I. 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.
II. 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 post marketing 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 post marketing 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.
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. 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.
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, 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.
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 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.
V. 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.