Federal Register, Volume 67 Issue 142 (Wednesday, July 24, 2002)

[Federal Register Volume 67, Number 142 (Wednesday, July 24, 2002)]
[Rules and Regulations]
[Pages 48370-48385]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-18610]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. 97N-0023]
RIN 0910-AA99

Use of Ozone-Depleting Substances; Essential-Use Determinations

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulation on the use of chlorofluorocarbon (CFC) propellants in self-
pressurized containers to make it consistent with other laws. FDA is
setting the standard it will use to determine which FDA-regulated
products that utilize an ozone-depleting substance (ODS) are essential
under the Clean Air Act. Under the Clean Air Act, FDA, in consultation
with the Environmental Protection Agency (EPA), is required to
determine whether an FDA-regulated product that utilizes an ODS is
essential. FDA is also removing current essential-use designations for
products no longer marketed and for metered-dose steroid human drugs
for nasal inhalation. FDA will add or remove specific essential-use
designations for other products by

[[Page 48371]]

engaging in separate notice-and-comment rulemaking.

DATES: Effective Date: This rule is effective January 20, 2003.
Applicability Date: The removal of the essential-use exemption for
metered-dose steroid human drugs for nasal inhalation applies as of
August 25, 2003.

ADDRESSES: This document and related information are available on the
Internet at http://www.fda.gov/cder/mdi.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, 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
II. Highlights of the Final Rule
A. Removal of the Term ``Propellant''
B. Change to Essentiality Determinations
C. Metered-Dose Steroid Human Drugs for Nasal Inhalation
D. Products No Longer Marketed
E. Petitions to Add New Essential Uses
F. Determinations of Continued Essentiality
III. Changes From the Proposed Rule
IV. Comments on the Proposed Rule
A. General Comments About the Proposed Rule
B. Number of Alternatives Proposed
C. Specific Comments on the Proposed Criteria for Phaseout
D. Patient Subpopulations
E. Postmarketing Data and Suggested Duration
F. Timing of Phaseout
G. Nasal Steroids
H. Incentives for Development of Alternatives
I. Cost of New Products
J. Environmental Impact of CFC-MDI Use
K. Generics
L. New Essential Uses
M. Additional Comments
V. Legal Authority
VI. Implementation Plan
VII. Analysis of Impacts
A. Regulatory Benefits
B. Regulatory Costs
C. Distribution Impacts
D. Small Business Impact
VIII. The Paperwork Reduction Act of 1995
IX. Reference

I. Background

FDA, in consultation with EPA, determines whether a medical product
is essential for purposes of Title VI of the Clean Air Act (42 U.S.C.
7671, et seq.) (Title VI). If a medical product is determined to be
essential, and meets the other elements of the definition found in
section 601 of the Clean Air Act, it will be considered a ``medical
device.'' ``Medical devices'' are exempt from the general prohibition
on nonessential uses of CFCs found in section 610 of the Clean Air Act.
If certain conditions are met, EPA may authorize production of ODS for
use in ``medical devices'' under an exemption from the general
prohibitions on production and consumption of ODS found in sections 604
and 605 of the Clean Air Act. FDA lists essential medical products in
Sec. 2.125 (21 CFR 2.125). Most of the medical products listed as
essential are metered-dose inhalers (MDIs). FDA will maintain the
designation of ODS medical products such as MDIs as essential until
non-ODS medical products adequately meet the needs of patients.
In the Federal Register of September 1, 1999 (64 FR 47719), FDA
published a proposed rule that sought public comment on the process FDA
would use to make essential-use determinations.\1\ FDA received 22
comments on the proposed rule and addresses those comments in section
IV of this document.
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\1\ FDA included in the proposed rule a summary of the comments
the agency received on the advanced notice of proposed rulemaking
(ANPRM) published in the Federal Register of March 6, 1997 (62 FR
10242).
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The United States, as a party to the international agreement called
the Montreal Protocol on Substances that Deplete the Ozone Layer
(Montreal Protocol) (September 16, 1987, S. Treaty Doc. No. 10, 100th
Cong., 1st sess., 26 I. L. M. 1541 (1987)), has agreed to phase out
production and importation of ODSs, including CFCs. The United States
has generally banned the use of CFCs in consumer aerosols for decades
and eliminated almost all manufacture and importation of CFCs as of
January 1, 1996. However, the Montreal Protocol permits parties to the
Protocol to continue to produce or import CFCs for use in essential
medical products if such production or importation is approved by the
parties, and the United States continues to do so at this time.
The twelfth meeting of the parties to the Montreal Protocol took
place in Ouagadougou, Burkina Faso. The parties issued Decision XII/2--
``Measures to facilitate the transition to chlorofluorocarbon-free
metered-dose inhalers.'' Decision XII/2 is contained in the Report of
the Twelfth Meeting of the Parties to the Montreal Protocol on
Substances that Deplete the Ozone Layer. The report can be found on the
United Nations Environment Programme Web site at http://www.unep.org/ozone/mop/12mop/12mop-9.e.shtml. Decision XII/2 states the following:

[A]ny chlorofluorocarbon metered-dose inhaler product approved after
31 December 2000 for treatment of asthma and/or chronic obstructive
pulmonary disease in a non-Article 5(1) Party is not an essential
use [under the Montreal Protocol] unless the product meets the
criteria set out in paragraph 1(a) of decision IV/25.

The United States is a non-Article 5(1) Party under the Montreal
Protocol. Paragraph 1(a) of Decision IV/25 provides that:

a use of a controlled substance should qualify as `essential' [under
the Montreal Protocol] only if:
(i) It is necessary for the health, safety or is critical for
the functioning of society (encompassing cultural and intellectual
aspects); and
(ii) There are no available technically and economically
feasible alternatives or substitutes that are acceptable from the
standpoint of environment and health.

Decision IV/25 is contained in the Report of the Fourth Meeting of the
Parties to the Montreal Protocol on Substances that Deplete the Ozone
Layer. The report can be found on the United Nations Environment
Programme Web site at http://www.unep.org/ozone/mop/04mop/4mop-15.e.shtml.
FDA believes that this rule is consistent with Decision XII/2. This
rule is also a key step in fulfilling the United States' obligation
under paragraph 5 of Decision XII/2 to develop a national transition
strategy that ``includes effective criteria and measures for
determining when chlorofluorocarbon metered-dose inhaler product(s) is/
are no longer essential.''
Title VI and the Montreal Protocol work in independent but
complementary ways. The Montreal Protocol deals primarily with
restrictions on the production and importation of new ODSs. Title VI
deals with the use of ODSs, as well as their production and
importation. The following hypothetical example may be helpful in
illustrating the interaction of Title VI and the Montreal Protocol. A
United States company makes CFC-propelled plastic party streamers using
recycled and stockpiled CFCs. This use of ODSs would not be impacted by
the Montreal Protocol because no newly manufactured or imported ODSs
were used. However, this use of ODSs would be prohibited by Title VI,
because CFC-propelled plastic party streamers are specifically banned
by section 610(b)(1) of the Clean Air Act.

[[Page 48372]]

The purpose of this rule is to implement Title VI. A determination
that a product that contains ODSs is essential under Title VI does not
guarantee that the manufacturer of that product will be allocated ODSs
for use in the product. As the example above illustrates, the ability
to manufacture and market an ODS-containing product requires compliance
with both the Clean Air Act and the Montreal Protocol.

II. Highlights of the Final Rule

FDA is making the following changes to Sec. 2.125:
Using the phrase ``ozone-depleting substance'' instead of
the word ``chlorofluorocarbon'' in the title and text of the
regulation;
Revising Sec. 2.125(b) to remove explanatory material that
has no regulatory effect;
In revised Sec. 2.125(b), defining a product that is
subject to Sec. 2.125 as any food, drug, device, or cosmetic that is,
consists in part of, or is contained in an aerosol product or other
pressurized dispenser that releases an ODS, rather than limiting the
definition to those products that use CFCs as a propellant;
Changing the designation of ODS products not listed in
Sec. 2.125(e) from adulterated and misbranded to nonessential;
Listing as a separate essential use each active moiety
marketed under the current essential uses for metered-dose steroid
human drugs for oral inhalation and metered-dose adrenergic
bronchodilator human drugs for oral inhalation;
Eliminating the essential-use designation in Sec. 2.125(e)
for metered-dose steroid human drugs for nasal inhalation;
Eliminating the essential-use designations in
Sec. 2.125(e) for products that are no longer marketed;
Setting the standard to determine when a new essential-use
designation should be added to Sec. 2.125;
Eliminating outdated transitional provisions in current
Sec. 2.125(g), (h), (i), (j), (k), and (l); and
Setting standards to determine whether the use of an ODS
in a medical product remains essential.
We are highlighting the most important portions of the final rule
here.

A. Removal of the Term ``Propellant''

The agency is defining the products that are subject to Sec. 2.125
as any food, drug, device, or cosmetic that is, consists in part of, or
is contained in an aerosol product or other pressurized dispenser that
releases an ODS, rather than limiting the application of Sec. 2.125 to
products that use a CFC as a propellant in a self-pressurized
container. This brings within the scope of the regulation medical
products that use ODSs for purposes other than as a propellant. This
provision is intended to encompass all products that are regulated by
FDA.

B. Change to Essentiality Determinations

Former Sec. 2.125(c) stated that any CFC product not found in
Sec. 2.125(e) was adulterated and/or misbranded in violation of the
Federal Food, Drug, and Cosmetic Act (the act). FDA is changing this
paragraph to reflect the agency's authority under the Clean Air Act to
determine whether an ODS product is essential. FDA notes that EPA is
responsible for enforcing the provisions of the Clean Air Act. However,
FDA is not stating by its removal of the adulterated and/or misbranded
provision from Sec. 2.125 that a nonessential ODS product is not
adulterated or misbranded. Such products may still be considered
adulterated and misbranded under the act.

C. Metered-Dose Steroid Human Drugs for Nasal Inhalation

FDA is removing the essential-use designation for metered-dose
steroid human drugs for nasal inhalation for the following reasons:
Adequate alternative non-ODS products for steroid human
drugs for nasal inhalation are currently available, including metering
atomizing pumps for administering nasal corticosteroids, other
nonsteroid nasal topical therapies, and systemic therapies;
Patients use the alternative products on a widespread
basis; and
These alternative products have been and continue to be
produced and supplied at sufficient levels to meet patient needs.
While it was not a factor in the agency's decision, FDA notes that,
unlike other ODS medical products currently being marketed, the
diseases for which these products are indicated are not life
threatening. FDA also notes that only the three active moieties
beclomethasone, budesonide, and triamcinolone are marketed as CFC-nasal
steroids and that these three moieties are also marketed in non-ODS
formulations.

D. Products No Longer Marketed

FDA is removing the essential-use designations for the following
ODS products that are no longer marketed:
Contraceptive vaginal foams for human use;
Intrarectal hydrocortisone acetate for human use;
Polymyxin B sulfate-bacitracin zinc-neomycin sulfate
soluble antibiotic powder without excipients, for use on humans; and
Metered-dose nitroglycerin human drugs administered to the
oral cavity.
These drug products are either no longer being marketed or are no
longer being marketed in a formulation containing CFCs. Additionally,
in instituting a list in Sec. 2.125 of each marketed active moiety for
metered-dose adrenergic bronchodilator human drugs for oral inhalation,
the following moieties will not be listed as essential uses of ODS, as
they are no longer being marketed in a formulation containing CFCs:
Isoetharine, isoproterenol, terbutaline.

E. Petitions To Add New Essential Uses

By this final rule, FDA is amending Sec. 2.125 to provide a process
for adding investigational uses to Sec. 2.125(e) and amending the
existing process for adding noninvestigational uses to Sec. 2.125(e).
FDA believes that it would be inappropriate to add new essential uses
to Sec. 2.125 in all but the most extraordinary circumstances because
of the relatively near-term phaseout of the production and importation
of ODSs and because of the United States' commitment to reducing its
consumption of ODSs. Therefore, FDA is requiring compelling evidence in
support of a petition for a new essential use. For purposes of this
rule, compelling evidence is evidence sufficient to establish with
reasonable scientific certainty the truth of the matter asserted. The
evidence should be detailed and capable of scientific analysis and
discussion. Unsupported, conclusory statements are not compelling
evidence. Because the Clean Air Act mandates an opportunity for public
comment before FDA makes a determination of essential use, a petitioner
must disclose all relevant information in a petition to add a new
essential use to Sec. 2.125(e). Such information will become publicly
available. FDA will use this information in issuing a proposed rule to
add the essential use if it finds that the petitioner has submitted
compelling evidence.
This new standard applies to all requests for essential-use
exemptions submitted after the effective date of this rule.
1. Noninvestigational Uses
Noninvestigational products are products that are not intended to
be used in preclinical or clinical

[[Page 48373]]

investigations of a medical product. Noninvestigational uses include
the use of ODSs in medical products that are commercially distributed
under an approved marketing application. FDA does not intend to
consider proposing a new essential use for a noninvestigational product
unless a petitioner submits:
Compelling evidence that substantial technical barriers
exist to formulating the product without ODSs;
Compelling evidence that the product will provide an
unavailable important public health benefit;
Information describing the cumulative release of ODS into
the atmosphere and a discussion of the significance of the release; and
The basis for why the release is warranted in view of the
unavailable important public health benefit.
2. Investigational Uses
FDA does not intend to consider proposing a new essential use for
an investigational use of an ODS medical product unless a petitioner
submits:
Compelling evidence that substantial technical barriers
exist to formulating the investigational product without ODSs;
Compelling evidence that a high probability exists that
the investigational product will provide an unavailable important
public health benefit;
Information describing the cumulative release of ODS into
the atmosphere and a discussion of the significance of the release; and
The basis for why the release is warranted in view of the
unavailable important public health benefit.
FDA notes that inclusion of an investigational use in
Sec. 2.125(e)(4) will not allow commercial manufacture and marketing of
an ODS product. A sponsor will need to file a separate petition under
Sec. 2.125(f)(1) for a new essential-use determination for commercial
marketing of the ODS product.
3. Requesting Addition of a New Essential Use
A party seeking a new essential use will need to file a citizen
petition under Sec. 10.30 (21 CFR 10.30) requesting that FDA initiate
rulemaking to add a new essential use. The petitioner will need to
include compelling evidence justifying addition of the new essential
use, as provided for in Sec. 2.125(e). FDA will deny the petition if
the petitioner has not submitted compelling evidence. If the petitioner
has submitted compelling evidence, FDA will grant the petition and
initiate notice-and-comment rulemaking to add the new essential use.
First, the petitioner must demonstrate through compelling evidence
that substantial technical barriers exist to formulating the product
without ODSs. Generally, FDA intends the term ``technical barriers'' to
refer to difficulties encountered in chemistry and manufacturing. To
demonstrate that substantial technical barriers exist, the petitioner
will have to establish that it evaluated all available alternative
technologies and explain in detail why each alternative was deemed to
be unusable to demonstrate that substantial technical barriers exist.
FDA notes that alternative technologies not suitable for use by general
patient populations may be suitable for use in a clinical investigation
due to the increased medical supervision provided and the limited use
of the investigational new drug (see FDA Response to Biovail Citizen
Petition, Docket No. 95P-0045). The agency might consider cost as a
technical barrier if the petitioner shows that the cost of using a non-
ODS in a product is prohibitively high in comparison to the cost of
using an ODS.
Second, the petitioner for a new essential use for a
noninvestigational product must include compelling evidence of an
unavailable important public health benefit. For investigational
products, FDA is requiring the petitioner to provide compelling
evidence that there is a high probability that the investigational
product will provide an unavailable important public health benefit.
``High probability'' means that it is substantially more likely than
not that the investigational product will provide an unavailable
important public health benefit.
The agency will give the phrase ``unavailable important public
health benefit'' a markedly different construction from the previous
phrase ``substantial health benefit.'' For example, the 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. The petitioner should also show that patients cannot access
non-ODS products and that no technology is readily available to produce
and distribute non-ODS products. In unusual cases, FDA might accept a
showing of nonclinical health benefit, such as the safety of the health
care practitioner using the product.
Third, the petitioner must submit compelling evidence showing that
the use of the product does not release significant amounts of ODS into
the atmosphere. Alternatively, the petitioner may show that the release
is warranted in view of the important public health benefit or, for an
investigational product, in view of a high probability of an important
public health benefit. The petitioner must submit a well-documented
statement of the number of products to be manufactured and the amount
of ODS to be released by each product.

F. Determinations of Continued Essentiality

In Sec. 2.125(g), FDA sets forth criteria to determine whether an
essential-use designation should be removed from Sec. 2.125(e).
1. Products No Longer Marketed
Under Sec. 2.125(g)(1), FDA will propose removal of an active
moiety from the essential-use list (Sec. 2.125(e)) if it is no longer
marketed in an ODS formulation. FDA believes failure to market
indicates nonessentiality because the absence of a demand sufficient
for even one company to market the product is highly indicative that
the use is not essential.
2. Products Marketed After January 1, 2005
Section 2.125(g)(2) provides that, after January 1, 2005, FDA may
propose that ODS products containing a particular active moiety are
nonessential if the moiety no longer meets the essential-use criteria
in Sec. 2.125(f). Even if a current essential-use active moiety is not
reformulated, sufficient alternative products may exist in the future
to fully meet the needs of patients. FDA would designate any remaining
active moieties marketed in ODS formulations as nonessential. FDA will
consult with an advisory committee and provide the opportunity for
public comment before making such a determination.
3. Products for Which Non-ODS Alternatives Containing the Same Active
Moiety Are Developed
Under Sec. 2.125(g)(3) and (g)(4), a moiety can remain on the
essential-use list until:
A non-ODS product(s) with the same active moiety is (are)
marketed with the same route of administration, for the same
indication, and with approximately the same level of convenience of
use;
Supplies and production capacity for the alternative(s)
exist or will exist at levels sufficient to meet patient need;
Adequate U.S. postmarketing data exist; and

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Patients who medically require the ODS product are
adequately served by available alternatives.
In addition, a CFC-MDI with an active moiety that is marketed under
more than one new drug application (NDA) will not be removed from the
essential-use list under Sec. 2.125(g)(4) unless at least two non-ODS
products with the same active moiety are marketed under more than one
NDA.
a. Same indication. In evaluating indications, FDA will require a
non-ODS alternative to have a broader indication or an indication or
indications identical to that of the ODS product containing the active
moiety to be removed from the list of essential uses, except for minor
wording changes that do not materially change the meaning of the
indication. For example, the non-ODS product could be indicated for
treatment of asthma and chronic obstructive pulmonary disease (COPD),
whereas the ODS product might only be indicated for asthma.
b. Same level of convenience of use. In evaluating whether an
alternative has approximately the same level of convenience of use
compared to the ODS product containing the same active moiety, FDA will
consider whether:
The product has approximately the same or better
portability;
The product requires approximately the same amount of or
less preparation before use; and
The product requires approximately the same or less
physical effort and dexterity.
c. Supplies and production capacity. In evaluating whether supplies
and production capacity for the non-ODS product(s) exist or will exist
at levels sufficient to meet patient need, FDA will consider whether a
manufacturer of a non-ODS alternative is able to manufacture the non-
ODS alternative in sufficient quantities to satisfy patient demand once
the ODS product containing the same active moiety is no longer
marketed. FDA generally will expect the non-ODS product to be
manufactured at multiple manufacturing sites if the ODS product was
manufactured at multiple manufacturing sites.
d. Postmarketing data. In evaluating postmarketing data, FDA will
look at a composite of all available information. FDA expects to see
data showing the acceptance of a non-ODS product in widespread use
outside of controlled trials and in subgroups not represented
adequately in the clinical trials that served as the basis for
marketing approval. FDA will also look for information on device
performance in uncontrolled settings, tolerability of products in
widespread use, unusual adverse reactions not previously identified in
premarketing studies, and effectiveness in broader patient populations.
FDA encourages sponsors to obtain postmarketing use data and to
assess the safety, effectiveness, tolerability, and patient acceptance
of possible alternatives in postmarketing clinical studies. In
particular, FDA encourages sponsors to seek data regarding patient
subpopulations not fully represented in premarketing clinical trials.
FDA will also evaluate data on acceptance, device performance,
tolerability, adverse events, and effectiveness by using postmarketing
studies and postmarketing use and surveillance data, including FDA's
MedWatch data.
In addition, FDA will consider foreign data supportive of U.S.
postmarketing use data if U.S. and foreign formulations, patient
populations, and clinical practices were the same or substantially
similar. FDA will monitor events related to the transition to non-ODS
alternatives in other developed nations for any information relevant to
the U.S. transition, including information regarding the safety,
effectiveness, tolerability, performance, and patient acceptance of
non-ODS alternative products.
e. Patients adequately served. FDA will evaluate whether patients
who medically require the ODS product are adequately served by
available alternatives by determining whether adequate safety,
tolerability, effectiveness, and compliance data for the available
alternatives exist for the indicated populations and other populations
known to medically rely on the ODS product. FDA anticipates that ODS
products of the same active moiety marketed in different strengths will
need to be replaced by non-ODS products of the same active moiety with
more than one strength to adequately serve patients. FDA will also
consider whether a high-priced non-ODS product is effectively
unavailable to a portion of the patient population because they cannot
afford to buy the product.
4. Opportunity for Public Comment
The public will have the opportunity to comment on the
acceptability of alternatives before FDA removes the essential-use
designation for any particular active moiety. FDA encourages health
care professionals and patients to submit medically significant data
based on actual use regarding the acceptability of alternatives and
whether alternatives adequately serve patients.

III. Changes From the Proposed Rule

Based on the comments it received on the proposed rule, FDA has
made some changes in this final rule.
FDA is finalizing Sec. 2.125(g)(2) to permit FDA to evaluate all
remaining ODS products after January 1, 2005, instead of just those
products that are not available without an ODS. FDA is making this
change in response to comments. FDA believes this change is important
to cover active moieties marketed as ODS products and represented by
two or more NDAs but for which only one non-ODS replacement is
marketed, as well as active moieties for which a non-ODS replacement is
developed that does not alone meet all of the criteria in
Sec. 2.125(g)(3). Under Sec. 2.125(g)(2), FDA will examine the entire
marketplace of products available to treat asthma and COPD in
determining whether an ODS product remains essential. By entire
marketplace, FDA means to include replacements containing the same
active moiety, other non-ODS products, as well as remaining CFC
products.
FDA is finalizing Sec. 2.125(g)(3)(iii) to require adequate U.S.
postmarketing data instead of at least 1 year of postmarketing data.
FDA is making this change in response to comments pointing out that
more or less data may be necessary depending on factors such as the
amount of foreign data available on the same product and the amount of
U.S. data that would be available by the time FDA finalized removal of
an essential use.
FDA is eliminating the proposal that Sec. 2.125(g)(4) require
active moieties marketed as ODS products and represented by multiple
strengths be replaced by at least two non-ODS products. FDA is making
this change in response to comments. FDA made this proposal to account
for different subpopulations that may require different strengths. FDA
believes it can adequately account for this need by requiring that
replacements adequately serve patients who medically require the ODS
product (see Sec. 2.125(g)(3)(iv)).
For consistency, FDA is also finalizing Sec. 2.125(g)(3) to
eliminate the phrase ``and one strength:''.
FDA is maintaining the requirement in Sec. 2.125(g)(4) to require
active moieties marketed as ODS products and represented by two or more
NDAs to be replaced by at least two non-ODS products.
FDA has determined, on its own initiative, that this rule will go
into effect 180 days after publication, rather than 1 year after
publication as was originally proposed. This change is

[[Page 48375]]

being made because of the length of this rulemaking process, the
anticipated length of future rulemakings to remove essential-use
exemptions, and the importance of eliminating ODSs in a timely manner.
The agency has also determined that the elimination of the essential-
use exemption for metered-dose steroid human drugs for nasal inhalation
will apply 1 year after the date of publication of this rule. Several
CFC-containing nasal steroid MDIs are still being marketed. The agency
believes that a 1-year period to dispose of existing stocks and to
complete the transition to non-ODS-containing alternatives remains
appropriate.

IV. Comments on the Proposed Rule

FDA sought comments on the proposed rule. In particular, FDA
requested comment on the following issues:
The criteria FDA should use to determine whether a
subpopulation is significant;
The type of postmarketing information FDA should consider
in evaluating the adequacy of alternatives; and
The timing of the removal of the essential-use designation
for nasal steroids.
FDA received 22 written comments on the proposed rule and held one
public meeting at the November 22, 1999, session of the Pulmonary and
Allergy Drugs Advisory Committee (PADAC). Comments were submitted by
individuals, health care providers, patient groups, prescription drug
manufacturers, professional associations, Congress, and a union. A
summary of the comments received and the agency's responses follow.

A. General Comments About the Proposed Rule

(Comment 1) Two comments supported the proposed rule as reasonable
and protective of patient choice. One comment noted that it is
difficult for patients to switch therapies and supported the proposed
rule as minimally disruptive of patient care. One comment supported the
proposed rule as protective of patients and the environment. One
comment supported the proposed rule as a reasonable and measured
approach. One comment encouraged FDA to finalize the proposed rule as
quickly as possible. One comment supported the proposed rule as an
improvement over the ANPRM (62 FR 10242, March 6, 1997) FDA published
on the same topic. PADAC members were generally supportive of the
proposed rule (Ref. 1, page 122 of the transcript).
FDA is generally adopting the rule as proposed, with the changes
noted in section III of this document.

B. Number of Alternatives Proposed

(Comment 2) Eight comments supported the moiety-by-moiety approach.
Two comments supported the moiety-by-moiety approach, including listing
each individual active moiety deemed essential. PADAC was generally
supportive of the moiety-by-moiety approach (Ref. 1, pp. 203 and 204 of
the transcript).
FDA is using the moiety-by-moiety approach overall, including
listing each individual active moiety deemed essential.
(Comment 3) Two comments said that FDA should make essentiality
determinations on a product-by-product rather than a moiety-by-moiety
approach. One of these comments argued that FDA applies such a product-
by-product approach to discontinued products and products outside the
classes listed in the proposal. One comment said that FDA should not
remove an essential use for an active moiety unless there is a non-ODS
alternative available. One comment requested that FDA not remove a
product from the essential-use list until it was no longer marketed.
FDA notes that some companies are unlikely to reformulate their CFC
products into non-ODS products because of economic considerations.
Therefore, FDA did not propose using a product-by-product approach or
waiting until a product was no longer marketed because such approaches
would not accomplish the eventual phaseout of CFC-MDIs as agreed to by
the United States.
FDA disagrees that drugs outside the classes listed in the proposal
and discontinued products are treated differently from drugs within the
classes. FDA is not listing particular products, but rather active
moieties. Although some of these active moieties are represented by one
product, as are most of the moieties within the classes listed in the
proposal, FDA is using the active moiety within the product as a basis
for classification, not the product itself.
(Comment 4) One comment stated that FDA should list as essential
uses all currently approved and available asthma-related MDIs,
including cromolyn. The comment also stated that some of the active
moieties included in table 1 of the proposed rule (64 FR 47719 at
47740, September 1, 1999) were not proposed as essential uses.
FDA proposed, and is including in this final rule, an essential use
for cromolyn at Sec. 2.125(e)(4)(iv). In evaluating this comment, FDA
compared table 1 in the preamble of the proposed rule with the proposed
codified language and found that the active moieties isoetharine and
isoproterenol were referenced in the table but not in the proposed
codified language. FDA did not include these active moieties in the
proposed codified language because the moieties are no longer marketed
in CFC formulations. FDA also researched whether any active moieties
listed in table 1 of the proposed rule are no longer marketed. FDA has
determined that terbutaline is no longer marketed in an ODS formulation
and, therefore, is finalizing this rule without including terbutaline
in the codified portion of this final rule.
(Comment 5) One comment requested that FDA provide additional
details regarding how it would treat over-the-counter (OTC)
bronchodilator products.
The only active moiety available as an OTC bronchodilator is
epinephrine. Epinephrine CFC-MDIs are manufactured under multiple NDAs.
FDA will evaluate the essentiality of epinephrine the same way it will
evaluate the essentiality of all active moieties manufactured under
multiple NDAs. FDA will not initiate rulemaking to eliminate the
essential-use designation for any individual active moiety marketed
under multiple NDAs until at least two non-ODS alternatives exist that
contain the same active moiety or, after January 1, 2005, until
adequate alternatives exist, as described in Sec. 2.125(g). FDA further
notes that any reexamination of the appropriateness of continuing the
OTC status for bronchodilators is quite separate from determinations on
the essential-use status of epinephrine CFC-MDIs.
(Comment 6) Five comments supported the proposal that more than one
non-ODS product be available for an active moiety for which more than
one CFC product is available currently. One comment stated that FDA
should clarify that under Sec. 2.125(g)(4) more than one product is
required only for active moieties represented by two or more NDAs.
PADAC supported this proposal generally but noted that the replacement
products should be adequate to serve the populations that were served
by the ODS product (Ref. 1, pp. 196 through 199 of the transcript).
FDA is including in this final rule a requirement that more than
one non-ODS product be available for active moieties currently
available under two or more NDAs. FDA acknowledges that it may be
difficult to argue that a higher strength replacement is an adequate
replacement for a product available in

[[Page 48376]]

multiple strengths if a population exists that specifically requires a
lower strength product (Ref. 1, pp. 197 and 198 of the transcript).
Therefore, FDA is removing the requirement that multiple-strength ODS
products be replaced by replacement products represented by multiple
NDAs. Instead, FDA will consider whether a multiple-strength ODS
product is adequately replaced by a non-ODS product by determining
whether patients are adequately served by the replacement.
(Comment 7) One comment asked FDA to require that before a
multiple-strength ODS product is found to be nonessential it must be
replaced by either one non-ODS product with the same active moiety in
at least two strengths, or two different non-ODS products with the same
active moiety in different strengths.
At the time FDA drafted the proposed rule, FDA considered carefully
whether to propose requiring replacing multiple strength ODS products
with multiple strength non-ODS products. Instead the agency decided to
require replacement by multiple non-ODS products for active moieties
for which more than one different product is currently available. FDA
chose not to propose to specifically require multiple strength
alternatives for multiple strength ODS products because of the
difficulty of equating therapeutic need with strengths. For example, if
an active moiety were available in two low potency strength
alternatives, it would meet the letter of the regulation, but might not
meet the therapeutic need for a high-potency formulation. On the other
hand, if a replacement product were twice as effective at half the
strength, requiring the replacement to be marketed in the same strength
would not necessarily serve the same population. FDA believes this
reasoning is still valid and declines to adopt the suggestion, but will
rather examine all aspects of an alternative's acceptability as a
replacement.
(Comment 8) One comment stated that proposed Sec. 2.125(g)(4) could
preclude replacement of a multiple-strength CFC-MDI by one non-ODS
product with two strengths.
FDA agrees that proposed Sec. 2.125(g)(4) could have prevented a
multiple-strength CFC-MDI from being replaced by one non-ODS product
with two strengths filed under the same NDA. Therefore, FDA is
finalizing Sec. 2.125(g)(4) to require only that ODS products
represented by two or more NDAs be replaced by at least two non-ODS
products. This criterion could be met by two products that differ in
strength and that are approved under one NDA. FDA is eliminating the
proposal that active moieties marketed in multiple distinct strengths
be replaced by at least two non-ODS products. FDA's intent in proposing
that multiple strengths be replaced by multiple products was to ensure
that patients who require different strengths are adequately served by
replacements. Section 2.125(g)(3)(iv) already requires that patients
who medically required the ODS product to be adequately served by the
non-ODS product(s) containing that active moiety and other available
products. Therefore, FDA does not believe that its original proposal
adds any additional protection. For consistency, FDA is also
eliminating the phrase ``and one strength'' from Sec. 2.125 (g)(3).

C. Specific Comments on the Proposed Criteria for Phaseout

(Comment 9) One comment stated that FDA should establish a
procedure to reinstate an essential use if a replacement is found
inadequate after removal of that essential use.
Section 2.125 does provide a mechanism to reinstate an essential
use if replacements are found inadequate after removal of that
essential use. A petitioner will need to apply under Sec. 2.125(f) to
add the essential use to Sec. 2.125(e).
(Comment 10) One comment stated that FDA should permit FDA-
regulated products using any ODS to remain on the market.
As explained below in detail in response to comment 52 of this
document, FDA-regulated products containing an ODS cannot remain on the
market once they are no longer essential.
(Comment 11) One comment stated that FDA should not propose removal
of an essential-use listing for an active moiety that does not have a
non-ODS replacement after January 1, 2005, unless FDA states the
criteria it will use to conclude that alternatives are adequate.
FDA will use notice-and-comment rulemaking if it proposes removal
of an essential-use listing for an active moiety that does not have a
non-ODS replacement. As part of this rulemaking, FDA will state the
criteria it will use to conclude that alternatives are adequate.
(Comment 12) One comment recommended that FDA establish an expert
panel to monitor all aspects of the transition. One comment stated that
FDA should state the qualifications of the people on the advisory
committee and should include members of the expert panel assembled by
the National Institutes of Health (NIH) and professionals selected by
the House Committee on Commerce's Subcommittee on Health and the
Environment.
PADAC comprises individuals possessing recognized expertise and
judgment in the fields of pulmonary and allergy medicine. Members have
the training and experience necessary to evaluate information
objectively and to interpret its significance under various, often
controversial, circumstances. Voting members of PADAC have expertise,
as demonstrated by training, education, and experience in pulmonary and
allergy medicine. To the extent feasible, voting members possess skill
and experience in the development, manufacture, or use of the types of
drugs to be referred to the committee. FDA strives to ensure that the
group of voting members reflects a balanced composition of scientific
expertise through members with diverse professional education,
training, and experience (21 CFR 14.80(b)(1)). Ad hoc committee members
who are representatives of consumer or patient interests, or who have
expertise in the particular disease or condition for which the drug
under consideration is proposed to be indicated, will be voting members
if: (1) They have the requisite scientific or technical expertise, and
(2) their participation is not prevented by conflict of interest laws
and regulations. Because of inherent conflict of interest concerns,
representatives of the drug manufacturing industry will not be voting
members of the committee. No person who is a regular full-time employee
of the U.S. Government and engaged in the administration of the act may
be a voting member of an advisory committee (section 505(n)(3) of the
act (21 U.S.C. 355(n)(3))).
The names and qualifications of the current members of PADAC are
available at each meeting and by written request mailed or faxed to the
following address: Food and Drug Administration, Freedom of Information
Staff (HFI-35), 5600 Fishers Lane, Rockville, MD 20857, FAX 301-443-
1726.
FDA may invite other individuals, such as members of the expert
panel assembled by NIH or professionals selected by the House Committee
on Commerce's Subcommittee on Health and the Environment, to serve as
ad hoc PADAC members if appropriate.
(Comment 13) Four comments supported proposed Sec. 2.125(g)(2).
Three comments recommended FDA undertake an evaluation of all ODS-MDI
products after January 1, 2005. One comment stated that FDA should not
limit proposed Sec. 2.125(g)(2) to products without a non-ODS
replacement.

[[Page 48377]]

FDA agrees with these comments and has therefore revised
Sec. 2.125(g)(2) to permit the agency to undertake an evaluation of all
ODS products after January 1, 2005, not just those products without a
non-ODS replacement.
(Comment 14) Three comments stated that FDA should permit
manufacturers to demonstrate an ability to meet patient need through a
single manufacturing site before requiring multiple manufacturing
sites. One comment supported FDA's proposal to require adequate
supplies and production capacity, but asked FDA to clarify that a
single facility could be adequate to meet patient demand.
FDA did not propose and is not finalizing in this rule a
requirement that replacement products be manufactured at multiple
sites. This final rule requires only that supplies and production
capacity for the non-ODS product exist at levels sufficient to meet
patient need. FDA notes, however, that multiple manufacturing sites
increase the likelihood that a manufacturer will be able to supply the
replacement drug in the event of an unforseen circumstance that shuts
down one site.
(Comment 15) Three comments supported the proposal that an
alternative be acceptable only if patients are adequately served and
the alternative is marketed for the same route of administration, for
the same indication, and with approximately the same level of
convenience of use as the product it is replacing.
In this final rule, FDA will not eliminate an essential use under
Sec. 2.125(g)(3) or (g)(4) unless patients are adequately served by
alternatives and an alternative is marketed for the same route of
administration, for the same indication, and with approximately the
same level of convenience of use as the product it is replacing.
(Comment 16) One comment asked FDA to confirm that only significant
variations in convenience that materially impede patient compliance are
a basis for consideration of whether a product has approximately the
same level of convenience of use.
FDA confirms that only significant variations in convenience that
materially impede patient compliance are a basis for consideration of
whether a product has approximately the same level of convenience of
use. For example, it is possible that a non-ODS MDI may use a
mouthpiece that is different from its CFC-MDI counterpart. Such a
difference would not normally constitute a significant inconvenience.
On the other hand, FDA is aware that physicians and patients value the
compact size and ease of use of MDIs. Therefore, a non-ODS product that
needed to be plugged in to be used would not have the same level of
convenience of use as a portable MDI.
(Comment 17) One comment supported FDA's statement that
approximately the same level of convenience of use should mean
approximately the same or better portability and the same amount of or
less preparation time.
In evaluating whether an alternative has approximately the same
level of convenience of use compared to the ODS product containing the
same active moiety, FDA will consider whether:
1. The product has approximately the same or better portability;
2. The product requires approximately the same amount of or less
preparation before use; and
3. The product does not require significantly greater physical
effort or dexterity.
(Comment 18) One comment asked FDA to revise the rule to state that
a non-ODS product need only provide a level of convenience that would
not significantly impair safe and effective use.
FDA is not revising this rule to state that convenience of use
means only that a non-ODS product does not significantly impair safe
and effective use. Although products exist already that are safe and
effective without providing the same level of convenience of use as
CFC-MDIs, such products do not represent sufficient treatment options.
For example, solutions for nebulization safely and effectively treat
asthma and COPD. However, nebulizers are generally not readily portable
and usually require an external power source to work. If such solution
products were the only means to treat asthma and COPD, patients with
these diseases would be highly restricted in where and how they could
receive their treatment. FDA does not believe such restrictions are
reasonable or medically appropriate.
(Comment 19) One comment asked that FDA eliminate essential uses
based on indications. One comment argued that FDA should eliminate
essential uses on an indication-by-indication basis and require revised
labeling accordingly.
FDA is not eliminating essential uses based on indications. It is
extraordinarily difficult to control to whom marketed drugs are
prescribed. FDA believes such an effort would be ineffective.
Therefore, FDA is not adopting this suggestion.
(Comment 20) Three comments supported removing essential use
designations for products no longer marketed.
FDA is removing the essential-use designations for products no
longer marketed and will continue to propose removal of such
designations under Sec. 2.125(g)(1) as products are removed from the
market.
(Comment 21) One comment stated that FDA should not eliminate an
essential use unless alternatives are found to be as safe, effective,
well tolerated, and inexpensive as CFC-MDIs.
In general, the criteria cited in this comment match the criteria
in this final rule. Although rigid cost comparison is not planned, FDA
will consider cost under the criterion of whether patients are
adequately served by the non-ODS alternatives.
(Comment 22) One comment suggested that FDA modify Sec. 2.125(f) to
specify that a petition to remove an essential use must submit
compelling evidence that the criteria in Sec. 2.125(g)(3) or (g)(4) are
met.
FDA is finalizing Sec. 2.125(g) to clarify that a petitioner must
submit compelling evidence that an essential use should be removed from
Sec. 2.125(e). If FDA grants the petition, FDA will propose removal of
that essential use through notice-and-comment rulemaking. During the
rulemaking period, the public will have the opportunity to comment on
the adequacy of the evidence in support of the proposal to remove the
essential use.
(Comment 23) One comment supported requiring that all patient
groups be adequately served.
FDA agrees with this comment and therefore is including in this
final rule a requirement that patients who medically required the ODS
product are adequately served by the non-ODS product(s) containing that
active moiety and other available products (Sec. 2.125(g)).
(Comment 24) One comment asked that FDA revise Sec. 2.125(g)(4) to
add the word ``each'' to clarify that each replacement product is
subject to independent evaluation using the substitution criteria.
FDA is not adding the word ``each'' to Sec. 2.125(g)(4). It is not
FDA's intent that each replacement product be subject to independent
evaluation using the substitution criteria. Rather, it is FDA's intent
to ensure that patients are adequately served by available options.

D. Patient Subpopulations

(Comment 25) One comment stated that every subpopulation is
significant. One comment asked that FDA consider the severity of impact
on patients rather

[[Page 48378]]

than the numbers in a subpopulation. PADAC noted that some subgroups
that might require particular attention are the elderly, pregnant
women, urban patients, low-income patients, minority populations, and
people who cannot cooperate at all in using a device because of
neurological or other health problems (Ref. 1, pages 171 to 196 of the
transcript). However, PADAC also acknowledged that these same groups
have problems with existing products and stated that FDA should not set
a standard for new products that cannot be met by existing products
(Ref. 1, pp. 187 and 196 of the transcript).
FDA recognizes that each patient is important. FDA also recognizes
that patients' asthma management programs are individualized and that
changes in these programs require patience, education, and consultation
with health care providers. FDA encourages patients to try appropriate
new therapies as they become available and will ask patients to provide
first-hand feedback to FDA as part of notice-and-comment rulemaking
proposing to remove an essential use. FDA will carefully consider all
such comments in determining whether a use remains essential. However,
FDA notes that, just as all patients are not served by one CFC-MDI, all
patients will not be served by a single alternative product. Therefore,
FDA does not believe it is appropriate to make essential-use
determinations on a patient-by-patient basis, just as the agency would
not make determinations about whether a drug should remain on the
market based on the experience of one patient or a small handful of
patients.
(Comment 26) One comment stated that FDA proposed to determine
essentiality based on the needs of patients who use the product for
unapproved uses and asked that FDA limit its evaluations to approved
uses. The comment cited the statement ``for the indicated populations
and other populations known to medically rely on the ODS product'' (64
FR 47719 at 47723).
Although FDA will generally concentrate on those populations for
whom a product is indicated in approved labeling, FDA also recognizes
that there are populations that medically rely on CFC-MDIs even though
the CFC-MDIs are not labeled for their use. FDA will consider
information from these populations in making its essential-use
determinations.
(Comment 27) One comment requested that FDA confirm that
alternatives would have to cover all significant indications before
being considered acceptable.
FDA confirms that the available alternatives should cover all
significant indications before the agency removes an essential use. In
general, non-ODS products with the same active moiety should be
approved for the same indications as their CFC counterparts prior to
being considered as alternatives. For example, if a CFC-MDI is approved
for use in the pediatric population as young as age 6 but the non-ODS
alternatives are only labeled for children age 12 and above, a
significant patient subpopulation would exist that might not be
adequately served by non-ODS products. Absent other data, the agency
would not eliminate the essential-use designation for the CFC-MDI based
on this factor alone. FDA notes, however, that FDA will examine all
available treatment options, not just the non-ODS product(s) containing
the moiety for which FDA proposes eliminating an essential use, in
determining whether patients are adequately served. FDA will examine
all replacement products, as well as remaining ODS products.
(Comment 28) One comment recommended that FDA revise
Sec. 2.125(g)(3)(i) to replace the word ``indication'' with
``indication(s)''.
After consideration, FDA has decided not to replace the words
``indication'' with ``indication(s)'' in Sec. 2.125(g)(3)(i). Multiple
non-ODS products may replace the ODS product, and FDA does not intend
to require each of those products to carry each of the indications
approved for the ODS product. Instead, FDA will examine whether all of
the products together cover the same indications as the ODS product.

E. Postmarketing Data and Suggested Duration

(Comment 29) One comment stated that FDA must use methods in
addition to MedWatch to collect postmarketing data.
FDA plans to use methods in addition to MedWatch to collect
postmarketing data. FDA will encourage sponsors to obtain postmarketing
use data and to assess the safety, effectiveness, tolerability, and
patient acceptance of possible alternatives in postmarketing clinical
studies. In particular, FDA will encourage sponsors to seek data
regarding patient subpopulations not fully represented in premarketing
clinical trials. FDA will also evaluate data on acceptance, device
performance, tolerability, adverse events, and effectiveness by using
postmarketing studies and postmarketing use and surveillance data,
including but not limited to FDA's MedWatch data.
(Comment 30) One comment supported use of foreign postmarketing
data in support of U.S. data.
FDA will consider foreign data supportive of U.S. postmarketing use
data if U.S. and foreign formulations, patient populations, and
clinical practices are the same or substantially similar.
(Comment 31) Two comments asked that FDA reduce the requirement for
1 year of U.S. postmarketing data if foreign postmarketing use data is
sufficient to support a finding that a CFC-MDI is no longer essential.
One comment asked that FDA permit the use of foreign data in
combination with U.S. data to make a total of 1 year of postmarketing
data.
In response to these comments, FDA has finalized
Sec. 2.125(g)(3)(iii) to require that adequate U.S. postmarketing data
exist for the non-ODS product. FDA may find that less than 1 year is
adequate if foreign data is relevant to the U.S. market. FDA notes that
it is interested in the acceptability of a product in the U.S.
population, its actual use in the United States, and its relation to
other products marketed in the United States. Foreign data may be used
to augment U.S. data when appropriate.
(Comment 32) One comment stated that FDA should use a longer than
1-year period to collect postmarketing data.
FDA is requiring adequate postmarketing data. This may mean more or
less than 1 year, depending on the particulars of the product under
consideration and the status of other alternatives.
(Comment 33) One comment stated that it does not support phase 4
studies in the postmarketing period. One comment supported FDA's
postmarketing requirements, but asked that FDA clarify that
postmarketing information need not necessarily be obtained through
phase 4 studies. One comment supported the proposal that a
postmarketing study not be required if other data are adequate to
establish the acceptability of an alternative. PADAC members had
differing points of view on the value of conducting formal
postmarketing studies (Ref. 1, pp. 136 through 171 of the transcript).
In general, FDA does not anticipate that sponsors will need to
conduct formal phase 4 studies in the postmarketing period to provide
adequate postmarketing data. FDA does anticipate, however, that
sponsors will need to collect some postmarketing data beyond standard
postmarketing surveillance to determine the acceptability of an
alternative.

[[Page 48379]]

(Comment 34) One comment asked that FDA retract its suggestion that
new data, and possibly new clinical studies, may be required to ensure
an additional level of proof of safety and effectiveness.
FDA will not require an additional level of proof of safety and
effectiveness in evaluating alternatives. FDA makes a determination
that a non-ODS product is safe and effective when FDA approves the
product for marketing. The question of whether the non-ODS product is
an acceptable alternative to an ODS-product is a separate question,
which FDA will answer by using the criteria set forth in Sec. 2.125(g).

F. Timing of Phaseout

(Comment 35) One comment requested that FDA accord priority review
to NDAs for non-ODS products. One comment stated that non-ODS products
should undergo expedited review.
The agency is committed to the timely review of all drug
applications. FDA does not believe that NDAs for non-ODS replacement
products meet the criteria for priority review at the current time.
(Comment 36) One comment stated that education is a very important
part of the transition process and asked FDA to take a leadership role
in continuing education.
FDA recognizes the need to educate patients, health care providers,
and interested parties about the planned phaseout of CFC-MDIs for the
transition to non-ODS products to occur as smoothly as possible. FDA
has been involved in public education on this issue for the past
several years. Members of the Center for Drug Evaluation and Research's
Division of Pulmonary and Allergy Drug Products have made presentations
and participated in panel discussions on the phaseout of CFCs at
national scientific and professional society meetings and will continue
to do so.
The division has also worked in close cooperation with the National
Asthma Education and Prevention Program (NAEPP), an ongoing
comprehensive program directed by the staff of the National Heart,
Lung, and Blood Institute of NIH. NAEPP educates physicians, other
health care providers, and patients about issues related to the
prevention and treatment of asthma, including the phaseout of CFCs. The
NAEPP Coordinating Committee formed a CFC Workgroup to educate patients
and physicians about the CFC phaseout. The NAEPP CFC Workgroup, in
cooperation with the International Pharmaceutical Aerosol Consortium,
developed a ``fact sheet'' for patients entitled ``Your Metered-Dose
Inhaler Will Be Changing * * * Here Are the Facts.'' The fact sheet is
available on the Internet at http://www.fda.gov/cder/mdi/. The NAEPP
CFC Workgroup is continuing to broaden its educational effort. FDA
provides appropriate advice and assistance to the NAEPP CFC Workgroup.
FDA has also published articles on the phaseout of CFCs in FDA
Consumer, Journal of the American Medical Association, and the FDA
Medical Bulletin to educate health care providers and patients about
FDA actions, or proposed actions, related to the transition to non-ODS
inhalation products.
The agency views these educational efforts as a critical component
of the transition process and intends to continue these efforts as the
transition to non-ODS products moves forward.
(Comment 37) One comment asked that FDA work with others to outline
clear deadlines and strategies for a complete transition to facilitate
necessary patient and health care provider education. One comment
stated that FDA should provide a detailed timeframe for the transition.
FDA understands that patients and health care providers are very
interested in knowing exactly when the transition will be complete.
However, FDA cannot provide an exact date at this time because the U.S.
transition is largely dependent on the availability of alternative
products. However, as described above, FDA will develop and participate
in patient and health care provider education that is appropriate for
each stage of the transition and as more information becomes available
regarding the timing of the transition.
(Comment 38) One comment requested that FDA carefully prepare its
regulatory materials; provide patient, medical professional, and public
education; and allow ample opportunity for interaction with FDA
advisory bodies and personnel before proposing removal of an essential-
use designation for an active moiety without a non-ODS replacement
containing that active moiety.
FDA plans to take all of these steps before proposing removal of an
essential-use designation under Sec. 2.125(g)(2) for an active moiety
without a non-ODS replacement containing that moiety. FDA notes,
however, that if an active moiety is no longer marketed in a CFC
formulation, FDA will propose removal of the essential-use designation
under Sec. 2.125(g)(1) without necessarily taking the additional steps
suggested in the comment.
(Comment 39) One comment asked that FDA reiterate that it will
determine the effective date of the removal of an essential use from
Sec. 2.125 on a case-by-case basis.
FDA will determine the effective date of the removal of an
essential use from Sec. 2.125(e) on a case-by-case basis determined as
a part of notice-and-comment rulemaking.

G. Nasal Steroids

(Comment 40) Three comments supported removal of the essential-use
designations for nasal steroids. PADAC supported the removal of the
essential-use designations for nasal steroids (Ref. 1, pp. 235 though
240 of the transcript).
In this final rule, FDA is eliminating the essential-use
designations for nasal steroids. This means that after the
applicability date of this rule, no ODS formulation of a nasal steroid
may be sold or distributed, or offered for sale or distribution, in the
United States (see 40 CFR 82.64(c) and 82.66(d)).
(Comment 41) One comment supported removal of nasal steroids
generally, but noted that only one nasal steroid containing CFCs is
approved to age 4 and asked that FDA not remove the essential use for
this product.
In response to this comment, FDA has reviewed the labeling for
nasal steroids. Fluticasone and mometasone, both available as non-ODS
products, are labeled for children as young as ages 4 and 3,
respectively. No CFC nasal products are approved for children as young
as age 4. Therefore, FDA does not believe it is medically necessary to
retain the essential use for any nasal steroid.

H. Incentives for Development of Alternatives

(Comment 42) One comment requested that FDA cooperate with other
government entities to implement suggestions outside of its authority.
The same comment asked FDA to seek changes to the Montreal Protocol if
necessary to protect patient health.
FDA is working closely with EPA and with the Department of State to
ensure that the transition is smooth. If FDA finds that patient health
is at risk as the transition progresses, FDA will take steps within its
own authority and will seek the assistance of other authorities to
continue to protect patient health.

I. Cost of New Products

(Comment 43) One comment stated that cost should be a priority in
determining whether non-ODS alternatives are adequate. One comment
stated that economic impacts must be taken into account before removal
of an

[[Page 48380]]

essential-use designation. One comment argued that FDA has not
adequately assessed the impact on public health from removal of generic
CFC-MDIs. Three comments stated that FDA should not consider cost in
determining essentiality. PADAC members agreed generally that cost
alone should not be a reason for retaining an essential use and that
the United States should work to find a way to deliver appropriate
drugs to people who cannot afford the medicine (Ref. 1, pp. 226 through
235 of the transcript).
FDA recognizes that cost is a concern for many patients and health
care providers. In part due to considerations such as those raised in
these comments, FDA is requiring that multiple-source CFC-MDI products
be replaced by at least two non-ODS alternative products. FDA will also
consider cost in determining whether alternatives meet patient needs.
In addition, FDA expects that the price for most non-ODS products will
approximate the price for branded CFC products. FDA bases this
expectation on statements by manufacturers.

J. Environmental Impact of CFC-MDI Use

(Comment 44) One comment argued that the elimination of CFC-MDIs is
not justified by the de minimis environmental benefit that will result.
The United States evaluated the environmental effect of eliminating
the use of all CFCs in an environmental impact statement (EIS) in the
1970s (see 43 FR 11301, March 17, 1978). As part of that evaluation,
FDA concluded that the continued use of CFCs in medical products posed
an unreasonable risk of long-term biological and climatic impacts (see
Docket No. 96N-0057). Congress later enacted provisions of the Clean
Air Act that codified the decision to fully phase out the use of CFCs
over time (see Title VI (enacted November 15, 1990)). FDA notes that
the environmental impact of individual uses of nonessential CFCs must
not be evaluated independently, but rather must be evaluated in the
context of the overall use of CFCs. Cumulative impacts can result from
individually minor but collectively significant actions taking place
over a period of time (40 CFR 1508.7). Significance cannot be avoided
by breaking an action down into small components (40 CFR
1508.27(b)(7)). Although it may appear to some that CFC-MDI use is only
a small part of total ODS use and therefore should be exempted, the
elimination of CFC use in MDIs is only one of many steps that are part
of the overall phaseout of ODS use. If each small step were provided an
exemption, the cumulative effect would be to prevent environmental
improvements. FDA is merely fulfilling its obligation to make
essential-use determinations for FDA-regulated products, in accordance
with the Clean Air Act.

K. Generics

(Comment 45) Two comments stated that FDA should not eliminate an
essential use unless a non-ODS generic is available for that essential
use.
Only one CFC-MDI, albuterol, is available in a generic formulation.
FDA is not requiring that more generics be available in non-ODS
formulations than are available in CFC formulations. It would seem
inappropriate to require the availability of a non-ODS generic drug
product when there is no generic version currently on the market and we
have no guaranty that a generic drug will ever be developed for any
given active moiety. When generic products become available is dictated
by manufacturers' decisions whether to produce a generic product, by
U.S. patent laws, by the exclusivity provisions of the act, by the
approvability of any particular generic drug application, and by the
manufacturers' eligibility to receive ODSs under the Montreal Protocol
and the Clean Air Act.
(Comment 46) Three comments said that FDA should not approve a new
CFC-containing MDI drug product if the active moiety in the drug
product is already marketed and appears on the essential-use list.
Three comments stated that FDA should not approve generic versions of
existing essential-use products. One comment stated that FDA should
approve generic versions of existing essential-use products. One
comment stated that patients will not be adversely affected in terms of
out-of-pocket cost of medications or quality of life if approval of
generic medications should cease. One comment said that FDA should not
approve any new CFC-containing drug product unless it provides an
unavailable important public health benefit. One comment requested that
FDA require all new drug products to demonstrate clinically significant
value before approval.
Section 505 of the act directs FDA to approve new drug and generic
products if all of the requirements in the act are met. There is no
exception in the act permitting FDA to refuse to approve new drug or
generic products simply because they contain an ODS. Therefore, FDA
will continue to approve new drug and generic applications that meet
the current requirements of the act.
(Comment 47) One comment stated that FDA should require companies
using essential-use designations to demonstrate that they are actively
pursuing reformulation.
FDA is not requiring companies to demonstrate that they are
actively pursuing reformulation to maintain the essential-use
designation of their products. However, after January 1, 2005, FDA may
propose to remove the essential-use designation for an active moiety
even if it has not been reformulated.

L. New Essential Uses

(Comment 48) One comment supported the criteria in the proposed
rule for the addition of new essential uses.
FDA is adopting the criteria for addition of new essential uses
that it had proposed.
(Comment 49) One comment supported the compelling evidence standard
generally but asked that FDA approve new essential uses if the product
offers a compelling therapeutic benefit to a significant, albeit small,
subpopulation.
FDA will consider adding a new essential use if the use is for a
product that will provide an unavailable important public health
benefit. FDA believes it is possible, under this criterion, for a
product that offers a compelling therapeutic benefit for a significant,
albeit small, subpopulation to qualify for an essential use. FDA would
carefully evaluate any evidence in support of such an essential use.

M. Additional Comments

(Comment 50) Three comments supported changing the designation of
ODS products not listed from adulterated and misbranded to
nonessential. One comment asked that FDA revoke the statements made in
the preamble to the proposed rule regarding the continued applicability
of the adulterated and misbranded provisions of the act. One comment
stated that FDA should retain the express authority to find a
nonessential product adulterated or misbranded if it contains CFCs.
The agency is amending Sec. 2.125 to state that a product in a
self-pressurized container that contains an ODS is not essential. This
change should not be interpreted to mean that FDA no longer believes
that such products are adulterated and/or misbranded. Such nonessential
products are adulterated and/or misbranded under certain act
provisions, including sections 402, 403, 409, 501, 502, 601, and 602 of
the act (21 U.S.C. 342, 343, 348, 351, 352, 361, and 362). The basis
for FDA's authority

[[Page 48381]]

to declare such products adulterated and/or misbranded is discussed in
the preambles for Sec. 2.125 and related rules and proposed rules (see
43 FR 11301, March 17, 1978; 42 FR 24536, May 13, 1977; 42 FR 22018,
April 29, 1977; and 41 FR 52071, November 26, 1976). However, FDA is
changing the regulation to conform to the authority delegated to it
under the Clean Air Act. FDA notes that EPA is responsible for
enforcement of the Clean Air Act.
(Comment 51) One comment argued that the transition will force
patients to abandon safe and effective products.
FDA is finalizing this rule to fulfill its responsibilities under
the Clean Air Act. Although it is true that CFC-MDIs are safe and
effective as approved, CFCs also deplete the ozone layer which has a
detrimental effect on the public health and the environment. The United
States has determined that, as a result, CFC-MDIs should be phased out.
(Comment 52) One comment asked for clarification on whether
elimination of an essential use from Sec. 2.125 would prohibit use of
stockpiled CFCs.
This comment raises questions under the Clean Air Act. Under 40 CFR
82.64(c), no person may sell or distribute, or offer to sell or
distribute, in interstate commerce any nonessential product. Under 40
CFR 82.66(d), any aerosol product or other pressurized dispenser that
contains a CFC is a nonessential product. Medical devices listed in
Sec. 2.125(e) are exempted from this prohibition (40 CFR
82.66(d)(2)(i)). However, once a medical device is removed from the
listing in Sec. 2.125(e), it can no longer be marketed (40 CFR
82.64(c)). FDA notes that it plans to include an implementation period
once the agency determines that a use is no longer essential. The
length of this implementation period will be determined through the
notice-and-comment rulemaking in which the essential use is eliminated.
(Comment 53) One comment stated that FDA must comply with Executive
Order 12898 on environmental justice.
Executive Order 12898 requires agencies to identify and address
disproportionately high adverse human health or environmental effects
on minority populations and low-income populations. As discussed in the
economic analysis prepared for this rule, the agency does not
anticipate that this final rule will have any adverse effects on human
health or the environment (see section VII of this document).
(Comment 54) One comment stated that FDA must comply with Executive
Order 12866 on economic and social cost-benefit assessments.
Executive Order 12866 directs agencies to assess all costs and
benefits of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits.
The agency has complied with this requirement to the extent necessary
(see section VII of this document).
(Comment 55) One comment stated that FDA must comply with Executive
Order 12630 on effects on private property. One comment argued that the
government cannot preclude the use of stockpiled CFCs because to do so
would result in a taking.
Executive Order 12630 requires government agencies to evaluate
whether a regulation has any takings implications. FDA does not believe
that this regulation has any takings implications. This regulation
simply sets the standard FDA will use to determine whether an ODS use
remains essential. The Clean Air Act then prevents marketing of those
ODS-containing products. The use of stockpiled CFCs is governed by the
Clean Air Act.
(Comment 56) One comment stated that FDA needs to complete an EIS
under the National Environmental Policy Act of 1969 (NEPA), as amended
(42 U.S.C. 4321-4347).
FDA has complied with NEPA. The agency has evaluated the
environmental effects of eliminating ODS-containing products and
provided opportunities for public comment on these issues. An EIS was
prepared on this issue (see 43 FR 11301, March 17, 1978). In addition,
environmental assessments (EAs) were prepared in conjunction with the
NDA approval process for products that are viewed as alternatives to
metered-dose steroid drugs for nasal inhalation containing ODSs.
Finally, FDA issued both an ANPRM (62 FR 10242) and a proposed rule (64
FR 47719) as part to this rulemaking. Both of these documents discuss
the environmental effects of eliminating ODS-containing products. The
agency received large numbers of comments and responded to them in the
proposed rule or this document. This document further discusses the
environmental effect of eliminating ODS- containing products.
Furthermore, those portions of the rule that set out the processes
for adding new essential uses and for determining that existing uses
are no longer essential are covered by a categorical exclusion from
NEPA's requirements. Section 25.30(h) of FDA's NEPA regulations (21 CFR
25.30(h)) provides that the ``[i]ssuance, amendment, or revocation of
procedural or administrative regulations * * *'' does not require the
preparation of an EIS or an EA. Finally, in the future, when FDA
undertakes rulemaking to add or remove an essential use, the agency
will prepare an EA and/or an EIS if required by NEPA.
However, to ensure that the public is given the fullest opportunity
to comment on this rulemaking, interested parties may submit comments
on the environmental effects of removing the essential-use designations
for products that are no longer being marketed and for metered-dose
steroid drugs for nasal inhalation for a period of 30 days after
publication of this rule. Unless the agency receives a comment that
leads it to believe that a change in the rule is appropriate, the
effective date of this rule will be January 20, 2003.
(Comment 57) One comment asked that FDA revise the proposal to
clarify that the nonessentiality determination applies only to products
marketed in the United States and not to exports.
FDA is not revising Sec. 2.125 to reflect that the nonessentiality
determination applies only to products in the United States and not to
exports because the act has specific provisions that address when a
product that would otherwise be adulterated and misbranded may still be
exported. Under section 801(e)(1) of the act (21 U.S.C. 381(e)(1)):
A food, drug, device, or cosmetic intended for export shall not
be deemed to be adulterated or misbranded under this Act if it--
(A) accords to the specifications of the foreign purchaser,
(B) is not in conflict with the laws of the country to which it
is intended for export,
(C) is labeled on the outside of the shipping package that it is
intended for export, and
(D) is not sold or offered for sale in domestic commerce.
A manufacturer seeking to export nonessential products could do so
under the act so long as the products for export met the requirements
of section 801 of the act.
FDA has consulted with EPA to determine whether EPA rules currently
allow export of nonessential products. FDA understands that current EPA
rules do not allow such export. However, depending on the pace of
transition in other countries and their possible continued short-term
need to have a small amount of additional time to effectuate their
timely and thoughtful phaseout, EPA may consider changing its rule at
some future date.
(Comment 58) One comment argued that the Clean Air Act requires
notice-and-comment rulemaking for addition of each drug product rather
than each moiety.
Section 601(8) of the Clean Air Act states that each ``medical
device'' must

[[Page 48382]]

have been determined to be essential. The section 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), and drug delivery system * *
*.'' Section 201(g)(1) of the act defines ``drug'' as:
(A) articles recognized in the official United States
Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United
States, or official National Formulary, or any supplement to any of
them; and
(B) articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man or other
animals; and
(C) articles (other than food) intended to affect the structure
or any function of the body of man or other animals; and
(D) articles intended for use as a component of any article
specified in clause (A), (B), or (C).
* * *
This definition permits the word ``drug'' to be read to mean either
``drug product,'' ``drug substance'' or ``active moiety.'' FDA has read
the word drug to have a specific meaning depending on the context in
which it is used. In this case, FDA believes it is appropriate to read
the word ``drug'' to mean ``active moiety.''
(Comment 59) Two comments stated that neither the Clean Air Act nor
the Montreal Protocol requires an eventual end to any and all essential
uses of CFCs within the United States.
In light of these comments, FDA has revisited the text of the Clean
Air Act, its legislative history, the text of the Montreal Protocol,
and decisions by the Parties to the Protocol. FDA also further
discussed its understanding of the Clean Air Act and the Protocol with
the EPA.
The text of the Clean Air Act states that EPA will, after notice
and opportunity for public comment and ``to the extent such action is
consistent with the Montreal Protocol, authorize the production of
limited quantities of class I substances solely for use in medical
devices * * *.'' (section 604(d)(2) of the Clean Air Act). The Clean
Air Act does not state specifically whether such essential-use
exemptions may continue indefinitely or must terminate at some future
time. However, the legislative history for this section of the Clean
Air Act makes it clear that the exemption is only permitted for a
limited time. The Senate Conference Report for this section of the
Clean Air Act states:
The Administrator [of EPA] is authorized on a conditional basis
to grant limited extensions of the termination date for production
of limited quantities of class I substances, to the extent such
action is consistent with the Montreal Protocol for: * * * medical
devices; * * *.
* * * * *
The centerpiece of the stratospheric ozone protection program
established by this title is the phaseout of production and
consumption of all ozone depleting substances.
(136 Cong. Rec. S16895 at 16946 and 16947 (daily ed. Oct. 27, 1990).)
These statements are consistent with the Montreal Protocol. The
Preamble to the Protocol states that the Parties are:
Determined to protect the ozone layer by taking precautionary
measures to control equitably total global emissions of substances
that deplete it, with the ultimate objective of their elimination on
the basis of developments in scientific knowledge, taking into
account technical and economic considerations and bearing in mind
the developmental needs of developing countries.
(Preamble to the Montreal Protocol (emphasis added).)
Decision IV/25 of the Protocol also indicates that essential-use
exemptions are temporary. This decision asks the Technology and
Economic Assessment Panel to determine an estimated duration for each
essential use, the steps necessary to ensure alternatives are available
as soon as possible, and whether previously qualified essential uses
should no longer qualify as essential.
Finally, FDA confirmed with EPA that it is also their understanding
that the Clean Air Act and the Montreal Protocol do not permit
essential-use exemptions to continue forever.
Thus, although it is true that there is no set date for termination
of essential-use exemptions, it is also clear that the exemptions will
not exist forever.

V. Legal Authority

This final rule to determine when FDA-regulated products using ODSs
are essential is authorized by the Clean Air Act. EPA regulations
implementing the provisions of section 610 of the Clean Air Act contain
a general ban on the use of CFCs in pressurized dispensers (40 CFR
82.64(c) and 82.66(d)). The Clean Air Act and EPA regulations exempt
from the general ban ``medical devices'' that FDA considers essential
and that are listed in Sec. 2.125(e) (section 610(e) of the Clean Air
Act; 40 CFR 82.66(d)(2)). Section 601(8) of the Clean Air Act defines
``medical device'' as any device (as defined in the act), diagnostic
product, drug (as defined in the act), and drug delivery system, if
such device, product, drug, or drug delivery system uses a class I or
class II ODS for which no safe and effective alternative has been
developed (and, where necessary, approved by the Commissioner of Food
and Drugs (the Commissioner)); and 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 in consultation with the Administrator of EPA (the
Administrator). Class I substances include CFCs, halons, carbon
tetrachloride, methyl chloroform, methyl bromide, and other chemicals
not relevant to this document (see 40 CFR part 82, appendix A to
subpart A). Class II substances include hydrochlorofluorocarbons (see
40 CFR part 82, appendix B to subpart A).
Essential-use products are listed in Sec. 2.125(e). Although
Sec. 2.125 includes a mechanism for adding essential-use products to
the regulations, the regulations do not include a mechanism for
removing products from the essential-use list. This rule provides a
mechanism for FDA to remove products from the essential-use list in an
orderly and rational fashion.
EPA has reviewed this rule and agrees with its issuance.

VI. Implementation Plan

This final rule is effective January 20, 2003. After January 20,
2003, FDA will evaluate products on the essential-use list according to
the criteria set forth in the rule. As the criteria for eliminating
essential uses are met, FDA will publish proposals to eliminate
essential uses for the appropriate individual active moieties. FDA
intends that such proposals will be published and finalized in an
expeditious manner.

VII. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (2 U.S.C. 1501 et seq.).
Executive Order 12866 directs regulatory agencies to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity).
Unless the agency certifies that the rule is not expected to have a
significant impact on a substantial number of small entities, the
Regulatory Flexibility Act requires agencies to analyze regulatory
options that would minimize any significant economic impact on small
entities. Section 202 of the Unfunded Mandates Reform Act requires that
agencies prepare an assessment of anticipated costs and benefits before
proposing any

[[Page 48383]]

rule that may result in expenditure by State, local, and tribal
governments, in the aggregate, or by the private sector of $100 million
in any one year (adjusted annually for inflation). The agency has
determined that the final rule is consistent with the principles set
forth in the Executive order and in these statutes. The final rule will
not result in costs in excess of $100 million and therefore no further
analysis is required under the Unfunded Mandates Reform Act. In
addition, FDA certifies that this regulation would not result in a
significant economic impact on a substantial number of small entities.
Thus, the agency need not prepare a final regulatory flexibility
analysis.
FDA published a detailed analysis of impacts when this regulation
was proposed in September 1, 1999 (64 FR 47719). No further information
has been submitted that would alter the findings of the analysis
submitted with the proposed regulation.
FDA is removing the essential-use designation for metered-dose
steroid human drugs for nasal inhalation. Four manufacturers market
CFC-nasal inhalation products, which constitute a small proportion of
the nasal inhalation product market. The affected CFC containing drug
products contain either beclomethasone, budesonide, or triamcinolone.
All three active moieties are also marketed in non-CFC formulations by
the same manufacturers of the CFC nasal inhalation products. Several
other steroid human drugs for nasal inhalation are marketed in non-CFC
formulations. These drug products provide therapeutic alternatives to
the CFC containing products.
FDA is also removing the essential-use designations for drug
products that are either no longer being marketed or are no longer
being marketed in a formulation containing ozone depleting substances.
In addition to removing these essential uses, this regulation
articulates the standards used by FDA to determine whether the use of
ozone-depleting substances in metered dose inhalers remains essential
under the Clean Air Act. The regulation has limited direct economic
impact because it primarily establishes the criteria FDA would use to
make essential use determinations. However, future application of the
procedure described in this regulation will generate both regulatory
benefits and costs. FDA has discussed the potential nature of these
impacts with the proposed rule and briefly describes them below.

A. Regulatory Benefits

The benefits of the procedure described in this regulation are the
environmental gains associated with the diminished use of ozone-
depleting substances in medical products. The Environmental Protection
Agency has estimated (in prior regulatory analyses) that the aggregate
public health benefit of phasing out the use of ozone-depleting
substances due to reduced cases of skin cancer, cataracts and other
health effects ranges between $8 and $32 trillion. FDA has crafted the
procedure described in this regulation to achieve a small fraction of
these benefits while maintaining adequate supplies of reformulated
products for patients treated for asthma and COPD. Most important, the
regulation ensures that adequate supplies of reformulated products with
comparable therapeutic roles are available prior to rescission of an
essential use designation. Although FDA cannot speak with certainty
about future events, the agency does not anticipate that significant
decreases in purchases of non-ODS alternatives, as compared to
purchases of CFC-MDIs, will occur after an essential-use exemption is
removed under the procedures set forth in this rule.
Similarly, removal of essential-use designations for steroid nasal
inhalation products would not affect the public health. Adequate
supplies of reformulated products with comparable therapeutic roles
exist with prices that are approximately the same as the CFC products
on a dose basis.

B. Regulatory Costs

FDA considers the costs of reformulation to be direct consequences
of the statutory requirements of the Clean Air Act rather than
forthcoming FDA regulatory activity. Sponsors who elect to reformulate
their products may incur costs to collect detailed clinical data, but
FDA has no empirical information to confirm the extent of these costs.
Manufacturers are well aware of the mandate to eliminate ozone-
depleting substances and are already engaged in the development of
reformulated products.
The same manufacturers that currently market steroid nasal
inhalation products containing CFCs also market non-CFC alternatives.
Thus, FDA does not anticipate a regulatory cost due to this regulation.
FDA realizes that the future elimination of essential-use
exemptions could have significant distributional and regulatory impacts
on various economic sectors. The agency will prepare detailed analyses
of impacts as part of each of these future rulemakings. The role that
the Montreal Protocol and the Clean Air Act will play in the eventual
prohibition of the production or importation of ODSs must also be kept
in mind.

C. Distributive Impacts

Potential distributive impacts will not be triggered until the
completion of future rulemaking on each specific product currently
using ozone-depleting substances. FDA plans on conducting specific
market analyses to determine the approximate magnitude of these effects
prior to removing essential use designations for specific products.
The agency recognizes that generic albuterol CFC-MDIs are currently
marketed and that these products cost less than currently marketed
albuterol sulfate MDI's which use hydrofluoroalkane (HFA) as a
propellant. At the appropriate time, FDA will evaluate the essential-
use status of albuterol under criteria established by this rule. In
determining whether patients are adequately served by non-ODS products
containing albuterol as the active moiety, FDA will consider the cost
of potential alternatives, such as the albuterol sulfate HFA-MDIs.
The agency does not believe that cost will be a significant factor
in determining whether patients are adequately served by non-ODS
products containing active moieties other than albuterol. There are
currently no generic versions for these other products and FDA expects
that the price for most non-ODS products will approximate the price for
branded CFC products. FDA bases this expectation on statements by
manufacturers.
FDA does not anticipate distributive impacts due to the removal of
essential-use designations for steroid nasal inhalation products. The
same manufacturers also currently market substitute, non-CFC products
at approximately the same price.

D. Small Business Impact

FDA conducted an interim Regulatory Flexibility Analysis that
resulted in a determination that this regulation would not have a
significant economic impact on a substantial number of small entities.
This analysis was included with the proposed regulation (64 FR 47719).
There are relatively few small manufacturers of products that could
potentially be affected. In addition, pharmaceutical wholesalers and
retailers are unlikely to be significantly affected because this
regulation will affect only a few of the thousands of products sold by
these firms. FDA

[[Page 48384]]

received no comments on the interim analysis. FDA also notes that this
regulation simply articulates a procedure that will be used in the
future to assess whether or not ozone-depleting substances in metered
dose inhalers are essential.
FDA further certifies that the removal of essential-use
designations for steroid nasal inhalation products that contain CFCs
will not have a significant impact on a substantial number of small
entities. The four affected manufacturers currently market alternative
products at comparable prices. Therefore no net impact is expected from
this regulation.

VIII. The Paperwork Reduction Act of 1995

This final rule does not require information collections subject to
review by the Office of Management and Budget (OMB) under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501-3520). Section 2.125(f) provides
that a person may seek to add or remove an essential use listed under
Sec. 2.125(e) by filing a petition under part 10 (21 CFR part 10).
Section 10.30(b) requires that a petitioner submit to the agency a
statement of grounds, including the factual and legal grounds on which
the petitioner relies. Section 2.125(f) describes the factual grounds
necessary to document a petition to add or remove an essential use, as
required by Sec. 10.30(b). The burden hours required to provide the
factual grounds for a petition have been calculated under Sec. 10.30
and have been approved under OMB control number 0910-0183, which
expires on February 28, 2003 (see 65 FR 12014, March 7, 2000).

IX. Reference

The following reference has been placed on display in the Dockets
Management Branch (HFA-305), 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. The reference may be seen by interested persons between 9 a.m.
and 4 p.m., Monday through Friday.
1. Food and Drug Administration, Center for Drug Evaluation and
Research, Pulmonary and Allergy Drugs Advisory Committee Transcript,
Friedman & Associates, November 22, 1999.

List of Subjects in 21 CFR Part 2

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

Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Clean Air Act and under authority delegated to the Commissioner of Food
and Drugs, after consultation with the Administrator of the
Environmental Protection Agency, 21 CFR part 2 is amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

1. The authority citation for 21 CFR part 2 is revised to read as
follows:

Authority: 15 U.S.C. 402, 409; 21 U.S.C. 321, 331, 335, 342,
343, 346a, 348, 351, 352, 355, 360b, 361, 362, 371, 372, 374; 42
U.S.C. 7671 et seq.

2. Section 2.125 is revised to read as follows:

Sec. 2.125 Use of ozone-depleting substances in foods, drugs, devices,
or cosmetics.

(a) As used in this section, ozone-depleting substance (ODS) means
any class I substance as defined in 40 CFR part 82, appendix A to
subpart A, or class II substance as defined in 40 CFR part 82, appendix
B to subpart A.
(b) Except as provided in paragraph (c) of this section, any food,
drug, device, or cosmetic that is, consists in part of, or is contained
in an aerosol product or other pressurized dispenser that releases an
ODS is not an essential use of the ODS under the Clean Air Act.
(c) A food, drug, device, or cosmetic that is, consists in part of,
or is contained in an aerosol product or other pressurized dispenser
that releases an ODS is an essential use of the ODS under the Clean Air
Act if paragraph (e) of this section specifies the use of that product
as essential. For drugs, including biologics and animal drugs, and for
devices, an investigational application or an approved marketing
application must be in effect, as applicable.
(d) [Reserved]
(e) The use of ODSs in the following products is essential:
(1) Metered-dose corticosteroid human drugs for oral inhalation.
Oral pressurized metered-dose inhalers containing the following active
moieties:
(i) Beclomethasone.
(ii) Dexamethasone.
(iii) Flunisolide.
(iv) Fluticasone.
(v) Triamcinolone.
(2) Metered-dose short-acting adrenergic bronchodilator human drugs
for oral inhalation. Oral pressurized metered-dose inhalers containing
the following active moieties:
(i) Albuterol.
(ii) Bitolterol.
(iii) Metaproterenol.
(iv) Pirbuterol.
(v) Epinephrine.
(3) [Reserved]
(4) Other essential uses. (i) Metered-dose salmeterol drug products
administered by oral inhalation for use in humans.
(ii) Metered-dose ergotamine tartrate drug products administered by
oral inhalation for use in humans.
(iii) Anesthetic drugs for topical use on accessible mucous
membranes of humans where a cannula is used for application.
(iv) Metered-dose cromolyn sodium human drugs administered by oral
inhalation.
(v) Metered-dose ipratropium bromide for oral inhalation.
(vi) Metered-dose atropine sulfate aerosol human drugs administered
by oral inhalation.
(vii) Metered-dose nedocromil sodium human drugs administered by
oral inhalation.
(viii) Metered-dose ipratropium bromide and albuterol sulfate, in
combination, administered by oral inhalation for human use.
(ix) Sterile aerosol talc administered intrapleurally by
thoracoscopy for human use.
(f) Any person may file a petition under part 10 of this chapter to
request that FDA initiate rulemaking to amend paragraph (e) of this
section to add an essential use. FDA may initiate notice-and-comment
rulemaking to add an essential use on its own initiative or in response
to a petition, if granted.
(1) If the petition is to add use of a noninvestigational product,
the petitioner must submit compelling evidence that:
(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.
(2) If the petition is to add use of an investigational product,
the petitioner must submit compelling evidence that:
(i) Substantial technical barriers exist to formulating the
investigational product without ODSs;
(ii) A high probability exists that the investigational product
will provide an unavailable important public health benefit; and
(iii) Use of the investigational product does not release
cumulatively significant amounts of ODSs into the atmosphere or the
release is warranted in view of the high probability of an unavailable
important public health benefit.
(g) Any person may file a petition under part 10 of this chapter to
request

[[Page 48385]]

that FDA initiate rulemaking to amend paragraph (e) of this section to
remove an essential use. FDA may initiate notice-and-comment rulemaking
to remove an essential use on its own initiative or in response to a
petition, if granted. If the petition is to remove an essential use
from paragraph (e) of this section, the petitioner must submit
compelling evidence of any one of the following criteria:
(1) The product using an ODS is no longer being marketed; or
(2) After January 1, 2005, FDA determines that the product using an
ODS no longer meets the criteria in paragraph (f) of this section after
consultation with a relevant advisory committee(s) and after an open
public meeting; or
(3) For individual active moieties marketed as ODS products and
represented by one new drug application (NDA):
(i) At least one non-ODS product with the same active moiety is
marketed with the same route of administration, for the same
indication, and with approximately the same level of convenience of use
as the ODS product containing that active moiety;
(ii) Supplies and production capacity for the non-ODS product(s)
exist or will exist at levels sufficient to meet patient need;
(iii) Adequate U.S. postmarketing use data is available for the
non-ODS product(s); and
(iv) Patients who medically required the ODS product are adequately
served by the non-ODS product(s) containing that active moiety and
other available products; or
(4) For individual active moieties marketed as ODS products and
represented by two or more NDAs:
(i) At least two non-ODS products that contain the same active
moiety are being marketed with the same route of delivery, for the same
indication, and with approximately the same level of convenience of use
as the ODS products; and
(ii) The requirements of paragraphs (g)(3)(ii), (g)(3)(iii), and
(g)(3)(iv) of this section are met.

Dated: April 15, 2002.
Lester M. Crawford,
Deputy Commissioner.
[FR Doc. 02-18610 Filed 7-18-02; 3:38 pm]
BILLING CODE 4160-01-S