32030 Federal Register / Vol. 72, No. 111 / Monday, June 11, 2007 / Proposed Rules 

FAA AD Differences 

Note: This AD differs from the MCAI and/ 

or service information as follows: No 

differences. 

Other FAA AD Provisions 

(g) The following provisions also apply to 

this AD: 

(1) Alternative Methods of Compliance 

(AMOCs): The Manager, New York Aircraft 

Certification Office (ACO), FAA, has the 

authority to approve AMOCs for this AD, if 

requested using the procedures found in 14 

CFR 39.19. Send information to ATTN: Ezra 

Sasson, Aerospace Engineer; New York ACO, 

FAA, 1600 Stewart Avenue, Suite 410, 

Westbury, New York 11590; telephone (516) 

228–7320; fax (516) 794–5531. Before using 

any approved AMOC on any airplane to 

which the AMOC applies, notify your 

appropriate principal inspector (PI) in the 

FAA Flight Standards District Office (FSDO), 

or lacking a PI, your local FSDO. 

(2) Airworthy Product: For any requirement 

in this AD to obtain corrective actions from 

a manufacturer or other source, use these 

actions if they are FAA-approved. Corrective 

actions are considered FAA-approved if they 

are approved by the State of Design Authority 

(or their delegated agent). You are required 

to assure the product is airworthy before it 

is returned to service. 

(3) Reporting Requirements: For any 

reporting requirement in this AD, under the 

provisions of the Paperwork Reduction Act, 

the Office of Management and Budget (OMB) 

has approved the information collection 

requirements and has assigned OMB Control 

Number 2120–0056. 

Related Information 

(h) Refer to MCAI Canadian Airworthiness 

Directive CF–2006–13, dated June 6, 2006; 

Bombardier Service Bulletin 8–27–89, 

Revision ‘‘E,’’ dated January 27, 2005; and 

Bombardier Service Bulletin 8–27–103, 

Revision ‘‘B,’’ dated January 24, 2007; for 

related information. 

Issued in Renton, Washington, on June 1, 

2007. 

Ali Bahrami, 

Manager, Transport Airplane Directorate, 

Aircraft Certification Service. 

[FR Doc. E7–11199 Filed 6–8–07; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 2 

[Docket No. 2006N–0454] 

RIN 0910–AF93 

Use of Ozone-Depleting Substances; 

Removal of Essential-Use 

Designations 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA), after 

consultation with the Environmental 

Protection Agency (EPA), is proposing 

to amend FDA’s regulation on the use of 

ozone-depleting substances (ODSs) in 

self-pressurized containers to remove 

the essential-use designations for oral 

pressurized metered-dose inhalers 

(MDIs) containing flunisolide, 

triamcinolone, metaproterenol, 

pirbuterol, albuterol and ipratropium in 

combination, cromolyn, and 

nedocromil. Under the Clean Air Act, 

FDA, in consultation with the EPA, is 

required to determine whether an FDAregulated product that releases an ODS 

is an essential use of the ODS. 

Therapeutic alternatives that do not use 

an ODS are currently marketed and 

appear to provide all of the important 

public health benefits of the listed 

drugs. If the applicable essential-use 

designations are removed, flunisolide, 

triamcinolone, metaproterenol, 

pirbuterol, albuterol and ipratropium in 

combination, cromolyn, and nedocromil 

MDIs containing an ODS could not be 

marketed after a suitable transition 

period. We will hold an open public 

meeting on removing these essential-use 

designations in the near future. 

DATES: Submit written or electronic 

comments by August 10, 2007. 

ADDRESSES: You may submit comments, 

identified by Docket No. 2006N–0454, 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Agency Web site: http:// 

www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting 

comments on the agency Web site. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier [For 

paper, disk, or CD–ROM submissions]: 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted directly to the 

agency by e-mail. FDA encourages you 

to continue to submit electronic 

comments by using the Federal 

eRulemaking Portal or the agency Web 

site, as described in the Electronic 

Submissions portion of this paragraph. 

Instructions: All submissions received 

must include the agency name and 

Docket No(s). and Regulatory 

Information Number (RIN) (if a RIN 

number has been assigned) for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm, including any personal 

information provided. For additional 

information on submitting comments, 

see the ‘‘Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents, comments, 

a transcript of, and material submitted 

for, the Pulmonary-Allergy Advisory 

Committee meeting held on June 10, 

2005, go to http://www.fda.gov/ohrms/ 

dockets/default.htm and insert the 

docket number(s), found in brackets in 

the heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Wayne H. Mitchell or Martha Nguyen, 

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 

A. CFCs 

B. Regulation of ODSs 

1. The 1978 Rules 

2. The Montreal Protocol 

3. The 1990 Amendments to the Clean 

Air Act 

4. EPA’s Implementing Regulations 

5. FDA’s 2002 Regulation 

II. Criteria 

III. Effective Date 

IV. 2005 PADAC Meeting 

V. Drugs We Are Proposing as 

Nonessential 

A. Flunisolide and Triamcinolone 

B. Metaproterenol and Pirbuterol 

C. Cromolyn and Nedocromil 

D. Albuterol and Ipratropium in 

Combination 

VI. Environmental Impact 

VII. Analysis of Impacts 

A. Introduction 

B. Need for Regulation and the 

Objective of this Rule 

C. Background 

1. CFCs and Stratospheric Ozone 

2. The Montreal Protocol 

3. Benefits of the Montreal Protocol 

4. Characteristics of COPD 

5. Characteristics of Asthma 


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1A metaproterenol MDI (Alupent MDI) was 

approved July 31, 1973, before the 1978 rule. 

2FDA has verified all Web site addresses cited in 

this document, but FDA is not responsible for any 

subsequent changes to the Web sites after this 

document has published in the Federal Register. 

3The summary descriptions of the Montreal 

Protocol and decisions of Parties to the Montreal 

Protocol contained in this document are presented 

here to help you understand the background of the 

action we are taking. These descriptions are not 

intended to be formal statements of policy regarding 

the Montreal Protocol. Decisions by the Parties to 

the Montreal Protocol are cited in this document in 

the conventional format of ‘‘Decision IV/2,’’ which 

refers to the second decision recorded in the Report 

of the Fourth Meeting of the Parties to the Montreal 

Protocol on Substances That Deplete the Ozone 

Layer. Reports of meetings of the Parties to the 

Montreal Protocol may be found on the United 

Nations Environment Programme’s Web site at 

http://ozone.unep.org/Meeting_Documents/mop/ 

index.asp. 

4Production of CFCs in economically lessdeveloped countries is being phased out and is 

scheduled to end by January 1, 2010. See Article 

2A of the Montreal Protocol. 

6. Current U.S. Market for CFC MDIs 

D. Benefits and Costs of the Proposed 

Rule 

1. Baseline Conditions 

2. Benefits of the Proposed Rule 

3. Costs of the Proposed Rule 

4. Effect on Medicaid and Medicare 

E. Alternative Phase-out Dates 

F. Sensitivity Analyses 

G. Conclusion 

VIII. Regulatory Flexibility Analysis 

IX. The Paperwork Reduction Act of 

1995 

X. Federalism 

XI. Request for Comments 

XII. References 

I. Background 

A. CFCs 

Chlorofluorocarbons (CFCs) are 

organic compounds that contain carbon, 

chlorine, and fluorine atoms. CFCs were 

first used commercially in the early 

1930s as a replacement for hazardous 

materials then used in refrigeration, 

such as sulfur dioxide and ammonia. 

Subsequently, CFCs were found to have 

a large number of uses, including as 

solvents and as propellants in selfpressurized aerosol products, such as 

MDIs. 

CFCs are very stable in the 

troposphere, the lowest part of the 

atmosphere. They move to the 

stratosphere, a region that begins about 

10 to 16 kilometers (km) (6 to 10 miles) 

above the Earth’s surface and extends 

up to about 50 km (31 miles) altitude. 

Within the stratosphere, there is a zone 

about 15 to 40 km (10 to 25 miles) above 

the Earth’s surface in which ozone is 

relatively highly concentrated. This 

zone in the stratosphere is generally 

called the ozone layer. Once in the 

stratosphere, CFCs are gradually broken 

down by strong ultraviolet light, 

releasing chlorine atoms that then 

deplete stratospheric ozone. Depletion 

of stratospheric ozone by CFCs and 

other ODSs allows more ultraviolet-B 

(UV-B) radiation to reach the Earth’s 

surface, where it increases skin cancers 

and cataracts, and damages some marine 

organisms, plants, and plastics. 

B. Regulation of ODSs 

The link between CFCs and the 

depletion of stratospheric ozone was 

discovered in the mid–1970s. Since 

1978, the U.S. Government has pursued 

a vigorous and consistent policy, 

through the enactment of laws and 

regulations, of limiting the production, 

use, and importation of ODSs, including 

CFCs. 

1. The 1978 Rules 

In the Federal Register of March 17, 

1978 (43 FR 11301 at 11318), FDA and 

EPA published rules banning, with a 

few exceptions, the use of CFCs as 

propellants in aerosol containers. These 

rules were issued under authority of the 

Federal Food, Drug, and Cosmetic Act 

(the act) (21 U.S.C. 321 et seq.) and the 

Toxic Substances Control Act (15 U.S.C. 

2601 et seq.), respectively. FDA’s rule 

(the 1978 rule) was codified as § 2.125 

(21 CFR 2.125). These rules issued by 

FDA and EPA had been preceded by 

rules issued by FDA and the Consumer 

Product Safety Commission requiring 

products that contain CFC propellants 

to bear environmental warning 

statements on their labeling (42 FR 

22018, April 29, 1977; 42 FR 42780, 

August 24, 1977). 

The 1978 rule prohibited the use of 

CFCs as propellants in self-pressurized 

containers in any food, drug, medical 

device, or cosmetic. As originally 

published, the rule listed five essential 

uses that were exempt from the ban. The 

second listed essential use was for 

‘‘[m]etered-dose steroid human drugs for 

oral inhalation,’’ and the third listed 

essential use was for ‘‘[m]etered-dose 

adrenergic bronchodilator human drugs 

for oral inhalation.’’ These provisions 

describe flunisolide, triamcinolone, and 

pirbuterol MDIs, so the list of essential 

uses did not have to be amended when 

these products were approved by FDA.1

The 1978 rule provided criteria for 

adding new essential uses, and several 

uses were added to the list, the last one 

in 1996. The 1978 rule did not provide 

any mechanism for removing essential 

uses from the list as alternative products 

were developed or CFC-containing 

products were removed from the 

market. The absence of a removal 

procedure came to be viewed as a 

deficiency in the 1978 rule, and was 

addressed in a later rulemaking, 

discussed in section II.C.5 of this 

document. 

2. The Montreal Protocol 

On January 1, 1989, the United States 

became a party to the Montreal Protocol 

on Substances that Deplete the Ozone 

Layer (Montreal Protocol) (September 

16, 1987, 26 I.L.M. 1541 (1987)), 

available at http://www.unep.org/ozone/ 

pdfs/Montreal-Protocol2000.pdf.2 The 

United States played a leading role in 

the negotiation of the Montreal Protocol, 

believing that internationally 

coordinated control of ozone-depleting 

substances would best protect both the 

U.S. and global public health and the 

environment from potential adverse 

effects of depletion of stratospheric 

ozone. Currently, there are 191 Parties 

to this treaty.3 When it joined the treaty, 

the United States committed to reducing 

its production and consumption of 

certain CFCs to 50 percent of 1986 

levels by 1998 (Article 2(4) of the 

Montreal Protocol). It also agreed to 

accept an ‘‘adjustment’’ procedure, by 

which, following assessment of the 

existing control measures, the Parties 

could adjust the scope, amount, and 

timing of those control measures for 

substances already subject to the 

Montreal Protocol. As the evidence 

regarding the impact of ODSs on the 

ozone layer became stronger, the Parties 

used this adjustment procedure to 

accelerate the phase-out of ODSs. At the 

fourth meeting of the Parties to the 

Montreal Protocol, held at Copenhagen 

in November 1992, the Parties adjusted 

Article 2 of the Montreal Protocol to 

eliminate the production and 

importation of CFCs by January 1, 1996, 

by Parties that are developed countries 

(Decision IV/2).4 The adjustment also 

indicated that it would apply, ‘‘save to 

the extent that the Parties decide to 

permit the level of production or 

consumption that is necessary to satisfy 

uses agreed by them to be essential’’ 

(Article 2A(4)). 

To produce or import CFCs for an 

essential use under the Montreal 

Protocol, a Party must request and 

obtain approval for an exemption at a 

meeting of the Parties. One of the most 

important essential uses of CFCs under 

the Montreal Protocol is their use in 

MDIs for the treatment of asthma and 

chronic obstructive pulmonary disease 

(COPD). The decision on whether the 

use of CFCs in MDIs is ‘‘essential’’ for 

purposes of the Montreal Protocol turns 

on whether: ‘‘(1) It is necessary for the 


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5Our obligation under XV/5 was met by our final 

rule eliminating the essential-use status of 

albuterol, effective December 31, 2008 (70 FR 

17168, April 4, 2005). 

6The Ozone Secretariat is the Secretariat for the 

Montreal Protocol and the Vienna Convention for 

the Protection of the Ozone Layer (the Vienna 

Convention) (March 22, 1985, 26 I.L.M. 1529 

(1985)), available at http://hq.unep.org/ozone/pdfs/ 

viennaconvention2002.pdf. 

Based at the United Nations Environment 

Programme (UNEP) offices in Nairobi, Kenya, the 

Secretariat functions in accordance with Article 7 

of the Vienna Convention and Article 12 of the 

Montreal Protocol. The main duties of the 

Secretariat include: Arranging for and servicing the 

Conference of the Parties, meetings of the Parties, 

their committees, the bureaus, working groups, and 

assessment panels; Arranging for the 

implementation of decisions resulting from these 

meetings; Monitoring the implementation of the 

Vienna Convention and the Montreal Protocol; 

Reporting to the meetings of the Parties and to the 

Implementation Committee; Representing the 

Convention and the Protocol; and Receiving and 

analyzing data and information from the Parties on 

the production and consumption of ODSs. 

7 In conformance with the adjustment contained 

in Decision IV/2, EPA issued regulations 

accelerating the complete phase-out of CFCs, with 

exceptions for essential uses, to January 1, 1996 (58 

FR 65018, December 10, 1993). 

health, safety, or is critical for the 

functioning of society (encompassing 

cultural and intellectual aspects) and (2) 

there are no available technically and 

economically feasible alternatives or 

substitutes that are acceptable from the 

standpoint of environment and health; 

* * * (Decision IV/25).’’ 

Since 1994 the United States and 

some other Parties to the Montreal 

Protocol have annually requested, and 

been granted, essential-use exemptions 

for the production or importation of 

CFCs for their use in MDIs for the 

treatment of asthma and COPD (see, 

among others, Decisions VI/9 and VII/ 

28). The exemptions have been 

consistent with the criteria established 

by the Parties, which make the grant of 

an exemption contingent on a finding 

that the use for which the exemption is 

being requested is essential for health, 

safety, or the functioning of society, and 

that there are no available technically 

and economically feasible alternatives 

or substitutes that are acceptable from 

the standpoint of health or the 

environment (Decision IV/25). 

Several decisions of the Parties have 

dealt with the transition to CFC-free 

MDIs, including the following 

decisions: 

• Decision VIII/10 stated that the 

Parties that are developed countries 

would take various actions to promote 

industry’s participation in a smooth and 

efficient transition away from CFCbased MDIs (San Jose, Costa Rica, 1996). 

• Decision IX/19 required the Parties 

that are developed countries to present 

an initial national or regional transition 

strategy by January 31, 1999 (Montreal, 

Canada, 1997). 

• Decision XII/2 elaborated on the 

content of national or regional transition 

strategies required under Decision IX/19 

and indicated that any MDI for the 

treatment of asthma or COPD approved 

for marketing after 2000 would not be 

an ‘‘essential use,’’ unless it met the 

criteria laid out by the Parties for 

essential uses (Ouagadougou, Burkina 

Faso, 2000). 

• Decision XIV/5 requested that each 

Party report annually the quantities of 

CFC and non-CFC MDIs and dry-powder 

inhalers (DPIs) sold or distributed 

within its borders and the approval and 

marketing status of non-CFC MDIs and 

DPIs. Decision XIV/5 also noted ‘‘with 

concern the slow transition to CFC-free 

metered-dose inhalers in some Parties’’ 

(Rome, Italy, 2002). 

• Decision XV/5 states that, at the 

17th meeting of the Parties (in December 

2005) or thereafter, no essential uses of 

CFCs will be authorized for Parties that 

are developed countries, unless the 

Party requesting the essential-use 

allocation has submitted an action plan 

for MDIs for which the sole active 

ingredient is albuterol. Among other 

items, the action plan should include a 

specific date by which the Party plans 

to cease requesting essential-use 

allocations of CFCs for albuterol MDIs to 

be sold or distributed in developed 

countries5 (Nairobi, Kenya, 2003). 

• Decision XVII/5 states that Parties 

that are developed countries should 

provide a date to the Ozone Secretariat6

before the 18th meeting of the Parties 

(October 30 to November 3, 2006) by 

which time a regulation or regulations 

will have been proposed to determine 

whether MDIs, other than those that 

have albuterol as the only active 

ingredient, are non-essential (Dakar, 

Senegal, 2005). 

3. The 1990 Amendments to the Clean 

Air Act 

In 1990, Congress amended the Clean 

Air Act to, among other things, better 

protect stratospheric ozone (Public Law 

No. 101–549, November 15, 1990) (the 

1990 amendments). The 1990 

amendments were drafted to 

complement, and be consistent with, 

our obligations under the Montreal 

Protocol (see section 614 of the Clean 

Air Act (42 U.S.C. 7671m)). Section 

614(b) of the Clean Air Act provides 

that, in the case of a conflict between 

any provision of the Clean Air Act and 

any provision of the Montreal Protocol, 

the more stringent provision will 

govern. Section 604 of the Clean Air Act 

required the phase-out of the production 

of CFCs by 2000 (42 U.S.C. 7671c),7

while section 610 of the Clean Air Act 

(42 U.S.C. 7671i) required EPA to issue 

regulations banning the sale or 

distribution in interstate commerce of 

nonessential products containing CFCs. 

Sections 604 and 610 provide 

exceptions for ‘‘medical devices.’’ 

Section 601(8) (42 U.S.C. 7671(8)) of the 

Clean Air Act defines ‘‘medical device’’ 

as 

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), or 

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 [of 

Food and Drugs]; 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 [of Food and Drugs] in 

consultation with the Administrator [of EPA]. 

4. EPA’s Implementing Regulations 

EPA regulations implementing the 

Montreal Protocol and the stratospheric 

ozone protection provisions of the 1990 

amendments are codified in part 82 of 

title 40 of the Code of Federal 

Regulations (40 CFR part 82). (See 40 

CFR 82.1 for a statement of intent.) Like 

the 1990 amendments, EPA’s 

implementing regulations contain two 

separate prohibitions, one on the 

production and import of CFCs (subpart 

A of 40 CFR part 82) and the other on 

the sale or distribution of products 

containing CFCs (40 CFR 82.66). 

The prohibition on production and 

import of CFCs contains an exception 

for essential uses and, more specifically, 

for essential MDIs. The definition of 

essential MDI at 40 CFR 82.3 requires 

that the MDI be intended for the 

treatment of asthma or COPD, be 

essential under the Montreal Protocol, 

and if the MDI is for sale in the United 

States, be approved by FDA and listed 

as essential in FDA’s regulations at 21 

CFR 2.125. 

The prohibition on the sale of 

products containing CFCs includes a 

specific prohibition on aerosol products 

and other pressurized dispensers. The 

aerosol product ban contains an 

exception for medical devices listed in 

§ 2.125(e). The term ‘‘medical device’’ is 

used with the same meaning it was 

given in the 1990 amendments and 

includes drugs as well as medical 

devices. 

5. FDA’s 2002 Regulation 

In the 1990s, we decided that § 2.125 

required revision to better reflect our 

obligations under the Montreal Protocol, 

the 1990 amendments, and EPA’s 


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8Section 314.108(a) of the act (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. When describing the various 

essential uses, we will generally refer to the active 

moiety, for example, cromolyn, as opposed to the 

active ingredient, which, using the same example, 

would be cromolyn sodium. When discussing 

particular indications and other material from the 

approved labeling of a drug product, we will 

generally use the brand name of the product, which, 

using the same example, would be INTAL MDI. In 

describing material from treatises, journals, and 

other non-FDA approved publications, we will 

generally follow the usage in the original 

publication. 

regulations, and to encourage the 

development of ozone-friendly 

alternatives to medical products 

containing CFCs. In particular, as 

acceptable alternatives that did not 

contain CFCs or other ODSs came on the 

market, there was a need to provide a 

mechanism for removing essential uses 

from the list in § 2.125(e). In the Federal 

Register of March 6, 1997 (62 FR 

10242), we published an advance notice 

of proposed rulemaking (the 1997 

ANPRM) in which we outlined our 

then-current thinking on the content of 

an appropriate rule regarding ODSs in 

products FDA regulates. We received 

almost 10,000 comments on the 1997 

ANPRM. In response to the comments, 

we revised our approach and drafted a 

proposed rule published in the Federal 

Register of September 1, 1999 (64 FR 

47719) (the 1999 proposed rule). We 

received 22 comments on the 1999 

proposed rule. After minor revisions in 

response to these comments, we 

published a final rule in the Federal 

Register of July 24, 2002 (67 FR 48370) 

(the 2002 final rule) (corrected in 67 FR 

49396, July 30, 2002, and 67 FR 58678, 

September 17, 2002). The 2002 final 

rule listed as a separate essential use 

each active moiety8 marketed under the 

1978 rule as essential uses for metereddose steroid human drugs for oral 

inhalation and metered-dose adrenergic 

bronchodilator human drugs for oral 

inhalation; eliminated the essential-use 

designations in § 2.125(e) for metereddose steroid human drugs for nasal 

inhalation and for products that were no 

longer marketed; set new standards to 

determine when a new essential-use 

designation should be added to § 2.125; 

and set standards to determine whether 

the use of an ODS in a medical product 

remains essential. 

This rulemaking fulfills our obligation 

under § 2.125, as well as the Clean Air 

Act, the Montreal Protocol, and our 

general duty to protect the public 

health, by removing ODS products from 

the marketplace when those products 

are no longer essential. 

II. Criteria 

Among other changes, the 2002 final 

rule, in revised § 2.125(g)(2), establishes 

a standard for removing an essential-use 

designation for any drug after January 1, 

2005, that would apply to a drug where 

there are no acceptable non-ODS 

alternatives with the same active 

moiety. This standard provides an 

incentive for manufacturers to 

reformulate their products in a timely 

manner. There are no acceptable nonODS alternatives available that have the 

same active moieties as the products 

marketed under the essential uses that 

are the subject of this proposed rule; 

therefore, we are proceeding with this 

rulemaking under the provisions of 

§ 2.125(g)(2). The process for removing 

the essential use designation under 

§ 2.125(g)(2) includes a consultation 

with a relevant advisory committee and 

an open public meeting, in addition to 

a proposed rule and a final rule. The 

criterion established for removing the 

essential use in such circumstances is 

that it no longer meets the criteria 

specified in revised § 2.125(f) for adding 

a new essential use (§ 2.125(g)(2)). The 

criteria in § 2.125(f) for adding an 

essential use are: 

(i) Substantial technical barriers exist to 

formulating the product without ODSs; 

(ii) The product will provide an 

unavailable important public health benefit; 

and 

(iii) Use of the product does not release 

cumulatively significant amounts of ODSs 

into the atmosphere or the release is 

warranted in view of the unavailable 

important public health benefit. 

Because the three criteria in § 2.125(f) 

are linked by the word ‘‘and,’’ failure to 

meet any single criterion results in a 

determination that the use is not 

essential. 

We discussed these criteria in the 

preamble to the 1999 proposed rule. A 

key point in our discussion of technical 

barriers was: ‘‘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.’’ (1999 proposed rule at 

47721.) 

In applying the ‘‘technical barriers’’ 

criteria, we look at the results of 

reformulation efforts for similar 

products as well as statements made 

about the manufacturer’s particular 

efforts to reformulate their product. 

Similarly, in discussing what is ‘‘an 

unavailable important public health 

benefit,’’ we said: ‘‘The agency intends 

to give the phrase ‘unavailable 

important public health benefit’ a 

markedly different construction from 

the [phrase used in the 1978 rule] 

‘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.’’ (1999 proposed 

rule at 47722.) 

One key point to note here is that we 

raised the hurdle for the public health 

benefit that needs to be shown. A use 

that was shown to have a ‘‘substantial 

health benefit’’ under the 1978 rule (all 

essential uses were established under 

the 1978 rule), will not necessarily be 

able to clear the higher hurdle of the 

2002 final rule’s ‘‘unavailable important 

public health benefit.’’ 

In determining if a drug product 

provides an otherwise unavailable 

important public health benefit, our 

primary focus is on the availability of 

non-ODS products that provide 

equivalent therapeutic benefits for 

patients who are currently using the 

CFC MDIs. If therapeutic alternatives 

exist for all patients using the CFC MDI, 

we would then determine that the CFC 

MDI does not provide an otherwise 

unavailable important public health 

benefit. 

Under the third criterion, the essential 

use must be eliminated unless we find 

that use of the product does not release 

cumulatively significant amounts of 

ODSs into the atmosphere, or that the 

release, although cumulatively 

significant, is warranted in view of the 

otherwise unavailable important public 

health benefit that the use of the drug 

product provides. In evaluating whether 

continuing the essential-use designation 

of these MDIs would result in the 

products releasing significant quantities 

of ODSs, in light of past policy 

statements (2002 final rule p. 48380) 

and the current state of the phase-out of 

ODSs, we tentatively conclude that the 

release of CFCs from MDIs containing 

flunisolide, triamcinolone, 

metaproterenol, pirbuterol, albuterol 

and ipratropium in combination, 

cromolyn, and nedocromil would be 

significant. The reasons for this 

tentative conclusion are discussed in 

the following paragraphs. 

The United States evaluated the 

environmental effect of eliminating the 

use of all CFCs in an environmental 

impact statement in the 1970s (see 43 

FR 11301). As part of that evaluation, 

FDA concluded that the continued use 


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9The text of § 2.125(g)(3) and (4) is as follows: 

(3) For individual active moieties marketed as 

ODS products and represented by one new drug 

application (NDA): 

(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 nonODS product(s) exist or will exist at levels sufficient 

to meet patient need; 

(iii) Adequate 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 

NDAs: 

(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. 

There are noteworthy procedural differences 

between § 2.125(g)(2) and § 2.125(g)(3) and (4). A 

rulemaking under § 2.125(g) (3) or (4) could have 

been started before January 1, 2005, and there is no 

requirement for either an advisory committee 

meeting or public meeting. The proposed rule for 

the removal of the essential-use designation for 

albuterol was published in the Federal Register of 

June 16, 2004 (69 FR 33602) and although the 

matter was discussed at a public meeting of the 

Pulmonary-Allergy Drug Advisory Committee on 

June 10, 2004, no separate public meeting on the 

matter was held. 

10These albuterol inhalers use the non-ozonedepleting hydrofluoroalkane HFA-134a (usually 

referred to as HFA) as a propellant. 

11Current information indicates that production 

of albuterol HFA MDIs will be adequate to meet the 

current demand for albuterol MDIs much earlier 

than December 31, 2008. 

of CFCs in medical products posed an 

unreasonable risk of long-term 

biological and climatic impacts (see 

Docket No. 1996N–0057 (formerly 96N– 

0057)). Congress later enacted 

provisions of the Clean Air Act that 

codified the decision to fully phase out 

the use of CFCs over time (see 42 U.S.C. 

7671 et seq. (enacted November 15, 

1990)). We note that the environmental 

impact of individual uses of 

nonessential CFCs must not be 

evaluated independently, but rather 

must be evaluated in the context of the 

overall use of CFCs. 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)). 

Currently, MDIs for the treatment of 

asthma and COPD are the only legal use 

of newly produced or imported CFCs 

(see EPA 2006 Allocation rule). 

Although it may appear to some that the 

CFCs released from MDIs represent 

insignificant quantities of ODSs, and 

therefore should be exempted, the 

elimination of CFC use in MDIs is one 

of the final steps in the overall phaseout of CFC use. The release of ODSs 

from some of the MDIs may be relatively 

small compared to total quantities that 

were released 2 or 3 decades ago, but if 

each use that resulted in the release of 

relatively small quantities of ODSs were 

provided an exemption, the cumulative 

effect would be to prevent the 

elimination of ODS releasing products. 

This would prevent the full phase-out 

envisioned by the Clean Air Act and the 

Montreal Protocol. Therefore, we 

tentatively conclude that the release of 

ODSs from these MDIs is cumulatively 

significant. 

Given this proposed finding, the 

essential use for each product must be 

eliminated under § 2.25(f)(1)(iii) unless 

we also find that the product provides 

an otherwise unavailable important 

health benefit which warrants the 

cumulatively significant release of the 

ODS. 

As noted previously, because the 

three criteria in § 2.25(f)(1) are linked by 

the word ‘‘and,’’ failure to meet any 

single criterion results in a 

determination that the use is not 

essential. Accordingly, if we find that 

any product fails to provide an 

otherwise unavailable important health 

benefit (criterion two), we would be 

required to find that the use of the 

product is not essential, and we would 

not need to reach the last step under the 

third criteria (balancing the important 

health benefit against the release of the 

ODS to determine if the release is 

warranted). Assuming, however that the 

first and second criteria in § 2.125(f) are 

met, because of our tentative conclusion 

that the release of ODSs from these 

MDIs is cumulatively significant, we 

would then need to conduct the 

balancing inquiry under the third 

criterion for that product. 

The criteria in § 2.125(f)(1) we are 

using in this rulemaking, as crossreferenced in § 2.125(g)(2), are different 

from those in § 2.125(g)(3) and (g)(4). 

Section 2.125(g)(2) specifically 

addresses the situation where there is 

no other marketed product containing 

the same active moiety in a non-ODS 

formulation, while § 2.125(g)(3) and (4)9

apply to situations where there is at 

least one other product marketed with 

the same active moiety in a non-ODS 

formulation. When we removed the 

essential-use designation for albuterol 

(70 FR 17168, April 4, 2005) we used 

the criteria found in § 2.125(g)(4) 

because there were more than one 

albuterol CFC MDI being marketed and 

there were two acceptable alternatives 

containing albuterol (Proventil HFA and 

Ventolin HFA) to the albuterol CFC 

MDIs. This contrasts to § 2.125(g)(2), 

which permits FDA to remove an 

essential use even if there are no 

alternatives available with the same 

active moiety, provided that sufficient 

alternative products with different 

active moieties exist to meet the needs 

of patients, because the essential use 

would then no longer provide an 

otherwise unavailable important health 

benefit. Therefore, the analyses we use 

here are not identical to the analyses we 

used under § 2.125(g)(4) in the albuterol 

rulemaking. In both the albuterol 

rulemaking and this rulemaking, the 

primary focus is on determining 

whether acceptable alternatives exist for 

the products that are marketed under 

the essential use, but with this 

rulemaking we are able to consider 

alternatives with different active 

moieties. Therefore, our analyses are 

similar, and we have found it useful to 

borrow concepts from the more specific 

provisions of § 2.125(g)(3) and (g)(4) to 

help give more structure to our analysis 

under the broader language of 

§ 2.125(f)(1). In general, as explained in 

the preamble to the 1999 proposed rule, 

‘‘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.’’ 

(1999 proposed rule at 47736.) Thus, we 

request comment on whether the 

available alternatives for each of the 

seven moieties are acceptable from a 

public health perspective. 

III. Effective Date 

We are proposing that any rule 

finalizing the removal of an essential 

use proposed in this document have an 

effective date of December 31, 2009. In 

determining the appropriate effective 

date or dates for this rulemaking, we 

will consider not only whether 

therapeutic alternatives are on the 

market but also whether adequate 

production capacity and supplies are 

available to meet the new, presumably 

increased, demand for the therapeutic 

alternatives once products marketed 

under the old essential use are no longer 

sold. Depending on the data presented 

to us in the course of the rulemaking, 

we may determine that it is appropriate 

to have different effective dates for 

different uses. 

In determining an appropriate 

effective date, we have kept in mind 

that albuterol HFA10 MDIs are primary 

therapeutic alternatives to drugs 

produced under three of the essential 

uses described in this rule. Sales of the 

products marketed under those essential 

uses have totaled approximately 14 


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12Nine different products, including two sizes of 

COMBIVENT and two flavors (plain and menthol) 

of AEROBID, are produced under the seven 

essential uses that are the subject of this rule. 

13A transcript of the meeting and other meeting 

material is available on the Web at http:// 

www.fda.gov/ohrms/dockets/ac/ 

cder05.html#PulmonaryAllergy. 

million MDIs a year. We are confident 

there will be adequate supplies of 

albuterol HFA MDIs to meet the needs 

of all current users of albuterol CFC 

MDIs by December 31, 2008 (the date on 

which albuterol MDIs will no longer be 

designated an essential use).11 Although 

we have limited data on production 

increases above current demand for 

2009 and later, we believe that, by 

December 31, 2009, albuterol HFA 

production will be able to meet any 

increased demand caused by this 

rulemaking. We specifically invite 

comments from manufacturers of 

albuterol HFA MDIs on this issue. 

We also believe that a December 31, 

2009 effective date is more than 

sufficient to allow patients to consult 

their health care providers and obtain 

prescriptions for therapeutic 

alternatives in an orderly fashion. 

In proposing a December 31, 2009, 

effective date, we expect that 2009 

would be a transition year characterized 

by declining production of the CFC 

MDIs that are the subject of this rule. If 

a December 31, 2009 effective date is 

established by this rulemaking, we 

anticipate that other administrative 

actions taken by EPA and FDA would 

reflect the concept of 2009 being a 

transition year. 

The sale of remaining stocks of CFC 

MDIs by manufacturers, wholesalers, 

and retailers was a consideration in 

setting the effective date of the albuterol 

rule (70 FR 17168 and 17179). We 

believe that this consideration also is 

appropriate for this rulemaking. In 

evaluating the period of time that is 

needed to sell remaining stocks of the 

CFC MDIs that are the subject of this 

rulemaking, a factor that must be 

considered is the expiration dating for 

the relevant products. One product has 

an expiration date set at 18 months after 

manufacture, five products have dates 

set at 24 months, and three products’ 

expiration dates are 30 months or more 

after production.12 Prescription drug 

products, particularly those for chronic 

diseases such as asthma and COPD, are 

generally dispensed well before the 

expiration date, allowing the patients a 

significant amount of time to use the 

drugs before they reach their expiration 

dates. Therefore, we believe that all of 

the products with 18-month and 24- 

month expiration dates manufactured 

prior to publication of a final rule based 

on this proposal will have passed their 

expiration dates and been dispensed or 

destroyed by December 31, 2009. We 

invite comments on the relationship 

between expiration dates and the 

distribution and dispensing of the 

products that are the subject of the 

rulemaking. 

IV. 2005 PADAC Meeting 

As required by § 2.125(g)(2), we 

consulted an advisory committee before 

drafting this proposed rule. We 

consulted with FDA’s Pulmonary and 

Allergy Drugs Advisory Committee 

(PADAC) at their July 14, 2005, meeting 

(2005 meeting) on the essential-use 

status of MDIs containing flunisolide, 

triamcinolone, metaproterenol, 

pirbuterol, albuterol and ipratropium in 

combination, cromolyn, and 

nedocromil. The opinions expressed by 

the PADAC members about each of 

these essential uses will be discussed 

below.13

This PADAC meeting should not be 

confused with the open public meeting 

that we will be holding in the near 

future on the essential-use status of 

these MDIs. We will publish a notice for 

the public meeting in the Federal 

Register shortly. 

V. Drugs We Are Proposing as 

Nonessential 

A. Flunisolide and Triamcinolone 

We are proposing to remove the 

essential-use designations for MDIs 

containing flunisolide (AEROBID) and 

triamcinolone (AZMACORT). AEROBID 

and AZMACORT are orally inhaled 

corticosteroids. AZMACORT is the only 

currently marketed drug product that 

provides orally inhaled triamcinolone. 

AEROBID and AZMACORT are the only 

two orally inhaled corticosteroids 

marketed that contain ODSs. Both drugs 

are indicated for the maintenance 

treatment and prophylaxis of asthma in 

patients as young as 6 and both are 

prescription drugs. Flunisolide and 

triamcinolone, as well as other 

corticosteroids, are not indicated for 

relief of acute bronchospasm. 

Inflammation is an important 

component in the development of 

asthma. The anti-inflammatory actions 

of corticosteroids contribute to their 

efficacy in asthma. Though effective for 

the treatment of asthma, corticosteroids 

do not appreciably affect asthma 

symptoms immediately. Individual 

patients experience a variable time to 

onset and degree of symptom relief. 

Maximum benefit may not be achieved 

for 1 to 2 weeks or longer after starting 

treatment. AEROBID was approved on 

April 23, 1982, and AZMACORT was 

approved on August 17, 1984. Their use 

was considered essential under the 1978 

rule, which stated that ‘‘[m]etered-dose 

steroid human drugs for oral inhalation’’ 

were essential. Flunisolide and 

triamcinolone were designated as 

essential as different active moieties in 

the 2002 rule. In addition to the ODScontaining AEROBID, AEROSPAN, a 

flunisolide HFA MDI, was approved 

January 27, 2006, but has not yet been 

introduced onto the market. 

We have tentatively concluded that 

the following orally inhaled 

corticosteroid drug products, which do 

not contain ODSs, collectively provide 

adequate therapeutic alternatives to 

AEROBID and AZMACORT: 

• Beclomethasone dipropionate MDI 

(QVAR), 

• Budesonide DPI (PULMICORT 

TURBUHALER), 

• Fluticasone propionate MDI 

(FLOVENT HFA), and 

• Mometasone furoate DPI 

(ASMANEX TWISTHALER). 

All of these drugs are indicated for the 

maintenance treatment and prophylaxis 

of asthma. All of the therapeutic 

alternatives have adequate safety 

profiles similar to those of AEROBID 

and AZMACORT. Our tentative 

conclusion that these four drugs 

collectively provide adequate 

therapeutic alternatives does not mean 

that each can be freely substituted for 

AEROBID and AZMACORT, or freely 

substituted one for another. Rather, we 

believe that at least one of those drugs 

should be an adequate therapeutic 

alternative for every patient currently 

using AEROBID or AZMACORT. There 

are significant differences among these 

drugs, for example FLOVENT HFA and 

ASMANEX TWISTHALER are both 

indicated for patients 12 and older, 

compared to AEROBID and 

AZMACORT, which are indicated for 

patients 6 and older. However, QVAR 

and PULMICORT TURBUHALER are 

indicated for patients as young as 5 and 

6, respectively. With these two drugs, 

younger pediatric patients who used 

AEROBID and AZMACORT should be 

more than adequately served. There are 

other notable differences: ASMANEX 

TWISTHALER contains lactose; there is 

clinical data on the use of inhaled 

budesonide by pregnant women in 

labeling for PULMICORT 

TURBUHALER; QVAR and FLOVENT 

HFA are MDIs; ASMANEX 

TWISTHALER and PULMICORT 

TURBUHALER are different types of 

DPIs. All of these elements, and more, 

may factor into a decision on which 

drug product to substitute for AEROBID 


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14References to outside publications or any other 

statements of fact or opinion in this document 

concerning a drug product are not intended to be 

equivalent to statements in labeling approved under 

section 505 of the act (21 U.S.C. 355) and part 314 

of our regulations (21 CFR part 314). 

15Metaproterenol, because it is less selective than 

pirputerol, albuterol, levalbuterol, and some other 

beta2-agonists, may present greater potential for 

excessive cardiac stimulation (Ref. 2, p. 64; Ref. 1, 

Appendix A–2). 

and AZMACORT for any individual 

patient. 

A therapeutic alternative to AEROBID 

and AZMACORT, primarily for patients 

who are using both salmeterol and 

either AEROBID or AZMACORT, is the 

ADVAIR DPI which contains fluticasone 

propionate and another asthma drug 

salmeterol, in combination, which is 

available in various strengths. . 

FDA has recently approved 

SYMBICORT, an HFA MDI combining 

budesonide and formoterol, a longacting beta-agonist. This drug product is 

expected to enter the U.S. market in 

mid-2007 and would be a logical first 

option for patients using both 

formoterol (FORADIL) and either 

AEROBID or AZMACORT. However, the 

lack of postmarketing data and the 

unavailability of information on future 

production capacity and supplies for 

SYMBICORT means that we cannot 

consider at this time the expected 

availability of SYMBICORT as grounds 

for eliminating the essential use of 

flunisolide under § 2.125(g)(2). The 

expected availability of SYMBICORT 

was not considered a material issue in 

our tentative determination that 

flunisolide MDIs are not an essential use 

of ODSs: there are more than a sufficient 

number of therapeutic alternatives to 

AEROBID and AZMACORT without 

considering SYMBICORT. 

We realize that inhaled 

corticosteroids are widely considered 

the drugs of choice, used in conjunction 

with other drugs, for treatment of severe 

persistent, moderate persistent, and 

mild persistent asthma in adults and 

children (Ref. 1, app. A–1).14 However 

certain health care providers and 

patients, particularly in cases of mild 

persistent asthma, may decide to switch 

from AEROBID and AZMACORT to 

drugs other than inhaled corticosteroids. 

If these other drugs do not release ODSs, 

such as leukotriene modifiers and 

theophylline, then they also provide 

alternative therapies. 

The recently approved AEROSPAN 

(flunisolide HFA MDI) may also be a 

therapeutic alternative to AEROBID and 

AZMACORT. However, as previously 

noted with SYMBICORT, the lack of 

postmarketing data and the 

unavailability of information on future 

production capacity and supplies for 

AEROSPAN mean that we cannot 

consider at this time the availability of 

AEROSPAN as grounds for eliminating 

the essential use of flunisolide under 

§ 2.125(g)(3). The availability of 

AEROSPAN was not considered a 

material issue in our tentative 

determination that flunisolide MDIs are 

not an essential use of ODSs: there are 

more than a sufficient number of 

therapeutic alternatives to AEROBID 

and AZMACORT without considering 

AEROSPAN. However, we do solicit 

comments on postmarketing data for 

AEROSPAN and its suitability as an 

alternative to AEROBID and 

AZMACORT. 

PADAC members expressed the 

opinion, without dissent, that 

flunisolide and triamcinolone were no 

longer essential uses of ODSs. 

We have tentatively come to the 

following conclusion: 

• The pharmaceutical industry has 

had success in formulating other orally 

inhaled corticosteroids without ODSs. 

In particular, the AEROSPAN 

flunisolide HFA MDI was approved by 

FDA. We have no evidence to suggest 

that the ODS containing triamcionolone 

or flunisolide oral inhalation drug 

products pose unique technical 

challenges to formulation without 

ODSs. Therefore, we tentatively 

conclude that no substantial technical 

barriers exist to formulating 

triamcinolone or flunisolide oral 

inhalation drug products without ODSs. 

• Flunisolide and triamcinolone 

MDIs do not provide an otherwise 

unavailable important public health 

benefit because of the available 

therapeutic alternatives. 

• The release of ODSs into the 

atmosphere from flunisolide and 

triamcinolone MDIs is cumulatively 

significant and is not warranted because 

they do not provide an otherwise 

unavailable important public health 

benefit. 

We, therefore, tentatively conclude 

that oral pressurized MDIs containing 

flunisolide and triamcinolone are no 

longer essential uses of ODSs and 

should be removed from the list of 

essential uses in § 2.125(e). 

B. Metaproterenol and Pirbuterol 

We are proposing to remove the 

essential-use designations for MDIs 

containing metaproterenol (ALUPENT 

MDI) and pirbuterol (MAXAIR). 

Metaproterenol and pirbuterol are shortacting beta2-adrenergic agonists used in 

the treatment of bronchospasm 

associated with asthma and COPD. They 

act as bronchodilators. Pirbuterol is only 

available in a CFC MDI, while 

metaproterenol is also available as a 

syrup, as tablets, and as an inhalation 

solution for use in nebulizers. This 

rulemaking will not affect any dosage 

form of metaproterenol other than the 

ALUPENT MDI which contains CFCs. 

ALUPENT MDI and MAXAIR are the 

only beta2-adrenergic agonist MDIs 

currently marketed containing CFCs 

(other than albuterol, whose essential 

use status will end December 31, 2008). 

ALUPENT MDI and MAXAIR are 

prescription drugs. Their use was 

considered essential under the 1978 

rule, which stated that ‘‘[m]etered-dose 

adrenergic bronchodilator human drugs 

for oral inhalation’’ were essential. 

Metaproterenol and pirbuterol were 

designated as essential as different 

active moieties in the 2002 rule. 

ALUPENT MDI was approved on July 

31, 1973, and MAXAIR was approved 

on November 30, 1992. 

We have tentatively concluded that 

the following beta2-adrenergic agonist 

MDIs, which use HFA-134a (1,1,1,2, 

tetrafluoroethane) as a propellant 

instead of ODSs, collectively provide 

adequate therapeutic alternatives to 

ALUPENT MDI and MAXAIR: 

• Albuterol sulfate MDI (PROAIR 

HFA), 

• Albuterol sulfate MDI (PROVENTIL 

HFA), 

• Albuterol sulfate MDI (VENTOLIN 

HFA), 

• Levalbuterol tartrate MDI 

(XOPONEX HFA). 

ALUPENT MDI, MAXAIR, and the 

therapeutic alternatives are all very 

similar drugs. They are all indicated for 

the relief of bronchospasms associated 

with asthma and COPD (although the 

labeled indications may be worded 

differently), have very similar safety 

profiles,15 and have similar dosing 

regimens. When we say that these 4 

drugs collectively provide adequate 

therapeutic alternatives, we are not 

saying that each can be freely 

substituted for ALUPENT MDI and 

MAXAIR, or freely substituted one for 

another. Rather, we are saying that one 

of those drugs should be an adequate 

therapeutic alternative for every patient 

currently using ALUPENT MDI or 

MAXAIR. ALUPENT MDI and MAXAIR 

are indicated for children as young as 

12, while the therapeutic alternatives 

are indicated for children as young as 4. 

The albuterol sulfate products are 

indicated for prevention of exerciseinduced asthma, while ALUPENT MDI, 

MAXAIR, and Xopenex are not. 

MAXAIR includes one product form 

that incorporates an ‘‘autohaler’’ device. 

This mechanism senses patient effort 

and delivers the dose in relationship to 

inhalation by the patient. While this 


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mechanism is believed to lessen issues 

with coordinating inhalation to 

actuation, there are no data to 

adequately document that this feature 

leads to improvements in therapy. 

However, the use of spacer devices with 

other alternative products may provide 

options for individuals who have 

difficulties in coordinating inhalation 

with MDI operation, allowing them to 

more satisfactorily use MDIs that do not 

have a breath-actuated mechanism. 

PADAC members gave their opinion, 

without dissent, that metaproterenol 

and pirbuterol were no longer essential 

uses of ODSs. 

We have tentatively come to the 

following conclusions: 

• The pharmaceutical industry has 

had success in formulating other orally 

inhaled beta2-adrenergic 

bronchodilators without ODSs. We have 

no evidence to suggest that the ODS 

containing metaproterenol or pirbuterol 

oral inhalation drug products pose 

unique technical challenges to 

formulation without ODSs Therefore, 

we tentatively conclude that no 

substantial technical barriers exist to 

formulating metaproterenol and 

pirbuterol oral inhalation drug products 

without ODSs. 

• Metaproterenol and pirbuterol MDIs 

do not provide an otherwise unavailable 

important public health benefit because 

of the available therapeutic alternatives. 

• The release of ODSs into the 

atmosphere from metaproterenol and 

pirbuterol MDIs is cumulatively 

significant and is not warranted because 

they do not provide an otherwise 

unavailable important public health 

benefit. 

We, therefore, tentatively conclude 

that oral pressurized MDIs containing 

metaproterenol and pirbuterol are no 

longer essential uses of ODSs and 

should be removed from the list of 

essential uses in § 2.125(e). 

C. Cromolyn and Nedocromil 

Cromolyn sodium and nedocromil 

sodium are members of the class of 

drugs called ‘‘cromones.’’ Although it is 

not entirely clear how cromones exert 

their clinical effect, cromones are 

thought to inhibit antigen-induced 

bronchospasm as well as the release of 

histamine and other autacoids from 

sensitized mast cells. Cromolyn is also 

available for use in treating asthma as an 

inhalation solution for use in a 

nebulizer. Both cromolyn and 

nedocromil are also used in ophthalmic 

products, and cromolyn is available for 

oral administration for an enteric 

indication. None of these formulations 

would be affected by this proposed 

action. 

The only cromolyn MDI (INTAL MDI) 

was approved for marketing on 

December 5, 1985. The essential-use 

designation for ‘‘[m]etered-dose 

cromolyn sodium human drugs 

administered by oral inhalation’’ was 

added to § 2.125(e) on February 6, 1986 

(51 FR 5190). 

The only nedocromil MDI (TILADE) 

was approved for marketing December 

30, 1992. The essential-use designation 

for ‘‘[m]etered-dose nedocromil sodium 

human drugs administered by oral 

inhalation’’ was added to § 2.125(e) on 

January 26, 1993 (58 FR 6086). 

No other cromone drug is marketed in 

an MDI or other dosage form. 

Both INTAL MDI and TILADE are 

indicated for the management of asthma 

in patients as young as 5 and 6, 

respectively. Both are prescription 

drugs. Neither drug is indicated for the 

relief of acute bronchospasm. 

We have tentatively concluded that 

the following orally inhaled 

corticosteroid drug products, which do 

not contain ODSs, collectively provide 

adequate therapeutic alternatives to 

INTAL MDI and TILADE: 

• Beclomethasone dipropionate MDI 

(QVAR), 

• Budesonide DPI (PULMICORT 

TURBUHALER), 

• Fluticasone propionate MDI 

(FLOVENT HFA), and 

• Mometasone furoate DPI 

(ASMANEX TWISTHALER). 

Inhaled corticosteroids are generally 

considered the preferred treatment for 

mild but persistent asthma, while 

cromolyn and nedocromil are 

considered to be alternative, or 

secondary, treatments (Ref. 1, appendix 

A–1, and p. 23). Cromolyn and 

nedocromil are generally regarded as 

having an excellent safety profile, but 

their clinical usefulness has been 

questioned, particularly when compared 

to inhaled corticosteroids (Ref. 1., p. 23; 

Ref. 2;). The clinical evidence of better 

effectiveness outweighs any minor 

concerns we may have about the slight 

differences that may exist between the 

safety profiles of the cromones 

(cromolyn and nedocromil) and the 

inhaled corticosteroids. QVAR, and 

PULMICORT TURBUHALER, as 

discussed in part V.A of this document, 

provide more than adequate therapeutic 

alternatives for younger pediatric 

patients. While low-dose inhaled 

corticosteroids are generally considered 

the drugs of choice for mild but 

persistent asthma in adults and 

children, health care providers and 

patients, particularly in cases of patients 

who do not tolerate corticosteroids, may 

decide to switch from INTAL MDI and 

TILADE to drugs other than inhaled 

corticosteroids. Also, there are noninhaled asthma medications, such as 

leukotriene modifiers and theophylline, 

which also provide alternative 

therapies. Leukotriene modifiers and 

theophylline (as well as cromolyn and 

nedocromil) have been suggested as 

alternative medications for moderate but 

persistent asthma in children older than 

5 and in adults (Ref. 1, app. A–1) 

Although we believe that patients 

using INTAL MDIs and TILADE will be 

adequately served by the inhaled 

corticosteroids and other therapeutic 

alternatives described previously, 

another therapeutic alternative may be 

the use of cromolyn inhalation solution 

in a portable nebulizer. We bring up this 

issue here because of the absence of 

MDIs and DPIs containing a cromone, 

and the availability of cromolyn in an 

inhalation solution. In the past we have 

downplayed, but never categorically 

rejected, the suitability of portable 

nebulizers as therapeutic alternatives to 

ODS-containing MDIs (see the 1999 

Proposed Rule at 47226, and the 2002 

Final Rule at 48377). We invite 

comment on the suitability of portable 

nebulizers as therapeutic alternatives to 

INTAL MDIs and TILADE, and whether 

use of a portable nebulizer would be 

necessary to serve all patients who are 

currently using INTAL MDIs and 

TILADE. 

PADAC members were closely 

divided at the 2005 meeting on whether 

cromolyn is essential. Several members 

questioned the drug’s effectiveness with 

some concluding that the drug was no 

longer essential, while others felt that 

the drug was preferable for treating 

some ‘‘niche’’ patient populations, even 

though inhaled corticosteroids were 

more generally effective. The two niche 

patient populations identified were 

patients who could not tolerate beta2- 

adrenergic agonists who experience 

exercised-induced bronchospasm, and 

patients who need prophylaxis for a 

specific allergy-induced bronchospasm, 

such as might happen when an allergic 

patient visits a house with a cat in it. 

One member said that for the small 

group of patients that have no other 

alternative than to use cromolyn, 

nebulizers, while somewhat 

inconvenient, may provide a therapeutic 

alternative for situations involving 

planned and known exposures to 

allergens. Another member disagreed 

with this opinion, responding that 

nebulizers are too inconvenient to 

provide a therapeutic alternative to 

MDIs. 

A consensus quickly developed 

among the PADAC members at the 2005 

meeting that nedocromil was not 

essential. One member questioned 


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16Other beta2-adrenergic bronchodilators, 

particularly older, less selective beta2-adrenergic 

bronchodilators, may not be as well tolerated. 

Salmeterol has specific safety concerns (see the 

boxed warning on the approved labeling of Serevent 

Diskus). However, albuterol is the most widely used 

beta2-adrenergic bronchodilator, and it is indicated 

for prophylaxis of exercise induced bronchospasm, 

so we feel comfortable in focusing our discussion 

on this single member of the class. 

17We have received a citizen petition from 

Boehringer Ingelheim Pharmaceuticals, Inc. (BI) 

(Docket No. 2006P-0428/CP1). The petition asks us 

to refrain from taking any action to remove the 

essential-use designation for COMBIVENT. We have 

not had adequate time to evaluate this lengthy 

petition and its 52 references. We will treat the 

petition as a comment on this proposal. The 

contents of this petition do not need to be 

resubmitted, but BI is free to submit any additional 

information or analysis they feel is relevant. 

whether TILADE was still on the market 

and another stated that he had assumed 

it was off the market. One member said 

that his view on nedocromil, which he 

viewed as very comparable to cromolyn 

(a view well supported by available 

literature), was influenced by the 

supposition that a cromolyn product 

would still be on the market. 

The issue of exercise-induced 

bronchospasm in determining the 

essential-use status of cromolyn and 

nedocromil is a difficult subject to 

address. Beta2-adrenergic agonists are 

generally regarded as the treatment of 

choice for prophylaxis of exercise 

induced bronchospasm (Ref. 3, p. 100). 

The labeling for PROVENTIL HFA, 

VENTOLIN HFA, PROAIR HFA, 

formoterol fumarate inhalation powder 

(FORADIL), and SEREVENT DISKUS 

includes indications for exercise 

induced bronchospasm. As stated at the 

2005 PADAC meeting, the primary issue 

then becomes one of prophylaxis of 

exercise induced bronchospasm in 

patients who do not tolerate beta2- 

adrenergic agonists. The size of this 

patient population is not well 

documented. Studies of albuterol in 

HFA MDIs show rates of adverse events 

that are not significantly different from 

the rates with a placebo, indicating that 

this is a very well-tolerated drug.16 If a 

patient population that cannot tolerate 

beta2-adrenergic agonists exists, it 

would seem to be very small. However, 

there appear to be therapeutic 

alternatives for INTAL MDIs and 

TILADE for this population. Long-term 

control therapy using corticosteroids 

may provide an appropriate therapeutic 

alternative for prophylaxis of exercise 

induced bronchospasm. Long-term 

control therapy, including 

corticosteroids and montelukasts 

(SINGULAIR), may decrease the 

bronchial hyperresponsiveness and 

therefore significantly lessen the need 

for immediate prophylaxis of exercise 

induced bronchospasm with a shorteracting drug, such as cromolyn, 

nedocromil, or albuterol. (Ref. 3, p. 100; 

Ref. 4; Ref. 5; Ref. 6). Portable nebulizers 

using cromolyn may provide an 

attractive therapeutic alternative for this 

patient population as well. A nebulizer 

too large to carry in a pocket or purse 

might be easily carried in a gym bag. 

Larger nebulizers using cromolyn may 

also provide an acceptable therapeutic 

alternative for prophylaxis of exercise 

induced bronchospasm, because 

exercise can be scheduled so that access 

to a nebulizer is available before the 

exercise. 

The issue of INTAL MDI and TILADE 

patients who needed prophylaxis for a 

specific allergy-induced bronchospasm, 

such as might occur when an allergic 

patient visits a house with a cat in it, is 

less well defined than the prophylaxis 

of exercise induced bronchospasm. We 

believe that our discussion of 

alternatives to INTAL MDIs and TILADE 

in regard to exercise induced 

bronchospasm would be equally 

relevant to this issue. 

We agree with the PADAC member 

that cromolyn and nedocromil are very 

comparable drugs (see Ref. 7 (cromolyn 

and nedocromil administered by MDI 

provide similar protection against 

exercise induced bronchospasm in 

children)). We request comment as to 

whether there is a medically sound 

rationale for treating them differently. It 

would seemingly make little sense to 

remove the essential use of one and 

retain the other without such a 

rationale. There would be no net 

decrease in the amount of ODSs 

released into the atmosphere if everyone 

currently using INTAL MDI switched to 

TILADE, or vice versa. Therefore, our 

analysis has treated the two drugs 

together. 

We have tentatively come to the 

following conclusion: 

• The pharmaceutical industry has 

had success in formulating other orally 

inhaled drugs with similar physical 

properties to cromolyn and nedocromil 

without ODSs, including the 

development of cromolyn and 

nedocromil HFA MDIs overseas. We 

have no evidence to suggest that the 

ODS containing cromolyn or 

nedocromil oral inhalation drug 

products pose unique technical 

challenges to formulation without 

ODSs. Therefore, we tentatively 

conclude that no substantial technical 

barriers exist to formulating cromolyn 

and nedocromil oral inhalation drug 

products without ODSs. 

• Cromolyn and nedocromil MDIs do 

not provide an otherwise unavailable 

important public health benefit because 

of the available therapeutic alternatives. 

However, given the issues raised during 

the discussion at the PADAC meeting, 

we request comment on our tentative 

conclusion. 

• The release of ODSs into the 

atmosphere from cromolyn and 

nedocromil MDIs is cumulatively 

significant and is not warranted, 

because they do not provide an 

otherwise unavailable important public 

health benefit. 

We, therefore, tentatively conclude 

that oral pressurized MDIs containing 

cromolyn sodium and nedocromil 

sodium are no longer essential uses of 

ODSs and should be removed from the 

list of essential uses in § 2.125(e). 

D. Albuterol and Ipratropium in 

Combination 

We are proposing to remove the 

essential-use designations for MDIs 

containing albuterol sulfate and 

ipratropium bromide in combination 

(COMBIVENT).17 COMBIVENT is a 

prescription drug. Albuterol is a beta2- 

adrenergic bronchodilator and 

ipratropium is an anticholinergic 

bronchodilator. Both are used in the 

treatment of bronchospasm associated 

with COPD. Albuterol is somewhat 

faster acting than ipratropium, while 

ipratropium is somewhat longer acting 

than albuterol. The primary advantage 

of using the two drugs in combination 

is that, by using two distinctly different 

mechanisms of action, the two drugs in 

combination should produce greater 

bronchodilator effect than using either 

drug alone. The essential use for MDIs 

containing albuterol sulfate and 

ipratropium bromide in combination 

was added to § 2.125(e) in the Federal 

Register of April 9, 1996 (61 FR 15700). 

Albuterol and ipratropium, in 

combination, are also sold as an 

inhalation solution (DUONEB) for use in 

a nebulizer. Nebulizers do not use CFCs. 

This current rulemaking will not affect 

the regulatory status of DUONEB. 

We have tentatively determined that 

an ipratropium bromide MDI 

(ATROVENT HFA) used with an 

albuterol sulfate HFA MDI (PROAIR 

HFA, PROVENTIL HFA, OR VENTOLIN 

HFA) will provide an acceptable 

therapeutic alternative to COMBIVENT. 

Using the two MDIs together will 

deliver the same dose of ipratropium (18 

mcg per inhalation) and essentially the 

same dose of albuterol (108 mcg versus 

103 mcg per inhalation). While the 

acceptability as a therapeutic alternative 

of the same two drugs delivered by two 

separate MDIs rather than by one may 

seem obvious, this opinion is not 

universally shared. A Boehringer 


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Ingelheim Pharmaceuticals, Inc. (BI), 

employee commented at the 2005 

PADAC meeting that having patients 

use albuterol and ipratropium in a 

single combination MDI resulted in 

higher patient compliance with the 

prescribed regimen of medication than 

having the patient use two separate 

MDIs. Several PADAC members agreed 

with BI that higher compliance rates 

among patients was a significant factor 

that justified continuing the essentialuse status of albuterol and ipratropium 

in combination. Other PADAC members 

stated that combining the two drugs was 

more of a convenience than an 

essentiality. One member noted that the 

hospital at which he practiced did not 

have COMBIVENT on its formulary, and 

albuterol and ipratropium are 

prescribed in separate MDIs. He 

concluded that providing the two drugs 

together in a combination MDI was not 

essential. One PADAC member pointed 

out that the increasing popularity of the 

tiotropium bromide DPI (SPIRIVA 

HANDIHALER) would decrease demand 

for COMBIVENT, because ipratropium 

cannot be used in conjunction with 

tiotropium. One PADAC member stated 

that the combination should remain 

essential for the time being because of 

the unnecessary anxiety that removing 

COMBIVENT from the market could 

cause. Opinion on whether the 

combination should retain its essentialuse status was evenly divided. 

We are aware of one health economics 

survey suggesting that a single inhaler 

containing both albuterol and 

ipratropium might increase compliance 

and decrease risk of emergency 

department visits and mean length of 

hospital stays compared to the effects 

achieved with separate inhalers for 

these two moieties (Ref. 8). However, we 

have not fully evaluated this survey. A 

patient’s failure to use albuterol and 

ipratropium as prescribed would be 

expected to lead to increased symptoms, 

but it would not affect the permanent 

underlying state of the patient’s lungs 

(Ref. 9). When the patient resumes using 

albuterol and ipratropium as prescribed 

(which he or she would have a major 

incentive to do), the symptoms should 

be relieved, with no significant changes 

in the patient’s health compared to the 

period before the patient stopped using 

the MDIs as prescribed. We welcome 

any reports of studies on these subjects. 

We request comment on whether 

increased compliance and increased 

quality of life would be compelling 

reasons for continuing the essential-use 

designation for albuterol and 

ipratropium in combination. We do not 

currently have sufficient information to 

say that continuing the essential use 

will significantly increase patient 

quality of life to support a claim of 

important public health benefit. 

Continuing the essential-use status of 

albuterol and ipratropium in 

combination is no longer supported by 

one of the rationales that BI proposed in 

their citizen petition requesting that 

MDIs containing albuterol sulfate and 

ipratropium bromide in combination be 

listed as essential in § 2.125(e). BI said 

that use of the COMBIVENT MDI could 

reduce the release of CFCs into the 

atmosphere, because patients would be 

using one CFC MDI for both albuterol 

and ipratropium, instead of two separate 

CFC MDIs (neither albuterol nor 

ipratropium was available in a non-ODS 

MDI at the time) (Citizen Petition, dated 

October 19, 1992, Docket No. 1992P– 

0403/CP1 (formerly 92P–0403)). We 

adopted this rationale in our rulemaking 

to add the essential use to § 2.125(e) (60 

FR 53725, October 17, 1995; 61 FR 

15699, April 9, 1996). Now, however, 

with ATROVENT HFA and albuterol 

sulfate HFA MDIs on the market, this 

rationale is no longer valid. 

We have tentatively come to the 

following conclusion: 

• Although a BI employee said at the 

2005 PADAC meeting that there were 

substantial technical barriers to 

formulating albuterol and ipratropium 

in combination without ODSs, we have 

not been supplied with any information 

to support this conclusion and we 

cannot make an initial determination on 

whether substantial technical barriers 

exist. 

• Albuterol and ipratropium in 

combination CFC MDIs do not provide 

an otherwise unavailable important 

public health benefit. However, given 

the issues raised during the discussion 

at the PADAC meeting, we request 

comment on our tentative conclusion. 

• The release of ODSs into the 

atmosphere from albuterol and 

ipratropium in combination MDIs is 

cumulatively significant and is not 

warranted, because they do not provide 

an otherwise unavailable important 

public health benefit. 

We, therefore, tentatively conclude 

that metered-dose ipratropium bromide 

and albuterol sulfate, in combination, 

administered by oral inhalation for 

human use is no longer an essential use 

of ODSs and should be removed from 

the list of essential uses in § 2.125(e). 

We would be able to reach this 

conclusion without reaching a 

conclusion about whether substantial 

technical barriers exist to formulating an 

ipratropium bromide and albuterol 

sulfate combination without ODSs 

because a CFC ODS product must meet 

all three criteria to remain designated as 

an essential use (see § 2.125(g)(2)). 

VI. Environmental Impact 

We have carefully considered the 

potential environmental effects of this 

action. We have tentatively concluded 

that the action will not have a 

significant adverse impact on the 

human environment, and that an 

environmental impact statement is not 

required. Our initial finding of no 

significant impact and the evidence 

supporting that finding, contained in a 

draft environmental assessment, may be 

seen in the Division of Dockets 

Management (see ADDRESSES) between 9 

a.m. and 4 p.m., Monday through 

Friday. We invite comments on the draft 

environmental assessment. Comments 

on the draft environmental assessment 

may be submitted in the same way as 

comments on this document (see 

DATES). 

VII. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866, the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). 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 agency 

believes that this proposed rule is a 

significant regulatory action as defined 

by the Executive Order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. The agency does not believe 

that this proposed rule would have a 

significant economic impact on a 

substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $118 

million, using the most current (2004) 

Implicit Price Deflator for the Gross 


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Domestic Product. FDA does not expect 

this proposed rule to result in any 1- 

year expenditure that would meet or 

exceed this amount. 

The Congressional Review Act 

requires that regulations that have been 

identified as being major must be 

submitted to Congress before taking 

effect. This rule is major under the 

Congressional Review Act. 

Limitations in the available data 

prevent us from estimating 

quantitatively the anticipated costs and 

benefits to society, so we focus instead 

on proxy measures. The costs of this 

proposed rule include the benefits lost 

by consumers who would have bought 

MDIs at current prices, but would not 

buy them at higher prices. Consumers of 

flunisolide MDIs (AEROBID) and MDIs 

delivering albuterol and ipratropium in 

combination (COMBIVENT) will face 

higher prices because available 

substitutes cost more. In contrast, users 

of triamcinilone MDIs (AZMACORT), 

metaproterenol MDIs (ALUPENT), 

pirbuterol MDIs (MAXAIR), cromolyn 

sodium MDIs (INTAL), and nedocromil 

sodium MDIs (TILADE) will be able to 

switch to less expensive alternatives. 

Consumers of these products may 

benefit as they are made aware of less 

expensive, therapeutically adequate 

alternatives to the MDIs they currently 

use. 

Net spending by consumers and thirdparty payers, including Federal and 

State Governments, will increase as 

patients switch to more expensive 

therapeutic alternatives; the potential 

for spending reductions by users of 

AZMACORT, ALUPENT, MAXAIR, 

INTAL, and TILADE is not enough to 

offset expected increases in spending by 

users of AEROBID and COMBIVENT. 

These spending increases, however, 

overstate social costs because, to some 

extent, they represent resources 

transferred from drug buyers 

(consumers and third-party payers) to 

drug sellers (drug manufacturers, 

wholesalers, pharmacies). We estimate 

that, when it occurs, the introduction of 

generic albuterol HFA MDIs to the 

market will eliminate price and 

spending increases resulting from this 

proposed rule. The benefits of this rule 

include the value of improvements in 

the environment and public health that 

may result from reduced emissions of 

ODSs (for example, the reduced future 

incidence of skin cancers and cataracts). 

The benefits also include improved 

expected returns on investments in 

environmentally friendly technologies 

and greater international cooperation 

and goodwill to comply with the 

Montreal Protocol. 

Estimated spending increases 

(summarized in tables 1 and 2 of this 

document) cannot be attributed solely to 

this rule. These increases result from 

COMBIVENT users switching to 

ATROVENT HFA and albuterol HFA 

MDIs. The increased spending from this 

switch, in turn, is driven by the switch 

from inexpensive generic albuterol CFC 

MDIs to more expensive albuterol HFA 

MDIs, which was mandated in earlier 

rulemaking (70 FR 17168). These 

estimated spending increases may also 

be attributed to the withdrawal of 

albuterol CFC MDIs (including all of the 

less-expensive generic albuterol MDIs) 

from the market (see 70 FR 17168). The 

rightmost column in table 1 of this 

document shows estimates of the 

amount of increased spending 

attributable to this proposed rule if 

COMBIVENT prices were to increase 

dramatically, as discussed in section 

VII.C.6 of this document, even in the 

absence of this proposed rule. These 

remaining costs would be attributable to 

this proposed rule until a mandatory 

phase-out of all CFCs under the 

Montreal Protocol. 

TABLE 1.—SUMMARY OF ANNUAL QUANTIFIABLE EFFECTS OF THE PROPOSED RULE

Patient Days of Therapy 

Affected 

Increased MDI Expenditures, in 2005 dollars 

Possible Reduction in 

Days of Therapy Used 

(millions) 

Reduced CFC Emissions from Phase-out 

(tonnes) 

Increased MDI Expenditures Attributable to this Proposed Rule Without 

Increase in Expenditures by 

COMBIVENT Users 

440 million $200–$400 million 0.7–11 310–365 -$70 to $70 million 

TABLE 2.—SUMMARY OF INCREASES IN IMPACTS RELATIVE TO HFA PATENT EXPIRATION

Date of HFA Patent Expiration Possible Decreases in Use of Asthma and 

COPD Therapy (million days of therapy) Discount Rate Increases in Expenditures on CFC-based MDIS, Present Value in 2006 (billions) 

2010 .68–11 3% $.19–$.38 

7% $.17–$.35 

2017 5.4–88 3% $1.3–$2.7 

7% $1.1–$2.2 

The decreased use of MDIs may 

adversely affect some patients, but we 

currently lack data that would allow us 

to characterize such effects 

quantitatively. We also are unable to 

estimate quantitatively the reductions in 

skin cancers, cataracts, and 

environmental harm that may result 

from the reduction in CFC emissions by 

310 to 365 tonnes during these years. 

Although we cannot estimate 

quantitatively the public health effects 

of the phase-out, based on a qualitative 

assessment, the agency concludes that 

the benefits of this regulation justify its 

costs. 

We state the need for the regulation 

and its objective in section VII.B of this 

document. Section VII.C of this 

document provides background on CFC 

depletion of stratospheric ozone, the 

Montreal Protocol, the albuterol MDI 

market, and the health conditions that 

albuterol is used to treat. We analyze the 

benefits and costs of the rule, including 

effects on government outlays, in 

section VII.D of this document. We 

assess alternative dates in section VII.E 

of this document, and discuss 

sensitivity analysis in section VII.F of 

this document. We present an analysis 

of the effects on small business in a 

regulatory flexibility analysis in section 

VII.G of this document. We discuss our 

conclusions in section VII.H of this 

document. 


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B. Need for Regulation and the 

Objective of this Rule 

This proposed regulation responds to 

U.S. obligations under the Montreal 

Protocol and the Clean Air Act. The 

Montreal Protocol itself recognizes that 

the regulation of ozone-depleting 

substances is necessary because private 

markets are very unlikely to preserve 

levels of stratospheric ozone sufficient 

to protect the public health. Individual 

users of CFC MDIs have no significant 

private incentive to switch to nonozone-depleting products because, 

under current regulations, the 

environmental and health costs of 

ozone-depleting products are external to 

end users. Moreover, should MDI users 

voluntarily internalize these costs by 

switching to alternative products, they 

would not receive the benefits of their 

actions. Each user would bear all of the 

costs and virtually none of the benefits 

of such a switch, as the environmental 

and health benefits would tend to be 

distributed globally and occur decades 

in the future. Thus, the outcome of a 

private market would likely be 

continued use of CFC MDIs, even if the 

social value of reducing emissions were 

clearly much greater than the price 

premium for non-ozone-depleting 

therapies and the possible adverse 

affects on some patients due to the 

decreased use of MDIs. 

The objective of this proposed rule is 

to respond to the Clean Air Act and the 

Montreal Protocol’s requirements that 

the United States, and other nations, 

reduce atmospheric emissions of ODSs, 

specifically CFCs. CFCs and other ODSs 

deplete the stratospheric ozone that 

protects the Earth from ultraviolet solar 

radiation. We are proposing to end the 

essential-use designation for ODSs used 

in MDIs containing triamcinilone, 

metaproterenol, pibuterol, cromolyn 

sodium, nedocromil sodium, 

flunisolide, and albuterol and 

ipratropium in combination, because we 

tentatively conclude that adequate 

therapeutic alternatives are available. 

Removing this essential-use designation 

will comply with obligations under the 

Montreal Protocol and the Clean Air 

Act, thereby reducing emissions that 

deplete stratospheric ozone. 

C. Background 

1. CFCs and Stratospheric Ozone 

During the 1970s, scientists became 

aware of a relationship between the 

level of stratospheric ozone and 

industrial use of CFCs. Ozone (O3), 

which causes respiratory problems 

when it occurs in elevated 

concentrations near the ground, shields 

the Earth from potentially harmful solar 

radiation when it is in the stratosphere. 

Excessive exposure to solar radiation is 

associated with adverse health effects 

such as skin cancer and cataracts, as 

well as adverse environmental effects. 

Emissions of CFCs and other ODSs 

reduce stratospheric ozone 

concentrations through a catalytic 

reaction, thereby allowing more solar 

radiation to reach the Earth’s surface. 

Because of this effect and its 

consequences, environmental scientists 

from the United States and other 

countries advocate ending all uses of 

these chemicals. 

2. The Montreal Protocol 

The international effort to craft a 

coordinated response to the global 

environmental problem of stratospheric 

ozone depletion culminated in the 

Montreal Protocol, an international 

agreement to regulate and reduce 

production of ODSs. The Montreal 

Protocol is described in section I.B.2 of 

this document. One hundred and 

eighty-eight countries have now ratified 

the Montreal Protocol, and the overall 

usage of CFCs has been dramatically 

reduced. In 1986, global consumption of 

CFCs totaled about 1.1 million tonnes 

annually, and by 2004, total annual 

production had been reduced to 70,000 

tonnes (Ref. 10). This decline amounts 

to more than a 90-percent decrease in 

production and is a key measure of the 

success of the Montreal Protocol. Within 

the United States, use of ODSs, and 

CFCs in particular, has fallen sharply— 

production and importation of CFCs is 

less than 1 percent of 1989 production 

and importation (Ref. 10). 

A relevant aspect of the Montreal 

Protocol is that production of CFCs in 

any year by any country is generally 

banned after the phase-out date unless 

the Parties to the Montreal Protocol 

agree to designate the use for which the 

CFCs are produced as ‘‘essential’’ and 

approve a quantity of new production 

for that use. 

Each year, each Party nominates the 

amount of CFCs needed for each 

essential use and provides the reason 

why such use is essential. Agreement on 

both the essentiality and the amount of 

CFCs needed for each nominated use is 

reached at the annual Meeting of the 

Parties. 

3. Benefits of the Montreal Protocol 

EPA has generated a series of 

estimates of the environmental and 

public health benefits of the Montreal 

Protocol (Ref. 11). The benefits include 

reductions of hundreds of millions of 

nonfatal skin cancers, 6 million fewer 

fatalities due to skin cancer, and 27.5 

million cataracts avoided between 1990 

and 2165 if the Montreal Protocol were 

fully implemented. EPA estimates the 

value of these and related benefits to 

equal $4.3 trillion in present value 

when discounted at 2 percent over the 

period of 175 years. This amount is 

equivalent to about $6 trillion after 

adjusting for inflation between 1990 and 

2004. This estimate includes all benefits 

of total global ODS emission reductions 

expected from the Montreal Protocol 

and is based on reductions from a 

baseline scenario in which ODS 

emissions would continue to grow for 

decades but for the Montreal Protocol. 

4. Characteristics of COPD 

The seven CFC MDI products that are 

the subject of this proposed rule, and 

COMBIVENT in particular, may be used 

to treat COPD. While there is some 

overlap between asthma patients and 

COPD patients, COPD encompasses a 

group of diseases characterized by 

relatively fixed airway obstruction 

associated with breathing-related 

symptoms (for example, chronic 

coughing, expectoration, and wheezing). 

COPD is generally associated with 

cigarette smoking and is extremely rare 

in persons younger than 25. 

According to the National Health 

Interview Survey (NHIS), an estimated 

10 million adults in the United Sates 

carried the diagnosis of COPD in 2000 

(table 1 of Ref. 12). The underlying 

surveys depend on patient-reported 

diagnoses and many affected 

individuals have not been formally 

diagnosed. Data from the National 

Health and Nutrition Examination 

Survey (table 3 of Ref. 12), which was 

not based on patient self-reporting, 

suggests that as many as 24 million 

Americans may actually be affected by 

the illness. The proportion of the U.S. 

population with mild or moderate 

COPD has declined over the last quarter 

century, although the rate of COPD in 

females increased relative to males 

between 1980 and 2000. Among 

smokers, the most effective intervention 

in modifying the course of COPD is 

smoking cessation. Symptoms such as 

coughing, wheezing, and sputum 

production are treated with medication. 

5. Characteristics of Asthma 

These seven CFC MDIs, with the 

exception of COMBIVENT, may be used 

to treat asthma, a chronic respiratory 

disease characterized by episodes or 

attacks of bronchospasm on top of 

chronic airway inflammation. These 

attacks can vary from mild to lifethreatening and involve shortness of 

breath, wheezing, coughing, or a 

combination of symptoms. Many 

factors, including allergens, exercise, 


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viral infections, and others, may trigger 

an asthma attack. 

According to the NHIS, approximately 

21 million patients in the United States 

reported they had asthma in 2004 (table 

7 of Ref. 13). The prevalence of asthma 

decreases with age, with the prevalence 

being 84.7 per 1,000 children ages 0-17 

(6.2 million children) compared to 63.9 

per 1,000 among adults ages 18-44 (7.1 

million), 69.4 per 1,000 among adults 

ages 45-64 (4.9 million), and 70.2 per 

1,000 among adults age 65 and over (2.4 

million) (table 7 of Ref. 13). 

The NHIS reported that, during 2004, 

about 12 million patients reported 

experiencing an asthma attack in the 

course of the previous year (table 10 of 

Ref. 13). According to the National 

Ambulatory Medical Care Survey and 

National Hospital Ambulatory Medical 

Care Survey, in 2004 there were 14 

million outpatient asthma visits to 

physician offices and hospital clinics 

and 1.8 million emergency room visits 

(table 19 of Ref. 13). According to the 

National Center for Health Statistics’ 

National Hospital Discharge Survey, 

there were 497,000 hospital admissions 

for asthma in 2004 (table 17 of Ref. 13) 

and 4,099 mortalities in 2003 (table 1 of 

Ref. 13). The direct medical cost of 

asthma (hospital services, physician 

care, and medications) was estimated as 

$11.5 billion for 2004 (table 20 of Ref. 

13). 

While the prevalence of asthma has 

been increasing in recent years, the 

Centers for Disease Control and 

Prevention (CDC) reports that the 

patients reported experiencing an 

asthma attack in the course of the 

previous year has remained fairly 

constant since 1997 (Ref. 14). NonHispanic Blacks, children under 17 

years old, and females have higher 

incidence rates than the general 

population and also have higher attack 

prevalence. The CDC notes that, 

although increases have occurred in the 

numbers and rates of physician office 

visits, hospital outpatient visits, and 

emergency room visits, these increases 

are accounted for by the increase in 

prevalence. CDC also reported declines 

in hospitalization for asthma and 

mortality. The declines may indicate 

early successes by asthma intervention 

programs that include access to 

medications. 

6. Current U.S. Market for CFC MDIs 

In the 2005 calendar year, we estimate 

that sales of these seven CFC MDIs 

provided roughly 440 million days of 

therapy, sufficient to treat roughly 1.2 

million COPD and asthma patients for a 

full year. We focus on days of therapy 

as a common metric because these MDIs 

vary in the number of inhalations 

provided, and the number of inhalations 

that the average user would use each 

day. We calculate the number of days of 

therapy provided by each MDI as equal 

to the number of MDIs sold multiplied 

by the number of inhalations contained 

by the MDI, divided by the 

recommended, or usual, daily 

inhalations described in the MDI’s 

physician labeling: [(Days of Therapy) = 

(MDIs) x (Inhalations/MDI) ÷ 

(Inhalations/day)]. We calculate MDI 

sales for each of the seven products 

using data from IMS Health’s National 

Sales Perspective (Ref. 15). 

We calculate the average price per day 

of therapy for a CFC MDI as the total 

revenue derived from sales of that 

product in 2005, as reported by IMS 

Health’s National Sales Perspective, 

divided by the number of days of 

therapy for that product: [(Price/Day of 

Therapy) = (Total Sales) ÷ (Total Days of 

Therapy)]. We use the same method to 

calculate the average price per day of 

therapy for the nine non-ozonedepleting products we consider the 

most medically appropriate alternatives 

to these seven CFC MDIs. We then 

estimate the price premium (or savings) 

associated with alternatives as the 

difference between price per day of the 

CFC product and the price per day of its 

most appropriate alternatives. 

TABLE 3.—SUMMARY OF CFC MDIS, NON-ODS ALTERNATIVES, AND EXPECTED PRICE CHANGES PER DAY OF THERAPY

(REF. 15) 

CFC MDI Non-ODS Alternatives 

Price Premium per Day of 

Therapy 

Maximum Minimum 

AEROBID 

AEROBID–M 

QVAR 

PULMICORT TURBOHALER 

FLOVENT HFA 

ASMANEX TWISTHALER 

$1.63 $0.27 

AZMACORT QVAR 

PULMICORT TURBOHALER 

FLOVENT HFA 

ASMANEX TWISTHALER 

$0.35 -$1.01 

ALUPENT PROAIR HFA 

PROVENTIL HFA 

VENTOLIN HFA 

XOPENEX HFA 

$0.07 -$0.14 

MAXAIR PROAIR HFA 

PROVENTIL HFA 

VENTOLIN HFA 

XOPENEX HFA 

-$0.23 -$0.53 

INTAL QVAR 

PULMICORT TURBOHALER 

FLOVENT HFA 

ASMANEX TWISTHALER 

-$0.33 -$1.69 


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18CFC MDI manufacturers disclose the CFC 

content of their MDIs to EPA as part of the process 

of requesting essential-use allocations; however, the 

CFC content of any particular MDI is considered a 

trade secret and may not be disclosed without the 

manufacturer’s consent. 

TABLE 3.—SUMMARY OF CFC MDIS, NON-ODS ALTERNATIVES, AND EXPECTED PRICE CHANGES PER DAY OF THERAPY

(REF. 15)—Continued 

CFC MDI Non-ODS Alternatives 

Price Premium per Day of 

Therapy 

Maximum Minimum 

TILADE QVAR 

PULMICORT TURBOHALER 

FLOVENT HFA 

ASMANEX TWISTHALER 

-$2.34 -$5.12 

COMBIVENT ATROVENT HFA + one of the following: 

PROAIR HFA 

PROVENTIL HFA 

VENTOLIN HFA 

XOPENEX HFA 

$1.22 $0.92 

Source: IMS Health, IMS National Sales Perspective (TM), 2005, extracted March 2006. 

Table 3 of this document shows each 

of the CFC MDIs that would no longer 

be marketed, the therapeutic 

alternatives that users of these CFC 

MDIs would be expected to purchase, 

and the range of differences in price per 

day of therapy. For example, an 

AZMACORT user would be expected to 

switch to QVAR, PULMICORT 

TURBOHALER, FLOVENT HFA, or 

ASMANEX TWISTHALER. The most 

expensive of these alternatives would 

cost roughly 35 cents more per day of 

therapy, and the least would cost 

roughly $1 less per day of therapy. 

COMBIVENT users would be expected 

to switch to both ATROVENT HFA and 

one of four albuterol HFA MDIs 

currently marketed. We make no 

attempt to forecast future price changes, 

but note that, during the past year, 

changes in prices of CFC MDIs did not 

differ systematically from the changes in 

prices of the proposed alternatives. 

We estimate that, on average, users of 

these seven CFC MDIs will pay 20 

percent to 50 percent more per day of 

therapy. If all users switched to the least 

expensive alternative therapy, the 

average price for users of these seven 

CFC MDIs, weighted by the number of 

days of therapy sold for each product in 

2005, would increase roughly 20 

percent; if all users switch to the most 

expensive alternative therapy, the 

average price per day of therapy would 

increase roughly 50 percent. These 

prices represent average exmanufacturer prices across all 

distribution channels, and do not 

incorporate retail markups or off-invoice 

discounts (Ref. 15). 

These estimated price increases may 

also be attributed to the withdrawal of 

albuterol CFC MDIs (including all 

generic albuterol MDIs) from the market 

(see 70 FR 17168). These estimated 

price increases are driven almost 

entirely by the large population of 

COMBIVENT users switching to both 

the ipratropium MDI (ATROVENT HFA) 

and albuterol HFA MDIs which, 

together, are more expensive. Through 

2003, the price for a day of therapy with 

COMBIVENT was roughly equal to the 

sum of a day of therapy with 

ATROVENT (the ipratropium CFC MDI 

which has been withdrawn from the 

market) and a day of therapy with a 

generic albuterol CFC MDI. Since 2003, 

the price of a day of COMBIVENT 

therapy has risen to be roughly equal to 

the sum of a day of therapy with 

ATROVENT HFA and a day of therapy 

with a generic albuterol CFC MDI, likely 

in anticipation of the withdrawal of 

ATROVENT from the market. One might 

predict that, with the withdrawal of 

albuterol CFC MDIs (including all 

generic albuterol MDIs) from the market 

(see 70 FR 17168), the price of a day 

COMBIVENT therapy would increase to 

the sum of a day of therapy with 

ATROVENT HFA and an albuterol HFA 

MDI. To the extent that this prediction 

is accurate, the price increases 

described previously, and the estimated 

spending increases derived from it, 

result not from this proposed rule, but 

from the earlier rule removing albuterol 

CFC MDIs from the market. Indeed, 

without the estimated increase in 

spending estimated for the price per day 

of COMBIVENT therapy, the expected 

average price per day of therapy would 

not increase; the midpoint of the range 

of spending changes shown in table 1 of 

this document, -$70 million to $70 

million, is zero. 

We estimate that these seven CFC 

MDIs are responsible for roughly 310 to 

365 tonnes of CFC emissions annually. 

The CFC content of the seven CFC MDIs 

ranges from about 6 to 20.5 grams per 

MDI. Multiplying the total 2005 sales of 

each of the CFC MDIs by its CFC 

content, and allowing for an additional 

10 percent loss in the production 

process, yields a total of 310 tonnes of 

CFC emissions annually, our low 

estimate. The CFC MDI manufacturers 

have requested roughly 365 tonnes of 

CFCs for production of the seven CFC 

MDIs in 2007, our high estimate.18

D. Benefits and Costs of the Proposed 

Rule 

We estimate the benefits and costs of 

a government action relative to a 

baseline scenario that in this case is a 

description of the production, use, and 

access to these seven CFC MDIs in the 

absence of this rule. In this section, we 

first describe such a baseline and then 

present our analysis of the benefits of 

the proposed rule. We also present an 

analysis of the most plausible regulatory 

alternative, given the Montreal Protocol. 

Next we turn to the costs of the rule and 

to an analysis of the effects on the 

Medicare and Medicaid programs. 

1. Baseline Conditions 

We developed baseline estimates of 

future conditions to assess the economic 

effects of prohibiting marketing of these 

seven CFC MDIs after December 31, 

2009. It is standard practice to use, as 

a baseline, the state of the world 

without the rule in question, or where 

this implements a legislative 

requirement, the world without the 

statute. For this proposed rule, the 

Montreal Protocol makes the baseline 

assumption of indefinite availability 

infeasible, but we can nevertheless use 

it as a point of reference. In addition to 

the baseline of indefinite availability, 

we also assess alternative phase-out 

dates for the final disappearance of CFC 

products. 


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Throughout this analysis, we assume 

that sufficient inventories of CFCs are 

available to meet demand for these 

seven CFC MDIs through December 31, 

2009, and that there will be sufficient 

therapeutic alternatives to meet demand 

after December 31, 2009. 

However, in the absence of this 

proposed rule, the parties to the 

Montreal Protocol are likely to consider 

restrictions on access to the CFCs 

needed to produce these seven CFC MDI 

products. These likely restrictions imply 

the costs detailed in section 3 of this 

document may very well accrue 

regardless of whether this proposed rule 

is made final. The cost-benefit analysis 

presented here would then reflect the 

withdrawal of the CFC-containing 

products from the market, rather than 

the specific effects of this rulemaking. 

2. Benefits of the Proposed Rule 

The benefits of the proposed rule 

include environmental and public 

health improvements from protecting 

stratospheric ozone by reducing CFC 

emissions. Benefits also include 

expectations of increased returns on 

investments in environmentally friendly 

technology, and continued international 

cooperation and goodwill to comply 

with the spirit of the Montreal Protocol, 

thereby potentially reducing future 

emissions of ODSs throughout the 

world. 

Failure to promulgate the 

requirements proposed in this proposed 

rule would likely lead the parties to the 

Montreal Protocol to consider restricting 

access to the CFCs required to 

manufacture these seven CFC MDI 

products, leading to a risk of 

unexpected disruptions of supplies of 

drug products which are still being used 

by patients with asthma and COPD. 

These disruptions could potentially 

harm the public health of the United 

States by preventing a smooth transition 

from CFC MDIs to non-CFC products. 

a. Reduced CFC emissions. Market 

withdrawal of these seven CFC MDIs 

will reduce emissions by approximately 

310 to 365 tonnes of CFCs per year. 

Current CFC inventories are substantial. 

Nominations for new CFC production 

are generally approved by the Parties to 

the Montreal Protocol 2 years in 

advance. The proposed rule would ban 

marketing of these seven CFC MDIs after 

December 31, 2009. There is some 

uncertainty with respect to the amount 

of inventory that will be available in the 

future, but we anticipate that existing 

inventory will allow EPA, in 

consultation with FDA, to avoid 

allocating any CFCs for 2009. Therefore, 

we estimate the proposed regulation 

will reduce CFC use by 310 to 365 

tonnes per year after the end of 2009, a 

benefit that will continue beyond the 

evaluation period. 

In an evaluation of its program to 

administer the Clean Air Act, EPA has 

estimated that the benefits of controlling 

ODSs under the Montreal Protocol are 

the equivalent of $6 trillion in 2004 

dollars. However, EPA’s report provides 

no information on the total quantities of 

reduced emissions or the incremental 

value per tonne of reduced emissions. 

EPA derived its benefits estimates from 

a baseline that included continued 

increases in emissions in the absence of 

the Montreal Protocol. We have 

searched for authoritative scientific 

research that quantifies the marginal 

economic benefit of incremental 

emission reductions under the Montreal 

Protocol, but have found none 

conducted during the last 10 years. As 

a result, we are unable to quantify the 

environmental and human health 

benefits of reduced emissions from this 

regulation. Such benefits, in any event, 

were included in EPA’s earlier estimate 

of benefits. 

As a share of total global emissions, 

the reduction associated with the 

elimination of the seven CFC MDIs 

represents only a fraction of 1 percent. 

Current allocations of CFCs for the 

seven MDIs account for less than 0.1 

percent of the total 1986 global 

production of CFCs (Ref. 10). 

Furthermore, current U.S. CFC 

emissions from MDIs represent a much 

smaller, but unknown, share of the total 

emissions reduction associated with 

EPA’s estimate of $6 trillion in benefits 

because that estimate reflects future 

emissions growth that has not occurred. 

Although the direct benefits of this 

regulation are small relative to the 

overall benefits of the Montreal 

Protocol, the reduced exposure to UV– 

B radiation that will result from these 

reduced emissions will help protect 

public health. The proposed rule will 

account for some small part of the 

benefits estimated by EPA. However, we 

are unable to assess or quantify specific 

reductions in future skin cancers and 

cataracts associated with these reduced 

emissions. 

b. Returns on investment in 

environmentally-friendly technology. 

Establishing a phase-out date prior to 

the expiration of patents on HFA MDI 

technology not only rewards the 

developers of the HFA technology, but 

also serves as a signal to other potential 

developers of ozone-safe technologies. 

In particular, such a phase-out date 

would preserve expectations that the 

government protects incentives to 

research and develop ozone-safe 

technologies. 

Newly developed technologies to 

avoid ODS emissions have resulted in 

more environmentally ‘‘friendly’’ air 

conditioners, refrigerants, solvents, and 

propellants, but only after significant 

private-sector investments. Several 

manufacturers have claimed 

development costs that total between 

$250 million and $400 million to 

develop HFA MDIs and new propellantfree devices for the global market (Ref. 

16). 

These investments have resulted in 

several innovative products in addition 

to HFA MDIs. For example, breathactivated delivery systems, dose 

counters, DPIs, and mini-nebulizers 

have also been successfully marketed. 

c. International cooperation. The 

advantages of selecting a date that 

maintains international cooperation are 

substantial because the Montreal 

Protocol, like most international 

environmental treaties, relies primarily 

on a system of national selfenforcement, although it also includes a 

mechanism to address noncompliance. 

In addition, compliance with its 

directives is subject to differences in 

national implementation procedures. 

Economically less-developed nations, 

which have slower phase-out schedules 

than developed nations, have 

emphasized that progress in eliminating 

ODSs in developing nations is affected 

by observed progress by developed 

nations, such as the United States. If we 

propose to adopt a later phase-out date, 

other Parties could attempt to delay 

their own control measures. 

3. Costs of the Proposed Rule 

The proposed rule would increase 

spending for needed medicines used to 

treat asthma and COPD. The social costs 

of the proposed rule include the benefits 

lost through decreased use of medicines 

that may result from increased prices. 

We discuss the increased spending and 

then the social costs in turn. We are 

unable to quantify the economic costs of 

reducing the variety of marketed 

products from which consumers, and 

their doctors, can choose, but we note 

that these costs may be substantial. 

Because we lack data that would enable 

us to measure the effects of a decreased 

number of products from which to 

choose, in this analysis we only 

quantify the effects on spending. 

In the absence of this regulation, we 

would expect 440 million days of 

therapy of these seven CFC MDIs to be 

sold annually. With this regulation, 

patients who would have used any of 

these seven CFC MDIs are expected to 

switch to one of several other products 

as described in table 3 of this document. 

Depending on whether asthma and 


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COPD patients use the most or least 

expensive of alternatives, once this 

proposed rule becomes final and goes 

into effect, private, third-party and 

public expenditures on inhaled 

medicines would increase by roughly 

$200 million to $400 million per year. 

These expenditure increases will be 

driven almost exclusively by 

COMBIVENT users changing to both 

ATROVENT HFA and one of four 

available albuterol HFA products. With 

most—perhaps all—of this increase 

coming from estimated increased 

spending on albuterol HFA MDIs, what 

happens to the prices of albuterol MDIs 

will largely determine the change in 

overall spending. As discussed in 

section VII.C.6, it is possible that, in 

response to earlier rulemaking removing 

generic CFC albuterol MDIs from the 

market, COMBIVENT prices would 

increase dramatically even in the 

absence of this proposed rule. If, even 

in the absence of this proposed rule, the 

cost of a day of COMBIVENT therapy 

were to increase to the sum of a day of 

albuterol HFA MDI and ATROVENT 

HFA therapy, this proposed rule would 

change private, third-party and public 

expenditures on inhaled medicines by 

roughly -$70 million to $70 million per 

year. This increased expenditure would 

continue until lower-priced non-ODS 

substitutes appear on the market. For 

many of these products it is difficult to 

predict when this might occur. With the 

exception of albuterol CFC MDIs, 

generic versions of prescription MDIs 

and DPIs for treatment of asthma and 

COPD have not been introduced, despite 

the expiration of the patents on many of 

the innovator products. However, the 

market for albuterol MDIs has a clear 

history of generic competition. A prior 

rulemaking (70 FR 17168) will remove 

albuterol CFC MDIs, including generic 

albuterol CFC MDIs, from the market by 

December 31, 2008. If these cheaper 

generic albuterol MDIs were somehow 

to remain on the market, the expected 

cost of switching from COMBIVENT to 

both ATROVENT HFA and an albuterol 

HFA MDI would be essentially 

eliminated. Because expenditure 

increases resulting from this proposed 

rule stem almost exclusively from the 

transition away from COMBIVENT, 

such increases would most likely be 

eliminated with the introduction of 

generic albuterol HFA MDIs to the 

market. Patents listed in Approved Drug 

Products with Therapeutic Equivalence 

Evaluations (Orange Book) for albuterol 

HFA MDIs expire in 2010 and 2017, 

making those possible dates for generic 

entry. Of course, unforeseen 

introduction of alternative therapies 

could reduce these expected increases 

in expenditures. 

These increased expenditures 

represent, to some extent, transfers from 

consumers and third-party payers, 

including State and Federal 

Governments, to pharmaceutical 

manufacturers, patent holders, and 

other residual claimants. However, to 

some extent, increased expenditures 

represent purchases of products that are 

more costly to manufacture and bring to 

market. We are unable to estimate the 

fraction of the increased expenditures 

that constitute societal costs. 

We expect that price increases 

resulting from market withdrawal of less 

expensive CFC MDIs could reduce use 

of inhaled therapy by 0.7 to 11 million 

days annually, equivalent to roughly 2 

to 30 thousand patient years of therapy. 

The impact of this reduction on health 

outcomes is too uncertain to quantify 

given available data, and we invite 

comments on this issue. We also invite 

comments on changes in copayments 

(resulting in higher out-of-pocket costs 

for insured consumers) and potential 

effect on therapy days. 

A recent article found that 

‘‘copayment increases led to increased 

use of emergency department visits and 

hospital days for the sentinel conditions 

of diabetes, asthma, and gastric acid 

disorder: predicted annual emergency 

department visits increased by 17 

percent and hospital days by 10 percent 

when copayments doubled.’’ (Ref. 17). 

However, the article proceeds to 

characterize these results as ‘‘not 

definitive.’’ This finding suggests that 

increased prices for medicines may lead 

to some adverse public health effects 

among the users of these seven CFC 

MDIs. This evidence is insufficient to 

permit us to quantify any adverse public 

health effects. We use expected 

reductions in days of therapy purchased 

as a surrogate measure of the impact. 

Our approach to estimating the effects 

of this proposed rule assumes that the 

primary effect of an elimination of these 

seven CFC MDIs from the market would 

be an increase in the average price of 

MDI and DPI therapy. Given the price 

increase expected, we have projected 

how the quantity of MDI and DPI 

therapy consumed may decline as a 

result of this rule. We assume that the 

reduction in the use of MDI and DPI 

therapy attributable to this rule can be 

calculated as the product of the 

sensitivity of use with respect to the 

price increase, the baseline use of these 

seven CFC MDIs among price-sensitive 

patients, and the price increase in 

percentage terms. We discuss these in 

turn. 

We have no information about how 

consumers react to increases in the price 

of these seven forms of CFC MDIs in 

particular, much less to what amounts 

to a compulsory switch to different, 

more expensive drugs. Economists have, 

however, researched the response of 

consumers to higher insurance 

copayments for drugs in general. 

Goldman et al. estimate price elasticities 

in the range of -0.33 (for all 

antiasthmatic drugs) to -0.22 (for 

antiasthmatic drugs among patients 

with chronic asthma), implying that a 

10 percent increase in insurance 

copayments apparently leads to a 

reduction in use of between 2.2 and 3.3 

percent (Ref. 17), but the authors report 

that there is wide variance based on the 

availability of over-the-counter 

substitutes. For example, for drugs with 

no over-the-counter substitutes—a set 

that includes all seven of these CFC 

MDIs—the reported price elasticity was 

-0.15 (Ref. 17, p. 2348). Drugs included 

as antiasthmatics in this study include 

anticholinergics, anti-inflammatory 

asthma agents, leukotriene modulators, 

oral steroids, steroid inhalers, 

sympathomimetics, and xanthines. We 

have used price elasticities of between 

-0.15 and -0.33 to estimate the potential 

effect of price increases on demand. 

To derive an estimate of the quantity 

of medicines not sold as a result of this 

rule, we need an estimate of the baseline 

use of these seven CFC MDIs by pricesensitive consumers. Based on IMS data, 

we estimate that asthma and COPD 

patients receive roughly 440 million 

days of therapy each year in the form of 

these seven CFC MDIs (Ref. 15). If users 

of these products are uninsured in 

proportion to the share of uninsured in 

the overall U.S. population (15.7 

percent) (Ref. 18), then uninsured 

asthma and COPD patients receive 

roughly 69 million days of therapy [(440 

million) x (15.7 percent)] in the form of 

these seven CFC MDIs, equivalent to 

roughly 188 thousand patient years. 

However, increases in the price of 

therapy will fall disproportionately on 

COMBIVENT users with COPD. In 1995, 

more than two-thirds of COPD patients 

were over the age of 65 (Ref. 19); these 

individuals would therefore be covered, 

at least in part, by Medicare. If the 

remaining, under-65 third of the COPD 

patients are uninsured in proportion to 

the uninsured share of the population, 

then only 23 million days of therapy 

[(440 million) x (15.7 percent) ÷ 3] are 

used by uninsured COPD patients each 

year. We are unable to estimate the 

extent to which Medicare’s Part D 

benefit will cover the increased costs to 

those patients over age 65. Because most 


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19Our estimate uses State drug utilization data for 

outpatient drugs paid for by State Medicaid 

agencies as part of the Medicaid Drug Rebate 

Program. The data is available at: http:// 

www.cms.hhs.gov/MedicaidDrugRebateProgram/ 

SDUD/list.asp#TopOfPage. 

of those over age 65 have insurance, 

15.7% likely understates the true 

percentage of individuals under 65 

without insurance. To the extent this is 

true, these estimates will understate the 

true impact of this proposed rule. 

Finally we estimate that users of these 

seven CFC MDIs face an average price 

increases of between 20 and 50 percent 

per day of therapy, depending on 

whether asthma and COPD patients 

switch to the most or least expensive of 

the proposed alternatives detailed in 

table 3 of this document. We calculate 

the low and high estimates as the 

average percentage price change of the 

least and most expensive alternatives to 

each of the seven CFC MDIs, weighted 

by the number of days of therapy of CFC 

MDIs sold in 2005. Excluding 

COMBIVENT, users of the other six CFC 

MDIs would face prices somewhere 

between 30 percent higher and 30 

percent lower. 

We combine different measures of 

price elasticities (-0.15 to -0.33), the size 

of the uninsured CFC MDI market (23 to 

69 million days of therapy), and 

estimated price increases (20 percent to 

50 percent) to estimate the impact of 

price increases on use. For example, 

assuming a price elasticity of -0.15 and 

23 million days of therapy sold to the 

uninsured annually, a 20 percent price 

increase would reduce demand for 

inhaled therapy by the uninsured by 

roughly 700,000 days of therapy 

annually. By contrast, assuming a price 

elasticity of -0.33 and 69 million days of 

therapy sold to the uninsured annually, 

a 50 percent price increase would 

reduce uninsured demand by roughly 

11 million days of therapy [(69 million 

days) x (-0.33 elasticity) x (50 percent 

price increase) = 11 million days of 

therapy]. We recognize that, because of 

varying measures of the size of the CFC 

MDI market for the uninsured, 

uncertainty about the magnitude of 

price increases, and consumer response, 

the true impact of the rule could fall 

outside this range. 

When we exclude COMBIVENT from 

the calculation, we get a much smaller 

effect. The expected price change of 30 

percent higher to 30 percent lower 

implies a -4.5 percent to 4.5 percent 

change in days of therapy if the price 

elasticity is -0.15 and a -10 percent to 

10 percent change in days of therapy if 

the price elasticity is -0.33. The 

expected change in days of therapy 

would be zero, the midpoint of the 

range. 

4. Effects on Medicaid and Medicare 

Based on 2005 Medicaid utilization 

data, we estimate this proposed rule 

would reduce Federal Medicaid 

spending by $40 million to $60 million 

annually. Based on Medicare Current 

Beneficiary Survey estimates of the 

Medicare population and estimates of 

the price difference between CFC MDIs 

and HFA MDIs, we estimate Federal 

spending on Medicare beneficiaries, as 

well as by Medicare beneficiaries 

themselves, will increase from $190 

million to $450 million annually. We 

recognize these estimates of increased 

Medicare spending suggest a broader 

range of potential spending increases 

than estimates of the overall impact of 

the proposed rule introduced in table 1 

of this document. We discuss data 

limitations that cause this in section 

VII.D.3.b of this document. 

a. Medicaid. Based on aggregated state 

Medicaid utilization data for 2005,19 we 

estimate this proposed rule will reduce 

Medicaid reimbursements by roughly 

$40 million annually, because Medicaid 

reimbursement rates for CFC MDI 

products are, on average, higher than 

reimbursement rates for the proposed 

HFA MDI alternatives. First, we 

estimate total days of therapy 

reimbursed by Medicaid in 2005 for 

each of the seven CFC MDIs and 

calculate the average reimbursement per 

day of therapy. Second, we estimate the 

average reimbursement per day of 

therapy for each alternative therapy. If 

all Medicaid beneficiaries using CFC 

MDIs switch to the most expensive of 

available alternatives and 

reimbursement rates remain unchanged, 

total reimbursements would decrease by 

approximately $40 million; if they all 

switch to the least expensive of 

available alternatives, total 

reimbursements would decrease by 

roughly $60 million. Because these 

estimates are based on 2005 data, they 

do not take into account decreases in 

Medicaid reimbursements that will 

occur as those individuals eligible for 

both Medicaid and Medicare, and who 

were covered by Medicaid in 2005, 

receive their 2006 coverage through 

Medicare. 

TABLE 4.—ESTIMATED IMPACT ON MEDICAID REIMBURSEMENTS BASED ON 2005 DATA

CFC MDIs Total Days of 

Therapy 

Total Expenditure 

Reimbursement 

per Day of 

Therapy 

Expenditure Premium Expenditure Change 

Maximum Minimum Maximum Minimum 

MAXAIR 7,248,876 $12,320,046 $1 .70 -$0 .36 -$0 .36 -$2,581,185 -$2,581,185 

AEROBID 1,513,499 $4,506,603 $2 .98 $1 .77 -$1 .42 $2,679,966 -$2,149,445 

AZMACORT 6,519,580 $19,408,252 $2 .98 $1 .77 -$1 .42 $11,548,769 -$9,254,506 

COMBIVENT 47,888,737 $138,485,222 $2 .89 -$1 .15 -$0 .93 -$54,987,774 -$44,318,563 

INTAL 550,246 $1,801,310 $3 .27 $1 .47 -$1 .72 $811,434 -$944,343 

TILADE 27,497 $151,039 $5 .49 -$0 .74 -$3 .94 -$20,474 -$108,214 

ALUPENT 0 $0 $0 $0 $0 $0 $0 

Total -$42,549,264 -$59,356,256 

b. Medicare. Based on 2003 data from 

the Medicare Current Beneficiary 

Survey and price estimates introduced 

in table 3 of this document, we estimate 

Federal Medicare spending, together 

with private expenditure by Medicare 

beneficiaries, will increase roughly $190 

million to $450 million. We estimate 

roughly 1.2 million beneficiaries used 


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these seven CFC MDIs in 2003. 

Excluding COMBIVENT, we estimate 

that this spending could increase by as 

much as $75 million or decrease by as 

much as $90 million. 

TABLE 5.—INCREASED SPENDING ON MEDICARE BENEFICIARIES

Number of 

Full-year Medicare users 

Price Premium Cost Per day Cost Per Year 

Max Min Max Min Max Min 

Aerobid 112,259 $1 .63 $0 .27 $183,219 .05 $30,151 .89 $66,874,952 .64 $11,005,440 .65 

Azmacort 185,035 $0 .35 -$1 .01 $65,250 .68 -$187,047 .39 $23,816,497 .79 -$68,272,296 .85 

Alupent 10,415 $0 .07 -$0 .14 $752 .26 -$1,505 .96 $274,574 .93 -$549,676 .92 

Maxair 26,909 -$0 .23 -$0 .53 -$6,109 .49 -$14,387 .81 -$2,229,962 .64 -$5,251,551 .32 

Intal 9,950 -$0 .33 -$1 .69 -$3,273 .69 -$16,840 .06 -$1,194,895 .82 -$6,146,620 .75 

Tilade 15,108 -$2 .34 -$3 .70 -$35,296 .79 -$55,896 .24 -$12,883,326 .74 -$20,402,126 .86 

Combivent 833,103 $1 .22 $0 .92 $1,019,601 .26 $763,304 .20 $372,154,460 .78 $278,606,034 .58 

Total 1,192,779 $446,812,300 .95 $188,989,202 .52 

The 1.2 million figure for the number 

of Medicare users presented previously 

includes people enrolled as of January 

2002 who lived in a community setting 

during 2003 and who filled a 

prescription for at least one of these 

MDIs in 2003. It excludes an additional 

102,000 users of these MDIs who were 

enrolled as of January 2002, lived in a 

facility for some or all of 2003, and 

filled at least one prescription. This 1.2 

million figure also counts each 

individual who used more than one of 

these MDI products one time for each 

kind of MDI used. An individual using 

more than one of these products will 

therefore be counted as a full year user 

of each product. These estimates 

exclude individuals who enrolled after 

January 2002. 

Based on the price per day of therapy 

of each of these products and of their 

alternatives, we estimate annual Federal 

spending on Medicare beneficiaries and 

private spending by Medicare 

beneficiaries will increase by $190 

million to $450 million, depending on 

whether beneficiaries switch to the 

least, or most, expensive of available 

alternatives. This calculation assumes 

that full-year beneficiaries that use each 

of these products use a full 365 days of 

therapy per year, and therefore likely 

overestimates spending increases, 

particularly in the case where an 

individual switched from one to another 

MDI in the course of a year. These 

estimates also combine estimates of the 

Medicare population with price 

estimates (introduced in table 3 of this 

document) based on the entire market. 

Actual prices paid by Medicare 

beneficiaries are likely to differ 

systematically from the market as a 

whole, though it is not clear that the 

relevant price premiums do. 

We are unable to estimate the extent 

to which these price increases will be 

paid by Medicare beneficiaries 

themselves or by the Federal 

Government. Whether individuals or the 

Federal Government will pay depends 

on beneficiaries’ aggregate drug 

spending in a given year and the plan 

they choose. Data from the Medicare 

Part D benefit, which would give us 

better estimates of prices paid and the 

public and private shares of the burden, 

are not yet available. 

E. Alternative Phase-out Dates 

We consider the impacts of the 

alternative phase-out date of December 

31, 2010, in table 6 of this document. A 

phase-out date set too far in the future 

would be incompatible with the 

timetable set by the Montreal Protocol. 

An earlier phase-out date would be 

impractical due to the time necessary to 

complete the regulatory process and to 

the risk of MDI shortages if the market 

has insufficient time to switch from CFC 

to HFA MDIs. This leaves a narrow 

window for consideration. 

TABLE 6.—SUMMARY OF IMPACTS OF A DECEMBER 31, 2010 PHASE-OUT RELATIVE TO HFA PATENT EXPIRATION

Date of HFA Patent Expiration Possible Decreases in Use of Asthma and 

COPD Therapy (million days of therapy) Discount Rate Increases in Expenditures on CFC-based MDIS, Present Value in 2006 (billions) 

2010 0 3% $0 

7% $0 

2017 4.9–77 3% $1.2–$2.4 

7% $0.9–$1.8 

Table 6 of this document shows the 

effect of different expiration dates for 

HFA MDI patents on the impact of the 

proposed rule. Listed HFA MDI patents 

expire in 2010 and 2017. We assume 

albuterol HFA MDIs are not inherently 

more costly to produce than albuterol 

CFC MDIs. Once the relevant patents 

have expired, generic competition 

should drive the price of albuterol HFA 

MDIs down to the current level of 

generic albuterol CFC MDIs. If generic 

albuterol HFA MDIs become available in 

2010, we estimate COMBIVENT users 

would not pay more to switch to both 


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albuterol HFA MDIs and ATROVENT 

HFA, due to lower prices of generic 

albuterol HFA MDIs. Therefore, current 

CFC MDI users would not, on average, 

pay more for MDIs as a result of this 

proposed rule. If current CFC MDI users 

would not pay more on average, they 

would not reduce their use of these 

products solely in response to higher 

prices. 

If, however, relevant HFA MDI 

patents do not expire until 2017, this 

proposed rule will cause current CFC 

MDI users to pay more for their MDIs 

until then, and to reduce their use of 

these MDIs in response to higher prices. 

F. Sensitivity Analyses 

The estimated impacts of this 

proposed rule summarized in table 1 of 

this document incorporate a range of 

estimates about the price increases 

consumers and other payers will face, 

the size of the affected market and how 

consumers will respond to price 

increases. This range represents the full 

uncertainty range for the estimated 

effects of this proposed rule. The full 

range incorporates the ranges of 

estimates for the individual uncertain 

variables in the analysis. 

In each section of the document, we 

show the ranges associated with each 

major uncertain variable. To estimate 

reduced use of inhaled medications, we 

estimate 23 million to 69 million days 

of therapy are used by uninsured 

individuals annually. We estimate that 

these consumers will face price 

increases in switching from CFC to HFA 

MDIs from 20 to 50 percent per day of 

therapy, depending on whether they 

switch to the most expensive or least 

expensive of the available alternatives. 

We use price elasticities ranging from 

-0.15 to -0.33 to estimate how 

consumers will reduce their MDI use in 

response to price increases. 

Similarly, estimates of the impact of 

the proposed rule on public and private 

spending depend on the overall size of 

the CFC MDI market and how much 

prices increase. We estimate the 

consumers purchase roughly 440 

million days of therapy in the form of 

CFC MDIs annually, and that prices will 

increase 20 to 50 percent depending on 

whether they switch to the most 

expensive or least expensive of available 

alternatives. If we exclude COMBIVENT 

from the calculation, the expected price 

effects range from a 30 percent increase 

to a 30 percent decrease, depending on 

whether they switch to the most 

expensive or least expensive of available 

alternatives. 

G. Conclusion 

Limits in available data prevent us 

from quantifying the costs and benefits 

of the proposed rule and weighing them 

in comparable terms. The benefits of 

international cooperation to reduce 

ozone emissions are potentially 

enormous but difficult to attribute to 

any of the small steps, such as this 

proposed rule, that make such 

cooperation effective. As discussed 

previously in detail, the benefits of the 

proposed rule include environmental 

and public health improvements from 

protecting stratospheric ozone by 

reducing CFC emissions. Benefits also 

include expectations of increased 

returns on investments in 

environmentally friendly technology, 

reduced risk of unexpected disruption 

of supply of CFC MDIs, and continued 

international cooperation to comply 

with the spirit of the Montreal Protocol, 

thereby potentially reducing future 

emissions of ODSs throughout the 

world. 

This proposed rule could potentially 

cost public and private consumers of 

CFC MDIs hundreds of millions of 

dollars annually, but it is difficult to 

link these costs to adverse public health 

outcomes. 

VIII. Regulatory Flexibility Analysis 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. FDA requests comment on this 

issue. This rule may have a significant 

impact on firms that manufacture the 

seven CFC MDIs, including firms that 

distribute CFC MDIs that are 

manufactured under contract for them. 

According to the U.S. Small Business 

Administration, ‘‘pharmaceutical 

preparation manufacturers’’ (North 

American Industrial Classification 

System (NAICS) code 325412) are 

considered small entities if they employ 

fewer than 750 people, and ‘‘drug and 

druggists’ sundries merchant 

wholesalers’’ (NAICS code 424210) are 

small entities if they employ fewer than 

100 people. None of the firms that 

manufacture the seven CFC MDIs, 

including firms that distribute CFC 

MDIs that are manufactured under 

contract for them, employ fewer than 

750 people and therefore none are small 

entities. 

We do not expect that premiums paid 

by small businesses or other small 

entities for employees’ prescription drug 

benefit plans will increase significantly 

as a result of this rulemaking. 

Accordingly, the agency does not 

believe that this proposed rule would 

have a significant economic impact on 

a substantial number of small entities. 

IX. The Paperwork Reduction Act of 

1995 

This proposed rule contains no 

collections of information. Therefore, 

clearance by the Office of Management 

and Budget under the Paperwork 

Reduction Act of 1995 is not required. 

X. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. We 

have determined that the rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. While this rule 

may result in States increasing spending 

for albuterol MDIs in programs such as 

Medicaid, the increased spending is not 

a substantial direct compliance cost, as 

the term is used in Executive Order 

13132. Accordingly, we have concluded 

that the rule does not contain policies 

that have federalism implications as 

defined in the Executive order and, 

consequently, a federalism summary 

impact statement is not required. 

XI. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments regarding this proposal. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper 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 Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

An upcoming public meeting on the 

essential-use status of MDIs containing 

flunisolide, triamcinolone, 

metaproterenol, pirbuterol, albuterol 

and ipratropium in combination, 

cromolyn, and nedocromil will provide 

an additional opportunity for public 

comment. We will provide details on 

the meeting in a notice published in the 

Federal Register in the near future. 

XII. References 

The following references have been 

placed on display in the Division of 

Dockets Management, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20852, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. FDA has verified the 


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Federal Register / Vol. 72, No. 111 / Monday, June 11, 2007 / Proposed Rules 32049 

Web site addresses, but we are not 

responsible for subsequent changes to 

the Web site after this document 

publishes in the Federal Register. 1. National Heart, Lung, and Blood 

Institute, Expert Panel Report: Update on 

Selected Topics 2002: Guidelines for the 

Diagnosis and Management of Asthma, NIH 

publication No. 02–5074, June 2003. 

2. Tasche, M. J. A. et al., ‘‘Inhaled 

Disodium Cromoglycate (DSCG) as 

Maintenance Therapy in Children with 

Asthma: A Systematic Review,’’ Thorax 

55:913–920, 2000; P. J. Helms, ‘‘Inhaled 

Disodium Cromoglycate as Maintenance 

Therapy for Childhood Asthma: Time to 

Consign to History?’’ (editorial), Thorax 

55:886, 2000; Letter from A. Edwards et al., 

and reply by Tasche et al., Thorax 56:331– 

2, 2001; Letter from G. Laszlo, and separate 

replies by Helms and Tasche et al., Thorax 

56:502–503, 2001; Letter from M. Silverman, 

and reply by Tasche, et al., Thorax 56:585, 

2001; Letter from H. K. Reddel and C. R. 

Jenkins, Thorax 56:896, 2001; Letter from 

Edwards et al. Thorax 57:282, 2002; Letter 

from Tasche, et al., Thorax 57:751–752, 2002. 

3. National Heart, Lung, and Blood 

Institute, Expert Panel Report 2: Guidelines 

for the Diagnosis and Management of 

Asthma, NIH publication No. 97–4051, July 

1997. 

4. Hofstra, W. B. et al., ‘‘Dose-Responses 

Over Time to Inhaled Fluticasone Propionate 

Treatment of Exercise-and MethacholineInduced Bronchoconstriction in Children 

with Asthma,’’ Pediatric Pulmonology, 

29:415–423, 2000. 

5. Jonasson, G. et al., ‘‘Low-Dose 

Budesonide Improves Exercise-Induced 

Bronchospasm in Schoolchildren,’’ Pediatric 

Allergy and Immunology, 11:120–123, 2000. 

6. Blake, K.V., ‘‘Montelukast: Data from 

Clinical Trials in the Management of 

Asthma,’’ Annals of Pharmacotherapy, 33 

(12):1299–314, December 1999 (errata, 

34:541, April 2000). 

7. de Benedictis, F. M. et al., ‘‘Cromolyn 

Versus Nedocromil: Duration of Action in 

Exercise-Induced Asthma in Children’’ 

Journal of Allergy and Clinical Immunology, 

96:510–4, 1995. 

8. Chrischilles, E. et al., ‘‘Delivery of 

Ipratropium and Albuterol Combination 

Therapy for Chronic Obstructive Pulmonary 

Disease: Effectiveness of Two-in-one Inhaler 

Versus Separate Inhalers’’ The American 

Journal of Managed Care, 8:902–911, 2002. 

9. Anthonisen, N. R. et al., 

‘‘Hospitalizations and Mortality in the Lung 

Health Study’’ American Journal of 

Respiratory and Critical Care Medicine, 

166:333–339, 2002. 

10. United Nations Environmental 

Programme, Production and Consumption of 

Ozone-Depleting Substances: 1986–2004, 

2005. 

11. U.S. Environmental Protection Agency, 

‘‘The Benefits and Costs of the Clean Air Act: 

1990–2010’’ (http://www.epa.gov/air/sect812/ 

copy99.html) (November 1999). 

12. Mannino, D. M. et al., ‘‘Chronic 

Obstructive Pulmonary Disease 

Surveillance—United States, 1971–2000,’’ 

Morbidity and Mortality Weekly Report, 

51(SS06):1–16, August 2, 2002. 

13. American Lung Association, ‘‘Trends in 

Asthma Morbidity and Mortality,’’ 

Epidemiology & Statistics Unit, Research and 

Program Services, July 2006. 

14. Mannino, D. M. et al., ‘‘Surveillance for 

Asthma—United States, 1980–1999,’’ 

Morbidity and Mortality Weekly Report, 

51(SS01):1–13, March 29, 2002. 

15. Analysis completed by FDA based on 

information provided by IMS Health, IMS 

National Sales Perspective (TM), 2005, 

extracted March 2006. These data are 

available for purchase from IMS Health. 

Please send all inquiries to: IMS Health, Attn: 

Brian Palumbo, Account Manager, 660 West 

Germantown Pike, Plymouth Meeting, PA 

19462. 

16. Rozek, R. P., and E. R. Bishko, 

‘‘Economics Issues Raised in the FDA’s 

Proposed Rule on Removing the EssentialUse Designation for Albuterol MDIs,’’ 

National Economic Research Associates, 

August 13, 2004 (FDA Docket No. 2003P– 

0029/C25). 

17. Goldman, D. P. et al., ‘‘Pharmacy 

Benefits and the Use of Drugs by the 

Chronically Ill,’’ JAMA: The Journal of the 

American Medical Association, 291:2344– 

2350, May 19, 2004. 

18. DeNavas-Walt, C., B.D. Proctor, and C. 

H. Lee, U.S. Census Bureau, Current 

Population Reports, P60–229, Income, 

Poverty, and Health Insurance Coverage in 

the United States: 2004, p. 18, 2005. 

19. Hurd, S., ‘‘The Impact of COPD on Lung 

Health Worldwide: Epidemiology and 

Incidence,’’ Chest, 117:2 (supplement):1S–4S, 

February 2000. 

List of Subjects in 21 CFR Part 2 

Administrative practice and 

procedure, Cosmetics, 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, 

after consultation with the 

Administrator of the Environmental 

Protection Agency, 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 continues to read as follows: 

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. 

§ 2.125 [Amended] 

2. Section 2.125 is amended by 

removing and reserving paragraphs 

(e)(1)(iii), (e)(1)(v), (e)(2)(iii), (e)(2)(iv), 

(e)(4)(iv), (e)(4)(vii), and (e)(4)(viii). 

Dated: June 4, 2007. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. 07–2883 Filed 6–6–07; 1:35 pm] 

BILLING CODE 4160–01–S 

DEPARTMENT OF THE INTERIOR 

Office of Surface Mining Reclamation 

and Enforcement 

30 CFR Part 943 

[Docket No. TX–057–FOR] 

Texas Regulatory Program and 

Abandoned Mine Land Reclamation 

Plan 

AGENCY: Office of Surface Mining 

Reclamation and Enforcement, Interior. 

ACTION: Proposed rule; reopening and 

extension of public comment period on 

proposed amendment. 

SUMMARY: We, the Office of Surface 

Mining Reclamation and Enforcement 

(OSM), are announcing receipt of 

revisions to a previously proposed 

amendment to the Texas regulatory 

program (Texas program) and the Texas 

abandoned mine land plan (Texas plan) 

under the Surface Mining Control and 

Reclamation Act of 1977 (SMCRA or the 

Act). The revisions concern 

‘‘determination of amount of penalty’’ in 

the Texas regulations and 

‘‘administrative penalties for violation of 

permit conditions’’ in the Texas statute. 

Texas intends to improve operational 

efficiency. 

This document gives the times and 

locations that the Texas program and 

Texas plan and proposed amendments 

to that program and plan are available 

for your inspection and the comment 

period during which you may submit 

written comments on the revisions to 

the amendment. 

DATES: We will accept written 

comments until 4 p.m., c.t., June 26, 

2007. 

ADDRESSES: You may submit comments, 

identified by Docket No. TX–057–FOR, 

by any of the following methods: 

• E-mail: athomas@osmre.gov. 

Include ‘‘Docket No. TX–057–FOR’’ in 

the subject line of the message. 

• Mail/Hand Delivery: A. Dwight 

Thomas, Acting Director, Tulsa Field 

Office, Office of Surface Mining 

Reclamation and Enforcement, 1645 

South 101st East Avenue, Suite 145, 

Tulsa, Oklahoma 74128. 

• Fax: (918) 581–6419. 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Instructions: All submissions received 

must include the agency name and 

docket number for this rulemaking. For 

detailed instructions on submitting 

comments and additional information 

on the rulemaking process, see the 

‘‘Public Comment Procedures’’ heading 


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