APRIL 2, 1998
STATEMENT BY
JOHN JENKINS, M.D.
DIRECTOR, PULMONARY DRUG PRODUCTS DIVISION
CENTER FOR DRUG EVALUATION AND RESEARCH
FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
BEFORE THE
COMMITTEE ON LABOR AND HUMAN RESOURCES
UNITED STATES SENATE
APRIL 2, 1998
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 postmarketing use data for
each product is available. These data should provide
persuasive evidence of patient acceptance in the United
States of each of the alternative products; and
Fourth, there is no persuasive evidence to rebut a
presumption that all significant patient subpopulations
are served by the alternative products.
Under this proposed policy, FDA recognizes that the essential-use
status for individual members of a therapeutic class would be
eliminated only when the essential-use status for the therapeutic
class as a whole is eliminated. FDA noted in the ANPR that this
approach may allow the essential-use status of an individual
member of a therapeutic class to be retained despite the
marketing of one or more technically feasible alternatives
containing the same active moiety, pending elimination of the
essential-use status for the therapeutic class as a whole.
In the ANPR, FDA also proposed an alternative policy for the
elimination of the essential-use status of individual members of
a therapeutic class in advance of elimination of the essential-use status for the therapeutic class as a whole. This
alternative proposed policy is sometimes referred to as the
"hybrid" approach for therapeutic classes. Under this proposed
"hybrid" approach, the essential-use status of an individual
active moiety within a therapeutic class would be eliminated when
one alternative product that contains the same active moiety is
being marketed and meets the four criteria for the therapeutic
class outlined earlier. Under the "hybrid" approach, therapeutic
classes would still be evaluated under the original proposed
therapeutic class policy. Alternative products used in the
evaluation of the essential-use status of an individual member of
the therapeutic class under the "hybrid" approach would also be
used in the evaluation of the class as a whole. FDA specifically
requested public comment on these approaches, and solicited other
possible approaches, for the elimination of the essential-use
status of individual members of the therapeutic classes and the
therapeutic classes as a whole in the ANPR.
With regard to examining the essential-use status of a drug that
is not a member of one of the two therapeutic classes described
above, the ANPR states that FDA would look at other drug products
containing the same active moiety as potentially technically
feasible alternatives. The proposed criteria that would have to
be met in order for the use of CFCs in any drug product that is
not a member of a therapeutic class to no longer be considered
essential are:
First, one alternative product containing the same
active moiety is being marketed, delivered by the same
route of administration, for the same indication, and
with approximately the same level of convenience of use
compared to the product containing the CFCs;
Second, it must be demonstrated that adequate supplies
and production capacity exist for the alternative
product to meet the needs of the population indicated
for the alternative drug product containing the active
moiety;
Third, at least one year of postmarketing use data for
the product are available. These data should provide
persuasive evidence of patient acceptance in the United
States of the alternative product; and
Fourth, there is no persuasive evidence to rebut a
presumption that all significant patient subpopulations
are served by the alternative product.
In the ANPR, FDA asked for public comment on the appropriateness
of the proposed "individual active moiety" criteria.
There are several important points regarding FDA's proposed
strategy for the transition to non-CFC alternative inhalation
products as described in the ANPR. First, FDA believes it
is premature to set a target date for the total elimination of
CFCs from MDIs for the treatment of asthma and COPD. While a
target date of the year 2005 has been suggested by some parties
and may prove to be obtainable, no target date has been adopted
by the Parties to the Montreal Protocol and no target date has
been proposed by FDA in the ANPR. FDA's primary objective in
meeting the statutory requirements to phase out CFC-based MDIs is
to ensure that the health and safety of the millions of patients
in the United States who rely on CFC-based MDIs for their health
and well-being are not compromised and that they continue to have
access to an adequate number of treatment options. FDA is a
public health agency and intends to protect patient needs while
recognizing and appropriately balancing the need to comply with
United States and international mandates to phase out CFC-based
MDIs.
Second, FDA is not proposing to accelerate the phaseout of
CFC-based MDIs for the treatment of asthma and COPD. Rather, FDA
has taken the first step to establish through formal rulemaking
the regulatory framework for future determinations of whether
essential-uses currently listed in 21 CFR 2.125 remain essential
as new non-CFC alternative products are approved and marketed.
After reviewing the comments to the ANPR, FDA will publish a
proposed rule, for which there will be another opportunity for
public comment. Only after thoroughly reviewing the comments on
the proposed rule will FDA publish a final rule establishing the
framework for these decisions. Moreover, the transition strategy
proposed in the ANPR, if finalized, may include publication of
proposed and final rules, which would include an opportunity for
public comment.
Third, the proposed criteria for elimination of the
essential-use status of the members of the two therapeutic
classes and the individual active moieties are the minimum
criteria that must be met before such an action will be
initiated. The proposed criteria were developed by Agency staff
who are experts in the diagnosis and treatment of lung disease
and who are also very intimately aware of the status of
development of alternatives to CFC-based MDIs. It is possible
that during the time required to issue a final rule eliminating
the essential-use from 21 CFR 2.125(e) that additional non-CFC
alternative products also may be approved for marketing.
Finally, FDA is fully aware of the concerns expressed by
the various stakeholders on this issue and is committed to
developing a final transition strategy that strikes the most
appropriate balance between the various competing interests. The
Agency's primary focus is, and will remain, the health and safety
of patients who currently use MDIs.
FDA tentatively has determined that certain uses of CFCs listed
in 21 CFR 2.125(e), in products other than MDIs, can no longer
be considered to be essential because of the availability of
alternative products or their removal from the market. The ANPR
announced that FDA is considering proposing to remove these uses
from the list of essential-uses in a rulemaking to be initiated
soon. These uses include metered-dose steroid human drugs for
nasal inhalation and several drug products that are no longer
marketed (i.e., Polymyxin B sulfate-bacitracin zinc-neomycin
sulfate soluble antibiotic powder without excipients, for topical
use on humans; and contraceptive vaginal foams for human use).
Steroid human drugs for nasal inhalation are indicated for the
treatment of allergic and non-allergic rhinitis and nasal polyps
and are currently available in drug products using metering pump
sprays in addition to CFC-based MDIs. The availability of such
pump spray products as Beconase AQ and Vancenase AQ
(beclomethasone dipropionate monohydrate), Nasarel and Nasalide
(flunisolide), Flonase (fluticasone propionate), and Nasacort
AQ (triamcinolone acetonide), and the widespread patient
acceptance of these products, indicate to FDA that using CFCs in
metered-dose steroid human drugs for nasal inhalation can no
longer be considered to be essential, and FDA tentatively has
determined to remove the use from 21 CFR 2.125(e). The Parties
to the Montreal Protocol have demonstrated their belief that CFCs
are not essential for this use by consistently denying requests
for essential-use exemptions from the ban on production and
consumption of CFCs for metered-dose steroid human drugs for
nasal inhalation.
The Agency's CFC Workgroup has now begun evaluating comments on
the ANPR in order to draft a proposed rule. When a proposed rule
is completed, it will respond to the comments submitted to the
docket for the ANPR. I can assure you that all the comments and
suggestions and other information available to the Agency will be
considered carefully as the work of drafting the proposed rule is
carried forward. The overarching principle of the CFC Workgroup
and the Agency is to ensure that the final transition strategy
will protect the health and safety of the millions of Americans
who rely on CFC-based MDIs while complying with the mandates of
the Clean Air Act and the Montreal Protocol. The Agency is
considering options for a possible additional open public meeting
on the proposed transition strategy to solicit further public
comment. FDA remains committed to seeking and considering pubic
input as we work toward development of a final transition
strategy.
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.
Recent Testimonies
(Hypertext updated by jch 1999-JUL-16)