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Testimony on Clean Air Act & Chlorofluorocarbons in Metered-Dose Inhalers by Murray M. Lumpkin, M.D.
Deputy Director for Review Management
Center for Drug Evaluation and Research
Food and Drug Administration
U.S. Department of Health and Human Services

Before the House Committee on Commerce, Subcommittee on Health and Environment
July 30, 1997

I. INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Murray M. Lumpkin, Deputy Director for Review Management for the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA or the Agency). I appreciate this opportunity to discuss our role in the implementation of Title VI of the Clean Air Act as it relates to the use of chlorofluorocarbons (CFCs) in metered-dose inhalers (MDIs). As requested, I will review the decisions related to the transition away from CFC- based MDIs made at the 8th Meeting of the Parties to the Montreal Protocol in Costa Rica, in November 1996 and the draft resolutions discussed at the open Ended Working Group Meeting in Nairobi, Kenya, in June. I also would like to provide the Committee with an overview of various FDA activities related to preparation for the transition to non-CFC alternative inhalation products and I will review FDA's Advance Notice of Proposed Rulemaking (ANPR) entitled, "Chlorofluorocarbon Propellants In Self-Pressurized Containers; Determinations That Uses Are No Longer Essential," which was published in the Federal Register for public comment on March 6, 1997 (62 Federal Register 10242).

FDA recognizes the extreme importance of protecting the health and safety of the millions of patients who rely on CFC- based MDIs for the treatment of their asthma and chronic obstructive pulmonary disease (COPD) during the phase out of CFCs and the transition to non-CFC alternative inhalation products. As an agency dedicated to the protection of the public health of the citizens of the United States, FDA is committed to meeting this challenge as we work to implement the national and international mandate to phase out the use of CFCs in order to protect the Earth's environment and the future health of its people.

II. BACKGROUND

As the Committee is aware, under Title 21, Code of Federal Regulations. (CFR) section 2.125 (21 CFR 2.125), any food, drug, device, or cosmetic in a self-pressurized container that contains a CFC propellant for a nonessential use is adulterated, or misbranded, or both, under the Federal Food, Drug, and Cosmetic (FDC) Act. Section 2.125(d) exempts from the adulteration and misbranding provisions of section 2.125(c) certain products containing CFC propellants that FDA determines provide unique health benefits that would not be available without the use of a CFC. These products are referred to in the regulation as - essential uses of CFCs and are listed in 21 CFR 2.125(e). The Environmental Protection Agency (EPA) regulations implementing the provisions of section 610 of the Clean Air Act (42 U.S.C. 7671i) contain a general ban on the use of CFCs in pressurized dispensers, such as MDIs (40 CFR 82.64(c) and 82.66(d)). These EPA regulations exempt from the general ban "medical devices' that FDA considers essential and that are listed in 21 CFR 2.125(e).

As the committee also is aware, production of ozone- depleting substances (ODS) is being phased out worldwide under the terms of the Montreal Protocol on Substances that Deplete the Ozone Layer (Montreal Protocol), September 16, 1987, S. Treaty Doc. No. 10, 100th Cong., 1st sess., 26 I.L.M 1541 (1987). In accordance with the provisions of the Montreal Protocol, under authority of Title VI of the Clean Air Act (section 601 et seq.), manufacture of CFCs in the United States was generally banned as of January 1, 1996. To receive permission to manufacture CFCs in the United States after the phase out date, manufacturers must obtain an exemption from the phase out requirements from the Parties to the Montreal Protocol. Procedures for securing an essential-use exemption under the Montreal Protocol are administered in the United States by EPA. Firms that wish to use CFCs manufactured after the phase out date in medical devices covered under section 610 of the Clean Air Act must receive exemptions for essential uses under the Montreal Protocol.

Since the general ban on the production of CFCs became effective on January 1, 1996, the United States has successfully secured essential-use exemptions from the Parties to the Montreal Protocol to allow the production of CFCs for MDIs for the treatment of asthma and COPD in 1996 and 1997. This is currently the only commercial purpose for which CFCs can be produced in the United States and other developed nations that are Parties to the Montreal Protocol. The United States has submitted a nomination to the Parties to the Montreal Protocol to extend this essential- use exemption to 1998. The United States' 1998 essential-use request for CFCs was evaluated and supported by the United Nations Environment Program (UNEP) Technical and Economic Assessment Panel (TEAP) in their report issued in April 1997 and was recommended to the Parties for approval by the open Ended Working Group at their meeting held in Nairobi, Kenya, in June 1997. It is anticipated that this request will be approved at the 9th Meeting of the Parties to the Montreal Protocol which will be held in Montreal in September 1997. The EPA will submit the 1999 United States nomination for essential-use exemptions for CFCs for MDIs to the TEAP for review in January 1998.

The United States will continue to seek essential-uses exemptions from the Parties for MDIs for the treatment of asthma and COPD pending the development and marketing of "technically feasible" and acceptable non-CFC alternative inhalation products that adequately serve the needs of patients who rely on CFC-based MDIs for their health and well being. It must be recognized, however, that the Montreal Protocol mandates an eventual complete ban on the production of ODS and that the essential-use exemptions allowed under the Protocol are not intended, or expected, to be permanent.

Faced with the statutorily mandated phaseout of CFCs, drug manufacturers are developing, or have developed, alternatives to MDIs that do not contain ODS. Examples of these alternative dosage forms include MDIs that use non-ozone depleting substances as propellants and dry-powder inhalers (DPIs). The current or future availability of "technically feasible alternatives to the use of a CFC" may mean that the existing listing of a use in 2.125(e) would no longer reflect current conditions. It is with this situation in mind that FDA developed the ANPRM regarding Agency determinations that certain uses of ODS are, or may in the future be, no longer essential.

At the 8th Meeting of the Parties to the Montreal Protocol held in San Jose, Costa Rica in November 1996, the Parties adopted several measures related to the transition to non-CFC alternative inhalation products. First, the Parties adopted a series of measures to "promote industry's participation in a smooth and efficient transition away from CFC-based MDIs." 1 Second, the Parties adopted measures designed to foster "information gathering on a transition to non-CFC treatments for asthma and chronic obstructive pulmonary disease for Parties not operating under Article 5." 2 These, and other, actions adopted at the 8th Meeting indicate the Parties' interest in fostering the development, marketing approval, and acceptance of non-CFC alternative inhalation products and development of national strategies in developed nations to accomplish the transition to non-CFC alternatives. The measures adopted included: 1) That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to demonstrate ongoing research and development of alternatives to CFC MDIs with all due diligence and/or collaborate with other companies in such efforts and, with each future request, to report in confidence to the nominating Party whether and to what extent resources are deployed to this end and progress is being made on such research and development, and what licence applications if any have been submitted to health authorities for non-CFC alternatives; 2) That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to demonstrate that they are undertaking individual or collaborative industry efforts, in consultation with the medical community, to educate health-care professionals and patients about other treatment options and the transition to non-CFC alternatives; 3) That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to demonstrate that they, or companies distributing or selling their product, are differentiating the packaging of the company's non-CFC MDIs from its CFC MDIs and are applying other appropriate marketing strategies, in consultation with the medical community, to encourage doctor and patient acceptance of the company's non-CFC alternatives subject to health and product- safety considerations; 4) That Parties not operating under Article 5 will request companies manufacturing, distributing or selling CFC MDIs and non-CFC alternatives not to engage in false or misleading advertising targeted at non-CFC alternatives or CFC MDIs; 5)That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to ensure that participation in regulatory proceedings is conducted with a view toward legitimate environmental, health and safety concerns; 6) That Parties not operating under Article 5 will request companies manufacturing CFC MDIs to take all economically feasible steps to minimize CFC emissions during the manufacture of MDIs; 7) That Parties not operating under Article 5 will request companies manufacturing, distributing or selling CPC MDIs to dispose of expired, defective, and returned MDIs containing CFCs in a manner that minimizes CFC emissions; 8) That Parties not operating under Article 5 will request companies manufacturing CFC MDIs to review annually CFC requirements and current MDI market forecasts, and to notify national regulatory authorities if such forecasts will result in surplus CFCs obtained under essential-use exemptions; 9) That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to provide information on the steps that are being taken to provide a continuity of supply of asthma and COPD treatments (including CFC MDIs) to importing countries; 10) That Parties not operating under Article 5 will request companies applying for MDI essential-use exemptions to provide information that demonstrates the steps being taken to assist the company's MDI manufacturing facilities in Parties operating under Article 5 and countries with economies in transition in upgrading the technology and capital equipment needed for manufacturing non-CFC asthma and COPD treatments. 2 The measures adopted included: 1) To request Parties not operating under Article 5 that have developed a national transition strategy to report to the Panel and its relevant Technical Options Committee on the details of that national transition strategy for non-CFC treatments of asthma and chronic obstructive pulmonary disease (COPD) in time for meetings of the Technical Options Committee, beginning in 1997; 2) To request the Technology and Economic Assessment Panel and its relevant Technical Options Committee to provide an interim report on progress in the development and implementation of national transition strategies in Parties not operating under Article 5 for non-CFC treatments of asthma and COPD and report to the open- Ended Working Group in preparation for the 9th Meeting of the Parties; 3) To request the Technology and Economic Assessment Panel to further examine and provide a progress report to the 9th Meeting of the Parties and a final report to the 10th Meeting of the Parties on issues surrounding a transition to non-CFC treatments of asthma and COPD in Parties not operating under Article 5 that is fully protective of public health. In so doing, the Technology and Economic Assessment Panel should consult with international bodies, such as the World Health organization and other institutions representing health-care professionals, patient-advocacy groups and private industry, and with national bodies and Governments. The Technology and Economic Assessment Panel should consider: (a) In the context of a transition phase, how decisions taken within the Montreal Protocol framework and national strategies might complement each other; (b) The impact an the right and ability of patients in Parties operating under Article 5, in countries with economies in transition, in Parties not operating under Article 5 with large disadvantaged communities and in importing countries to receive CFC-based MDIs where medically acceptable and affordable alternatives are not available due to reductions in essential use exemptions in Parties not operating under Article 5 for CFC-based MDIs; (C) The influence of potential transferable essential use exemptions as well as existing and potential trade restrictions by individual countries on a smooth transition and access to affordable treatment options; (d) The international markets and fluidity of trade in CFC-based MDIs an well as alternative treatments for asthma and COPD; (e) The implications for patient subgroups which may have continuing compelling medical needs after a virtual phase out; (f) The range of regulatory and non-regulatory incentives for, and impediments to, research and development of alternative treatments for asthma and COPD and market penetration of alternative treatments for asthma and COPD; (9) The degree to which dry powder inhalers (DPIs) and other treatment options may be considered medically acceptable and affordable alternatives for CFC-based MDIs in consultation with the above bodies, and as a result, the factors which may influence their ability to act as substitutes in different countries; (h) The relative implications for the phase out of ozone-depleting substances of different policy options that facilitate the transition to non-CFC treatments; and (;) Steps that could be taken to facilitate access to affordable non-CFC treatment options and technology.

At the Open Ended Working Group Meeting in June 1997, the United Nations' TEAP suggested that the transition to CFC-free inhaled therapy should occur as rapidly as possible without compromising patient safety. The TEAP suggested that this transition should occur within an overall international environmental framework, but with national responsibility for developing a national transitional policy. The TEAP also reported that: 1) it should be feasible to eventually commercialize alternatives to most of the commonly used MDIs; 2) significant reductions in the use of CFCs for MDIs could be achieved by the year 2000, with a virtual phase out of CFCs for MDIs by the year 2005 in developed nations; 3) due to the many uncertainties, it was too early to draft a global framework for the phase out of CFCs for MDIs; and 4) national transition strategies were necessary to facilitate a major reduction in CFC use for MDIs by the end of the year 2000. A resolution was introduced and approved for submission to the Parties for consideration at the 9th Meeting in Montreal to urge all Parties. to develop a national transition strategy for moving away from CFC-based MDIs for the treatment of asthma and COPD. The proposed resolution would further require that Parties submitting essential-use nominations for CFCs for MDIs for the treatment of asthma and COPD present to the Ozone Secretariat of UNEP an initial national transition strategy by January 31, 1999.

Although the year 2005 has been discussed as a possible date for a virtual phase out of CFCs for MDIs in developed nations, it is important to emphasize that the Parties to the Montreal Protocol have not adopted 2005, or any other date, for ending essential use exemptions for CFCs for use in MDIs for the treatment of asthma and COPD. At the current time, FDA believes it is premature for the Parties, or the United States, to set any firm date for the complete elimination of CFCs in MDIs. This position is based on the fact that there is currently only one non-CFC MDI approved in the United States. While there are a number of non- CFC MDIs and other alternative inhalation products currently under development, it is not possible at this time to predict when these products will be approved for marketing in the United States and whether the alternative products will adequately serve the needs of patients. Rather than setting a target date for the elimination of CFCs from MDIs, FDA has attempted to describe in the ANPR the criteria it proposes to apply in making determinations that current uses listed in 21 CFR 2.125 are no longer essential as non-CFC alternative inhalation products are approved in the United States are shown to be accepted by patients and to adequately meet patient needs.

FDA believes that its actions to date on issues related to the transition to non-CFC alternative inhalation products are consistent with its statutory obligations under the Clean Air Act and the stated intentions of the Parties to the Montreal Protocol as discussed above. While the Parties to the Montreal Protocol have not yet adopted an international transition strategy or firm target date for the complete phase out of CFCs from MDIs for the treatment of asthma and COPD, the Parties have expressed their interest in encouraging individual countries to develop national transition strategies. As noted earlier, the Parties will be considering a resolution at the 9th Meeting in Montreal in September 1997 which would require that members submitting essential-use requests for CFCs for MDIs for the treatment of asthma and COPD have an initial transition strategy by January 31, 1999.

As the members of the Committee are aware, on March 6, 1997, FDA published a proposed transition strategy for the United States in an ANPRM entitled, Chlorofluorocarbon Propellants in Self- Pressurized Containers; Determinations That Uses Are No Longer Essential" (62 Federal Register 10242). While the United States was the first developed nation to announce a proposed transition strategy, we are not alone in this effort. FDA is aware of draft transition strategies that have been developed by Australia and the European Union and, recently, an FDA official was invited to attend as an observer at a "stakeholders" meeting organized by Health Canada and Environment Canada where the process of drafting a transition strategy for Canada was begun.

FDA strongly believes that the best way to accomplish the transition to non-CFC alternative products in the United States, and in other developed nations, is for each country to develop a national transition strategy that correctly matches the unique characteristics of the regulatory, health care, and marketing environment of the individual country, rather than attempting to develop a "one size fits all' international transition strategy. Such a position was recently supported by the TEAP in its April 1997 report in which it recognized "that no single strategy will be applicable to all countries" and encouraged preparation of national transition policies. While a ""one size fits all" international transition strategy might work well in particular countries, it could potentially cause significant problems if applied to the United States. Being the first developed nation to propose a national transition strategy may provide the United States a leadership role in any future international strategies or timelines in a way that serves the interests of patients in the United States who rely on CFC-based MDIs.

III. FDA ACTIVITIES RELATED TO THE TRANSITION TO NON-CFC MDIs

Mr. Chairman, I now would like to provide a brief overview of the efforts FDA has taken to lay the groundwork, in cooperation with the pharmaceutical industry and other stakeholders, for the transition to non-CFC alternative inhalation products. FDA's efforts have been focused on 5 fronts: 1) maintaining an adequate supply of pharmaceutical grade CFCs for the manufacture of MDIs as CFC production decreases worldwide; 2) assisting the pharmaceutical industry in selecting potential alternative propellants; 3) providing guidance to the pharmaceutical industry regarding the pre-clinical and clinical testing requirements for the alternative propellants and new non- CFC drug product formulations to assure that the new non-CFC MDIs are safe and effective and comparable to the CFC-based MDIs they will replace; 4) working closely with EPA to prepare essential- use requests to the Parties to the Montreal Protocol for CFCs for MDIs for the treatment of asthma and COPD; and 5) working closely with interested stakeholders to educate patients and physicians about the need to phase out CFCs and the transition to non-CFC alternative inhalation products.

Let me begin in the area of chemistry and manufacturing controls of CFC and non-CFC MDIs. Early in the process of developing alternatives, the chemistry staff in FDA's Division of Pulmonary Drug Products, CDER, the Division responsible for regulating MDIs for the treatment of asthma and COPD, provided advice to the pharmaceutical industry on the selection of potential alternative propellants. The Division's chemistry staff also recognized that with the planned global phase out of CFCs, the traditional producers of pharmaceutical grade CFCs might scale back their production capacity or stop producing CFCs entirely. This, in turn, could force MDI manufacturers to stockpile CFCs for future use or to seek alternative suppliers. Each of these possibilities could significantly impact upon the purity and quality of CFCs used to manufacture MDIs which could in turn affect the performance and safety of MDIs. To address these concerns, and to help assure that MDI manufacturers could maintain an uninterrupted supply of pharmaceutical grade CFCs during the transition, the Agency, in cooperation with the pharmaceutical industry, developed 'universal' quality control specifications for CFCs for use in MDIs. These specifications are designed to ensure that the CFCs used in MDIs during the transition to non-CFC alternative inhalation products are at least as pure and as safe as those used historically in the United States. The adoption of these 'universal' CFC specifications also makes it easier, and less burdensome from a regulatory standpoint, for MDI manufacturers to change their supplier of CFCs if necessary to avoid an interruption of supply.

Finally, FDA has worked pro-actively with individual sponsors to provide guidance on the development of non-CFC alternative inhalation products. This effort has included numerous meetings with sponsors to provide advice tailored to their specific alternative products and developmental problems, as well as presentations on issues related to development and quality control of inhalation products at various scientific and regulatory meetings.

Turning now to the pre-clinical, or non-human testing of non-CFC. alternative inhalation products, the pharmacology staff in the Division of Pulmonary Drug Products worked closely with the International Consortium of Aerosol Manufacturers, or IPAC, to develop the pre-clinical testing programs for HFA-134a and HFA227, two of the most promising of the alternative propellants. This program consisted of a full battery of pre-clinical testing of each propellant to establish its safety for chronic use in humans, similar to the program that would normally be required for a new active drug substance. The rationale for such extensive pre-clinical testing of the new propellants is related to the relatively large amount of propellant verse-clinical safety of the new propellants, the Division of Pulmonary Drug Products agreed to review the pre-clinical data on the new propellants under drug master files which were submitted by IPAC well in advance of any NDAs for HFA-based MDIs.

With regard to the clinical testing of non-CFC alternative inhalation products, the Division of Pulmonary Drug Products issued a Points to Consider Document entitled, "Clinical Development Programs for MDI and DPI Drug Products," in September 1994. This document details Division recommendations for the clinical development of MDIs containing alternative propellants as well as DPIs, another potential form of non-CFC alternative to CFC-based MDIs. Given the extensive clinical safety and efficacy database available for the drug substances already approved in MDIs in the United States, the recommended programs represent a "bridging" approach to the development of the clinical data necessary to support approval of the alternative formulations. Again, this 'bridging" approach significantly reduces the regulatory burden for clinical testing of new non-CFC formulations without compromising FDA's ability to evaluate the safety and effectiveness of the new product. In addition to demonstrating the safety and effectiveness of the alternative products as required under the FDC Act, the clinical programs recommended by the Division are designed to provide data to establish that the new non-CFC alternatives are comparably safe and effective as the currently e-clinical safety of the new propellants, the Division of Pulmonary Drug Products agreed to review the pre-clinical data on the new propellants under drug master files which were submitted by IPAC well in advance of any NDAs for HFA-based MDIs.

With regard to the clinical testing of non-CFC alternative inhalation products, the Division of Pulmonary Drug Products issued a Points to Consider Document entitled, "Clinical Development Programs for MDI and DPI Drug Products," in September 1994. This document details Division recommendations for the clinical development of MDIs containing alternative propellants as well as DPIs, another potential form of non-CFC alternative to CFC-based MDIs. Given the extensive clinical safety and efficacy database available for the drug substances already approved in MDIs in the United States, the recommended programs represent a "bridging" approach to the development of the clinical data necessary to support approval of the alternative formulations. Again, this 'bridging" approach significantly reduces the regulatory burden for clinical testing of new non-CFC formulations without compromising FDA's ability to evaluate the safety and effectiveness of the new product. In addition to demonstrating the safety and effectiveness of the alternative products as required under the FDC Act, the clinical programs recommended by the Division are designed to provide data to establish that the new non-CFC alternatives are comparably safe and effective as the currently marketed CFC MDIs. The Division's emphasis on demonstrating that the non-CFC alternative products are comparably safe and effective as the currently available MDIs is part of the Agency's overall strategy to accomplish the transition to non-CFC products in as seamless a way as possible.

Using the Points to Consider Document as a guidepost, the Division's clinical staff have interacted closely with individual sponsors of non-CFC alternative formulations to tailor the recommendations to fit the numerous variables raised by each new clinical development program, without compromising on the document's basic principles of assuring that the alternative products are safe and effective and comparable to currently marketed CFC MDIs.

In preparation for the transition to non-CFC alternative inhalation products, FDA also plays an active role in the United States' involvement in the Montreal Protocol. While the Department of State and EPA are the primary official United States representatives to the Montreal Protocol, FDA has developed a close working relationship with the staff at both the State Department and EPA on CFC-related issues. FDA's interactions with EPA include providing technical medical advice in the preparation of the yearly United States essential-use nominations to the Parties to the Montreal Protocol requesting CFC exemptions for production of MDIs for the treatment of asthma and COPD. In addition, Dr. Babatunde Otulana, a medical officer in the Division of Pulmonary Drug Products, serves as an expert member of the Aerosols Technical Options Committee (TOC) of TEAP of the UNEP, the organization that administers the Montreal Protocol. The Aerosols TOC is the primary technical subcommittee that makes recommendations to the Parties to the Montreal Protocol on issues related to CFCs and MDIs. Dr. Otulana's involvement with the Aerosols TOC allows FDA to monitor closely and to respond to international developments related to the phase out of CFC-based MDIs. FDA staff also regularly attend Montreal Protocol meetings as part of the United States delegation and provide expert clinical advice to the Chair of the United States delegation and to the other Parties to the Montreal Protocol on pharmaceutical drug-related issues.

FDA also recognizes that in order for the transition to non- CFC alternative inhalation products to occur in as seamless a way as possible, it is necessary to educate patients, physicians, nurses, pharmacists, and other health care providers and interested parties about the planned phase out of CFC-based MDIS. and the transition to non-CFC alternatives. For the past several years, staff from the Division of Pulmonary Drug Products have made presentations and participated in panel discussions on the phase out of CFCs and the transition to non-CFC alternatives at national scientific and professional society meetings. The Division also has worked in close cooperation for the past year with the staff from the National Heart, Lung, and Blood Institute of the National Institutes of Health, members of the American Lung Association's CFC Stakeholders Group, and other patient advocacy organizations to develop educational materials and programs related to the phase out of CFC-based MDIs. The Agency also has published, or will be publishing in the future, articles on the phase out of CFCs in FDA Consumer, Journal of the Medical Association (JAMA), and the FDA Medical Bulletin. The Agency views these educational efforts as a critical component of the transition process and is committed to continuing and intensifying these efforts as the United States moves forward with the transition to non-CFC alternative inhalation products.

We believe that we have laid the foundation for the development of safe and effective non-CFC alternative inhalation products and that these efforts will result in the approval of a number of such products over the next several years.

Let me now make a few brief comments on the status of development of non-CFC alternative inhalation products. First, I want to emphasize to the Members of the Committee that the MDI is a very complex device and that the pharmaceutical industry's efforts to reformulate these devices to use non-CFC propellents have proven to be quite challenging. The reformulation of CFC- based MDIs is not a matter of simply substituting a non-CFC propellant for the CFC propellant. It has proven necessary in many cases to make substantial changes to the active and inactive ingredients and to the various components of the delivery device (e.g., canister, valves, gaskets, actuator, etc.) in order to develop a product that performs reliably and is well tolerated by patients. I would like to commend the pharmaceutical industry for its hard work and commitment of resources to this task. We are now beginning to see the fruits of these labors. As you know, FDA approved the first non-CFC MDI in August 1996. Proventil HFA contains albuterol sulfate and uses HFA-134a as the propellant. Proventil HFA was developed by 3M Pharmaceuticals and is marketed in the United States by Schering-Plough. Numerous other non-CFC MDIs are currently in various stages of clinical development and are expected to be approved in the United States over the next several years. In addition to its efforts directed at developing non-CFC MDIs, the pharmaceutical industry also is actively developing a significant number of DPIs and other novel aerosol delivery systems, such as miniature hand-held nebulizers. These devices do not require propellant for aerosol delivery of the drug substance to the patient. As these alternative products are approved over the next several years, they will provide patients and physicians with an important new range of choices of devices. for the delivery of drugs directly to the lungs in patients with asthma and COPD.

IV. ADVANCE NOTICE OF PROPOSED RULEMAKING

As I noted earlier, on March 6, 1997, FDA published an ANPR announcing the proposed transition strategy for phase out of essential-use exemptions for CFC-based MDIs (62 Federal Register 10242). In developing the transition strategy, FDA is carrying out the duties assigned to it by Title VI of the Clean Air Act. In passing Title VI of the Clean Air Act, Congress directed EPA to promulgate regulations banning the sale or distribution of products that release ODS into the atmosphere as well as mandating the phase out of the production of ODS. EPA's final rule implementing the ban on the sale or distribution of products that release ODS into the atmosphere was published on January 15, 1993, and the general ban on CFCs in aerosol products, such as MDIs, went into effect January 17, 1994. Title VI of the Clean Air Act and EPA's implementing regulations, however, exempt from the general ban on the sale or distribution of products that release ODS into the atmosphere medical products that FDA has determined to be essential. The recently published ANPR proposes a process for FDA to review the essential use determinations that may no longer be valid, or may be rendered invalid in the future, because of development of non-CFC alternative inhalation products and/or the withdrawal from the United States market. FDA's efforts in this area will serve to ensure that these Congressionally mandated determinations remain current and are consistent with the Montreal Protocol.

Before describing some of the important details of the proposed strategy, I would like to review for the Committee the process FDA followed in developing the proposed transition strategy. The proposed transition strategy detailed in the ANPR was developed by the CFC Workgroup of CDER's Medical Policy Coordinating Committee (MPCC), the oversight committee responsible for coordinating medical policy development and implementation throughout CDER. The CFC Workgroup was formed in early 1996 and was charged with evaluating all the scientific, technical, regulatory, and clinical issues relevant to the transition to non-CFC alternative inhalation products and developing a proposed transition strategy. CFC Workgroup members were drawn from those areas of CDER with expertise in regulation of MDIs and other inhalation dosage forms as well as experts in policy development.

The clinical members of the CFC Workgroup, include three Pulmonologists from the Division of Pulmonary Drug Products who are experts in the diagnosis and treatment of diseases related to the lungs and are each still engaged in the clinical care of patients with asthma and COPD.

The CFC Workgroup decided early in the process that the best way to solicit public input from the numerous interest groups who have a stake in the phase out of CFC-based MDIs was for the Agency to develop a proposed transition strategy that could then. be published for public comment as an ANPR.

FDA's primary objective in the development of a transition strategy is to ensure that all of the millions of patients in the United States with asthma and COPD who rely on MDIs for their health and well being are protected and have access to an adequate number of safe and effective treatment options. our goal has been, and remains to be, to make the transition to non-CFC alternative inhalation products as seamless as possible. The Agency is not proposing to accelerate the phase out of CFC-based MDIs as has been suggested by some, nor does the ANPR propose to eliminate any CFC-based MDIs approved for the treatment of asthma and COPD from the market at this time. Rather, the ANPR represents the first step in the notice and comment rulemaking process by which the Agency will lay the groundwork for how FDA will determine in the future whether essential uses currently listed in 21 CFR 2.125 are no longer essential uses of CFCs. The proposed transition strategy outlined in the ANPR specifies the minimum number of non-CFC alternatives that must be available prior to such a determination and is designed to ensure that non- CFC alternatives are widely available, accepted by patients and physicians, shown to be safe and effective, and fulfill the needs of all significant patient subpopulations currently served by the corresponding CFC-based-MDIs. The proposed transition strategy should be viewed as a conservative approach that places the interests and the safety of patients with asthma and COPD first.

The ANPR has been widely distributed to various interest groups and has had the desired effect of stimulating significant public input. This is reflected by the approximately 9,400 comments to the docket that were received during the formal 60- day period for public comment. The Agency is currently engaged in a thorough review of the comments received and will carefully consider those comments as a Proposed Rule is developed. The vast majority of comments received were from individual patients who wrote to express their concerns about the proposal to phase out MDIs from the market. Many of the patients expressed the concern that FDA is 'accelerating' the phase out of MDIs or that FDA is planning to remove all CFC-based MDIs immediately now that one non-CFC MDI has been approved. These concerns are unwarranted and are addressed in the ANPR. A significant number of the responses to the ANPR were submitted by patients, professional organizations, pharmaceutical manufacturers, patient advocacy groups, or environmental groups, which provided valuable critiques of FDA's proposals and suggested alternatives.

The ANPR also was discussed at a public meeting of the FDA's Pulmonary and Allergy Drugs Advisory Committee on April 11, 1997. At that meeting, more than 25 individuals representing various pharmaceutical manufacturers, health care professional groups, environmental groups, and patient advocacy groups participated in the open public hearing to share their views on the proposed transition strategy. The Agency received valuable input from the expert members of the committee and the open public hearing speakers that will be considered as part of the public comments on the ANPR.

Let me now briefly describe the proposed transition strategy described in the ANPR. A copy of the Federal Register notice containing the full text of the ANPR is attached to this document for the Committee's reference.

As stated in the ANPR, FDA tentatively has determined that certain uses of CFCs listed in 21 CFR 2.125(e) can no longer be considered to be essential. The ANPR announces that FDA is considering proposing to remove these uses from the list of essential-uses in a rulemaking to be initiated soon. These uses include metered-dose steroid human drugs for nasal inhalation and several drug products that are no longer marketed (i.e., Polymyxin B sulfate-bacitracin zinc-neomycin sulfate soluble antibiotic powder without excepients, for topical use on humans; and contraceptive vaginal foams for human use).

Steroid human drugs for nasal inhalation are indicated for the treatment of allergic and non-allergic rhinitis and nasal polyps and are currently available in drug products using metering pump sprays in addition to CFC-based MDIs. The availability of such pump spray products as Beconase AQ(R) and Vancenase AQ(R) (beclomethasone dipropionate monohydrate), Nasarel(R) and Nasalide (R) (flunisolide), Flonase (R) (fluticasone propionate), and Nasacort AQ(r) (triamcinolone acetonide), and the widespread patient acceptance of these products, indicate to FDA that using CFCs in metered-dose steroid human drugs for nasal inhalation can no longer be considered to be essential, and FDA has tentatively determined to remove the use from 21 CFR 2.125(e). The Parties to the Montreal Protocol have demonstrated their agreement with FDA's tentative determination that CFCs are not essential for this use by consistently denying requests for essential-use exemptions from the general ban on production of CFCs for metered-dose steroid human drugs for nasal inhalation.

In addition to stating which uses currently listed in 21 CFR 2.125(e) FDA considers to no longer be essential, the ANPR defines the proposed criteria FDA will-apply in making future determinations that uses of CFCs currently listed in 21 CFR 2.125(e) are no longer essential as new technology develops. The first component of the proposed criteria is a grouping of many of the drug products currently marketed under 21 CFR 2.125(e) into two therapeutic classes, the members of which may be considered to be treatment alternatives based on their closely related pharmacologic effects and indications for usage. In evaluating whether a use remains essential, FDA believes that it is appropriate to evaluate these treatment alternatives together as a therapeutic class. FDA tentatively has determined that metered- dose corticosteroid human drugs for oral inhalation (i.e., beclomethasone, dexamethasone, flunisolide, fluticasone, triamcinolone) and metered-dose short-acting adrenergic bronchodilator human drugs for oral inhalation (i.e., albuterol, bitolterol, isoetharine, isoproterenol, metaproteronol, pirbuterolrecognizes that the essential use status for individual members of a therapeutic class would only be eliminated when the essential-use status for the therapeutic class as a whole is eliminated. FDA noted in the ANPR that this approach may allow the essential-use status of an individual member of a therapeutic class to be retained despite the marketing of one or more technically feasible alternatives containing the same active moiety, pending elimination of the essential-use status for the therapeutic class as a whole. In the ANPR, FDA also proposed an alternative Policy for the elimination of the essential-use status Of individual members of a therapeutic class in advance of elimination of the essential-use status for the therapeutic class as a whole. This alternative proposed policy is sometimes referred to a the "hybrid" approach f or therapeutic classes Under this proposed "hybrid" approach, the essential-use status of an individual active moiety within a therapeutic class would be eliminated when one alternative product that contains the same active moiety is being marketed and meets all the other provisions of the four criteria for the therapeutic class that I outlined earlier. Under the "hybrid" approach, therapeutic classes would still be evaluated under the original proposed therapeutic class policy. Alternative products used in the evaluation of the essential-use status of an individual member of the therapeutic class under the "hybrid" approach would also be used in the evaluation recognizes that the essential use status for individual members of a therapeutic class would only be eliminated when the essential-use status for the therapeutic class as a whole is eliminated. FDA noted in the ANPR that this approach may allow the essential-use status of an individual member of a therapeutic class to be retained despite the marketing of one or more technically feasible alternatives containing the same active moiety, pending elimination of the essential-use status for the therapeutic class as a whole. In the ANPR, FDA also proposed an alternative Policy for the elimination of the essential-use status Of individual members of a therapeutic class in advance of elimination of the essential-use status for the therapeutic class as a whole. This alternative proposed policy is sometimes referred to a the "hybrid" approach f or therapeutic classes Under this proposed "hybrid" approach, the essential-use status of an individual active moiety within a therapeutic class would be eliminated when one alternative product that contains the same active moiety is being marketed and meets all the other provisions of the four criteria for the therapeutic class that I outlined earlier. Under the "hybrid" approach, therapeutic classes would still be evaluated under the original proposed therapeutic class policy. Alternative products used in the evaluation of the essential-use status of an individual member of the therapeutic class under the "hybrid" approach would also be used in the evaluation of the class as a whole. FDA specifically requested public comment on these approaches, and solicited other possible approaches, for the elimination of the essential-use status of individual members of the therapeutic classes and the therapeutic classes as a whole in the ANPR.

With regard to examining the essential-use status of a drug that is not a member of one of the two therapeutic classes described above, the ANPR states that FDA will look at other drug products containing the same active moiety as potentially technically feasible alternatives. The proposed criteria that must be met in order for the use of CFCs in any drug product that is not a member of a therapeutic class to no longer be considered essential are:

• First, one alternative product containing the same active moiety is being marketed, delivered by the same route of administration, for the same indication, and with approximately the same level of convenience of use compared to the product containing the CFCs;
  
  
• Second, it must be demonstrated that adequate supplies and production capacity exist for the alternative product to meet the needs of the population indicated for the alternative drug product containing the active moiety;
  
  
• Third, at least one year of postmarketing use data for the product are available. These data should provide persuasive evidence of patient acceptance in the United States of the alternative product; and
  
  
• Fourth, there is no persuasive evidence to rebut a presumption that all significant patient subpopulations are served by the alternative product.

In the ANPR, FDA specifically asked for public comment on the appropriateness of the proposed "individual active moiety" criteria.

In summary, let me clarify several important points regarding FDA's proposed strategy to transition to non-CFC alternative inhalation products as described in the ANPR. First, FDA is not proposing to accelerate the phase out of CFC-based MDIs for the treatment of asthma and COPD; rather, FDA is establishing the regulatory framework for future determinations of whether essential-uses currently listed in 21 CFR 2.125 remain essential as new non-CFC alternative products are approved and marketed. FDA's actions are consistent with its statutory mandate under the clean Air Act and are consistent with recent decisions made by the Parties to the Montreal Protocol. Second, FDA believes it is premature to set a target date for the total elimination of CFCs from MDIs for the treatment of asthma and COPD. While a target date of the year 2005 has been suggested by TEAP and may prove to be obtainable, no target date has been adopted by the Parties to the Montreal Protocol and no target date has been proposed by FDA in the ANPR. FDA's primary objective in meeting the statutory requirements to phase out CFC-based MDIs is to ensure that the health and safety of the millions of patients in the United States who rely on CFC-based MDIs for their health and well-being are not compromised and that they continue to have access to an adequate number of treatment options. FDA is a public health agency and intends to protect patient needs while recognizing, and appropriately balancing, the need to comply with United States and international mandates to phase out CFC-based MDIs to protect the ozone layer and the future health of the Earth's human populations and environment. Fourth, the proposed criteria for elimination of the essential-use status of the members of the two therapeutic classes and the individual active moieties are the minimum criteria that must be met before such an action will be undertaken through further notice and comment rulemaking. The proposed criteria were developed by Agency staff who are experts in the diagnosis and treatment of lung disease and who are also very intimately aware of the status of development of alternatives to CFC-based MDIs. Once these minimum criteria are judged by FDA to have been met, there will be opportunities for the public to comment on the Agency's determination during the notice and comment rulemaking procedures to eliminate the essential-use listing from 21 CFR 2.125(e). It is possible that during the time required to issue a Final Rule eliminating the essential-use from 21 CFR 2.125(e) that additional non-CFC alternative products may also be approved for marketing. Finally, FDA is fully aware of the concerns expressed by the various stakeholders on this issue and is committed to developing a final transition strategy that strikes the most appropriate balance between the various competing interests. However, the Agency's focus is, and will remain, the health and safety of patients who currently use MDIs.

V. CONCLUSION