# Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Flunisolide, etc.)

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URL: https://www.frixlaw.com/law-library/documents/fr%3A2010-8467

## Record

- **Collection:** Federal Register
- **Document type:** Rule
- **Published:** April 14, 2010
- **Citation:** 75 FR 19213

## Text

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 2
[Docket No. FDA-2006-N-0304] (formerly Docket No. 2006N-0262)
RIN 0910-AF92
Use of Ozone-Depleting Substances; Removal of Essential-Use Designation (Flunisolide, etc.)

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Final rule.

SUMMARY:

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

DATES:

Removal of § 2.125(e)(2)(iii) and § 2.125(e)(4)(vii) is effective June 14, 2010. Removal of § 2.125(e)(1)(v) and § 2.125(e)(4)(iv) is effective December 31, 2010. Removal of § 2.125(e)(1)(iii) is effective June 30, 2011. Removal of § 2.125(e)(2)(iv) and § 2.125(e)(4)(viii) is effective December 31, 2013.

ADDRESSES:

For access to the docket to read background documents or comments received, go to

http://

www.regulations.gov

and insert the docket number, 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:

Martha Nguyen, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6352, Silver Spring, MD 20993-0002, 301-796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction and Highlights of the Rule

II. 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

III. Criteria

IV. Comments on the 2007 Proposed Rule

A. Flunisolide, Triamcinolone, Metaproterenol

B. Cromolyn and Nedocromil

C. Pirbuterol

1. Do Substantial Technical Barriers To Formulating Pirbuterol Products Without ODSs Exist?

2. Do Pirbuterol MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

a. Does Pirbuterol Provide a Greater Therapeutic Benefit Than Similar Adrenergic Bronchodilators?

b. Does the Breath-Actuated Device Associated With Pirbuterol MDIs Provide an Important Public Health Benefit?

3. Does Use of Pirbuterol MDIs Release Cumulatively Significant Amounts of ODSs Into the Atmosphere and Is the Release Warranted Because These MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

4. Additional Comments on Miscellaneous Issues

a. Sufficiency of Advisory Committee and Open Public Meetings

b. Sufficiency of Proposed Rule

c. Regulatory Flexibility Act

d. National Environmental Policy Act

D. Albuterol and Ipratropium in Combination

1. Do Substantial Technical Barriers To Formulating Products Containing Albuterol and Ipratropium in Combination Without ODSs Exist?

2. Do MDIs Containing Albuterol and Ipratropium in Combination Provide an Otherwise Unavailable Important Public Health Benefit?

3. Does Use of MDIs Containing Albuterol and Ipratropium in Combination Release Cumulatively Significant Amounts of ODSs Into the Atmosphere and Is the Release Warranted Because These MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

4. Additional Comments on Miscellaneous Issues

a. Criteria Used in Rulemaking

b. Intent to Reformulate

c. Deadline for Overall CFC Phase-Out

d. Sufficiency of Advisory Committee Meeting

E. Effective dates

F. Conclusions

V. Environmental Impact

VI. 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

6. Current U.S. Market for CFC MDIs

D. Benefits and Costs of the Final Rule

1. Baseline Conditions

2. Benefits of the Final Rule

a. Reduced CFC Emissions

b. Returns on Investment in Environmentally-Friendly Technology

c. International Cooperation

3. Costs of the Final Rule

4. Effects on Medicare and Medicaid

a. Medicaid

b. Medicare

E. Alternative Phase-Out Dates

F. Sensitivity Analyses

G. Conclusion

VII. Regulatory Flexibility Analysis

VIII. The Paperwork Reduction Act of 1995

IX. Federalism

X. References

I. Introduction and Highlights of the Rule

With this rule, FDA removes the last remaining essential-use designations for chlorofluorocarbons (CFCs) used in MDIs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). This regulatory action is the culmination of many years of efforts to protect the environment by limiting the production and use of ODSs. It began with a rulemaking in 1978 and involved an international treaty, legislation, and rulemakings as described in the background section. After the effective date of this rule, there will remain only three essential uses of ODSs: (1) Anesthetic drugs for topical use on accessible mucous membranes of humans where a cannula is used for application; (2) metered-dose atropine sulfate aerosol human drugs administered by oral inhalation; and (3) sterile aerosol talc administered intrapleurally by thoracoscopy for human use (21 CFR 2.125(e)(4)(iii), (vi), and (ix)).

On June 11, 2007, FDA published a proposed rule in the
Federal Register
(72 FR 32030) (the proposed rule), proposing to remove the essential-use designations for oral pressurized MDIs containing flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil. These MDIs containing chlorofluorocarbons (CFCs) or other ODSs may not be marketed without an essential-use designation. There are three criteria that must all be met for each of these MDIs to retain their essential-use designation. For each of these MDIs to retain its essential-use designation, we must find that:

1. Substantial technical barriers exist to formulating the product without ODSs;

2. The product will provide an unavailable important public health benefit; and

3. 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.

With respect to MDIs containing flunisolide, triamcinolone, metaproterenol, pirbuterol, cromolyn, and nedocromil, we tentatively found in the proposed rule that no substantial technical barriers exist to formulating them without ODSs, they do not provide an otherwise unavailable important public health benefit because of the availability of therapeutic alternatives, and the release of ODSs into the atmosphere from these MDIs is cumulatively significant and is not warranted because they do not provide an otherwise unavailable important public health benefit. In addition, we had proposed an effective date for this rule of December 31, 2009.

After considering the information received at the August 2, 2007, public meeting and written comments submitted in response to the proposal, FDA has concluded that there are no

substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, cromolyn, and nedocromil as products that do not release ODSs, and therefore flunisolide, triamcinolone, metaproterenol, pirbuterol, cromolyn, and nedocromil no longer meet the criteria to be an essential use of ODSs. We have also determined that the appropriate effective date for the removal of the essential-use designation for metaproterenol and nedocromil MDIs is June 14, 2010, the appropriate effective date for the removal of the essential-use designation for triamcinolone and cromolyn MDIs is December 31, 2010, and the appropriate effective date for the removal of the essential-use designation for flunisolide is June 30, 2011. In addition, we have determined that the appropriate effective date for pirbuterol is December 31, 2013, because this date provides over 3 years for Maxair Autohaler (pirbuterol acetate inhalation aerosol) users who are accustomed to a breath-actuated device to consult with their health care providers, evaluate options, and transition to appropriate therapeutic alternatives. We will discuss our determinations on the criteria and the effective date in section IV of this document, “Comments on the 2007 Proposed Rule.”

With respect to MDIs containing albuterol and ipratropium in combination, we were unable to determine initially whether substantial technical barriers exist to formulating them without ODSs. In the proposed rule, we tentatively found that these MDIs do not provide an otherwise unavailable important public health benefit and the release of ODSs into the atmosphere from these MDIs is cumulatively significant and is not warranted because they do not provide an otherwise unavailable important public health benefit. Again, we proposed an effective date for this rule of December 31, 2009.

After considering the information received at the August 2, 2007, public meeting and written comments submitted in response to the proposal, FDA has concluded that there are no substantial technical barriers to formulating albuterol and ipratropium bromide in combination as a product that does not release ODSs, and therefore albuterol and ipratropium bromide in combination no longer meets the criteria to be an essential use of ODSs. We have determined that the appropriate effective date for the removal of the essential-use designation for albuterol and ipratropium bromide in combination is December 31, 2013, because this date provides over 3 years to disseminate information about the transition to Combivent Inhalation Aerosol users who may have multiple health conditions that may make the transition to therapeutic alternatives more difficult. The transition period allows these individuals time to consult with their health care providers, evaluate options, and transition to appropriate therapeutic alternatives. We will discuss our determinations on the criteria and the effective date in section IV of this document “Comments on the 2007 Proposed Rule.”

II. 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 self-pressurized 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 stratospheric 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), 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 exempt from the ban. The second listed essential use was for “[m]etered-dose steroid bronchodilator human drugs for oral inhalation.” This use describes flunisolide MDIs and triamcinolone MDIs. The third listed essential use was for “[m]etered-dose adrenergic bronchodilator human drugs for oral inhalation.” This use describes metaproterenol MDIs and pirbuterol MDIs.
1

1
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 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). The essential-use designation for “[m]etered-dose ipratropium bromide and albuterol sulfate, in combination, administered by oral inhalation” was added on April 9, 1996 (61 FR 15700).

The 1978 rule provided criteria for adding new essential uses, and several uses were added to the list using these criteria, 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.B.5 of this document.

2. The Montreal Protocol

On April 21, 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 ODSs 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 196 Parties to this treaty.
3
When it joined the treaty, the United States committed to reducing production and consumption of certain CFCs to 50 percent of 1986 levels by 1998-99 (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)). Under the treaty's rules of procedure, an essential-use decision requires a two-thirds majority vote by the Parties to the treaty, although, to date, all such decisions have been made by consensus. 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.

2
FDA 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
.

3
The 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
.

4
Production of CFCs in economically less-developed countries is being phased out and is scheduled to end by January 1, 2010. See Article 2A of the Montreal Protocol.

One of the most important essential uses of CFCs under the Montreal Protocol is their use in MDIs for the treatment of asthma and 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 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).

Each request and any subsequent exemption is for only 1 year's duration (Decision V/18). 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).

Phasing out the use of CFCs in MDIs for the treatment of asthma and COPD has been an issue of particular interest to the Parties to the Montreal Protocol. 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 CFC-based MDIs (San Jose, Costa Rica, 1996).

• Decision IX/19 required developed country Parties that submitted essential-use nominations for CFC-propelled MDIs 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. 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 countries
5

(Nairobi, Kenya, 2003).

5
Our obligation under XV/5 was met by our final rule eliminating the essential-use status of albuterol (70 FR 17168, April 4, 2005).

• Decision XVII/5 states that Parties that are developed counties should provide a date to the Ozone Secretariat
6

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 nonessential (Dakar, Senegal, 2005).

6
The 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://ozone.unep.org/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 the following:

• Arranging for and servicing the Conference of the Parties, Meetings of the Parties, their Committees, the Bureaux, 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.

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 requires 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:

7
In conformance with 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).

“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 § 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 FDA regulations have interpreted the term “medical device” to refer to any product that contains an active moiety that appears on the essential-use list found in § 2.125.

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 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 moiety
8

marketed under the 1978 rule as essential uses for metered-dose 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 metered-dose 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.

8
Section 314.108(a) (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, pirbuterol, as opposed to the active ingredient, which, using the same example, would be pirbuterol acetate. 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 Maxair. In describing material from treatises, journals, and other non-FDA approved publications, we will generally follow the usage in the original publication.

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.

III. Criteria

The 2002 final rule revised 21 CFR § 2.125(g)(2) to establish a standard for removing an essential-use designation after January 1, 2005, for any drug for which there is no acceptable non-ODS alternative with the same active moiety. As explained in the proposed rule, we have reviewed the essential-use designation for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil under that authority. The process for removing the essential-use designation under § 2.125(g)(2) includes 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 the use no longer meets the criteria specified in revised § 2.125(f) for adding a new essential use (21 CFR § 2.125(g)(2)). The criteria in § 2.125(f) 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.”

The three criteria in § 2.25(f)(1) are linked by the word “and.” Because the three criteria are linked by “and” (as

opposed to “or”), failure to meet any single criterion results in a determination that the use is not essential.

As noted in the 2002 proposed rule, we intend the term “technical barriers” to refer to difficulties encountered in chemistry and manufacturing. To demonstrate that substantial technical barriers exist, it would have to be established that all available alternative technologies have been evaluated and that each alternative is unusable (67 FR 48370 at 48373). In applying the “technical barriers” criterion, we look at the results of reformulation efforts for similar products, as well as statements made about the manufacturer's particular efforts to reformulate its product or products.

In discussing what is “an unavailable important public health benefit,” we have 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.” One key point to note here is that the 2002 final rule (67 FR 48370) 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.” A petitioner seeking to add an essential-use designation should show that the use of an ODS-containing MDI 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 (64 FR 47719 at 47722).

In determining whether a drug product provides an otherwise unavailable important public health benefit, our primary focus is on the availability of non-ODS products that provide similar therapeutic benefits for patients who are currently using the CFC MDIs. If therapeutic alternatives to the CFC MDI exist, we can determine that the CFC MDI does not provide an otherwise unavailable important public health benefit.

The third criterion in § 2.125(f)(1) provides that the essential use must be eliminated unless we find either: (a) The use of the product does not release cumulatively significant amounts of ODSs into the atmosphere; or (b) 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.

Based on an extensive record dating back to the 1970s, we reached a tentative conclusion in the proposed rule that the release of ODSs into the atmosphere from the MDIs that are the subject of this rulemaking is cumulatively significant. We noted that the use of CFCs in MDIs for the treatment of asthma and COPD is the only legal use in the United States of newly produced or imported CFCs; all other uses of newly produced or imported CFCs are prohibited by the Montreal Protocol. We noted 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 that take place over a period of time (40 CFR 1508.7).

The criteria in § 2.125(g)(2) (which refers to those found in § 2.125(f)(1)) that we are using in this rulemaking 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 marketed non-ODS product containing the active moiety listed as an essential use, while § 2.125(g)(3) and (g)(4) apply to situations where there is at least one marketed non-ODS product with the listed active moiety. Section 2.125(g)(2) permits FDA to remove an essential use even if a current essential-use active moiety is not reformulated, provided that sufficient alternative products exist to meet the needs of patients, because the essential use would no longer provide an otherwise unavailable important health benefit. As we explained in the proposed rule, the analysis we use here is different from the analysis we used under § 2.125(g)(4) in the rulemaking to remove the essential use for albuterol (70 FR 17168, April 4, 2005). However, the basic concern of protecting the public health underlies all of the criteria. 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).

Section 2.125(g)(2) requires that we consult an advisory committee and hold an open public meeting before we remove an essential-use designation when there is no non-ODS product with the same active moiety. Prior to publishing the proposed rule, on July 14, 2005, we consulted with FDA's Pulmonary and Allergy Drugs Advisory Committee (PADAC) on the essential-use status of MDIs containing flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil (PADAC meeting) (see 70 FR 24605, May 10, 2005).
9

9
A transcript of the meeting and other meeting material is available on the Internet at
http://www.fda.gov/ohrms/dockets/ac/cder05.html#PulmonaryAllergy
.

On August 2, 2007, following publication of the proposed rule, we held the required open public meeting to discuss the issues involved in removing the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil MDIs (see the
Federal Register
of July 9, 2007 (72 FR 37137)). Input from the open public meeting is considered and discussed in section IV of this document together with the written comments that were submitted in response to the proposed rule.

IV. Comments on the 2007 Proposed Rule

We received over 4,000 comments in response to the proposed rule. They were submitted by consumers, health care providers, patient advocacy groups, professional groups, manufacturers, a Congressional caucus, and industry organizations. The speakers who participated in the open public meeting on August 2, 2007, also submitted written comments. In the discussion that follows, we address the oral presentations and written comments submitted at or following the open public meeting, and the written and electronic comments submitted to the docket in response to the 2007 proposed rule.

To make it easier to identify comments and our responses, the word “Comment,” in parentheses, appears before the comment's description, and the word “Response,” in parentheses, appears before our response. We have numbered each comment to help distinguish between different comments. Similar comments are grouped together under the same comment number. The number assigned to each comment is purely for organizational purposes and does not signify the comment's value or importance or the order in which it was received.

In reviewing these comments we are particularly focused on our proposed findings relating to the criteria in § 2.125(f) of our regulations. As discussed above, we must remove the

essential-use designation for a CFC-containing drug product unless we find that all of the following are met: (1) Substantial technical barriers exist to formulating the product without ODSs; (2) the product provides an unavailable important public health benefit; and (3) use of the product does not release cumulatively significant amounts of ODSs into the atmosphere or, if the release is significant, it is warranted in view of the unavailable important public health benefit. As discussed in the proposed rule, the failure to meet any one of these criteria results in our determination that the use is not essential.

A. Flunisolide, Triamcinolone, Metaproterenol

We are removing the essential-use designations for MDIs containing flunisolide (Aerobid Inhaler System) and triamcinolone (Azmacort Inhalation Aerosol). Aerobid and Azmacort are orally inhaled corticosteroids. Azmacort is the only currently marketed drug product that provides orally inhaled triamcinolone. Both Aerobid and Aerospan Inhalation Aerosol provide orally inhaled flunisolide, but Aerobid is the only currently marketed flunisolide drug product that contains ODSs. 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 6 years of age and older, 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 ODS-containing Aerobid, Aerospan Inhalation Aerosol, a new drug application (NDA) for a flunisolide HFA MDI, was approved January 27, 2006 (NDA 21-247), but has not yet been introduced onto the market.

We are also removing the essential-use designation for MDIs containing metaproterenol (Alupent Inhalation Aerosol). Metaproterenol is a short-acting beta
2
-adrenergic agonist used in the treatment of bronchospasm associated with asthma and COPD. It acts as a bronchodilator. 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 Inhalation Aerosol which contains CFCs. Alupent Inhalation Aerosol is a prescription drug. Alupent Inhalation Aerosol's use was considered essential under the 1978 rule, which stated that “[m]etered-dose adrenergic bronchodilator human drugs for oral inhalation” were essential. Metaproterenol was designated as essential as an active moiety in the 2002 rule. Alupent Inhalation Aerosol was approved on July 31, 1973. Boehringer Ingelheim Pharmaceuticals, Inc., the manufacturer of Alupent Inhalation Aerosols, has informed us that they discontinued U.S. distribution of Alupent Inhalation Aerosols as of November 14, 2008.

In the proposed rule, we tentatively concluded that there are no technical barriers to formulating flunisolide, triamcinolone, and metaproterenol MDIs without ODSs (72 FR 32030 at 32036-37). We did not receive any substantive comments disagreeing with our tentative conclusion. Therefore, we conclude that that there are no technical barriers to formulating flunisolide, triamcinolone, and metaproterenol MDIs without ODSs. As stated earlier, flunisolide has been reformulated in an HFA MDI, but the product is not yet marketed. We also did not receive any substantive comments on the second and third criteria in § 2.125(f)(1).
10

As explained in section III of this document, because the three criteria are linked by the word “and,” failure to meet any single criterion results in a determination that the use is not essential. Accordingly, because we have found in this rule that there are no substantial barriers to reformulating these products, we are required to find that the use of the products is not essential, and we do not need to reach a decision on the second or third criteria in § 2.125(f)(1).

10
Abbott Laboratories, the NDA holder for Azmacort Inhalation Aerosol, submitted and later withdrew its comment. Therefore, we do not address the comment submitted by Abbot in response to the proposed rule.

B. 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 treatment of symptoms associated with mastocytosis. Only MDI formulations are affected by this rulemaking.

The only cromolyn MDI (Intal Inhaler) 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 Inhaler) was approved for marketing on 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). Intal Inhaler and Tilade Inhaler are indicated for the management of asthma in patients 5 years and older and 6 years and older, respectively. Both are prescription drugs. Neither drug is indicated for the relief of acute bronchospasm. On November 21, 2008, King Pharmaceuticals, Inc., the manufacturer of Tilade Inhaler, informed us that they had discontinued manufacturing of Tilade Inhaler in July 2008.

In the proposed rule, we tentatively concluded that there are no technical barriers to formulating cromolyn and nedocromil MDIs without ODSs (72 FR 32030 at 32038). We did not receive any substantive comments disagreeing with our tentative conclusion. Therefore, we conclude that there are no technical barriers to formulating cromolyn and nedocromil MDIs without ODSs. As explained in section III of this document, because the three criteria in § 2.125(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, because we have found in this rule that there are no substantial barriers to reformulating these products, we are required to find that the use of the products is not essential, and we do not need to reach a decision on the second or third criteria in § 2.125(f)(1).

However, we received several comments addressing the second and third criteria with respect to cromolyn and nedocromil, and we respond to these comments below.

(Comment 1) We received one comment arguing that there are no acceptable treatment alternatives for cromolyn and nedocromil.

(Response) In the proposed rule, we identified several orally inhaled corticosteroids that do not contain CFCs as therapeutic alternatives to Intal Inhalers and Tilade Inhalers, including beclomethasone dipropionate inhalers, budesonide inhalers, fluticasone propionate inhalers, and mometasone furoate inhalers (72 FR 32030 at 32037). We believe that most patients using Intal Inhalers and Tilade Inhalers as a controller medication should be adequately served by at least one of these currently marketed formulations. The comment did not provide explanation as to why the proposed alternatives are insufficient, so it is difficult to address this comment more fully. In addition to the active moieties described in the proposed rule, oral montelukast may be an appropriate therapeutic alternative. Also, cromolyn is available in a solution for use in nebulizers. For patients who use Intal Inhalers to treat exercise-induced bronchospasm, inhaled beta
2
-agonists such as albuterol, salmeterol, and formoterol are considered suitable therapeutic alternates.

(Comment 2) One comment notes that Intal inhalers are safe for pregnant women and protect against pet allergen exposure.

(Response) Current FDA regulations on labeling for use during pregnancy require the classification of each drug product under one of five pregnancy categories (A, B, C, D, or X) on the basis of risk of reproductive and developmental adverse effects or, for certain categories, on the basis of such risk weighed against potential benefit. 21 CFR § 201.57(c)(9)(i)(A)(2). Intal Inhalers are classified as a Pregnancy Category B drug. Pregnancy Category B indicates that animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women. In the proposed rule, we identified several non-CFC orally inhaled corticosteroids as therapeutic alternatives to cromolyn and nedocromil MDIs. One of these orally inhaled corticosteroids, budesonide inhalers (marketed as Pulmicort Turbuhaler and Pulmicort Flexhaler), is also classified as a Pregnancy Category B drug. We believe that budesonide inhalers are an appropriate non-CFC therapeutic alternative for pregnant women who are currently using Intal Inhalers.

We have no data to suggest that Intal is more effective than the therapeutic alternatives at preventing asthma symptoms triggered by pet allergens. Although we believe that current Intal and Tilade users will be adequately served by the inhaled corticosteroids identified above, we also note the availability of cromolyn sodium in a nebulized solution, which may provide a therapeutic alternative for situations involving planned and known exposures to allergens.

(Comment 3) One comment suggested that the amount of CFCs released from Intal and Tilade Inhalers is inconsequential.

(Response) As we have noted in previous rulemakings, the environmental impact of CFCs used in MDIs, including Intal and Tilade MDIs, 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, including Intal and Tilade, 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 Intal and Tilade 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 phase-out of CFC use. The release of ODSs from some of the MDIs, including Intal and Tilade, 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.

C. Pirbuterol

We are removing the essential-use designations for MDIs containing pirbuterol (Maxair Autohaler). Pirbuterol is a short-acting beta
2
-adrenergic agonist used in the treatment of bronchospasm associated with asthma and COPD. Pirbuterol acts as a bronchodilator. Pirbuterol is only available in a CFC MDI. Maxair Autohaler is one of two beta
2
-adrenergic agonist MDIs currently marketed as a prescription drug which contains CFCs. The other product, Alupent Inhalation Aerosol, is addressed in section IV.A of this document. Albuterol is also a beta
2
-adrenergic agonist, but it is no longer marketed as a CFC MDI. Albuterol was addressed in a separate rulemaking, which removed its essential-use designation effective December 31, 2008. Maxair Autohaler is a prescription drug that was approved on November 30, 1992. Maxair Autohaler's use was considered essential under the 1978 rule, which stated that “[m]etered-dose adrenergic bronchodilator human drugs for oral inhalation” were essential. Pirbuterol was designated as essential as an active moiety in the 2002 rule. Maxair Autohaler has a breath-actuated delivery system.

1. Do Substantial Technical Barriers To Formulating Pirbuterol Products Without ODSs Exist?

We proposed a finding that there are no technical barriers to formulating pirbuterol MDIs without ODSs (72 FR 32030 at 32037).

(Comment 4) One comment, Graceway Pharmaceuticals, LLC (Graceway), the manufacturer of Maxair Autohaler, states that there are substantial barriers (chemistry, manufacturing, and engineering) to reformulating Maxair Autohaler without ODSs. Graceway also states these barriers are complicated by the breath-actuated system, which is more sensitive with respect to particle size and energy force.

(Response) When determining whether technical barriers to formulating pirbuterol MDIs without ODSs exist, we consider whether all available alternative technologies have been evaluated and whether each alternative is unusable (64 FR 47719 at 47721, September 1, 1999). In addition, we look at results of reformulation efforts for similar products, as well as statements made about the manufacturer's particular efforts to reformulate their product or products. Graceway has not demonstrated that the breath-actuated system is more sensitive with respect to particle size and energy force or explained how any such sensitivity poses a barrier to reformulating Maxair without ODSs. As noted in the proposed rule, the pharmaceutical industry has had success in formulating other orally inhaled beta
2
-adrenergic bronchodilators without ODSs. At least nine different active moieties have been

formulated as HFA MDIs for the treatment of asthma and COPD in the United States and abroad.
11

HFA MDIs have been formulated with both suspensions and solutions. Pirbuterol is a close chemical analog to albuterol and levalbuterol. Given the chemical similarity between them and the success with reformulating albuterol (as albuterol sulfate in ProAir HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and Ventolin HFA Inhalation Aerosol) and levalbuterol (as levalbuterol tartrate in Xopenex HFA Inhalation Aerosol), there appears to be no technical reason why pirbuterol cannot be successfully reformulated into an HFA MDI.

11
The nine moieties formulated as HFA MDIs are albuterol, beclomethasone, budesonide, fenoterol, fluticasone, flunisolide, formoterol, ipratropium, and salmeterol. While a salmeterol DPI (SEREVENT) has been approved in the United States, salmeterol HFA MDIs have only been approved overseas. There are no approved fenoterol or formoterol HFA products in the United States, but fenoterol HFA MDIs and formoterol HFA MDIs have been approved in several foreign countries.

Furthermore, Graceway has not demonstrated that it evaluated all available alternative technologies and found each alternative unusable—the standard described in section III of this document (64 FR 47719 at 47721, September 1, 1999). At the time the proposed rule published, we had no evidence to suggest that the ODS containing pirbuterol oral inhalation drug product posed unique technical challenges to formulation without ODSs. Since the time the proposed rule published, no data have been submitted to change that conclusion. Therefore, after consideration of the public comments on the issue, we conclude that there are no technical barriers to the development of a non-ODS pirbuterol product.

2. Do Pirbuterol MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

In the proposed rule we tentatively found that pirbuterol MDIs do not provide an otherwise unavailable important public health benefit (72 FR 32030 at 32037). Because we have reached a conclusion that there are no substantial technical barriers to formulating pirbuterol into a non-ODS product, we do not believe it is necessary to reach a conclusion on the public health benefits of pirbuterol MDIs. However, we received a large number of comments in response to the proposed rule addressing the public health benefits of pirbuterol MDIs, and we believe it is appropriate to address the public health benefits in light of these comments.

a.
Does Pirbuterol provide a greater therapeutic benefit than similar adrenergic bronchodilators?
(Comment 5) In its comment in response to the proposed rule, Graceway claims that Maxair Autohaler provides important public health benefits that would otherwise be unavailable to substantial numbers of patients who have asthma or COPD. Graceway states that Maxair Autohaler is an alternative for those who do not tolerate or respond to albuterol and levalbuterol. Graceway bases this conclusion in part on the distinct chemical structure of pirbuterol, which Graceway claims is different from albuterol and levalbuterol, and also on variation among patients. In its comment, Graceway presents statements from physicians and patients claiming that many patients experience intolerance or allergic reaction to albuterol, but succeed on pirbuterol. In addition, we received many comments from pirbuterol users and physicians who prescribe pirbuterol, detailing experiences with pirbuterol and alternative MDIs, such as albuterol. The comments describe reactions to and intolerance experienced with albuterol and success with pirbuterol. Furthermore, many of the comments from the physicians and pirbuterol users claim that experience indicates that pirbuterol MDIs are more effective than albuterol MDIs.

(Response) Albuterol and pirbuterol are both short-acting beta
2
-adrenergic bronchodilators. Bronchodilation occurs primarily through stimulation of the beta
2
-adrenergic receptor. Albuterol MDIs are therapeutic alternatives to pirbuterol MDIs and are, by far, the most widely prescribed short-acting bronchodilators. We are not aware of any studies that support the comments' contentions that albuterol inhalers are not an appropriate alternative for pirbuterol inhalers. Moreover, we disagree with the contention that the pirbuterol MDIs provide any unique therapeutic or other advantage over the available alternatives. The labeling for Maxair Autohaler does not contain any superiority claims based on controlled clinical trials and we do not believe that anecdotal evidence is adequate to support such a conclusion.

Four prescription HFA MDIs with two different forms of albuterol are approved and currently available:

• ProAir HFA (albuterol sulfate) Inhalation Aerosol;

• Proventil HFA (albuterol sulfate) Inhalation Aerosol;

• Ventolin HFA (albuterol sulfate) Inhalation Aerosol; and

• Xopenex HFA (levalbuterol tartrate) Inhalation Aerosol.

These products use HFA, which does not affect stratospheric ozone as a replacement for ODSs. Maxair Autohaler 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, and have similar dosing regimens. At least one of the currently available albuterol drug products should be an adequate therapeutic alternative for patients currently using Maxair Autohaler.

We are not aware of any adequate and well-controlled studies which support the comments' views that individuals who do not respond to or tolerate albuterol and levalbuterol would find pirbuterol MDIs more effective or better tolerate pirbuterol, or that pirbuterol MDIs are more effective than other asthma MDIs, including albuterol HFA MDIs. The National Asthma Education and Prevention Program, Expert Panel Report 3 (NAEPP EPR-3) recommends that short-acting beta
2
-adrenergic bronchodilators, in particular albuterol, levalbuterol, and pirbuterol, are the most effective medications for relieving acute bronchospasm. (Ref. 1) The NAEPP EPR-3 does not distinguish pirbuterol as providing any unique therapeutic or other advantage over the available alternatives.
12

Furthermore, the opinion of all PADAC members who voted on the issue was that pirbuterol is no longer an essential use of ODSs (72 FR 32030 at 32037). The studies and literature cited by Graceway in its comment provide cases of non-response or inadequate response to albuterol and levalbuterol. Graceway did not present studies comparing pirbuterol to albuterol or showing that pirbuterol would be more effective for those users who do not respond to or inadequately responded to albuterol. In fact, in its comment (Comment No. 4), Graceway stated that clinical studies have not been conducted to establish whether patients may respond differently to pirbuterol.

12
In the United States, the generally recognized standard of care for asthma is set forth in the National Heart, Lung, and Blood Institute's National Asthma Education and Prevention Program, Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3) (Ref. 2). The National Heart, Lung, and Blood Institute is one of the National Institutes of Health. In the 2007 update, we find the latest updates to the standard. The Guidelines represent best practices and are recognized as the clinical standard of care for treatment of asthma. See, e.g.,
http://www.asthmanow.net/care.html
;
http://www.colorado.gov/bestpractices/index.html
;
http://www.doh.wa.gov/CFH/asthma/publications/plan/health-care.pdf
.

As stated previously, if therapeutic alternatives exist for users of the CFC MDI, we can determine that the CFC MDI does not provide an otherwise unavailable important public health benefit. We have carefully considered these comments asserting that Maxair Autohaler is a more effective alternative to other asthma MDIs. However, no data were submitted to the agency as part of this rulemaking, and the agency is not aware of any data that allow us to reach the conclusion that pirbuterol provides a greater therapeutic benefit than similar adrenergic bronchodilators. Thus, we believe that patients will be adequately served by alternative MDIs.

(Comment 6) Graceway also argues that pirbuterol is more likely than albuterol to select beta
2
receptors, which presents less risk of cardiac side effects.

(Response) As stated in response to the previous comment, albuterol and pirbuterol are both short-acting selective beta
2
-adrenergic bronchodilators that achieve bronchodilation primarily through the beta
2
-adrenergic receptor. Therefore, they both bind to the same receptor that causes bronchodilation. The studies Graceway submitted to support the conclusion that pirbuterol is more likely than albuterol to select beta
2
-adrenergic receptors do not demonstrate that there is any difference in clinical efficacy or safety between the two drugs. Moreover, the Maxair Autohaler label warns of the same cardiovascular effects as other inhaled beta adrenergic agonists. The NAEPP EPR-3 states that albuterol, levalbuterol, and pirbuterol are all effective agonists and have few negative cardiovascular effects. Accordingly, we disagree that there is less risk of cardiac side effects with use of pirbuterol MDIs than with use of albuterol MDIs.

b.
Does the breath-actuated device associated with pirbuterol MDIs provide an important public health benefit?
(Comment 7) Graceway, as well as many other comments, stresses the importance of Maxair Autohaler's breath-actuated device in providing an otherwise unavailable important public health benefit. Many people claim they cannot operate traditional press-and-breathe MDIs. They further claim that it is extremely inconvenient and more challenging to use a traditional press-and-breathe MDI with a spacer device to assist with coordination problems. Because spacers are bulky and less portable, people are less likely to carry them, and because they require additional maintenance, people are less likely to use them. The comments argue that Maxair Autohaler's ease of use, convenience, and portability allow for increased compliance. Graceway argues that the compliance obstacles will lead to an increase in morbidity, as well as an increase in missed school/work days and physician, hospital, and emergency department visits.

(Response) While some individuals or groups of people may have difficulty operating the alternative MDIs that use traditional press-and-breathe devices, and Maxair Autohaler's Autohaler device may be convenient, there are other options for these individuals and groups to treat their asthma or COPD. We understand the difficulties for certain groups of people, such as young children, older adults, and the physically or mentally disabled, of coordinating inhalation with MDI activation. Learning how to properly maintain medical devices and administer medication is a sometimes difficult, but necessary task for many patients with chronic diseases. It would certainly be more convenient to have available many different devices to meet the individual and distinct needs of every patient group. However, we do not believe that this type of patient convenience provides a basis to conclude that a product provides an otherwise unavailable health benefit. Because therapeutic alternatives exist, use of pirbuterol MDIs is not absolutely necessary to save lives, to reduce or prevent asthma morbidity, or to significantly increase patient quality of life.

The use of spacer devices with alternative products provides options for patient groups who have difficulties coordinating inhalation with MDI operation, allowing them to more satisfactorily use MDIs that do not have a breath-actuated delivery mechanism. A spacer is a device that adds space between the mouthpiece of an MDI and the patient's mouth and is used to increase the effectiveness of an MDI. Some have valves that result in the aerosol from the MDI being briefly held in a reservoir from which the patient subsequently inhales the aerosolized medication. Nebulizers provide another option for individuals or patient groups with coordination problems. Systematic reviews and meta-analyses have suggested that each of the aerosol delivery devices can work equally well in patients who can use them correctly. (Ref. 2) The availability of alternatives for those individuals or patient groups who are unable to operate traditional press-and-breathe devices supports a conclusion that any added convenience of a breath-actuated device for patients who have been prescribed drugs for the treatment of asthma or COPD does not provide an unavailable important public health benefit within the meaning of 21 CFR 2.125(f)(1)(ii).

Furthermore, we are not removing the breath-actuated delivery mechanism from the market; rather, as a result of this rule, the CFC-propelled pirbuterol may no longer be marketed. Graceway, or another company, may develop a breath-actuated delivery system with pirbuterol or other drugs of the class that do not use CFCs.

(Comment 8) Graceway also claims that it will be more costly to switch to one of the proposed alternatives. Increased costs include higher copayments for branded HFA MDIs, extra visits to health care providers to adjust treatment, purchase of spacers, and the cost of failing to adequately manage asthma or COPD. Graceway contends that the use of alternative MDIs is more costly because Maxair Autohaler contains 400 inhalations per MDI, twice the number of inhalations of alternative MDIs.

(Response) The bases Graceway identifies in support of its argument that it will be more costly to switch from Maxair Autohaler to an alternative MDI are largely invalid. First, Maxair Autohaler, the only marketed pirbuterol drug product, is a branded, rather than a generic, product. The therapeutic alternatives for Maxair Autohaler are also branded products. Therefore the purchase of an alternate branded HFA (hydrofluoroalkane HFA-134a) inhaler would require no greater copayment. Second, for most patients with asthma or COPD who use inhalers, regular doctor visits to adjust treatment plans are routine. There is no reason to believe that patients who use alternative HFA inhalers require any more adjustment in treatment than patients who use pirbuterol inhalers with a CFC propellant. Finally, no data have been presented to demonstrate that the cost of failing to adequately manage asthma or COPD is greater for individuals who use alternative HFA inhalers than for those who use Maxair Autohaler. As discussed in section VI of this rule, we anticipate the price per day of therapy to decrease after patients transition from Maxair to alternative therapies. Nevertheless, some individual patients might face higher costs, perhaps related to the costs of additional copayments associated with fewer numbers of inhalations provided by an alternative MDI.

We recognize that the pirbuterol breath-actuated MDIs may provide some public health benefits; however, nothing in this rulemaking suggests that continued use of these MDIs provides an unavailable important health benefit as previously defined. We do not

believe that we can conclude on the basis of the record in this rulemaking that continued use of Maxair Autohaler is necessary to save lives, to reduce or prevent asthma morbidity, or to significantly increase patient quality of life, particularly given the availability of albuterol MDIs as therapeutic alternatives, and the availability of spacers and nebulizers for use in lieu of breath-actuated MDIs.

In any case, given that we have already found no technical barriers to reformulation of pirbuterol MDIs under § 2.125(g)(2), a finding on the public health benefit issue is not necessary to this rulemaking, and we decline to make a specific finding on that issue in this final rule.

3. Does Use of Pirbuterol MDIs Release Cumulatively Significant Amounts of ODSs Into the Atmosphere and Is the Release Warranted Because These MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

As explained in the proposed rule and above, because we have found in this rule that there are no substantial technical barriers to reformulating pirbuterol, we are required to find that the use of the product is not essential, and we do not need to reach a decision on the third criterion in § 2.125(f)(1). Nonetheless, based on the criteria described above and in the proposed rule, the quantity of CFCs used in pirbuterol MDIs is a significant portion of the total quantity of newly manufactured CFCs used, and therefore eventually released, in the United States. Accordingly, we tentatively concluded that any release of CFCs from pirbuterol MDIs is cumulatively significant (72 FR 32030 at 32033, 32034, and 32037). We received comments on the amount of CFCs released into the atmosphere from pirbuterol MDI use.

(Comment 9) Graceway asserts that the use of Maxair Autohaler does not release cumulatively significant amounts of ODSs into the atmosphere, and its de minimis release is warranted in view of the essential health benefits provided by the product. Graceway claims that Maxair Autohaler releases fewer CFCs than other MDIs because it releases fewer CFCs per puff than other MDIs and has a smaller market share. Graceway argues that without calculating the quantity of CFCs released from use of Maxair Autohaler alone, the agency admitted the quantity would, in any event, be minor. Graceway further argues that the agency has not shown how aggregate release of CFCs from all seven moieties has a significant impact on the environment.

(Response) Although we based our tentative conclusion that pirbuterol MDIs release cumulatively significant amounts of ODSs on previous policy statements about the environmental impact of CFCs, the basis for removing the essential-use designation for pirbuterol in this rulemaking is no significant barriers exist to reformulating pirbuterol MDIs without ODSs. We need not reach a conclusion that pirbuterol MDIs release cumulatively significant amounts of ODSs. Furthermore, as discussed previously, it is not necessary for us to reach a conclusion on the public health benefits of Maxair Autohaler, or to conduct the balancing test to reach a determination as to whether the release of CFC ODSs is warranted in view of the public health benefits. Regardless of outcome, the balancing test would not affect the ultimate finding in this rulemaking that, because there are no significant technical barriers to reformulation of the product, pirbuterol is no longer an essential use of ODSs and should be removed from the list of essential uses in § 2.125(e).

4. Additional Comments on Miscellaneous Issues

a.
Sufficiency of advisory committee and open public meetings.
(Comment 10) Graceway submitted a number of comments claiming insufficiencies of the two meetings held concerning the proposed rule to remove the essential-use designations of the seven moieties that are the subject of this final rule. Graceway asserts that the Pulmonary and Allergy Drugs Advisory Committee (PADAC) meeting held on July 14, 2005, did not fulfill the 21 CFR 2.125(g)(2) requirement for consultation with an advisory committee because the notice of the meeting did not identify the products and moieties at issue, state that the meeting was intended to fulfill requirements of 21 CFR 2.125(g)(2), or discuss the purpose and scope of the meeting. Therefore, informed views from independent experts could not be obtained because interested persons/companies either had no knowledge of the meeting or had insufficient time to adequately prepare for the meeting. Graceway also asserts that the background memorandum provided to the PADAC was inadequate and that committee members were confused. In addition, Graceway asserts that the agency did not properly consult with the committee members as to the health benefits of the moieties at issue and failed to consider the committee's advice or recognize issues raised by the committee members.

(Response) FDA may remove an essential-use designation under section 2.125(g)(2) if it no longer meets certain criteria after consultation with a relevant advisory committee and after holding an open public meeting. FDA made clear in the 1999 rule proposing criteria for removing essential-use designations that, before removing any essential-use designation, it would consult with an advisory committee and provide opportunity for public comment (64 FR 47719 at 47722). FDA published a notice in the
Federal Register
on May 10, 2005 (70 FR 24605), that the PADAC would be convening on July 14, 2005, to discuss the continued need for the essential-use designations of prescription drugs for the treatment of asthma and COPD. The notice further stated that interested persons could present data, information, or views, orally or in writing, on the issues pending before the committee. This notice provided sufficient time for those persons or companies with an interest in the essential-use designations of any moieties used in drugs that treat asthma or COPD to provide the committee members with any information they believed would be pertinent to the decision to remove a designation.

It was noted at the meeting that the committee was convened to determine whether changes in medical practice and the availability of alternatives render the products listed as essential no longer essential. The background memorandum provided to the PADAC described the regulatory criteria for removing essential uses and advised the committee to focus attention on the criterion related to the important public health benefits of the moieties. The background memorandum also listed those products containing CFCs that were still marketed and for which there were no current reformulations or direct alternative products, and products currently approved or marketed that do not contain CFCs. These lists were provided to assist the committee when considering whether adequate alternative therapy is available. The opportunity to ask clarifying questions was provided at the meeting, and presentations were made by an association representing manufacturers of MDIs, particular MDI manufacturers, and an interested person. Therefore, we disagree with the assertion that informed views from independent experts could not be or were not obtained.

After the presentations, the committee discussed the individual moieties, including pirbuterol, with regard to their essentiality. A majority of the members agreed that pirbuterol is

nonessential. The transcript of the meeting, available at
http://www.fda.gov/ohrms/dockets/ac/cder05.html#PulmonaryAllergy
, does not reveal any confusion on the part of the committee members. In the proposed rule, we stated that we consulted with the PADAC at their July 14, 2005, meeting on the essential-use status of MDIs containing, among other moieties, pirbuterol, and that the PADAC members gave their opinions, without dissent, that pirbuterol was no longer an essential use of ODSs (72 FR 32030 at 32035, 32037). Thus, FDA has taken full consideration of the opinions of the committee members.

(Comment 11) Graceway asserts that the agency failed to meet the spirit of the 21 CFR 2.125(g)(2) public meeting requirement to enrich notice-and-comment rulemaking. Graceway stated that scheduling the meeting with less than 3 weeks' notice, the lack of publicity, and the decision to hold a single meeting in one location were barriers to participation by patients, clinicians, and outside experts. Graceway also stated that the agency failed to solicit feedback on patients' experience with HFA alternatives and thus limited the scope of the administrative record.

(Response) FDA published a notice in the
Federal Register
on July 9, 2007 (72 FR 37137), that the public meeting would be held on August 2, 2007, at FDA's Center for Drug Evaluation and Research Advisory Committee conference room in Rockville, MD. The notice stated that the meeting was to solicit comments on the proposed rule amending the regulation on the use of ODSs to remove the essential-use designations for certain MDIs, and invited written or electronic comments for consideration at the meeting, as well as requests to speak at the meeting. We believe we provided sufficient notice of the meeting to allow for widespread participation and did not create barriers to participation by patients, clinicians, and outside experts. Accordingly, we disagree with Graceway's implication that the agency did not comply with the regulatory requirement for an open public meeting. Furthermore, in the proposed rule, we solicited any comments related to the removal of the essential-use designations for MDIs containing pirbuterol and other moieties, and in the notice of the public meeting we invited discussion of issues on which we asked for comments in the proposed rule. In fact, we received thousands of comments on patients' experiences with HFA alternatives to pirbuterol in particular. Therefore, we strongly disagree that the scope of the administrative record was limited in any way.

b.
Sufficiency of proposed rule.
(Comment 12) Graceway argues that FDA failed to publicize the proposed rule through a press release, public announcement, or on the Internet, and inhibited public participation in the rulemaking process.

(Response) Interested persons have had ample notice that FDA was considering removing the essential-use designation for pirbuterol and the six other drugs that are the subject of this rulemaking. This issue was first considered at the July 14, 2005, PADAC meeting (see 70 FR 24605). The trade press reported on this meeting, and minutes and a transcript of the meeting were placed on the Internet and are available at
http://www.fda.gov/OHRMS/DOCKETS/ac/cder05.html#PulmonaryAllergy
. We also announced our intention to publish a proposed rule in the unified agendas published in the
Federal Register
on December 11, 2006 (71 FR 73195 at 73223), and April 30, 2007 (72 FR 22489 at 22516). As stated previously, we published the proposed rule in the
Federal Register
on June 11, 2007 (72 FR 32030). These publications put the public on notice of our intent to remove the essential-use designations, and invited comments on our proposal. In addition, we held an open public meeting, as discussed previously, for which we solicited input from interested parties. Several companies, including Graceway, gave presentations at the open public meeting. Furthermore, our MDI Web site,
http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm063054.htm
, discusses the phase-out of all essential use designations and contains copies of all relevant documents, including the June 11, 2007, proposed rule. Our receipt of thousands of comments on the proposed rule further shows that the public was well aware of our intent to remove the essential-use designations and that public participation was not inhibited.

(Comment 13) Graceway also argues that FDA must give weight to the quality and quantity of comments submitted in response to the proposed rule because the number of comments is material where the degree of public interest is a legitimate factor for consideration. Graceway states that with regard to this rule, input from patients, physicians, and pharmacists is crucial because the decision-making involves weighing important and competing public policy considerations.

(Response) We have given due weight and full consideration to all comments submitted in response to the proposed rule. We have read each comment individually and provided responses to all unique comments submitted. When comments were duplicative in substance, we provided one response to all like comments. We fully understand the concern with removal of the essential-use designations and have weighed the public policy considerations, as discussed previously. After weighing the important and competing public policy considerations, and considering the nature and number of comments, we have concluded that the public is best served by the decision to remove the essential-use designations that are the subject of this rule.

(Comment 14) Graceway asserts that FDA's failure to create a confidential docket prevented companies from commenting on issues related to development of non-ODS formulations of pirbuterol.

(Response) There is no provision in our regulations for creating a confidential docket. As we commented previously with regard to technical barriers, the pharmaceutical industry has had success in formulating other orally inhaled beta
2
-adrenergic bronchodilators without ODSs. Given the chemical similarity between the moieties used in these other bronchodilators and pirbuterol, and the success with reformulating albuterol and levalbuterol, there appears to be no technical reason why pirbuterol cannot be successfully reformulated into an HFA MDI or other non-ODS inhalation delivery system. Moreover, Graceway could have readily provided general comments related to development of a non-ODS delivery system.

(Comment 15) Graceway stated that FDA's concerns over the availability of CFCs beyond 2009 are more properly addressed through negotiation at Montreal Protocol meetings, rather than through removal of essential-use designations.

(Response) As a Party to the Montreal Protocol, the United States Government committed to eliminating all non-essential uses and reducing essential uses of CFCs. The Preamble to the Protocol states that the Parties are: “Determined to protect the ozone layer by taking precautionary measures to control equitably total global emissions of substances that deplete it,
with the ultimate objective of their elimination
” (Preamble to the Montreal Protocol (emphasis added.)). FDA's actions in this rulemaking are consistent with the United States' position in meetings regarding the Montreal Protocol. Discussion of the United States' position with regard to the Montreal Protocol is more appropriately directed to the

Department of State, which heads the United States delegation to meetings regarding the Montreal Protocol. If any company wants the United States to alter any of the positions taken with the Parties to the Protocol, it should present its views to appropriate officials in the State Department.

c.
Regulatory Flexibility Act.
(Comment 16) Graceway asserts that FDA erroneously concluded that none of the firms that manufacture the seven CFC MDIs is a small entity under the Regulatory Flexibility Act because none employs fewer than 750 people, and therefore the proposed rule would not have a significant economic impact on a substantial number of small entities. Graceway states that it is a small entity because it employs fewer than 750 people. It also claims that it constitutes a significant number of small entities because Graceway makes up more than 5 percent of the total number of affected entities (the five NDA holders for prescription CFC MDI products) and 100 percent of the affected small entities. Graceway also states that the rule would have a significant economic impact on it because Maxair comprises 15 percent of Graceway's U.S. revenues.

(Response) As explained in our Regulatory Flexibility Analysis (see section VII), for purposes of determining whether a substantial number of small entities are affected by this rule, the affected industry sector includes all manufacturers of pharmaceutical products in the United States. The effects of this final rule are not limited to the five NDA holders who are marketing the seven ODS drug products. Thus, the industry sector which will be directly affected by this rule includes all U.S. “pharmaceutical preparation manufacturers.” The same industry sector was considered to be affected by the Albuterol final rule (70 FR 17191, April 4, 2005).

According to the U.S. Department of Commerce, the industry of “pharmaceutical preparation manufacturers” includes 901 establishments controlled by 723 companies (Ref. 3). Of these establishments, 822 have fewer than 500 employees. Only one of these companies, Graceway, has claimed that it is a small business and that the rule will cause it substantial economic harm. We do not need to determine if Graceway is in fact a small business, because even if it is, one single small affected entity among an industry of hundreds does not constitute a “substantial number” under the Regulatory Flexibility Act. Department of Health and Human Services Guidance
13

defines “substantial number” as 5 percent or more of the affected small entities within an identified industry. Graceway does not constitute 5 percent of the small entities in the “pharmaceutical preparation manufacturers” sector.

13
Guidance on Proper Consideration of Small Entities in Rulemakings of the U.S. Department of Health and Human Services (May 2003).

Because this rule would not affect a substantial number of small entities, we do not need to determine whether it would have a significant economic impact upon Graceway. Thus, we continue to believe that this rule would not have a significant economic impact on a substantial number of small entities and decline to reverse our previous determination under the Regulatory Flexibility Act.

d.
National Environmental Policy Act.
(Comment 17) Graceway asserts that FDA erroneously concluded that the rule would not have a significant adverse impact on the human environment. Graceway states that HFA alternatives to Maxair Autohaler and the overall shift of the market to HFA products have a significant global warming impact. Consequently, Graceway claims that FDA must provide evidence and analysis in support of its determination not to prepare an environmental impact statement. In particular, it maintains that FDA must discuss the impact of the proposed action and alternative approaches.

(Response) 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. These alternatives generally use HFC-134a (CH
2
FCF
3
), or, to a lesser degree, HFC-227ea (C
3
HF
7
) as a propellant. While HFC-134a and HFC-227ea are greenhouse gases (the global warming potentials (GWPs) are around 1300 GWP
14

and 2600 GWP, respectively),
15
the CFCs that were previously used are ozone disrupting compounds that have much higher global warming potentials of 5000 to 11,000.
16
In addition, considering the density of the HFC propellant is about 30 percent lower than for the CFC propellant, on a mass basis, the quantities emitted are reduced by 30 percent (Ref. 4).

14
GWP: Global warming potential; represents how much a given mass of chemical contributes to global warming over a given time period compared with the same mass of carbon dioxide (GWP =1). It is defined as the ratio of the time-integrative radiative forcing from the instantaneous release of 1 kg of a trace substance relative to that of 1 kg of a reference gas (in most cases CO
2
). All GWP values represent global warming potential over a 100-year time horizon.

15
U.S. Environmental Protection Agency, Global Warming Potentials of ODS Substitutes:
http://www.epa.gov/Ozone/geninfo/gwps.html
. Accessed 5/21/2009.

16
U.S. Environmental Protection Agency. Class I Ozone-depleting Substances:
http://www.epa.gov/Ozone/science/ods/classone.html
. Accessed 5/21/2009.

Considering this data, we concluded that there will be an overall improvement in the levels of potent greenhouse gases released annually from the use of oral pressurized MDIs as a result of this action. Therefore, the removal of the essential-use designations results in a net improvement on the environmental effects of the use of these devices. Because there is no net negative environmental impact of this action, alternative actions will not be addressed. We encourage the development of new forms of propellants with even lower GWPs, as well as other delivery possibilities, but in the absence of such alternatives we reaffirm the removal of the essential-use designations for CFC-propelled MDIs as an environmentally sound action.

D. Albuterol and Ipratropium in Combination

We are removing the essential-use designations for MDIs containing albuterol sulfate and ipratropium bromide in combination (Combivent Inhalation Aerosol).
17

Combivent Inhalation Aerosol is a prescription drug. Albuterol is a beta
2
-adrenergic bronchodilator and ipratropium is an anticholinergic bronchodilator. Both are used in the treatment of bronchospasm associated with COPD. 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 Inhalation Solution) for use in a nebulizer. Nebulizers do not use CFCs. This current rulemaking will not affect the regulatory status of DuoNeb Inhalation Solution.

17
As noted in the proposed rule, we 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 Inhalation Aerosol. We have treated the petition as a comment on this proposal.

1. Do Substantial Technical Barriers to Formulating Products Containing Albuterol and Ipratropium in Combination Without ODSs Exist?

In the proposed rule, we noted that we had not been supplied with any information to support a conclusion that substantial technical barriers exist and could not make an initial determination on whether such barriers exist. We received several comments about technical barriers to reformulating Combivent Inhalation Aerosol without CFCs, one of which provided additional information about Combivent Inhalation Aerosol's reformulation efforts.

(Comment 18) In its comment in response to the proposed rule, Boehringer Ingelheim Pharmaceuticals, Inc. (BI), argues that substantial technical barriers have hampered the development of a CFC-free Combivent Inhalation Aerosol. Specifically, BI notes that Combivent Inhalation Aerosol's combination of two active ingredients with different physico-chemical properties presents unique challenges for formulating a Combivent HFA Inhalation Aerosol, including the development of different valves and materials for the HFA product. According to BI, significant problems arose during the clinical trial phase, including clogging and valve sticking. In addition, multiple formulations have been developed. BI also provides more detailed information on its current progress in developing a non-HFA CFC-free Combivent. Specifically, BI stated that it anticipated filing an NDA for Combivent Respimat at the end of 2008, permitting FDA review and approval to be completed by 2010 or 2011.

(Response) We have carefully reviewed the information provided by BI on its reformulation efforts. We have considered whether all available alternative technologies have been evaluated and whether each alternative is unusable. The information available to the agency suggests that viable alternatives exist or are in development. BI representatives stated at the Public Meeting in August 2007 and BI stated in its comment to the proposed rule that it is in the process of developing Combivent Respimat. BI's comments suggest that they anticipate being ready to commercially produce and legally distribute, and have the capacity to meet current market demand for, a non-CFC alternative Combivent product by 2011. In addition, BI's actions to date indicate that it has overcome difficulties in chemistry and manufacturing as it has developed and tested a Combivent Respimat product (see clinicaltrials.gov at Respimat Combivent Trial in Chronic Obstructive Pulmonary Disease (COPD), ClinicalTrials.gov identifier #NCT00400153 (completed April 2008)). We also note that both albuterol and ipratropium bromide have been successfully reformulated as non-CFC products. We believe that the success of BI's reformulation efforts to date demonstrates that although difficulties may have been encountered, they do not pose a substantial barrier to reformulating as described in section III of this document. Therefore, we conclude that substantial technical barriers to the development of a non-CFC combination albuterol and ipratropium product do not exist.

2. Do MDIs Containing Albuterol and Ipratropium in Combination Provide an Otherwise Unavailable Important Public Health Benefit?

In the proposed rule, we solicited comments on the public health benefits of Combivent Inhalation Aerosols (72 FR 32039). We tentatively concluded that Combivent Inhalation Aerosol does not provide an otherwise unavailable public health benefit and based this tentative conclusion on our tentative determination that an ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI would provide an acceptable therapeutic alternative to Combivent Inhalation Aerosol. Because we have reached a conclusion that there are no substantial technical barriers to formulating Combivent Inhalation Aerosol into a non-ODS product, we do not believe it is necessary to reach a conclusion on the public health benefits of Combivent Inhalation Aerosol. However, we sought and received multiple comments in response to the proposed rule addressing the public health benefits of Combivent Inhalation Aerosol, and we believe it is appropriate to address the public health benefits in light of these comments.

(Comment 19) For a number of reasons, BI disagrees with our tentative conclusion that Combivent Inhalation Aerosol does not provide an otherwise unavailable important public health benefit. BI claims that Combivent Inhalation Aerosol users are elderly and have COPD and co-morbid conditions, making them an especially vulnerable population. BI asserts that noncompliance is a significant problem among this population because many users have multiple medical conditions requiring multiple medications. According to BI, switching Combivent Inhalation Aerosol users to two separate inhalers would decrease compliance, increase medication errors due to incorrect administration, and increase treatment delays due to patient confusion over which inhaler to use. BI explains that compliance might decrease because ipratropium bromide has a longer onset of action, and patients may perceive a lack of efficacy if ipratropium bromide is administered separately from albuterol, which would lead patients to either overuse the product or not use it at all. BI also argues that some patients with COPD suffer from hyperinflation of the lungs, which makes it more difficult to take the deep breaths required for optimal dosing of medications, and doubling the number of inhalations to approximate the same therapeutic effect of Combivent Inhalation Aerosol would significantly increase the burden on the patient. We also received comments from patients who claim that using two inhalers would be too bulky. Several other comments raise similar concerns about compliance, and one comment raises these concerns with respect to patients with cystic fibrosis. Our response below addresses all such comments.

(Response) We believe that the ipratropium bromide HFA MDI and the albuterol sulfate HFA MDI, when used together, provide similar therapeutic benefits to Combivent Inhalation Aerosol. Using the two MDIs together will deliver the same dose of ipratropium (18 micrograms (mcg) per inhalation) and essentially the same dose of albuterol (108 mcg versus 103 mcg per inhalation) as the dose delivered by Combivent Inhalation Aerosol. As we noted in the proposed rule, the primary advantage of using the two drugs in combination is that by using two distinctly different mechanisms of action (albuterol is a beta
2
-adrenergic bronchodilator while ipratropium bromide is an anticholinergic bronchodilator), the two drugs in combination should produce greater bronchodilator effect than using either drug alone. Combivent Inhalation Aerosol is a combination of convenience that is intended to facilitate patient use of the two drug products together.

Although it is not necessary for this rulemaking to evaluate whether the non-CFC therapeutic alternative has approximately the same level of convenience as the product it replaces, the analysis may be useful in light of the comments. As we stated in the 2002 rule, “in evaluating whether an alternative has approximately the same level of convenience of use compared to the ODS product containing the same active moiety, FDA will consider whether: (1) The product has approximately the same or better portability; (2) the product requires

approximately the same amount of or less preparation before use; and (3) the product does not require significantly greater physical effort or dexterity” (67 FR 48370 at 48374).

The proposed non-CFC alternatives to Combivent Inhalation Aerosol, an ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI, are MDIs like Combivent Inhalation Aerosol and are similarly portable. Both the CFC product and the HFA products require priming if they have not been used for a period of time, and therefore both products require approximately the same amount of preparation. We note that priming is only required when the product has not been used for a period of time. Because these inhalers are intended for daily use, we do not anticipate that regular priming would be necessary. And although twice as many puffs are required to deliver the dose of separate albuterol and ipratropium bromide into the lungs, the additional puffs do not require significantly greater physical effort or dexterity. In addition, we have not found any data to suggest that administering twice the number of puffs would be a significant burden for patients with hyperinflation. We acknowledge that carrying two inhalers is twice as bulky as carrying one, and some patients may find Combivent Inhalation Aerosol more convenient to use, but we believe that the therapeutic alternatives are only marginally less convenient, and any convenience provided by the availability of Combivent Inhalation Aerosol does not reach the level of essentiality.

We also acknowledge that some patients, particularly those with co-morbid conditions who are taking multiple medications, may be more compliant when using a Combivent Inhalation Aerosol than when using an ipratropium bromide HFA MDI with an albuterol sulfate HFA MDI. We believe that concerns about patient compliance can be appropriately addressed with patient outreach campaigns that provide education on how to use HFA MDIs correctly and the benefits of using both MDIs together. As we have stated elsewhere in this document, learning how to properly maintain and administer medications is a sometimes difficult, but necessary, task for many patients with chronic diseases. During the transition period, we intend to conduct this type of patient outreach campaign, and we encourage other stakeholders to work with us in educating Combivent Inhalation Aerosol users on the therapeutic alternatives. Because patient compliance may be greater with combination products such as Combivent Inhalation Aerosol, we intend to closely monitor the availability of any reformulated combination MDI product and the transition to the therapeutic alternatives identified in this rule, including albuterol and ipratropium delivered in single-ingredient MDIs, and modify the patient outreach efforts as appropriate.

(Comment 20) BI and other comments also argue that a decrease in compliance would lead to increased exacerbations and an increase in overall health care costs.

(Response) In one nonrandomized retrospective study comparing use of two separate inhalers to use of Combivent Inhalation Aerosol, Chrischilles et al. concluded that Combivent Inhalation Aerosol users were more compliant and had significantly lower average monthly health care costs compared to users of two separate inhalers (Ref. 5). Although the validity of the results depends on the authors' ability to control for important differences in the patient populations, we do not disagree with the conclusion that using two inhalers may be more expensive than using one combination inhaler, and we have identified and assessed those costs in our Analysis of Impacts.

(Comment 21) BI further argues that the proposed CFC-free therapeutic alternatives to Combivent Inhalation Aerosol (an ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI) have not been shown to provide similar therapeutic benefits. One comment claims that clinical studies have shown that a single inhaler of Combivent Inhalation Aerosol is more effective for the treatment of COPD than two separate inhalers. Several comments oppose the market removal of Combivent Inhalation Aerosol, arguing the combination of two medications that must be taken separately is not a substitute for the single product, Combivent Inhalation Aerosol.

(Response) As stated earlier, 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) as the dose delivered by Combivent Inhalation Aerosol. We are not aware of any data demonstrating that Combivent Inhalation Aerosol is clinically superior to an ipratropium bromide HFA MDI used with an albuterol sulfate HFA MDI. Other than the study by Chrischilles discussed earlier, most of the data cited by BI refers to older studies that did not study albuterol and ipratropium in combination inhalers. And as discussed earlier, we acknowledge that use of a combination inhaler may increase compliance, but we believe compliance can be increased with proper patient education, and we do not consider this factor to be determinative of public health benefit.

Neither the Chrischilles study nor any other study available to us or cited by BI demonstrates that Combivent Inhalation Aerosol is clinically superior to the two inhalers used together. We believe that the ipratropium bromide HFA MDI and the albuterol sulfate HFA MDI used together provide similar therapeutic benefits to the Combivent Inhalation Aerosol. We also note that albuterol and ipratropium bromide in combination are also available as an inhalation solution for use in a nebulizer (marketed as DuoNeb Inhalation Solution). DuoNeb Inhalation Solution is an option for patients who prefer a combination drug product. The availability of these therapeutic alternatives supports a conclusion that Combivent Inhalation Aerosol does not provide an otherwise unavailable important public health benefit.

3. Does Use of MDIs Containing Albuterol and Ipratropium in Combination Release Cumulatively Significant Amounts of ODSs Into the Atmosphere and Is the Release Warranted Because These MDIs Provide an Otherwise Unavailable Important Public Health Benefit?

As explained in the criteria in section III of this document, because we have found in this rule that there are no substantial technical barriers to reformulating Combivent Inhalation Aerosol, we are required to find that the use of Combivent Inhalation Aerosol is not essential, and we do not need to reach a decision on the third criterion in § 2.125(f)(1). However, we received several comments about this criterion, which we address below.

(Comment 22) BI argues that removing Combivent Inhalation Aerosol from the market would not significantly decrease the cumulative release of CFCs into the atmosphere and would have a negligible effect on the recovery of the stratospheric ozone layer. They also argue that any effect would not outweigh treatment disruption, health risks, and costs to Combivent Inhalation Aerosol users as a result of the market removal. According to BI, Combivent Inhalation Aerosol usage is expected to account for approximately 175 to 200 metric tons of annual CFC emissions in the coming years. Several comments assert that the amount of ODSs released from Combivent Inhalation Aerosol is insignificant, and eliminating their use would not provide a significant environmental benefit.

(Response) As we stated in the proposed rule and elsewhere in this document, the environmental impact of individual uses of nonessential CFCs must be evaluated in the context of the overall use of CFCs. The quantity of CFCs released from Combivent Inhalation Aerosol represents a significant portion of the total quantity of CFCs released from MDIs in the United States. FDA has not been assigned the task of determining what amount of environmental benefit would result from the removal of CFC-containing medical devices, diagnostic products, drugs, and drug delivery systems from the market. FDA is required to determine whether such products are essential uses of ODSs, and this rulemaking fulfills that obligation with respect to Combivent Inhalation Aerosol.

(Comment 23) BI argues that the proposed rule did not provide data or analysis demonstrating the amount of CFCs which constitutes a significant release. BI also comments that the criterion under the essential-use regulation was established to determine an individual product's release and its effect on the ozone layer, not whether it is significant relative to the release from other products. BI argues that our standard for determining whether a product releases significant amounts of ODSs into the atmosphere is not supported by science and should be developed in accordance with notice-and-comment rulemaking procedures.

(Response) We do not agree that the proposed rule did not provide data or analysis demonstrating the amount of CFCs which constitutes a significant release. We also disagree that our standard is not science-based or was developed without the opportunity for public comment. In reaching our tentative conclusion in the proposed rule that any release of CFCs from Combivent Inhalation Aerosol is cumulatively significant, we discussed our reasoning at length and cited multiple policy statements and other sources in support of our conclusion. We also solicited and received comments on our tentative conclusion. Through previous legislative and administrative actions, the United States has evaluated the environmental effect of eliminating the use of all CFCs and has made a decision to fully phase out the use of CFCs over time. Our conclusion that any release is cumulative is based on these legislative and administrative actions and reflects environmental science policies that have been developed over time through a public process.

(Comment 24) A few comments claim that CFCs used in Combivent Inhalation Aerosol do not have an adverse impact on the environment because the CFCs are inhaled rather than released into the environment.

(Response) As we have noted in previous rulemakings, nearly all of the CFCs inhaled into the lungs from an MDI are almost immediately exhaled into the environment (70 FR 17168 at 17179, April 4, 2005; 73 FR 69532 at 69540, November 19, 2008). The small amounts of CFCs absorbed into the body are later excreted and exhaled without being broken down. Essentially all of the CFCs released from an MDI end up in the atmosphere with resulting harm to the stratospheric ozone layer.

(Comment 25) One comment argues that the CFCs released from Combivent Inhalation Aerosol are less damaging to the ozone layer than the fumes from one diesel truck.

(Response) This comment appears to confuse CFCs with other greenhouse gases such as carbon dioxide and nitrous oxide. FDA's regulations at 21 CFR 2.125 reflect an international effort to reduce the production, importation, and use of substances that deplete the ozone layer. We are publishing this rule because the criteria in § 2.125 have been met, rather than because of any contribution CFCs may be making towards global warming.

(Comment 26) Another comment suggests FDA retain the essential-use designation for Combivent Inhalation Aerosol and instead remove other inhalants, such as aerosol hair sprays, spray paint, and perfumes.

(Response) The use of CFCs in cosmetics such as aerosol hair sprays, deodorant, shaving cream, and perfume was banned in 1978, along with the use of CFCs in spray paint, and household, food and automotive products.

4. Additional Comments on Miscellaneous Issues

a.
Criteria used in rulemaking.
(Comment 27) BI argues that the criteria in 21 CFR 2.125(g)(3)(ii), (g)(3)(iii), (g)(3)(iv), and (g)(4)(ii)
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should be applied to any proposed CFC-free replacement. According to its comment, ignoring or failing to fully consider these criteria could result in patients being switched to “therapeutically inferior” alternatives. At a minimum, BI argues that this rulemaking should incorporate the analysis used in the albuterol rulemaking.

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Included in 21 CFR 2.125(g)(3)(ii), (g)(3)(iii), and (g)(3)(iv) are some of the criteria for removing an essential-use designation for individual active moieties marketed as ODS products and represented by one new drug application. They require, among other criteria, that supplies and product capacity for the non-ODS product(s) exist or will exist at levels sufficient to meet patient need; adequate U.S. postmarketing data are available for the non-ODS product; and patients who medically require the ODS product are adequately served by the non-ODS product(s) containing that active moiety and other available products. Section 2.125(g)(4)(ii) incorporates these criteria by cross-reference and requires that they be met prior to removing the essential-use designation for individual active moieties marketed as ODS products that are represented by two or more NDAs.

(Response) The criteria in § 2.125(f)(1) we are using in this rulemaking, as cross-referenced in § 2.125(g)(2), are different from those in the albuterol rulemaking. Although the analysis used here is not identical to that 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. Section 2.125(g)(2) 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. In the case of Combivent Inhalation Aerosol, both active moieties have been reformulated without CFCs, and FDA disagrees that the albuterol HFA MDI and the ipratropium bromide HFA MDI are therapeutically inferior to Combivent Inhalation Aerosol. As stated earlier, we find them to be therapeutically equivalent, and we believe the two MDIs used together will meet the needs of current Combivent Inhalation Aerosol users.

b.
Intent to reformulate.
(Comment 28) BI argues that removing Combivent Inhalation Aerosol's essential-use designation before a replacement can be developed preempts BI's good faith efforts to reformulate (a requirement under the Montreal Protocol).

(Response) Nothing about this decision precludes BI from reformulating. A reformulated product can be approved at any time after FDA has determined an NDA meets approval standards. Based on BI's assertions, it is possible a replacement will be available prior to the effective date of this rule for Combivent Inhalation Aerosol.

c.
Deadline for overall CFC phase-out.
(Comment 29) BI comments that the Montreal Protocol and the Clean Air Act do not set a firm deadline for the phase-out of CFC usage in MDIs, and FDA should exercise greater flexibility in its essential-use rulemakings.

(Response) As stated in the 2002 final rule, we reviewed the text of the Clean Air Act, its legislative history, the text of the Montreal Protocol, and decisions by the Parties to the Protocol. FDA also further discussed its understanding of the Clean Air Act and the Protocol with the EPA. The Clean Air Act does not state specifically whether such essential-use exemptions may continue indefinitely or must terminate at some future time. However, the legislative history for section 604(d)(2) of the Clean Air Act makes clear that the exemption is only permitted for a limited time. Specifically, the Senate Conference Report for this section of the Clean Air Act states: The centerpiece of the stratospheric ozone protection program established by this title is the phase-out of production and consumption of all ODSs (136 Cong. Rec. S16895 at 16946 and 16947 (daily ed. Oct. 27, 1990)). These statements are consistent with the Montreal Protocol. The Preamble to the Protocol states that the Parties are: Determined to protect the ozone layer by taking precautionary measures to control equitably total global emissions of substances that deplete it,
with the ultimate objective of their elimination
(Preamble to the Montreal Protocol (emphasis added)). Decision IV/25 of the Parties to the Protocol also indicates that essential-use exemptions are temporary. This decision asks the Technology and Economic Assessment Panel to determine an estimated duration for each essential use, the steps necessary to ensure alternatives are available as soon as possible, and whether previously qualified essential uses should no longer qualify as essential. Thus, although it is true that there is no set date for termination of essential-use exemptions, it is also clear that the exemptions were intended to be limited in number and duration and were not intended to exist forever.

d.
Sufficiency of advisory committee meeting.
(Comment 30) BI argues that little public notice was provided for the 2005 PADAC meeting and the notice contained little guidance on public participation and did not seek specific public input. BI also argues that the straw poll conducted at the PADAC meeting did not take into account the status of BI's CFC-free Combivent development programs. BI claims that had the PADAC members been provided a more complete record upon which to base their opinions, a majority would have recommended continuation of Combivent Inhalation Aerosol's essentiality and rejected the proposed therapeutic alternatives.

(Response) As stated earlier in this document, FDA, after consultation with a relevant advisory committee and after holding an open public meeting, may remove an essential-use designation under section 2.125(g)(2) if it no longer meets certain criteria. FDA made clear in the 1999 rule proposing criteria for removing essential-use designations that before removing any essential-use designation, it would consult with an advisory committee and provide opportunity for public comment (64 FR 47719 at 47722). FDA published a notice in the
Federal Register
on May 10, 2005 (70 FR 24605), that the PADAC would be convening on July 14, 2005, to discuss the continued need for the essential-use designations of prescription drugs for the treatment of asthma and COPD. The notice further stated that interested persons could present data, information, or views, orally or in writing, on the issues pending before the committee. This notice provided sufficient time for those persons or companies with an interest in the essential-use designations of any moieties used in drugs that treat asthma or COPD to provide the committee members with any information they believed would be pertinent to the decision to remove or continue a designation. Therefore, we disagree with the assertion that little public notice was provided for the 2005 PADAC meeting and the notice contained little guidance on public participation and did not seek specific public input.

We also disagree with the assertion that PADAC members were not provided a complete record upon which to base their opinions. At the PADAC meeting, an FDA representative made a detailed presentation to committee members on the Montreal Protocol and the essential-use process and rulemakings, including identification and description of the current essential uses and their therapeutic alternatives, as well as the criteria for removing the essential-use designations. After the FDA presentation, committee members had the opportunity to ask clarifying questions, and additional presentations were made by an association representing manufacturers of MDIs, specific MDI manufacturers, and an interested person. Committee members had additional time to discuss the individual moieties after these presentations were made. We believe that the record demonstrates the PADAC was provided ample information on which to render a vote.

E. Effective date

In the proposed rule, we proposed an effective date for removal of the essential-use designations for all seven moieties of December 31, 2009, and we solicited comments on this proposed effective date. We noted in the proposed rule that, depending on the data presented to us during the course of the rulemaking, we may determine that it is appropriate to have different effective dates for different uses.

We did not receive any substantive comments on the proposed effective date for metaproterenol and nedocromil. Alupent Inhalation Aerosol and Tilade Inhaler have been discontinued by BI and King Pharmaceuticals, Inc., respectively. BI has informed us that any Alupent Inhalation Aerosols that may be in retail or wholesale stocks will have passed their expiration date by December 2009. Accordingly, we have determined that the appropriate effective date for the removal of the essential-use designations for metaproterenol and nedocromil is June 14, 2010.

We did not receive any substantive comments on the proposed effective date for triamcinolone, and cromolyn. To allow an adequate length of time for patients to transition to the therapeutic alternatives identified in this rule, we have determined that December 31, 2010, is an appropriate effective date for removing the essential-use designations for triamcinolone and cromolyn. The additional period ensures more time to disseminate information about the phase-out to patients to ensure an orderly transition that is protective of public health.

We received one comment regarding the effective date for flunisolide from Forest Laboratories, Inc., the exclusive distributor for Aerobid (flunisolide) Inhaler System via a licensing agreement with Roche Palo Alto, the NDA holder for Aerobid. Forest requests an 18-month delay in the effective date of the rule. In its comment, Forest states that a June 30, 2011, effective date would allow time for Forest to commercially produce and market its non-CFC flunisolide formulation, Aerospan Inhalation Aero

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2010-8467. Public record. Not legal advice.