99-22887. Use of Ozone-Depleting Substances; Essential Use Determinations  

  • [Federal Register Volume 64, Number 169 (Wednesday, September 1, 1999)]
    [Proposed Rules]
    [Pages 47719-47741]
    From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
    [FR Doc No: 99-22887]
    
    
    =======================================================================
    -----------------------------------------------------------------------
    
    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.
    
    -----------------------------------------------------------------------
    
    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\
    ---------------------------------------------------------------------------
    
        \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.
    ---------------------------------------------------------------------------
    
         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.
    ---------------------------------------------------------------------------
    
        \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.
    ---------------------------------------------------------------------------
    
    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.
    ---------------------------------------------------------------------------
    
        \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.
    ---------------------------------------------------------------------------
    
         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.
    ---------------------------------------------------------------------------
    
        \4\ The petitioner must show only a high probability of an 
    important public health benefit for an investigational product.
    ---------------------------------------------------------------------------
    
    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\
    ---------------------------------------------------------------------------
    
        \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.
    ---------------------------------------------------------------------------
    
         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.
    ---------------------------------------------------------------------------
    
        \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.
    ---------------------------------------------------------------------------
    
         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
    
    
    

Document Information

Published:
09/01/1999
Department:
Food and Drug Administration
Entry Type:
Proposed Rule
Action:
Proposed rule.
Document Number:
99-22887
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.
Pages:
47719-47741 (23 pages)
Docket Numbers:
Docket No. 97N-0023
RINs:
0910-AA99: Use of Ozone-Depleting Substances
RIN Links:
https://www.federalregister.gov/regulations/0910-AA99/use-of-ozone-depleting-substances
PDF File:
99-22887.pdf
CFR: (3)
21 CFR 2.125(e)
21 CFR 2.125
21 CFR 10.30