I. INTRODUCTION
Mr. Chairman and Members of the Subcommittee, I am Dr. John Jenkins, Director of the
Division of Pulmonary Drug Products at the Center for Drug Evaluation and Research (CDER),
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 Subcommittee 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), including an update on FDA
activities since we discussed this matter with the Subcommittee on July 30, 1997. I also will
provide the Committee with an overview of FDA activities to educate patients, physicians, and
other health care professionals about the Congressionally mandated phase out of CFC-containing
MDIs and the transition to non-CFC alternative inhalation products. As requested, I will provide
comments on H.R. 2968.
I would like to assure the Committee that 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. As a pulmonologist, I am particularly aware of the sincere concerns
that patients with asthma and COPD and their health care providers may have regarding this
transition and I am personally committed to working to insure that the interests of these patients
are protected as we work to develop and safely implement a transition strategy for the
United States.
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 essential-use 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 CFC-containing products (40 CFR ..
82.64 and 82.66(d)). These provisions exempt from the ban "medical devices" for which no safe
and effective alternative has been developed and that FDA, in consultation with EPA, determines
to be essential and are listed in Title 21 Code of Federal Regulations (CFR) Section 2.125 (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 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. Furthermore, FDA has not proposed that the
essential-use status of any CFC-based MDI drug product that is currently listed as essential in 21
CFR . 2.125(e) be removed at this time. Rather, consistent with national policy and our
obligations under the Montreal Protocol and the Clean Air Act, 42 U.S.C. . 7671,
FDA is working to develop a regulatory strategy by which such future determinations can be
made once sufficient non-CFC alternative inhalation products become available in the
United States; and the products are demonstrated to meet the needs of patients who currently rely
on CFC-based MDIs.
II. ADVANCE NOTICE OF PROPOSED RULEMAKING
As noted above, on March 6, 1997, FDA published an ANPR setting forth a potential transition
process in connection with CFC-based MDIs. In developing a transition process, 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 exempt medical products that FDA, in consultation with
EPA, has determined to be essential. The ANPR set forth a potential process for FDA to review
the essential-use determinations of currently marketed CFC-MDIs in order to
determine whether the availability of acceptable non-CFC alternative inhalation products make
the use of CFCs no longer essential. 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 ANPR, I would like to review for the
Subcommittee the process FDA followed in developing the potential transition process. The
potential transition process 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 process. 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 an allergist from the Division of Pulmonary Drug
Products who are experts in the diagnosis and treatment of diseases related to the
lungs.
The CFC Workgroup and the Agency decided early that the best way to fairly and equally 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 an initial proposed transition process that could then be
published for public comment as an ANPR. This approach was designed to allow the Agency to
receive the broadest possible public comment and input on this complex issue from interested
stakeholders prior to proceeding to the formal rulemaking process.
FDA's primary objective in the development of a transition process has been, and continues to
be, to safely manage the mandated phaseout of CFCs-based MDIs in such a way as to ensure
that the millions of patients in the United States with asthma and COPD who rely on CFC-based
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 the essential-use listings for any CFC-based MDIs at this time.
Rather, the ANPR represents only the first step in the process by which the Agency will establish
the criteria that would be used in the future to determine whether essential-uses currently listed in
21 CFR . 2.125 are no longer essential-uses of CFCs.
It is important to emphasize that the potential transition process outlined in the ANPR specifies
the minimum number of non-CFC alternatives that would have to be available prior to a
determination that a use of CFCs is no longer essential. The process was also designed to ensure
that non-CFC alternatives are safe and effective, widely available, achieve patient acceptance,
and meet the needs of patients currently served by the corresponding CFC-based MDIs. FDA
intends to adopt a conservative approach that places the health and safety of patients with asthma
and COPD first.
The ANPR was distributed widely to various interest groups and stakeholders 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 submitted by
patients, professional organizations, pharmaceutical manufacturers, patient advocacy groups, and
environmental groups provided valuable critiques and suggested alternatives. The CFC
Workgroup is carefully evaluating these comments, critiques, and suggestions as it works to draft
a proposed rule.
The vast majority of comments received on the ANPR were from individual patients who wrote
to express their questions and concerns about the phaseout of MDIs from the market. Many of
the patient comments expressed general support for the overall environmental goals of the CFC
phaseout, but also 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, but highlight the
critical importance of patient education on this issue. In order to address this need, FDA will
continue its efforts to educate patients and health care providers regarding any proposed Agency
actions relating to the phaseout of CFCs and the transition to non-CFC alternative inhalation
products. In particular, we will continue to reassure patients that FDA takes their concerns on
this issue very seriously and is committed to ensuring that their needs for an adequate number of
safe and effective medications for the treatment of asthma and COPD are met during the
transition process and once the transition is completed.
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, 18 individuals representing various
pharmaceutical manufacturers, health care professional groups, environmental groups, and
patient advocacy groups participated to share their views on the potential transition process. 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. A list of the
speakers at that meeting is included with this testimony as Attachment A.
The ANPR sets forth possible 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 technologies
develop. The first component of the criteria is a grouping of many of the drug products currently
marketed under 21 CFR . 2.125(e) into two therapeutic classes based on their closely related
pharmacologic effects and indications for usage. In evaluating whether a use remains essential,
FDA suggested that it may be appropriate to evaluate these treatment alternatives together as a
therapeutic class. FDA suggested 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 suggested 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 set forth 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 suggested:
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 potential approach, 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 set forth an alternative approach 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 approach 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 therapeutic
class approach. 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 suggested that FDA would look at other drug
products containing the same active moiety as potentially technically feasible alternatives. The
suggested 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 "individual active
moiety" criteria.
There are several important points regarding the suggested process 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 was suggested by FDA in the ANPR. FDA's primary objective in meeting its
statutory obligations in connection with the Congressionally mandated phaseout of 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 fully intends to protect the health and safety of patients who rely on CFC-based
MDIs while also 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 a 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 carefully reviewing and evaluating all the comments to the ANPR, FDA will
publish a proposed rule, for which there will be another opportunity for public comment. During
the public comment period for the proposed rule, FDA plans to hold an open public meeting,
similar to the meeting held on April 11, 1997, in order to provide interested stakeholders an
additional opportunity to state their comments and concerns about the revised proposal. FDA
plans to ensure that the public meeting is widely announced to all interested stakeholders in order
to solicit the broadest possible range of comments on the proposed rule. Only after thoroughly
reviewing the comments on the proposed rule will FDA publish a final rule establishing the
framework for these future determinations. Moreover, the transition process suggested in the
ANPR, if adopted, may include publication of proposed and final rules, including an opportunity
for public comment, prior to any Agency determination that a use of CFCs in an MDI for the
treatment of asthma or COPD is no longer essential.
Third, the suggested criteria for elimination of the essential-use status of the members of the two
therapeutic classes and the individual active moieties would be the minimum criteria that
would need to be met before such a determination would be made. The suggested 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. The Agency specifically sought public comment in the ANPR on the appropriateness of
the criteria for the determination that the use of CFCs in MDIs is no longer essential. The
Agency has not made any final decisions regarding the suggested criteria for such
determinations.
Finally, FDA is fully aware of the concerns expressed by the various stakeholders on this issue
and is committed to developing a final transition process that strikes the most appropriate
balance between the various competing interests. The Agency's primary focus is, and will
remain, protecting the health and safety of patients who currently use MDIs.
The Agency is aware that many parties have raised concerns about the possible impact on costs
to patients and health care providers that may result from the mandated transition to non-CFC
inhalers. The Agency acknowledges that these concerns are important and is currently
considering this issue carefully as we continue the work of drafting a proposed rule. It is
important to note, however, that FDA has no direct regulatory authority in the area of drug
product pricing.
Many of the comments related to concerns over the possible increased costs of non-CFC
products have centered on the issue of generic competition for non-CFC products. The Agency
acknowledges these concerns, but reminds the Committee that the Agency is bound by existing
patent and exclusivity laws with regard to the approval of generic versions of innovator products,
including non-CFC MDIs. It is important to note for clarity on this issue that, in the present
market, only 1 of the 17 active moieties currently approved in CFC-based MDIs for the treatment
of asthma and COPD is currently available as a generic; i.e., albuterol. Furthermore, only 3 of
the 17 active moieties currently approved in CFC-based MDIs for the treatment of asthma
and COPD now are available as products produced by more than one pharmaceutical sponsor;
i.e., albuterol, beclomethasone, and epinephrine. Thus, the majority of active moieties currently
approved in CFC-based MDIs for the treatment of asthma and COPD are only available from one
sponsor.
In the ANPR, FDA suggested that certain uses of CFCs listed in 21 CFR . 2.125(e) can no
longer be considered to be essential because of the availability of alternative products or based on
the fact that the products are no longer being marketed by manufacturers in formulations that
contain CFCs. The ANPR announced that FDA is considering proposing to remove these uses
from the list of essential-uses in 21 CFR . 2.125(e). 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 that it would be appropriate to eliminate the
essential-use listing in 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, based on the availability of non-ozone
depleting alternatives.
The Agency's CFC Workgroup is continuing to evaluate the comments on the ANPR and has
begun work on drafting a proposed rule. The CFC Workgroup has found the input received in
response to the ANPR and the resulting public debate on this issue insightful and very useful.
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 process protects 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. As I noted earlier, the Agency plans to hold an additional open
public meeting on the proposed transition process during the comment period for the proposed
rule in order to solicit further public comment. FDA remains committed to seeking and
considering pubic input as we work toward development of a final transition strategy.
III. 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. As part of this effort, I made a presentation
on the CFC phaseout and FDA activities at the 1998 International Conference of the American
Lung Association/American Thoracic Society in Chicago on April 27, 1998. 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. 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.
IV. 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
and, required by 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, essential-use
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 facilitated for the United States by EPA, and the U.S. State
Department 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 the year 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 availability of safe and effective 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, which should provide useful information for consideration by all Protocol Partners.
It should be noted that at the Open Ended Working Group Meeting in June 1997, the TEAP
issued an interim report which expressed a belief 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 the year 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 an
absolute date for the elimination of CFCs from MDIs, FDA has attempted to suggest in the
ANPR the criteria it would 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. FDA participates with the Department of State, EPA and
other agency representatives as United States delegates to meetings of 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 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 provide its expertise to this important global effort as well as to monitor closely and 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 the
year 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 plans to
continue to support the attendance by FDA staff at important Montreal Protocol meetings as
requested by the Chair of the United States delegation.
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 adopted any 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.
Other countries, such as Australia and New Zealand, have also submitted initial strategies, and
the 15 member 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 develop a national transition process 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.
V. 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 Productsworked 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 could 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 by IPAC member
companies to the Agegcy for review.
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.
While certain the information regarding the development of non-CFC alternative inhalation
products is proprietary, I would like to provide the Committee with a general overview of the
current status of the activities of the pharmaceutical industry to reformulate currently approved
CFC-based MDIs. Currently approved CFC-based MDIs indicated for the treatment of asthma
and COPD contain a total of 17 different active moieties. The Agency is aware that
pharmaceutical sponsors are actively developing and testing, or have already received FDA
approval for, one or more non-CFC formulations (i.e., non-CFC-based MDIs, dry powder
inhalers, or other non-CFC inhaler technologies) for 9 of the 17 active moieties. The Agency
also is aware of preliminary interest by pharmaceutical sponsors in developing non-CFC
formulations of two additional active moieties. At this time, the Agency is not aware of any
efforts or interest in developing non-CFC formulations for the remaining six active moieties.
The nine active moieties for which non-CFC formulations are under active development or
already have been approved represent the most frequently prescribed products for the treatment
of asthma and COPD and may be viewed by sponsors as the agents most likely to generate a
reasonable return on the investment costs associated with bringing a non-CFC formulation to
market. The six active moieties that are not currently being reformulated into drug products
using non-CFC technology are less frequently prescribed and may not be viewed by sponsors as
having adequate potential for commercial viability to warrant reformulation efforts. It must be
noted that the data described above reflect the Agency's current knowledge of reformulation
efforts and could change over time (i.e., active moieties currently being reformulated may be
dropped by the sponsor for various reasons or active moieties not currently being reformulated
may be the subject of such efforts in the future).
It is difficult at this time to accurately predict what may happen in the future to CFC-based MDIs
that are not reformulated to non-CFC versions. The Agency, however, will continue to work
closely with EPA and the Department of State to strongly support and defend United States
requests to the Parties for essential-use exemptions for CFC-based MDIs for the treatment of
asthma and COPD until such time that CFC-based MDIs are no longer considered essential due
to development and approval of an adequate number of non-CFC alternatives that are shown to
meet patient needs. It should be noted, however, that it is also possible that sponsors
of currently marketed CFC-based MDIs for the treatment of asthma and COPD may choose on
their own to discontinue marketing of their product(s) in the future for commercial, economic, or
other reasons rather than pursuing reformulation efforts. Thus, it remains possible, and
somewhat likely given the current state of development of alternatives, that products based on 1
or more of the 17 active moieties may never be reformulated using non-CFC technology and that
the CFC-based MDI versions of these drugs may eventually disappear from the U.S. market.
The Agency is concerned about the possible impact such events may have on patients with
asthma and COPD and will continue to work closely with the pharmaceutical industry to
encourage and facilitate the development of non-CFC formulations of current CFC-based MDIs
to the greatest extent possible.
VI. LEGISLATION
You also asked me to discuss the position of the Food and Drug Administration with respect to
H.R. 2968. The Administration believes that H.R. 2968 is unnecessary. I would like to make a
few points as to how the bill relates to FDA's ANPR and our future administrative rulemaking
activities.
Section 1 of the bill would require that in publishing any regulations which may remove
essential-use designations, the Secretary of Health and Human Services (HHS) shall certify to the
Congress that alternatives to CFC-based inhalers are available that, for all populations of users,
are comparable in terms of safety, effectiveness, therapeutic indications, dosage strength, cost,
and retail availability. These criteria illustrate that any process eventually implemented with
regard to elimination of an essential-use designation will need to address a range of important
issues. While some of the criteria in the bill are similar to those set forth in the ANPR, we
believe the ANPR's approach would provide important additional protections for
asthma and COPD patients. Statutorily limiting FDA's flexibility in the administrative
rulemaking process would reduce the Agency's ability to provide such protections as
circumstances change in the marketplace and as the Agency obtains additional information
during its proposal and comment process. We believe it would be in the public interest to permit
the Agency to complete its rulemaking process.
Section 2 of the bill would direct the Commissioner of FDA to withdraw the March 6, 1997
ANPR and issue another ANPR after the 10th Meeting of the Parties to the Montreal Protocol.
The ANPR has no actual regulatory effect, but was published in order to stimulate public
discussion and input to the FDA. FDA's purpose in publishing a possible transition approach in
the ANPR was to solicit comments from the public on the elements of such an approach and
possible alternatives. That purpose was fully accomplished, as evidenced by the over 9,400
comments received by the Agency. It would be unfortunate if we were required to terminate
consideration of those comments, thereby, forcing citizens with a vital health interest at stake to
comment on a second ANPR. That would be the practical effect of this bill. Finally, FDA
already has undertaken the consultation with patients, physicians, manufacturers and other
stakeholders that would be required by the bill. The public will have another opportunity to
participate during the comment period of a proposed rule. Additionally, we are making the
commitment to you today to hold another public meeting after publishing a proposed
rule.
VI
I. CONCLUSION
Mr. Chairman, I hope that my testimony here today provided the members of the Subcommittee
with a better understanding of what actions FDA has taken, and is considering, to facilitate the
development and approval of non-CFC alternative products. The potential transition approach
outlined in the ANPR represents only the first step in the process FDA proposes to follow to
develop and implement a transition process that protects 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
Subcommittee again that FDA is not proposing to accelerate the phaseout process. We are
committed to the development and implementation of a transition process that fully serves the
vital medical 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.
ATTACHMENT A |
List of Speakers
Open Public Meeting
Pulmonary and Allergy Drugs Advisory Committee
April 11, 1997 |
Speaker |
Representative of |
Nancy Sander |
Allergy and Asthma Network/Mothers of
Asthmatic, Inc. (AAN/MA) |
Michael Sauter |
Strategic Insights, Inc. |
Ian Penn |
Friends of the Earth |
Benjamin DeAngelo |
Natural Resources Defense Council |
Malcolm Ko |
Atmospheric and Environmental Research, Inc. |
John Craighead |
University of Vermont School of Medicine |
Nancy Ostrum |
Allergy and Asthma Medical Group and Research
Center |
Janet Remetta |
Chairperson, International Pharmaceutical
Aerosol Consortium |
J. Douglas Wilson |
Senior Vice President, Medical and Drug
Regulatory Affairs, Boehringer Ingelheim
Pharmaceutical, Inc |
Kathleen Rickard |
Director, Respiratory, US Medical Affairs,
Glaxo Wellcome, Inc |
Dean Handley |
Director, Scientific Affairs, Sepracor, Inc. |
Mary Worstell |
Executive Director, The Asthma and Allergy
Foundation of America |
Alfred Munzer |
Past President, American Lung Association |
John W. Georgitis |
Chair, American College of Chest Physicians |
Daniel Ein |
President Elect, Joint Council of
Allergy,Asthma, and Immunology |
Charles Rice |
National Association of Pharmaceutical
Manufacturers |
Gene Colice |
Associate Director, Clinical Research,
3M Pharmaceuticals |
Mark DuVal |
Division Counsel, 3M Pharmaceuticals |