[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]


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

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.

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

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

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

    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

[[Page 48374]]

     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