[Federal Register Volume 64, Number 169 (Wednesday, September 1, 1999)]
[Proposed Rules]
[Pages 47719-47741]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 99-22887]


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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 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 (g) per 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 g and 84 
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