Implementation of Title VI of the Clean Air Act and chlorofluorocarbons in metered-dose inhalers

Statement of

John Jenkins, M.D.
Director
Pulmonary Drug Products Division
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services

before

the Senate Committee on Labor and Human Resources

April 2, 1998

INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. John Jenkins, Director of the Pulmonary Drug Products Division at the Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration (FDA or the Agency). I appreciate the opportunity to discuss FDA's 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 provide the Committee with an overview of 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 (FR) for public comment on March 6, 1997 (62 FR 10242). I also will provide the Committee with an overview of FDA activities to educate patients and physicians about the mandated phaseout of CFC containing MDIs and the transition to non-CFC alternative inhalation products.

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 phaseout 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 help implement the national and international mandate to phase out the use of CFCs.

Pursuant to 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), the production (manufacture) and consumption of ozone-depleting substances (ODS) (e.g., CFCs) is being phased out worldwide. Under the provisions of the Montreal Protocol, codified into law in Title VI of the Clean Air Act, 42 U.S.C. 7671, the production and consumption of CFCs in the United States was banned as of January 1, 1996, unless an exemption is approved annually by the Parties to the Montreal Protocol.

Section 610 of the Clean Air Act and the Environmental Protection Agency (EPA) implementing regulations contain a ban on the sale and distribution of CFCs in pressurized dispensers, such as MDIs (40 CFR 82.64(c) and 82.66(d)). These provisions exempt from the ban "medical devices" that FDA, in consultation with EPA, determines to be essential and are listed in 21 CFR 2.125(e).

Under 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. The provisions of 21 CFR 2.125(d) exempt from the adulteration and misbranding provisions of 21 CFR 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).

It needs to be emphasized strongly that FDA is not proposing to accelerate the phaseout of CFC-based MDIs as has been suggested by some parties. FDA has not proposed that any CFC-based MDI drug products be removed from the market at this time. Rather, consistent with national policy and our obligations under the Clean Air Act, 42 U.S.C. 7671, FDA is working to develop a regulatory strategy by which such determinations can be made once sufficient non-CFC alternative inhalation products become available in the United States; the products are demonstrated to be accepted by patients; and the products are able to meet the needs of patients who currently rely on CFC-based MDIs.

ADVANCE NOTICE OF PROPOSED RULEMAKING

As noted above, on March 6, 1997, FDA published an ANPR announcing the proposed transition strategy for phaseout of essential-use exemptions for CFC-based MDIs. In developing a transition strategy, FDA is carrying out the duties assigned to it by Title VI of the Clean Air Act. In passing Title VI, Congress directed EPA to promulgate regulations banning the sale or distribution of products that release ODS into the atmosphere as well as mandating the phaseout 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 statutory 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 medical products that FDA in consultation with EPA has determined to be essential. The ANPR proposed a process for FDA to review the essential use determinations of currently marketed CFC-MDIs in order to determine the availability of non-CFC alternative inhalation products. FDA's efforts in this area will serve to ensure that these Congressionally mandated determinations remain current and are consistent with the Montreal Protocol and the Clean Air Act.

Before describing some of the important details of the proposal, 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, 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 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 from experts in policy development. The clinical members of the CFC Workgroup include pulmonologists and allergists from the Division of Pulmonary Drug Products who are experts in the diagnosis and treatment of diseases related to the lungs.

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 phaseout 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 is to make the transition to non-CFC alternative inhalation products as seamless as possible. Again, as noted above, the Agency is not proposing to accelerate the phaseout of CFC-based MDIs as some may suggest or believe, 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 rulemaking process by which the Agency will determine 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 would have to be available prior to such a determination and is designed to ensure that non-CFC alternatives are safe and effective, widely available, accepted by patients, and fulfill the needs of the significant patient subpopulations currently served by the corresponding CFC-based MDIs. FDA is taking a conservative approach that places the interests and the safety of patients with asthma and COPD first.

The ANPR was distributed widely to various interest groups and had the desired effect of stimulating significant public interest and comment. This interest is reflected by the approximately 9,400 comments to the docket that were received during the formal 60-day period for public comment, which closed on May 5, 1997. Approximately 200 comments were received after the formal comment period ended. The Agency recently has completed a review of the comments received and will carefully consider those comments as a proposed rule is developed. 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 vast majority of comments received were from individual patients who wrote to express their questions and concerns about the proposal to phase out MDIs From the market.

Many of the patient comments expressed concern that FDA is "accelerating" the phaseout 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, as is made clear in the ANPR proposal. FDA, however, will continue its efforts to educate patients and health care providers regarding any proposed Agency actions regarding the phaseout of CFCs and the transition to non-CFC alternative inhalation products.

The ANPR also was discussed at a public meeting of 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 to share their views on the proposed transition strategy. The valuable input received from the expert members of the Advisory Committee and the public meeting speakers is being considered with the public comments on the ANPR.

The ANPR sets forth the proposed criteria FDA would 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 proposed that it may be 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, pirbuterol, terbutaline) are appropriate therapeutic classes for essential uses determinations. FDA also has determined tentatively that drug products containing active drug substances that are not members of either therapeutic class should be evaluated as essential uses of CFCs based on an individual active moiety approach.

The ANPR proposes four criteria that would have to be met in order for the use of CFCs in any product that is a member of a therapeutic class to no longer be considered essential. For each therapeutic class the following criteria are proposed:

First, three distinct alternative products, representing at least two different active moieties, are being marketed, with the same route of delivery, for the same indication, and with approximately the same level of convenience of use as the products containing CFCs. In addition, at least two of the three products must be MDIs;

Second, it must be demonstrated that adequate supplies and production capacity exist for the alternative products to meet the needs of the population indicated for the therapeutic class;

Third, at least one year of postmarketing use data for each product is available. These data should provide persuasive evidence of patient acceptance in the United States of each of the alternative products; and

Fourth, there is no persuasive evidence to rebut a presumption that all significant patient subpopulations are served by the alternative products.

Under this proposed policy, FDA recognizes that the essential-use status for individual members of a therapeutic class would be eliminated only 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 as the "hybrid" approach for 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 the four criteria for the therapeutic class 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 would look at other drug products containing the same active moiety as potentially technically feasible alternatives. The proposed criteria that would have to 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 asked for public comment on the appropriateness of the proposed "individual active moiety" criteria.

There are several important points regarding FDA's proposed strategy for the transition to non-CFC alternative inhalation products as described in the ANPR. 

First, 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 some parties 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.

Second, FDA is not proposing to accelerate the phaseout of CFC-based MDIs for the treatment of asthma and COPD. Rather, FDA has taken the first step to establish through formal rulemaking 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. After reviewing the comments to the ANPR, FDA will publish a proposed rule, for which there will be another opportunity for public comment. Only after thoroughly reviewing the comments on the proposed rule will FDA publish a final rule establishing the framework for these decisions. Moreover, the transition strategy proposed in the ANPR, if finalized, may include publication of proposed and final rules, which would include an opportunity for public comment.

Third, 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 initiated. 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. 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 also may 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. The Agency's primary focus is, and will remain, the health and safety of patients who currently use MDIs.

FDA tentatively has determined that certain uses of CFCs listed in 21 CFR 2.125(e), in products other than MDIs, can no longer be considered to be essential because of the availability of alternative products or their removal from the market. The ANPR announced 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 excipients, 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 and Vancenase AQ (beclomethasone dipropionate monohydrate), Nasarel and Nasalide (flunisolide), Flonase (fluticasone propionate), and Nasacort AQ (triamcinolone acetonide), and the widespread patient acceptance of these products, indicate to FDA that using CFCs in metered-dose steroid human drugs for nasal inhalation can no longer be considered to be essential, and FDA tentatively has determined to remove the use from 21 CFR 2.125(e). The Parties to the Montreal Protocol have demonstrated their belief that CFCs are not essential for this use by consistently denying requests for essential-use exemptions from the ban on production and consumption of CFCs for metered-dose steroid human drugs for nasal inhalation.

The Agency's CFC Workgroup has now begun evaluating comments on the ANPR in order to draft a proposed rule. When a proposed rule is completed, it will respond to the comments submitted to the docket for the ANPR. I can assure you that all the comments and suggestions and other information available to the Agency will be considered carefully as the work of drafting the proposed rule is carried forward. The overarching principle of the CFC Workgroup and the Agency is to ensure that the final transition strategy will protect the health and safety of the millions of Americans who rely on CFC-based MDIs while complying with the mandates of the Clean Air Act and the Montreal Protocol. The Agency is considering options for a possible additional open public meeting on the proposed transition strategy to solicit further public comment. FDA remains committed to seeking and considering pubic input as we work toward development of a final transition strategy.

EDUCATIONAL EFFORTS

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, other health care providers and interested parties about the phaseout of CFC-based MDIs and the transition to non-CFC alternatives. For the past several years, staff from CDER's Division of Pulmonary Drug Products have made presentations and participated in panel discussions on the phaseout of CFCs and the transition to non-CFC alternatives at national scientific and professional society meetings. The Division staff will continue to make such presentations in an effort to inform physicians and other health care professionals about FDA activities related to the phaseout of CFC-based MDIs and the transition to non-CFC alternative inhalation products. The Division is currently exploring ways to further increase its ability to communicate updates on FDA activities to these professional groups.

The Division also has worked in close cooperation with the National Asthma Education Prevention Program (NAEPP), an ongoing comprehensive national asthma education, treatment, and prevention program directed by the National Heart, Lung, and Blood Institute of the National Institutes of Health. NAEPP works to educate patients, physicians, and other health care providers about the phaseout of CFCs and the transition to non-CFC alternative inhalation products. The membership of the NAEPP includes a broad array of representatives of health care provider professional organizations, patient advocacy and educational organizations, and various Federal agencies involved in matters related to asthma, including FDA. The NAEPP Coordinating Committee has formed a CFC Workgroup tasked with educating patients and physicians about the CFC phaseout and the transition to non-CFC alternative inhalation products. I am a member of the NAEPP Coordinating Committee and its CFC Workgroup. The NAEPP CFC Workgroup, in cooperation with the International Pharmaceutical Aerosol Consortium (IPAC) recently developed a "fact sheet" for patients entitled, "Your Metered-Dose Inhaler Will Be Changing . . . Here Are The Facts." The fact sheet is written in a question and answer format in language that can be understood easily by patients with asthma and other chronic obstructive pulmonary diseases. Supplies of the fact sheet have been provided to all member organizations of the NAEPP Coordinating Committee for distribution to patients and health care providers. The NAEPP CFC Workgroup is exploring additional educational efforts to continue and broaden this educational effort. FDA will continue to provide appropriate advice and assistance to the NAEPP CFC Workgroup as this important educational effort continues.

The Agency also has published, and will be publishing in the future, articles on the phaseout of CFCs in FDA Consumer, Journal of the American Medical Association, and the FDA Medical Bulletin. These articles are intended to educate health care providers and patients about the phaseout of CFCs and FDA actions, or proposals, related to the transition to non-CFC alternative inhalation products.

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.

PROVISIONS OF THE MONTREAL PROTOCOL

As noted above, the production and consumption of ODS is being phased out worldwide under the terms of the Montreal Protocol. In accordance with the provisions of the Montreal Protocol, as codified in Title VI of the Clean Air Act, the production, importation, and consumption of CFCs in the United States were banned as of January 1, 1996. Currently, exemptions are allowed by the Parties to the Montreal Protocol for the production of CFCs for use in the manufacture of MDIs for the treatment of asthma and COPD. Firms that wish to manufacture MDI-containing CFCs after the phaseout date for use in medical devices covered under section 610 of the Clean Air Act must receive annual production allowance exemptions for essential uses under the Montreal Protocol. Procedures for securing essential-use exemptions under the Montreal Protocol are administered for the United States by EPA, which is responsible for making nominations on behalf of the United States.

Since the ban on the production of CFCs became effective, the United States has secured essential-use exemptions allowing the production of CFCs for MDIs for the treatment of asthma and COPD through 1999. This is currently the only commercial purpose for which new CFCs can be produced in the United States and other developed nations. The United States has submitted a nomination to the Parties to the Montreal Protocol to extend this essential-use exemption to 2000, and this nomination is currently under review by the Parties.

The United States will continue to seek essential-use exemptions to permit the use of CFCs for MDIs pending the development and marketing of "technically feasible" 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 and Clean Air Act mandate an eventual complete ban on the production of ODS and that the essential-use exemptions allowed under the Protocol are clearly not intended, or expected, to be permanent.

The Parties to the Montreal Protocol have adopted several decisions related to the transition to non-CFC alternative inhalation products. These measures include: 1) a series of measures designed to promote industry's participation in a smooth and efficient transition away from CFC-based MDIs; 2) measures designed to foster information gathering on a transition to non-CFC treatments for asthma and COPD in developed nations (i.e., Parties not operating under Article 5); and 3) a decision to require Parties submitting nominations for essential-use allowance exemptions for CFCs for MDIs for the treatment of asthma and COPD to present to the Ozone Secretariat an initial national transition strategy by January 31, 1999 for circulation to all Parties.

These and other actions adopted by the Parties to the Montreal Protocol indicate an interest in fostering the development, marketing approval, and acceptance of non-CFC alternative inhalation products and the development of national strategies in developed nations to accomplish the transition to non-CFC alternatives.

At the Open Ended Working Group of the Parties to the Montreal Protocol meeting to be held in Geneva in July 1998, it is expected that the United Nations Environment Program (UNEP) Technical and Economic Assessment Panel (TEAP) will present for review and discussion its final report on issues surrounding a transition to non-CFC treatments of asthma and COPD in developed nations that is fully protective of public health, as requested by the Parties at their 8th Meeting in Costa Rica in November 1996. FDA looks forward to the release of the final TEAP report and will carefully review it to determine its impact on the transition to non-CFC alternative inhalation products in the United States.

It should be noted that at the Open Ended Working Group Meeting in June 1997, the TEAP issued an interim report which suggested that the transition to CFC-free inhaled therapy should occur as rapidly as possible without compromising patient safety. The TEAP interim report suggested that this transition should occur within an overall international environmental framework, but with national responsibility for developing a national transitional policy. The TEAP interim report also suggested 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 phaseout 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 phaseout 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.

Although the year 2005 has been discussed as a possible date for a virtual phaseout of CFCs for MDIs in developed nations, it is important again 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 view 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 and shown to adequately meet patient needs.

In preparation for the transition to non-CFC alternative inhalation products, FDA also plays an advisory role in the United States' involvement in the Montreal Protocol. Although the Department of State and EPA are the official United States representatives to the Montreal Protocol, FDA has developed a working relationship with the staff at both the Department of State 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. Robert Meyer, a medical Team Leader 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. Meyer's involvement with the Aerosols TOC allows FDA to monitor closely and to respond to international developments related to the phaseout of CFC-based MDIs. Dr. Meyer attended the most recent meeting of the Aerosols TOC where the CFC essential-use nominations for 2000 were reviewed. FDA plans to continue to support actively Dr. Meyer's involvement on this critical committee.

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 believes that its actions to date on issues related to the transition to non-CFC alternative inhalation products are consistent with its primary mission of protecting patient health and 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 phaseout of CFCs from MDIs for the treatment of asthma and COPD, the Parties have adopted a requirement that individual developed countries submit an initial draft national transition strategy to the Ozone Secretariat by January 31, 1999. FDA believes that the ANPR published on March 6, 1997, is a step toward meeting this requirement.

While the United States was the first developed nation to announce a proposed transition strategy, we are not alone in this effort. Australia, the European Union, and Canada are actively developing respective transition strategies. FDA continues to believe 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 reflects the characteristics of the regulatory, health care, and marketing environments of the individual country, rather than attempting to develop a "one size fits all" international transition strategy. This position was supported by the TEAP in its April 1997 interim report which stated "that no single strategy will be applicable to all countries." 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 should 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.

FDA TRANSITION ACTIVITIES

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).

FDA has undertaken efforts to lay the groundwork for the transition to non-CFC alternative inhalation products in cooperation with the pharmaceutical industry and other stakeholders. 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 mandated phaseout of CFCs and the transition to non-CFC alternative inhalation products.

Early in the process of developing alternatives, the chemistry staff in FDA's Division of Pulmonary Drug Products, CDER, 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 phaseout of CFCs, the traditional producers of pharmaceutical grade CFCs might scale back their production capacity or stop producing CFCs entirely. This, in turn, could lead 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 proactively 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.

The pharmacology staff in the Division of Pulmonary Drug Products worked closely with IPAC to develop the pre-clinical testing programs for HFA-134a and HFA-227, 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 based on a number of factors including: the relatively large amount of propellant versus active drug and other inactive ingredients in MDI formulations (the propellant generally represents more than 90 percent of the total formulation by weight); the inhaled route of administration (which can be associated with greater toxicity than other routes of administration in humans); the target patient population (patients with asthma and COPD have hyper-reactive airways and are poorly tolerant of inhaled irritants); and the likely chronic use of the new non-CFC products by the target patient population. The pre-clinical testing of propellants HFA-134a and HFA-227 was conducted by IPAC for shared use in the support of New Drug Applications (NDAs) expected to be submitted to the Agency for review by IPAC member companies.

In recognition of the extensive pre-clinical testing of the new propellants undertaken by IPAC under this program, and the extensive existing pre-clinical and clinical database on the currently marketed drug substances and inactive ingredients used in MDIs, the Division of Pulmonary Drug Products agreed with IPAC that a "bridging" approach was appropriate for the pre-clinical testing of the new formulations of propellant, drug substance, and inactive ingredients. This "bridging" approach substantially reduces the regulatory requirements for pre-clinical studies to be conducted prior to approval for each new non-CFC MDI product. To expedite the development of new formulations containing the alternative propellants and to give sponsors Agency feedback on the pre-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.

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 FDAs 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 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 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, effective and comparable to currently marketed CFC-MDIs.

We believe that FDA has helped to lay the foundation for the development of safe and effective non-CFC alternative inhalation products and that these efforts, coupled with the work of the pharmaceutical industry, will result in the approval of a number of such products over the next several years.

The development of non-CFC alternative inhalation products continues. The MDI is a very complex device and the pharmaceutical industry's efforts to reformulate these devices to use non-CFC propellants 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. The pharmaceutical industry should be commended for its hard work and commitment of resources to this task. We are now beginning to see the fruits of these labors.

FDA approved the first non-CFC MDI, Proventil HFA, 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 to develop non-CFC MDIs, the pharmaceutical industry also is actively developing a significant number of DPIs and other novel aerosol delivery systems. These devices do not require propellant for aerosol delivery of the drug substance to the patient. In the past year, FDA has approved three new multi-dose DPIs for marketing in the United States. The three new products include Pulmicort Turbuhaler (Astra), which contains budesonide, a corticosteroid; Flovent Rotadisk (Glaxo-Wellcome), for use with the Diskhaler device which contains fluticasone propionate, a corticosteroid; and Serevent Diskus (Glaxo-Wellcome), which contains salmeterol xinofoate, a long-acting bronchodilator. These three new multi-dose DPIs which are currently entering the United States market, along with numerous other alternative products currently under development, will provide patients and physicians with an important new range of choices of products for the treatment of patients with asthma and COPD.

CONCLUSION

Mr. Chairman, I hope that my testimony here today provided the members of the Committee with a better understanding of what actions FDA has taken, and is proposing to take, to facilitate the development and approval of non-CFC alternative products. The proposed transition strategy outlined in the ANPR is designed to ensure the health and safety of patients who rely on CFC-based MDIs as the transition to non-CFC alternative products, and the phaseout of CFCs as mandated by statute and international treaty, are accomplished. We want to assure the Committee again that FDA is not accelerating the phaseout process. We are committed to the development and implementation of a transition strategy that protects the needs of current MDI users while striving to meet the mandated complete phaseout of CFCs in order to protect the environment and the future health of Earth's population.