant quantities of ODSs, and 
therefore should be exempt, the elimination of CFC use in MDIs is one 
of the final steps in the overall phase-out of CFC use. The release of 
ODSs from some of the MDIs may be relatively small compared to total 
quantities that were released 2 or 3 decades ago, but if each use that 
resulted in the release of relatively small quantities of ODSs were 
provided an exemption, the cumulative effect would be to prevent the 
elimination of ODS releasing products. This would prevent the full 
phase-out envisioned by the Clean Air Act and the Montreal Protocol. 
Therefore, we tentatively conclude that the release of ODSs from 
epinephrine MDIs is cumulatively significant.
    Given this proposed finding that the first part of the third 
criterion is not satisfied, the threshold for the removal of the 
essential-use designation for epinephrine under Sec.  2.125(f)(1)(iii) 
is met if we also find that the second part of the third criterion is 
not satisfied: it provides an otherwise unavailable important public 
health benefit which warrants the cumulatively significant release of 
the ODS.
    As noted previously, because the three criteria in Sec.  
2.125(f)(1) are linked by the word ``and,'' failure to meet any single 
criterion may result in a determination that the use is not essential. 
Accordingly, if we find that the product fails to provide an otherwise 
unavailable important health benefit (criterion two), this would meet 
the threshold under the regulation for a finding that the use of the 
product is not essential, and we would not necessarily need to reach 
the last step under the third criterion (balancing the important health 
benefit against the release of the ODS to determine if the release is 
warranted). Assuming, however that we do analyze the third criterion, 
then, because of our tentative conclusion that the release of ODSs from 
epinephrine MDIs is cumulatively significant, we would need to conduct 
the balancing inquiry under the second part of the third criterion. We 
will discuss our tentative conclusions on how the second part of the 
third criterion applies to OTC epinephrine MDIs in section V.C of this 
document.
    The criteria in Sec.  2.125(g)(2) (which refers to those found in 
Sec.  2.125(f)(1)) that we are using in this rulemaking are different 
from those in Sec.  2.125(g)(3) and (g)(4). Section 2.125(g)(2) 
specifically addresses the situation where there is no marketed non-ODS 
product containing the active moiety listed as an essential use, while 
Sec.  2.125(g)(3) and (g)(4) apply to situations where there is at 
least one marketed non-ODS product with the listed active moiety. 
Section 2.125(g)(2) permits FDA to remove an essential use even if a 
current essential-use active moiety is not reformulated, provided that 
sufficient alternative products exist to meet the needs of patients, 
because the essential use would no longer provide an otherwise 
unavailable important health benefit. Therefore, the analysis we use 
here is not identical to the analysis we used under Sec.  2.125(g)(4) 
in the recent rulemaking to remove the essential use for albuterol (70 
FR 17168, April 4, 2005). However, the basic concern of protecting the 
public health underlies all of the criteria. Therefore, our analyses 
are similar, and we have found it useful to borrow concepts from the

[[Page 53716]]

more specific provisions of Sec.  2.125(g)(3) and (g)(4) to help give 
more structure to our analysis under the broader language of Sec.  
2.125(f)(1).

III. Effective Date

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

    \8\Neither HFA MDIs nor DPIs release ODSs. HFA MDIs and DPIs are 
generally considered to be the non-ODS drug products that are most 
comparable to CFC MDIs in terms of portability and ease of use.
    \9\Current information indicates that production of albuterol 
HFA MDIs will be adequate to meet the current demand for albuterol 
MDIs much earlier than December 31, 2008.
---------------------------------------------------------------------------

    In proposing a December 31, 2010, effective date, we expect that 
2010 would be a transition year characterized by declining production 
of OTC epinephrine MDIs. If a December 31, 2010, effective date is 
established by this rulemaking, we anticipate that other administrative 
actions taken by EPA and FDA would reflect the concept of 2010 being a 
transition year.
    The sale of remaining stocks of CFC MDIs by manufacturers, 
wholesalers, and retailers was a consideration in setting the effective 
date of the albuterol rule (70 FR 17168, 17179, April 4, 2005). We 
believe that this consideration is appropriate for this rulemaking 
also. In evaluating the period of time needed to sell remaining stocks 
of OTC epinephrine MDIs, a factor that must be considered is the 
expiration dating for the relevant products. Both PRIMATENE MIST and 
the OTC epinephrine MDIs made by Armstrong Pharmaceuticals, Inc. 
(Armstrong) have expiration dates set at 24 months after manufacture. 
Drug products are not generally sold right up to the expiration date. 
Drugs are generally sold well before the expiration date, allowing the 
purchasers a significant amount of time to use the drug before it 
reaches its expiration date; therefore, we believe that all OTC 
epinephrine MDIs manufactured prior to publication of a final rule 
based on this proposal should be sold by December 31, 2010.
    We are tentatively proposing a December 31, 2010, effective date 
based on our preliminary assumption that there will not be an inhaled 
epinephrine OTC drug product that does not contain ODSs on the market 
in the foreseeable future. We strongly urge interested individuals to 
submit detailed information on whether inhaled-epinephrine will be 
available in a non-ODS formulation and when a non-ODS inhaled 
epinephrine product can reasonably be expected to be on the market. We 
also specifically request comment on whether publishing a final rule or 
the effective date of any such rule should be affected by the 
additional information that we receive concerning the availability of 
an inhaled epinephrine OTC drug product that does not contain ODSs.

IV. 2006 NDAC/PADAC Meeting

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

[[Page 53717]]

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

    \10\The transcript of the NCPAC/PADAC meeting, slides used in 
presentations made at the joint meeting, and written material 
presented to the committees for the meeting may be found at https://
www.fda.gov/ohrms/dockets/ac/cder06.html.
---------------------------------------------------------------------------

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

V. Epinephrine

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

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

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

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

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

[[Page 53718]]

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

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

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

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

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

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

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

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

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

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

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

    \19\The Guidelines represent best practices and are recognized 
as the clinical standard of care for treatment of asthma. See, e.g., 
https://www.asthmanow.net/care.html; https://www.colorado.gov/
bestpractices/; https://www.doh.wa.gov/CFH/asthma/
publications/plan/health-care.pdf.
---------------------------------------------------------------------------

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

[[Page 53719]]

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

    \20\EPR-2 was updated in 2002 (Ref. 6) (EPR--Update 2002). 
References to outside publications or any other statements of fact 
or opinion in this document concerning a drug product are not 
intended to be equivalent to statements in labeling approved under 
section 505 of the act (21 U.S.C. 355) and part 314 of FDA 
regulations (21 CFR part 314).
    \21\The EPR-2 is very similar to other published standards of 
care (See the Australian Asthma Management Handbook: 2002 (Ref. 7) 
and the ``Canadian Asthma Consensus Report, 1999'' (Ref. 8).
---------------------------------------------------------------------------

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