[Federal Register: September 1, 1999 (Volume 64, Number 169)]
[Proposed Rules]
[Page 47719-47741]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr01se99-38]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

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

Use of Ozone-Depleting Substances; Essential Use Determinations

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulation on the use of chlorofluorocarbon (CFC) propellants in
self-pressurized containers to make it consistent with other laws. FDA
is proposing to set the standard it will use to determine when the use
of an ozone-depleting substance (ODS) in a product regulated by FDA is
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 the use of an ODS in an FDA-regulated
product is essential. FDA is also proposing in this rule to remove
current essential-use designations for products no longer marketed and
for metered-dose steroid human drugs for nasal inhalation. FDA would
add or remove specific essential use designations for other products by
engaging in separate notice-and-comment rulemaking.

DATES: Written comments on the proposed rule should be submitted by
November 30, 1999. See section V of this document for the proposed
effective date of a final rule based on this document.

ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. See section III.B.15 of this document for
electronic access addresses.

FOR FURTHER INFORMATION CONTACT: Leanne Cusumano, 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. Description of the Proposed Rule
    A. Major Changes From the ANPRM
    B. ``Ozone-Depleting Substance'' versus ``Chlorofluorocarbon''
    C. Elimination of Current Sec. 2.125(b)
    D. Removal of the Term ``Propellant''
    E. Change to Essentiality Determinations
    F. Listing of Active Moieties
    G. Metered-Dose Steroid Human Drugs for Nasal Inhalation
    H. Products No Longer Marketed
    I. Petitions to Add New Essential Uses
      1. Commercially Marketed Drugs
      2. Investigational New Drugs
      3. Evidence to Support New Essential Uses for Investigational
and Noninvestigational Products
    J. Elimination of Outdated Transitional Provisions
    K. Determinations of Continued Essentiality
 III. Comments on the ANPRM
    A. General Comments About the ANPRM
    B. Specific Comments on the ANPRM
      1. Number of Alternatives Proposed
      2. Specific Comments on the Proposed Criteria for Phaseout
      3. Intolerance or Allergy to Drug Products or Propellants
      4. Patient Subpopulations
        a. Children
        b. Elderly
        c. Other subpopulations
      5. Experimental Nature of Alternative MDI's
      6. Choice of Technically Feasible Alternatives
      7. Proventil HFA
      8. Postmarketing Data and Suggested Duration
      9. Timing of Phaseout
      10. Nasal Steroids
      11. Miscellaneous Comments
      12. Incentives for Development of Alternatives
      13. Cost of New Products
      14. Environmental Impact of CFC-MDI Use
      15. Proposed Mechanism for Phaseout
      16. International Mandate (Montreal Protocol)
      17. Legal Arguments
IV. Legal Authority
V. Proposed Implementation Plan
VI. Request for Comments
VII. Analysis of Impacts
    A. Introduction
    B. Economic Impacts
      1. Regulatory Benefits
      2. Regulatory Costs
      3. Distributive Impacts
    C. Small Business Impact
      1. Initial Analysis
      2. Description of Impact
      3. Analysis of Alternatives
    D. Conclusion
VIII. The Paperwork Reduction Act of 1995
IX. References

I. Background

     The United States, as a party to an 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 ODS's, including CFC's. The United States
has generally banned the use of CFC's in consumer aerosols for decades
and eliminated almost all manufacture and importation of CFC's as of
January 1, 1996. The Montreal Protocol permits Parties to the Protocol
to continue to produce or import CFC's for use in essential medical
products upon approval by the Parties.
     FDA, in consultation with EPA, determines whether a medical
product is essential under 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 (MDI's). FDA
will continue to designate ODS medical products such as MDI's as
essential until non-ODS medical products adequately serve the needs of
patients. The United States, through EPA, must apply annually to the
Parties to the Montreal Protocol for a specific CFC production or
importation allowance for CFC-MDI's that FDA has designated as
essential. However, the United States has agreed to eventually phase
out all uses of CFC's. FDA is developing a strategy to ensure that the
health and safety of patients in the United States are protected during
the transition away from CFC use in medical products.
    In the Federal Register of March 6, 1997 (62 FR 10242), FDA
published an advanced notice of proposed rulemaking (ANPRM) that sought
public comment on transition options. One approach that FDA suggested
was that ODS products be considered nonessential if: (1) Alternative
product(s) is (are) being marketed (a) with the same active moiety, (b)
by the same route of administration, (c) for the same indication, and
(d) with approximately the same level of convenience of use compared to
the product containing CFC's; (2) adequate supplies and production
capacity exist for the alternative products to meet the needs of the
population; (3) at least 1 year of postmarketing use data for each
product are available and persuasive evidence shows patient acceptance
of the alternative product(s) in the United States; and (4) there is no
persuasive evidence to rebut a presumption that all significant patient
subpopulations are served by the alternative product(s). FDA received
almost 10,000 comments on the ANPRM, and addresses those comments later
in this proposed rule.

[[Page 47720]]

II. Description of the Proposed Rule

    FDA is proposing to make the following changes to Sec. 2.125: (1)
Use the phrase ``ozone-depleting substance'' instead of the word
``chlorofluorocarbon'' in the title and text of the regulation; (2)
eliminate current Sec. 2.125(b) because it is explanatory material that
has no regulatory effect; (3) in current Sec. 2.125(c), define 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 definition to those products that use CFC's as a
propellant; (4) change the designation of ODS products not listed in
Sec. 2.125(e) from adulterated and misbranded to nonessential; (5) list
as separate essential uses 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; (6) eliminate the essential-use designation in current
Sec. 2.125(e) for metered-dose steroid human drugs for nasal
inhalation; (7) eliminate the essential-use designations in current
Sec. 2.125(e) for products that are no longer marketed; (8) set the
standard to determine when a new essential-use designation should be
added to Sec. 2.125; (9) eliminate outdated transitional provisions in
current Sec. 2.125(g), (h), (i), (j), (k), and (l); and (10) set
standards to determine whether the use of an ODS in a medical product
remains essential.

A. Major Changes From the ANPRM

     This proposed rule contains many changes from the ANPRM. FDA is
proposing these changes in response to comments received and as the
agency's thinking on the issue evolved. This document discusses in
detail the changes and the reasons for the changes. FDA is highlighting
the following major components here to allow for a clearer
understanding of the proposed rule:
     1. The agency is not proposing to use a therapeutic class approach
as discussed in the ANPRM. FDA proposes to use a moiety-by-moiety
approach to determine whether the use of an ODS in a medical product
remains essential. An active moiety is the part of a drug that makes
the drug work the way it does. Many different drug products may be
marketed with the same active moiety.
    21 CFR 314.108(a) defines active moiety as ``the molecule or ion,
excluding those appended portions of the molecule that cause the drug
to be an ester, salt (including a salt with hydrogen or coordination
bonds), or other noncovalent derivative (such as a complex, chelate, or
clathrate) of the molecule, responsible for the physiological or
pharmacological action of the drug substance.''\1\
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    \1\ For purposes of this proposed rule, an essential use for an
active moiety would cover all enantiomers of molecules containing
the active moiety, as well as racemic and nonracemic mixtures of
those enantiomers. In cases where an enantiomer has substantial
clinical differences from the racemate, a petition could be
submitted under proposed Sec. 2.125(f) to list the use of the
enantiomer as a new essential use.
    Stereoisomers are molecules that have the same constitution
(i.e., molecular formula and chemical connectivity), but differ in
the spatial orientation of the atoms. When two stereoisomers are
mirror images, but are not superimposable upon each other (like left
and right hands), they are referred to as enantiomers. Enantiomeric
molecules are identical in all physical and chemical properties,
except in an environment that is also chiral (characterized by
handedness). Polarized light is such an environment, and pairs of
enantiomers rotate the plane of polarization by equal amounts in
opposite directions. Enantiomers may be either right-handed (dextro-
rotary) S(+)-isomers or left-handed (levo-rotary) R(-)-isomers.
Racemates are equimolar mixtures of enantiomers of the same
molecule. See 62 FR 2167, January 15, 1997, for additional
explanation.
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     2. FDA is proposing to require more than one acceptable non-ODS
alternative per an active moiety to be marketed before FDA would
consider removing an essential use designation for the same active
moiety if that active moiety is represented by multiple products or
multiple strengths.
     3. FDA had planned to publish a separate proposed rule to
reorganize and update Sec. 2.125 and to change the criteria for adding
new essential use listings. FDA has decided not to publish a separate
proposed rule. FDA combined the proposals into this proposed rule to
prevent confusion and to present all proposed revisions to Sec. 2.125
in the same proposed rule.

B. ``Ozone-Depleting Substance'' Versus ``Chlorofluorocarbon''

     FDA is proposing to use the term ``ozone-depleting substance''
instead of the word ``chlorofluorocarbon'' in Sec. 2.125. The use of
the term ``ozone-depleting substance'' would bring Sec. 2.125 into
conformity with other Federal laws governing ODS's. The term would be
defined by cross-reference to the list of substances subject to control
under the Clean Air Act (40 CFR part 82, subpart A, appendices A and
B). The Clean Air Act contains comprehensive lists of chemical
substances considered by EPA to be ozone-depleting. CFC's are only one
of the many ODS's listed by EPA. If the change from the term CFC to ODS
does bring additional products within the scope of Sec. 2.125,
manufacturers of those products must seek an essential-use exemption
under Sec. 2.125 in compliance with the Clean Air Act. However, FDA
believes the only ODS's released by FDA-regulated products are the
CFC's released by drug products already listed in Sec. 2.125(e).
Accordingly, the agency does not believe that this change will have any
substantive effect on FDA regulated products in use today.

C. Elimination of Current Sec. 2.125(b)

     The agency is proposing to eliminate current Sec. 2.125(b), which
describes the effects of CFC's on the atmosphere. This explanatory
material has no regulatory effect.

D. Removal of the Term ``Propellant''

     FDA is proposing to eliminate the definition of propellant under
current Sec. 2.125(a) because the word is not used in the proposed
regulation. The agency is proposing to define 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 the use of a CFC as a propellant in a
self-pressurized container. This definition is intended to encompass
all products that are regulated by FDA.

E. Change to Essentiality Determinations

     FDA proposes to change the adulterated and misbranded provisions
of current Sec. 2.125(c). Current Sec. 2.125(c) states that any CFC
product not found in Sec. 2.125(e) is adulterated and/or misbranded in
violation of the Federal Food, Drug, and Cosmetic Act (the act). FDA is
proposing to make Sec. 2.125 correspond with its 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 are still
adulterated and misbranded under the act.
     Current Sec. 2.125(c) will become Sec. 2.125(b) once current
Sec. 2.125(b) is eliminated.

F. Listing of Active Moieties

     FDA is proposing to reorganize the list of essential uses for
metered-dose steroid human drugs for oral inhalation (current
Sec. 2.125(e)(2))\2\ and metered-

[[Page 47721]]

dose adrenergic bronchodilator human drugs for oral inhalation (current
Sec. 2.125(e)(3)). FDA is proposing to list separately each currently
marketed active moiety designated as essential in proposed
Sec. 2.125(e)(1) and (e)(2). This reorganization would not change the
essential-use listings substantively. Any person wishing to market a
product not listed in Sec. 2.125 that uses an ODS would need to
petition the agency under proposed Sec. 2.125(f) to have the use of the
active moiety added to Sec. 2.125.
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    \2\ FDA proposes to use the term corticosteroids rather than the
general term steroids to describe the marketed metered-dose steroid
human drugs for nasal and oral inhalation.
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G. Metered-Dose Steroid Human Drugs for Nasal Inhalation

     FDA is proposing to remove the essential-use designation in
current Sec. 2.125(e)(1) for metered-dose steroid human drugs for nasal
inhalation. FDA bases this proposal on the following: (1) Adequate
alternative non-ODS products for steroid human drugs for nasal
inhalation are currently available, including metering atomizing pumps
for administering nasal corticosteroids, other nonsteroidal nasal
topical therapies, and systemic therapies; (2) patients use the
alternative products on a widespread basis; and (3) these alternative
products have been and continue to be produced and supplied at
sufficient levels to meet patient needs. FDA notes that, unlike other
ODS medical products currently being marketed, the diseases for which
these products are indicated are not life threatening and the Parties
to the Montreal Protocol no longer grant essential-use allocations for
nasal steroids. FDA also notes that only the three active moieties
beclomethasone, budesonide, and triamcinolone are marketed as CFC-nasal
steroids. Beclomethasone and triamcinolone are also marketed in non-CFC
formulations.

H. Products No Longer Marketed

     FDA proposes to remove the essential-use designations listed in
current Sec. 2.125(e)(4), (e)(6), (e)(7), and (e)(9), respectively, for
the following no longer marketed ODS products: (1) Contraceptive
vaginal foams for human use; (2) intrarectal hydrocortisone acetate for
human use; (3) polymyxin B sulfate-bacitracin zinc-neomycin sulfate
soluble antibiotic powder without excipients, for use on humans; and
(4) 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 CFC's (see section
II.K of this document).

I. Petitions to Add New Essential Uses

     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 ODS's.
     FDA is proposing to require compelling evidence in support of a
petition for a new essential use. For purposes of this proposed 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 filed under proposed Sec. 2.125.
Such information will become publicly available.
1. Commercially Marketed Drugs
     FDA is proposing to limit initiation of rulemaking to establish a
new essential use for those noninvestigational products for which
compelling evidence shows: (1) Substantial technical barriers exist to
formulating the product without ODS's; (2) the product will provide an
unavailable important public health benefit; and (3) use of the product
does not release cumulatively significant amounts of ODS into the
atmosphere or the release is warranted in view of the unavailable
important public health benefit.
     This new standard would apply to all requests for essential-use
exemptions submitted after the effective date of the final rule.
2. Investigational New Drugs
     FDA is proposing to amend Sec. 2.125 to remove paragraphs (i) and
(j) and to revise paragraph (f) to provide a process for adding
investigational uses to Sec. 2.125(e). FDA would permit investigational
use of an ODS medical product if compelling evidence shows: (1)
Substantial technical barriers exist to formulating the investigational
product without ODS's; (2) a high probability that the investigational
product will provide an unavailable important public health benefit;
and (3) use of the investigational product does not release
cumulatively significant amounts of ODS into the atmosphere or the
release is warranted in view of the high probability that the
investigational product will provide an unavailable important public
health benefit.
     Although FDA regulations at current Sec. 2.125(j) allow an
investigational drug product sponsor to collect data to demonstrate
that a CFC use is essential upon a lesser showing than that required
under current Sec. 2.125(f),\3\ the sponsor is not permitted by EPA
regulations to obtain CFC's until the sponsor's proposed use is listed
in Sec. 2.125(e). This has prevented any investigational new drug use
from being added to current Sec. 2.125(e) as an essential use.
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    \3\ Under current Sec. 2.125(j), a sponsor may use a CFC product
under an investigational new drug application (IND) if the sponsor
explains why a CFC propellant is used in the product rather than
another propellant or another dosage form, the benefit the
investigational product is believed to have, and the benefit the
sponsor hopes to demonstrate by the studies.
    Under current Sec. 2.125(f), a sponsor cannot market a CFC
product unless the sponsor demonstrates that there are no
technically feasible alternatives to the use of a CFC in the
product; that the product provides a substantial health benefit,
environmental benefit, or other public benefit that would not be
obtainable without the use of the CFC; and that the use does not
involve a significant release of CFC's into the atmosphere or that
the release is warranted in view of the consequence if the use were
not permitted.
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     FDA would decide whether an investigational use should be added to
Sec. 2.125(e) in response to a citizen petition submitted under
Sec. 10.30 (21 CFR 10.30) and after notice-and-comment rulemaking. If
FDA amended proposed Sec. 2.125(e)(4) to include an investigational
use, that determination would not allow commercial manufacture and
marketing of an ODS product. A sponsor would need to file a separate
petition under Sec. 2.125(f)(1) to provide for a new essential-use
determination for commercial marketing of the ODS product.
3. Evidence to Support New Essential Uses for Investigational and
Noninvestigational Products
     First, the petitioner must demonstrate through compelling evidence
that substantial technical barriers exist to formulating the product
without ODS's. Generally, FDA intends the term ``technical barriers''
to refer to difficulties encountered in chemistry and manufacturing. A
petitioner would have to establish that it evaluated all available
alternative technologies and explain in detail why each alternative was
deemed to be unusable to demonstrate that substantial technical
barriers exist. 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). Also, if a petitioner
shows that the cost of using

[[Page 47722]]

a non-ODS in a product is prohibitively high in comparison to the cost
of using an ODS, the agency might consider cost as a technical barrier.
     Second, the petitioner for a new essential use for a
noninvestigational product must include in their petition compelling
evidence of an unavailable important public health benefit. For
investigational products, FDA proposes requiring a 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 intends to give the phrase ``unavailable important
public health benefit'' a markedly different construction from the
current phrase ``substantial health benefit.'' A petitioner should show
that the use of an ODS would save lives, significantly reduce or
prevent an important morbidity, or significantly increase patient
quality of life to support a claim of important public health benefit.
A 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 proposed new criteria require a showing supported by
compelling evidence that the use of the product does not release
significant amounts of ODS into the atmosphere or that the release is
warranted in view of the important public health benefit.\4\ A
petitioner should submit a well-documented statement of the number of
products to be manufactured and the amount of ODS to be released by
each product.
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    \4\ The petitioner must show only a high probability of an
important public health benefit for an investigational product.
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J. Elimination of Outdated Transitional Provisions

     FDA is proposing to eliminate Sec. 2.125(h). Section 2.125(h)(1)
is an out-of-date transition provision requiring the submission of new
drug applications (NDA's) for products without an NDA but covered under
Sec. 2.125. Section 2.125(h)(2) describes which drug products may be
the subject of an abbreviated new drug application (ANDA). This
provision predates passage of the Drug Price Competition and Patent
Term Restoration Act of 1984 (Public Law 98-417) (the Hatch-Waxman
Amendments). The Hatch-Waxman Amendments and regulations implementing
the Hatch-Waxman Amendments govern the generic drug approval process
and have rendered Sec. 2.125(h)(2) out of date. FDA is proposing to
eliminate Sec. 2.125(g), (k), and (l) because they are also transition
provisions.
     Section 2.125(d) is reserved in this proposal so that proposed
Sec. 2.125(e) will correspond to current Sec. 2.125(e), which is cross-
referenced in 40 CFR 82.66.

K. Determinations of Continued Essentiality

     In Sec. 2.125(g), FDA proposes criteria to determine whether an
essential-use designation should be removed from Sec. 2.125(e).
     Under proposed Sec. 2.125(g)(1), FDA would propose to remove an
active moiety from the essential-use list (Sec. 2.125(e)) if it were no
longer marketed in an ODS formulation. FDA believes failure to market
indicates nonessentiality because the absence of a demand for the
product sufficient for even one company to market it is highly
indicative that the use is not essential.
     Under the proposed second criterion, after January 1, 2005, FDA
could find a CFC product containing a particular active moiety
nonessential if the product no longer met the essential-use criteria
(Sec. 2.125(f)). Even if all current essential-use moieties are not
reformulated, sufficient alternative products may exist in the future
to fully meet the needs of patients. FDA would designate any remaining
CFC products as nonessential. FDA would consult with an advisory
committee and provide the opportunity for public comment before making
such a determination.
     Under proposed Sec. 2.125(g)(3) and (g)(4), an ODS product would
remain essential until: (1) 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; (2) supplies and production capacity for the alternative(s)
exist or would exist at levels sufficient to meet patient need; (3) at
least 1 year of U.S. postmarketing data exist; and (4) patients who
medically require the ODS product are adequately served by available
alternatives.
     In addition, under Sec. 2.125(g)(4), an active moiety containing
ODS that is marketed under more than one NDA or marketed in multiple
strengths would not be removed from the essential-use list unless at
least two non-ODS products with the same active moiety were marketed.
FDA anticipates that ODS products of the same active moiety marketed in
distinct strengths will need to be replaced by non-ODS products of the
same active moiety with more than one strength.
     In evaluating indications, FDA will require a non-ODS alternative
to have a broader indication or (an) identical indication(s) 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.\5\
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    \5\ 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.
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     In evaluating whether an alternative has approximately the same
level of convenience of use, FDA will consider whether the product has
approximately the same or better portability and requires approximately
the same amount of or less preparation before use as the ODS product
containing the same active moiety. FDA is aware that the MDI is the
most widely used delivery system for administering drugs by oral
inhalation for the treatment of asthma, chronic obstructive pulmonary
disease (COPD), and other respiratory diseases. Physicians and patients
value the compact size and ease of use of MDI's. At present, FDA
considers non-ODS MDI's and multiple-dose dry powder inhalers (DPI's)
to have approximately the same level of convenience of use as MDI's.\6\
FDA does not consider single-dose DPI's currently marketed in the
United States to have the same level of convenience of use as CFC-MDI's
because patients must carry the device and a supply of the drug and
must load the device prior to each use. Manufacturers may develop
additional products that FDA will evaluate on a case-by-case basis to
determine whether the products have approximately the same level of
convenience of use as MDI's.
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    \6\ Although multiple-dose DPI's may offer a similar level of
convenience of use, FDA is not at this time proposing that they meet
the other criteria in Sec. 2.125(g) necessary to qualify as
acceptable alternatives.
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     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

[[Page 47723]]

longer marketed. FDA expects that the non-ODS product will be
manufactured at multiple manufacturing sites if the ODS product was
manufactured at multiple manufacturing sites. FDA will always work to
ensure that no harm to the public health of the United States occurs
because of drug product shortages during the transition to non-ODS
products.
     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 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
exist for the indicated populations and other populations known to
medically rely on the ODS product.
     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 FDA's
MEDWATCH data. Health professionals who monitor for and report serious
adverse events and product problems to FDA either directly or through
the manufacturer are integral to this process. MEDWATCH makes it easier
for health professionals to report adverse events and product problems
to FDA by operating a single system for reporting. The MEDWATCH program
is supported by over 140 organizations, representing health
professionals and industry, that have signed on as MEDWATCH Partners to
help achieve these goals.
     CDER's Office of Post-Marketing Drug Risk Assessment actively
analyzes MEDWATCH data on adverse drug reaction reports from hospitals,
health care providers and lay persons to identify Adverse Drug Reaction
patterns that might indicate a public health problem (a ``signal'').
FDA staff trained in the analysis of these data critically and
individually review the reports of serious adverse events to detect
serious unlabeled reactions. FDA staff epidemiologists and the relevant
review division evaluate these signals for further action.
     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, tolerabiltiy, performance, and patient acceptance of
non-ODS alternative products.
     In addition, 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 patient subpopulations.
     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.

III. Comments on the ANPRM

     FDA received 9,596 comments on the ANPRM. FDA categorized the
comments as general comments about the ANPRM and specific comments on
the proposed criteria for phaseout. Unless otherwise noted, the
comments address the criteria FDA proposed to use to determine when to
eliminate the essential-use designations for metered-dose steroid human
drugs for oral inhalation and metered-dose adrenergic bronchodilator
human drugs for oral inhalation.

A. General Comments About the ANPRM

     FDA received 8,979 general comments about the ANPRM. The general
comments were submitted by 7,371 users of MDI's, 1,015 parents of MDI
users, 847 relatives of MDI users, 417 health care professionals, 160
organizations, 3 industry members, 1 consultant, and 42 government
entities. Many comments fell within multiple submitter categories.
     1. Approximately 4,000 of these comments expressed general
opposition to the phaseout of CFC-MDI's. The Clean Air Act requires the
phaseout of CFC-MDI's, when they are no longer essential.
     FDA is issuing this proposed rule as part of a transition process
to ensure that the phaseout is safe for the users of MDI's. FDA expects
CFC-MDI's to remain on the market until FDA determines under the
criteria in this proposed rule that safe and effective alternatives
exist.
     2. More than 1,400 comments asked that the agency not remove MDI's
until alternatives are available. Nearly 800 comments requested that
the agency not remove any MDI's until alternatives exist for all CFC-
MDI's.
     The agency will not remove essential-use designations for MDI's
until sufficient alternatives are available to serve the patients who
require these CFC-MDI's. This was the intent of the ANPRM, and is the
mandate under the Clean Air Act and the Montreal Protocol. However, the
agency cannot require companies to produce a non-CFC product for every
CFC-MDI currently marketed. Accordingly, the agency cannot guarantee
that every CFC-MDI on the market today will be replaced by a non-CFC
product containing the same active moiety. However, users of CFC-MDI's
not replaced by non-CFC products with the same active moiety could use
other non-CFC alternatives. Thus, there may be a time, even if all
currently available CFC-MDI's are not replaced by non-CFC products with
the same active moiety, that the use of CFC's in MDI's would no longer
be essential. The public will have the opportunity to comment on all
essential use designations and the removal of any designation.
     3. Over 500 comments asked that the agency proceed cautiously.
     The agency is proceeding with full caution. To obtain the largest
possible number of public comments, the agency first published an ANPRM
before proceeding with rulemaking. FDA is now in rulemaking, a process
that includes publishing this proposed rule, receiving and
incorporating further comments on the proposal, and issuing a final
rule. As proposed, the final rule would not phase out any CFC-MDI for
the treatment of COPD or asthma. Rather, the final rule will finalize
the criteria by which FDA will determine whether to begin rulemaking to
eliminate an essential use because of the existence of acceptable non-
CFC alternative products. Any such rulemaking would provide to the
public the opportunity for further comment.

[[Page 47724]]

     4. Over 1,500 comments stated that there are problems switching
between products, and about 600 comments requested a long transition
period. About 1,000 comments stated that MDI's provide benefits
unavailable with alternatives.
     FDA is working to ensure that the patient's transition from CFC to
non-CFC products is as easy as possible. The agency wants patients to
have adequate time to find acceptable replacement products. In
recognition of the fact that MDI's provide certain benefits not
available with some current alternatives, the agency is proposing to
require that an alternative have the same route of delivery,
indication, and approximate level of convenience of use as a CFC-MDI.
     5. More than 900 comments expressed concern about the cost of
replacement products and the removal of generics.
     As part of any subsequent proposed rule to eliminate an essential-
use listing for a CFC-MDI, FDA will consider the cost of alternative
products in determining whether patients are adequately served by the
non-ODS products.
     6. Approximately 890 comments did not discuss the ANPRM, 21
comments were indecipherable, 2 comments were abusive or insulting, and
1 comment was threatening.
     FDA will not address these comments.
     7. Numerous comments focused on the environmental impact of CFC
use. About 1,700 comments stated that MDI's are responsible for minimal
amounts of CFC's, 117 comments said that there was no proof that CFC's
harm the environment, 10 comments said they wanted MDI's to remain on
the market regardless of the effect on the environment, 254 comments
said FDA should focus on other sources of CFC's, 271 comments said FDA
should focus on consumer aerosols, 743 comments said FDA should focus
on other environmental problems, and 400 comments said that MDI's do
not release CFC's into the atmosphere because they are inhaled.
     Through the Clean Air Act and the Montreal Protocol, the United
States has committed to eliminate the use of all CFC's, including use
of CFC's in MDI's when no longer essential. The agency notes that EPA
has found the release of CFC's to be harmful. MDI's do release CFC's
into the atmosphere after inhalation because the vast majority of the
aerosol puff released is CFC, and the CFC contained in each puff is
either directly released into the atmosphere or inhaled and
subsequently exhaled by the patient. The agency also notes that, for
nearly two decades, no consumer aerosols other than CFC-MDI's and other
products listed in Sec. 2.125 have been allowed to use CFC's in the
United States.

B. Specific Comments on the ANPRM

     FDA received a number of specific comments on the phaseout
criteria proposed in the ANPRM. The agency categorized the comments and
responds to them in the following section of this document.
1. Number of Alternatives Proposed
     In the ANPRM, FDA sought comments on phasing out CFC-MDI's using
either a therapeutic class approach or a moiety-by-moiety approach.
Under the therapeutic class approach, FDA would eliminate the
essential-use designation for a class of CFC-MDI's once three
acceptable non-CFC alternatives existed for the class. FDA would
require two of the three alternatives to contain different active
moieties. Under the moiety-by-moiety approach, FDA would eliminate the
essential-use designation for an active moiety's CFC-MDI's once at
least one acceptable non-CFC alternative existed that contained that
active moiety.
     8. Five comments requested that FDA phase out a CFC product once
one non-ODS product was on the market. One comment requested that the
agency allow phaseout only if there were a non-ODS product for each
active moiety. One comment said it was very important that the non-ODS
product contain the same active moiety.
     FDA is proposing to use the moiety-by-moiety approach overall.
However, FDA notes that some companies are unlikely to reformulate
their CFC products into non-ODS products because of economic
considerations. Some manufacturers of CFC-MDI's with small market
shares have already stopped marketing their products. Therefore, in
addition to using the moiety-by-moiety approach, FDA is proposing a
process to remove products from the essential-use list if the products
are no longer marketed or, after January 1, 2005, if available non-ODS
products fully meet the needs of patients who previously required the
product on the essential-use list.
     9. One comment requested that FDA phase out long-acting CFC-MDI's
but permit rescue inhalers to remain on the market as CFC-MDI's.
     U.S. law does not permit CFC use to continue once acceptable
alternatives exist. FDA is proposing this rule to protect the public
health by setting criteria designed to ensure that adequate treatments
exist throughout the CFC phaseout.
     10. One comment asked that FDA not allow a phaseout until there
are at least three or more non-CFC containing alternatives.
     FDA is proposing to require that at least one acceptable
alternative for each active moiety be marketed before elimination of an
essential-use designation. This means that many alternatives
representing many different active moieties will exist before the
transition to non-ODS products is complete.
     11. Four comments stated that two different active moieties within
a therapeutic class were not sufficient, but did not explain why or
offer an alternative number. One comment stated that the therapeutic
class approach would not permit sufficient alternatives to serve all
patient subgroups because it would reduce the number of products
available once three non-CFC products were available. Nine comments
claimed that there are medically significant differences among
individual members within the therapeutic classes of drugs proposed by
FDA. One comment stated that the various short-acting beta-2 agonists
on the market such as albuterol, terbutaline, and pirbuterol are
essentially identical. One comment asked that no CFC products be
removed until 75 percent of all products had been replaced, but did not
provide a justification for using an exact percentage. Six comments
stated that the proposal to eliminate all CFC products within a class
once two alternatives were on the market could lead to a situation in
which no high-potency formulations, such as fluticasone propionate,
were available. The comments noted that the high-potency formulations
are more convenient to use because they require fewer puffs per dose.
One comment asked that FDA require one low-, one medium-, and one high-
potency inhaled steroid to maintain asthma control and compliance. One
comment requested that FDA ensure that alternatives existed for not
only fast-acting MDI's, but also corticosteroids. One comment requested
that inhaled salmeterol not be banned without an exact replacement. One
comment stated that 30 percent of patients using inhaled corticosteroid
use Aerobid, yet Aerobid could be deemed nonessential if three other
products reach the market first.
     After careful consideration of the public comments, FDA has
decided not to propose to use the therapeutic class approach. Rather,
FDA is proposing to use a moiety-by-moiety approach. This means that
FDA would not propose eliminating the essential use for an

[[Page 47725]]

active moiety unless patients had access to the same active moiety in
at least one non-ODS product. FDA is proposing to require at least two
different non-ODS products for an active moiety if an active moiety is
marketed under multiple NDA's or exists in multiple strengths.
     12. Three comments requested that more than one alternative for
albuterol exist before phaseout of albuterol CFC-MDI's.
     FDA is proposing to require at least two acceptable alternative
non-CFC products for all active moieties manufactured under multiple
NDA's from multiple sponsors, including albuterol, before it will
consider eliminating the essential use designation for that active
moiety.
     13. Two comments stated that not all short-acting bronchodilators
or inhaled steroids are therapeutically equivalent. One comment
requested that the agency require well-documented bioequivalency before
CFC-MDI's are removed from the market. One comment requested that FDA
demonstrate that all products within a class are substitutable for all
patient subpopulations. One comment suggested considering safety and
efficacy, potency, delivery to target, bioavailability, and
bioequivalence in evaluating replacements.
     The agency will evaluate safety and efficacy, potency, product
quality, and bioavailability in the course of evaluating new non-CFC
products for approval, as it does in evaluating all new drugs. The
agency agrees that not all drugs for the treatment of asthma and COPD
are therapeutically equivalent or bioequivalent. However, drugs need
not be strictly therapeutically equivalent or bioequivalent to each
other to provide effective alternative treatment for a disease. It is
not the agency's goal to replace CFC-MDI's with only bioequivalent non-
ODS products. Rather, it is the agency's goal to ensure that adequate
acceptable alternatives exist to meet the needs of patients who have
relied on CFC-MDI's.
     14. One comment stated that there are few scientific studies that
demonstrate the equivalent doses between different inhaled
corticosteroid preparations.
     FDA agrees that such data are for many reasons lacking for the
currently available CFC products. FDA is encouraging sponsors of
alternative products to submit clinical trials with comparator arms
using a currently available CFC formulation to provide data to assess
comparability of clinical effects.
     15. One comment stated that anti-inflammatories, also called
corticosteroids, are the mainstay of asthma control, and therefore FDA
should not phase out CFC corticosteroids until there are sufficient
non-CFC corticosteroids.
     As explained previously, FDA is not proposing to eliminate the
essential-use designation for any individual active moiety until at
least one non-CFC alternative exists that contains the same active
moiety or, after January 1, 2005, until adequate alternatives exist, as
described in proposed Sec. 2.125(g).
     16. Five comments stated that over-the-counter (OTC) epinephrine-
containing bronchodilator drugs should not be given an essential-use
exemption. Of those comments, one stated that FDA's assertion that OTC
medications are used only by the poor or those without access to
medical care was not supported by their research. One comment stated
that OTC-MDI's are relied upon by people who do not choose traditional
medicine or who do not have access to medical care.
     Epinephrine CFC-MDI's are manufactured under multiple NDA's. FDA
will evaluate the essentiality of epinephrine the same way it will
evaluate the essentiality of all active moieties manufactured under
multiple NDA's. As explained previously, FDA is not proposing to
eliminate the essential-use designation for any individual active
moiety marketed under multiple NDA's until at least two non-CFC
alternatives exists that contain the same active moiety or, after
January 1, 2005, until adequate alternatives exist, as described in
proposed Sec. 2.125(g).
     17. Two comments stated that the use of spacers may affect the
delivery and effectiveness of new drugs. One of the comments stated
that even with the same drug and dose, different delivery systems could
result in different distribution of particle size with different
spacers and, therefore, different patterns of deposition in the lung
and different effectiveness levels. The other comment stated that in
the case of albuterol, the actuator orifice with the CFC-based product
is 0.022 inch while the hydrofluoroalkanes (HFA) orifice is 0.009 inch,
with both canisters having the same internal pressure. The comment
stated that the difference in orifice size results in significant
differences in aerosol characteristics when used with an improperly
sized adaptor and requested that the manufacturers of adapters be
provided adequate time to modify their products to accommodate the new,
HFA-based preparations.
     FDA agrees that interactions between spacers and non-ODS-MDI's and
CFC-MDI's may differ, given the different pharmaceutical properties of
these products. However, spacers and holding chambers are usually
approved for general use rather than for use with specific products. A
patient decides with his or her health care practitioner whether to use
such a device with an MDI, regardless of whether the MDI is a CFC-MDI
or a non-CFC alternative.
2. Specific Comments on the Proposed Criteria for Phaseout
     18. One comment requested that FDA compress the time it takes to
develop a final regulation and to phase out nonessential CFC-MDI's.
     FDA recognizes that it often takes an extended period of time to
publish a final rule. However, this time is necessary, particularly in
the context of this rule, for FDA to fully consider the comments
provided and to make sound policy decisions based on strong science and
responsiveness to important public concerns.
     19. Two comments requested that FDA define the terms
``postmarketing surveillance, subpopulations, therapeutic class, [and]
convenience of use'' to reduce the likelihood and viability of
administrative or legal challenges.
     Since FDA has chosen not to propose to use the therapeutic class
approach, FDA is not defining the term ``therapeutic class.'' FDA has
provided explanations regarding its proposed application of the other
terms in section II of this document.
     20. One comment requested that FDA require the same delivery
system rather than the same route of delivery for replacements.
     FDA believes advances in technology may bring even more convenient
delivery systems to market, and therefore it is not requiring the same
delivery system.
     21. One comment stated that FDA's requirement of ``same
indication'' should include all current indications and patient
populations covered by CFC products containing the same active moiety.
One comment asked FDA to require replacements for all currently
approved indications, including indications for exercise-induced asthma
and for children age 4 and older.
     FDA agrees generally that non-CFC 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 down to age 6
but non-ODS products are only labeled down to age 12, a significant
patient subpopulation would exist that would not be adequately served
by non-ODS products. Absent other data, the agency would not eliminate
the

[[Page 47726]]

essential-use designation for the CFC-MDI based on this factor alone.
     22. One comment stated that evaluation of the level of convenience
should consider dosing regimes, including number of refills per month;
type, size, and shape of the product; and physical and mental ability
of the patient to operate the product, taking into account patient
education. One comment said it is appropriate to consider tolerability,
patient compliance, or convenience only if these factors relate to
safety and effectiveness.
     FDA will consider such factors in determining whether replacement
products are adequate replacements, even if the factors do not directly
affect efficacy and safety. For instance, FDA would not consider a
product that needs to be administered with an air-pressure driven
nonportable nebulizer a viable replacement for a CFC-MDI because of its
lack of portability and ease of use, even if it were as safe and
effective as an MDI.
     23. One comment stated that FDA should require convincing evidence
of adequate production capacity and component supply from non-CFC
product manufacturers. One comment said that a manufacturer should not
be required to demonstrate supply capacity as long as there is a
reasonable transition period, and that supply capacity should be
considered inadequate only if due to limited capacity or manufacturing
problems. One comment said that FDA needs to account for the potential
risk of an out of stock situation in implementing any phaseout.
     FDA already has mechanisms in place to determine whether a drug
shortage exists and to manage supply (see Manual of Policies and
Procedures (MAPP) 4730.1--Drug Shortage Management, Center for Drug
Evaluation and Research, FDA). FDA will use such procedures to evaluate
whether non-CFC product manufacturers have sufficient production
capacity and potential capacity to manufacture non-CFC products for all
patients who currently use the CFC product(s).
     24. Two comments requested that the agency collect scientific
evidence on the effectiveness of alternatives.
     FDA will continue to require NDA's to comply with all applicable
new drug laws and regulations (see, e.g., section 505 of the act (21
U.S.C. 355)). As with all new drug products, FDA is requiring clinical
data from adequate and well-controlled trials to establish the safety
and effectiveness of non-CFC products prior to approval. FDA is also
requiring at least 1 year of postmarketing data on the use of
alternatives by the general population before it will propose removing
the essential-use designation for any CFC-MDI.
     25. One comment requested that the agency not base the phaseout
proposal on the assumption that manufacturers are developing
alternatives.
     The agency is not assuming that manufacturers are developing
alternatives, nor is it projecting a timetable for availability of any
such products. Rather, FDA is establishing a framework to use once
alternatives are available.
     26. One comment asked that FDA eliminate broad exemptions from
Sec. 2.125.
     The agency is proposing to narrow the exemptions in Sec. 2.125 by
listing the individual active moieties exempted rather than listing
classes of drugs. For convenience, FDA proposes listing each active
moiety under a heading describing its use.
     27. One comment suggested that FDA follow the Australian model for
phaseout. Australia has proposed reducing CFC use over time by simply
eliminating a percentage of the amount of CFC's used in MDI production
each year.
     FDA is not proposing this approach because it is concerned that in
the U.S. market such an approach would not ensure that patients' needs
were met throughout the transition.
3. Intolerance or Allergy to Drug Products or Propellants
     28. Eleven comments pointed out that many asthmatics are allergic
to propellants and inactive ingredients such as alcohol, sulfate, oleic
acid, trisorbitan oleate, lecithin, and lactose. Two comments stated
specifically that albuterol alone was not a sufficient alternative
because of patient intolerance. One comment requested that, with a
doctor's written authorization, patients be permitted to continue to
use CFC-MDI's until a non-CFC alternative to which they were not
allergic was available. One comment noted that some patients develop a
potentially fatal addiction to the aerosol component of MDI's and
requested that FDA require manufacturers to put warnings on CFC-MDI
labels and develop nonaerosol alternatives.
     FDA acknowledges that intolerance and sometimes true allergies or
addiction to drug products or components are a concern for patients any
time new medications are used, regardless of whether the medication is
CFC-based. To address this concern, FDA is requiring at least 1 year of
postmarketing data to ensure that subpopulations are served by the
available alternatives without widespread intolerance or allergy. If
subpopulations of patients cannot use a product because of intolerance
or allergic reactions and no other medically suitable options exist for
those patients, that product would not be considered an acceptable
alternative to the CFC-MDI counterpart.
     29. One comment stated that the side effects experienced from one
drug within a class might not be experienced in using another drug in
the same class. One comment stated that asthma patients need to change
drugs over the course of the disease, since one drug does not always
continue to work.
     FDA agrees that patients may tolerate some drugs better than
others or might need to switch therapies and therefore is proposing a
transition strategy that would ensure that many acceptable alternatives
exist before the transition to non-CFC products is complete.
4. Patient Subpopulations
     a. Children
     30. One comment stated that one of the major problems for asthma
patients, particularly children, is getting the drug to the site of
action.
     FDA agrees that children present special concerns in terms of
optimally utilizing inhalation devices. FDA intends to consider such
factors when assessing the adequacy of an alternative as a replacement
for a CFC-based product.
     31. One comment stated that not all alternatives, including DPI's,
are acceptable alternatives for children.
     FDA acknowledges that devices relying on patient inspiratory
efforts for the delivery of drug, such as DPI's, may not be acceptable
alternatives in very young children or those with severe airflow
obstruction. However, FDA anticipates that multiple-dose DPI's will
serve as viable alternatives for at least some patients. In practice,
FDA expects that non-ODS MDI's will most commonly serve as replacements
for CFC-MDI's.
     32. One comment expressed the belief that the proposed phaseout
would limit access to asthma treatments and might endanger the medical
stability of children with asthma.
     It is not FDA's intent to limit access to therapies for any
patient group. Rather, by developing a transition strategy, FDA is
attempting to ensure patient access to acceptable and safe treatment
throughout the mandated phaseout of CFC's.
     33. One comment noted that, in the past, new products have
generally been marketed without a pediatric indication

[[Page 47727]]

and asked how FDA would address this issue.
     FDA is working on several pediatric initiatives to encourage the
labeling of drugs for pediatric use. FDA recently published a final
rule requiring certain sponsors to submit pediatric studies and
labeling (see 63 FR 66632, December 2, 1998). In addition, the Food and
Drug Administration Modernization Act of 1997 (the Modernization Act)
(Public Law 105-115) provides incentives for sponsors to perform
pediatric studies. Section 505A of the act (21 U.S.C. 355a) permits
certain applications to obtain an additional 6 months of exclusivity
if, in accordance with the requirements of the statute, a sponsor
submits information relating to the use of a drug in the pediatric
population. The Modernization Act also exempts from payment of
prescription drug user fees supplements to NDA's proposing to include a
new indication for use in pediatric populations. FDA anticipates that
these provisions will result in increased pediatric labeling. Of
course, FDA will evaluate whether patients, including pediatric
subpopulations, are served by acceptable alternatives before proposing
to remove essential-use exemptions for CFC-MDI's.
     b. Elderly
     34. One comment stated that the elderly require special education
and an extended time period to become comfortable with new medications.
     FDA acknowledges this comment (though disagreeing with it as a
statement of general applicability to all elders) and reiterates that
the intent of the proposed rule is to allow for such considerations in
all patient subgroups.
     c. Other subpopulations
     35. One comment stated that medical studies have documented that
African-Americans, especially in Chicago, IL, experienced consistently
higher asthma mortality than Caucasians between 1968 and 1991. Two
other comments stated that a study conducted in Brooklyn, NY, found
that the prevalence of asthma was significantly higher among Hispanics,
African-Americans, and children from the lowest income families.
Another comment stated that African-Americans represent a
disproportionate share of asthma sufferers and requested that any new
rule issued by FDA ensure that it does not have a disproportionate
adverse impact, either perceived or real, on minority persons.
     FDA is aware of epidemiological data that show minorities and
inner-city residents disproportionately experience asthma morbidity and
mortality compared to the general population. FDA intends to take into
account the needs of the entire asthma population. FDA plans to take
into account the medical needs of demographic subgroups, including
racial and ethnic groups, economic groups, or other socioeconomic or
medical groups.
     36. One comment stated that many patients in Hawaii, for genetic
reasons, are sensitive to alcohol and therefore cannot use non-ODS
products that contain alcohol. FDA would invite data in support of
special sensitivities to be submitted to the agency at the time that
any removal of an essential-use listing is proposed.
     FDA stresses that the intent of the proposed rule is to ensure
that adequate numbers of alternatives exist at all times in the
transition to address such concerns.
     37. One comment suggested that if a patient subpopulation is not
served by non-ODS products, FDA allow the CFC product to remain on the
market but: (1) Require the labeling to be changed to reflect use for
that subpopulation only, and (2) reduce the manufacturer's CFC
allowance.
     The use of CFC's in a product is either nonessential or essential.
If there is a portion of the population that cannot be medically served
by the available alternatives, then such CFC use would remain
essential.
     38. One comment stated that only one CFC-MDI, terbutaline, is
rated Pregnancy Category B, and that all others are rated Pregnancy
Category C.
     FDA acknowledges this comment. FDA believes that not all
manufacturers will perform human pregnancy studies for alternative
products. However, the moiety-by-moiety approach proposed is not
intended to and should not reduce the number of MDI's available within
each pregnancy category.
     39. Two comments stated that acceptance in ``significant''
subpopulations is not a sufficient measure of the adequacy of
alternatives. One comment stated that, to an asthma patient, a
significant group is one. One comment asked that FDA require an
affirmative showing that all patient subpopulations are served before
eliminating the essential use for any product.
     As the mandated phaseout of CFC's occurs, FDA intends to ensure
that the U.S. market contains an acceptable number of products at all
times to meet patient needs. Just as all patients are not served by one
CFC-MDI, all patients will not be served by any single alternative
product. FDA is proposing to make determinations of essentiality on a
moiety-by-moiety approach. FDA will take into account all other
available therapies, whether CFC-based or non-CFC-based, in making a
determination about the essentiality of a product.
5. Experimental Nature of Alternative MDI's
     40. One comment stated that the person had seen an alternative MDI
manufactured by Glaxo Pharmaceuticals in limited use and that the
alternative did not receive a favorable response from most of the
patients who tried it. Another comment stated that the person had
participated in Glaxo Wellcome studies on the non-CFC Ventolin and
found that the delivery method was not as effective. One comment stated
that the person had participated in a University of Arizona study to
test a new drug and had to drop out before the 12-week study was over
because he did not do as well with the new drug. One comment stated
that five new studies on potential asthma medications were being
conducted at the University of Nebraska Medical Center and that the
studies should be have been completed in late 1997.
     FDA is aware that sponsors are conducting extensive research to
determine which CFC-MDI replacements are safe and effective in the
treatment of asthma and COPD patients. FDA expects that, as a result of
reformulation efforts and extensive clinical programs, asthma and COPD
patients will have adequate treatment alternatives throughout the
transition. FDA also expects that not every treatment alternative will
be equally effective for every patient, just as not every CFC-MDI works
the same for every patient. However, in making essential-use
determinations, FDA will assess whether the entire market, including
specific non-ODS alternatives for a particular CFC-MDI, other non-CFC
products, and remaining CFC products, is adequate to serve patient
needs.
     41. One comment stated that Pulmicort is a good alternative. Two
comments stated that budesonide is a good alternative that does not use
CFC's and asked when it would be approved in the United States.
     Budesonide (Pulmicort) is approved for marketing in the United
States as a multiple-dose DPI. Because budesonide is not marketed as a
CFC-MDI in the United States or listed as an essential-use exemption in
Sec. 2.125(e), the factors proposed in this rule would not apply to
budesonide. However, FDA will consider all available treatment options,
including budesonide DPI's, in evaluating whether the use of CFC's
remains essential.
     42. One comment stated that the long-term effect of using other
medications with CFC replacements is unknown and

[[Page 47728]]

that replacements may be endocrine disruptors or have other adverse
effects.
     All drugs, including CFC-MDI replacements, are required to meet
FDA standards of safety and effectiveness before approval. After
approval, FDA may require sponsors to collect and report use data that
characterizes the long-term safety of the drug in humans. FDA is
proposing to require at least 1 year of postmarketing data on
alternatives before FDA would propose to eliminate the essential-use
designation for any CFC product. Sponsors have already collected a
large amount of animal and human safety data for alternative
propellants used in non-CFC products. Sponsors have collected and
reported pharmacology and toxicology data on alternative propellants at
levels comparable to or in excess of that developed for many new drug
substances and at greater levels than for most other drug product
excipients.
     43. One comment stated that most physicians are brand loyal and
therefore will not prescribe a CFC-free product. The comment went on to
state that even if a physician does prescribe the CFC-free product, a
pharmacist may substitute a cheaper generic CFC product to comply with
third-party payer rules.
     FDA plans to continue to work with other government and
nongovernment bodies to further a campaign of physician, pharmacist,
and patient education to address these issues and to ensure that
patients are allowed the opportunity to try non-CFC products. FDA
anticipates that the non-CFC products will not be rated as
bioequivalent to the CFC-MDI's. Therefore, pharmacists will not be able
to substitute a CFC-MDI for a prescription written specifically for a
non-CFC product.
6. Choice of Technically Feasible Alternatives
     44. Numerous comments discussed DPI's. One comment said that DPI's
are not an alternative to MDI's. Another comment said that powders are
not the answer because one is not certain if the dosage has been
inhaled or how much powder remains. Three comments said powders did not
work for them. Two comments said that powders cannot be used in certain
areas of the country because of high humidity. Two comments said that
powders aggravate or cause dry mouth. Three comments said that many
patients, most notably elderly and children, are not capable of
properly using DPI's. One comment said that DPI's require patients to
breathe at an inspiratory flow rate <ls-thn-eq>60 1/minute, which may
not be possible for all patients. One comment said that DPI's should
not be considered a substitute because not all drugs are available as
powders. One comment said that DPI's cannot be used with spacers to
reduce systemic side effects and oral candidiasis and dysphonia. One
comment said that Swedish experience shows that DPI's can be used by 80
to 90 percent of asthma patients. One comment said that DPI's are
better than CFC-MDI's and their use should be expedited.
     Manufacturers began marketing the first multiple-dose DPI's in the
United States very recently. At present, FDA cannot predict whether any
multiple-dose DPI will be an acceptable alternative to a CFC-MDI. FDA
will use the factors determined by this rulemaking and through public
comment to determine whether any particular multiple-dose DPI is an
acceptable alternative.
     45. One comment said that atomizers do not deliver consistent
doses. Two comments said that spinhalers, because they use dry powder,
can irritate the lungs. Two comments said that sometimes, when using
spinhalers, the whole top of a capsule will break off, causing the user
to inhale the top of the capsule and choke. One comment said that
spinhalers do not deliver even dosages. One comment said that
spinhalers could be used as an alternative. One comment said that
breath activated inhalers are useless during a full-blown attack
because there is minimal breath available to actuate the inhaler. One
comment said that turbuhaler dispensers do not force the medication
into the lungs and therefore are not a good alternative for fast-acting
MDI's. One comment said that rotohalers are not a good replacement
because it is difficult to insert the pill into the rotohaler while
having an asthma attack. Three comments said that nebulizers should not
be considered an alternative because they are large and not portable,
require a source of electricity, and take about 15 minutes to deliver
treatment. One comment said that MDI's have advantages over all
alternatives.
     FDA cannot predict which products will be acceptable alternatives
to CFC-MDI's. FDA anticipates that non-CFC MDI's will be the primary
replacements for CFC-MDI's. However, advances in technology may mean
that manufacturers develop new alternatives that are even better than
CFC-MDI's. In addition, non-MDI products can serve at least a portion
of the patient population, even if they cannot serve the entire
population. Accordingly, FDA is not limiting the rule to require that
all CFC-MDI's be replaced by non-CFC MDI's. FDA will consider such
products as part of an overall determination regarding whether the
patient population is adequately served by available alternatives.
     FDA notes that MDI's do not force medication into the lungs. MDI's
deliver the medication to the mouth, but the patient must breathe in
the medicine at the time they use the MDI or no medicine will reach
their lungs. DPI's can be used more effectively by some patients
because patients do not need to go through a two-step process to get
the medicine to their lungs. Patients deliver the medication to their
lungs as they inhale from the DPI.
     46. Three comments said that the new inhalers should be able to
use the same old Aerochambers. Two comments said that use of steroid
inhalers without an Aerochamber leads to tooth decay and oral
candidiasis and dysphonia. One comment suggested that manufacturers use
a carbon dioxide cartridge to propel the medicine from disposable
inhalers. One comment said that the specifications for a replacement
inhaler should include: (1) Pocket size, (2) lightweight, (3) easy to
clean, and (4) separate medicine from propellant. Five comments
recommended that manufacturers put MDI's into another form, like
spinhalers, injections, pumps, glass atomizers, or hand-pumped
dispensers.
     FDA does not control the design of new drug products. FDA is
attempting to ensure that new alternatives are adequate by requiring
these alternatives to meet the criteria in this proposed rule before
FDA will propose the elimination of an essential use of CFC's for any
active moiety.
7. Proventil HFA
     47. Numerous patients commented on whether Proventil HFA, the
first non-CFC MDI approved in the United States, which contains the
active moiety albuterol, should replace all albuterol CFC-MDI's.
     Because FDA is not proposing to eliminate the essential-use
designation for albuterol in this proposed rule or in the resulting
final rule, these comments will not be addressed here.
8. Postmarketing Data and Suggested Duration
     48. Many comments suggested varying lengths of time to collect
postmarketing data. One comment suggested that CFC-MDI's should be
banned immediately. One comment stated that patient acceptance should
be judged in a shorter time than 1 year. One comment suggested
collecting data during the first 6 to 12 months of marketing. One
comment suggested 12

[[Page 47729]]

months for phaseout of individual products and 6 months for phaseout of
classes. One comment said that FDA should require at least 1 year of
postmarketing data on alternatives before removing any comparable
inhalers. One comment said FDA should wait to ban any CFC-MDI's until 1
year after all the replacements are in place. Two comments said that a
postmarketing evaluation cannot be completed in less than 1 year. One
comment said that inhalers should be phased out within 18 months of
availability of an alternative. Two comments said FDA should require 2
to 3 years of postmarketing data. One comment recommended at least 5
years notice before banning CFC-MDI's. One comment requested that the
phaseout not be completed until 2005. Three comments said FDA should
allow a 10- to 15-year phaseout period. Two comments said that 1 year
of postmarketing data is insufficient because most asthmatics must try
a number of medications and different seasons affect the efficacy of
medications. Four comments said that 1 year of postmarketing data is
insufficient because it will not reveal the side effects of long-term
usage.
     Under this proposed rule, FDA will not begin to assess the
acceptability of an alternative product as a replacement for any CFC-
MDI until at least 1 year of postmarketing data is available for the
non-ODS product. FDA stresses that even after it does issue a proposed
rule to amend Sec. 2.125(e) to remove an essential-use listing for a
particular active moiety, the public will have time to comment on the
proposal before it is finalized. FDA also anticipates that any final
rule to remove an essential-use listing will permit some time for
patient use of already manufactured CFC-MDI's.
     49. One comment recommended that FDA implement the use of non-CFC
products as rapidly as possible, provided that all patient protection
and physician education elements and safeguards explained in the ANPRM
are in fact carried out.
     FDA does not dictate medical practice. FDA is proposing this rule
to ensure that patients have medically acceptable treatments. FDA
agrees that patient and health care practitioner education is an
important part of the transition and is therefore actively
participating in education efforts.
     50. One comment said that MDI's should not be phased out until
manufacturers produce a full range of MDI products with highly
effective delivery, at practical prices, and a sound degree of
availability. One comment requested that phaseout not occur until
patients have sufficient experience with alternatives. One comment said
that phaseout should not occur until replacements: (1) Are as effective
as the present products, (2) are tested by FDA, and (3) cost the same
as the products they replace.
     FDA believes that the criteria proposed in this rule (see section
II of this document) will ensure that sufficient experience exists with
a full range of alternative products with highly effective delivery, at
practical prices, and with a sound degree of availability before any
CFC-MDI's are phased out. FDA expects that the price of replacement
products will be equivalent. However, FDA does intend to consider
relative costs in considering whether alternatives adequately serve
patients.
     51. One comment requested that FDA set a specific timeframe for
the elimination of the essential-use exemption once alternatives are
available but did not recommend a particular timeframe. One comment
said that it is difficult to set an arbitrary time period for
determining patient acceptance, because the length of time a product is
on the market does not necessarily measure usage.
     FDA believes it is premature to set a specific timeframe for the
elimination of all essential-use exemptions because too many variables
exist as to when applications for new products will be submitted to the
agency, when they will gain approval, and when the products might be
considered clinically acceptable alternatives to CFC-MDI's.
     52. Another comment suggested that FDA should not designate a CFC-
MDI as nonessential if the sponsor is exercising due diligence in
developing, testing, and evaluating an alternative.
     FDA expects that under the moiety-by-moiety approach in this
proposal companies will not lose essential-use exemptions prior to
approval of an alternative product if they are exercising due diligence
in reformulating their products. However, FDA cannot guarantee that a
company's CFC-MDI will remain essential merely because a company is
exercising due diligence.
     53. One comment stated that FDA should leave it to physicians,
patients, and the market to establish when the switch to non-CFC
products should be completed. Another comment said that FDA should let
patients choose which product meets their needs.
     Patients and their health care providers can now and will continue
to be able to choose any product available on the market. However, the
Clean Air Act will not allow CFC products to remain on the market if
the products are not essential. FDA is required by U.S. law and
regulations to determine, in conjunction with EPA, whether a medical
product remains an essential use of CFC's. FDA wants to ensure through
development of a planned transition strategy that the transition occurs
in a manner that protects the safety of patients.
     54. Another comment stated that the phaseout should not occur
before 5 years of marketing because at least 5 years on the market in
combination with widespread exposure in all patient subgroups is
necessary to detect serious or important adverse events (citing 61 FR
51625 at 51629, October 3, 1996).
     FDA notes that the alternative products will contain the same
active moieties as the CFC products. Therefore, FDA has more than 5
years of exposure information from U.S. marketing for the large
majority of these moieties. FDA does not believe it is necessary to
have 5 years of marketing data before proposing the elimination of an
essential-use designation because the active moieties in the non-ODS
products will not be newly marketed.
     55. One comment said that postmarketing data should address not
only market penetration but also physician education; patient
education; patient acceptance, particularly in the subpopulations of
children and the elderly; and patient compliance. One comment said that
FDA should contact patients through their doctors and have them
complete a survey to determine what kind of asthmatic they are, what
substitute medications have already been tried, and the result. Another
comment suggested that FDA survey a representative sample of all
allergists, including private practitioners, rather than relying on
drug companies or selected clinics in assessing the adequacy of
replacements. Another comment said that FDA should let pharmacists, not
MDI manufacturers, determine the adequacy of supplies, effectiveness,
and other criteria through customer surveys. One comment said that new
products should contain an insert that makes comment possible or that
consists of a brief ``satisfaction survey'' to be filled out. Another
comment said that FDA should require objective postmarketing studies
that include a sample of at least 20 percent of diagnosed asthmatics.
One comment said that any postmarketing study should be limited to
showing that adverse events related to a new CFC-free formulation, but
not found in the CFC product's labeling: (1) Occur at very low rates;
(2) do not develop in patient populations not generally included in

[[Page 47730]]

premarketing trials; or (3) expose drug-drug or drug-disease
interactions not seen in the pivotal clinical trials, as determined by
the equivalent of 100,000 patient years of exposure or a more formal
postmarketing surveillance study, at the manufacturer's discretion.
     One comment said that postmarketing evaluation should include
FDA's factors and an analysis of the first year's postmarketing
experience with regard to adverse event reports, consumer and health
care professional comments, and extent of market uptake; an assessment
of the ability of the manufacturer to meet the market demand for the
CFC-MDI with the replacement product; and an assessment of the need for
revised patient and health care professional education efforts to
facilitate conversion to the replacement. Another comment said that
patient acceptance should be measured through postmarketing reports
that evaluate: Efficacy of the product compared to the previously used
CFC product (this can include quality of life); whether the replacement
product is compatible with other CFC products that the patient is also
using (i.e., the new combination of inhalers); confusion regarding
changes in daily dose regimens; product taste, feel, and device
dimensions; mechanical performance of inhalation device; and confidence
that the new product is a dependable replacement. One comment simply
said that FDA should disclose the types of studies that it believes are
necessary to demonstrate product comparability for phaseout purposes.
     FDA's intent in requesting at least 1 year of postmarketing use
data and in suggesting a postmarketing study is to gain data that
demonstrate the acceptance of the product in widespread use outside of
controlled clinical trial settings and in subgroups not represented in
clinical trials. Although FDA will have found newly marketed products
to be safe and effective through its approval process, FDA cannot
assess the ability of a new non-CFC product to adequately replace in
widespread use an existing CFC product without additional postmarketing
data. FDA believes issues such as device performance in uncontrolled
settings and tolerability of the product in widespread use are
important. FDA believes that properly designed postmarketing studies
would characterize the acceptability of these products better than
standard postmarketing data that rely on anecdotal self-reporting.
     56. One comment said that FDA should not consider the absence of a
postmarketing study the basis for extending an exemption.
     FDA will not require a postmarketing study if available data,
including more traditional postmarketing surveillance data, are
sufficient to support a finding that the CFC product is no longer
essential.
     57. One comment said that European postmarketing data are just as
valid as United States data and should be accepted by FDA.
     FDA may accept European postmarketing data and find the
information useful. However, dramatic differences exist between U.S.
and European health care practices and drug pricing systems. For
example, products available in Europe are not necessarily
pharmaceutically equivalent to those marketed in the United States.
Although FDA would consider European data in making essential-use
determinations, FDA would not propose to eliminate an essential-use
designation unless it had additional data from U.S. populations.
     58. One comment noted that medications may be accepted in
different ways by patients, different medicines may not compare on a
microgram (<greek-m>g) per <greek-m>g basis, and taste may affect
patient acceptance. Another comment stated that propellants can have a
significant effect on the distribution of the medication into the
airways and, therefore, the effectiveness of the treatment.
     FDA will evaluate these issues through premarketing comparability
testing and postmarketing data before proposing the elimination of an
essential-use designation from Sec. 2.125(e).
     59. One comment said that FDA may not be able to enforce current
good manufacturing practice (CGMP) regulations at companies making one
of three alternatives if the United States is dependent on the
companies to supply the patient population.
     FDA is committed to ensuring that CGMP standards are met by all
manufacturers, including those producing CFC products and new
alternatives. FDA does not believe that CGMP violations are any more
likely to occur with alternatives than with currently available
products.
9. Timing of Phaseout
     60. Four comments suggested that FDA should allow the sale of CFC-
MDI's in conjunction with alternatives.
     Under the proposed rule, CFC-MDI's and alternatives will
necessarily be sold at the same time for a period.
     61. Two comments suggested that FDA require the use of non-CFC
products at home and work, and CFC-MDI use only as necessary.
     FDA is proposing this rule to fulfill its obligation under the
Clean Air Act to make essential-use determinations that will lead to
the eventual phaseout of CFC-MDI's. Once FDA has determined that a
product is essential, a consumer can use the product for the essential
use as needed and prescribed.
     62. One comment asked why FDA is preparing this proposal now.
     The Parties to the Montreal Protocol, through the Technical and
Economic Assessment Panels, have asked that all Parties develop
transition strategies. Parties were required to present a draft
transition strategy no later than January 31, 1999, and were encouraged
to present a strategy before January 31, 1998. In publishing the ANPRM,
FDA provided a draft proposal for public comment and consideration
domestically and internationally. FDA recognizes that rulemaking can
take many months or years to complete. FDA published the ANPRM early to
give the public time to comment and to give FDA time to develop a final
rule that would be most protective of public health.
     63. One comment asked why one is able to obtain CFC's for a car
air conditioner but not for MDI's.
     A consumer can obtain recycled CFC's to use in a car air
conditioner but cannot obtain new CFC's. Since 1996, no new CFC's have
been manufactured or imported into the United States for any use other
than those uses designated as essential under the Clean Air Act.
Recycled CFC's can contain impurities that would prohibit use in MDI's
inhaled directly into human lungs on a chronic, recurrent basis.
Manufacturers must use pharmaceutical grade CFC's in CFC-MDI's to
ensure that they are safe to use.
     64. One comment said that patient safety should take precedence
over all other factors. One comment said that FDA should allow the
phaseout to occur according to the Montreal Protocol timeframe and
should not take any steps to phase out CFC-MDI's. One comment said that
once patients understand the FDA proposal, they agree that it makes
more sense to set up guidelines now, rather than waiting until no CFC-
MDI's remain on the market and insufficient non-CFC products exist to
meet patient needs.
     FDA's priority is to protect and promote the public health. FDA is
proposing this rule to develop a transition strategy as required under
the Montreal Protocol. Through this rule, FDA seeks to ensure that
public and patient health and safety are determining factors in
deciding whether alternatives can replace CFC-MDI's.
     65. One comment said that as more people use non-ODS products, CFC
use

[[Page 47731]]

will decrease and the problem of CFC use will solve itself.
     Although it is possible that the phaseout would occur without
intervention, Title VI of the Clean Air Act mandates FDA involvement in
the process. Accordingly, FDA is issuing this proposal to develop a
phaseout process that will ensure that patients have adequate
alternatives.
10. Nasal Steroids
     66. One comment stated that nasal pumps cause postnasal drip,
which can aggravate an asthmatic cough. Another comment stated that
nasal pumps cause liquid to drain down the throat, so they cannot be
used by people with gastroesophageal reflux disease and ulcers. Another
comment claimed that nasal pumps make symptoms worse and are not
appropriate for all patients. Two comments said that for noses that are
very swollen and inflamed, wet sprays do not work. Another comment said
that there are still substantial numbers of patients who cannot stand
the sensation/taste/smell of the aqueous solutions and much prefer the
aerosols.
     One comment said that alternative propellants should be developed
for nasal steroids, and these should be considered alternatives.
Another comment suggested FDA first limit nasal steroid inhalers, which
are available as both aqueous preparations and CFC-propellant
preparations. Another comment stated that nasal steroid inhalers need
not be exempted because there are sufficient alternatives.
     For the reasons set forth previously, FDA is proposing to remove
the essential-use designation in current Sec. 2.125(e)(1) for metered-
dose steroid human drugs for nasal inhalation. FDA notes that the
Parties to the Montreal Protocol have not granted essential-use
exemptions for manufacture of nasal steroid CFC-MDI's since the general
ban on CFC production went into effect in industrialized nations on
January 1, 1996. The Parties do not consider CFC-based nasal steroids
to be medically essential products because of the available
alternatives. Any CFC-based nasal steroids currently being manufactured
are presumably being manufactured with CFC's manufactured prior to
1996. In addition, the indications for which these products are
approved and used are not life threatening.
     67. One comment claimed that topical nasal dexamethasone is more
effective than any other product in treating nasal polyps and
sinusitis. Another comment claimed that nasal steroids are superior for
treatment of nasal polyps because they permit effective penetration of
the nose.
     FDA is unaware of any substantiating data to support the clinical
superiority of any one MDI over all aqueous formulations for these or
any other indications, and these comments did not themselves include
any data substantiating these assertions.
     68. One comment asked that FDA grant an exception for Dexacort
Turbinaire because clinical trials are being done to show it has unique
potential in the treatment of chronic sinusitis.
     An applicant should apply for an essential-use exemption if data
shows a unique use for a particular CFC product.
     69. One comment said that Vancenase AQ does not dispense properly
and therefore is not an adequate replacement for the old Vancenase.
     FDA approved both Vancenase AQ formulations (42 <greek-m>g and 84
<greek-m>g) as safe and effective and, therefore, concluded that the
product was of sufficient quality. FDA has no basis to believe this
determination to be in error. A CFC-based nasal corticosteroid could,
in theory, meet the proposed standards to become an essential use of
CFC's, and the manufacturer could successfully petition the agency for
a new listing under Sec. 2.125(e). However, at this time, FDA does not
believe that the current nasal corticosteroid CFC-MDI's meet the
standards of essential use.
11. Miscellaneous Comments
     70. One comment stated that FDA is intruding on the practice of
medicine.
     FDA is not intruding on the practice of medicine. FDA is
fulfilling its statutorily mandated obligation to determine whether a
medical product remains essential under the Clean Air Act.
     71. One comment asked whether FR-12 is a replacement for CFC's in
MDI's.
     FR-12 is another term for CFC-12, a chlorofluorocarbon that cannot
be used as a replacement.
     72. One comment said that the United States was really phasing out
CFC's because they can be used to make bombs.
     FDA is unaware of any such motivation on the part of the United
States. The Parties to the Montreal Protocol, including the United
States, have agreed to phase out the use of CFC's to protect the ozone
layer and the public health.
     73. One comment stated that people with asthma should be on the
deciding committee.
     Thousands of patients provided their input through the public
comment process. FDA will seek further input from patients when
individual drug moieties are proposed for removal from the list of
essential uses of CFC's.
     74. One comment suggested that instead of removing CFC-MDI's, FDA
should remove sulfites from the U.S. food supply, and that doing so
would lead to a decrease in CFC-MDI use.
     These issues are independent. FDA is required to make essential-
use determinations under the Clean Air Act and the Montreal Protocol,
regardless of the amount of sulfites in the food supply.
     75. One comment said that FDA should only allow CFC-MDI use in
minimally acceptable dosages for physician-certified, life threatening
risks.
     If the use of a CFC-MDI remains medically necessary to treat life-
threatening conditions and no satisfactory alternatives exist, then the
CFC use would remain essential.
     76. Two comments said that FDA should publicize the proposal more,
define terms for laymen, and allow adequate time for response to
encourage more comments. One comment argued against granting any
extension of the comment period.
     FDA received approximately 9,600 comments on the ANPRM, more than
on almost any other proposal in the history of the agency. The public
will have further opportunities for comment as FDA finalizes the
transition process and proposes to remove individual moieties from the
essential-use listing. FDA plans to publicize these additional
opportunities for comment in its educational programs, through its
Internet site, and through press releases.
     77. One comment said that if benefit outweighs risk, FDA should
allow drugs to stay on the market.
     FDA intends to use the criteria proposed to ensure public and
patient health and safety before elimination of an essential use for an
active moiety.
     78. One comment said that FDA must reveal the amount of CFC's
companies have stockpiled for interested parties to evaluate whether a
rational basis exists for the proposed rule.
     FDA does not have these data. If FDA did have the data, FDA could
not disclose the data because the information is confidential and
exempt from disclosure. FDA notes that the Technology and Economic
Assessment Panel (TEAP) recently recommended to the Parties to the
Montreal Protocol that members be permitted to maintain a maximum of 1
year of stockpiled CFC's (April 1998 TEAP Report at p. 16, section
1.2.4).
12. Incentives for Development of Alternatives
     79. Fourteen comments stated that FDA should accelerate approval
of CFC replacement products.

[[Page 47732]]

     The agency is committed to the timely review of all drug
applications. FDA does not believe that NDA's with CFC replacement
products meet the criteria for priority review at the current time.
     80. Eight comments stated that FDA should halt approval of new
CFC-MDI's. One comment stated that FDA should not approve any CFC-MDI's
for an active moiety for which there is an approved non-ODS product,
even if it has not yet determined that the non-ODS product is an
alternative.
     FDA will not withhold approval for a drug product that contains a
moiety listed as an essential use under Sec. 2.125(e). FDA will not
approve ODS-products not currently listed in Sec. 2.215(e) unless FDA
has determined they are essential.
     81. Four comments stated that FDA should impose fines on companies
who do not produce alternatives within a reasonable time or institute a
tax advantage for introducing an approved replacement.
     FDA does not have the authority to take either of these actions.
     82. Five comments requested that FDA require MDI manufacturers to
pursue the development and marketing of alternative propellants with
due diligence. Two comments stated that FDA should set standards for
evaluating industry's pursuit of alternatives. One comment stated that
elimination of an essential use because of a lack of due diligence on
the part of the manufacturer unfairly penalizes patients.
     The Parties to the Montreal Protocol, including the United States,
request MDI manufacturers that receive CFC allowances to demonstrate
that they are pursuing alternatives with due diligence.
     83. Ten comments requested that FDA support research and
development of safe and effective alternatives. One comment stated that
FDA should organize research using pooled resources to develop new,
unpatented delivery systems.
     FDA is working with industry to facilitate the development of safe
and effective alternatives.
     84. One comment stated that FDA should seek money from the tobacco
industry for research to develop safe and effective MDI's that do not
contain CFC's.
     FDA does not have the statutory authority to require funding of a
particular research project.
     85. One comment stated that inventors of non-CFC products should
be rewarded with the same patent protections as all other inventors.
One comment stated that non-CFC formulations of CFC-MDI's should not be
patented.
     The Patent and Trademark Office of the United States awards
patents in compliance with laws enacted by the U.S. Congress. FDA has
no authority to award patents to new drug products.
     86. One comment requested that FDA ease the rules for generic
availability by allowing a non-CFC generic to become immediately
available for each MDI class which has a CFC generic.
     FDA does not have the authority to permit this. The act, as
enacted by Congress, governs when FDA may approve a generic. FDA does
not have the authority to change the act.
     87. One comment stated that FDA should demand more effective
delivery systems.
     FDA believes that the modern MDI is an effective delivery system.
Although FDA encourages advances in delivery systems, the Montreal
Protocol does not mandate changes to delivery systems.
     88. One comment stated that FDA should reward those who develop
CFC-free products by phasing out CFC products.
     FDA plans to eliminate essential uses according to the standards
it develops through this rulemaking process. FDA is not considering
whether any particular standard rewards non-CFC product developers. FDA
is simply promoting and protecting the public and patient health and
safety as it complies with the terms of the Clean Air Act and the
Montreal Protocol.
     89. One comment stated that FDA should allow non-CFC product
manufacturers to advertise performance improvements without conducting
clinical trials to prove those benefits.
     FDA requires all claims to be supported by adequate evidence. FDA
does not permit manufacturers to make claims of superior performance
without supporting comparative evidence.
     90. One comment stated that manufacturers should be allowed to
advertise important technological attributes of the CFC-free MDI's.
     Manufacturers may advertise claims supported by adequate evidence.
     91. One comment stated that the Federal Government should favor
the reimbursement of non-CFC products.
     FDA does not have the authority to control drug costs or
reimbursement.
     92. One comment stated that it is not within FDA's statutory
purview to offer incentives to spur market innovation to phase out CFC-
MDI's. One comment said that it is not necessary for FDA to offer
development incentives since incentives exist. Another comment said
that FDA should focus on market-oriented incentives rather than
``command and control'' techniques.
     FDA does not have the authority to offer incentives. FDA is simply
determining whether the use of an ODS in an FDA regulated product is
essential.
     93. One comment said that instead of implementing the proposal in
the ANPRM, FDA should: (1) Stop production of CFC's, (2) tighten
issuance of essential-use allowances, (3) reimpose an excise tax, (4)
subsidize use of non-CFC propellants, (5) purchase CFC stockpiles, and
(6) allow production and use of CFC-MDI's until stockpiles are
exhausted.
     FDA does not have the authority to take these measures. FDA can
only make determinations in consultation with EPA regarding whether the
use of CFC's in an MDI is essential.
     94. Four comments stated that users should be required to recycle
their empty inhalers.
     FDA does not have the authority to require specific types of CFC-
MDI disposal.
     95. Two comments said that the release of CFC's at MDI
manufacturing plants should be regulated.
     FDA may regulate the release of CFC's at manufacturing plants if
the release violates CGMP's. FDA notes that the Parties to the Montreal
Protocol, including the United States, encourage manufacturers to
release the lowest possible amount of CFC's during manufacturing.
     96. One comment stated that no new exemptions should be granted
unless there is a demonstration of special medical need and benefit
(e.g., an indicated use that is not available for any other approved
product with the same moiety).
     FDA is proposing in this rule the standards it will use to grant
and maintain essential use exemptions. FDA believes the standards
require a showing of special medical need and benefit.
13. Cost of New Products
     97. Two comments stated that FDA should consider whether lack of
competition will increase costs. Another comment requested that FDA not
allow phaseout unless alternative products are manufactured by at least
two independent manufacturers. A third comment requested that FDA not
allow phaseout until there are at least three competitors available in
each of the three categories: Quick-acting, 12-hour, and cortisone-
based inhalers. One comment asked that FDA not eliminate CFC-MDI's
until generic competition for the non-CFC products exists. Two comments
said that if CFC substitutes are produced using proprietary

[[Page 47733]]

technology, phaseout should not be mandated until the technology is in
the public domain. Another comment asked that asthma medicine continue
to be available at the lowest possible prices. One comment stated that
non-CFC products would likely be higher priced than current MDI's. Five
comments stated that FDA's proposal, if implemented, would have an
enormous financial impact for state Medicaid drug costs, Medicare
patients, and uninsured or inadequately insured individuals who could
not afford the new non-CFC agent. Another comment evaluated their
institution's cost of replacing generic albuterol CFC-MDI's with
Proventil HFA and concluded that the annual cost for albuterol MDI's
would increase from approximately $25,000 to more than $200,000.
     FDA recognizes that cost is a concern for many patients and health
care providers. However, 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,
and by the approvability of any particular generic drug application.
The agency notes that in the current market of CFC-MDI's, only the four
active moieties of epinephrine, isoetharine, albuterol, and
beclomethasone are marketed by more than one sponsor. Generic products
are available for only one active moiety: albuterol. In part due to
considerations such as those raised in these comments, FDA has proposed
requiring that multiple-source CFC-MDI products be replaced by at least
two non-CFC alternative products. FDA has also proposed to consider
cost in determining whether alternatives meet patient needs. In
addition, FDA expects that the price for most non-CFC products will
approximate the price for branded CFC products (see section VII of this
document).
     98. Another comment stated that any FDA action should consider the
research and development costs borne by all parties who strive to
replace CFC in their inhalants. One comment stated that FDA should
evaluate the cost of postmarketing requirements because they could also
drive up costs. One comment asked how much the transition will cost.
Two comments predicted that increased costs will result in decreased
compliance. One comment stated that lack of generics and additional
physician visits due to medication switching will increase costs.
     FDA has completed an analysis of the economic impact of its
proposal that addresses these issues (see section VII.B of this
document).
     99. Four comments stated that FDA should undertake a cost/benefits
study comparing the benefits of removing CFC-MDI's from the market to
the benefits of allowing continued marketing of CFC devices. One
comment stated that FDA should determine whether to eliminate CFC
products based on sound science that includes a cost/benefit study
whose methodology is published in the Federal Register.
     FDA has not completed such a study because a statute mandates the
removal of nonessential CFC-MDI's from the market.
     100. One comment said that large- and small-volume nebulizers and
the hand-held ultrasonic nebulizers have been discontinued as covered
Medicare devices. The comment asked that FDA work with the Health Care
Financing Administration to reverse this policy.
     At this time FDA does not consider traditional nebulizers to be
alternatives to MDI's because they are not as portable. Therefore, the
cost of these products is not addressed in this proposed rule.
     101. One comment requested that FDA require new inhalers to be
dispensed in the same number of ``puffs'' as the old inhalers to
prevent a cost increase.
     Manufacturers determine the number of puffs or the amount of
medication given per puff.
     102. One comment asked that new medications be available in less
expensive sample sizes to allow patients to determine whether they are
effective.
     FDA cannot mandate the creation or distribution of physician
samples. However, manufacturers generally produce such samples for new
products to promote familiarity with the new product.
     103. One comment requested that FDA require medicine and hospital
treatments for asthma and COPD to be free to patients, or otherwise
insure all asthma and COPD patients with health and life insurance.
     FDA does not have the authority to require either the free
distribution of medicine or the provision of health insurance.
14. Environmental Impact of CFC-MDI Use
     104. One comment claimed that a continuing exemption for MDI's is
permitted under the Montreal Protocol, Title VI of the Clean Air Act,
and the regulatory and policy actions of EPA. The comment went on to
question whether termination of the essential-use exemption for MDI's
will materially advance stratospheric ozone protection and whether this
benefit outweighs the potential social and economic costs of phaseout.
     Eight comments stated that the pharmaceutical use of CFC aerosols
accounts for less than 1 percent of worldwide consumption. One comment
stated that only 0.1 percent of the fluorocarbons in today's world are
generated by MDI's used for the treatment of asthma. One comment stated
that only one-half of 1 percent of CFC's are generated by MDI's. One
comment stated that the environmental impact of CFC's used in MDI's is
minimal; therefore, it would be an inefficient use of limited
regulatory resources to eliminate CFC-MDI's. One comment stated that
there is no way to quantify the effect of eliminating CFC use in MDI's.
One comment asked whether the continued use of CFC's in MDI's would be
fatally detrimental to the health and well-being of the people of the
world.
     Three comments stated that CFC's do not cause ozone depletion.
Four comments questioned how CFC's could reach the ozone layer.
     One comment asked whether anyone knows how thick the ozone layer
is supposed to be.
     One comment requested that FDA provide figures for: (1) Stockpiled
amounts of CFC's; (2) a comparison of CFC amounts to be released over
the next decade, particularly MDI and air conditioning use; and (3)
measurable change in CFC release due to FDA policy.
     One comment asked whether use of an aerochamber reduces CFC
release into the atmosphere and requested that if it does, FDA mandate
that MDI's be manufactured with the adapters. Another comment asked
whether there is a way to use inhalers without releasing CFC's into the
atmosphere.
     Two comments stated that CFC replacements, including the ones
approved for use in MDI's, also cause ozone depletion, but to a lesser
extent, and asked why FDA is planning to replace CFC's, which have a
long history of safe use in humans, with toxic chemicals that also may
be phased out.
     One comment stated that FDA is required to prepare an
environmental impact statement under the National Environmental
Protection Act.
     One comment stated that stratospheric ozone is our main global
protectant against ultraviolet B light (UVB), and international
restrictions on CFC releases will allow the progressive destruction of
stratospheric ozone to cease and begin to rebuild in the early 21st
century. The comment also noted

[[Page 47734]]

that the current generation of children face a 1:70 risk of melanoma.
In addition, the comment stated that basal and squamous cell carcinoma,
cancer precursor lesions, premature skin aging (spotting, wrinkling,
fragility, sallow color, sagging), photo-induced medication reactions,
autoimmune disease (i.e. lupus), immune suppression, porphyria, and
regular sunburn are all exacerbated by the UVB rays in sunlight, which
will become more intense on an increasing basis by 2010 due to ozone
depletion.
     One comment asked that FDA cut the CFC allocations for companies
manufacturing products with technically feasible alternatives rather
than for all companies across the board.
     One comment stated that FDA should not assess the potential
beneficial effects of reducing CFC emissions from drug products since
the United States has already assessed the effects and made the
decision to eliminate CFC's.
     The United States evaluated the environmental effect of
eliminating the use of all CFC's in an environmental impact statement
in the 1970's (see 43 FR 11301, March 17, 1978). As part of that
evaluation, FDA concluded that the continued use of CFC's 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 CFC's over time (see 42 U.S.C. 7671 et seq.
(enacted November 15, 1990)). FDA notes that the environmental impact
of individual uses of nonessential CFC's must not be evaluated
independently, but rather must be evaluated in the context of the
overall use of CFC's. 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 CFC
use and therefore should be exempted, the elimination of CFC use in
MDI's is only one of many steps that are part of the overall phaseout
of CFC 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.
     FDA notes that CFC-MDI's do release CFC's as part of their
intended use. Tube spacers, inhalation techniques, and other factors do
not alter this release.
15. Proposed Mechanism for Phaseout
     105. One comment requested that FDA publish this proposed rule by
September 1997.
     FDA was not able to meet this request. The comment period for the
ANPRM did not close until May 5, 1997. During the comment period, FDA
received approximately 9,400 comments and has since received
approximately another 200 comments. FDA required a sufficient amount of
time to carefully review and analyze these numerous comments, and
therefore could not publish this proposed rule by September 1997.
     106. One comment said that FDA should establish target dates by
which significant reductions in CFC-MDI use should be accomplished. The
first date should be by the end of the year 2000.
     FDA's authority under the Clean Air Act is to determine whether
ODS products are essential. This proposed rule is designed to set forth
the criteria FDA will use to make those determinations.
     107. One comment requested that, as part of the phaseout
procedure, FDA require industry to educate physicians and patients
that: (1) CFC's serve no medical purpose, and (2) the transition is not
about removing drugs but about getting rid of CFC's. Two comments said
that FDA should require patient and physician education. One comment
said that a seamless transition scheme should be developed and should
include patient and health care provider educational resources and
programs as well as public awareness campaigns well before projected
phaseout dates. Another comment said that transition should be
undertaken as a joint project by FDA, the National Asthma Education and
Prevention Program (NAEPP) of the National Heart, Lung and Blood
Institute of the National Institutes of Health (NIH), industry (e.g.,
International Consortium of Pharmaceutical Aerosol Manufacturers
(IPAC), professional organizations (e.g., American Lung Association)
and patient advocacy groups (e.g., Mothers of Asthmatics) to ensure
dissemination of consistent information. The comment went on to say
that educational efforts should include presentations at national
scientific and professional meetings and seminars, consultations with
public interest groups, one-on-one instruction, and publications in
professional as well as lay media (e.g., flyers, posters, newspaper
articles, videos, stories, plays). One comment said that FDA should
consider psychological factors that could result in slow acceptance of
new products. Ten comments said that patients, physicians, and managed
care companies need education.
     FDA recognizes the need to educate patients, health care
providers, and interested parties about the planned phaseout of CFC-
MDI's for the transition to non-CFC products to occur as smoothly as
possible. Although FDA cannot require industry to undertake an
educational plan, FDA has been involved in public education for the
past several years. Members of the Center for Drug Evaluation and
Research's (CDER's) Division of Pulmonary Drug Products have made
presentations and participated in panel discussions on the phaseout of
CFC's at national scientific and professional society meetings and will
continue to do so.
     The division has also worked in close cooperation with the NAEPP,
an ongoing comprehensive national asthma education, treatment, and
prevention 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 CFC's. The NAEPP
Coordinating Committee formed a CFC Workgroup to educate patients and
physicians about the CFC phaseout. The NAEPP CFC Workgroup, in
cooperation with IPAC, recently developed a ``fact sheet'' for patients
entitled ``Your Metered-Dose Inhaler Will Be Changing * * * Here Are
the Facts.'' The fact sheet is available through the FDA web site
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 CFC's in FDA
Consumer, Journal of the American Medical Association (JAMA), 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.
     108. One comment stated that FDA must provide notice and an
opportunity for hearing before withdrawing any drug.
     FDA uses the procedures in 21 CFR 314.200 to withdraw approval of
a drug. Under proposed Sec. 2.125, FDA is not

[[Page 47735]]

proposing to withdraw approval of any drug. FDA is simply proposing a
process for determining whether the use of an ODS in a particular
medical device continues to be essential. To maximize public input, FDA
will use notice-and-comment rulemaking to evaluate whether a moiety
should remain on the list of essential uses.
     109. One comment stated that, upon publication of a proposed rule,
FDA must disclose in appropriate detail and specificity the data and
technical information upon which the agency relied in reaching its
policy decisions.
     FDA has disclosed in the ANPRM and in this proposed rule the data
and technical information upon which it relied in drafting this
proposal.
16. International Mandate (Montreal Protocol)
     110. Three comments said that FDA should take no further action
until the plenary meeting of the Montreal Protocol Parties scheduled
for November 1998.
     Although FDA did not publish this proposed rule before the
November 1998 meeting, it has continued to work to develop the
proposal. The Parties to the Montreal Protocol suggested that Parties
requesting essential-use allowances submit an initial transition
strategy by January 31, 1998, and required these Parties to submit an
initial strategy no later than January 31, 1999. FDA is acting now to
ensure that patients in the United States are not put at risk by the
phaseout.
     111. Three comments stated that medical use of CFC's should be
permitted and should be the only worldwide exception. One comment noted
that although the total amount of CFC's used in MDI's represents a
small portion of total use, that use is increasing and it is
inconsistent with the Montreal Protocol to claim that a small use
justifies delay.
     The Clean Air Act requires the phaseout of nonessential CFC MDI's.
17. Legal Arguments
     112. Seven comments challenged FDA's authority to withdraw an
application because of failure to meet the essential-use requirements
of Sec. 2.125.
     FDA is not proposing to withdraw approval of any applications in
applying proposed Sec. 2.125. Rather, FDA is determining whether the
use of a CFC in a particular medical device remains essential as
alternative products become available and are accepted. Even when a
moiety is removed from the essential-use listing of Sec. 2.125(e), the
NDA's for the affected moiety need not necessarily be withdrawn under
section 505(e) of the act. FDA notes that manufacturers may not be
eligible to receive CFC allowances under the Montreal Protocol and the
Clean Air Act even if they have approved applications.
     One comment stated that FDA has no legal authority to prohibit the
continued use of existing inventories of CFC's used in medical devices.
     This proposed rule does not necessarily prohibit the continued use
of existing inventories of CFC's in medical devices. Rather, the
proposal sets forth the factors FDA would use to determine whether the
use of CFC's in a medical product is essential.
     113. Several comments stated that FDA does not have the statutory
authority under the act to declare that a drug product is adulterated
or misbranded simply because the product contains an ODS.
     The agency is proposing to remove the provisions of Sec. 2.125
that state that a product in a self-pressurized container that contains
an ODS is adulterated and/or misbranded. This change should not be
interpreted to mean that FDA agrees with these comments. 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 to declare such products adulterated and/or
misbranded is discussed in the preambles for the current 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 provisions of the Clean Air
Act.
     114. One comment stated that all CFC-MDI's with the same active
moiety as an approved non-CFC alternative must be phased out upon
approval of the non-CFC alternative because: (1) Section 601(8) of the
Clean Air Act (42 U.S.C. 7671(8)) indicates that as soon as a non-CFC
product receives FDA approval, all CFC-MDI's for which the non-CFC
product is an alternative can no longer qualify as essential; and (2)
non-CFC product approval by FDA constitutes a formal administrative
adjudication by FDA that there is a technically feasible alternative to
the use of CFC's in certain adrenergic bronchodilator MDI's.
    FDA disagrees with this comment. Section 601(8) of the Clean Air
Act (42 U.S.C. 7671(8)) defines which medical products may continue to
use ozone-depleting substances. The definition states:
    (8) Medical device. The term ``medical device'' means 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--
    (A) if such device, product, drug, or drug delivery system
utilizes a class I or class II substance for which no safe and
effective alternative has been developed, and where necessary,
approved by the Commissioner; and
    (B) if such device, product, drug, or drug delivery system, has,
after notice and opportunity for public comment, been approved and
determined to be essential by the Commissioner in consultation with
the Administrator.
    The comment wrongly assumes that a non-CFC product with the same
active moiety as a CFC product is a ``safe and effective alternative''
to that CFC product. A non-CFC product simply having the same active
moiety as a CFC product is only one factor to be considered. Other
factors, such as whether the non-CFC product has the same route of
administration, the same indication, and can be used with approximately
the same level of convenience, are important considerations.
Additionally, FDA must consider whether patients who medically need the
CFC product are adequately served by the non-CFC product. In those
instances where an active moiety is marketed by two or more NDA's or
marketed in multiple, distinct strengths, at least two non-CFC products
that contain the same active moiety must be marketed to adequately
serve the consumer.
    This comment also demonstrates a misunderstanding of the meaning of
an FDA-approval of a non-CFC product. FDA's approval of a non-CFC
product is a determination that the product is safe and effective, but
it is not a determination that the product is a safe and effective
alternative to any other product. That requires a separate and distinct
analysis.
    The comment is correct to the extent that it indicates that once a
non-CFC product that is a safe and effective alternative is approved,
the CFC-product must be phased out. Those factors described previously
and those incorporated into this proposed rule are factors to be
considered when determining whether a non-CFC product is a safe and
effective alternative to a CFC-product. FDA believes these factors are
also an important part of the analysis used to determine whether a
product is essential. FDA and EPA will be consulting to determine
whether such medical products are essential and safe and effective
alternatives.

[[Page 47736]]

     115. One comment stated that under the Montreal Protocol, for use
of an ODS in a product to be no longer essential there must be multiple
alternatives and the alternatives must be: (1) Technically feasible,
(2) economically feasible, (3) acceptable from an environmental
standpoint, and (4) acceptable from a health standpoint. The comment
stated that FDA is responsible for making determinations (1), (2), and
(4), and that EPA is responsible for making the third determination.
     Under this proposal, FDA is requiring the existence of feasible
alternatives that are acceptable from a health standpoint before it
will find any CFC-MDI no longer essential.
     116. Two comments stated that there is no need for FDA to make a
determination of essential use under the Clean Air Act, although it
does have the authority to do so, because the determination is to be
made under the Montreal Protocol.
     Section 601 of the Clean Air Act explicitly directs ``the
Commissioner [of FDA] in consultation with the Administrator'' of EPA
to determine whether a device, product, drug, or drug delivery system
is essential under the Clean Air Act (42 U.S.C. 7671(8)). This
determination is different from the essential use determination made
under the Montreal Protocol.
     117. One comment stated that the Clean Air Act does not require a
preferable or popular alternative but only an alternative that is FDA
approved (safe and effective) and technically feasible.
     As explained previously, although FDA approval does constitute a
determination that a product is safe and effective on its own, this
finding does not constitute a determination regarding whether one
product is a medically acceptable alternative for another.
     118. One comment discussed extensively products EPA has allowed to
stay on the market and concluded that FDA should not ban MDI's.
     First, FDA is not banning any MDI's. Rather, FDA is making a
determination regarding whether the use of CFC's in particular medical
products continues to be essential. Second, FDA cannot speak on behalf
of EPA regarding why certain products may remain on the market.
However, FDA notes that the comment's analysis relies on 42 U.S.C.
7671i(e), which states specifically that it does not apply to medical
devices as defined in the Clean Air Act (42 U.S.C. 7671(8)).
     119. One comment stated that FDA cannot find products nonessential
if they do not have a therapeutically equivalent replacement.
     Neither the Clean Air Act or the Montreal Protocol requires
alternative products to be therapeutically equivalent to a CFC product
before the CFC product can be considered nonessential.
     120. One comment stated that the ANPRM conflicts with the Drug
Price Competition and Patent Term Restoration Act of 1984 by impeding
generic competition, because under section 505(c)(3)(D) of the act,
products with an active ingredient that do not contain a new chemical
entity will receive 3 years of market exclusivity and products with an
active ingredient that is a new chemical entity will receive 5 years of
market exclusivity. Further, patent protections may extend the time
during which generic competition is prevented.
     FDA recognizes that the phaseout of CFC-MDI's may affect the
availability of generic products, depending on whether the phaseout
occurs before generic versions of non-CFC products may be marketed.
However, the Clean Air Act and the Montreal Protocol mandate the
phaseout of non-essential uses of CFC's.
     121. One comment noted that, in the case of Seldane, FDA
acknowledged that not all patients are well-served when there are only
two drugs available, and questioned whether the therapeutic class
approach proposed in the ANPRM is consistent with this.
     Although FDA disputes this interpretation of the Seldane notice of
opportunity for hearing (62 FR 1889, January 14, 1997), FDA is no
longer proposing to use the therapeutic class approach to remove
essential uses from Sec. 2.125(e).
     122. One comment noted that FDA expressed concern about the
differences between MDI's in its proposed rule to amend the OTC
monograph for bronchodilator drug products (60 FR 13014, March 9,
1995).
     FDA did express concern about the differences between MDI's in the
OTC proposed rule. FDA noted that the differences meant that all new
MDI's should be approved by FDA under an NDA supported by clinical
trials designed to examine the effect of MDI differences. In
recognition of the complexities of this dosage form, FDA is requiring
each non-CFC MDI to be reviewed as a new NDA, rather than as a
supplement to an existing CFC-MDI NDA. In addition, FDA has been
encouraging sponsors to include in these clinical trials comparators
representing the currently available CFC-based products. FDA believes
its action regarding the development of the non-ODS products is
consistent with its concerns expressed in the OTC proposal of March 9,
1995.
     123. One comment noted that de minimis exemptions from statutory
requirements are permitted and therefore requested that MDI's be
exempted from the Clean Air Act requirement that all uses of CFC's
cease.
     FDA does not have the discretion to decide how to implement the
Clean Air Act because EPA is the primary agency charged with
implementing these provisions. However, as a matter of general
statutory construction, provision of a specific exemption for medical
products makes it unlikely that de minimis exemptions for medical
products would also be permitted under the Clean Air Act.
     124. One comment posited that FDA is operating under a false
construct whereby the agency assumes it must follow environmental
recommendations made by EPA and Parties to the Montreal Protocol.
     FDA is not taking this action as a result of recommendations made
by EPA or the Parties to the Montreal Protocol. Rather, FDA is
complying with the statutory mandate of U.S. law as embodied in the
Clean Air Act, which implements the Montreal Protocol and requires the
phaseout of CFC use. FDA is taking this action to ensure that patient
health is protected throughout the transition.
     125. Two comments stated that FDA must comply with Executive Order
12866. One of those comments also said that FDA must comply with
Executive Orders 12291, 12606, 12898, and the Regulatory Flexibility
Act.
     Executive Order 12291 was revoked by Executive Order 12866 section
11. 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).
     Executive Order 12606 was revoked and replaced by Executive Order
13045 section 7-702. Executive Order 13045 applies only to regulatory
actions initiated after the date of the Executive Order (Executive
Order 13045 section 2-202). The ANPRM was published on March 6, 1997,
before the Executive Order was signed on April 21, 1997. Accordingly,
this proposed regulatory action is exempt from Executive Order 13045.
In addition, Executive Order 13045 applies only to significant
regulatory actions that concern an environmental health risk or safety
risk that an agency has reason to believe may

[[Page 47737]]

disproportionately affect children. First, this proposal is not a
significant regulatory action because it is not anticipated that it
will have an annual net effect on the economy of $100 million or more,
nor would it adversely affect in a material way the economy, a sector
of the economy, productivity, competition, jobs, the environment,
public health or safety, or State, local, or tribal governments or
communities. Second, the phaseout of CFC-MDI's is not an environmental
health risk. Rather, the phaseout constitutes an environmental health
benefit, since reduction in CFC use could decrease ongoing damage to
the ozone layer and thereby decrease related health problems. In
particular, children will benefit from a phaseout because they are more
susceptible to skin cancers due to increased sensitivity and lifetime
exposure. Therefore, Executive Order 13045 does not apply to this
proposal.
     Executive Order 12898 requires agencies to identify and address
disproportionately high adverse human health or environmental effects
on minority populations and low-income populations. The agency does not
anticipate that this proposed rule, if implemented, will have any
adverse effects on human health or the environment.
    The Regulatory Flexibility Act (5 U.S.C. 601 et seq.) requires
agencies to analyze regulatory options that would minimize any
significant impact of a rule on small entities. The agency has complied
with this requirement (see section VII.A of this document).
    126. One comment stated that FDA must assess environmental impacts
under 2 U.S.C. 1532 and 1535.
    The primary purpose of the Unfunded Mandates Reform Act (2 U.S.C.
1501 et seq.) is to end the imposition of unfunded Federal mandates on
other governments without the full consideration of the Federal
Government (2 U.S.C. 1501(2)). However, the Unfunded Mandates Reform
Act does also ask agencies to estimate the impact of unfunded Federal
mandates on the private sector (2 U.S.C. 1501(3)). As part of that
estimate, the agency is to examine the effect of the Federal mandate on
health, safety, and the natural environment. FDA has complied with this
requirement (see section VII of this document). In addition, FDA
believes that environmental benefits are analyzed with the regulations
implementing the Clean Air Act.

IV. Legal Authority

    FDA's proposal to determine when CFC uses are essential in medical
devices is authorized by the Clean Air Act. EPA regulations
implementing the provisions of section 610 of the Clean Air Act (42
U.S.C. 7671i) contain a general ban on the use of CFC's 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) (42 U.S.C.
7671i(e); 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 ozone-depleting substance 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
CFC's, 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 (HCFC's) (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 proposed rule,
if enacted, would provide a mechanism for FDA to remove products from
the essential-use list in an orderly and rational fashion.

V. Proposed Implementation Plan

    FDA proposes that any final rule that may issue based on this
proposal become effective 1 year after its date of publication in the
Federal Register. After that date, FDA would 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.

VI. Request for Comments

    Interested persons may, on or before November 30, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
     In particular, FDA seeks comment on the following issues:
    1. The criteria FDA should use to determine whether a subpopulation
is significant;
    2. The type of postmarketing information FDA should consider in
evaluating the adequacy of alternatives; and
    3. The timing of the removal of the essential-use designation for
nasal steroids.

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed 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 economic 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 of a rule
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 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 conducted analyses of the proposed rule, and
has determined that the rule is consistent with the principles set
forth in the Executive Order and in these statutes. FDA finds that this
proposed 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

[[Page 47738]]

proposed regulation would not result in a significant economic impact
on a substantial number of small entities. Thus, the agency need not
prepare an interim Regulatory Flexibility Analysis.
    This proposed rule would amend the regulation that permits the use
of ODS's in particular circumstances by setting the standards that FDA
will use to determine when the use of ODS's in FDA-regulated products
is essential under the Clean Air Act. In 1987, the United States became
a party to an international agreement known as the Montreal Protocol.
The Parties to the Protocol have agreed to eventually eliminate all
uses of ODS's. However, the Parties currently permit the use of ODS's
in essential medical products. FDA, in consultation with EPA, must
determine whether the uses of ODS's in medical products are essential.
Currently, the United States has secured essential-use designations for
the use of CFC's (which are ODS's) in MDI's through the year 2000 and
will continue to seek such designations until acceptable alternatives
make CFC-MDI's nonessential.
    CFC's are presently used as propellants in MDI's. FDA has approved
17 active moieties that use CFC's in MDI's, although only 16 are
marketed as either prescription or OTC products (see Table 1 of this
document). These CFC-MDI's are approved for the treatment of asthma and
other COPD's. Several manufacturers are in the process of reformulating
their CFC-MDI's to use non-ODS propellants in the United States. In
some foreign markets, reformulated products are already in the process
of displacing or have already displaced products containing ODS's.
     FDA is also proposing to remove the essential-use designation for
metered-dose steroid human drugs for nasal inhalation. Four
manufacturers market five CFC-nasal inhalation drug products, which
constitute less than 20 percent of the nasal inhalation product market.
The drug products contain either beclomethasone, budesonide, or
triamcinolone. Beclomethasone and triamcinolone are also marketed in
non-CFC formulations. The manufacturer of budesonide has represented
publicly that it intends to market a non-CFC formulation.

B. Economic Impacts

    The proposed regulation articulates the standards used by FDA to
determine whether the use of CFC-MDI's is essential. This proposal
would not have any economic impact, since it simply establishes the
criteria FDA would use to make essential-use determinations. However,
application of the rule in future rulemakings would generate both
regulatory benefits and costs. FDA discusses some of those possible
benefits and costs here, but notes that it would conduct additional
analyses as part of its notice-and-comment rulemaking for essential-use
designations for particular products.
1. Regulatory Benefits
    The potential benefits of the rule are the environmental gains
associated with the diminished use of ODS's in medical products. FDA
has not attempted to quantify the value of these environmental
improvements, which would constitute only a small fraction of the
overall benefits of compliance with the Clean Air Act and Montreal
Protocol. Nevertheless, even a relatively small percentage would
represent a significant value. EPA has estimated in prior regulatory
impact analyses that the aggregate public health benefit of the
phaseout of ODS's due to reduced cases of skin cancer, cataracts, and
other health effects ranges between $8 and $32 trillion (Ref. 1).
    Currently, about 14.6 million patients are being treated for asthma
and COPD (Ref. 2). FDA believes that these patients are treated with
MDI's. Over 120 million prescriptions for the affected drug substances
are dispensed each year. Although the Clean Air Act and the Montreal
Protocol require the eventual elimination of essential-use designations
for these products, the agency has carefully structured its rule to
avoid negative impacts on the nation's public health. Most importantly,
the proposed regulation would ensure that adequate supplies of
reformulated products with comparable therapeutic roles are available
prior to recision of an essential-use designation. An alternative
product that could not demonstrate comparable therapeutic outcomes
would not be considered a medically acceptable alternative and the
essential-use designation for the CFC-MDI would remain in place. Thus,
the rule would ensure that treatment outcomes would not be threatened
as products are reformulated with acceptable, non-ODS propellants.
    FDA notes that upon approval, new non-ODS products could be
eligible for market protections under the Hatch-Waxman Amendments.
Thus, existing lower-priced generic CFC-MDI's could disappear from the
market if their active moiety were no longer designated as essential.
However, FDA finds that the total number of pharmaceutical
prescriptions purchased has not typically increased following the
introduction of generic competition (Ref. 3). Consequently, FDA does
not anticipate a significant decrease in the total number of
prescriptions purchased due to curtailment of generic competition.
However, these impacts may vary for particular products or markets and
FDA asks for public comment on this issue, with particular attention to
evaluating effects on patient affordability.
     FDA also notes that removal of the essential-use designation for
nasal steroids would not have a negative impact on the nation's public
health. Adequate supplies of reformulated products with comparable
therapeutic roles exist and are used widely by patients for the
treatment of seasonal and perennial allergic rhinitis. FDA also notes
that the price of the alternative nasal inhalation drugs are
approximately the same as for the CFC-products on a dose per dose
basis.
2. Regulatory Costs
    Sponsors who elect to reformulate their products will incur
significant costs to collect the detailed clinical data necessary for
approval of reformulated products. One sponsor that has developed
alternative formulations has stated that the total development costs of
reformulated MDI's have approached $250 million (Ref. 4). FDA has no
empirical data to confirm these costs, but notes that these outlays
imply global expenses for replacing propellants, as required by various
environmental agreements, such as the Montreal Protocol. Product
manufacturers are well aware of the mandate to eliminate the marketing
of ODS's and are already engaged in the development of reformulated
products. Because these international development activities will
continue regardless of FDA's precise standards for rescinding
essential-use determinations, FDA considers these reformulation costs a
direct consequence of the statutory requirements of the Clean Air Act,
rather than of FDA's forthcoming regulation. Postmarketing studies of
reformulated products would be part of these development costs. Thus,
FDA finds that the aggregate costs of the rule are directly
attributable to the enactment of the Clean Air Act.
     For nasal steroids, FDA does not anticipate any regulatory costs
as a result of this proposal, since the manufacturers that market the
CFC-products are the same manufacturers that market non-CFC
alternatives or have filed an application to do so.
3. Distributive Impacts
    The future establishment of specific rules for the elimination of
essential-use designations could have significant

[[Page 47739]]

distributional impacts on various economic sectors. In particular,
FDA's essential-use designation recisions would determine when
individual generic CFC-MDI's would no longer be considered essential.
Such decisions could force generic consumers to switch to higher-priced
reformulated, branded products until non-ODS generic products became
available. These consumers could face significant cost increases, of
which third-party payers, including the nation's Medicaid system, might
bear roughly 70 percent. Alternatively, patients that use brand name
products should experience little change in either costs or outcomes
due to this rule. Experience from the United Kingdom (Ref. 4) and
comments from potential manufacturers indicate that the reformulated
brand name products would likely be priced comparably to current brand
name products. Diminished generic alternatives are not expected to
alter this expectation, as several studies have shown that the
availability of generic substitutes has had little impact on the price
of branded products (Refs. 3, 5, 6, 7, and 8).
    Distribution systems (warehouses, distribution centers, and retail
pharmacies) for pharmaceutical products are reported to generate higher
profit rates per prescription for generic products than for branded
products (Refs. 9 and 10).\7\ Accordingly, each branded prescription
substituted for a generic prescription could result in lost revenue for
distributors and retailers. Generic manufacturers could also lose sales
revenues following the recision of an essential-use designation,
although these firms might mitigate these losses by shifting production
resources to other generic products. In total, therefore, patients,
third-party payers, distributors, and generic manufacturers could
experience overall sector losses due to the removal of a product from
the essential-use list in Sec. 2.125.
---------------------------------------------------------------------------

    \7\ Data indicate this to be true in both absolute and
proportional terms.
---------------------------------------------------------------------------

    On the other hand, manufacturers of reformulated branded products
would receive increased revenues, because sales of branded products
would increase by capturing the current demand for generic
prescriptions.
    These distributional impacts will not be triggered, however, until
the completion of a future rulemaking on each ODS-containing product.
FDA plans to conduct specific market analyses to determine the
approximate magnitude of these economic effects prior to determining
the essentiality of these ODS products.
     FDA does not anticipate any distributive impacts due to the
removal of the essential-use designations for nasal inhalation products
because the alternative products are marketed by the same
manufacturers.

C. Small Business Impact

1. Initial Analysis
    The proposed standards provide a framework for FDA's future
decisions regarding essential-use designations for particular CFC-MDI's
and would remove the essential-use designations for metered-dose
steroid human drugs for nasal inhalation. FDA certifies that this rule
would not have a significant impact on a substantial number of small
entities. Nevertheless, FDA has prepared the elements of an Initial
Regulatory Flexibility Analysis to alert any potentially affected small
entities of the opportunity to submit comments to the agency. FDA notes
that the direct regulatory costs are attributable to the Clean Air Act
and Montreal Protocol mandate to phase out the use of ODS's and are not
dependent upon the enactment of this proposed rule.
2. Description of Impact
    The objective of the proposed regulation is to provide the basis
for essential-use designations for ODS's in FDA-regulated products,
without jeopardizing the public health. The proposed regulation would
accomplish this objective by articulating the standards to be used for
revising essential-use designations for approved drug products. The
statutory authority for the proposed rulemaking is discussed in section
IV of this document.
    The industry primarily affected by the rescission of essential-use
designations would be manufacturers of pharmaceutical preparations
(Ref. 11, SIC 2834). Census data indicate that more than 92 percent of
the approximately 700 manufacturing establishments and 87 percent of
the 650 firms in this industry have fewer than 500 employees. The Small
Business Administration (SBA) considers firms with fewer than 750
employees in this sector to be small, but census size categories do not
correspond to the SBA designation. Nevertheless, when the procedures of
this proposed regulation are implemented, the major impact would likely
be incurred by fewer than five small manufacturers of generic products
and even fewer small manufacturers of branded products.
    Table 1 of this document shows that seven drug substances will be
eligible for generic competition in the next several years. However,
even in the absence of any FDA decision, many of these drug substances
are unlikely to attract generic competition because of their relatively
small market share and the knowledge that ODS's are to be removed from
the market. In fact, several drug substances that have lost market
exclusivity have not been subject to generic competition.
     FDA notes that metered-dose steroid human drugs for nasal
inhalation are manufactured by four manufacturers, none of whom are
small. Therefore, FDA does not expect its proposal to remove the
essential-use designation for metered-dose steroid human drugs for
nasal inhalation to have a significant impact on a substantial number
of small entities.
    FDA does not expect significant impacts on wholesalers of
pharmaceutical products (Ref. 11, SIC 5122) or retail pharmacies (Ref.
11, SIC 5912) because only a few of the thousands of pharmaceutical
products sold by these firms is likely to be affected.
3. Analysis of Alternatives
    FDA examined several alternatives to the proposed rule. First, FDA
considered denying new essential-use designations but allowing
currently exempted drug products to continue to use ODS's. This
alternative would continue the availability of current therapies at no
additional transfer of costs. However, there would be no incentive to
reformulate products. Thus, this alternative would not meet the
environmental requirement to eliminate the use of ODS's.
    Next, FDA considered allowing essential-use designations for all
CFC-MDI's to remain in place until a specific time. However, this
alternative imposes a risk of significant market disruption when
products are removed. FDA preliminarily estimated that disruption of
therapies and additional costs of shortages could cost almost $1
billion. In addition, allocations of ODS's are not guaranteed. The
United States must seek and be granted allocations through procedures
established by the Montreal Protocol. As part of those procedures, the
United States has committed to a yearly examination of essential-uses.
    FDA also considered removing essential-use designations for all
drug products within a therapeutic class as soon as any two active
moieties within the class were available in non-ODS formulations.
Defining alternative therapies to include all active moieties within a
therapeutic class would hasten the removal of ODS's from the
environment. However, FDA rejected

[[Page 47740]]

this alternative because of concerns about the ability of a few
products to replace all products within a therapeutic class.
    Another option would have been for the United States to remove
essential-use designations for products on a regular basis or by
reduction in CFC allocations. FDA is not encouraging selection of this
option because there would be inadequate consideration of the public
health impact of essential-use designations.

D. Conclusion

    This analysis examined the impact of FDA's proposed rule to set the
conditions and standards for determining the essentiality of using
ODS's in MDI's and to remove the essential-use designations for
metered-dose steroid human drugs for nasal inhalation. FDA believes
that this rule would ensure adequate product availability without
jeopardizing the desired therapeutic outcomes associated with the
affected products. Also, the agency finds that its rule would impose
nominal net societal costs, although FDA recognizes that removing
essential-use designations for products for the treatment of asthma and
COPD could generate substantial losses and gains for particular sectors
of the economy. As each essential-use removal for such products would
be made through notice-and-comment rulemaking, FDA would examine the
particular impact of each essential-use designation at the time of the
specific proposal.

                 Table 1.--Description of the Affected Drug Substance (as of September 1998)\1\
----------------------------------------------------------------------------------------------------------------
                                                      Number Distributed
    Drug Substance in MDI       Generic Available?         Annually       Approximate Market    Off Patent Date
                                                          (millions)        Share (percent)
----------------------------------------------------------------------------------------------------------------
Albuterol                     Yes                            48.80\2\            40.5         Off
Beclomethasone                No                             21.31               17.7         December 1999
Ipratropium                   No                             13.47               11.2         Off
Triamcinolone                 No                              9.26                7.7         October 1999
Salmeterol                    No                              6.84                5.7         January 2012
Flunisolide                   No                              4.45                3.7         June 2007
Fluticasone                   No                              3.37                2.8         November 2003
Albuterol/Ipratropium         No                              2.15                1.8         June 2015
Pirbuterol                    No                              2.07                1.7         May 2004
Metaproterenol                No                              1.52                1.3         Off
Cromolyn                      No                              1.47                1.2         September 2000
Nedocromil                    No                              0.87                0.7         October 2006
Bitolerol                     No                              0.12                0.1         Off
Isoetharine                   No                              0.07                0.1         Off
Terbutaline                   No                              0.02                0.0         Off
Total                                                       115.79               96.2\3\
----------------------------------------------------------------------------------------------------------------
\1\ Source: FDA CDER data and Approved Therapeutic Drug Products, 19th ed.
\2\ Including 34.96 million generic and relabeled prescriptions.
\3\ Percentages do not add to 100 percent because data are not available for epinephrine and isoproterenol.

VIII. The Paperwork Reduction Act of 1995

    The proposed 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 No. 0910-0183,
which expires on June 30, 2000.

IX. References

    The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
    1. ICF Inc., Regulatory Impact Analysis: Compliance with Section
604 of the Clean Air Act for the Phaseout of Ozone Depleting
Chemicals, ch. 6, July 1, 1992.
    2. U.S. National Center for Health Statistics, Vital and Health
Statistics, Series 10, No. 193, 1996.
    3. Caves, R. E. et al., ``Patent Expiration, Entry, and
Competition in the U.S. Pharmaceutical Industry,'' in ``Brookings
Papers on Economic Activity: Microeconomics,'' edited by M. N.
Brady, pp. 1-66, 1991.
    4. ``Glaxo Ventolin Evohaler U.K. Launch Stresses Consistency
With Predecessor,'' Pink Sheet, vol. 60:37, 1998.
    5. Grabowski, H. G., and J. M. Vernon, ``Brand Loyalty, Entry,
and Price Competition in Pharmaceuticals After the 1984 Drug Act,''
Journal of Law and Economics, 35:10(331-350), 1992.
    6. Wiggins, S., and R. Maness, ``Price Competition in
Pharmaceutical Markets,'' PERC Working Paper No. 9409, Texas A&M
University, Economics Department, 1993.
    7. Ellison, S. F. et al., ``Characteristics of Demand for
Pharmaceutical Products: An Examination of Four Cephalosporins,''
RAND Journal of Economics, 28:3(426-446), 1997.
    8. Frank, R. G., and D. S. Salkever, ``Generic Entry and the
Pricing of Pharmaceuticals,'' Journal of Economics and Management
Strategy, 6:1(75-90), 1997.
    9. Grabowski, H. G., and J. M. Vernon, ``Longer Patents for
Increased Generic Competition in the United States: The Waxman-Hatch
Act After One Decade,'' PharmacoEconomics, 10 (Suppl. 2):110-123;
1996.
    10. U.S. Congressional Budget Office, How Increased Competition
From Generic Drugs Has Affected Prices and Returns in the
Pharmaceutical Industry, 1998.
    11. U.S. Small Business Administration, Table of Size Standards,
1996.

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, it is proposed that 21 CFR part 2 be 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:

[[Page 47741]]

    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 ODS's 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) Terbutaline.
    (vi) 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
amend paragraph (e) of this section to add or remove an essential use.
    (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 ODS's;
    (ii) The product will provide an unavailable important public
health benefit; and
    (iii) Use of the product does not release cumulatively significant
amounts of ODS's 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 ODS's;
    (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 ODS's into the atmosphere or the
release is warranted in view of the high probability of an unavailable
important public health benefit.
    (g) FDA will use notice-and-comment rulemaking to remove the
essential-use listing of a product in paragraph (e) of this section if
the product meets any one of the following criteria:
    (1) The product using an ODS is no longer being marketed; or
    (2) After January 1, 2005, the product is not available without an
ODS and FDA determines that the product 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) and one strength:
    (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) At least 1 year of 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 NDA's or marketed in multiple distinct
strengths;
    (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: August 19, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-22887 Filed 8-30-99; 12:40 pm]
BILLING CODE 4160-01-F