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

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.

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

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 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 AQ and

Vancenase AQ (beclomethasone dipropionate monohydrate),

Nasarel and Nasalide (flunisolide),

Flonase (fluticasone propionate), and Nasacort 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.

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

\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.''

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

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:

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

\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.

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

beclomethasone

dexamethasone

flunisolide

fluticasone

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'':

albuterol

bitolterol

isoetharine

isoproterenol

metaproterenol

pirbuterol

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:

Metered-dose ergotamine tartrate drug products administered by

oral inhalation for use in humans.

Intrarectal hydrocortisone acetate for human use.

Anesthetic drugs for topical use on accessible mucous

membranes of humans where a cannula is used for application.

Metered-dose nitroglycerin human drugs administered to the

oral cavity.

Metered-dose cromolyn sodium human drugs administered by oral

inhalation.

Metered-dose ipratropium bromide for oral inhalation.

Metered-dose atropine sulfate aerosol human drugs administered

by oral inhalation.\3\

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

\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.

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

Metered-dose nedocromil sodium human drugs administered by

oral inhalation.

Metered-dose ipratropium bromide and albuterol sulfate, in

combination, administered by oral inhalation for human use.

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.

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

\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.

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

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