[Federal Register Volume 62, Number 44 (Thursday, March 6, 1997)]
[Proposed Rules]
[Pages 10242-10247]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-5495]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

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


Chlorofluorocarbon Propellants in Self-Pressurized Containers; 
Determinations That Uses Are No Longer Essential; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is seeking public 
comment on the policy it is considering for adoption on making and 
implementing determinations that uses of chlorofluorocarbons (CFC's) 
currently designated essential will no longer be deemed essential under 
the Clean Air Act due to the availability of safe and effective medical 
product technology that does not use CFC's. Essential-use products are 
exempt from FDA's ban on the use of CFC propellants in FDA-regulated 
products and the Environmental Protection Agency's (EPA's) ban on the 
use of CFC's in pressurized dispensers. The agency is taking this 
action because it is responsible for determining which products 
containing CFC's or other ozone-depleting substances are an essential 
use under the Clean Air Act. FDA is soliciting comments on this policy 
to assist the agency in striking an appropriate balance that will best 
protect the public health, both by ensuring the availability of an 
adequate number of treatment alternatives and by curtailing the release 
of ozone-depleting substances.

DATES: Written comments by May 5, 1997.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Under Sec. 2.125 (21 CFR 2.125), any food, drug, device, or 
cosmetic in a self-pressurized container that contains a CFC propellant 
for a nonessential use is adulterated, or misbranded, or both, under 
the Federal Food, Drug, and Cosmetic Act. This prohibition is based on 
scientific research indicating that CFC's reduce the amount of ozone in 
the stratosphere and thereby increase the amount of ultraviolet 
radiation reaching the earth. An increase in ultraviolet radiation will 
increase the incidence of skin cancer, and produce other adverse 
effects of unknown magnitude on humans, animals, and plants. Section 
2.125(d) exempts from the adulteration and misbranding provisions of 
Sec. 2.125(c) certain products containing CFC propellants that FDA 
determines provide unique health benefits that would not be available 
without the use of a CFC.
    These products are referred to in the regulation as essential uses 
of CFC's and are listed in Sec. 2.125(e). Under Sec. 2.125(f), any 
person may petition FDA to request additions to the list of uses 
considered essential. To demonstrate that the use of a CFC is 
essential, the petition must be supported by an adequate showing that: 
(1) There are no technically feasible alternatives to the use of a CFC 
in the product; (2) the product provides a substantial health, 
environmental, or other public benefit that would not be obtainable 
without the use of the CFC; and (3) the use does not involve a 
significant release of CFC's into the atmosphere or, if it does, the 
release is warranted by the consequence if the use were not permitted.
    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, such as metered-dose inhalers (MDI's) 
(40 CFR 82.64(c) and 82.66(d)). These EPA regulations exempt from the 
general ban ``medical devices'' that FDA considers essential and that 
are listed in Sec. 2.125(e). Section 601(8) of the Clean Air Act (42 
U.S.C. 7671(8)) defines ``medical device'' as any device (as defined in 
the Federal Food, Drug, and Cosmetic Act), diagnostic product, drug (as 
defined in the Federal Food, Drug, and Cosmetic 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).
    Production of ozone-depleting substances is being phased out 
worldwide under the terms of the Montreal Protocol on Substances that 
Deplete the Ozone Layer (Montreal Protocol), Sept. 16, 1987, S. Treaty 
Doc. No. 10, 100th Cong., 1st sess., 26 I.L.M. 1541 (1987). In 
accordance with the provisions of the Montreal Protocol, under 
authority of Title VI of the Clean Air Act (section 601 et seq.), 
manufacture of CFC's in the United States was generally banned as of 
January 1, 1996. To receive permission to manufacture CFC's in the 
United States after the phaseout date, manufacturers must obtain an 
exemption from the phaseout requirements from the Parties to the 
Montreal Protocol. Procedures for securing an essential-use exemption 
under the Montreal Protocol are described in the most recent request by 
EPA for applications for exemptions (60 FR 54349, October 23, 1995). 
Firms that wish to use CFC's manufactured after the phaseout date in 
medical devices (as

[[Page 10243]]

defined in section 601(8) of the Clean Air Act) covered under section 
610 of the Clean Air Act must receive exemptions for essential uses 
under the Montreal Protocol.
    Faced with the statutorily mandated phaseout of the production of 
CFC's, drug manufacturers are developing or have developed alternatives 
to MDI's and other self-pressurized drug dosage forms that do not 
contain ozone-depleting substances. Examples of these alternative 
dosage forms are MDI's that use such non-ozone-depleting substances as 
propellants and dry-powder inhalers (DPI's). FDA has recently approved 
the first CFC-free MDI, 3M Pharmaceuticals Inc.'s albuterol sulfate 
product, Proventil<Register> HFA; although a determination has not yet 
been made on whether this product is a technically feasible alternative 
to the use of CFC's, this approval gives the subject matter of this 
advance notice of proposed rulemaking (ANPRM) a particular timeliness. 
The current or future availability of ``technically feasible 
alternatives to the use of a [CFC]'' may mean that the existing listing 
of a use in Sec. 2.125(e) would no longer reflect current conditions. 
It is with this situation in mind that FDA is publishing this ANPRM 
regarding agency determinations that certain uses of ozone-depleting 
substances are no longer essential.
    FDA has determined that it would be most productive to set out the 
following tentative policy on the elimination of essential uses in an 
ANPRM. The agency believes that providing an opportunity for the 
fullest public participation at the earliest possible stage in the 
agency decisionmaking process in this matter is appropriate to assist 
FDA in striking an appropriate balance that will best protect the 
public health, both by ensuring the availability of an adequate number 
of treatment alternatives and by curtailing the release of ozone-
depleting substances. In striking this balance, FDA intends to assess a 
number of factors and is interested in public comment on them. In 
establishing its policy on the elimination of essential uses, FDA will 
assess the potential beneficial effects of reducing CFC emissions from 
drug products broadly, based on the amount of CFC emissions that would 
be avoided, the stratospheric ozone depletion that would be averted, 
and the resulting decline in incidence of UV-B-related adverse human 
health effects, including human cancers and cataracts. FDA will also 
assess the beneficial public health effects of continued availability 
of CFC-containing drug products broadly, based on the availability, 
safety, and efficacy of alternatives, in full consideration of 
differences in patients' medical circumstances, physiological 
sensitivity, and acceptability of use, among others. FDA is 
specifically soliciting comments on how it should develop information 
to assist in striking this balance and how it should further balance 
the need for timely action. FDA also believes that there is adequate 
time to publish an ANPRM and respond to comments but will endeavor to 
complete this rulemaking process in a timely fashion. Because the first 
potential technically feasible alternatives are just now coming on the 
market, it will take a significant amount of time for manufacturers to 
collect and present the postmarketing safety and patient acceptance 
data that the agency will need to determine if the products are, in 
fact, technically feasible alternatives (see section II.B. of this 
document).

II. Proposed Policy

    FDA has tentatively determined that certain uses of CFC's, listed 
in Sec. 2.125(e) as essential, can no longer be considered to be 
essential. FDA is considering proposing to remove these uses from the 
list of essential uses in a rulemaking to be initiated soon. Uses no 
longer considered essential are discussed in section II.A. of this 
document. FDA also expects that certain uses still considered to be 
essential will cease to be considered essential as new technology 
develops. Section II.B. of this document describes the policy that FDA 
has tentatively determined will be used in making determinations that 
these uses of CFC's are no longer essential. FDA has worked closely 
with EPA in developing the following policy and this ANPRM reflects 
those discussions. This policy will also be the subject of a notice of 
proposed rulemaking to incorporate the policy into FDA regulations.

A. Listed Uses That Are No Longer Considered Essential

1. Metered-Dose Steroid Human Drugs for Nasal Inhalation
    Steroid human drugs for nasal inhalation are currently available 
using metering atomizing pumps rather than nasal MDI's. The 
availability of such products as Beconase<Register> AQ and 
Vancenase<Register> AQ (beclomethasone dipropionate monohydrate), 
Nasarel<Register> and Nasalide<Register> (flunisolide), 
Flonase<Register> (fluticasone propionate), and Nasacort<Register> AQ 
(triamcinolone acetonide), and the widespread patient acceptance of 
these products, indicate to FDA that using CFC's in metered-dose 
steroid human drugs for nasal inhalation can no longer be considered to 
be essential and FDA has tentatively determined to remove the use from 
Sec. 2.125(e).
2. Drug Products That Are No Longer Being Marketed
    Several of the essential uses listed in Sec. 2.125(e) exempt only a 
single approved drug product and, in a few cases, that drug product is 
no longer being marketed (or is no longer being marketed in a 
formulation containing CFC's). FDA has tentatively determined that an 
essential use for which no drug product is currently being marketed 
should no longer be considered to be essential. 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. Therefore, FDA has 
tentatively determined to remove the following uses from Sec. 2.125(e): 
Polymyxin B sulfate-bacitracin zinc-neomycin sulfate soluble antibiotic 
powder without excipients, for topical use on humans; and contraceptive 
vaginal foams for human use.

B. Criteria for Determination That a Use Is No Longer Essential

1. Therapeutic Classes
    In evaluating petitions submitted under Sec. 2.125(f) requesting 
that a new use be listed as essential, FDA has not required a showing 
that technically feasible non-CFC alternatives to a product contain the 
same active ingredient or active moiety\1\ as the drug product that 
would be the subject of the proposed essential use. Thus, if other drug 
products, containing other active moieties, are available for treatment 
of the same condition, they may be considered technically feasible 
alternatives to the proposed essential-use product. Many of the drug 
products marketed under Sec. 2.125 are pharmacologically closely 
related, are indicated for the treatment of the same conditions, and 
may be considered to be treatment alternatives. In evaluating whether a 
use remains essential, FDA believes that it is appropriate to evaluate 
these treatment alternatives together as a therapeutic class. In this 
regard, FDA has tentatively determined that metered-dose corticosteroid 
human drugs for oral inhalation and metered-dose short-

[[Page 10244]]

 acting adrenergic bronchodilator human drugs for oral inhalation are 
appropriate therapeutic classes for essential-use determinations. The 
determination of whether drug products that are not members of either 
therapeutic class represent essential uses of CFC's will be made under 
the criteria set out in section II.B.2. of this document.
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    \1\ 21 CFR 314.108(a) defines active moiety as meaning ``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.''
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    FDA has tentatively determined that all drugs currently marketed 
under Sec. 2.125(e)(2) should be considered to be members of the 
therapeutic class ``metered-dose corticosteroid\2\  human drugs for 
oral inhalation.'' These drugs contain the following active moieties:
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    \2\ The active ingredients in all drug products currently 
marketed under the essential use for metered-dose steroid human 
drugs for oral inhalation are members of the subclass of substances 
known as corticosteroids. FDA has tentatively determined that it 
would be more accurate to use the more specific term corticosteroids 
rather than the more general term steroids to describe the 
therapeutic class.
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<bullet> beclomethasone
<bullet> dexamethasone
<bullet> flunisolide
<bullet> fluticasone
<bullet> triamcinolone
    FDA has tentatively determined that drugs containing the following 
active moieties currently marketed under Sec. 2.125(e)(3) should be 
considered to be members of the therapeutic class ``metered-dose short-
acting adrenergic bronchodilator human drugs for oral inhalation'':
<bullet> albuterol
<bullet> bitolterol
<bullet> isoetharine
<bullet> isoproterenol
<bullet> metaproterenol
<bullet> pirbuterol
<bullet> terbutaline
    Adrenergic bronchodilator drug products containing the active 
moiety salmeterol are not included in the therapeutic class because of 
the longer duration of action and different indication of usage of 
salmeterol as compared to metered-dose short-acting adrenergic 
bronchodilator human drugs for oral inhalation. Adrenergic 
bronchodilator drug products containing the active moiety epinephrine 
are also not included in the class because epinephrine is the only 
active moiety used in drug products sold over-the-counter (OTC). These 
OTC drug products are available to patients who may not have access to 
prescription drugs. Therefore, FDA has tentatively determined that 
prescription drug products should not be considered as alternatives to 
drug products containing epinephrine. The determination of whether a 
drug product containing salmeterol or epinephrine constitutes an 
essential use would be considered under the criteria for an individual 
active moiety discussed in section II.B.2. of this document.
    The use of CFC's in any drug product that is a member of a 
therapeutic class described above would no longer be considered 
essential if, for each therapeutic class:
    1. Three distinct alternative products, representing at least two 
different active moieties, 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 products containing CFC's. At least 
two of the three alternative products must be MDI's.
    2. Adequate supplies and production capacity exist for the 
alternative products to meet the needs of the population indicated for 
the therapeutic class.
    3. At least 1 year of postmarketing use data for each product are 
available. There should be persuasive evidence of patient acceptance in 
the United States of each of the alternative products.
    4. There is no persuasive evidence to rebut a presumption that all 
significant patient subpopulations are served by the alternative 
products.
    FDA believes that making essential-use determinations for an entire 
class of closely related drug products will expedite the elimination of 
drug products that release ozone-depleting substances. FDA recognizes 
that there may be limited incentives to develop alternative products 
containing every active moiety currently marketed under essential-use 
exemptions. By eliminating the essential use by therapeutic class, FDA 
will ensure that these drugs do not remain on the market longer than 
necessary.
    FDA also hopes that the knowledge that the essential use covering a 
given product may be eliminated, even though no alternative product 
exists containing the same active moiety as that product, may provide 
added incentive for the manufacturer of that product to develop an 
alternative product containing the same active moiety. In addition, the 
agency believes that requiring multiple alternative drug products 
containing multiple active moieties should ensure that all significant 
patient populations have safe and effective alternatives to CFC-
containing drug products.
    A discussion of the application of these criteria can be found in 
section II.B.3 of this document.
    Under the proposed policy being considered for elimination of the 
essential-use status of the therapeutic classes, the essential-use 
status for individual members of a therapeutic class would only be 
eliminated when the essential-use status for the therapeutic class as a 
whole is eliminated. FDA recognizes that this approach may allow the 
essential-use status of an individual member of a therapeutic class to 
be retained despite the marketing of one or more technically feasible 
alternatives containing the same active moiety, pending elimination of 
the essential-use status for the therapeutic class as a whole. In 
addition to the policy FDA is considering for elimination of the 
essential-use status of the therapeutic classes described above, FDA is 
considering a policy for elimination of the essential-use status of 
individual members of a therapeutic class in advance of elimination of 
the essential-use status for the therapeutic class as a whole. Under 
this proposed policy, the essential-use status of an active moiety 
within a therapeutic class would be eliminated when one alternative 
product that contains the same active moiety is being marketed. All 
other elements of the policy regarding therapeutic classes would apply, 
including: The alternative product is delivered by the same route of 
administration, for the same indication, and with approximately the 
same level of convenience of use; there are adequate supplies and 
production capacity; at least 1 year of postmarketing use data are 
available; and there is no persuasive evidence to rebut a presumption 
that all significant patient subpopulations using that active moiety 
are served by the alternative product. Therapeutic classes would still 
be evaluated under the proposed therapeutic class policy, and 
alternative products used in the evaluation of the essential-use status 
of a member of the therapeutic class under the proposed additional 
policy would also be used in the evaluation of the class as a whole. 
FDA requests public comment on these approaches, and other possible 
approaches, for the elimination of the essential-use status of 
individual members of the therapeutic classes and the therapeutic 
classes as a whole.
2. Individual Active Moieties
    In examining the essential-use status of drug products when FDA has 
not already made a tentative determination that a currently listed 
essential use can no longer be considered to be essential, or when the 
drug is not a member of one of the therapeutic classes described in 
section II.B.1. of this document, FDA will look at other drug products 
containing the same active moiety as possible technically feasible 
alternatives. The use of CFC's in any drug product that is not a member 
of a

[[Page 10245]]

therapeutic class described in section II.B.1. of this document would 
no longer be considered essential if:
    1. One alternative product containing the same active moiety is 
being marketed, delivered by the same route of administration, for the 
same indication, and with approximately the same level of convenience 
of use compared to the product containing CFC's.
    2. Adequate supplies and production capacity exist to meet the 
needs of the population indicated for the alternative drug product 
containing the active moiety.
    3. At least 1 year of postmarketing use data for the product are 
available. There should be persuasive evidence of patient acceptance in 
the United States of the alternative product.
    4. There is no persuasive evidence to rebut a presumption that all 
significant patient subpopulations are served by the alternative 
product.
    A discussion of the application of these criteria can be found in 
section II.B.3. of this document.
    Drug products marketed under the following current essential uses 
would generally be evaluated under the above ``individual active 
moieties'' criteria:
<bullet> Metered-dose ergotamine tartrate drug products administered by 
oral inhalation for use in humans.
<bullet> Intrarectal hydrocortisone acetate for human use.
<bullet> Anesthetic drugs for topical use on accessible mucous 
membranes of humans where a cannula is used for application.
<bullet> Metered-dose nitroglycerin human drugs administered to the 
oral cavity.
<bullet> Metered-dose cromolyn sodium human drugs administered by oral 
inhalation.
<bullet> Metered-dose ipratropium bromide for oral inhalation.
<bullet> Metered-dose atropine sulfate aerosol human drugs administered 
by oral inhalation.\3\ 
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    \3\ The evaluation of the essential use status of drug products 
containing atropine sulfate may be an exception to the application 
of the criteria set out in section II.B. of this document. Drug 
products containing atropine sulfate were never commercially 
marketed under Sec. 2.125, but were manufactured for the U.S. Army 
for use by armed services personnel. The unique status of this use 
may require that other criteria be applied to it.
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<bullet> Metered-dose nedocromil sodium human drugs administered by 
oral inhalation.
<bullet> Metered-dose ipratropium bromide and albuterol sulfate, in 
combination, administered by oral inhalation for human use.
<bullet> Sterile aerosol talc administered intrapleurally by 
thoracoscopy for human use.
    As discussed in section II.B.1. of this document, the essential-use 
status of drugs containing the active moieties epinephrine and 
salmeterol will also be evaluated under the ``individual active 
moieties'' criteria.
    FDA requests public comment on the appropriateness of potentially 
eliminating such essential uses and criteria outlined here.
3. Discussion of Criteria
    In arriving at the tentative criteria for evaluating the essential-
use status of the two therapeutic classes, FDA has kept in mind that 
the MDI is the most widely accepted delivery system for administering 
drugs by oral inhalation for the treatment of asthma and chronic 
obstructive pulmonary disease. Physicians and patients value an MDI's 
compact size and ease of use. Because these factors are important and 
help ensure that patients receive appropriate medical treatment, FDA 
would require that at least two of the alternative products be 
available as an MDI. FDA is also aware that not all patients may 
tolerate a given drug product. Accordingly, FDA has reached the 
tentative conclusion that there must be products representing at least 
two different active moieties before FDA will consider that there are 
technically feasible alternatives to the therapeutic class. FDA is 
proposing that there be three distinct drug products. FDA wishes to 
ensure that there are substantial differences among the alternative 
products in order to give patients a wide variety of therapeutic 
options. Therefore, a drug product and a second generic drug product 
that refers to the first drug product to gain approval, under section 
505(j) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)), 
would not generally be considered to be two distinct drug products for 
purposes of evaluating the essential-use status of the drug.
    For most of the essential uses that would be evaluated under the 
``individual active moieties'' criteria, there is only one product 
being marketed under each essential use. Therefore, requiring the 
availability of more than one alternative would appear to be 
inadvisable.
    Because of their larger size and relative lack of convenience of 
use, FDA does not consider currently available nebulizers to be 
technically feasible alternatives to MDI's. Currently available 
delivery systems that FDA considers to be technically feasible 
alternatives to MDI's using CFC's are multiple-dose DPI's\4\  and MDI's 
that do not contain CFC's. Continuing changes in technology may give 
FDA reason to revisit this tentative determination.
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    \4\ Single-dose DPI's that are currently marketed in the United 
States would not be considered technically feasible alternatives to 
MDI's using CFC's. The agency has tentatively determined that these 
single-dose DPI's do not approximate the convenience of MDI's 
because patients must carry both the single-dose DPI device and a 
supply of the drug. The patient must also load the device prior to 
each use. The comparative inconvenience of single-dose DPI's does 
not warrant their being considered technically feasible 
alternatives. The agency also believes that these single-dose DPI's 
have not shown adequate levels of patient acceptance.
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    In evaluating whether adequate supplies and production capacity 
exist for the alternative product or products to meet the needs of the 
patient population indicated for drug products covered by an essential 
use, FDA's analyses will be flexible, but with one overarching 
principle: To ensure that there are no significant shortages of drug 
product that could harm the public health of the United States. Factors 
such as multiple production sites, to secure a steady supply if there 
is an interruption at one site, would be considered favorably in this 
regard.
    In evaluating postmarketing use data and evidence of patient 
acceptance under the third criterion, FDA anticipates that it may be 
useful for sponsors of alternative products to conduct large 
postmarketing studies, preferably in the U.S. clinical practice 
setting, directly comparing their product which does not contain CFC's 
to the CFC-containing product for which it would be considered an 
alternative. It may also be possible for several sponsors to jointly 
commission a large postmarketing clinical study of their common 
products. In addition to the formal studies described above, 
manufacturers of alternative products, or other persons requesting the 
elimination of an essential use, may wish to submit to FDA a review of 
postmarketing surveillance data from FDA's MEDWATCH program, the 
spontaneous reporting systems of other countries, and all other 
available postmarketing data after a potential alternative product has 
been marketed in the United States for a period of 1 year. FDA has 
tentatively concluded that foreign data would not be considered 
acceptable as the sole evidence of patient acceptance, but these data 
will be considered in addition to U.S. postmarketing use data in cases 
where U.S. formulations and foreign formulations have been shown to be 
the same or substantially similar. The term ``patient acceptance'' here

[[Page 10246]]

assumes that the alternative products have adequate safety, 
tolerability, effectiveness, and compliance. Because information 
regarding patient acceptance is not routinely captured by postmarketing 
surveillance, such assessments should be incorporated into the proposed 
formal clinical studies.
    In evaluating the last criterion, that there is no persuasive 
evidence to rebut a presumption that all significant patient 
subpopulations are served by the alternative product, FDA believes that 
there should be a strong presumption that, if the first three criteria 
are met, then all relevant subpopulations will be adequately served by 
alternative products. If FDA is not already in possession of evidence 
indicating the presence of a subpopulation served only by a product 
containing CFC's, then the burden of producing compelling scientific 
evidence that there is a subpopulation served only by a product 
containing CFC's would be placed on anyone opposing the determination 
that a use is no longer essential.

C. Implementation

    FDA currently intends to publish a notice of proposed rulemaking 
after the comment period for this ANPRM closes. That proposed rule 
would eliminate essential uses for steroid human drugs for nasal 
inhalation and for drugs that are no longer marketed. The proposed rule 
would also codify the criteria for elimination of essential uses 
discussed in section II.B. of this document. FDA intends to use the 
preamble of the proposed rule to respond to comments on this ANPRM.
    As the criteria for eliminating essential uses are met, FDA will 
propose elimination of essential uses for the appropriate therapeutic 
classes or individual active moieties. FDA intends that such proposals 
will be published and finalized in an expeditious manner.
    FDA is aware that the proposed policy contained in this ANPRM is, 
to a certain degree, predicated on the assumption that drug 
manufacturers are aggressively developing alternatives to products 
containing CFC's. If this assumption is less than fully met, FDA 
recognizes that it may have to take an even more active role in 
encouraging the development of technically feasible alternatives. 
Furthermore, FDA contemplates reexamining the effectiveness of the 
policy set out in this ANPRM 1 to 3 years after the publication of the 
first final rule implementing the policy set out in this ANPRM. If this 
reexamination reveals that alternatives to CFC's are not being 
aggressively developed, FDA will consider eliminating essential uses 
where manufacturers of drug products covered by those uses have not 
demonstrated due diligence in developing alternative products.

D. Analysis of Impacts

    FDA is required to examine the impacts of its proposed rules under 
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612). 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 
(including potential economic, environmental, public health and safety, 
and other advantages; distributive impacts; and equity). The Regulatory 
Flexibility Act requires agencies to analyze regulatory options if the 
proposed rule is expected to have a significant impact on a substantial 
number of small entities. FDA is soliciting information and data to 
help it examine the impacts that a proposed rule based on this advance 
notice would have. In order to help the agency prepare these analysis, 
FDA requests comments on the following impact questions:
    1. Are the incentives discussed in the ANPRM adequate to spur the 
needed market innovation? Are there alternative means of introducing 
appropriate market incentives?
    2. Assuming that an alternative product is approved for marketing, 
what is the estimated cost of obtaining postmarketing data supporting 
the new product as a technologically feasible alternative? How much 
time would be necessary? What other costs should the agency consider?
    3. How much would it cost to obtain the data including the 
postmarketing study discussed in the ANPRM? How much would it cost to 
obtain the data excluding such a postmarketing study? What are the 
components of this estimate (e.g., person-hours, contract dollars, 
etc.)?
    4. How much time should be allowed for phasing out a CFC-containing 
product no longer considered essential?
    5. Are there other alternative policies that the agency should 
consider that would achieve the stated goals and be less burdensome to 
patients that use these products and/or to the industry that provides 
the products?

III. Other Rulemaking Proceedings Regarding CFC's

    In the very near future, FDA intends to propose a rule regarding 
criteria to be applied in agency determinations to add new essential 
uses to Sec. 2.125(e). The agency is not soliciting comments on this 
separate rulemaking proceeding, and is only mentioning the matter here 
to provide a more complete picture of FDA's current plans regarding the 
regulation of CFC-containing drug products. FDA does not intend to 
respond to any comments regarding this issue at this time; those 
persons wishing to comment on this issue should wait until the proposed 
rule is published.
    Consistent with the phaseout provisions of the Clean Air Act, the 
proposed rule regarding the addition of new essential uses will provide 
new and substantially more stringent criteria for determining that a 
use is essential. Specific criteria will be proposed for both 
investigational drugs and commercially marketed drugs.
    FDA currently intends that this proposed rule will provide a 
restructuring of Sec. 2.125(e) to eliminate essential uses that cover 
an entire class of drugs, such as current Sec. 2.125(e)(3) ``metered-
dose adrenergic bronchodilator human drugs for oral inhalation.'' In 
their place, FDA will propose to list the use of every active moiety 
currently marketed under the current class essential use. This will 
mean that an individual wishing to market, for example, an adrenergic 
bronchodilator where the active moiety is not listed will need to 
petition FDA to amend Sec. 2.125(e) to add the use of the active 
moiety.
    The proposed rule would also eliminate out-of-date transitional 
provisions, and make other similar nonsubstantive housekeeping changes.
    The agency has determined to go directly to a proposed rule on 
these provisions of the agency's policy, rather than requesting comment 
on them in this or another ANPRM, in order to accelerate consideration 
of the new more stringent criteria for determining when new uses are 
essential. FDA believes that as the agency will soon be eliminating 
essential uses, it would be a waste of scarce agency resources, as well 
as inconsistent with the general policy favoring the phase out of 
ozone-depleting substances, to create new essential uses unless an 
extraordinary showing of public benefit can be made.
    Interested persons may, on or before May 5, 1997, submit to the 
Dockets Management Branch (address above) written comments regarding 
this ANPRM. 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.


[[Page 10247]]


    Dated: February 28, 1997.
William B. Schultz,
Deputy Commissioner for Policy
[FR Doc. 97-5495 Filed 3-5-97; 8:45 am]
BILLING CODE 4160-01-F