1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
PULMONARY-ALLERGY DRUGS ADVISORY
COMMITTEE
Holiday Inn
The Ballroom
2
PARTICIPANTS
MEMBERS
Carolyn M. Kercsmar, M.D.
Fernando
D. Martinez, M.D.
Theodore
F. Reiss, M.D. (Industry Rep)
Michael
Schatz M.D., M.S.
Karen S. Schell, RRT, (Consumer Rep)
Erik R. Swenson, M.D.
SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS
(VOTING)
T. Prescott Atkinson, M.D.,
Ph.D.
I. Marc Moss, M.D.
Wayne
Mitchell, M.D.
3
C O N T E N T S
PAGE
Call to Order and Opening Remarks:
Introductions 6
Conflict of Interest Statement:
Opening Remarks:
Robert Meyer, M.D. 10
History of the
Medical Considerations:
Eugene Sullivan, M.D. 40
Economic Considerations:
Randall Lutter, Ph.D. 60
Questions from the Committee to the
Speakers 76
Open Public Hearing (1)
Pamela Wexler, U.S.
Stakeholders Group 93
Elaine
Jones, Ph.D. GlaxoSmithKline
104
Ron
Garutti, M.D., Schering-Plough
119
Open Public Hearing (2)
Ballard Jamieson, Jr.,
International 143
Pharmaceutical Aerosol
Consortium
Neil Flanzraich, IVAX
Corporation 149
Richard Rozek, Ph.D., National
Economic 162
Research Associates
David Doniger, Natural
Resources 172
Defense Council
Joseph Rau, M.D., American
Association 181
for Respiratory Care
Jodi Finder, Asthma Therapy
Coalition 183
Steven Bernhardt, M.D., 190
Honeywell Chemicals
4
C O N T E N T S
(Continued)
Open Public Hearing (2) (Continued)
Nancy Sander, Allergy and
Asthma Network 193
Mothers of Asthmatics
Anthony Marinelli, M.D.,
American 198
Thoracic Society
Ira Finegold, M.D.,
Asthma and Immunology
Spenser Atwater, M.D., Joint
Council on 207
Allergy, Asthma and
Immunology
(statement read by Ms. Jain)
Committee Discussion 211
Adjournement
282
5
P R O C E E D I N G S
Call to Order and Opening
Remarks
DR. CHINCHILLI: Good morning, everyone.
This is a meeting of the
Pulmonary-Allergy Drugs
Advisory Committee. We are here today to discuss
whether the use of chorofluorocarbons as
propellants in albuterol-metered dose
inhalers in
no longer an essential use under the
criteria as
set forth in the Code of Federal
Regulations 12 CFR
1.125.
My name is Vern
Chinchilli. I am the
Acting Chair today for the
committee. So we will
have some opening remarks. The first thing I
usually do is introduce--I will ask each
committee
member--we will go around the table--to
introduce
themselves. Please make sure you hit the
microphone button so it is on.
Why don't we start with Dr.
Reiss. Oh; he
is not here? Dr. Atkinson?
DR. ATKINSON: I am
Allergy and Immunology at
Birmingham.
6
DR. SCHELL: Karen Schell,
Consumer
Representative from
DR. MARTINEZ: I am Fernando Martinez from
the
Arizona.
DR. SCHATZ: I am Michael Schatz,
Allergy
and Immunology, Kaiser
Permanent,
DR. KERCSMAR: Carolyn Kercsmar, pediatric
pulmonology, Rainbow Babies and
Children's Hospital
in
DR. MOSS: Mark Moss, Pulmonary and
Critical Care,
DR. CHINCHILLI: Vern Chinchilli. I am a
biostatistician from the Penn State
Hershey Medical
Center.
MS. JAIN: Shalini Jain, Exec Sec, Acting,
and, at this point, for this meeting for
the
Pulmonary-Allergy Drugs Advisory
Committee.
DR. SWENSON: Erik Swenson, Pulmonary and
Critical Care Medicine at the University
of
Washington in Seattle.
7
DR. LUTTER: Randy Lutter, Economics, with
the Office of the Commissioner in FDA.
DR. MITCHELL: Wayne Mitchell, Office of
Regulatory Policy in the Center for Drug
Evaluation
and Research. I am the draftsman on the rule.
DR. SULLIVAN: I am Gene Sullivan. I am
the Deputy Director of the Division of
Pulmonary
and Allergy Drug Products at FDA.
DR. MEYER: I am Bob Meyer. I am the
Director of the Office of Drug Evaluation
II in the
Center for Drugs at FDA.
DR. CHINCHILLI: Thank you, everyone, for
attending.
Next, Shalini Jain will talk
about the
Conflict of Interest Statement.
Conflict of Interest
Statement
MS. JAIN: The following statement
addresses the issue of conflict of
interest with
respect to this meeting and is made part
of the
record to preclude even the appearance of
such at
this meeting.
Based on the agenda, it has
been
8
determined that the topics of today's
meeting are
issues of broad applicability and there
are no
products being approved at this
meeting. Unlike
issues before a committee in which a
particular
product is discussed, issues of broader
applicability involve many industrial
sponsors and
academic institutions. All special government
employees have been screened for their
financial
interests as they may apply to the
general topic at
hand.
Because there has been reported
interest
in pharmaceutical companies, the Food and
Drug
Administration has granted
general-matters waivers
to the special government employees who
require a
waiver under Title 18, United States Code
Section
208 which permits them to participate in
today's
discussion.
A copy of the waiver statement
may be
obtained by submitting a written request
to the
agency's Freedom of Information Office,
Room 12A-30
of the Parklawn Building. Because general topics
impact so many entities, it is not
prudent to
9
recite all potential conflicts of
interest as they
apply to each member, consultant and
guest speaker.
FDA acknowledges that there may
be
potential conflicts of interest but,
because of the
general nature of the discussion before
the
committee, the potential conflicts are
mitigated.
With respect to FDA's invited industry
representative, we would like to disclose
that Dr.
Theodore Reiss is participating in this
meeting as
an industry representative acting on
behalf of
regulated industry. Dr. Reiss is employed by
Merck.
In the event that the
discussion involves
any other products or firms not already
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement
and their
exclusion will be noted for the record.
With respect to all other
participants, we
ask, in the interest of fairness, that
they address
any current or previous financial
involvement with
any firm whose products they may wish to
comment
10
upon.
Thank you.
DR. CHINCHILLI: Thank you, Ms. Jain.
We are ready to start the
regular part of
the agenda. Dr. Meyer, the Director of the Office
of Drug Evaluation II, will have some
opening
remarks.
Opening Remarks
DR. MEYER: Good morning.
Although I
service Director of the Office of Drug
Evaluation
II in the Center for Drugs, I, for many
years,
served for the Center Lead on issues
related to the
Montreal protocol and phase-out of CFCs
from
FDA-regulated medical products,
specifically MDIs
for asthma and COPD.
So, on behalf of the FDA, I
wish to
welcome all the participants in today's
meeting of
the Pulmonary and Allergy Drugs Advisory
Committee.
I want to thank you in advance for your
time and
your efforts and your thoughtfulness in
your
discussions and advice.
When we were originally
planning this
11
meeting, we had hoped the meeting would
coincide
with the open public comment period of a
proposed
rule to delist albuterol as an essential
use of
ozone-depleting substances, specifically
CFCs.
This is now, indeed, the case although
the rule
just went on display at the Federal
Register and,
subsequently, on our web page yesterday
afternoon.
I believe you have been provided copies.
I would point out that,
although the
proposed rule is posted on these sites, it is not
officially published until June 16 so
what you have
in hand is a pre-publication version that
means
some dates are missing and the pagination
will
change when it is officially published in
the
Federal Register.
I would also point out that the
six-day
comment period starts on the day of
official
publication which will be June 16
although,
clearly, the discussions today will be
considered
as part of the docket for us to consider
in coming
to the final rule.
We particularly look foreword
today to
12
input from the public in our public
hearing portion
of the meeting and I thank those
individuals and
organizations who are presenting or have
otherwise
submitted materials for the record.
All of the presentations,
submissions and
the deliberations of the committee and
advice given
today will be entered into the docket, as
I said,
and will help us to move forward towards
finalizing
this rule with a target of Summer of
2005.
I would note to the committee
that we are
not seeking any formal votes today on a
particular
question but do, very much, seek your
counsel on
the matter at hand whether the use of
CFCs in
albuterol metered-dose inhalers remains
an
essential use under the provisions of our
regulations.
We will have three speakers
from the FDA
today.
I will first speak, giving a history of the
Montreal Protocol and FDA's regulations
regarding
essential use of CFCs. Dr. Eugene Sullivan, from
the Division of Pulmonary and Allergy
Drug
Products, will then follow with
considerations
13
related to the current situation with
albuterol and
its essentiality as well as some related issues.
To close FDA's presentations,
Randy
Lutter, who is FDA's Chief Economist in
the Office
of Planning, will speak on economic
considerations
related to the potential for delisting
albuterol as
an essential use.
Again, we would like to thank
you for your
time in being here and look forward to
today's
discussion.
DR. CHINCHILLI: Thank you, Dr. Meyer.
I believe you are on the agenda
next for
your presentation.
History of the Montreal Protocol and
21 CFR 1.125
DR. MEYER: Good morning, again, from this
venue.
When I arrived at the agency about ten
years ago this July, I can assure you
that I never
envisioned I would be standing here
representing
the FDA on the issue of ozone
protections. As a
pulmonologist, it was not something that
entered my
mind at that point.
But life is full of happy
occurrences.
14
This picture on my title slide is from
NASA's web
page and shows the largest recorded ozone
hole over
the Antarctic which actually was shot
last
September of 2003. This serves as a fitting
graphic to start a talk on the history of
the
Montreal Protocol as well as the FDA
regulations
that related to chlorofluorocarbons and
ozone-depleting substances.
The stratosphere is a region of
the
earth's atmosphere that begins roughly
ten to
fifteen kilometers above the earth's
surface,
depending on the particular part of the
earth one
is focused on, and extends up to 50
kilometers.
Most of the ozone, over 90 percent of the
ozone, in
the atmosphere is in this stratosphere
where it
acts, in part, to filter ultraviolet B
radiation by
absorbing this band of wave length from
sunlight.
Increases in UV-B reaching the
earth's
surface are detrimental to human health
in a number
of ways as well as to other life forms
and to
synthetic materials. The human consequences of
most note are increases in skin cancer as
well as
15
cataracts and alterations in
immunity. Those skin
cancers are both of the melanoma type as
well as
non-melanoma.
This, then, is the background
as to why
there is a worry about protecting the
ozone layer.
Also, by way of background, since we are
talking
about regulations, I would like to
explain how
rules are made. The FDA operates under laws or
statutes, most notably the Food, Drug and
Cosmetic
Act, as well as other statutes.
However, no matter how well
written or
detailed a law may be, it cannot provide
sufficient
detail to inform the specific process of
regulation. This is accomplished by the writing of
rules which, when finalized, have the
force of law
behind them as it represents the agency's
implementation of the respective law that
we are
operating under.
The usual pathway for reaching
a final
regulation or rule is by what is called
Notice and
Comment Rulemaking. Formally, that involves the
FDA publishing a Notice of Proposed
Rulemaking, or
16
NPR, in the Federal Register such as will
shortly
occur for albuterol.
An NPR typically has a comment
period
between 60 and 90 days--again, that, for
the rule
at hand is 60 days beginning on June
16--during
which time comments from the public,
including the
regulated industry, are solicited. These comments
are then individually considered and
addressed in
reaching a final rule. Rulemaking is an integral
part of the CFC non-essentiality determinations. I
will speak more on this later.
The purpose of my talk, then,
this
morning, is to give a history and
background of the
Montreal Protocol and to FDA's
regulations with
regard to ozone protection. The timeframes for
these, as they developed, overlap and,
obviously,
the efforts intersect. So I will interweave the
two topics in my talk.
Back in the mid-1970s, two
scientists
operating out of trial University of
California at
Irvine posited that chlorofluorocarbons
were
reaching the stratosphere were UV
radiation slowly
17
would cleave off the chloride atoms that,
in turn,
catalyze the destruction of ozone. This work was
by Molina and Rowland, who later was
awarded the
Nobel Prize.
At the time that this article
came out,
chlorofluorocarbons, or CFCs, were
ubiquitous in
use in multiple applications. They became
widespread for a number of reasons. Amongst these
were that CFCs are quite non-toxic which,
parenthetically, makes them excellent for
use in
inhalers, very stable and had
physical-chemical
properties that were advantageous for use
in
refrigerant systems, air conditioners and
aerosols.
The stability of these gasses
is, in part,
why they are so devastating to the
stratosphere.
They have a very long half-life when they
reach the
stratosphere and, therefore, damage the
ozone layer
for many, many years.
In 1978, really in a fairly
remarkably
short time after the seminal publication
by Rowland
and Molina, the U.S. Government acted to
address
the issue of CFCs and to place a general
ban on the
18
use of CFCs as propellants in consumer
aerosol
products.
This was accompanied by a rule from FDA
in the relevant chapter of the Code of
Federal
Regulations or what we call the CFR, and
that, for
the FDA, is the 21st Chapter, banning the
use of
CFCs in all regulate products except for
those
deemed as essential uses.
This rule is now called 2.125
because that
is the citation where it is
published. That is how
we will be referring to it throughout
much of the
day.
Notably exempt at that time were
broad
classes of asthma and allergy products such as
a
nasal steroids, the inhaled steroids, and
adrenergic bronchodilators.
In 1987, as the science of
ozone depletion
advanced and as there was further
evidence
accumulated about ozone reductions, a
global treaty
known as the Montreal Protocol on
substances that
deplete the ozone layer was
initiated. At that
time, 27 nations, including the USA, were
signatories.
I would note, just to make this
topical to
19
sort of current events, that this was
during the
latter years of the Reagan
Administration. The
original protocol now has at least 184
signatory
countries. As of the time that I queried the web
page for the Secretariat of the Ozone
Efforts about
a month, it was 184 countries. Countries are also
called parties under the terms of the
protocol.
This is widely considered a successful
example of global, environmental
cooperation.
Indeed, there is evidence that the
chloride levels
in the stratosphere have stabilized in
recent years
and it is expected that the stratospheric
ozone
layer will slowly recover to levels that
were seen
in the early 1980s by the middle part of
this
current century.
The original phase-out of CFCs
was slated
for the Year 2000. That was taken in London in
1990.
This was moved up, however, by meeting of
the parties in Copenhagen which occurred
in 1992.
It was moved up to 1995, at the end of
'95, because
of increasing evidence of marked ozone
depletion,
particularly over the extreme southern
hemisphere,
20
as you saw in my first slide.
This phenomenon is commonly
called an
ozone hole. It is not really a true hole but an
area of extreme depletion. I should point out
that, although it is a depletion that is
particularly prominent over the southern
hemisphere, it has occurred globally.
I should also point out that,
while we are
focussing on CFCs today because that is the
relevant topic for the FDA, the protocol,
itself,
has controls on many other
ozone-depleting
substances such as halons, HCFCs,
methylbromide,
carbon tetrachloride and other substances.
So, while the CFCs are an
important issue
to FDA and, indeed, to the Montreal
Protocol, I do
want to be clear that the protocol is a
much
broader effort in scope than simply the
chlorofluorocarbons.
In accordance with the Copenhagen
Amendment to the protocol, the production
and
importation of CFCs became illegal in
economically
developed countries including the United
States as
21
of January 1, 1996. The rest of the world is
expected to have phased out new CFCs by
2010.
Metered-dose inhalers, or MDIs, for
asthma and COPD
are currently considered as potentially
acceptable
essential uses of CFCs. I say potentially
acceptable because there is a nomination
process
that parties undergo if they want to
produce or
import CFCs for use in MDIs.
These nominations have to be
done annually
and
the process generally begins nearly two years
prior to the year in question. So, for instance,
the U.S. had to submit its nomination for
2006 in
early 2004.
I would also point out that
nominations
are historically approved by consensus of
the
parties to the Montreal Protocol but,
actually, if
the consensus process fails, there is a
mechanism
within the protocol to default to a
two-thirds
majority decision.
I wanted to go through sort of
how the
protocol has evolved over time This is a decision
of the parties from the Copenhagen
meeting.
22
Decision IV, or this IV, means that it
was from the
fourth meeting of the parties and it was
the 25th
decision taken at that meeting. This was the
definition at the time that they decided
the
phase-out would begin on January 1, 1996,
or the
ban on CFCs, that stated that, "All
essential uses
of CFCs would have to be based on
products being
necessary for public health and that
there were not
adequate alternatives." The failure to have
adequate alternatives could either be
based on
technical problems or economical
problems.
But this was macroscopic in
terms of both
this determination as well as the general
use. In
other words, it was widely accepted at
that point
in general that the uses of CFCs and MDIs
for
asthma and COPD could be considered an
essential
use.
However, over time, the
protocol evolved
so that, as the phase-out progressed, as
alternatives became available, this sort
of more
generally and broad interpretation of what
was an
essential use became narrower and
narrower in
23
scope.
In Beijing, at the twelve
meeting of the
parties in the Year 2000, another
decision was
taken that said that any product approved
after
December, 2000, must individually meet
these
criteria for essentiality under Decision
IV-25.
So, in other words, it is not just a general
consensus any longer that the use of CFCs
for
asthma and COPD was acceptable but, in
this case,
any new product would have to
individually meet
this.
So this was a product-centered
determination of essentiality that
essentially
precluded new CFC generics and, actually,
many
other new CFC products. It essentially was
shutting the door, for all intents and
purposes,
except under extraordinary circumstances
for any
new CFC MDIs.
This past year, in Nairobi, a
further
decision was taken by the parties that
became even
more narrow and specific in scope. It stated that
essential-use nominations from parties
which, in
24
the past, had been lumped and general and
not
parsed out for the purposes of the
protocol's
evaluation, or the Montreal Protocol
evaluation.
Now it stated that essential-use
nominations have to be specific; for
example, a
country might say they need some
undetermined--well, they would have to
give a
specific number, but some number of tons
for
albuterol. No quantity of essential-use CFCs would
be authorized for albuterol. This is, I think,
particularly germane today--that no
quantity of
essential uses of CFCs would be
authorized,
period--actually, this is a little bit of
a
misstatement in the way this is terms--if
a country
does not submit to the meetings of the
party--beginning of the open-ended
working group,
excuse me, in the summer of 2005--a clear
plan for
when albuterol, specifically, would no
longer be
essential.
Let me go through that again,
because this
is key.
Countries who request essential uses,
including the United States, will have to
submit to
25
the Ozone Secretariat of the Open-Ended
Working
Group in the summer of 2005 a plan or a
date-certain for when albuterol will no
longer be
considered essential. If parties fail to
do that,
including the U.S., we will not receive
and
essential-use allocation at all.
Now, turning a little bit from
the
evolution of the Montreal Protocol back
to our
rules and regulations, the Clean Air Act
Amendments
of 1990 codified the Montreal Protocol
into U.S.
law.
The implementing EPA regulations specifically
call for FDA to define what is an
essential medical
use and refers to our 2.125 as the source
of the
listing of those essential products.
I remind you, however, that
1.125 was
finalized before the Montreal Protocol
existed and
before the Clean Air Act Amendments.
The rule, as promulgated in
1978, stated
that a
CFC-containing product regulated by FDA was
misbranded or adulterated under the
FD&C Act; that
is, it would be illegal under our
authority unless
deemed essential and listed in
2.125. The
26
definition of essential was that there
would be no
technically feasible alternatives; that
the use of
CFCs in that particular product provided
substantial health, public or
environmental
benefit; and that the release of the CFC
was small
or justified given the public-health
benefit.
Notably, the FDA rule had no
mechanism to
determine when things were no longer
essential and,
therefore, to delist them. It did have ways to add
new classes of drugs to the list and, in
fact, that
was done over the years. But it had no specified
way for delisting things.
Another important feature of
the rule that
needed to be correct is that many drugs,
including
albuterol, were not specifically
mentioned as
essential uses but, rather, there were
broad
definitions of drug classes, if you will,
such as
albuterol and other beta-agonists being
under the
general term of adrenergic
bronchodilators for
human use.
So, realizing that we needed to
correct
some things about this rule that was
written prior
27
to the Montreal Protocol and the Clean
Air Act, and
specifically to develop a mechanism for
delisting
things that were no longer essential,
FDA, in 1996,
undertook revisions. Because of wanting to do
these revisions in the very most public
and
informed manner, the FDA took an additional
step to
the steps that I gave you earlier for the
publication of a rule, doing something
called an
Advance Notice of Proposed Rulemaking
which,
actually, starts with another cycle of
notice and
comment.
This effort proved very successful if
measured by the number of comments. We got close
to 10,000 comments to this Advance Notice
of
Proposed Rulemaking, many of which, I
would point
out, were actually patient-based comments
sparked
by lobbying efforts.
We then took all 10,000
comments and
reviewed them and responded to them. I would note
that there were many fewer substantive
comments but
still all of the comments were carefully
reviewed
and considered. That resulted in the publication
28
of a Notice of Proposed Rulemaking in
1999.
That proved to be less
controversial in
many ways and it received many fewer
substantive
comments and comments overall and, as I
said, had
seemingly much less controversy. So FDA moved
forward with amending 2.125 in July of
2002 and
this went into effect six months later.
The 2002 revisions did a number
of things.
First of all, it listed essential uses as
individual moieties. I would point out that, to
coincide more correctly with the Montreal
Protocol,
it no longer referred simply to
chlorofluorocarbons
but to ozone-depleting substances. But, for the
purposes of today and for all intents and
purposes,
most of FDA's activities, you can
consider ODS, or
ozone-depleting substances, as being
synonymous
with CFCs in terms of this discussion.
So, for instance, albuterol is
now
separately listed rather than there just
being a
broad class without any citation of
individual
moieties.
The revisions also added a
higher hurdle
29
for investigational new drugs to be
developed with
CFCs and it raised the bar for new
listings of
essential uses as well. There was also a list of
criteria, importantly for today, for
determining
when individual uses were no longer
considered
essential.
One other revision I would
point out that
is not on this slide was that we shifted
the rule,
because of the re-write of the Clean Air
Act, to
state that if something was no longer
essential, it
would be considered illegal to market it
under the
Clean Air Act and not under the Food,
Drug and
Cosmetic Act.
Let me go through these important
nonessentiality criteria. I would point out that
Dr. Sullivan will revisit these in his
talk
specific to albuterol, but I think they
are worth
hearing a couple of times.
For a specific moiety to be considered
nonessential, there would have to be at
least one
non-ozone-depleting-substance product--in
other
words, a non-CFC product--with that same
active
30
moiety, and here I am only talking about
a moiety
where there is only one marketed-brand
product or
one marketing strength, so, at least one
active
moiety with the same indications, same
route of
administration--in other words, oral
albuterol
would not be considered an alternative
under these
criteria--and about the same level of
convenience.
We stated in the preamble to
the final
rule that, although dry-powdered inhalers
might fit
this description, we felt that MDIs would
most
neatly do so and, I think, most logically
do so.
In addition to this, these
alternatives
would have to have adequate postmarketing
data to
prove that they are not only safe and
effective for
approval purposes but will serve as an
adequate
alternative in the marketplace. Importantly, there
would have to be production capabilities
and
supplies that are adequate to meet the
needs of
patients who depend on the use of this
moiety for
the treatment of their asthma or COPD and
patients
who require the CFC product are
adequately served.
I would state, and I am sure
that Gene
31
will bring this up as well, that, under
the
considerations for adequately served, is
the issue
of price in that--not so much whether
there will be
any impact on the price to the patients
but will
patients be disaffected or unable to get
the
medicine if there is a price
differential.
We didn't build that in as an
explicit
consideration, the cost issue, but it was
mentioned
in the preamble because many of the
comments to the
ANPR and to the PR as we developed this
re-write of
2.125, brought up the issue of
affordability.
Now, specific to albuterol
which
has--actually, this should say one
branded product
available and three generics
marketed--for moieties
with more than one available product or
strength
such as albuterol, you would need at
least two
non-ozone-depleting-substance products
with the
same active moiety, the same indication,
route of
administration, about the same level of
convenience, and the other criteria were
the same.
So, in other words, if the
moiety was
represented in the marketplace by
different
32
strengths or different numbers of
products from
different manufacturers, we felt it
important that
there be sort of at least--if not a full
match to
the range, at least alternatives that
represented
some choice.
Let me just show you, to wrap
up this
background, where all this has led over
time. This
is a graph of the global situation for
CFC
essential uses. Let me go through the two lines
here.
This is 1996. The open space is
actually
the year, not the hatch mark, so we go
from 1996
out to 2006 on the X axis. On the Y axis, we are
talking about metric tons. A metric ton is 2200
pounds, so these are metric tons of total
CFC used
for essential-use allowances in these
developed
countries.
The red line is the amount that
was
exempted--in other words, the amount that
was
nominated and approved by the
parties. The blue
line is the amount that was actually used
over
time.
The green line is the stockpiles.
So these
are the amounts held by the countries
that don't
33
represent new production.
You can see that the peak of
the use
worldwide, or at least in these developed
countries
that were putting in essential uses, was
just about
9,000 metric tons occurring in the
1997-1998 range.
This has fallen by 2003 down to just a
little bit
over 4,000 tons. One would project from the amount
nominated, which generally has been
historically
higher than the amounts actually used,
that this
will further fall in the coming two years
rather
dramatically. So the amounts nominated in 2006 are
down below 3,000 metric tons.
I apologize for this being a
little harder
to see.
I could not manipulate this as easily as
the
last one. But this is the situation for
the
United States, itself. Again, this is metric tons
per year on the Y axis, years on the X
axis. I
know that will be very difficult for
people in the
audience to see but the main point here
is this is
the blue line, which is the amount used
for
metered-dose inhalers in the United
States.
You can see, for the most part,
that it
34
has
been reasonable stable from the
pre-Montreal-Protocol years through the
time period
of the Montreal Protocol, although there
was a
rather substantial fall in the last
couple of
years--this goes out to 2002--at which
time the
total use was just a little bit over 1500
metric
tons in the United States. I would point out that
the use for albuterol is a substantial
portion of
the United States nomination.
Let me also now talk about the
transition
within the United States, itself. What we have
here is a slide that attempts to display
the
original listings under the 2.125 and
then the
specific listings under 2.125, and then
to display
changes over time.
So, originally, 2.125 had the
broad class
of beta-adrenergic agents: inhaled
corticosteroids;
nasal steroids; the cromones--cromolyn
and
nedocromil were actually separately
listed;
ipratropium; atropine, which was actually
approved
for use in Desert Storm; a combination
product,
albuterol and ipratropium.
35
I think it is important for me
to point
out, if Dr. Sullivan does not and if it
is
repeated, I think it is still and
important thing;
we are not talking about a combination
product
today.
We are only talking about those products
that solely contain albuterol as their
active
ingredient; and then a number of other
products,
many of which were actually, as you can
see, not
MDIs.
So we had talc, contraceptive foams, rectal
foams, ergotamine MDIs, polymxin,
anesthetic drugs
including those that directly use CFCs,
and
nitroglycerine.
When the re-write of 2.125 was
finalized
in 2002, those products listed in red
were taken
out, many of these because they either
did not meet
the criteria any longer or were not considered
essential under the Montreal Protocol, or
they were
no longer marketed.
So, at the time of the
finalization,
isoetharine, isoproterenol, the nasal
steroids as a
class, contraceptive foams, rectal foams,
polymyxin
and nitroglycerine all came out and were
not
36
separately listed in 2.125.
The products in yellow could be
considered
as potential for delisting soon, these
because they
are no longer available, marketed as CFC
products.
One of the things in 2.125 re-write that
was said
was that, if a product was not marketed
for a
substantial period of time, one could consider
it
to be not essential. Those would include
bitolterol, salmeterol, which was
discontinued by
the manufacturer, dexamethasone, talc,
ergotamine
MDIs and anesthetic drugs.
Beclomethasone is no longer
marketed, the
MDIs, at least not newly produced MDIs,
and there
are alternatives. So that is another potential
delisting. Albuterol, I guess I did not put in
yellow here because that is what we are
here to
discuss today is whether that has met the
criteria
that we laid out in the revisions of
2.125.
So, to conclude my talk, the
U.S.
Government moved proactively to address
the issue
of ozone depletion shortly after the
development of
the
ozone science, and the U.S. Government had a
37
key role in the formation and the conduct
of the
Montreal Protocol. The Montreal Protocol is
considered a successful treaty that has
led to
important reductions in CFCs and other
ozone-depleting substances and, as I
mentioned,
there are data to suggest that the
recovery of the
stratospheric ozone layer is in the early
stages.
Now, the Montreal Protocol, as I pointed
out from the evolution of some of the
decisions
taken, is increasingly moving towards
control in
its specific essential uses, notable
amongst those
would be albuterol.
Just as a transition slide, I chose
another picture off the NASA web page of
the ozone
depletion. Remember that I said we would recover
to the early '80's levels by the mid part
of this
century.
This shows the Antarctic region in 1983
and the Antarctic region in 1993. You can see the
difference where the white is the thicker
ozone.
You can see the difference in the ozone
layer in
that decade.
So, thank you very much.
38
DR. CHINCHILLI: Thank you, Dr. Meyer.
You finished a few minutes
early so let's
see if there are any questions from our
committee
members.
I have one, Dr. Meyer. What was
the
rationale behind the decision about not
pursuing
this with the--not considering the
dry-powdered
inhalers as a similar moiety?
DR. MEYER: What we said was that we
thought they could serve as an
alternative but it
would not be as automatic as an MDI. So, in fact,
I think if there were an albuterol
dry-powdered
inhaler that met those criteria
otherwise, we would
consider it.
I think, at the time we were
writing it,
we had considerations such as, at that
point,
albuterol was available in a capsule, an
individual
capsule, rotohaler-type device where one
would
place it in, turn it and breathe. We did not feel
that that had sort of the same level of
convenience
and portability and so on as an MDI. So I think we
wanted to not exclude all dry-powdered
inhalers out
of hand but say that they would have to
meet
39
certain levels of convenience and patient
acceptability.
Again, the presumption in the
preamble to
rule was that the MDIs would most neatly
do that
because they are very much similar.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: Dr. Meyer, in your
multicolored slide, there was some
products in
white.
I presume those will continue to be
available by way of CFCs and includes
epinephrine,
for example; is that correct?
DR. MEYER: Some of those products in
white are, in fact, under development in
that are
alternatives being developed. Some are not.
One
of the provisions in the rule that I
didn't bring
up today because it wasn't fully germane
but I
would be happy to answer as a part of
your question
is the fact that, beginning next year, we
will have
the ability to call this body into
meetings, have
the
advisory committee come to meetings, to discuss
those products that remain on the list
that are not
being reformulated and whether they
remain
40
essential.
I think, just parenthetically,
epinephrine
will be something that will be important
for us to
discuss at some time in the future.
DR. CHINCHILLI: Any other questions from
the committee? If not, thank you, again, Dr.
Meyer.
I guess we will move forward
with Dr.
Sullivan, the Deputy Director of the
Division of
Pulmonary Drug Products.
Medical Considerations
DR. SULLIVAN: Good morning.
I am Gene
Sullivan.
I am a pulmonologist. I am also
the
Deputy Director of the Division of
Pulmonary and
Allergy Drug Products at FDA. For the next twenty
or thirty minutes, I am going to be
discussing some
of the medical considerations in regard
to this
proposal to remove albuterol from the
list of drug
substances that are considered essential
uses for
CFCs.
Following my talk, you will
hear from Dr.
Lutter, as Dr. Meyer mentioned. Dr. Lutter will go
41
into more depth in regard to the economic
aspects
of this question. Then, following that, you will
hear some very important information from
interested parties who will be speaking
during the
open public hearing.
So this slide provides a
background
overview of my talk. Dr. Meyer has just given a
very nice background on the overarching issues
about the Montreal Protocol and the FDA
Regulation
2.125, so my background remarks will be
brief.
Then, also, briefly, I will review the
currently
marketed albuterol MDI products. But the bulk of
my talk will be in this section
specifically
looking at the criteria that Dr. Meyer
mentioned
that are included in the Amended 2.125,
so the
currently existing regulation, and
specifically
examining those criteria in regard to how
they
apply in the case of albuterol.
Then, finally, I will touch on
a couple of
other issues which, although they are not
directly
responsive to the criteria laid out in
2.125, I
think are clearly important issues to
consider when
42
deciding on a path forward with regard to
albuterol.
So, again, Dr. Meyer has
provided very
nice background on the Montreal Protocol
and on the
FDA regulation concerning the
essential-use
determinations, that being 21 CFR 2.125
and, as Dr.
Meyer mentioned, I will be referring to
it as 2.125
from now on.
As you know, the agency is
currently
considering whether albuterol, in fact,
has met the
criteria that are listed in 2.125 for
removal from
the list of essential uses. This process that we
are embarking on is in keeping with the
goals of
the Montreal Protocol, specifically, the
goal of
phasing out production and importation of
ozone-depleting substances including
chlorofluorocarbons.
I think the step forward with
albuterol is
an important step in that direction
particularly
because approximately half of the annual
essential-use CFC allocation in the U.S.
is for
albuterol. We are moving forward in this direction
43
in light of the fact that there now exist
two
alternative, non-CFC albuterol
metered-dose
inhalers on the market in the U.S., that
being
Proventil HFA and Ventolin HFA.
In addition, in 2003, the
American Lung
Association submitted a citizen petition
on behalf
of a group of organizations, collectively
referred
to as the U.S. Stakeholders Group. That petition
requested that the agency move forward
with this
rulemaking process in order to remove
albuterol
from this list.
That citizen petition is
included in your
background materials. Your background materials
also include other communications we
received from
the Stakeholder's Group as well as the
submissions
to the public docket that were submitted
by various
interested parties and organizations in
response of
the citizen petition.
So what are the currently
marketed
albuterol metered-dose inhalers? Obviously, they
can be divided into those that contain
CFCs, which
are ozone-depleting substances, and those
that
44
don't contain CFCs. In terms of the CFC MDIs,
there are several. First of all, there is the
branded product, Proventil, marketed by
Schering-Plough. This was approved in 1981. In
addition, there is a product marketed
under a
Warrick label which is marketed under the
same NDA.
Then there are several generic
versions.
Actually, four have been approved. The first of
these was approved in 1995. Currently, three of
these are being marketed. As you may know, in
1981, there were actually two branded
albuterol CFC
MDIs that were approved, the other one
being
Ventolin.
That is not listed here because it is no
longer marketed within the U.S.
Now moving to the non-CFC MDIs
or, and I
will use the shorthand, as alternatives,
these
don't use CFCs. Rather they use HFA 134A which is
a substance that does not affect the
ozone layer.
There are two of these HFA products;
Proventil HFA,
which was approved and initially marketed
in 1996
and, more recently, Ventolin HFA, which
was
approved in 2001 and was marketed in
2002.
45
So this is the regulation,
obviously, that
is at the heart of today's discussion,
2.125,
called the Use of Ozone Depleting
Substances in
Food, Drugs, Devices or Cosmetics. Among a number
of thing, one of the things that it does
is it
lists specific drug moieties for which
the use of
CFCs is considered essential.
In addition, as Dr. Meyer
mentioned, it
sets forth criteria. There are four such criteria
that must be met in order to remove a
drug moiety
from the list of essential uses.
I will run through these again. Dr. Meyer
has been through them. I will run through again,
though, because I think they are the
heart of
today's discussion. First of all, and here I am
referring to active moieties represented
by two or
more NDAs which is the case, as I
mentioned, with
albuterol.
The first criterion for
removing a drug
from the list of essential uses would be
that at
least two non-ozone-depleting-substance
products
that contain the same active moiety are
being
46
marketed with the same route of delivery
for the
same indication with approximately the
same level
of convenience as the ozone-depleting
product.
The second criterion is that
supplies and
production capacity for the alterative
must exist
or be expected to exist at levels that
would be
sufficient to meet patient need.
The third criterion is that
adequate
postmarketing-use data should be
available for the
non-ozone-depleting products. Again, as Dr. Meyer
mentioned, that is to provide some
reasonable
assurance that no unanticipated
limitation of the
alternative product emerges during the
postmarketing, so real-world experience
that was
not detected prior to approval.
Then, finally, the fourth
criterion is
that patients who medically require the
product
would be adequately served by
non-ozone-depleting
products containing the same active
moiety and
other available products.
So now I am going to walk
through each of
these criteria and look at how they apply
to
47
albuterol. The first criterion; again, at least
two products containing the same active
moiety, the
same route of delivery, the same
indication and
approximately the same convenience of use. So,
clearly, the alternatives that we are
discussing,
Ventolin HFA and Proventil HFA, both have
the same
active moiety, albuterol. Both are delivered by
the same route of delivery, oral
inhalation, and
carry the same indication, prevention and
relief of
bronchospasm and patients with reversible
obstructive airway disease and prevention
of
exercise-induced bronchospasm.
I should point out the initial
NDA,
Proventil, was approved down to the age
of 12 and
Ventolin was approved down to the age of
four.
Both of the alternative products are
approved down
to the age of four.
Finishing up with the first
criterion, the
final bit of it is the same level of
convenience.
Now, when we looked at the same level of
convenience, we described, in the
Preamble, various
aspects of what we might mean by
that. We looked
48
at things like portability, preparation
before use
and the physical effort of manual
dexterity that
might
be needed to administer the drug.
The CFC and HFA MDIs are quite
similar and
so have very similar portability and
require
similar degrees of physical effort and
dexterity to
use.
I should mention, in regard to preparation
before use, that, in the early experience
with the
first HFA that was approved, the
Proventil HFA, we
became aware that there were occasional
instances
of clogging of the actuator if they were
not
cleaned properly.
Now, the CFC and the HFA
inhalers have
actually very similar cleaning
instructions. It is
just evident that patients using the HFA
inhalers
need to pay more attention to the
cleaning
instructions that are already in the
label for both
products.
The second criterion is a
little bit more
difficult to definitively establish at
this point.
This is the criterion that states that
supplies and
production capacity for the alternatives
need to be
49
at levels that would be sufficient to
meet patient
needs.
At least in part, because of the price
differential between the generics and the
currently
marketed FHA products, the market share
for the HFA
products, at this point in time, is much
smaller in
comparison than the market share of the
CFC
products.
So, if the CFC products were to
become
unavailable suddenly today, the current
supplies
and production capacity of the HFA
alternatives are
not sufficient to meet patient need. That is
because, simply, that the manufacturers
would need
time to ramp up production. However,
GlaxoSmithKline, in its statement in
response to
the citizen petition submitted to the
docket and
included in your background package has
stated that
it is confident that additional internal
and
external capacity can be installed to
insure
adequate supplied and production capacity
for
Ventolin HFA and that this could be
accomplished
within twelve to eighteen months.
In addition to this statement
in the
50
docket, GlaxoSmithKline and, also,
Schering-Plough,
will be speaking today and I expect that
at least a
portion of their comments may address
specifically
this criterion.
The third criterion that we are
applying
is that adequate U.S. postmarketing data
be
available for the alternatives, again,
looking for
unexpected real-world problems with the
alternatives. At this point in time, we have
Proventil HFA which has been marketed for
seven
years and Ventolin HFA which has been
marketed for
two years.
Apart from the early reports of
actuator
clogging that I mentioned, the available
postmarketing use data does not suggest
any
problems in terms of safety, efficacy,
tolerability
or patient acceptance of these two
alternatives.
Perhaps the most difficult of
the criteria
to address is the fourth. This is the criterion
that states that patients who medically
require the
ODS are adequately served by the
alternative. This
term, "adequately served," is
fairly broad and it
51
encompasses a number of things.
Clearly, the most important is
that the
available data on the alternatives must
demonstrate
sufficient efficacy and safety and
tolerability and
so forth such that the alternatives could
be
considered reasonable replacements for
the CFC
MDIs.
This type of data was submitted with the NDA
and has accumulated in a postmarketing
period and
seems to imply that the alternatives do
meet these
criteria.
But there is a further subtlety
to the
adequately served phrase here and that is
cost. As
Dr. Meyer mentioned, during the process
of the ANPR
and the proposed rule, there were
comments about
the effect of this rule on the price of
medications. In the Preamble, in the Federal
Register, the Preamble to the 2002
Amendment where
these criteria were established, the FDA
clearly
stated that it will consider cost in
determining
whether the alternatives meet patient
needs.
So I am going to take a couple
more slides
to just look at this cost issue a little
bit in
52
more depth. As with most drugs, branded CFC
products cost more than their generic
counterparts.
As
it turns out, in this very complicated
healthcare system that we have in the
U.S. in which
the specific price of a medication varies
according
to a number of factors including who is
paying, it
is somewhat difficult to arrive at
"the" price of a
drug.
Therefore, it is somewhat
difficult to
arrive at a clear statement of the
differential
between the cost of a branded product and
a generic
product.
Dr. Lutter will go into this in a little
bit more depth and talk about the various
sources
of data that are available for the price
of a
medication and how complicated that issue
is.
I have provided on this slide
some data
from an FDA website that highlights the
cost
savings to a patient that can be achieved
with
generic products. The web address is in your
handouts.
On this site, data on the average
national retail price, which was data
from IMS
Health, were used to generate this
information so
53
that the retail cost per day for an
asthmatic
patient who used Ventolin would be $1.44
whereas
the CFC generic would be 69 cents per
day.
Of course, this is a comparison
between a
CFC generic and a CFC branded, so it is
important
to note the branded HFAs, in general, are
priced
comparably to the branded CFC products
although not
exactly the same price.
The other element to this is
that there
are a number of existing patents and, due
to these
patents, there are currently no generic
HFA
products available. These patents are listed to
expire, the first one in 2010 and the
final patent
in 2015.
So, given the current realities, the
removal of the essential-use status of
albuterol
would result in an increase in the price
of
albuterol MDIs.
The public-health consequences
of such an
increase in price are not known and are,
in fact,
very difficult to predict. One possibility would
be that patients who are prescribed
albuterol
metered-dose inhalers may be either
unable or
54
unwilling to pay for that and so may not
purchase
the albuterol inhalers.
It is also possible that an
increase in
the price of an albuterol MDI, which is
an
acute-reliever drug from which patients,
as you
know, perceive an immediate benefit,
might result
in them forgoing filling prescriptions of
other
medications such as asthma-controller
drugs from
which they don't receive the same
immediate
feedback.
But, as you know, controller drugs are
quite important in the appropriate
management of
asthma.
So, as I mentioned, Dr. Lutter
will
discuss in greater depth these economic
aspects
including descriptions of the various
sources of
price data that are available and means
for
estimating how changes in the price of
albuterol
MDI might affect the utilization.
As I mentioned, that is a
difficult task
in and of itself, how will an increase in
price of
an MDI translate into a change in
utilization of
albuterol and, even if we were able to
establish
55
that firmly, the next question that begs
answering
would be how does the change in
utilization
translate into important health
outcomes. Of
course, that is an open question as well.
So, before I close, as I
mentioned, I want
to bring up a couple of other issues that
are not
directly responsive to the criteria in
2.125 but,
nonetheless, may be quite important in
considerations regarding a path forward
on
albuterol. Both of these issues relate to the
future availability of
chlorofluorocarbons.
The first issue has to do with
production
facilities. Currently, the only source of
pharmaceutical-grade CFC 11 and 12 for
use in the
U.S. is Honeywell's plant in the
Netherlands. CFC
11 and 12 are the particular
chlorofluorocarbons
that are contained in the albuterol CFC
MDIs.
The Dutch Government has
informed
Honeywell that CFC production at that
factory will
no
longer be permitted after 2005. So that
might
jeopardize the supply of CFCs that are
necessary
for the manufacture of albuterol MDIs but
also all
56
of the other MDIs that use
pharmaceutical-grade
CFCs.
However, Honeywell has stated in its
submission to the docket in response to
the citizen
petition that it will begin production of
pharmaceutical-grade CFC 11 and 12 at a
U.S. plant
and
will be able to supply CFCs beyond 2005.
Honeywell will also be speaking during
the open
public hearing session today.
The second issue that touches
on the
future availability of the CFCs refers to
potential
actions that might be taken by the parties to the
Montreal Protocol. So, as Dr. Meyer mentioned,
each year the U.S. and other countries
who request
to manufacture CFC MDIs, go through a
nomination
process whereby specific quantities of
CFCs are
requested of the parties.
Thus far, the parties have
respected the
U.S. determination that albuterol is, in
fact,
essential and have granted the volumes
requested by
the U.S.
However, more recently, the parties have
very pointed noted the availability of
two non-CFC
alternatives within the U.S. and some
have
57
questioned the continued need for
chlorofluorocarbons for this
purpose. It is not at
all clear how long the parties will
continue to
grant CFC requests for use in albuterol
MDIs.
So, with that, I will
close. I have
listed on this slide the questions or
topics for
discussion that have been provided to you in a
handout format. Essentially, the agency is asking
you to discuss the extent to which you
believe the
criteria that are established in the
2.125 for
removal of a drug substance from the list
of
essential uses of CFCs have been met in
the case of
albuterol. Beyond that, we are open to hearing
from you any suggestions of additional
data,
additional information or other issues
you think
should be considered as we move forward
in this
process of determining the essential-use
status of
albuterol.
With that, I will close.
DR. CHINCHILLI: Thank you, Dr. Sullivan.
Again, we are ahead of schedule so we can
take some
questions from committee members if there
are any
58
questions. Yes, Dr. Atkinson?
DR. ATKINSON: Can you comment on whether
the existence of the patents on the new
HFA devices
are going to preclude the development of
any
generics until that time period? Are there any
pending applications for generic devices?
DR. SULLIVAN: Of course, we can't comment
on any pending applications. The analysis of
patents is a complex issue that the FDA
doesn't
really directly do. Companies claim they have
patents which protect them. If a generic firm
wants to challenge that patent, they
can. I think,
beyond that, perhaps I will invite Wayne
Mitchell
to comment more specifically, if he can.
MR. MITCHELL: I really can't say much
more.
We don't have any institutional expertise on
patent law. Patents are listed in our Orange Book.
The patents are listed through 2015. That is about
all we really can say.
DR. CHINCHILLI: Any other questions? Dr.
Sullivan, I have a question. In one of your
slides, when you talked about Proventil
HFA, you
59
said that early reports of actuator
clogging were
available. Does that imply that there are no
longer reports of this problem? Were there
modifications to the device? I just was confused
by the word "early" reports of
actuator clogging.
DR. SULLIVAN: That refers to the fact
that when the product first went on the
market--and
it is not unusual to get more reports on
a
particular drug when it first hits the
market, but
the agency became aware that patients
were having
problems with the clogging of the
actuator and an
effort was made to better publicize the
necessity
of cleaning these products because,
although the
cleaning instructions were included in
the CFC
versions, they may not have been followed
by
patients.
It was determined that if the
instructions
are actually followed, there are fewer
reports. I
believe that the number of such reports
has
declined.
That was sort of an early phenomenon.
DR. CHINCHILLI: Thank you.
Any other
questions? Okay; if not, then we will move on to
60
Dr. Lutter.
Economic Considerations
DR. LUTTER: My name is Randy Lutter. I
manage a small economics group within the
Office of
Policy and Planning, Office of the
Commissioner at
FDA.
It is my pleasure to be here.
I would like to talk to you
today about
the question of whether or not delisting
albuterol
will have effects on--whether the
patients will be
adequately served by delisting albuterol.
Let me begin by giving you an
overview.
The key conclusion is that delisting
albuterol CFCs
will deter the use of a number of
prescribed MDIs
that is large in absolute terms but small
relative
to the market. Our analysis is ignoring an
announced giveaway by GlaxoSmithKline of
2 million
MDIs per year because we lack a basis to
evaluate
that quantitatively. We also find that the effects
on public health are too uncertain to
quantify.
Let me give you some brief
institutional
background of how an economist ends up in
the
position of speaking before a group of
esteemed
61
pulmonary and allergy advisors to
FDA. There is an
executive order, 12866, signed by
President Clinton
in '93 and it actually follows one signed
by
President Reagan in '81. It directs the agencies
to assess the costs and benefits of all
regulatory
actions developed through the notice and
comment
rulemaking that Dr. Meyer described
earlier.
The office that I had at FDA
develops the
economic analyses required by that
executive order.
The method of economic analysis that we
developed
follows the constraints of OMB Circular
A-IV which
is the latest in a series of circulars
developed by
the Federal Office of Management and
Budget
directing agencies on how to conduct
economic
analyses.
The executive order directs
agencies to
assess the cost and the benefits and to
take
regulatory actions which are
cost-effective but
economics also is reflected in the
decisions of the
Montreal Protocol. Drs. Meyer and Sullivan have
mentioned the term "essential,"
and "essential
use," turns on whether there are
available
62
technically and economically feasible
alternatives
or substitutes that are acceptable from
the
standpoint of environment and health and
that is in
Decision IV-25. Section 2.125 uses the phrase
"adequately served." As described by Dr. Meyer,
that has economic content.
So there are actually three
institutional
reasons why economics matters for the
current
decision.
A brief discussion of economic
fundamentals. The issue here is that delisting
would remove albuterol MDIs with
CFCs. Those are
currently the only generic albuterol MDIs
on the
market.
Therefore, one would anticipate on that
basis an increase in the price. So the broad
question is whether or not that increase
in price
has effects on whether or not patients
are
adequately served.
To comply with the executive
order, we
need to assess the benefits of delisting
and, in
particularly, a relatively earlier
delisting as
opposed to a later one, and also the
costs of
63
earlier delisting.
The benefits come in four
separable
categories. The first is a controlled transition.
You have already heard presentations
about the
nature of the international cooperation
and the way
that that might affect the availability
of CFCs by
offering a relatively--by proceeding with
this
rulemaking, FDA hopes to establish an
opportunity
for a controlled transition to CFC-free
MDIs.
The second category of benefits
is clearly
the
environmental ones that Dr. Meyer has
described. Reduced emissions would lead to
reductions in skin cancers, cataracts and
UVB-related ecological benefits. For this, our
proposal, FDA has not been able to
quantify the
benefits in terms of skin cancers,
cataracts or
UVB-related ecological benefits.
Some analysis in quantitative
terms has
been conducted previously by other
federal agencies
including the EPA. The difficulty that we face is
in translating their estimates of
aggregate
benefits to the benefits from the much
smaller
64
reductions of CFC emissions that might be
achieved
from this rulemaking, and we haven't been
able to
do that for this proposal.
A fourth category of benefits
pertains to
international cooperation. Dr. Meyer did not
understate in any way the importance of
the
Montreal Protocol. It is a flagship treaty for
successful international environmental
protection
and it enjoys wide respect and esteem for
that
reason.
A final category of benefits is
that this
rulemaking may encourage innovation in
environmental safe technologies.
In terms of the costs, I would
like not to
focus on the increased spending
associated with a
higher price of MDIs but, instead, focus
on a
related question of whether or not the
increased
prices may deter appropriate usage. I think that
is the appropriate issue for this panel
and that is
the one that I am going to devote the
rest of my
time to.
Also, by way of background in
economics, a
65
key notion is what are we comparing the
world to
when we do our analysis. We need to describe what
is the baseline relative to which we are
assessing
the effects of delisting. The baseline in this
instance is the continued availability of
generic
CFC albuterol. So the analysis that we are
conducting is relative to a world in
which the CFC
albuterols continue to be available and,
therefore,
the generic CFCs also continue to be
available.
What I am going to focus on is
a
relatively standard and conventional
economist
approach to estimating the response to
higher
prices.
It really focuses, in particular, on the
estimated quantity of metered-dose
inhalers that
may not be consumed as a result of the
increased
price.
It interprets this as the
product, really, of three things. One is the price
increase in percentage terms. The
other one is a
measure of the consumer sensitivity to
the price
increase, a measure the economists
typically
describe using the word
"elasticity," and, lastly,
the MDIs sold in the baseline to
price-sensitive
66
consumers. So these are three parameters that I
will draw your attention to.
With respect to the price
increase, the
prices are, of course, variable in a
particular
way.
The vary with market conditions and they vary
also in response to the marketing
decisions made by
the different companies marketing the
products. As
a result, the assessments of the price
are
difficult not only because of the data
deficiencies
but also because, ideally, we need to be
looking
forward to what the price difference
might be
between a world where the albuterol CFCs
are
delisting and a world where they would
continue to
be available.
That forward-looking approach
requires and
association of these prices that takes
the
variability into account. For the purposes of our
analysis, that is too complicated and we
are,
instead, going to take the current price
differences as a measure of the price
increases
from the delisting. The merits of this approach
are simplicity, transparency and also
consistency
67
with an announced policy of GSK that it
would
freeze wholesale prices through December,
2007.
Where does one go for
information on
prices?
In the modern day, Google comes to mind as
a source of all information. If you go to Google
and look for prices, you come to
drugstore.com. It
listed generic MDIs with albuterol on the
24th of
March for $14. HFA at drugstore.com sold a
Proventil. The Proventil HFA was sold at $39.61
and Ventolin HFA sold at $38.99. Those prices I
have checked twice and they were
relatively
unchanged in the recent period.
That gives an increase of about
180
percent just comparing the generics to
the HFA.
But these web-based prices are really
unrepresentative. They neglect the
brick-and-mortar outlets. They neglect shipping
costs.
Ideally, what one would want are average
retail market prices for the cash-paying
customers
who would be sensitive to price
increases.
We have not acquired these idea
data for
the analysis that we have conducted for
this
68
proposal.
So, instead, I am going to talk to you
about data we have acquired which are the
best
available proxies at this moment.
The Medical Expenditure Panel
Survey of
the Agency for Healthcare Research and
Quality
provides some information on prices. This survey
assesses expenditures by the
noninstitutionalized
people age less than 65 in the
non-Medicare
population. It provides information on the average
retail prices among all payer types, the
insured
and the uninsured alike, for CFC
albuterol inhaler
prescriptions 2000 to 2001.
The information is that the
generics are a
little bit less than $25. I also report here the
standard error. The brand is $39. You have heard
Professor Sullivan mention that the
branded price
of the CFC tends to be close to the
branded price
of the HFA. In this instance, the data on the HFA
prices are too rare to report.
We also looked using the MEPS
survey at a
sensitive population that lacks insurance
or has
only private non-group insurance which,
in the
69
judgment of experts at ARC would
typically exclude
coverage for drugs. We looked among this group at
people with incomes less than 400 percent
of the
federal poverty level. This was a convenient
cutoff, given the data constraints of
MEPS.
Within this group, the
estimated average
retail prices were $22 for the generic
inhalers
and, again, in this instance, the data on
the
branded inhaler prices were too rare to
be
reportable. This group had about 2.8 million
albuterol prescriptions annually.
A second source of data on
prices that we
consulted is proprietary information from
IMS
Health, their national prescription audit
for the
first quarter of 2004. Note the distinction in
dates.
The MEPS is 2000-2001 and this is 2004.
There is no more recent information on
MEPS. For
the IMS price information, we have prices
measured
using the average pharmacy's revenues
from
uninsured customers, insured customer and
Medicaid
beneficiaries alike. So this is basically across
all payer types.
70
This includes chain,
independent,
food-store pharmacies. It excludes the Internet.
It excludes mail-order and long-term-care
pharmacies.
Information on prices from IMS
suggests
that the median price for the generic
albuterol
MDIs is $19.70 and for the albuterol HFA
MDIs, the
price is $43.00, the price difference of
about
$23.00.
This suggests an increase of about 120
percent.
It is important to view these
data as
approximate for a variety of reasons. I have
acknowledged the proxies for the
conceptually
correct measure. In addition, the HFA prices have
been changing. The MDI data suggests that there
has been an increase of about 18 percent
over the
twelve months preceding the sample of the
first
quarter in 2004. Again, these prices reflect the
full price for the insured and the
uninsured alike.
The next part of the puzzle is
to assess
the response to the increase in price
that one
might expect among consumers. In general, there is
71
an extensive economics literature that
reports
small effects of price increases on
consumption.
It
rarely distinguishes, however, among drugs.
There is a very recent article by Dana
Goldman of
Rand in JAMA that surveys more than a
half million
people in 52 health plans over four
years.
interestingly, it reports
responses to
increases in co-pay among different
categories of
medicines. With respect to anti-asthmatics, as the
average co-pay for anti-asthmatics
doubles, the
average number of days of treatment
supplied fell
by more than 30 percent. The authors report that
albuterol was the most common
anti-asthmatic
including albuterol sulfate.
They also assess the effects on
public
health.
Let me back up a moment. They
also assess
for drugs with no OTC substitutes, the
set that
presumably includes albuterol MDIs. The response
in utilization described as I just did in
the
average number of days of treatment
supplied is
0.15.
So there is substantial uncertainty about
what would be the relevant number.
72
With respect to average co-pay
for
anti-asthmatics as a group, the response
is 0.3.
But, if one then looks at drugs with no
OTC
substitutes which would also include
albuterol, the
effect is 0.15.
The authors go on to talk about
the effect
of these increases in co-pay on ER visits
and on
hospital days for the class of drugs
diabetes,
asthma and gastric-acid disorder
together, ER
visits grew by 17 percent and hospital
days by 10
percent when co-pays doubled. The authors
acknowledge that these results are
"not definitive"
for reasons of data limitations.
As a result, we are unable to
quantify any
effects on public health because of the
nature of
the limitations to the data.
Let me offer a summary of what
we know
about the response to a price
increase. I have
mentioned that an analysis would have,
really,
three parts. With respect to the MDIs sold to a
price-sensitive population, MEPS suggests
that
there are 2.8 million MDI albuterol
prescriptions
73
going to the uninsured patients with
incomes of
less than 400 percent of the poverty line
who are
not Medicare eligible and under age 65.
If one takes, instead, data
from the
National Health Interview survey and
combines that
with data on the distribution of MDIs as
described
in the proposal, one ends up with a
larger number
of MDIs that would be used by the
price-sensitive
population.
With respect to the price
increase, we
really have two estimates. One is 120 percent
increase.
That is from the IMS National
Prescription Audit reflecting average
prices for
all payer types including those that are
insured.
We also have the 180 percent which
reflects the
Internet information.
A key question pertaining to
the analysis
is the estimated elasticity, or the
nature of the
consumer response. JAMA, as I mentioned, reports
two numbers that may be plausible. I think the
0.15 is one that we focus on. That reflects their
estimate of the response to increases in
co-pay for
74
drugs with no OTC substitutes. I think that is
also consistent with other economics
literature.
The next question pertains to
the
interpretation of these. The JAMA paper really
focuses on consumer response for insured
patients
to higher co-pays. They report an average co-pay
of a little bit more than $12. So that co-pay and
the increase are roughly the same order
of
magnitude as the price and the price
increase that
one would anticipate for uninsured
patients.
So, if one applies that
increase in price
implicit in both the IMS data and in the
Internet
data and the consumer response implicit
in the JAMA
paper to the MDIs sold in the
price-sensitive
population, then it is reasonable to
infer a
quantity response among the uninsured
population in
the high hundreds of thousands. It is very
difficult to be more precise. This is a daunting
exercise with data that are imperfect, as
we have
acknowledged. But the numbers that we have
presented in particular are 0.4 million
to 1
million.
These are clearly approximate.
75
Let me offer some empirical
caveats. I
have neglected the response of insured
patients to
any increases in co-pays. The JAMA paper measured
these and we know that the co-pays for
branded
products are much higher than co-pays for
generics.
But this delisting of albuterols would
have no
direct effect on the co-pays. The co-pays may
change only in response to the changes of
the
insurance companies. We, therefore, believe these
are too uncertain for us to quantify at
this time.
Let me reiterate that the
estimates of the
price-sensitive population of the price
increase
and the consumer response, or the
elasticity, are
all relatively uncertain.
There is another caveat with
respect to
the interpretation of these estimates.
GlaxoSmithKline wrote to FDA on May 3 of
2004
stating that 2 million complementary
samples of
Ventolin would be made available each
year to
physicians who may choose to reserve
these inhalers
for their lower-income patients.
We are unable to assess
quantitatively
76
what this might do for any reductions in
utilization because of the uncertainty
associated
with how they might actually be
distributed in
physicians' offices. The GSK letter also said that
it would freeze wholesale acquisition costs
or
prices thereby suggesting that the
eventual HFA
prices at the retail level would also be
relatively
constant.
As I have mentioned, that is an
assumption that we maintain.
The giveaway, in general, may
significantly offset the loss of canisters provided
it is well targeted to the most
price-sensitive
patients.
Thank you for the opportunity
to talk. I
would be happy to take questions.
DR. CHINCHILLI: Thank you, Dr. Lutter.
Are there any questions from the
committee? Dr.
Schatz?
Questions from the Committee to
the Speakers
DR. SCHATZ: My question is the
relationship between elasticity and
over-the-counter substitutes. I gather that, with
77
more over-the-counter substitutes, then
elasticity
is theoretically increased?
DR. LUTTER: Yes.
DR. SCHATZ: Then I would submit that
there may be an over-the-counter
substitute which
is Primotine so that I think that, in
consideration, one might have the higher
elasticity
and that patients doing that might be not
as well
served.
DR. LUTTER: Lacking your medical
expertise, I will leave the judgment and
the
discussion about the substitutability of
the OTC to
you.
Let me simply say that the availability of
OTC substitutes would affect the response
in that
way.
DR. SCHATZ: And it could make the higher
value that they found more relevant than
the lower
value potentially.
DR. LUTTER: Yes.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: Certainly with the caveat
which we may discuss later, but Primotine
is not
78
albuterol and, thus, a potential consequence
that
has not been thought of is that
individuals who
cannot afford albuterol anymore will
start using
over-the-counter Primotine which is
associated with
a completely different set of side
effects which
need to be seriously considered.
DR. CHINCHILLI: Ms. Schell, you had a
question?
MS. SCHELL: Yes, thank you. I just have
a question about the shift of production
of the CFC
to the United States from the Netherlands
in 2005.
Do you project an increase in the CFC
MDIs' cost
with that shift of production coming to
the U.S.?
DR. LUTTER: That is not something we have
taken into account in the analysis. We have no
information on which to assess that
question.
MS. SCHELL: Thank you.
DR. CHINCHILLI: Do any of the FDA
representatives want to respond to that
or the
previous question?
DR. MEYER: I think, as far as that
question--I don't think we have data that
could say
79
one way or the other. Not the least of the
considerations there is how much in the
price does
the
actual cost of CFCs play, and I don't think we
know that.
As far as the earlier question
and point,
I think it is something we can certainly
consider
as we consider all the input from today.
DR. CHINCHILLI: Dr. Swenson, you had a
question?
DR. SWENSON: Yes.
Regarding that JAMA
article, did you pursue at all the cost
implications of this greater ER and
hospitalization
rate that might arise from some of these
shifts
that you have postulated?
DR. LUTTER: No, largely because of the
uncertainty in quantifying those
increases. As I
mentioned, there were three categories of
therapeutic classes that they grouped together
only
one of which was asthma. Albuterol is only one
treatment for asthma and, therefore, we
thought
that inferring--that the judgment of the
applicability of those estimates to this
delisting
80
appeared to--is that we have no basis to
accept
those estimates to predict quantitative
reductions,
quantifiable reductions, in the ER visits
or days
in the hospital. So, therefore, we don't really
want to estimate either the cost of
reductions or
increases associated with those either.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: I work at Grady Memorial
Hospital which serves an indigent-care
patient
population. About 40 percent of the patients there
are self-pay which means they don't have
insurance.
It is nice way of saying that. One of the big
problems in the hospital is the
in-hospital
pharmacy costs. Do you have any information or is
there a way to figure out how the
changing cost of
inhalers would affect operating at a
hospital that
serves indigent-care patients or is there
a way to
figure that out?
DR. LUTTER: There probably is a way to
figure it out. It is not something we have done.
DR. CHINCHILLI: Dr. Kercsmar?
DR. KERCSMAR: The transition to HFA
81
inhalers has been made in a number of
other
developed and industrialized
countries. Are there
any data that are comparable to that that
has been
published in the JAMA article? You referenced that
might give other insight into the
elasticity
problem, changes in morbidity, lack of
prescription
refills or, because of the difference in
economic
structure and drug reimbursement in these
countries, are there no data
available? Are there
lessons to be learned from countries that
have
already made the transition?
DR. LUTTER: It is a good question. We
thought of that. Other countries lack the
uninsured population that exists in the
United
States and generally control prices. In
particular, the price discrepancy that I
have
described here is unusual if not unique.
DR. CHINCHILLI: Any other questions by
the committee members for Dr. Lutter?
MR. MITCHELL: Just before the break there
is something I would like to say.
DR. CHINCHILLI: Yes; please go ahead.
82
MR. MITCHELL: This is addressed to the
people who are watching this procedure
through the
webcast.
The proposed rule that we have been
discussing is available on FDA's website
if you go
to www.fda.gov. In the middle column, you should
see FDA advanced display. If you click on that,
you should be able to see another link
which goes
to advanced publication display. Click on that and
you should see something about a special
filing,
publishing, on June 16, 2004. That should get you
to the Notice of Proposed Rulemaking.
Thank you, Mr. Chairman.
DR. CHINCHILLI: Thank you, Dr. Mitchell.
Yes; Ms. Schell?
MS. SCHELL: I am not sure who to direct
this question to, but I have a
question. Several
of you talked about what the ozone
depletion does
in cataracts, skin cancer and that, but
no one has
mentioned how it affects asthmatics of
COPD
patients, the depletion of the ozone
layer and how
that would increase, if we didn't do
something now,
how the ozone depletion would affect
asthmatics in
83
the future. Would we be causing more asthmatics to
have problems with their breathing?
Thank you.
DR. MEYER: I will try to answer that. I
think it is unclear to us that asthma or
COPD
patients would be differentially affected
in terms
of the environmental consequences of
ozone
depletion. You were not asking this, but, for the
public, I think it is hard for them to
understand
that ozone in the lower regions of the
atmosphere
is bad for asthmatics, particularly, and
probably
for COPD as well. But ozone in the stratosphere
probably has no bearing on the
development of
asthma and COPD that we know of.
So we would assume that the
consequences
to the asthmatic and COPD population
would be the
same as to consequences to other
populations. One
could perhaps try to parse that out more
closely in
that it is potential that inhaled
corticosteroids,
for instance, may somewhat increase the
predisposition to cataracts. Whether that would be
even more the case in the circumstances
of a
84
thinned ozone layer, who knows. But, again, we
have no basis at this point to believe
that there
would be a differential effect on those
patients.
DR. CHINCHILLI: Any other questions from
committee members for our FDA
representatives?
Yes?
DR. MEYER: I just wanted to make the
point--I realize that the people sitting
around
this table probably are fairly well
versed in this
but, for the purposes of the public, I
realize that
we didn't really sort of step back and
make this
point.
But albuterol has really become a prime
drug for both the treatment of asthma, in
particular, but also for COPD in a way
that, even
when we began the advanced notice of
proposed
making in '96, I don't think we have
fully
anticipated.
It is now clear that
approximately 50
million or more canisters of albuterol
are
necessary to treat patients with asthma
and COPD in
the United States. It is, again, by far and away
the bronchodilator or short-acting
reliever of
85
choice in patients with asthma and COPD.
Again, I think the people
around the table
know this but, for the matter of the
public record,
I just wanted to get on the table the
kind of
numbers we are talking about. This is a very
important drug that is sold widely and is
really
critical in the asthma armamentarium and
very
important in the COPD armamentarium as
well.
DR. CHINCHILLI: Thank you, Dr. Meyer.
Dr. Martinez?
DR. MARTINEZ: I have one question
regarding worldwide distribution of
sales. What is
the situation in the underdeveloped
world? Which
are the products that are sold there and
what are
the projected consequences of this
regulation in
that particular market?
DR. MEYER: From the FDA perspective, I
don't think we have a lot of information
on that.
I also am involved in the Montreal
Protocol on a
working group on aerosols, medical
aerosols. I can
say that the United States actually
exports
relatively few of its MDIs as opposed to
the EU
86
where much of their production is
exported.
So most of what we are talking
about here
is for domestic consumption and will not
really
have much bearing on the rest of the
world. I
would parenthetically note that there is
a lot of
attention paid in the Montreal Protocol
about how
this phase-out in the developed world
will affect
that in the developing world because it
is a very
important issue.
Unfortunately, in much of the
developing
world, the use of MDIs is not very common
because
they are--although they are cheap per
dose, to
actually buy one requires you to buy a
certain
number of doses as opposed to oral
medications
which may be more expensive per dose but
cheaper
where you can just buy a few.
So there is probably
undertreatment in the
developing world in general and
specifically there
is not a lot of use of MDIs relative to
the
developed world.
DR. CHINCHILLI: Before we proceed with
other questions, I would like to welcome
Dr. Reiss
87
to the committee. Would you turn on your
microphone and introduce yourself to
everyone?
DR. REISS: Sure.
I apologize for being
late this morning. I am Ted Reiss from Merck
Research Labs. I am the industry non-voting
representative on the committee.
DR. CHINCHILLI: Thank you.
Any other
questions? Yes; Dr. Swenson?
DR. SWENSON: Dr. Meyer, a couple
questions. I didn't see anywhere in the data,
either in the background information, if
you could
go back to the initial signing of the
protocol. At
that point, how much CFC was being
produced and
now, of that amount, what does the
present use of
CFC in albuterol represent in a
percentage term or
absolute amount?
DR. MEYER: I am sorry that I don't
actually have those particular figures
available.
I can say that the use of CFCs for MDIs
when the
protocol was signed was a relatively
small
proportion of the CFC use because CFCs
were then
used in refrigerators, auto air
conditioners, home
88
air conditioners, foams and so on.
Now that the provisions of the
Copenhagen
Amendments went into place, the use of
CFCs for
MDIs in the developed world is the large
majority
of these CFCs but it is still a small
fraction
compared to what was the total in 1987.
Albuterol in both the United
States and in
the rest of the world has been a
prominent use of
CFCs.
As I mentioned, for the United States, it
amounted to about half, or does amount to
about
half, of our essential-use
denomination. So I am
not giving you specific numbers, but I
hope I am
sort of giving you a qualitative feel.
DR. SWENSON: Okay.
The next question I
have then is, on Slide 24 or one of the
similar
slides that you had in your talk, was the
projected
return, or this idea of a projected
return, of
normal stratospheric ozone levels by
mid-century
based on the present use right now which
includes
our use of CFCs or was that based on
complete
elimination of CFCs?
DR. MEYER: Those projections, and just to
89
be clear, they are actually projecting
the recovery
to early 1980s levels which was still not
normal
but a recovery nonetheless, are based on
the
successful conduct of the Montreal
Protocol. So it
is based on the Montreal Protocol as
currently
amended being successfully carried out
into the
future.
DR. CHINCHILLI: Ms. Schell?
MS. SCHELL: I am sorry.
I would like one
more question on the 50 million uses of
Ventolin or
albuterol. Have you looked at the overuse of
albuterol and the underuse of the
anti-inflammatory? Is there any look at overuse?
As we know, asthmatics, a lot of the
time, don't
have the proper education in the use of
the
anti-inflammatory so they overuse their
albuterol.
Are there any numbers reflecting that?
Thank you.
DR. MEYER: We do not have such numbers.
It is certainly something that we
considered. As
Dr. Lutter said, there are a lot of
things we would
wish to consider in an ideal
analysis. One of the
90
complications of projecting a
public-health
consequence of some drop in the number of
albuterol
MDIs distributed or used relates to these
questions, relates to the possibility
that when
beta-adrenergic bronchodilators are
overused that
that might, itself, have detrimental
effects.
But these things, although
clearly we
think about them, are not something we
can
reasonably quantitate. So we have not.
DR. CHINCHILLI: Any other questions from
the committee? If not, I want to thank the FDA for
enlightening us on these issues. We are scheduled
for a break at 10:00. We are about eight minutes
before that, so we will take the break
early. But
I would like to reconvene at 10:10.
Thank you.
(Break.)
DR. CHINCHILLI: I do have one
announcement and that is if you have a
cell phone
and it must be on, it would be preferable
if you
put it on vibrating mode and then, if it
does go
off, that you take your call outside the
room.
91
Thank you.
Before we go on to the open
public
hearing, the first session that we will
have this
morning, I just want to make sure that
the
committee members don't have any other
questions
for the FDA representatives. Are there any other
questions from the committee? Any final comments
from the FDA?
If not, then we are going to
move into the
open public hearing.
Open Public Hearing
(Session 1)
DR. CHINCHILLI: One other announcement I
am supposed to make. Both the Food and Drug
Administration and the public believe in
a
transparent process for information
gathering and
decision making. To ensure such transparency at
the open public hearing session of the
advisory
committee meeting, the FDA believes that
it is
important to understand the context of an
individual's presentation.
For this reason, the FDA
encourages you,
the open public hearing speaker, at the
beginning
92
of your written or oral statement, to
advise the
committee of any financial relationship
that you
may have with any company or any group
that is
likely to be impacted by the topic of
this meeting.
For example, the financial
information may
include a company's or a group's payment
of your
travel, lodging or other expenses in
connection
with your attendance at the meeting. Likewise, the
FDA encourages you, at the beginning of
your
statement, to advise the committee if you
do not
have any such financial relationships.
If you choose not to address
this issue of
financial relationships at the beginning
of your
statement, it will not preclude you from
speaking.
So that is important for our
open public
hearing speakers to recognize that and to
make
acknowledgments. I probably will repeat this
statement when we start the afternoon
session as
well.
We are ready for our first
speaker during
the open public hearing. Please be sure to
introduce yourself and pay attention to
the
93
statement I just made.
MS. WEXLER: Good morning.
I am Pamela
Wexler.
Since 1997, I have served as attorney and
advisor to the U.S. Stakeholders Group on
MDI
transition. I have no financial interest in any of
the companies or participants today.
I would like to start by
telling you a
little bit about the U.S. Stakeholders
Group. It
is a consortium of nine leading patient
and medical
professional organizations. Members of the
organizations include patients with
asthma, chronic
obstructive pulmonary disease and other
respiratory
diseases.
Collectively, the member organizations
represent and reach 25 million Americans
who suffer
from asthma and other respiratory
diseases and they
include organizations that educate and
advocate for
individual patients and their families through
local chapters.
Members of the Stakeholders
Group also
include physicians, respiratory
therapists and
other healthcare professionals who
specialize in
respiratory care and they are recognized
leaders
94
among the healthcare community. The stakeholders,
as a group, and its member organizations
individually collaborate with various
other
interested organizations in the U.S. and
around the
world.
In the eight years since the
Stakeholders
Group has acted formally, neither its
membership
nor its procedures have changed. The American Lung
Association convenes the U.S. Stakeholders
Group.
The member organizations elect
representatives to
the stakeholders process and these
individuals
meet, in person, once or twice a year and
communicate regularly.
Oftentimes, the leadership of
these
organizations attends stakeholder
meetings and
participates in the deliberations. Other times,
the government and the private sector are
invited
to attend as well and make
presentations. Any
action taken under the name of the
stakeholders is
approved by each member organization.
Now, I would like to turn to
our petition.
Eighteen months ago, we petitioned FDA to
consider
95
albuterol essentiality. The petition was not
precipitous. It, in fact, was requesting the
agency merely consider essentiality. It was FDA,
itself, in a rulemaking process that
started in
1997 and lasted five years that set up
these
essentiality criteria, the conditions
under which
any drug substance would be delisted and
no further
CFCs would be available.
The stakeholders petition
asserted that
the criteria had been met or, with the
case of
manufacturing capacity, that the criteria
could be
met or that information could be
ascertained and,
hence, it was time for FDA to consider
removing the
essential-use designation.
Now, there are a number of
reasons why the
stakeholders petitioned FDA. I will just take a
moment to touch on them. First and foremost is the
environmental imperative. I won't spend too much
time on this because I think that the
importance of
repairing the ozone layer is well
established, both
by the Montreal Protocol and the U.S.
Clean Air Act
on which, by the way, the U.S. has been a
leader
96
since the beginning on the international
process.
FDA, in its July, 2002 Final Rule
establishing the
essentiality criteria actually offered a
very
concise and clear explanation of why
every use of
CFCs must be eliminated, even seemingly
small
amounts like those used in MDIs.
I won't spend too much time on
the second
sub-bullet either because a physician
from one of
our member organizations in the next
session, later
this afternoon, will present more on the
opportunity to improve disease
management. But let
me just say that, from its inception, the
stakeholders position on the potential of
transition has not changed and that is
that we
understand the potential of a switch in
medication
and we have worked, and we hope to
continue to
work, to ensure that that experience
provides an
opportunity to improve patient care.
On the third and the last, and
probably
the most pressing, issue for patients and
physicians is the issue of CFC supply and
how it
might affect the availability of
medications. As I
97
am sure you will hear more about today,
the future
of CFCs to make MDIs is uncertain and
fundamentally
the stakeholders want FDA to sufficiently
plan for
that and for CFC-free medications to be
available
and widely accepted before CFC supply can
have any
impact on product availability or price.
Since the petition was filed,
in the
eighteen months since the stakeholders
filed the
petition to consider albuterol
essentiality, a lot
has changed and we have learned a lot
more. As to
supply, anyone who follows this knows
that, in the
past three to five years, there has been
a lot of
new and often conflicting information
about where
PhRMA-grade CFCs were going to come from
after
December 31, 2005.
Remember, that is an issue
simply for the
U.S. market because, for the most part,
developed
countries will not need these chemicals
after that
date.
They are on pace to phase out the use of
CFCs in MDIs.
The stakeholders have never had
full
information on the future of CFC
supply. We heard
98
originally, maybe two years ago, there
were going
to be two plans, one in Europe and one
here. They
we heard that that wasn't going to
happen. Then
the issue of certification was raised,
that plants
had to be certified, the CFCs produced
had to be
certified, and that the production that
would
replace the production that is going to
be lost in
Europe would be a different kind of
production and
that different specifications would be
required.
We heard, now, recently,
despite a letter
from Honeywell indicating its stated
intent to
supply CFCs at a plant in Baton Rouge,
Louisiana,
that we still had questions about
certification as
that was not mentioned in the letter and
we have
never heard anything further about FDA on
what,
exactly, that requires.
So the stakeholders,
themselves, have
limited information on which they could
base a
conclusion that the CFC supply would be
without
problems.
Recently, a non-governmental
organization, NRDC, wrote the EPA
suggesting that
it would be illegal to produce CFCs in
Baton Rouge.
99
So, again, we are faced with not a lot of
clear
information on how we will go forward.
As to the second sub-bullet,
even if the
Baton Rouge plant is not a problem, we
certainly
see an increase in pressure on the part
of the
international community to limit future
supply of
CFCs especially where there are
alternatives as in
the case of albuterol. We heard recently that the
U.S. request that was recently put into
the parties
was approved but with the strong
suggestion that
the U.S. come back to the parties after
this
rulemaking was complete since it wasn't
clear that
those quantities would be needed.
So it is obvious that the
parties are
signalling the intent to stop authorizing
new CFC
production for MDIs, again, in the case
of a drug
like albuterol where there are safe
alternatives.
Also, since the petition was
filed, we
have, in the FDA docket, an independent
analysis
conducted by National Economic Research
Associates,
NERA, that provided us a much better
picture of the
albuterol market. I expect that we will hear more
100
about the NERA analysis this afternoon,
but it gave
us a very good picture of how the market
is
supplied, how patients who rely on
albuterol pay
for their drugs.
It estimates the price and what
the market
might look like once HFA alternatives are
introduced. More importantly, NERA projects how
the increased costs might be distributed
and
allocated among the different classes of
patients,
managed care and other payers including
Medicare
and Medicaid.
Now, you know, the stakeholders
are
medical and patient advocates, medical
professionals and patient advocates. We are not
economists. So we aren't here to speak to the
specific numbers in the NEAR report but
we do
believe that the general thrust of the
report
comports with what we have always
believed about
the albuterol market and our
understanding of how
increases, not just in medications but in
all sorts
of other medical procedures and services
rise and
are absorbed in the healthcare system.
101
Now, there is no mistake about
the need to
ensure patient access to medication. In our
petition to FDA, we were clear that FDA
needed to
take into account price and how it would
affect
patients and their ability to obtain
medication and
comply with their treatment
regimens. But we think
that, between the manufacturers, the stakeholders
and FDA, collective, we can adequately
protect the
potentially at-risk subgroups and we can
do it in a
variety of ways.
On the part of the
manufacturers, we have
one submission already in the docket from
an HFA
manufacturer outlining what it intends to
do. We
would hope that we would see similar
commitments
from other manufacturers as we move
forward about
increasing the number of samples and
enhancing
patient-assistance programs.
On the part of the
stakeholders, our
member organizations are committed to
working with
the agency and the manufacturers to
develop an
educational strategy for communicating
the
availability of free and discounted
albuterol. We
102
can work with our member organizations
and our
network to deploy these messages in
advance of
transition to patients, to specialty, general
physicians and the rest of the healthcare
community.
As for FDA, we think that there
also might
be mechanisms that the agency can
consider to
protect, again, these potentially at-risk
populations. One thing we have discussed within
stakeholder meetings is for FDA to
monitor the
patient compliance or access to HFA
albuterol and
reserve the right to allow a certain
number of CFC
MDIs to be sold in the case of a real
emergency so,
if you will, a phase-down process that
allows the
potential--and that is the potential in
both CFC
supply and manufacturing capacity to not
be gone
before we are out of transition, so a
phase-down
period that protects that at-risk
population.
I think that if FDA acts in a
relevant
timeframe, there would still be enough
stockpile to
be able to incorporate such a mechanism.
Last, I would like to turn to
the timing
103
of transition. There has been a lot of talk about
when the right time is. Now, it is no secret that
the stakeholders have long supported
December 31,
2005 as the effective date for removing
CFC
albuterol from sale in the U.S. As early as 1996,
in fact, before we had ever heard the
word "TEFA"
or "WEERT," we embraced the
idea of a target date.
We embraced the eventuality
that these
chemicals as slated for elimination. We understood
that it was useful to have a target date
so that
manufacturing capacity could be put into
place.
That idea of an aim, a target, a goal,
has proven
successful as is evidenced by the fact
that the
rest of the world or the rest of the
developed
countries also adopted that date and or
on pace to
meet it.
We saw transition as an
opportunity to
educate physicians and patients about the
learning
that has been done, especially in the
last decade,
regarding asthma treatment and
management.
But, in 1996, we saw December
2005 as a
goal, not an imperative. Eight years later, we now
104
know that WEERT will close. We know there are
additional uncertainties regarding the
Baton Rouge
facility.
We know that there are two alternatives
ready to go and a third on the way. Given that,
December 31, 2005 makes a lot of sense.
Again, I just want to go back
to
mechanisms for actually proceeding
through
transition. Ending at December 31 is sensible and
it is achievable and, most importantly,
it is
near-term enough that any problems with
HFA
production, any problems with patient
access, any
problems with affordability, compliance,
any
unforeseen consequences, can be
discovered and
addressed before CFCs are unavailable and
before
the capacity to produce additional CFC
products is
gone.
Thanks very much.
DR. CHINCHILLI: Thank you very much.
We will move on now to our
second speaker.
DR. JONES: Good morning.
My name is
Elaine Jones and I am Vice President of
U.S.
Regulatory Affairs at
GlaxoSmithKline. On behalf
105
of GlaxoSmithKline, I would like to thank
the
advisory committee and the agency for
opportunity
to present our commitment to the
transition from
albuterol CFC-free metered-dose inhalers,
or MDIs,
which are ozone-depleting to albuterol HFA
MDIs,
which are non-ozone-depleting.
Principally, during this
presentation, I
will address the two questions that have
been posed
to us by the agency that relate to the
FDA's
criteria for transition.
The first question concerns our
manufacturing capacity for Ventolin HFA
and the
second, what GSK programs are, or will be
put in
place to help ensure that patients are
adequately
served during the transition from albuterol
CFC to
albuterol HFA and thereafter.
To set the stage for discussion
of the two
principle questions, I would like to
review the
timing of Ventolin HFA development in
relation to
implementation of the Montreal Protocol.
Development of Ventolin HFA started
before the
Montreal Protocol was ratified and
resulted in
106
submission of a new drug application in
1998.
Filing of this NDA was the result of over
ten years
of research and development including a
technically
challenging reformulation effort under
comprehensive clinical program.
After gaining FDA approval, GSK
launched
Ventolin HFA in 2002 and stopped the sale
of
Ventolin CFC. Currently, GSK sells Ventolin HFA in
165 countries around the world which has
resulted
in over 20 million patient years of
experience.
Also, in 2002, FDA published its final
rule
outlining the criteria for transition
from CFC
MDIs, which was the culmination of a
lengthy
process that took five years to complete.
Quoted on this slide is one of
the
criteria for transition from the 2002
Final Rule.
FDA has asked us, as one of the
manufacturers of
the replacement products for albuterol
CFC MDIs to
address this criterion which relates to
the issue
of adequate supply and production
capacity.
Specifically, the question is, can GSK,
in
conjunction with other manufacturers of
the
107
replacement albuterol product,
manufacture
sufficient quantities to satisfy patient
demand
after the CFC products are no longer
available.
To help answer this question,
here is a
graphical representation of GSK's
manufacturing
capacity over time in relation to the
overall
albuterol market. Other manufacturers can be
expected to contribute to the supply as
well. At
present, patient need for albuterol MDIs
is about
50 million per year, as shown by the
yellow shading
in this graph. This demand has remained fairly
constant over the past five years and is
expected
to remain constant into the future.
The blue shaded portions of the
graph
represent two distinct components of
GSK's ability
GSK's ability to contribute to meeting
this demand
with CFC-free MDIs. The darker shaded blue area
reflects currently installed capacity and
the
lighter shaded blue area reflects
expansion
capacity.
The sum total of both components is
about 30 million MDIs per year, or about
60 percent
of the expected market.
108
Now, I would like to discuss in
detail our
current capacity. GSK manufacturers Ventolin HFA
at a facility in Zebulon, North Carolina,
which has
a long history of manufacturing MDIs
including the
now discontinued Ventolin CFC. At this facility,
we already have installed the capacity to
manufacture 15 million Ventolin HFA MDIs. At
present, since transition has yet to take
place, we
are utilizing only 2 percent of our
installed
capacity.
Production of up to 5 million
MDIs could
be achieved immediately and this could be
progressively increased to the full 15
million MDIs
within six to twelve months. To achieve this
capacity is a relatively straightforward
process.
We would need to hire additional staff
and
reconfigure existing space.
As illustrated on the graph I presented
earlier, GSK is prepared to increase
production
capacity by an additional 15 to 18
million MDIs.
This would entail significant capital
investigation
on the part of GSK, would take approximately
twelve
109
to eighteen months to complete and would
require
the installation of additional
manufacturing
equipment and securing of MDI components.
This could be undertaken simultaneously
with a previous increase in
production. This
expansion, in addition to our current
capacity,
would deliver a total of approximately 30
million
MDIs.
I would now like to address the
second
question posed to us by the agency which
concerns
another one of the criteria in the 2002
Final Rule
on Essential Use Determinations and is
reflected on
this slide. The issue is whether a high-priced,
non-ODS, product is effectively unavailable
to a
portion of the patient population because
they
cannot afford to buy the product.
Payers, and the healthcare
system overall,
may experience higher costs as the market
transitions to CFC-free albuterol. But the
relevant question under FDA's 2002 Final
Rule is
how individual patients will be impacted
by this
transition, specifically whether they
will have
110
adequate access to CFC-free formulations
of
albuterol.
The larger policy questions
regarding a
balancing of societal cost against
environmental
benefits have already been resolved by
the Montreal
Protocol.
In order to assess the economic
impacts of
an albuterol transition, GSK commissioned
a study
by the National Economic Research
Associates. The
analysis proceeded on the basis of data collected
from a variety of sources as shown on
this slide.
Although the economic report examined
impacts on
payers as well as patients, our focus
today is on
the impact a transition will have on the
access to
albuterol HFA MDIs for individual
patients.
To understand the impact on
patients, one
must appreciate that albuterol is
dispensed to
patients in different settings including
retail
pharmacies, hospital pharmacies, clinics
and
federal healthcare facilities. As represented by
the large green slices of pie chart, 84
percent of
dispensing takes place at retail
pharmacies. The
111
remaining 16 percent takes place in other
settings;
for example, a Veterans Administration
Hospital
where financial impacts on patients, of
changes in
drug prices, are likely to be quite
limited.
The pie chart on the right
reflects a
further breakdown of the retail-pharmacy
segment.
Within the retail portion, 72 percent of
MDIs are
covered by private drug insurance and 15
percent
are covered by Medicaid. About 13 percent of
albuterol MDIs dispensed by retail
pharmacies go to
patients who pay cash. GSK recognizes that it is
within this group of patients that the
greatest
concern exists regarding access to
albuterol MDIs
after a transition.
As we consider the patients who
pay cash
for their prescriptions, it is important
for us to
emphasize our long-standing dedication to
helping
those in need obtain access to our
medicines. For
over two decades, GSK and its Heritage
Companies
have been committed to helping patients
without
public or private drug insurance to get
the
medicines that they need. To this end, we have had
112
in place various patient assistant
programs.
I will now describe Bridges to
Access, the
GSK program which is directed at patients
of all
ages who require financial
assistance. For those
who qualify, GSK offers its medicines,
including
Ventolin HFA, at no cost or at a minimal
retail-pharmacy dispensing fee.
Individuals with annual incomes
up to
$25,000 or families at or below 250
percent of the
federal poverty level are eligible for
Bridges to
Access.
Patients who enroll can receive their
medication the same day that it is
prescribed.
This program also includes a spend-down
option that
allows patients to deduct medical bills
from their
income for purposes of determining
eligibility
requirements.
Patients are not required to be
U.S.
citizens to qualify for Bridges to
Access.
Patients who apply also receive
assistance in
finding additional healthcare programs for
which
they qualify such as Medicaid, AIDS
drug-assistance
programs, state children's health
insurance and
113
state elderly drug-assistance programs.
In this visual illustration, we
use the
federal poverty level as a baseline to
compare the
income eligibility levels for Medicaid
and Bridges
to Access. The yellow line represents the federal
poverty level income for households of
different
sizes ranging from one to four
members. The blue
lines represent the average income
eligibility
ceiling for Medicaid which is 135 percent
of the
federal poverty level.
Each orange bar represents the
maximum
qualifying income under Bridges to Access
for a
household of that size. This maximum qualifying
income level is $25,000 for households
with one
individual or 250 percent of the federal
poverty
level for households with more than one
individual.
I might add that certain
patients who do
not meet
Medicaid's eligibility requirements
despite meeting the income requirements
could
potentially qualify for Bridges to
Access. For
lower-income patients who do not have
public or
private drug insurance, for whatever
reason,
114
Bridges to Access is, thus, a valuable
resource.
GSK's experience with Bridges
to Access
for Ventolin HFA from June 2003 to May
2004
illustrates the program benefits for
patients. We
have distributed nearly $3 million worth
of product
representing approximately 100,000
inhalers to
nearly 14,000 patients. During this period of
time, the total amount of Ventolin HFA
distributed
was approximately 400,000 MDIs which
means that one
out of four Ventolin HFA MDIs went to a
Bridges to
Access patient.
GSK has generated awareness of
this
program through various avenues including
half a
million letters sent to advocates at the
launch of
the program, training for healthcare
providers and
partnerships with public agencies and
professional
associations. In addition, we maintain a public
website with extensive information about
our
program including application forms.
These activities represent some
of the
significant efforts GSK has made to raise
awareness
of the program and we look forward to
continuing
115
our outreach efforts. We are committed to provide
Ventolin HFA to all eligible patients in
the event
of an increased need at the time of
transition. In
order to show more clearly the estimated
financial
impact of a transition to CFC-free
albuterol on
individuals, I would like to now
illustrate how a
lower-income patient might fare in a
transition
both with and without the benefit of
Bridges to
Access.
Our hypothetical patient is an
individual
who makes less than $25,000 a year and,
thus,
qualifies for Bridges to Access and who
also uses
four albuterol inhalers. To make this calculation,
we compared the current average wholesale
price of
Ventolin HFA to the mean of the average
wholesale
prices for the three top selling generic
albuterol
inhalers.
Average wholesale price, or
AWP, is
commonly used as a pricing reference
point for
distributors and payers in the healthcare
system
and is calculated and reported by
commercial data
vendors.
GSK does not set an AWP for its products
116
or sell its products according to AWP and
we
recognize published AWPs are different
from actual
prices paid in the marketplace.
Based on the AWP comparison,
the current
difference in price between Ventolin HFA
and
generic albuterol is $9.49. Therefore, in our
example, if the patient did not enroll in
Bridges
to Access, the extra cost per month would
be $3.16
or $37.96 a year.
With assistance from Bridges to
Access,
the cost of Ventolin HFA would be limited
to a
one-time charge of $10.00 for the
patient's first
60-day retail pharmacy fill. The patient would
then experience no added cost for further
prescription. In fact, the medicine would be
entirely free from that time forward.
Keep in mind that this
hypothetical
patient, if not enrolled in Bridges to
Access prior
to the transition, would previously have
been
paying out of pocket for that generic
albuterol.
For seniors or disabled
persons, in
addition to Bridges to Access, GSK offers
the
117
saving programs, Orange Card and Together
Rx to
help make GSK medicines more
affordable. The GSK
Orange Card was the first of its
kind. It is
available for Medicare beneficiaries
without any
prescription-drug insurance and incomes
of up to
$30,000 for an individual and up to
$40,000 for a
married couple.
Orange Card offers savings on
GSK products
including Ventolin HFA to eligible
Medicare
beneficiaries of up to 40 percent
depending on a
pharmacy's usual and customary price for
the
medicine.
The program, Together Rx, is a
multi-company savings program and, as
such,
provides access to a larger number of
medicines.
This program was modeled after the GSK
Orange Card
and has similar eligibility criteria.
Although the arrival of a
Medicare drug
benefit in January 2006 should
substantially lessen
the need for assistance of this kind,
GSK's
commitment to helping patients access our
medicines
will remain.
In addition, GSK has committed
to provide
118
at least 2 million professional samples
of Ventolin
HFA each year beginning a
transition. Although
samples are distributed to physicians
with no
conditions attached, we understand,
anecdotally,
that many physicians do take medication-access
considerations into account in allocating
samples
among their patients. Furthermore, GSK has
committed to freeze the price of Ventolin
HFA from
November 5, 2003 until December 31, 2007.
In summary, GSK is committed to
and has
global experience in transition to
ozone-friendly
formulations. GSK has currently installed
production capacity to produce 15 million
Ventolin
HFA MDIs per year. We are prepared to expand the
total capacity to approximately 30
million MDIs per
year.
GSK has demonstrated an abiding
commitment
to helping patients gain access to our
medicines
and, towards this end, has
patient-assistance
programs in place to help ensure access
to Ventolin
HFA at transition. Finally, GSK has committed to
provide professional samples and freeze
the price
119
of Ventolin HFA.
We expect that the criteria for
transition, as outlined in the 2002 Final
Rule,
will be met with the support of all
currently
approved albuterol HFA suppliers. Therefore, GSK
supports a transition date of December
31, 2005
which would allow for a smooth and
orderly
transition for patients.
I would like to conclude by,
once again,
thanking the advisory committee and the
agency for
allowing GlaxoSmithKline the opportunity
to present
today.
Thank you.
DR. CHINCHILLI: Thank you, Dr. Jones.
Let's have our third speaker
for this
morning.
DR. GARUTTI: Members of the committee,
Food and Drug Administration, invited
guests,
ladies and gentlemen, good morning. My name is Dr.
Ron Garutti. I am a pediatrician and I am Group
Vice President of Global Regulatory
Affairs at
Schering-Plough Research Institute.
120
On behalf of Schering-Plough
Corporation,
I want to thank the FDA for the
opportunity to
address the advisory committee today.
Let me say, at the outset, that
our
company firmly supports the principles of
the
January 29, 2003 petition of the U.S.
Stakeholders,
which you have heard about, which
requests an end
to the exemption for albuterol CFC-based
in
inhalers.
As pointed out, this exemption, after
all, was never intended to be permanent.
Now, I will not devote any of
my
discussion today to the rationale for
removing CFCs
from albuterol inhalers as I believe that
that
rationale is well understood and accepted
by most
interested parties as the right and
necessary thing
to do.
In so removing CFCs, the United
States
would be accomplishing the transition to
a non-CFC
environment that has already successfully
been
implemented by most of the European
Union, Canada,
Australia, Japan and other countries.
So the important question,
then, today,
121
for
the committee is not if the transition should
be done but when. It can be done as soon as FDA,
in conjunction with the healthcare
community and
the industry, is prepared to initiate the
transition.
It has been pointed out that in
July,
2002, the FDA issued a final rule which
set forth
the conditions that would have to be met
before an
essential-use designation for albuterol
inhalers
could be removed. Both Drs. Meyer and Sullivan
have noted them. Schering believes that all of the
necessary elements to remove the
essential-use
designation can be met as early as
December 31,
2005.
We acknowledge the proposed
rule
distributed today and we are pleased to
learn that
FDA plans to publish this on June
16. We are
hopeful that today's discussion will lead
to the
establishment of a firm date.
As a company with more than
twenty years
of respiratory experience and the first
with our
partner 3M to introduce an HFA inhaler to
the
122
United States, Schering understands that
we, in
conjunction with all of you and other
members of
the professional asthma community, will
be asking
millions of patients to change their
behavior.
We recognize the significance
of this
transition to patients and providers
alike and we
are sensitive to the fact that ongoing
communication efforts will be essential
elements to
ensuring that the transition is smooth
and
successful.
To accomplish this effectively,
however,
it is critical that FDA establish a clear
timeline
to end the exemption because we believe
that only
in doing so will there be the necessary
stimulus to
drive the kind of provider and
patient-behavior
change that will be required. Schering's
contribution, as well as that of others,
to
effecting a successful transition hinges
on
implementing the various elements of the
transition
at the right time in relation to the
effective
date.
In the absence of such a date,
it will be
123
difficult to manage these various aspects
efficiently. For example, patients may not be
receptive to targeted communication
efforts until a
fixed date has been established. It has been
pointed out, in addition, that
significant planning
decisions and resource commitments
required to
increase current production capacity need
to be
made and, for us, we need about eighteen
months in
advance of a known effective date.
That being said, Schering is
poised to
play a part in a planned orderly
transition and we
could be ready for an HFA-only
environment as early
as the end of next year. We believe that for the
FDA to remove the exemption, certain
assurances are
required.
These are that safe and effective
alternatives are available, that patients
and
providers are knowledgeable about and
comfortable
with the use of the inhalers and that
industry can
adequately meet the demand.
In the next few minutes, I will
point out
that we do have safe and effective
alternatives
right now and Schering will have
educational
124
programs ready so that patients and
providers will
be knowledgeable about and comfortable
with their
HFA alternatives and that we can have an
adequate
supply and production capacity of
Proventil HFA
available again as early as December 31,
2005 or
within eighteen months of an established
transition
date.
Now, regarding the safe and
effective
alternatives, following the issuance of
the
Montreal Protocol in 1987 and after years
of
research and development, Schering was
the first
company to market, in collaboration with
our
partner 3M, a non-CFC inhaler in the
United States
in 1997.
Industry researchers had created HFAs
that
were more environmentally friendly than
CFCs.
These HFAs were then extensively tested
to ensure
that they possessed the desired
characteristics of
an MDI propellent. A wide range of toxicology
studies, comparable in scope to that for
a new
molecular entity and consisting of acute,
chronic
reproductive genetic and carcinogenicity
125
evaluations, established that certain HFA
molecules
were, in fact, suitable candidates to
replace CFCs
in inhaled delivery systems.
The new technology was then
applied to
Proventil and, after a comprehensive
clinical
program established that Proventil HFA was both
safe and effective, the FDA approved the
product
for marketing clearance in 1996. In addition to
the clinical studies that were included
in the NDA,
3M also conducted a robust observational
postmarketing program which studied more
than 6,000
patients.
In the nearly eight years of
postmarketing
patient experience to date, more than 17
million
prescriptions for Proventil HFA have been
written.
Spontaneously reported adverse events, as
you have
heard, have been consistent with the
product's
labeling and similar in nature to that of
its CFC
counterpart.
Taken together, available data
clearly
support the established safety profile of
Proventil
HFA and so, yes, we do have safe and
effective
126
non-CFC alternatives available right now
and, in
fact, with Glaxo's HFA product, there
are, as said,
two such products available.
Let's turn now to another
assurance
required before removing the exemption,
that
relating to education and
communication. Schering
is committed to playing its part in
communicating
important information around the
transition to both
patients and providers. Including in that
important information is reiteration of
the message
that HFA inhalers are as safe and effective
as the
CFC inhalers to which most patients are
accustomed.
The HFA inhalers are also similar in size
and shape
and as convenient to use.
Now, we all recognize,
especially those
who treat asthma patients, that there can
be a
significant psychological and emotional
component
to asthma and its treatment. Asthma patients come
to rely on their inhalers and expect a
certain type
of experience in using them. They tend to
associate activity of the drug and
subsequent
relief with the forceful sensation of the
spray
127
from a CFC inhaler has on the back of the
throat.
I would point out that, with an
HFA
inhaler, however, there is a softer spray
and less
sensation although, of course, the active
drug is
still effectively delivered to the
lung. This fact
must this communicated to patients to
ensure the
appropriate use of the product. Patients will also
need to be comfortable with the fact the
drug from
an HFA inhaler may taste and smell
slightly
different than that from a CFC inhaler.
Schering has always had
educational
programs in support of our
respiratory-care
business and messages such as those I
have just
noted will be included in our developing
multipoint
communication and awareness programs
intended to
facilitate a safe and orderly transition.
Educational information will be
accessible
via many channels including informational
websites,
written materials available in
physician's offices
and through our professional sales
representatives.
Schering has traditionally had strong
collaborative
working relationships with relevant
national
128
medical associations including both the
American
Academy and the American College of
Allergy, Asthma
and Immunology, the Academy of Family of
Physicians. We will continue to work with these
associations and others to develop
appropriate
educational materials for patients and
providers.
We especially appreciate the
efforts of
organizations such as the allergy and
asthma
network Mothers of Asthmatics in their
own
commitments to educating and supporting
the needs
of asthma patients.
Schering is also one of the
founding
sponsors of the National Patient Safety
Foundation
and has held a seat on its board of
directors since
1997.
This group is dedicated to improving patient
safety through educational programs and
initiatives
and Schering will continue to provide
input and
leadership on issues related to safe
medication
use.
As I stated in my introduction,
the impact
of an expanded successful patient and
provider
education campaign will be highly dependent
on
129
implementing the various elements at the
right time
in relation to a proposed effective
date. These
programs, to be maximally effective, will
need to
be timed in coordination with the
transition date
established by FDA so that the asthma
community can
be optimally prepared.
On other point related to the
transition,
it is, unfortunately, a fact and well
known that
many asthma patients do not regularly
visit their
healthcare provider. Schering believes, in
agreement with the U.S. Stakeholders,
that the
transition will offer a good opportunity
for
physicians and patients to increase their
general
dialogue about asthma management.
A visit to the healthcare
provider,
prompted by the switch to an HFA inhaler,
will
allow for a reassessment of the patient's
condition
and adjustment of treatment if deemed
appropriate.
It will be especially useful for those
patients who
may not have seen a physician for some
time.
A third assurance required
before removing
the exemption is that an adequate supply
and
130
production capacity of the HFA
alternative will
exist.
FDA has stated, and you have heard several
times today, that over 50 million albuterol
canisters are sold or distributed in the
U.S. each
year.
Schering currently supplies approximately
30 million units annually.
Our manufacturing partner, 3M,
stands
ready to expand production in its facilities
to
manufacture this amount of Proventil HFA
and
Schering and 3M both have confidence that
the
necessary capacity can be in place to
meet our
share of the expected demand.
While much of the preparatory work
to
expand capacity is well underway,
advanced planning
activities and significant resource
commitments
necessary to formally initiate this
process require
some assurance of the timing of the
transition.
The overall lead time to execute these
steps,
including scale-up to current market
demand, is
approximately eighteen months, again,
thus, making
a fixed transition date established by
FDA critical
for us and our partner.
131
In conclusion, the time to set
a
transition date is now. Schering is confident that
we can meet our share of the demand and
ensure that
asthma patients who need Proventil HFA
are
adequately served. The focus throughout the
transition from CFC to HFA inhalers must
be on
education and communication efforts
towards
patients and providers. Schering is committed to
playing its part in effecting a
successful
transition and supports the removal of
the CFC
exemption.
The first step requires that a
proposed
final rule be published and a clear date
communicated so that all asthma
stakeholders can
act
together. Finally, Schering believes the
U.S.
can join the group of countries who have
already
undergone a successful removal of the
exemption
because we do have safe and effective FDA
alternatives now. We will be educating patients
and providers and ensure their comfort
level with
the transition and industry can
adequately meet the
supply and demand.
132
Thank you.
DR. CHINCHILLI: Thank you, Dr.
Garutti.
Do the committee members have any
questions of our
three open presenters this morning? Dr. Schatz?
DR. SCHATZ: I guess a question for the
stakeholders. The presentation talked, actually,
about two aspects of concern. One was CFC
availability, itself, and then,
obviously, the
detrimental aspects. But I was trying to get some
sense as to what the relative concerns
were and if,
in fact, if CFC availability were
assured, would
that change the thinking in terms of a
time line?
MS. WEXLER: If CFC availability was--
DR. SCHATZ: A fair amount has been
emphasized about the concern as to
whether CFCs
will continue to be available in terms of
the
production as a rationale for the
December 2005
date.
My question was to what extent that one
factor is important and if CFC
availability were
assured, if the production were not an
issue, would
that affect your thinking in terms of a
transition
date?
133
MS. WEXLER: No. I
think that they work
together to signal that these chemicals
are being
eliminated. There is a reason that Honeywell has
been asked to shut the manufacturing
plant in the
Netherlands and that is because the Dutch
government does not want CFCs produced on
its soil.
It is a political statement about getting
out of
these chemicals.
To answer your question
specifically, if
Baton Rouge were able to produce, it is
not clear
that the international community would
continue to
authorize those quantities and that would put the
stakeholders in the position of
suggesting that we
don't care about international
commitments.
The U.S., the government, has
made a
commitment to comply with the Montreal
Protocol and
so producing in Baton Rouge is only part
of the
equation.
It is that gets us the potential to use
them.
But the right to use them legally needs to
be granted by the parties to the
protocol. So they
have to work together in order for us to be
able to
go forward.
134
I think what, in some ways, you
are asking
is would we support renouncing the
protocol?
DR. SCHATZ: No. It is a matter of would
the date, would your date, change. I was trying to
get the sensitivity of your position to
CFC
availability versus other considerations
relative
to the date you suggest.
MS. WEXLER: Again, I think that they work
together.
Given what we know about the timeline,
the U.S.--forgive me; I want to make sure
it is
clear.
We ask to use CFCs, wherever we get them
from.
Regardless of where they are produced, each
country must ask the international
process sort of
at the beginning of the year. We just put in our
request and those requests are two years
in
advance.
So the request that the U.S.
recently
submitted was for 2006 quantities. That request
was not welcomed completely. It was suggested that
the U.S. might want to reconsider that
nomination
in light of this rulemaking or the rule
that is go
forward.
135
So even if supply weren't
necessarily an
issue, I think that it would be foolish
for us to
believe that the international community
is going
to continue to provide authorization to
use those
CFCs indefinitely. So we are talking about a
2005-2006 timeframe for getting out of
this and not
worrying about either of those
conditions, of CFC
supply or the international community not
granting
authorizations.
I think that, as we have heard,
the
process of transitioning, making sure
that the
HFA-installed capacity is there, making
sure we
don't do anything precipitous and have a
problem
and then have no CFC production
capability and the
stockpiles of the CFCs that are available
sort of
suggest that we want to kind of look
towards the
sooner rather than later so that we buy
ourselves
some time.
In other words, I don't think the
protocol
parties will look kindly at a nomination
for 2007
or 2008 regardless of whether Baton Rouge
actually
ends up coming on line in a legal way.
136
DR. CHINCHILLI: Thank you.
Dr.
Atkinson?
DR. ATKINSON: I sort of get the
impression that one of the big concerns
among the
committee members and the FDA also is the
possibility that a small percentage of
asthma
patients might be unable to purchase the
HFA units
that they need. GSK has a program, or described a
program, that was going to assist with
that. I
wanted to ask Dr. Garutti if Schering had
any such
program and if they were considering
creating one
if they don't have one now.
DR. GARUTTI: Let me say this is a patient
group and a provider group that we care
very deeply
about.
We are committed to the respiratory
business.
We have been in it a long time and we
are going to do whatever is necessary to
serve our
patient population.
First and foremost there is to
make sure
that there is Proventil HFA available
when we do
transition to the HFA-only
environment. Currently,
as I have pointed out, that will entail a
137
significant ramp-up and a significant
expenditure
of cost to get there. And we are confident we will
get there.
In fact, Schering-Plough does
have a
patient assistance program. It is called SP Cares.
We have had it since, I believe, the
mid-1990s. It
has
similar eligibility requirements to those of
Glaxo's program, not entirely the same
but similar.
Last year along we provided free drug of
our
primary-care products including Proventil
HFA to
some 75,000 low-income uninsured
patients.
Periodically, we review the
elements of
this program and criteria and we are
committed to
continuing this program.
DR. CHINCHILLI: Thank you.
Dr. Moss; you
had a question?
DR. MOSS:
I was going to ask something
along the same lines. Maybe the people from GSK
and Schering can talk about how they are
going to
market those programs for the uninsured,
if they
have any plans for how to make physicians
aware of
these programs.
138
MS. WEXLER: I wanted to point out that,
in anticipation of this move, the
stakeholders, on
our website which is at inhalertransition.org,
has
listed all of the patient-assistance
programs and
has link to them so that our member
organizations
can now start to disseminate that
information. So
we also will work with the companies to
promote
these.
DR. JONES: Yes.
Bridges to Access,
actually, at the moment, has 435,000
patients in
its program. We have done a lot and will endeavor
to meet and strive towards this end. We have put a
lot of programs in place in order to be
able to
reach as many people as possible and we
will
continue to have these outreach efforts
in place to
allow physicians and their associates to
actually
be aware of these programs.
But, as I say, we have 435,000
at the
moment in the Bridges to Access program.
DR. CHINCHILLI: Thank you.
Dr. Garutti?
DR. GARUTTI: I am not sure there is much
more we can add. As we have indicated, we are
139
developing many aspects of our
communication
program.
This is one element of them, the
awareness of the SP Cares program and we
are going
to be working with various organizations
that we
mentioned to make sure that it is more
widely
communicated now as we transfer to an
HFA-only
environment.
DR. CHINCHILLI: Any other questions from
committee members? If not, we are going to break
for lunch. I'm sorry; Dr. Meyer. I didn't see
you.
DR. MEYER: Sorry; not to delay lunch. I
did want to make a clarification on an
issue that
was left open from Ms. Wexler's talk
earlier about
how the CFC sources is handled by the FDA
because I
think she left that as kind of an open
question.
Without getting into the
details of the
Baton Rouge situation, what I would say
is that the
FDA does not approve a CFC source, per
se. What we
have done is we set standards for the
purity that
is acceptable for CFCs when used in
metered-dose
inhalers.
It is the expectation that the sponsor
140
of a product that uses those CFCs will
provide us
evidence, both from the manufacturer as
well as
their own testing, that the CFCs meet
those
specifications and, if they do, then, in
fact, they
can be used in that product.
DR. CHINCHILLI: Thank you for the
clarification. Let me make sure nobody else has
anything.
Okay. We will break for
lunch. We plan
to start promptly at 12:30 so please
return to your
seats a few minutes before 12:30 so that we
can
start at that time.
Thank you.
(Whereupon, at 11:22 a.m., the
proceedings
were recessed to be resumed at 12:30
p.m.)
141
A F T E R N O O N P R O C E E D I N G S
(12:30 p.m.)
DR. CHINCHILLI: We are ready to resume
our afternoon session.
Open Public Hearing (Session 2)
We have a number of speakers
for our open
public hearing this afternoon. But, before we get
started, I want to read the announcement
again that
I read this morning for our speakers.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and decision
making. To
ensure such transparency at the open
public hearing
session of the advisory committee
meeting, the FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, the FDA
encourages you,
the open public hearing speaker, at the
beginning
of
your written or oral statement, to advise the
committee of any financial relationship
that you
may have with any company or any group
that is
likely to be impacted by the topic of
this meeting.
142
For example, the financial
information may
include a company's or a group's payment
of your
travel, lodging or other expenses in
connection
with your attendance at the meeting. Likewise, the
FDA encourages you, at the beginning of
your
statement, to advise the committee if you
do not
have any such financial relationships.
If you choose not to address
this issue of
financial relationships at the beginning
of your
statement, it will not preclude you from
speaking.
Now, in addition to that,
unlike this
morning, we are going to time the
presentations
because we have a number of presentations
and a
short amount of time. Ms. Jain is going to be
running a timer and, when the green light
comes on,
that means you can start with your
presentation.
The yellow light means that you have one
minute
remaining and the red light means you are
finished.
Now, we don't have a hookup
here to pull
you, so we would appreciate if you comply
with
this.
Please try to finish when you see the red
light.
143
So we are ready for Speaker No.
4 for this
afternoon.
MR. JAMIESON: Good afternoon. My name is
Jim Jamieson and I am here today on
behalf of IPAC,
the International Pharmaceutical Aerosol
Consortium. IPAC is an association of leading
manufacturers of MDIs for the treatment
of asthma
and COPD.
My remarks today are made on behalf of
AstraZeneca, Aventis,
Boehringer-Ingelheim, Chiesi
Farmaceutici, GlaxoSmithKline and IVAX.
IPAC was created in response to
the
mandates of the Montreal Protocol. Since its
inception over fifteen years ago, IPAC
has sought a
smooth and efficient transition from CFC
MDIs that
balances public health and environmental
protection. IPAC is firmly committed to the
transition from CFC MDIs as evidenced by
the
extraordinary investments and efforts
that its
members have undertaken over more than a
decade.
I have been personally involved in this
process for twelve years and have served
as IPAC's
principal point of contact with the FDA,
EPA, the
144
State Department and other U.S.
Government agencies
on issues related to the MDI
transition. I
appeared before this committee five years
ago
during consideration of the FDA's rule
establishing
the criteria for determining an MDI to be
nonessential.
IPAC's position on the FDA's
albuterol
rulemaking may be summarized as
follows. First,
IPAC fully supports FDA's Final Rule on
the MDI
transition issued on July 24, 2002. This rule
adopts a moiety by moiety approach to the
transition and establishes the four
criteria for
determining the nonessentiality of CFC
MDIs. Once
these criteria are met, FDA must
undertake the
requisite rulemaking process to promptly
remove
nonessential MDIs from the marketplace.
Second, IPAC fully supports the
Stakeholders' petition and has urged FDA
to issue a
final rule declaring these products
nonessential by
March, 2005 with an effective date no later
than
December, 2005.
Let me explain why IPAC
embraces these
145
positions. First, and most important and as you
have now heard, there are two safe and
effective
CFC-free albuterol products on the U.S.
market and
the criteria set forth in the July, 2002
Final Rule
either have been or can be met by
December 2005.
This position has also been advanced, as
you have
heard, by the Stakeholders Group.
Second, numerous other
developed
countries--Canada, Japan, Australia and
at least
twelve European nations--have already
successfully
transitioned patients to CFC-free albuterol
products.
There is no reason to believe that the
United States cannot do the same. While we are
focused today on a domestic rulemaking
process, it
is critical to understand the overarching
international context. The United States' ability
to secure CFC supply for MDIs is based
upon
essential-use authorizations allocated by
the
parties to the Montreal Protocol.
The international community has
recognized
that the completion of the albuterol MDI
transition
is crucial since these products represent
at least
146
half of the CFC MDI market in the United
States and
around the world. In light of the progress by many
other developed countries and the wide
availability
of CFC-free albuterol products around the
world, it
is unclear how much longer the
international
community will be willing to approve CFC
volumes
for use in single moiety albuterol
products. This
uncertainty has significant implications
for
patient care.
In response to the clear
directive from
the United States and international
community to
reformulate MDIs and to do it as soon as
possible,
as soon as feasible, IPAC member
companies and
other MDI companies began the difficult
work of
developing CFC-free alternatives.
This effort was not simply a
matter of
switching from one available aerosol
propellent to
another.
It was a lengthy, challenging process
requiring full R&D programs including
extensive
clinical trials. This effort required substantial
investment from reformulating MDI
companies well in
excess of $1 billion and the work
continues.
147
Almost fifteen years ago, MDI
companies
and the United States government embarked
on an
extraordinary and unprecedented
partnership. The
goal of this partnership was and is to
balance the
critical environmental interest of ozone
protection
with the equally vital objective of
ensuring
patient care, something that could not be
achieved
absent a strong and durable
collaboration.
Industry's core responsibility
in this
partnership is to diligently research and
develop
safe, effective CFC-free
alternatives. For its
part, the United States undertook a
parallel
responsibility to secure essential-use
CFCs during
the development process and to ensure
prompt
removal of nonessential CFC MDIs as soon
as new and
reformulated products became available.
The pharmaceutical industry has
acted in
good faith and made extraordinary
investments to
develop ozone-friendly MDIs. It is now appropriate
for the United State to honor its
commitments
toward the phase-out of ozone-depleting substances
by declaring CFC single-moiety albuterol
MDIs
148
nonessential.
Finally, IPAC concurs with the
Stakeholders that, rather than presenting
a
possible risk to patients, the phase-out of
CFC
albuterol MDIs will actually bring
benefits to
patients in terms of improved treatment
regimens.
IPAC further believes that available
patient-assistance programs will promote
access to
adequate treatment for potential
vulnerable patient
subpopulations.
IPAC is pleased that the FDA
has issued
the Notice of Proposed Rulemaking. Based on the
considerations that I have mentioned
above, IPAC
urges FDA to grant the Stakeholders'
request and
issue a final rule removing nonessential
single-moiety albuterol CFC MDIs
effective December
31, 2005.
In closing, IPAC is grateful
for the
opportunity to present its views
today. We stand
ready to serve as a resource throughout
this
rulemaking process and future ones to
progress the
transition to a timely and smooth
conclusion
149
consistent with patient health.
Thank you.
DR. CHINCHILLI: Thank you, Dr. Jamieson.
Speaker No. 5?
MR. FLANZRAICH: Good afternoon. My name
is Neil Flanzraich and I am here today on
behalf of
IVAX Corporation. I would like to thank the FDA
and the Pulmonary-Allergy Drugs Advisory
Committee
for giving us the opportunity to comment
on the
regulatory issues before the committee
and to
register our support for the timely
removal of
single-moiety albuterol MDIs from the
list of
essential uses of ozone-depleting
substances.
IVAX is a multinational company
engaged in
the research, development, manufacture
and
marketing of generic and branded
pharmaceuticals
and veterinary products in the U.S. and
internationally. We are perhaps best known as one
of the world's leading generic
companies. We were
the company that brought the first
generic and
first inhaled generic, albuterol aerosol,
and the
first extended-release generic, verapamil
HCL ER
150
tablet, products to the U.S. market as
well as many
other important generic products; for
example,
paclitaxel injection.
IVAX also has a formidable
commitment to
proprietary medicine with an extensive
proprietary
pipeline that addresses important
therapeutic
categories including oncology, central
nervous
system, urological and endocrinologic
disorders.
We also have a strong focus on developing
proprietary products for respiratory
conditions.
Our position, as both a generic
and
propriety company, gives us a clear and
sympathetic
understanding of both sides of this
issue. Indeed,
our experience with the issues facing
this
committee goes much deeper. IVAX received a final
approval from the FDA for a CFC albuterol
and
metered-dose inhaler, the generic
equivalent of
Glaxo-Wellcome's CFC Ventolin, and was
the first
company in the U.S. to market a generic
albuterol
aerosol product.
Prior to the approval of this generic,
IVAX worked with the FDA for five years
to
151
establish a sensitive pharmacodynamic
bioequivalence study which paved the way
for the
approval of other generic albuterol
inhalation
aerosol products in the U.S. market. This resulted
in significant extended use of albuterol
inhalers.
IVAX' entry into the market, as
well as
the other companies that followed,
significantly
decreased the cost of albuterol to U.S.
consumers.
Importantly, this significant reduction
in
albuterol's price was a result of
competition in a
free-market economy. We sell, we continue to sell,
this generic CFC albuterol product in
both the U.S.
and abroad and it has been and continues
to be a
contributor to our companies revenues and
profits.
From the time seventeen years
ago that the
FDA and the EPA first encouraged U.S.
companies to
develop CFC-free aerosol products, IVAX
has been a
leader in developing and introducing
environmentally friendly CFC-free
respiratory
products.
In 1997, in France and Ireland, we
became the first company in the world to
win
approval for, and to market, CFC-free
152
beclomethasone in a metered-dose inhaler.
Our CFC-free beclomethasone,
QVAR, was the
first HFA corticosteroid for asthma on
the U.S.
market.
We have also developed another CFC-free
product, our patented dry-powder inhaler,
Airmax,
which has recently been approved in
several
countries in Europe and which is
presently being
studied in a clinical trial in the U.S.
with one of
our innovative proprietary compounds for
the
treatment of asthma.
IVAX as also become a major
supplier in
the U.S. and around the world of
inhalation
solution products for nebulization which
are also
CFC-free products. Most pertinent to the matters
concerning this committee, in January of
2003, we
submitted a new drug application for an
HFA
formulation of albuterol in a
metered-dose inhaler
and it received an approvable letter from
the FDA
on this application on November 28, 2003.
In August, 2003, we submitted
another new
drug application for an HFA formulation of
albuterol in our patented
breath-activated
153
Easi-Breathe inhaler.
IVAX has, therefore, not only
been a
participant but a pioneer and leader in
both the
generic CFC albuterol and CFC-free
branded
albuterol markets. Our company is committed to
supplying safe, affordable and
environmentally
responsible products and we don't believe
that
these goals are in conflict with each
other.
As has been stated by the U.S.
Stakeholders Group on MDI transition in
its
citizens petition, the impact of CFC
emissions in
accelerating depletion of ozone in the
earth's
stratosphere and, thus, increasing our
exposure to
ultraviolet radiation is scientifically
well
established.
Presently, CFC emissions from
metered-dose
inhalers are the dominant dose of CFC
emissions
produced by the United States. While the
significant impact of these emissions are
better
addressed by the scientists and
environmentalists
appearing before this committee, given
the current
status of the weakened stratospheric
ozone layer,
154
these CFC emissions remain a
public-health concern.
We believe their continued use remains a
breach of
faith with the international accords to
which the
U.S. is a party and to the international
community
that views these emissions as serious
hazards.
Additionally, removing the
albuterol CFC
products from the U.S. market will also
strengthen
the hand of the governments and agencies
seeking to
encourage other countries to discontinue activities
that release even greater volumes of CFCs
into the
atmosphere.
In response to the U.S. laws
and
international agreements calling for the
phase-out
of ozone-depleting substances, the
leadership of
other nations on this issue and the FDA's
instructing the pharmaceutical industry
that the
Montreal Protocol and the Clean Air Act
mandate an
eventual complete ban on the production
of
ozone-depleting substances.
IVAX has invested many millions
of dollars
over the past seventeen years to bring
CFC-free
products to the U.S. and European
markets. We
155
fully concur with GlaxoSmithKline's
argument that,
having urged the MDI industry for over a
decade to
reformulate their products to CFC-free
formulations, it would be manifestly
inconsistent
for the U.S. government to punish the
companies
that have invested so much and to reward
other
companies which have made no effort to
phaseout CFC
use by proposing an inappropriate delay
in
albuterol nonessentiality.
As previously mentioned, we
currently sell
QVAR, the only CFC-free aerosol
corticosteroid for
asthma on U.S. market and have filed new
drug
applications for an HFA formulation of
albuterol in
a metered-dose inhaler in our patented
breath-activated Easi-Breathe inhaler.
The FDA is well aware of the
status of
these NDAs and, hopefully, the products
covered by
them will join GlaxoSmithKline's Ventolin
HFA and
Schering-Plough's Proventil HFA on the
market in
the near future. Both of our HFA albuterol
products will meet the FDA's final rule
in regard
to same active moiety, same route of
156
administration, same indications,
approximately the
same level of convenience of use as the
CFC
albuterol products presently on the
market.
IVAX would be willing to supply
to FDA
with at least one-year postmarketing
surveillance
data for our HFA formulation of albuterol
that we
sell in Europe which is the equivalent to
the HFA
formulation of albuterol that we have
filed NDAs on
in the U.S.
Our HFA formulation in an MDI
and in our
Easi-Breathe inhaler will be manufactured
in our
FDA-approved plant in Waterford,
Ireland. We
expect our capacity for HFA products to
be 50 to 60
million units a year in the near
term. Given what
we have heard this morning about
GlaxoSmithKline's
and Schering-Plough's capacities for
manufacturing
CFC-free albuterol units, the combined
manufacturing capability of these three
companies
will be more than enough to satisfy the
needs of
the U.S. market.
For IVAX, there is also an
issue of
availability of CFC propellants. Whatever the
157
availability will be for U.S.
manufacturers, it may
be even more problematic for IVAX. Since we
manufacture our products in Ireland,
European
Community approval is needed to obtain
supplies.
Since CFC availability is decreasing
rapidly in
Europe, such approval may not be
forthcoming.
The effect of an interruption of
IVAX's
supply would be to decrease competition
in the U.S.
and increase prices of the CFC products
still on
the market. This is particularly likely since IVAX
is the major supplier of true generic CFC
albuterol
MDIs in the U.S.
We believe that IVAX is well
credentialed
to discuss the issue of pricing. We are one of the
world's leading generic companies and
have
demonstrated during our entire
seventeen-year
existence a commitment to provide
affordable
medicine to the public.
We have also demonstrated this
commitment
with our two main branded respiratory
products in
the United States, both QVAR, our
CFC-free
corticosteroid for asthma, and Nasarel,
our
158
intranasal steroid for rhinitis, are the
lowest-cost medicines in their
categories. QVAR,
our branded asthma medicine costs
approximately 50
percent less and Nasarel approximately 20
percent
less than the average price of the other
products
in its category.
We appreciate that there is a
concern that
the prices of these new branded CFC-free
albuterol
products will exceed those of the four
CFC generic
albuterol products currently on the
market one of
which is an IVAX product. We believe that the best
way to control the costs of these new
branded
CFC-free albuterol products is the
traditional
American way, through the dynamics of
competition
in a free-market economy.
Presently, there are two
competitors on
the market, Schering-Plough's Proventil
HFA and
GlaxoSmithKline's Ventolin HFA. We expect that
IVAX will be joining them in the near
future with
our two HFA albuterol products. These products are
not presently approved and we have not
yet set our
pricing, but we reiterate that IVAX has
an
159
historical commitment to providing the
public with
affordable medicine.
We are also committed to
pursuing a
substantial free sampling program as well
as a
patient-assistance program. In due course, we will
provide the agency with additional
information
concerning these proposed programs. The agency's
proposed rulemaking, which we have just
received,
sees the future entry of generics as the
way to
lower the current pricing of HFA
albuterol. We
respectively suggest that the entry of
generics is
still a long way off and that the agency
has not
properly taken into account in this
regard the
entry of IVAX's new HFA albuterol
products that are
currently pending at the agency.
It was IVAX's entry as the
third
competitor into the CFC albuterol market
years ago
that dramatically impacted these
prices. It is our
understanding that Sepracor may also have
a
CFC-free short-acting beta-agonist
molecule closely
related to albuterol on the market a
well. The
competition from these products will create
160
downward pricing pressure and there could
certainly
be additional CFC-free albuterol
products, brand
and generic, entering the market in the
future.
It has been alleged by an opponent of the
removal of CFC albuterol from the
essential-use
list that the FDA's removal of CFC
albuterol
products from the list would be
inconsistent with
the stated priority of carrying out its
mandate
under the Hatch-Waxman Amendments to
promote
affordability of prescription drugs by
increasing
the availability of generic drugs.
As a company deeply involved
with the
Hatch-Waxman Act selling over 8 billion
generic
tablets and capsules in the U.S. a year
with a
clear understanding of both the letter
and the
spirit of those amendments, we see no
mandate to
sell affordable drugs that put the
environment and
the
public's health at risk.
There is no inconsistency in
recognizing
and abiding by what has always been true,
that in
the pyramid of healthcare values,
"Do no harm," has
always come first. The primacy of this principle
161
is universally accepted and, at present,
twelve
European countries, as well as Canada,
Australia
and Japan, have eliminated the use of
CFCs in
albuterol MDIs.
Because we believe that the removal
of CFC
albuterol products is important, because
we believe
that the FDA's conditions and criteria
for removing
CFC albuterol products from the
essential-use list
have been met, because we believe that
the enormous
investment we and other pharmaceutical
companies
have made to reformulate our MDI products
in
reliance on the urgings of the FDA was
correct and
responsible corporate behavior that
should not be
ignored nor published, because we believe
that the
United States has pledged its support for
removal
of these products to the citizens of the
United
States and the international community
through the
Clean Air Act and Montreal Protocol, and
because we
believe that leading the CFC albuterol
products on
the U.S. market for an extended period
will have a
considerable, if difficult to calculate,
cost on
the environment, on public health, on the
U.S.
162
government's relationship with the
international
community and on its future success with
volunteer
collaborative pharmaceutical-industry
action and
because we believe that the cost of HFA
albuterol
products can be effectively dealt with by
various
mechanisms including, among others, free
sampling
and patient assistance programs and, of
course,
IVAX's entry into this market, we respectfully
request that the FDA promptly issue a
final rule
removing the albuterol MDI products from
its list
of essential uses no later than December
31, 2005.
Thank you.
DR. CHINCHILLI: Thank you, Mr.
Franzraich.
Speaker No. 6.
DR. ROZEK: Good afternoon. I appreciate
the opportunity to appear before this
committee
today.
My name is Richard Rozek. I am an
economist and a Senior Vice President of
National
Economic Research Associates, a firm that
has been
providing research on business and public
policy
issues for a variety of industries since
1961.
163
Personally, I have been
involved in the
pharmaceutical industry for over
twenty-five years
in various academic, government--federal
government, I should say--and
private-sector
positions.
In 2003, GlaxoSmithKline, or
GSK, asked
NERA to assess whether patients will be
adequately
served if the FDA designates albuterol
CFC MDIs
nonessential products. To address this issue, my
colleague, Emily Bishko, and I performed
an
economic analysis of the cost impact on
patients
and third-party payers in the first year
after the
FDA would implement this policy change.
Our initial results, which were
submitted
to the docket in response to the Citizens
Petition,
as well as my comments today, represent
the results
of our own independent research on these
issues
related to the current and projected
market
environments for selling albuterol.
Now, as we have heard this
morning, the
FDA established criteria that it was
considering
designation albuterol a
nonessential. Given these
164
criteria, which I have summarized on this
slide,
they really fall into two categories; the
product
issues and then the patient issues, I
think. We
focused on the economic factors
surrounding whether
patients would be adequately served. Specifically,
our concern was whether patients will
have access
to albuterol MDIs after the FDA policy
change.
To begin our analysis, we
examined public
data on the pharmaceutical industry
generally and
albuterol specifically. My experience in the
pharmaceutical industry suggests that
looking at
general industry trends does not
constitute a
sufficient basis to analyze the effects
of an FDA
policy change as that proposed here.
Detailed information on the
specific uses
of albuterol in the U.S. is
required. But two
important characteristics emerged from
our review
of the data on the pharmaceutical
industry in
general and on albuterol.
First, there is a complex
vertical
structure in the pharmaceutical industry
by which
products flow, generally, from
manufacturers, both
165
brand and generic, to patients. This is a
schematic to look at that structure and
we have
noted the data in percentages is
albuterol-specific
data.
As we saw this morning, approximately 84
percent of the albuterol MDIs--these are
units as
opposed to dollars--flows through the
retail sector
to patients. The remaining 16 percent flows
through either clinics, universities or
HMOs as a
group, non-federal hospitals or federal
facilities.
The retail sector, obviously, is very
important in
this regard.
Our second result has to do
with the usage
of albuterol over time. We examined data from IMS
covering the period 1992 to 2002, which
was the
last year for which we had data,
although,
subsequent to our submitting our report,
2003 data
are available.
We noticed stability of the
demand for
albuterol over time. Albuterol demand stayed
constant at approximately 50 million MDIs
per year
and that was even in the face of
increasing
population which is the red line at the
top of the
166
chart, and also in the face of generic
entry which
occurred in approximately 1996. The first generic
sales for albuterol appeared in the data
that we
looked at in January, 1996. So stable demand was
an important factor in our subsequent
analysis of
these issues.
To facilitate our analysis, we
made
several simplifying assumptions, as
economists like
to do, in order to make the analysis
tractable. We
assumed that there is a minimal, if any,
market
response to the FDA policy change. What this meant
for our analysis is that we assumed no
additional
samples, no manufacturer rebates to
government
programs above those legally mandated, no
market
entry beyond the two existing HFA MDI
products and
no discounts to other payers above
current levels
for the HFA MDI products. That is really a
manifestation of the last point which is
that there
was no additional price competition for
the HFD MDI
products than what had existed before or
what
exists currently.
Under these assumptions, we looked
at
167
several different perspectives. But I think, since
our concern was the patient, we will focus on that
first.
Under these assumptions, we calculate the
increase in cost to patient per MDI for
each of the
six channels of distribution that we
noted on the
vertical flow chart earlier.
Specifically, patients
obtaining albuterol
through the retail cash and the retail
private-insurance channels would
experience an
increase, in our analysis, of $8.61 per
MDI in the
first year after the policy change and
those people
going through the retail private-insurance
channel
would pay an increase of $10.57 per MDI,
respectively.
In the private-insurance
channel, the
effect was due to the increase in
copayment that a
patient would have to incur for a branded
product
versus a generic products. We had
data on average
copayments. Generic product through the
private-insurance channel has a copayment
of $10.00
and a branded product has an average
copayment of
$22.00.
Shifting to only branded HFA products
168
available, we assume the patient would
shift to the
higher copayment amount, hence the
increase in that
channel.
Now, going a step above to a
broader
perspective, looking at patients and
third-party
payers, assuming, again, that the volume
stays
constant at 50 million units, we estimate
that the
first-year increase in the price of
albuterol MDIs
for all payers, whether it be the patient
or a
third-party payer, and in all forms of
the product
prior to the policy change, there is HFA,
CFC,
brand and generic, so that is included in
our
pre-policy-change analysis.
The price would increase, in our
calculation, from $18.38 prior to the
policy change
per MDI to $28.25 after the policy
change. That is
the top line in this chart. That is a cost
increase, overall, of $9.87 per MDI. The patient
incurs $7.33 of that increase of $9.87
and the
third-party payer incurs an increase of
$2.54.
That is not uniform across all
third-party
payers but that is the average for all
third-party
169
payers here. If you remember the first charge,
that includes federal facilities,
hospitals--excuse
me; it includes the federal government as
well as
private insurance and other programs.
Looking at these data as a
daily increase
in cost, we see that it was a half a cent
per
capita or 4.4 cents per asthma and COPD
patient,
per diagnosed asthma and COPD
patient. Looking at
it in the first-year impact collectively,
this
translates to $1.69 per capita or $16.02
per
diagnosed asthma and COPD patient.
Based on the historical stable
market
demand for this product, the use of
albuterol as a
rescue medication and the relatively low
market
price for a prescription of albuterol
relative to
the average prescription product, in my
view, the
cost increases to patients and payers
that we
calculated are unlikely to have a
material effect
on the future use of albuterol MDIs.
By comparison, even with
branded product
only, we are talking about a prescription
price of
about $30.00. The average prescription price for a
170
branded price in 2003 was over $80.00, to
put this
in perspective.
Now, that was our quantitative
analysis.
We subsequently looked at other market
factors.
These other market factors, both current
and
expected, further ensure that no patient
will have
to forego albuterol MDIs. These other market
factors we have heard about already,
patient-assistance programs, those are
both public
and private. D.C. Healthcare Alliance is a public
patient-assistance program. Bridges to Access is a
private patient-assistance program.
There are patient discount
programs such
as GSK Orange Card and Together Rx. There is
better information about these
programs. We heard
about the Stakeholders website, the
PhRMA, the
trade association for the research-based
pharmaceutical industry has a
website. GSK has
promised 2 million additional samples in
the first
year alone.
We have heard about additional
competition
from IVAX, from Sepracor, from other 3M
licensees.
171
3M is willing to license the HFA
technology and
albuterol, itself, is not
patent-protected. We now
have also heard today about Medicare drug
coverage
beginning in 2006 to further benefit the
elderly
patient.
Another factor that is very
important in
the pharmaceutical industry is buyer
power; that is
the ability of certain buyers to move
market share
and to create competition among
sellers. If you
recall the period between the mid-'80s
and the
mid-'90s, Glaxo and Schering competed
with only
branded albuterol in CFC form. These companies
competed vigorously against each
other. Now, it is
up to the buyers to create that
competition again
if it is only Schering and Glaxo competing.
So, for a variety of reasons,
these
factors, together with our quantitative
analysis,
lead me to conclude that patients will
continue to
have access to albuterol after the FDA
designates
albuterol CFC MDIs nonessential.
Thank you very much.
DR. CHINCHILLI: Thank you, Mr. Rozek.
172
It is time for Speaker No. 7.
MR. DONIGER: Thank you very much for the
opportunity to talk to this panel. I am David
Doniger.
I represent the Natural Resources Defense
Council.
We have more than a half a million
members across the country dedicated to
protecting
public health and the earth's critical natural
systems.
I, personally, worked on
protecting the
ozone layer, phasing out the
ozone-depleting
chemicals and constructing and
implementing the
Montreal Protocol and the Clean Air Act
Provisions
for more than twenty years.
The Montreal Protocol is the
most
successful international environmental
agreement
ever.
Developed countries are way along the way to
completing the phase-out of CFCs. Basically the
use in inhalers is the last significant
use of CFCs
in this country. Developing countries are
beginning on their scheduled phase-out of
ozone-depleting chemicals, too. Many of them
actually have completed the phase-out as
well.
173
We are here because some uses
have been
deemed temporarily essential by the
protocol
parties and have not yet been
eliminated. But the
ozone layer continues to suffer from the
remaining
emissions of these substances. In 2003, the hole
in the Antarctic ozone layer grew to near
record
size so this program is not finished yet.
For close to a decade, the protocol
parties have been working to eliminate
the
remaining uses as they become
nonessential
including CFCs in albuterol MDIs. As you have
heard, other developed countries with
economies and
patients similar to our own, including
Australia,
Canada, Japan and many members of the
European
Union have already completed the
phase-out of these
products.
The United States has the
single greatest
use of ozone-destroying CFCs still
allowed. It is
our view that they are no longer truly
essential,
unnecessarily harmful to the ozone layer
and it is
now of the utmost importance to complete
the MDI
CFC albuterol phaseout as quickly as
possible.
174
Now, viewed individually, the
amount of
CFCs in these products may not appear to
be
significant compared to the general
phase-out of
CFCs, but the emissions of ozone-depleting
substances from all sources, no matter
how small,
must be viewed in a cumulative
manner. The
emissions are cumulative and long
lasting. The CFC
11 and 12 used in these products have atmospheric
lifetimes of 50 and 100 years
respectively.
Emissions of ozone-depleting
chemicals
anywhere in the world contribute to
depletion of
the ozone layer above the United
States. Thus, the
impact of FDA's decisions regarding the
phase-out
of CFC albuterol MDIs will go far beyond
just the
products used in the U.S. It will have a
significant impact both here and abroad
in
protecting the ozone layer.
There is a ripple effect
here. By
adhering to the letter and spirit of its
commitments under the protocol and
eliminating
these CFC uses as soon as they become
nonessential,
the United States sets an example for
other
175
nations--actually, I was going to say to
follow,
but other nations are ahead of us in
following.
But the opposite is also
true. Where the
U.S. drags its feet on the removal of
nonessential
CFC uses, it makes it easier for other
countries to
delay their phase-outs of other
chemicals, of other
uses, and we really do risk the
possibility that
the repair of the ozone layer will not
occur on
schedule if others, including our
country, drag
their feet.
The health effects of ozone
depletion are
serious.
There are serious increases in
skin-cancer rates, cataracts, suppression
of immune
systems and premature skin aging. The 2002
scientific association for ozone
depletion
estimated that, absent the controls
implemented
under the protocol, there would be nearly
a half
billion excess cases of skin cancer by
2040,
worldwide. But we have to keep at this and
complete the phase-out if we are going to
eliminate
the excess risk from depletion.
Somewhat ironically, ozone
depletion, by
176
CFC emissions from the MDIs may even
contribute to
the very problem the MDIs are intended to
treat.
Higher levels of U.V. radiation result
from
depletion and those exacerbate there
chemical
reactions that produce ground-level ozone
smog.
Smog is one of the things which compounds
the
problem of asthma and COPD impacting the
very
patients who rely on the MDIs.
There is also a potential
indirect effect
of an FDA delay to consider and that is
that there
may not be new CFC production available
after 2005
for this product. We know that the U.S.'s primary
source of drug quality CFCs in the
Netherlands will
be closed down under that government's
regulations
at the end of 2005.
In response to this shutdown,
Honeywell,
the producer in the Netherlands, has
proposed
shifting CFC production to its plant in
Baton
Rouge, Louisiana. However, producing CFCs that are
not currently produced at the Baton Rouge
plant,
including CFC 11 required for CFC
albuterol MDIs,
would violate U.S. law and the Montreal
Protocol.
177
It should also be expected that
the
protocol parties will not continue to
grant the
U.S. essential use authorizations for CFC
albuterol
MDIs, certainly not in the kinds of
volume which
have been granted in the past. For the first time
since the inception of the essential-use
exemption
more than a decade ago, the protocol's
expert panel
that reviews essential-use nominations
has
recommended only a conditional approval
of the U.S.
nomination for 2006, in large part due to
the fact
that 70 percent of the U.S. nomination
was for CFC
albuterol MDIs that other countries have
been able
to phase-out.
The way the Clean Air Act
works, if the
parties to the protocol do not authorize
the
production and consumption of CFCs for an
essential
use, then EPA may not authorize such
production or
consumption, and that includes import,
for this use
domestically.
Honeywell has stated that it
believes
that, by the end of 2005, the volume of
pharmaceutical-grade CFCs available from
the
178
Netherlands plan coupled with existing
CFC
inventories may be enough to satisfy the
U.S.
market until 2008, raising the question
of why
anything would need to be produced after
2005 with
the closing of that plant anyway. We are pursuing
that point with EPA.
But it is true that this stock
is a
limited, finite amount and, in our view,
it is
better directed, if used at all, at other
kinds of
MDIs, not albuterol MDIs, where the
reformulation
may be proceeding more slowly. In other words,
every kilogram that is used in a
nonessential
albuterol MDI is one less kilogram that
could be
used in higher-value products for which
the
substitutes are coming more slowly.
So, due to the impending
closure of the
plant in the Netherlands and the
likelihood that
the protocol parties will not continue to
grant
these exemptions, there is a very real
possibility
that CFCs will not be available for
albuterol
inhalers as long as FDA appears to be
assuming. I
think this is a key point. A policy based on a
179
false assumption of continued CFC supply
is
actually the one most dangerous for
patients
because the false assumption is slowing
the
transition to CFC-free products and, if
CFCs become
unavailable sooner than FDA is supposing,
patients
may be caught short.
The solution is to proceed
swiftly with
the
transition to CFC products declaring CFC MDIs
nonessential now, CFC albuterol MDIs
nonessential
now, and relying on the safe and
effective CFC-free
products to cover the needs of
patients. This can
be done as early as 2006.
So, to conclude, completing the
phase-out
of the CFC albuterol MDIs will have a
significant
positive impact on the environment, on
public
health generally, on the well-being of
asthma and
COPD patients specifically and delay will
have the
opposite effect.
For these reasons, the
committee should
support a finding that the CFC albuterol
MDIs are
no longer essential and should be removed
from the
market, we think, as soon as January 1 of
next
180
year.
Now, one final note. In nearly a quarter
century that I have been engaged on
working on this
issue, protecting the ozone layer, I have
heard
over and over again from industries and
certain
government agencies that it is infeasible
to
phase-out various uses of ozone-depleting
substances and that taking timely action
to protect
the ozone layer would destroy businesses,
cause
economies to collapse and even cause
elderly people
to die due to the lack of air
conditioners.
Invariably, these dire
predictions have
proved unfounded and dozens of uses of
ozone-depleting substances have been
phased out
successfully. Based on this historic perspective,
and not intending to minimize at all the
very real
health considerations for the patients at
issue
here ,I am confident that the phase-out
of CFC
albuterol MDIs can be completed this year
or next
without adverse consequences.
Thank you for the opportunity
to present
to you.
181
DR. CHINCHILLI: Thank you, Mr. Doniger.
Speaker No. 8.
DR. RAU: Thank you for the opportunity to
provide comments to the committee. My name is
Joseph Rau. I am Chair of Cardiopulmonary Care
Sciences at Georgia State University in
Atlanta and
I am speaking on behalf of the American
Association
for Respiratory Care, the AARC. I want to say at
the outside I have no financial interest
or
conflicts of interest with any of the
products that
are being deliberated upon today.
The AARC is the national
professional
association representing over 34,000
respiratory
therapists who provide care to patients
with
asthma, emphysema and other chronic
obstructive
pulmonary diseases. I have submitted a written
statement which offers more detail on the
brief
comments that I would like to offer
today.
The AARC support phasing out of
the use of
chlorofluorocarbon or CFC propellants for
aerosolized inhaled medications and, in
particular,
the removal of the essential-use
designation for
182
CFC albuterol metered-dose inhalers.
In addition, the AARC, however,
wants to
recommend monitoring the consequences of
such a
change on cost and patient
compliance. There is no
generic HFA albuterol and we have seen,
with data
presented today, that there is some price
difference between the HFA formulations
compared to
the currently available generic CFC
formulations.
The AARC, in general,
recommends an
approval process for new HFA formulation
new drug
applications that is as efficient and
expeditious
as possible to promote availability and
competitive
pricing of replacement drugs for
bronchodilators as
well as other drug classes. There is uncertainty
over pharmaceutical manufacturers
production of
non-CFC MDI bronchodilators and other
classes of
inhaled drugs.
The AARC believes that this
uncertainty
can be reduced or, perhaps, even
eliminated, if the
phase-out and replacement of CFC MDIs is
driven by
a planned transparent timeframe agreed to
by the
FDA and pharmaceutical manufacturers
rather than
183
dictated by the unavailability of
CFCs. In
particular, the AARC does support the
proposed
December, 2005 timeframe for the
phase-out of CFC
albuterol MDIs.
Thank you.
DR. CHINCHILLI: Thank you, Dr. Rau.
Speaker No. 9.
MS. FINDER: Hello.
My name is Jodi
Finder.
I am here as special counsel to the Asthma
Therapy Coalition. First, I would like to thank
the agency and this committee for the
opportunity
to present ATC's views this afternoon.
What we are not debating here
is that FDA
is an agency that is charged with
protecting
America's health. FDA is, therefore, unequivocally
obligated to make decisions about a
drug's
marketing status that are based on facts
and
economic realities.
If this transition is
inevitable and CFC
albuterol
MDIs must lose their essential-use
designation, then this transition away
from access
to affordable albuterol rescue inhalers
cannot
184
ignore the dire medical needs of the
population
that relies on them the most.
Asthma is on the rise in this
country, one
of the most chronic and fastest-growing
diseases in
America.
There were 20 million asthmatics in 2002.
In that same year, there were more than
1.9 million
ER visits that were attributable to this
chronic
condition. What is also not at issue here, in
addition to FDA's role, is that
bronchodilators are
an integral part of asthma management.
There has been a
disproportionate increase
of asthma prevalence in the poorest and
most
cost-sensitive segments of society. I think we
know who we are talking about here; the
uninsured,
the underinsured, the Medicaid
recipients, the
urban population--for example, inner-city
children--the elderly patients who are on
fixed
incomes, and minorities.
Another population that we
don't talk
about very often that hasn't really been
discussed
in this debate thus far is the rural
population.
The West Virginia Education and Prevention
Program
185
has done a study on this population that
has shown
that the prevalence rate in rural West
Virginia is
greater than the national rate and this
number is
growing.
For your reference, I have
included to the
committee an executive summary of that
study.
A recent Journal of the
American Medical
Association study that looked at chronic
conditions
including asthma reveals that increasing
copayments
can decrease prescription drug use up to
32 percent
and even more in some conditions. To give you a
sense of what the study included, it look
at
diabetes, arthritis, asthma, depression
and a few
other chronic conditions.
The medical and financial cost
of a
premature ban on CFC albuterol
metered-dose
inhalers would far exceed the
environmental
benefit.
We all know that generic CFC albuterol
MDIs retail for more than $20 less than
brand
alternatives. The agency and the committee don't
seem to be questioning this discrepancy.
The near-term removal of
generic
186
alternatives would raise treatment costs,
according
to conservative estimates, by $500
million annually
totalling approximately upward to $5
billion or
more until the time that HFA inhalers
come
off-patent and generic alternatives may
enter the
market.
In fact, FDA, though, has
actually said,
in the rule that was issued, the proposed
rule that
was issued yesterday, that this number
really is a
conservative estimate. FDA is now saying that this
number of $1 billion annually. Let me repeat that.
$1 billion we are looking at as the
increased cost
of taking these products off the market
prematurely.
In contrast to the cost here,
the
near-term environmental impacts are
negligible. It
will take fifty years for stratospheric
chlorine
loading to reach adequate levels to
improve the
environment. Even if all CFC albuterol MDIs were
eliminated this year, the environmental
benefit
would be insignificant.
Let me explain this in a little
greater
187
detail.
This graph shows the cumulative ODS
production. What you see here is actually over
approximately a 50-year period. But if you look
over approximately a 70-year period, you
will see
that ODS production totalled 23 million
ODP tons
worldwide.
If you look towards 2002, you see an
extreme downward trend from the peak year
in 1988.
The sum of all CFCs reported in 2002
equalled a
mere 3 percent of the total peak year
from 1988, so
what you are seeing, that small bar at
the end, is
3 percent of that large bar you are
seeing that
represents the peak year of 1988.
Less than 1 percent of the 2002
ozone-depleting-substance production is
attributable to U.S. CFC albuterol inhaler
production. What that means is, you look at that
little bar, less than 1 percent of that
small
bar--this would be an imperceptible line
on this
chart--is attributable to CFC albuterol
MDI
production in this country.
What this means is, if we look
at having a
188
reasonable transition here, if a
transition is
inevitable, and we are looking into the
next
decade, that approximately eight to ten
more years
of CFC albuterol MDI production in this
market
would amount to less than 0.01 million
ODP tons in
contrast to that 23 million you see
represented on
this bar chart.
What does this mean? A moment ago, I said
that it would take 50 years for the
environment to
reach a full recovery after taking ODS
products off
the market. So, what we are talking about in
allowing this reasonable transition and
in allowing
these cost-effective products to stay on
the market
until generic alternatives can enter the
market,
bring competition and keep prices down,
we are
going to delay that 50 years that it
already going
to take the environment to recover by a
matter of
days, if that much. We are talking about days, 50
year plus days.
What is not in question here is
that FDA
cannot undermine the Hatch-Waxman
Amendments. The
Hatch-Waxman, we all know, has
revolutionized the
189
normal life cycle of
pharmaceuticals. The
pharmaceutical market has come to
progress from
brand exclusivity, high dollars, towards
generic
competition, meaning affordable drugs,
not the
other way around.
Barring entry prematurely of
generic
alternatives for nearly a decade would
represent a
clear abrogation of FDA's clear mandate
to promote
affordability by promoting competition.
So what the Asthma Therapy
Coalition is
here to do today is ask the agency and
the
committee to consider some very important
questions
as it makes an ultimate decision here. First,
given the price sensitivity to
prescription drug
use, what will be the ripple effect
throughout the
healthcare system and is this acceptable?
We are looking at increased
hospitalizations, increased
emergency-room visits,
increased morbidity, increased mortality
rates.
Another question; which groups will be
most likely
affected and how can we prevent this
adverse
impact?
How successful, really, will the current
190
proposed government and/or private-sector
programs
be?
What direct environmental and patient benefits
are gained by eliminating CFC albuterol
MDIs before
generic alternatives may enter the
market?
Shouldn't the billions of dollars we are
talking
about here, that FDA is already talking
about, be
spent in more impactful areas such as
research and
development and prevention.
Again, thank you to the agency
and to the
Pulmonary-Allergy Advisory Committee for
this
opportunity to participate in the
rulemaking
process today. The Asthma Therapy Coalition would
be happy to serve as a resource
throughout this
rulemaking process.
DR. CHINCHILLI: Thank you very much.
Speaker No. 10.
DR. BERNHARDT: I am pleased to have the
opportunity today to address this meeting
and offer
considerations for planning the U.S.
program for
CFC propellants used in metered-dose
inhalers, or
MDIs.
I am Dr. Steven Bernhardt,
Global Director
191
of Regulatory Affairs for Honeywell
Chemicals.
Honeywell is a $23 billion diversified
technology
and manufacturing leader. We employ over 100,000
people and serve customers worldwide with
components, engines and related products
and
services for commercial airlines,
business and
regional aircraft and spacecraft,
automation and
control technologies for homes,
buildings, industry
sites and airports, turbochargers for
transportation systems and chemicals,
films,
advanced fibers and custom intermediates.
We are leading global producer
and
marketer of fluorine-based products
including both
CFCs and HFCs and, as such, are vitally
interested
in the proceedings and recommendations of
the FDA
regarding MDI propellants.
Honeywell is a supplier of
propellants for
MDIs manufacturers. We are committed to meet the
needs of our customers and patients in
this
critical life-saving application. We support to
orderly transition from the use of CFC
propellants
to non-ozone-depleting propellants such
as HFCs.
192
Honeywell has manufactured CFCs
for MDI
propellent applications in the U.S. and
in Europe.
In recognition of the expected gradual
decrease in
demand for CFCs as propellent for
products such as
albuterol, we are planning to rationalize
our
global manufacturer to a single site
located in
Louisiana.
Our plan is to continue
manufacturer of
CFCs to meet patient demand for this
choice of
product until such time as a transition
to HFCs has
proceeded to the point that continued
operation can
no longer be justified. Supply to meet market
needs can be from just-in-time CFC
manufacturer as
well as judicious use of inventory of
propellent as
preferred by our customers.
Our business plans call for us
to be a
supplier of CFCs, HFCs or both. It is vital that
FDA and the Aerosol Technical Options
Committee for
UNEP is aware that supply of both options
will be
available and shortage of supply ought
not to be a
consideration for your recommended
national
transition plan.
193
We welcome working closely with
both
organizations to provide you with the
necessary
assurance that we will continue to be a
partner who
you can rely on for the years to come to
support
this elected phase-out schedule.
I, again, thank you for this
opportunity
to communicate Honeywell's position on
the supply
situation.
DR. CHINCHILLI: Thank you very much, Dr.
Bernhardt.
Speaker No. 11.
MS. SANDER: Good afternoon. I am Nancy
Sander.
I am President and Founder of the Allergy
and Asthma Network Mothers of Asthmatics,
a
nonprofit patient and family-education
and advocacy
organization based right in the
neighborhood,
actually, just a few miles away so all
expenses
associated with this trip are donated by
me.
On behalf of the AANMA Board of
Directors
and more than 17 million Americans
diagnosed with
asthma, I want to thank you for the
opportunity to
be here and represent patient
perspectives.
194
AANMA takes the position that
the use of
chlorofluorocarbons as propellants in
albuterol
metered-dose inhalers no longer meets the
requirements for essential use under the
criteria
set for in the Code of Federal
Regulations.
This is a poster that I see
some of you
have picked up already but it is newly
published by
our organization in cooperation with the
American
College of Allergy Asthma and Immunology
with the
MARC emergency-care physicians as
well. This
poster was developed to help patients
identify the
medications that they were on when they
go to an
emergency room and they don't remember
the names of
what they are taking.
But it also helps me with a
presentation
today where, if you will notice that in
your top
left-hand corner, you will see, across
the top row
and then the two in the middle row, that
we have
albuterol bronchodilators. Prior to the
introduction of generic albuterol in
1996,
albuterol sulfate was only sold as
Ventolin and
Proventil. Today, patients use albuterol sulfate
195
sold in generic, Ventolin HFA and
Proventil HFA
formulations.
So, with the phase-out, and I
do mean
phase-out, of CFC-propelled albuterol
MDIs,
albuterol does not disappear. So we are very
confident about its availability. Will this
represent a threat to patients who no
longer have
access to generic or less-expensive MDI
bronchodilators? We think, actually, not,
especially after hearing the presentation
by IVAX
and by GlaxoSmithKline and by Schering
earlier
today.
Because, also, the transition takes place
over time. Inhalers don't go away one day as a
result of a calendar-day change. So, because it
takes place over time, manufacturers,
health
insurers, patients and their physicians
have time
to plan accordingly.
As an organization, we have
been helping
patients make this planning transition
for a number
of years and also make them aware of
various
patient-assistance programs that various
companies
have.
196
Of the remaining short-acting
inhaled
bronchodilators up here, that would be
Alupent,
Maxair, Autohaler, Atrovent and
Combivent. All of
them contain CFC propellent. According to everyone
today, they eventually go away as
well. I think we
can learn a lot about how transitions
happen by
paying close attention to what happens
with
albuterol.
The new drug application
submitted by
Sepracor for Xopenex and the discussions
from IVAX
earlier today are encouraging as well
because they
both utilize HFA propellants.
This brings me to one of my
favorite
subjects and that is, while the
pressurized
metered-dose inhaler is an absolutely
elegant
economic and portable device. It is also very
complex and user-dependent. Even experienced users
even have difficulty using the MDIs even
though
they have been taught numerous times.
The MDI is the only
FDA-approved
medication delivery system where a
patient cannot
reliably tell if they have medication left as they
197
continue to use it. There is no window. There is
no mark on the side that says,
"After this level,
you have no medication." There is no dose counter
or indicator. So there is no way to know when a
patient has reached 200 doses, if that is
the fill
capacity.
So it is not obvious at all when a
patient is running low or needs to get a
prescription refill.
The FDA and manufacturers say
that shake,
float and spray-testing techniques
commonly
employed by patients and their physicians
when
trying to determine or guess the amount
of
medication remaining inside of their MDI
are
unreliable. Float testing, where the MDI is dunked
in water, may actually damage the device.
There was research that showed
that
clearly 82 percent of patients use empty
MDIs. So
when parents send children with asthma to
school
each day, is the MDI full or empty and no
one can
say for sure. That is why the organization
continues to encourage manufacturers to
adopt FDA
guidance to industry and why we view that
MDI
198
transition presents the best opportunity
to
incorporate dose counting and
dose-indicator
technology and into new devices and HFA
devices.
Cost, access and education issues
will
never go away but they can be improved,
particularly in the underserved
population. We do
not support an essential-use exemption
for CFC
albuterol. We do, however, support a united front
with the FDA and with manufacturers and
health
insurers and other interested parties in
making
sure that patients make very smooth
transition
together.
Thank you very much.
DR. CHINCHILLI: Thank you, Ms. Sander.
Speaker No. 12.
DR. MARINELLI: Good afternoon. My name
is Dr. Anthony Marinelli. I am a member of the
American Thoracic Society Clinical
Practice
Committee and I am here to present the
views of the
American Thoracic Society, an
organization of
15,000 pulmonary-physician and other
health-professional members. I have no financial
199
relationships to disclose.
It is the position of the
American
Thoracic Society that the FDA should move
forward
quickly to delist CFC albuterol from the
essential-use category and prepare the
U.S.
marketplace for the elimination of CFC
albuterol.
There are four key reasons why
the ATS
supports delisting CFC albuterol from the
essential-use category. First, I think it is
important to keep in mind what is driving
this
process, the hole in the ozone layer. The fact
that there is a hole in the ozone layer
and that
the hole is caused by human
activity--namely, the
release of ozone-depleting substances--is
clearly
established.
The good news is that the steps taken so
far to reduce global use of
ozone-depleting gases
has helped reduce the size of the hole in
the ozone
layer.
So, what the global community has been
doing so far is working. The bad news is that the
hole is still there and it will not fully
repair
itself until further reductions in
ozone-depleting
200
emissions are made. Delisting CFC albuterol is an
essential step for the U.S. to take in
contributing
to the global effort to preserve the
ozone layer.
Second, the market is ready for
a
transition. There are two drug manufacturers who
have FDA approval to sell HFA albuterol
in the
United States and there is a third
manufacturer, as
we have heard today, expected to enter
the market
in 2005.
With three companies in the marketplace,
there is appropriate competition to keep
drug
prices in check and appropriate manufacturing
capacity to ensure that the U.S. market
will be
fully supplied with HFA albuterol. Delisting CFC
albuterol should cause no albuterol
supply
disruption in the United States.
Third, the transition provides
clinicians
a teachable moment to review and improve
asthma-care plans with their
patients. I use the
National Asthma Education and Prevention
Program
Guidelines for managing my patients with
asthma and
I encourage patients to know and avoid
their asthma
triggers, to use appropriate maintenance
201
medications to control asthma and to have
immediately available rescue medications
for acute
exacerbations.
Despite my best efforts, I know
many of my
patients rely too much on rescue
medications,
underutilize their maintenance
medications and
don't take the simple steps to reduce
exposure to
their asthma triggers. The switch from CFC to HFA
albuterol gives me an opportunity to,
again, teach
patients to know and avoid asthma
triggers and to
review the proper role of the many medications
needed to manage their asthma.
I think our goal in the
transition process
is use the switch as a teachable moment
to review
and hopefully improve the care of
patients with
asthma.
Delisting CFC albuterol will provide
clinicians and patients alike an
opportunity to
review and improve their asthma-care
plan.
Fourth, clinicians have
experience helping
patients get their medications. Several observers
have suggested that the United States
should not
delist CFC albuterol from the
essential-use
202
category because of the cost impact it
will have on
patients who use generic CFC albuterol.
It is true the price of HFA
albuterol will
be more than the generic CFC
albuterol. So, if the
FDA does delist CFC albuterol, the prices
for
albuterol will go up. Despite the cost proposed
and the increases that are inevitable in
medications and in virtually all aspects
of
healthcare, I am still able to provide,
and my
patients are still able to access,
high-quality
care.
The cost increase of albuterol
in
isolation from the rest of the healthcare
sector
cannot be used as justification for
slowing efforts
to reduce ozone-depleting gas
emissions. The U.S.
healthcare system will adjust. Clinicians have
experience in assisting patients get the
care that
they need. Physicians and their office staff walk
patients through the process of public
and private
assistance programs.
We use drug samples. We come up with
alternative drug sources. We work with or around
203
insurers to ensure patients get the care
they need.
For example, if I write a prescription
for a 90-day
supply of medicine instead of a 30-day
supply of
medicine, the yearly co-pay to that
patient will go
down.
While there will be cost
implications, the
delisting of CFC albuterol will not
increase access
barriers to therapy for patients with
asthma or
other lung-related diseases.
On behalf of the American
Thoracic
Society, I appreciate the opportunity to
present
our views. Thank you.
DR. CHINCHILLI: Thank you, Dr. Marinelli.
Speaker No. 13. I want to committee to
realize this is the last speaker.
DR. FINEGOLD: That is a great
introduction. Thank you.
DR. CHINCHILLI: I didn't want to detract.
I just wanted to get their attention.
DR. FINEGOLD: Well, thank you again for
allowing me to participate in this
meeting. I am
Dr. Ira Finegold. I am an allergist and I practice
204
in
New York City. I am also Chief of
Allergy at
St. Luke's Roosevelt Hospital in New
York. I run
the Allergy Clinic there and I am
Director of the
R.A. Cook Institute of Allergy.
I take care of asthmatic
patients who are
insured, pay out of pocket, and those who
are
covered by assistance programs. I am also a Past
President of the American College of
Allergy,
Asthma and Immunology. This is a professional
association of 4,000 allergists and
immunologists
dedicated to improving the quality of
patient care
through a research, advocacy and
professional and
public education.
I am also the College's
representative for
the last ten years to the U.S.
Stakeholders Group
who you are all very familiar with. I have no
financial disclosures of significance.
We believe--and that is the
College's
position--that eliminating CFC-containing
MDIs are
important for the ozone-layer recovery,
which you
have heard so much about, improving
patient
outcomes.
By that, we echo the previous speaker
205
regarding this as an opportunity to talk
to
patients about asthma and decrease,
actually, the
use of albuterol-containing rescue
medication and
increase appropriate therapies such as
inhaled
corticosteroids and, for allergic
patients with
asthma, allergy immunotherapy and, for
some
patients, anti-IgE therapy.
Also, we think outcomes do
improve because
some of the newer HFA products are
actually
superior devices and have less of the
shortcomings
of some of the earlier CFC-containing
metered-dose
inhalers.
Also, we feel it is important to protect
our patients to ensure a supply of rescue
medication for them.
That leads to the whole
question about the
CFC supply and, as I come away from what
I knew
before and what I hear today, one thing I
am
certain is that I am uncertain about the
supply.
This becomes important to patients so
that suddenly
CFC-containing medication doesn't
disappear without
an orderly transition or that some of
these other
products that so far are not making the
transition
206
to an HFA product still relying on CFCs
are still
available for patients such as Alupent,
Maxair, and
these drugs.
We think that the phase-out
date of
December 31, 2005 seems reasonable. From what we
hear today and what we knew before, we
believe the
manufacturers can meet the demand and
that, with
the two products already on the market,
that this
is an acceptable alternative with the
uncertainty
of the CFC supply that is another
imperative with
it and, given the fact that sooner or
later, CFCs
will disappear, we think we might as well
keep
moving this process forward.
However, even though we are in
agreement
with this process and have been since its
inception, we thoroughly recognize the
cost of the
transition cannot be ignored and, to some
extent,
it would seem that costs can be addressed
by the
competitive market by a certainty that
this will
occur with a given date so people will
move things
forward, and communication, informing our
patients
that rescue medication is not the whole
treatment
207
for asthma and that we need to use
controlling
medication.
In effect, what we want to see
is patients
who use one or two canisters per year as
opposed to
the patients who use one canister of a
metered-dose
inhaler of a fast-acting agent once a
month.
Thank you so much for allowing
me to make
these comments.
DR. CHINCHILLI: Thank you, Dr. Finegold.
And thank you to all the speakers during
the open
public hearing session.
Committee members, I would ask
that you
indulge me a little bit. I would like to deviate
from the agenda as we have it here. We are
scheduled for a break at 2:30. I would suggest
that we see if there are any questions of
the
speakers, if the committee members have
any
questions because I think we will need some
uninterrupted time to have our
discussion.
Before we do that, though, Ms.
Jain has a
statement that she needs to read.
MS. JAIN: I have a statement from the
208
Joint Council of Allergy, Asthma and
Immunology.
They submitted a written statement. However, they
were unable to send a
representative. So I am
going to read that to you. Each of you have a copy
in your folders as well.
"On behalf of the Joint
Council of
Allergy, Asthma and Immunology, JCAAI,
whose
mission is to act on behalf of the
specialty of
allergy-immunology and the patients it
serves, we
are writing to express our views on the
pending
issue regarding the possible removal of
the
essential-use designation of albuterol.
"While we support the
removal of CFC
products from the U.S. market, we are
very
concerned about the adverse impact that
removal of
CFC-propellent albuterol products from
the current
market would have on some of our patients
due to
cost issues.
"Currently, CFC-propellent
albuterol
products cost much less than the non-CFC
albuterol
products.
By our analysis, the CFC-containing
albuterol products cost, on average,
about $22
209
while, at the same time, the non-CFC
albuterol
costs almost double at about $44 per
inhaler.
"Removal of the CFC
albuterol will double
the costs of treatment for our
patients. The
consequences of such action will more
than likely
mean that some patients will forego their
prescribed drug-treatment plan that will
eventually
lead to increased overall health costs
through
increased asthma attacks, increased
emergency-room
visits and, perhaps, death.
"According to a new study
by the Agency
for Healthcare Research Quality, AHRQ,
May 18,
2004, increases in copayments for
prescription
drugs can lead to much costlier medical
programs as
asthma patients and others forego drugs
and see
their conditions worsen. This study found doubling
the out-of-pocket copayments patients are
required
to pay resulted in a decline in the use
of key
drugs used to control asthma.
"We hope that these factors
will be
considered as the committee deliberates
over this
important issue.
210
"Sincerely, Spenser
Atwater, M.D.,
President, JCAAI."
Thank you.
DR. CHINCHILLI: So, committee members, do
any of you have questions of our speakers
that we
have had, the ten speakers we have seen
this
afternoon? Dr. Schatz?
DR. SCHATZ: I had a question for Mr.
Rozek.
There has definitely been the concern
raised about cost but your analysis
actually tried
to present some data on that. I wanted to make
sure I understand what you were saying
that, given
your simplifying assumptions and assuming
no
mitigating factors, you estimated 50
million
canisters would increase in cost by $10 a
canister--that is, the total cost to the
healthcare
system, approximately, leading to an
increased cost
during that first year of $500 million.
I wanted to clarify if that is,
in fact,
what your findings showed.
DR. ROZEK: Yes.
We actually presented,
in our comments to the docket, that total
number.
211
I think it was $493 million,
exactly. But that is
to the entire healthcare system and that
was the
first-year impact.
DR. CHINCHILLI: Thank you.
Committee
members, any other questions? Okay; I have that it
is 1:55.
Let's take a fifteen-minute break.
Please be back at your seats by 2:10 and
then we
will have our discussion for the committee
members.
(Break.)
Committee Discussion
DR. CHINCHILLI: Committee members, you
have been asked to sit through lots of
presentations. You have absorbed lots of
information. Now it going to be your opportunity
to talk and discuss.
I would ask that you turn to
the last page
that is attached to your agenda because
that is
going to help us focus our
discussion. So I will
give everybody a minute until they are
with me.
MS. JAIN: It is attached to your agendas,
if you look on the last page of your
agenda, after
the rosters.
212
DR. CHINCHILLI: The FDA has listed three
issues for discussion. We will take them in order.
The first one, and I will read it for
everyone's
benefit, "Please discuss the extent
to which you
believe the criteria established in 21
CFR 2.125
for removal of a drug substance from the
list of
essential uses for CFCs have been met for
albuterol."
There are the four bullets with
the four
criteria, so let us discuss them. We will take
them one at a time. The first criterion is as
follows: "At least two
non-ozone-depleting
substances, non-ODS, that contain the
same active
moiety 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 ozone-depleting products."
So, is there any
discussion. Do any
committee members have any questions,
comments,
points of discussion, that they want to
make about
this particular criterion?
Dr. Moss.
213
DR. MOSS: I had a question for anybody
here from the open public hearing part of
it. It
says at least two, but it was raised
today that
there might be more than that. I think that would
be an important issue in terms of
cost. So I was
wondering if anybody from the IVAX people
or some
of the other companies here that can talk
about
where the other new drugs, not the
SmithKline or
Schering, are in terms of things and when
they
expect them to come to market? Or not?
DR. CHINCHILLI: Please identify yourself
and
your affiliation.
MR. FLANZRAICH: Hello.
Once again, my
name is Neil Flanzraich. I am the Vice Chairman
and President of IVAX. Just to repeat, in terms
of, in addition to the two present
products on the
market, IVAX has two NDAs currently pending
at the
FDA.
One is for an HFA formulation of albuterol in
a standard inhaler. The other is for an HFA
formulation of albuterol in our patented
breath-activated Easi-Breathe inhaler.
With respect to the standard
inhaler,
214
which we filed in January of '03, in
November of
'03, we had an approvable letter from the
FDA and
we have responded to it. So it is in the hands of
the agency. We filed our application, our NDA, for
Easi-Breathe in August of '03 and that is
also
pending at the FDA.
So we hope, within some
reasonable
timeframe, both those applications can be
approved
and we will have two HFA albuterol
products on the
market.
We are also informed, just having heard
what was said publicly by another
opportunity,
Sepracor, that they are also developing
an HFA
formulation of a closely related molecule
to
albuterol, another short-acting
beta-agonist.
So, presumably, that product--I
think it
is called Xopenex--in an MDI with an HFA
formulation will, at some point, be approaching
the
market.
I did make the point in my presentation
that one can wait for an indefinite
period of time
for a generic to come. IVAX is one of the leading
generic companies in the world. We chose to
address this market and we thought it
would
215
actually be a quicker route to the
marketplace with
an NDA, a new drug application. But that does not
mean that we will not be responsive to
the costs
and the issues in this marketplace.
We said, for example, that the
current
asthma product that we have on the U.S.
market, it
is an HFA formulation of a
corticosteroid. It is a
maintenance medicine called QVAR. It is the only
CFC-free corticosteroid, aerosol
corticosteroid, on
the U.S. market. We sell it at 50 percent of the
average prices of the other products on
the market
in that category.
We certainly would expect to
sell this at
a competitive price and something that
would
benefit the marketplace. Really, IVAX has had a
long history. I think we have a proven record of
being committed to making medicine
affordable. We
were the first generic of the very
product we are
talking about removing from the market
now, the CFC
albuterols. In that case, and in many others which
I could list, we like to think we have
contributed
to reducing billions of dollars from the
costs that
216
American consumers have to pay for
medicine.
We will certainly bring that
same
tradition and commitment to the HFA
albuterol
marketplace
DR. CHINCHILLI: Thank you.
MR. McVICKER: Hi. My
name is William
McVicker and I am from Sepracor. I just wanted to
confirm that our company has, indeed,
submitted an
NDA
for Leave Albuterol, an HFD MDI, within the
recent pass. The availability of that on the
market will obviously depend on the
review to go
forward from here.
DR. CHINCHILLI: Thank you very much.
Committee members, before we
start talking
more about the marketplace, that is
actually going
to be related to one of the other bullet
points.
Any further discussion or questions or
comments
about the first criterion, that at least
two
non-ozone-depleting substances, et
cetera, have are
available. Comments?
Questions? Yes; Dr. Schatz.
DR. SCHATZ: I think I would just make the
comment that no comments are probably
interpreted
217
to mean that we believe that those
criteria are
fulfilled. But I think maybe we better clarify
that.
DR. CHINCHILLI: Okay.
DR. SCHATZ: That we be my interpretation
of the "no comments."
DR. CHINCHILLI: Since our committee
members are so shy, are there any
committee members
who disagree with that statement? It doesn't
appear so. Now, we are not really voting; okay?
We are really just discussing and making
recommendations to the FDA. So, unlike other
advisory-committee meetings, we really
are not
taking person-by-person votes today.
So it looks like we can move on
from that
particular criterion. The second criterion was
that supplies and production capacity for
the
non-ODS products exists or will exist at
levels
sufficient to meet patient need. We heard this
morning and some this afternoon from
different
pharmaceutical representatives that they
can
ratchet up their production and think
that they can
218
meet the need for non-ODS MDIs in the
United
States.
Any comments, discussion,
questions from
the committee members about this
issue? Dr. Moss?
DR. MOSS: I will just reiterate what I
said before. It seems to me that it has been
well-explained that the companies could, within an
18-month period of time, increase their
production
to fulfill the marketplace.
DR. CHINCHILLI: Dr. Atkinson, you had a
question?
DR. ATKINSON: Yes. I
was just going to
add that if the FDA acts expeditiously to
set a
deadline for judging CFC-containing
albuterol MDIs
as nonessential, then that will
presumably set in
motion the events that these companies
need to ramp
up their production. So it is really kind of
dependent on what happens in the next
several weeks
or months.
DR. CHINCHILLI: Dr. Schatz?
DR. SCHATZ: I think that does bring up
the question that I probably would like
to hear
219
from the companies involved. In terms of the
timing of this, before we were led to
believe that,
from the final rule, essentially, until
implementation, companies would need 12
to 18
months.
I wonder whether that is still the concept
and is it closer to 18? I just sort of wanted to
be sure, I guess, I understood that
timeframe.
DR. CHINCHILLI: Any comments from one of
the company representatives?
DR. GARUTTI: Ron Garutti,
Schering-Plough. We did say that if the date were
somehow magically to be announced
tomorrow, we
could be ready as early as December 31,
2005. And
we believe that. For any date further out,
however, we think about an 18-month
timeframe is
the appropriate lead time.
Now, the industry and
Schering-Plough and
3M were kind of energized around this
issue right
now to do it. The longer this goes on, other
decisions may have to be made. Other commitments
may fall into place. So we are saying eighteen
months now but who knows what the
environment will
220
be if the date is not announced for
another two,
three years?
DR. CHINCHILLI: Thank you.
Comments from
any other company representatives?
MS. FLANZRAICH: Neil Flanzraich from
IVAX.
I just wanted to say that IVAX will be ready
on December 31 of 2005 to supply--as we
said, we
have a capacity that will be 50 to 60
million units
and we will be ready at that time. So, whether you
tell us now or you tell us a year before
or six
months before, we will be ready then.
DR. SCHATZ: Based on an approval of your
medication.
MR. FLANZRAICH: Currently, the products
are
not approved but we would have the capacity if
the products are approved.
DR. JONES: Elaine Jones, Vice President
of Glaxo.
It would take us six to twelve months to
ramp up to manufacture 15 billion
MDIs. It would
take us approximately twelve to eighteen
months to
ramp up to the total of 30 million
MDIs. So,
within eighteen months, starting from
now, we could
221
manufacture 30 million MDIs of the HFA
formulation.
DR. MARTINEZ: May I add another question?
That would also be true if, at any time
in the next
year, the decision is made. There is no other
alternative decision that the company
needs to make
that could change that?
DR. JONES: That's correct. We only would
make the decision point--it would take
us, say, six
to twelve for the 15 and twelve to
eighteen for the
30 million depending on, actually, when
that
decision point was made.
DR. CHINCHILLI: Thank you.
Yes; Dr.
Mitchell.
MR. MITCHELL: We have announced in the
Unified Agenda, which is a publicly
available
document published in the Federal
Register, that
currently we are planning to publish the
final rule
sometime in March of next year. That takes into
account the 60-day comment period, the
complexity
and sensitivity of the issue and the need
to
consult with our sister agencies on these
very
important issues.
222
DR. CHINCHILLI: Thank you.
Any other
comments on this particular criterion? Are the
committee members satisfied with
this? Okay.
Let's move on to the third
criterion--oh;
sorry.
DR. SCHATZ: I'm sorry.
I guess the only
thing I would say in response to that
last comment
is that if, in fact, the final rule is
published in
March and it calls for December of 2005,
which is a
nine-month lead, then I am a little
concerned from
what I have heard because that won't be
the twelve
to eighteen months.
Now, I realize maybe something
could start
now, but I guess I would question whether
that--is
that correct, that a final rule--do the
companies
think, or do other people believe, from
what you
are hearing, that if a final rule is
published in
March of 2005, that a December 2005 date
is too
early to have adequate supply?
DR. CHINCHILLI: Does the FDA want to
respond to that?
DR. MEYER: I think that is something that
223
we would like to hear a discussion
on. We have
heard the statements from the industry as
to what
their lead time needs to be. As Mr. Mitchell had
pointed out, we are talking today about a
situation
where we have just published a proposed
rule. We
will not be to the final rule until next
spring,
early-summer, range.
So December would be only then,
perhaps,
six, seven, eight, nine months at
most. We are
hearing from the companies that that may
be faster
than they could fully ramp up to
produce. I think
it is a difficulty at this point in time
to know
where in the mix the IVAX product may or
may not be
so that, obviously, the input from their
company is
a legitimate observation, perhaps, but,
as of
today, is speculation.
But I think it would be
important,
perhaps, if the committee shares your
concern to
hear a little bit of discussion about
that issue.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: I think that, together with
that, an additional issue needs to be
taken into
224
account which is that, if there is a rule
and it
says that, say, December 2005, the rule
will start
to take effect, producers of CFC products
will tend
to decrease the amount of their product
with time
and there could be even a period which is
not the
period between twelve or eighteen but
earlier
during which there will be less CFC
products and
not enough HFA products.
I am concerned that, because of
the issues
of the market, the FDA needs to take into
account
issues like the one I have said so that
patients
with asthma are not going to be left with
this
product which is essential and
life-saving.
DR. CHINCHILLI: Dr. Swenson.
DR. SWENSON: Just to the point of the
timing of this transition. It is not written in
stone that it has to be December,
2005. I think if
it were pushed back one year, that
wouldn't, in any
large way, go against the spirit of this
transition
simply to make for practical applications
and the
ability to make the transition more
smoothly. Am I
correct?
225
DR. MEYER: I guess with the one caveat
that we cannot necessarily predict what
the
response of the parties to the Montreal
Protocol
would be to, say, a December 31, 2006
timeframe.
Otherwise I would agree with your
statement.
With regard to what Dr.
Martinez just
said, I would state that the U.S.
nomination for
2005, which included a substantial
allotment of
CFCs for the production of albuterol, has
been
approved by the parties. So we don't have any
expectation at this point that there will
be a
shortage of CFCs for the production of
albuterol
through 2005.
So I can't definitively say
that there
wouldn't be some dropout in the market at
this
point but we at least expect that, as
long as it is
legal to sell these products, that the
manufacturers would do so.
DR. CHINCHILLI: Dr. Reiss?
DR. REISS: I would just like to know what
the factors are that lead to the March
date why
that date is March and not at an earlier
possible
226
timeframe given the concerns that Fernando
raised.
MR. MITCHELL: This is obviously a very
sensitive issue. So it is something we would need
time to consider. We are looking at a 60-day
comment period. We need time to evaluate those
comments. In response to the Advance Notice of
Proposed Rulemaking which we published
some years
ago to set up, start the regulatory
process, to
allow us to use essential uses.
We received over 10,000
comments. We
don't expect anything on that order of
magnitude,
but that is the thing that keeps me awake
at night.
Then, in addition to that, to
the inherent
sensitivity, this is an issue which we,
under the
Clean Air Act, we have to consult with
EPA because
it implements the Montreal Protocol. We consult
with the State Department. There is the Council in
Environmental Quality so it is a very
complicated
rulemaking procedure and it does take
time.
DR. MEYER: On the other hand, I did want
to point out that, under the Montreal
Protocol, we
do have to--they have called for us to
have a final
227
rule by the Open-Ended Working Group in
the summer
of 2005.
That date has not been set yet but it is
generally in June or July, mid-July.
DR. CHINCHILLI: Dr. Atkinson?
DR. ATKINSON: If I recall correctly, the
Shareholders Group proposed a possible
additional
amount of CFC-containing product to be
sold during
2006, I suppose, as a supplement. If there was a
shortage, if there was a shortfall, how
would
that--if limited supplies in sort of
quota fashion
could be available. Would that be possible from
the FDA's standpoint, I guess?
MR. MITCHELL: I mean, there are
difficulties with that. If this final rule goes
into place on the effective date, it will
be
illegal to sell, for any manufacturer to
sell, any
wholesaler to sell, any retailer to
dispense, these
drugs.
There is always the possibility
of
enforcement discretion by EPA but that is
something
I really can't comment on and, also, one
wonders
how many CFC MDIs would be produced when
those
228
manufacturers are looking at an effective
date. So
I am not sure how viable that sort of
option is.
DR. CHINCHILLI: Yes; Dr. Martinez?
DR. MARTINEZ: I expressed my concern in
the face of these uncertainties that we
are hearing
about.
I am not an economist, but I am sure that
companies that are producing CFC
products, in the
same way that they need time to ramp up,
they need
time to ramp down.
I am not so sure that they can
very
precisely calculate until December
31. Again, I
would need the help of an economist. How many of
these products are going to be sold and,
if they
work for profit as they should, they are
going to
be on the safe side than producing
excessively that
they have to throw away if it is going to
be
considered later a poison that cannot be
used.
So, at this point, my concern
is that
because needs to be done in a way that
the
transition occurs so that nobody is left
without
these products, which are life-saving, it
would be
very important to have guarantees that
the products
229
are going to be available and that that
transition
is going to be dealt with in a way that
the
patients are going to be covered.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: Can we have some of the
companies maybe talk about those
issues. I know
GSK doesn't make the CFC ones but maybe
Schering
can talk about how they were going to
deal with the
transition phase to make sure that
patients are not
without medications on December 25,
Christmas Day.
DR. GARUTTI: Thank you.
Ron Garutti,
Schering-Plough. So we are the largest supplier of
CFC albuterol inhalers. We are not going to walk
away from this patient population. As long as the
essential-use exemption remains in place,
we will
supply this product to the patients and
providers
who need them along with our HFA
product. So you
can be assured about that.
DR. CHINCHILLI: Dr. Meyer, did you have a
comment?
DR. MEYER: I was just going to point out
that I very much appreciate Dr.
Martinez's
230
concerns.
I think we certainly share those.
But,
to some degree, your concern is
irrespective of the
actual date that we are talking
about. Whether it
is tomorrow, whether it is ten years from
now, that
concern remains. I think it will entail the FDA
working with the industry as well as the
advocacy
groups to assure that there is good communication
and that the supply does remain adequate.
DR. MARTINEZ: Your point is very precise
and very good.
DR. CHINCHILLI: Dr. Schatz?
DR. SCHATZ: Dr. Meyer, you raised the
question as to whether, even if we or you
decide
that 2006 would be the better date, the
Montreal
Protocol decision makers may feel
differently. It
talks about criteria laid out by the
parties for
essential uses. Are those substantially different
than these four, because it would seem,
if they are
not and we believe that the supplies
won't be
adequate, then the fact that would come
to a
different conclusion seems less
likely. But maybe
if you could explain what differences
there might
231
be.
DR. MEYER: Let me answer that to the best
degree I can. Up until the very recent past, and
I, perhaps, didn't spend enough time on
this in my
slides, the Montreal Protocol very much
deferred to
the individual party to make the
determinations
within their own border, within their own
use, what
was essential and what was not.
Unless it seemed on its fact to be
nonsensical or against the Montreal
Protocol, those
were approved. Obviously, over time, there has
been a ratcheting up in terms of
decisions, in
terms of how closely the individual uses
are looked
at by the Protocol.
A lot of it now gets back to
the decision
IV/25 that we showed a few times where it
basically
says that if there are technically and
economically
feasible alternatives available, then the
use is no
longer essential. I think how that is interpreted
perhaps has changed a little bit with as
well.
So I think, depending on how
rigorous you
were in looking at what is a technically
and
232
economically feasible alternative, you
could say
that these are sufficiently stringent or
not
sufficiently stringent. I think that it is just
hard to predict at this point because it
has been a
little bit of a changing reality as far
as how the
Montreal Protocol has regarded the
nominations.
DR. CHINCHILLI: So, Dr. Meyer, if the
date were, say--went beyond December 31
of 2005,
would the Montreal Protocol and the other
participating countries have no real say
in what
happens in the United States but there
could be
some political fallout from delaying it
much beyond
December 31 of 2005.
DR. MEYER:
Let me just be very clear.
The reason I sort of raised this caveat
before
about the parties was just to make clear
that we
are not in control of all the variables
here, but
not to suggest, necessarily, that the parties
would
definitely find it unacceptable to go
beyond
December 31, 2005. I don't know, but I just wanted
to say that that is really something we
can't
determine as an agency.
233
In terms of what you just
asked, though,
if we were to get to a point where we
considered a
use essential and pressed on, despite the
Montreal
Protocol telling us that they no longer
considered
that an essential use, then that might
set up a
scenario where we would be producing CFCs
that they
had not authorized us to produce. If that
happened, we would be out of compliance
with the
Montreal Protocol, which I don't believe
we want to
do.
At least in principle, this is
a very--as
folks have said, this is a very
successful treat.
The United States has played an important
role in
the treaty and is committed to the
Montreal
Protocol.
So, certainly, the best path forward
would be one that meets our commitments
to patient
safety and access to important medicines
but, also,
meets our obligations under the Montreal
Protocol.
DR. CHINCHILLI: Dr. Lutter, did you have
a comment?
DR. LUTTER: No comment.
DR. CHINCHILLI: Dr. Martinez?
234
DR. MARTINEZ: Dr. Meyer, the decision,
and looking here at your Slide No. 12,
just as a
point of clarification; Decision IV-25
that you
showed to is that a plan could be
presented in
order to be in compliance with the
Montreal
Protocol and submitted by the Summer of
2005 for
the continued use of CFCs.
So it could be that, if we all
consider--and I am not saying that I am
proposing
that, but simply saying that if we would
consider
that since we cannot have the final rule
before
March that we could propose that this
date is not
December 31 but September, 2006. That could be
presented as part of Decision IV-25 to
the Montreal
Protocol and be within the stipulations
of the
protocol.
Am I right.
DR. MEYER: I think that is a correct
observation. Under that kind of scenario, I think
it would be quite reasonable for us to
point out
issues of ramping up production in meeting
the
critical need of patients. So I think that would
235
still meet the spirit of what was asked
for.
What is asked for in Decision
IV-25 is for
us to name a date-certain at which time
we will no
longer consider albuterol to be
essential. It
doesn't state to us what that date should
be.
DR. MARTINEZ: I think the spirit of the
committee, if I may say, is that sufficient
time
needs to be dedicated for us to be able
to assure
patients that this product will be
there. Thus, I
would say that a period of at least
eighteen months
from the moment in which a final rule
comes out
would need to be present for this to be
fulfilled.
DR. CHINCHILLI: Mr. Mitchell?
MR. MITCHELL: In looking at dates, I
think there are no finite legal limits to
the dates
the committee can look at or FDA can look
at.
Obviously, the longer in the future that
we are,
the more problems we might have with the
Montreal
Protocol.
But, in the Notice of Proposed
Rulemaking, our focus is basically we
talked about
dates between twelve months after
publication of
the final rule up to the end of this
decade.
236
So that is sort of range we are
focusing
on.
Obviously, people are free to comment, suggest
any dates--in the next century, but I
mean, how
much consideration they will be given is
another
question.
DR. CHINCHILLI: Dr. Reiss?
DR. REISS: Just the comment that you just
made, then, suggests that the end of 2005
data is
really not possible at this point given
the
12-month timeframe that you were just
alluding to.
MR. MITCHELL: No; quite the contrary.
Based on preliminary discussions we have
had
internally in FDA and externally, that is
the range
of dates we think are probably most
likely. But if
we are presented with data during the
comment
period, including the data that we have
heard
today, then there is nothing to stop us
from
finalizing a date that is any possible
date. I
mean, that was just suggested to try to
help guide
discussion or guide comments.
DR. CHINCHILLI: Dr. Jones, did you have a
comment?
237
DR. JONES: Elaine Jones, GlaxoSmithKline.
I just wanted to make one additional
comment. We
know that the data of the final rule is
obviously
something that would be that decision
point but, in
addition to that, I just wanted to say
that some
indication from the agency about what
date they
were considering, even without the
publication of
the final rule, would be sufficient for
us to
consider to ramp-up our manufacturing
processes.
MR. MITCHELL: That is very difficult for
us.
The only way we can speak on this issue is
through notice and comment rulemaking in
the final
rule.
I could give you a date this moment, but it
wouldn't be worth the paper it is not
written on.
So that is the way the Administrative
Procedure
Acts works and our hands are pretty much
tied.
DR. CHINCHILLI: Yes; Dr. Reiss?
DR. REISS: Along the same lines, I would
actually like to hear from my
colleagues. If a
date is published in March of next year
and then
the date that is published is the end of
2005, sort
of given what you have said today, or
given what
238
has been discussed about a year or
eighteen months,
how would everybody sort of deal with
that issue
right now? Would we start ramping up now or would
you wait until March?
DR. JONES: Elaine Jones, GlaxoSmithKline.
If the rule was published in March and it
was
December '05 timeline, as I say, we have
committed
to be able to produce 15 million MDIs within
six to
twelve months. It is not an impossibility to
produce 30 and it would require
considerable
investment on behalf of GSK, and
considerable time.
So it is something that we had not
discussed
previously and so can't give a definitive
answer.
But, obviously, if that is what
the agency
would like us to do, then it is certainly
something
that we would consider.
DR. GARUTTI: Ron Garutti,
Schering-Plough. I have a proposal for you. The
proposed rule, the rule that has been
distributed
outside today, is not yet published, as I
understand it. It is theoretically possible. You
will tell me why it is not
practical. You could
239
withhold that for a day or two or
three. There is
a lot of information. You have already a lot of
information from the major stakeholders
that could
lead one towards December 31, '05, as
being a
proposed date now subject to comment.
DR. CHINCHILLI: What is your reaction to
that?
MR. MITCHELL: Complete and utter dismay.
I, personally, started drafting this
thing in
August of last year. It will publish next week.
There is absolutely no realistic
possibility of us
being able to make significant revisions
to that
document, clearing it through our sister
agencies,
clearing it through OMB and getting it
published in
any sort of meaningful timeframe that
would allow
us to get a final rule published in time
for the
Open-Ended Working Group that meets next summer.
DR. CHINCHILLI: I think we expected that
response.
Dr. Kercsmar?
DR. KERCSMAR: I think what we are hearing
is that, in the absence of having a firm
date,
nothing will happen as far as increasing
production
240
from the current manufacturers of HFA
albuterol
right now. So I guess I just need somebody to tell
me that what I am hearing is that this
date is not
realistic, because I think what I am
hearing, the
corollary is that nothing will happen without
a
date and a date that is realistic.
MR. FLANZRAICH: Neil Flanzraich, again,
from IVAX. Again, with the very important
understanding that, of course, our
products are not
approved yet, I think I heard Glaxo say
that it
wasn't definitive that they would try to
accommodate even a shorter warning
period. We
certainly, with the hope and expectation
that our
products will come to the market, are
ready to
supply a very substantial part of the
U.S. market.
I am sure that Schering, even
though they
made a very good proposal just now, would
also try.
So I don't think you can assume that the
answer is
that there is no way that that date could
be met.
DR. MARTINEZ: But, with all due respect,
patients are not saved by trying. They are saved
with the medicine available. While you try, they
241
may die.
MR. FLANZRAICH: But I think what you will
get more definitive answers--people are
saying they
can't speak today, but you will hear,
between now
and the final proposal of the rule from
the
manufacturers, and they may be able to
accommodate
a shorter period of time. And then there will be
the kind of clarity that you need for the
patients.
So we should not rule out the possibility
of having
this come into effect by the December 31,
'05.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: I think it is important to
reiterate what Dr. Martinez said. I mean, if we
run out of these medications for patients,
they
will end up in the emergency room. There will be
increased morbidity and potentially
mortality. So
I think, in this situation--I think
everyone is
sort of saying the same thing, but we
should make
sure we are playing it safe, that there
is clearly
going to be the supply of medications for
these
patients so that we don't run into that
problem.
That would not be a good thing.
242
DR. MEYER: Dr. Moss, can I just
paraphrase what I think I heard you say
just so I
am clear for the record.
DR. MOSS: Absolutely.
DR. MEYER: To the degree that there is
uncertainty in setting a date when the
time comes
for us to do so, what you are saying is
that when
we face those uncertainties, we should
take a more
conservative approach in setting the date
that errs
on the side of patient safety over sort
of an
aggressive timetable in terms of the
environmental
considerations.
DR. MOSS: What I would say is that the
company said twelve to eighteen
months. You know,
if you thought twelve to eighteen months from
July
1, it fits perfectly for the 18-month
thing to
think that now, all of a sudden, we are
going to
rush things and speed things up and hope
it all
works.
I think there is a safety issue there.
So
I just wanted to note that.
DR. CHINCHILLI: Dr. Schatz?
DR. SCHATZ: Again, to be as specific as
243
possible, it sounds to me like the most
conservative and, I think, acceptable
approach
would be to plan no sooner than eighteen
months
from the final rule because we have a lot
of
assurances that everybody can get ready
by then.
Anything else sounds like it could be
just trying.
DR. CHINCHILLI: Dr. Meyer, I think you
have heard the committee's feelings on
this.
Any other final comment on this
criterion?
Okay.
Thank you. Let's move on to the
next one.
"Adequate U.S. postmarketing-use
data is available
for the non-ODS products." So, were the committee
members satisfied with what they heard
today in
terms of postmarketing data for non-ODS
products?
Any comments, questions? Is it related to their
previous criterion? You are satisfied we have
resolved this one?
Dr. Swenson?
DR. SWENSON: Just for the agency, we
really didn't see any data regarding the
safety and
the track record. Can you give us a brief
synopsis?
I suspect, because they have been out as
244
long as they have, they are probably
safe. But can
you tell us so from your data monitoring?
DR. MEYER: I think for the purposes of
the proposed rule, we really didn't
contest that
this was not the case. In other words, these
products have substantial worldwide
experience. We
have some postmarketing, formal
postmarketing data,
available, particularly for the EM
product as well
as some analyses for the GSK product.
At this point, the
postmarketing
experience that we have seen, both from
more formal
data and from the informal safety
reporting, is
that these products do not appear to be
substantially different from the CFC
products in
terms of how they perform. So we have not
expressed any concern in that regard.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: Does the agency have
information that will allow us to believe
that
puff-for-puff the two products are
equally
effective in producing bronchodilation?
DR. MEYER: The approval for these were
245
both based on comparisons to CFC products
as well
as--they stood on their own as far as
safety and
efficacy, showing of safety and efficacy,
but they
included programs where they were
directly compared
head-to-head with the CFC products.
Both in terms of the
pharmacodynamic
effect in FEV1 with one, two, four puffs,
that type
of consideration in sort of a short-term
study as
well in longer-term treatment studies, we
didn't
see any substantial differences. As was stated
earlier by one of the manufacturers, and
I forget
which one--I think it was
Schering-Plough--the
mouth feel of these can be somewhat
different. I
am sure individual patients may feel some
allegiance to one over the other.
But, in looking at those kinds
of reports,
we have a lot of reservations because I
remember
days when I worked for the V.A. and,
depending
on--back before there were generics
available, the
Ventolin source would shift from
seemingly quarter
to quarter. I know that those products were very,
very similar at that time, the Proventil
and the
246
Ventolin.
Veterans would come in saying,
"You know,
this one doesn't work as well as the one
you gave
me last month. I just doesn't." Unfortunately,
both asthma and COPD are diseases where
patients
get better and worse irrespective of the
specific
medicine.
But they want to tie it into something
so, if their medicine happened to be
changed at the
time they were feeling somewhat worse,
they blame
it on the medicine.
So we do get those kinds of
reports. But
all the data in the NDAs at this point
really
showed very comparable results both in
terms of the
pharmacodynamics as well as how they
looked in a
12-week study, treatment study.
DR. CHINCHILLI: Thank you.
Mr. Mitchell?
MR. MITCHELL: There is a study we cite in
the proposed rule. It was evaluating the vehicle
Evohaler, which is the HFA inhaler
marketed in the
U.K., which is very similar to, but not
quite
identical, to the Ventolin HFA
product. That
study, even given the differences in the
product,
247
does give us some assurance that we are
not looking
at any serious problems.
DR. CHINCHILLI: Any other comments on
this particular criterion? If not, we will move on
to the fourth one because I do believe we
will
spend some time on this. "Patients who medically
require the ODS product are adequately
served by
the non-ODS products containing the
active moiety
and other available products."
Remember, the FDA is
interpreting
"adequately served" to include
the economic issue.
So who would like to start with this
one? Dr.
Schatz?
DR. SCHATZ: I think Dr. Garutti pointed
out what I think we all believe, that
this isn't a
question of if, it is a question of
when. But that
"when," as in the proposed
rule, has a lot to say
in terms of the total cost of the
healthcare
system.
We have heard a lot of good
reasons to
make this transition as soon as possible,
but the
only thorn, as you could probably tell
from my
248
questioning, is the extra cost, which it
sounds to
me is at least $500 million a year. Yes; there are
some things that could raise it and some
things
that could lower it, but I think that
that is as
good an estimate as we could come to.
In a system that doesn't have
unlimited
resources, that is an important
consideration. So
that is going to be a problem, no matter
what to
some extent, but I just have to raise the
concern.
I would certainly like to spend that $500
million
on something other than albuterol.
But I think the only real
lesson is to
make sure that however this transition
occurs, we
do it in a way that tries to mitigate, as
much as
possible.
There are clearly some things that could
do that, that extra cost. But that is a very
disturbing number to me.
DR. CHINCHILLI: Dr. Swenson?
DR. SWENSON: I had some questions to Mr.
Rozek about the NERA study, if he is here. I think
he is coming to the microphone. I will go ahead
and start my question. On your slide that was
249
entitled "Overall Impact on Patients
and
Third-Party Payers in the First
Year," the final
figure you give in the first year,
increase in cost
per asthma or COPD patient is $16.00
which doesn't
sound that high.
But what I want to ask you is
that that is
a global average figure and the group
that we are
most concerned about is the
cost-sensitive--those
people that probably fall into the
underserved
category.
As I do my math here, I think
that if
there are 50 million MDIs prescribed in
the United
States per year and we say, for purposes
of just
simplicity, we have 20 million patients
using those
50 million, that comes out to about
two-and-a-half
canisters per year. Am I right on that?
DR. ROZEK: Yes.
In our calculation for
the $16.00, we used 20 million asthma
patients and
10 million COPD patients. So we added those
together and got about 30, or slightly
over 30,
million, total.
DR. SWENSON: So that figure of $16.00,
250
then, is calculated in that fashion. But I am
worried that those patients that may be
most
sensitive to transition here may be using
probably
one or maybe even more canisters per
month so that
the cost impact to them comes down quite
heavily at
maybe something around $100 per year.
Did you go into a breakdown on
those
costs?
DR. ROZEK: We looked at--to calculate
that particular number, we used the total
recalculated as a cost to the healthcare
system and
then the number of diagnosed asthma and
COPD
patients.
We, then, pointed out, though, that
there were other programs available to
ensure
access to people who might have
difficulty
affording one, two, three or four
canisters a year
such as the patient-assistance programs,
Together
Rx, GSK Orange Card, the public-assistance
programs
such as the D.C. Healthy Families, D.C.
Healthcare
Alliance.
The additional samples would be
available to people who would need
additional
canisters of the product as well.
251
So we felt that there
were--certainly what
we presented were average results and
that there
may be variation within that, some people
using one
canister, some people may be using three
or four.
For the people that couldn't afford three
or four,
there would be these patient-assistance
programs.
DR. SWENSON: Do you, or possibly the
companies, have any idea of the
effectiveness of
these assistance programs? Are they 80 percent
effective to the target groups?
DR. ROZEK: I think we heard today from
Glaxo in terms of the total number of
people that
have been helped with albuterol-specific
programs.
Glaxo has a relatively small share of the
total
albuterol being used today. I believe it is about
3 percent, and they were spending
significant
resources, or valuing the albuterol that
went
through their patient-assistance problem
quite
significantly for that 3 percent
marketshare that
they currently have.
Schering indicate they had a
similar
program.
I would assume that Glaxo would expand
252
its program as its marketshare expanded
and that
there would be more people who would be
aware of
the Glaxo program as a result of
information
available about the Glaxo product.
DR. SWENSON: While I have you up here,
just one more question, slightly
different, and
that is you made what appears to be a
very
conservative, maybe almost
worst-case, scenario
here because you simplified and didn't
assume any
changes in the outreach of the companies and
other
changes that they might do and the way
prices may
fluctuate.
Given that we might have maybe
two more
and possibly other players in this
market, what
number of companies competing really make
a
difference in price. There might be examples
within the pharmaceutical industry on
this issue or
maybe more broadly in the business
world. What
number of competitors really begins to
make a
difference on price? When does
competition really
come into play?
DR. ROZEK: That is an interesting
253
question that economists debate all the
time. Many
of the answers that relate to specific
industries--when I worked at the Federal
Trade
Commission, for example, there was a
study that one
of my colleagues there put out that we
used to use
in deciding when to bring merger
investigations.
It had to do with the strong third-firm
effect.
When you have a strong third
firm in the
marketplace, that was effective at
alleviating any
market power that the first two firms
might have.
So if you were looking at a merger of two
firms
that would create a strong third firm,
that was
considered to be a beneficial effect on
market
competition.
But, again, this is an
industry-specific
issue.
Interestingly enough, I did a study on
competition in the pharmaceutical
industry from the
following perspective. I looked at all of the
products that were identical
chemicals. Ventolin
and Proventil appeared in that list, if
you looked
at data from the late '80s and early
'90s.
Erythropoietin would be another example
of that
254
kind of competition where they were
identical
chemicals--no generics--identical
chemicals
marketed by the branded company.
You can see, when you have only
two, in
that particular case, you get a lot of
competition
for marketshare, for getting onto
formularies, for
disseminating information about the
product and
distinguishing the product one from the
other even
though they are the exact, same chemical
in terms
of what kinds of patient-assistance
programs are
available, what kinds of benefits you can
provide
to patients other than the drug, itself,
in terms
of registries for use of the product and
reminders
and that sort of thing.
So, in the pharmaceutical
industry, I did
do a study of competition between two
players when
it was the exact identical product and
there was no
threat of generic competition. You can see there
that marketshares move quickly back and
forth and
that prices do respond in a downward
direction when
the
two are there, assuming that you have enough
big buyers who can move marketshare and
can extract
255
that kind of gain.
Now, that is not to say that
the gain
flows to everybody from that type of
competition
because it does help to have a very
aggressive
buyer side of the market to gain
that. But I would
say generally a strong third firm is very
helpful.
If you look at the Department of
Justice-Federal
Trade Committee Merger Guidelines, they
like to see
about five equally sized firms in a
market. But
sometimes they will approve mergers with
four.
I think we are approaching, in
the case of
albuterol with Sepracor and with IVAX and
with the
availability of licensing opportunities
from 3M,
for example, to anyone who has an
albuterol product
they want to package in the HFA
technology, that
threat of competition, as well, adds to
the overall
competitive structure in the marketplace.
So two could be enough for
competition in
a pharmaceutical product, three for sure
and, if
you are going to four or five, you
wouldn't have
even any problem with the Federal Trade
Commission
or the Department of Justice, in my view,
saying
256
anything was amiss in that kind of a
market
structure.
DR. CHINCHILLI: Thank you, Dr.
Rozek, for
answering those questions. Further comments,
statements from the committee? Yes; Dr. Lutter?
DR. LUTTER: If I could offer one piece of
data in response to one of the questions
just
asked, we looked, as I described, at the
MEPS data,
the Medical Expenditure Panel
Survey. Among the
people surveyed, which is the
noninstitutionalized,
under 65, population, if you look further
at those
who have family incomes less than 400
percent of
the poverty line and who are either
uninsured or
who have non-group insurance, they had
3.8
prescription per year for albuterol MDIs.
DR. CHINCHILLI: Dr. Martinez, did you
have a comment?
DR. MARTINEZ: No.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: I have a question for some of
the companies. This is not the first country where
we talk about transitioning so this has
happened in
257
other countries. Realizing the healthcare systems
work differently, but what happened in
the prices
of the Proventil and Ventolin HFA in
other
countries where this has been
approved? Did their
prices go down? If so, why?
DR. CHINCHILLI: Anybody respond to that?
DR. JONES: Elaine Jones, GlaxoSmithKline.
As you said, actually, the pricing system
in the
European countries where we have done
this and also
in Australia and Canada are totally
different. So
the scenario can't be applied.
DR. MOSS: Good.
Now that I have you up
here, what is the price compared--if you
convert to
American dollars, how do these products
compare in
other countries compared to the United
States.
That is really what I wanted to get you
to say.
DR. JONES: Actually, I don't know the
price.
I don't know whether any of our commercial
colleagues here know the price of
Ventolin HFA
across Europe. I don't think we have that
information here, but we could--sorry; I
don't have
that information.
258
DR. CHINCHILLI: Any other questions,
comments, from the committee? Dr. Martinez.
DR. MARTINEZ: I think this is the issue.
For any practicing physician, this is the
issue
because, particularly for the
pediatrician, the
main group of patients that we see with
severe
asthma coming to our emergency rooms are
minority
patients who are either in poverty or are
disenfranchised or don't speak good
English or have
many of the other difficulties that make
them
particularly susceptible to severe
disease.
Thus, considering this very
attentively is
a need because our main objective is to
provide the
public with the best possible medicines
that we can
have at prices that are affordable and
that will
allow them, in this case, to survive
because this
could be a life-threatening disease.
The main concern I have is the
conflict in
which, in this case, is not a conflict of
interest
of but a conflict of care. We all care about the
earth and about the environment and we
all would
love for it to become better and better.
259
Certainly, there are many other ways, by
the way,
in which we could make it better, but I
know that
we are not discussing this here. We are discussing
this issue very specifically.
What we are asking the public,
and that is
the first point I wanted to make, is to
spend,
according to the proposed document that
Dr.
Mitchell has so clearly written, that, in
the best
possible scenario if the rule comes in 2006,
the
public will transfer to the
pharmaceutical industry
$6.9 billion between 2006 and 2015.
That will happen because, as a
society, we
have decided that we will take care of
the
environment. If that were the society as a whole,
the issue would be clear and simple. But my
opinion is that it is not. The reason why I say
that is that, although we have been given
means of
distributions of cost by patient, any
practicing
physician knows that these distributions
are so
tremendously skewed that, in this case,
the mean
has no meaning.
Most of the patients who really
spend most
260
of the money are a small group, perhaps
10 percent
of all patients with asthma, who spend
probably 80
percent of the cost. That is not only for
hospitalizations. It happens that those patients
are primarily poor, disenfranchised, and
not
participating in the system, not knowing
about the
system, no knowing about their rights.
I was telling about an
anecdote. Two or
three weeks ago, I was on call. A young girl who I
had followed for two years and not seen
for two
years came to the emergency room dying of
asthma.
When I asked the parents why is it that
the girl
was there, they said, well, we didn't
have money to
buy the inhalers and we didn't even have
money to
buy the albuterol. But you have the right. They
didn't know that they had the right.
Now, this is not going to
change from one
day to the next. So the difficulty when we take a
measure like this and when we do
something like
this is that we affect, or may affect,
significantly the lives of a lot of
people. That
needs to be considered because it is part
of our
261
everyday life in our practice.
I do understand, and I commend
them for
that, that industry has made significant
efforts to
palliate this by providing for free these
products
to
individuals and patients who will not have
access to these products. The difficulty is that,
in the same way that those patients don't
know of
the existence of these rights that they
may have in
many states, even if they don't have
insurance for
their children to have insurance, they
also don't
know about these systems and, thus,
cannot use
them, don't have the opportunity to use
them.
The greatest difficulty, then,
is that I
think this ruling, or this rule,
inevitably, by the
way in which our system is built, will
significantly affect the poor and the
disenfranchised and that, unless an
effort is made,
and I haven't heard of any systematic
effort to
ensure that this will be palliated in the
best
possible way, like it has been done with
other
measures that, as a society, we have
taken.
For example, for persons with
disabilities
262
now, we have a lot of things that are
going well
for them, certainly, they are not
enough. But
society, as a whole, is paying a price
for that
because, for example, at least in our
state,
businesses that put up ramps for people
who need
them and that are disabled can get a tax
cut, or
something of that sort.
I don't see any of those
measures being
thought about here and I am completely
convinced,
given my experience in my practice, that this
will
significantly affect the disenfranchised
and the
poor.
So, in the end, what we are
really doing
is, for the sake of the atmosphere which
will be
good for all of us, we are, once again,
charging
the disenfranchised and the poor. I don't know if
there is a solution for that because of
the way in
which our system is made, but, for a
practicing
physician, this is something that cannot
be denied.
It is true, as a representative
of the
American Thoracic Society said, and I
completely
agree with him, that many other costs are
263
increasing and that, in the end, we
cannot, every
time we make a decision, think about who
and whom
is going to be affected. But I think it is very
important for us to take all these issues
into
consideration.
DR. CHINCHILLI: Dr. Moss.
DR. MOSS: That is why I asked the
question about the marketing for these
programs
because I agree with you. I don't see them--you
know, the companies talk about hundreds
of
thousands of people but I don't know
about them and
I don't think a lot of people know about
them.
I think there are other
trickle-down
effects which is what I talked about
before where
only 6 percent of the medications are
prescribed in
the hospital. Everyone is worried about the retail
side of it, but there are indigent-care
hospitals
around the United States where they are
on the
means of falling apart. I mean, all these
hospitals--and there are huge financial
strains.
Maybe private practitioners outside of
Chicago can
deal with stuff, but those of us that
care for the
264
indigent-care patients, it is about to fall
apart.
It is cracking and crumbling.
States are not giving the money
back. The
pharmaceutical budgets are going up. Activated
protein series Agras is a good example of
that.
They were afraid that that one compound
might
destroy the entire Grady Hospital
system. It is a
$7,000 drug and it is very
expensive. Different
situation here. Not as expensive, but a much more
common disease.
So I agree. I think that is the bottom
line is the cost issue here and the
companies need
to address that. That is why I asked the question
in a round about way, how much do these
medications
cost in other countries. If they are less, why are
they less and how are the companies going
to deal
with this issue. I think everyone agrees that this
needs to be done, but the cost issue will
impact
patient care.
DR. CHINCHILLI: Any response from the
companies? We heard about some of your programs
this morning. Okay.
So committee members? Do you
265
have any specific recommendations to the
FDA in
proceeding forward with this, in terms of
the
economic issue, in terms of the problems
that the
poor and the indigent will encounter with
their
asthma because of this? Dr. Schatz?
DR. SCHATZ: The one thought that comes to
my mind is that the longer the transition
period,
presumably the more certain things might
happen in
terms of additional competitors,
additional
experience with what is going to
happen. I mean,
again, I think the concept of thinking of
some more
specific ideas and things that various
people,
including the companies, could do to
mitigate it is
important, too, but it does seem like
that the
longer the timeframe involve, the less
this impact
would be, not only because it becomes a
year or two
or three closer to generic, but other
market
factors as well.
So I guess that would be my
most immediate
thought.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: Not to sound too wishy-washy
266
here, but, on the flip side, I think it
is very
important that companies have made the
effort to
come up with environmentally friendly medications
and should be commended for that and
receive some
compensation for that. So I think that would be a
bad precedent to say that this stuff is
not
important to go through.
So, as I just said, the price is
an issue
but I think this has to be looked at a
little as an
issue longer term, that the message
should not be
given to pharmaceutical companies that
having
environmentally friendly strategies are
not felt to
be important.
DR. CHINCHILLI: Any other comments,
recommendations by the committee? Dr. Jones?
DR. JONES: Elaine Jones.
We talked a lot
about Bridges to Access as well as the
other
GlaxoSmithKline programs. We have endeavored to
reach everyone and we have done
considerable things
in order to be able to reach
everyone. We try.
Obviously, we haven't reached
everyone. You
haven't heard of some of the programs
that we have
267
done, but we are committed to actually
getting our
message to everyone and are willing to
work with
the agency in means to achieve this.
We have, currently, 435,000
patients
registered in the Bridges to Access
program which
actually gives free medicine to the
population that
you are speaking about. There is no ceiling to
that.
Any patient who is eligible will receive
medicine and they won't just receive one
medicine.
They will receive Ventolin or any
preventative
medicine as well if they are prescribed.
As I say, we will continue to
strive to
get the messages about GSK's programs to
everyone
and, as I said, we will work with the
agency, if
they have any ideas about how we can
expand and get
these messages across. We believe it is a very
valuable program.
DR. CHINCHILLI: Thank you.
Dr. Schatz?
DR. SCHATZ: Again, I don't want anything
to think that I also don't appreciate the
efforts
of the pharmaceutical-company industry in
trying to
respond to this, but, again, the cost
issue--but I
268
wanted to raise that there has been an
emphasis on
the people who would be eligible for the
Bridges to
Access and similar programs and that is
appropriate. This is clearly an impacted group.
But I take care of the working
patients in
an HMO and I can tell you that these
patients, who
would absolutely not be eligible for
this, are also
impacted when their co-pay goes from $10
for a
generic to $25 for a brand. We have had some
changes recently that we are hearing from
a lot of
patients.
These change make a difference also.
So, while I absolutely agree
that the
typically impacted may be more impacted,
this is
something that is going to affect, as the
whole
healthcare crisis is more and more, a
much bigger
segment of society, and I don't think we
can forget
that either.
DR. CHINCHILLI: That is a good point.
Dr. Reiss?
DR. REISS: I just wanted to point out
that, while everyone is raising really
good issues,
we are really not here to debate the
healthcare
269
system and how the healthcare system
works. We are
here to debate the merits of making this
transition
and its impact. A lot of the things that have been
raised really have to do with the form
and
structure of the healthcare system and
not
necessarily whether this is an
appropriate or
inappropriate thing to do.
DR. MARTINEZ: I respectfully disagree
because, if I read correctly, it says,
"Patients
who medically require the ODS product are
adequately served by non-ODS products
containing--," and one of the issues
that we have
been told that needs to be considered is
cost. We
are not discussing the healthcare system
here. We
are just reading very precisely what it
says here.
Here it says, very precisely, "If
they are going to
be adequately served by non-ODS products
containing
the active moiety."
Well, if they can't buy them,
they are not
being adequately served. So it is not an issue of
the healthcare system. My opinion is that a
significant number of patients are not
going to be
270
adequately served. I am not saying that what we
have to recommend or our opinion should
be that
this is not done. It is just very important for
those who make the decision to understand
that.
DR. CHINCHILLI: Dr. Schatz?
DR. SCHATZ: Again, I would just add that
what we are talking about is a change in
our
healthcare system, so we have to bring up
our
healthcare system. I don't think anyone that I
have heard has done it to discuss the
healthcare
system. It is how this change
makes an impact in
our healthcare system.
DR. JONES: Elaine Jones, GlaxoSmithKline.
I just wanted to make one additional
comment to the
previous comment. The current marketplace has no
samples in it, professional samples, or
very few
for albuterol CFC. GlaxoSmithKline has committed
to giving at least 2 million professional
samples
each year during the transition periods.
DR. CHINCHILLI: Dr. Meyer, and Dr.
Sullivan, you have heard some of the
discussion by
the committee members. Do you have any reactions,
271
any comments? This is a dilemma, this particular
issue, and we knew this would be the
thorniest
issue to deal with.
DR. MEYER: I would just say that I very
much appreciate the thoughts that we have
heard
expressed and I actually would also like
to
express, again, thanks to the people who are
making
public statements including the regulated
industry.
I think you understand our
dilemma in
proposing the rule and I think we will
get to
questions--or, not questions, but points,
subsequent here whether there is anything
else that
you think we could ask for or other
things that you
would suggest that we do to help us get
to a final
rule.
So we very much appreciate the
comments
and look forward to any suggestion you
might have
as to ways to sort of help get through
this
dilemma.
This is a very important issue.
DR. CHINCHILLI: Why don't we use that as
a segue, then, into Items, Issues, 2 and
3.
Committee members, please suggest any
additional
272
data or information you believe would be
important
to consider in making a determination
regarding the
essential-use status of albuterol. Also, please
comment on any additional issues you
believe would
be important to consider in making a
determination
regarding the essential-use status of
albuterol.
Is there anything we can
recommend to the
FDA, to the agency, about any additional
data or
information that might help them proceed
with this
decision?
Dr. Moss?
DR. MOSS: I don't know if it is
possible--it sounds like a lot of this
economic
stuff is based on a lot of assumptions,
but it
might be helpful to see how the economic
impact
would change if there is a third or
fourth drug
since, if that is not going to happen
right away,
that might happen down the road, and it
might lower
the burden of the economic impact which
would
address the issues that everyone has
raised here.
So I don't know how feasible
that is, or
how good the data is, but that might help
give
better information upon the effect of
cost. If the
273
cost goes down, then there would be more
access to
patients and the negative effects of not
having
access to medications would be alleviated
to some
extent.
DR. CHINCHILLI: Dr. Swenson?
DR. SWENSON: If I could ask the agency
members here, and, again, this may be
beyond your
powers and your charge, but, in going
before the
Montreal Protocol for these medical
exemptions,
have the issues, not so much of the
availability of
other products that are satisfactory and
equal but,
in fact, the issues of the cost
implication to
patients, been discussed? Do they turn a deaf ear
to these discussions?
I get the sense that we are
being pushed
to come to full compliance here and we
have such a
unique situation in the United States that,
in this
case, has the case been made to attempt
some, at
least prolongation of this transition to
allow for
the peculiar and unique nature of our
healthcare
system?
DR. MEYER: I certainly don't want to
274
characterize the Montreal Protocol, the
response of
either the body as a whole or individual
parties to
these kinds of considerations but, yes,
the issue
of the unique circumstances of the United
States
healthcare system and the impacts that
are more
significant in the United States, we
don't have
numbers to talk about here, but I can
assure you
that the differential we are talking
about here is
greater in the United States and the
overall cost
of these medications is greater in the
United
States than the other countries that have
been
referred to where the phase-out has
occurred for
albuterol.
Those issues have been presented and
argued to the meeting of the Montreal
Protocol.
DR. CHINCHILLI: Dr. Lutter?
DR. LUTTER: Let me offer another insight
in response to that same question. I was in
Nairobi last October, November, where
this most
recent decision by the Montreal Protocol
parties
was taken. At that time, the decision on the table
was what would be the date by which each
party
275
would have to set a date-certain to
delist.
But also on the table was a
proposal to
set a date-certain. We offered two explanations to
other parties in the Montreal
Protocol. One is
that we have an Administrative Procedures
Act. We
have a very different form of government
than a
parliamentary system that exists in other
countries. That lays forth a different process for
delisting that, necessarily, is more time
consuming
but also, of course, the economic one.
I think the sympathies were
mixed. Some
countries were much more attuned to the
idea that
the U.S. system is unusual if not unique
and others
view this is a problem that we would have
to solve.
So I am not sure I have
clarified the
understanding very much, but it was
brought up, it
was debated, and we had sort of a mixed
reaction.
DR. CHINCHILLI: Committee members, I
don't know if we are running out of steam
or we
just have nothing else to offer. This is complex.
Any other comments, recommendations,
questions?
DR. MARTINEZ: May I ask a question?
276
DR. CHINCHILLI: Sure.
I am begging for
questions.
DR. MARTINEZ: Members of Congress and
state legislatures and so forth are
considering the
possibility of opening the U.S. market to
importations of medicines from other
countries with
the idea that this could decrease costs
of these
medicines. In which way such a process would, or
will, affect--I am asking the agency--issues
regarding this particular medicine. This is from a
person who lives 60 miles from the border
and knows
how much these medicines cost in Nogales,
Arizona.
MR. MITCHELL: By the terms of our
regulations, we are really focussing on
products
that are approved in the United
States. We cannot
really consider prices or supplies of
drugs in
Canada, Mexico or any off-shore
sources. The
answer is no, we are not really looking
at those
sorts of issues in this process.
DR. CHINCHILLI: Dr. Schatz?
DR. SCHATZ: I mean, again, the only other
perspective or question--there are a lot
of things
277
we have heard about that theoretically
could
mitigate what we are all concerned about
but that
is nothing that can be written into a
rule, I would
guess.
We could all hope it happens.
So I think we do need to focus
on what
sorts of things this rule could do to
mitigate
this.
That is where I said that the only thing I
can think of is delaying it some. Again, I don't
like the idea that that doesn't reward
companies
that we should feel positive toward who
have taken
these steps towards something we all
eventually
want.
But I can't think of any other
way to
write this rule in a way that makes a
certainty
less of a financial impact. I would open that up
to other people because everything else,
while I
hope it happens and it could happen, it
is actually
nothing that I can think of that the rule
can do
anything about.
DR. CHINCHILLI: When we discussed the
issue of patient safety with one of the
previous
criteria, it is related to that, that
waiting, not
278
shooting for December 31, 2005 when the
announcement may not appear until March
of 2005,
there is an issue of concern about
patient safety
and enough inhalers being available. So I think,
yes; the two are tied together.
Yes; Ms. Schell?
MS. SCHELL: I guess I need a point of
clarification probably from the
companies. But if
this is inevitable that this will be
going to
happen but the date is unclear and it may
be
delayed, why can't you start production
eighteen
months anytime and still be ready for
whenever the
date appears?
DR. MEYER: I was going to answer on their
behalf, but I will let them answer.
DR. GARUTTI: Ron Garutti,
Schering-Plough. It is not in anybody's interest
for the industry to produce a great deal
of HFA
product that is not going to essentially
really be
used until the kind of behavior change
that we
alluded to, provider- and patient-wise,
has the
impact of, this is here, this is now,
this is
279
happening and everyone is focused on it.
It would not be to any of our
interests
for a product to be produced and run past
its
expiration and have to be destroyed.
MR. MITCHELL: Also, to reiterate a point
that was made earlier, the companies
would be
expending large amounts of capital in
order to get
this capacity on line. To ask them to spend that
capital and then not generate any revenue
with it
seems, just as a personal point, to be
somewhat
impractical.
DR. CHINCHILLI: Committee members, last
change.
Final comments, questions, issues?
Dr.
Reiss?
DR. REISS: Just one other point to follow
up on the questions about the economic
analyses
that we were talking about before. It might also
be helpful to do a more detailed economic
analysis
where we are talking about mean values,
and one
might be hidden within those mean values
and what
not, to be able to really sort of
understand who is
the real population at risk that might be
affected,
280
might shed and provide some additional
light on the
topic as a follow up.
DR. CHINCHILLI: Thank you.
Dr. Meyer, it
looks like the committee has exhausted
itself.
DR. MEYER: I am not sure whether there
were any other observations. We asked about data
and so on, but I guess the other thing is
you have
perhaps, or hopefully, had a chance to
read through
the proposed rule. You have certainly heard a lot
of presentations and discussion
today. Is there
anything else you think we are missing in
this? Is
there some other element that we need to
consider
that we, perhaps, haven't considered?
It is perfectly acceptable if
you don't
have any, but I just wanted to be clear
on that,
whether there is anything else we have
missed.
DR. CHINCHILLI: I guess not.
DR. MEYER: If not, then I would like to
certainly thank you all for your careful
deliberations today and for your
attendance, your
thoughts.
This, obviously, has been quite an
undertaking to get to this point and I
think we
281
will take very careful thought on our
part moving
forward.
We appreciate your adding to the
considerations that we need to take as we
do move
forward.
I would state that, apart from
this effort
with the albuterol, the transition to
non-CFC
products is actually, I think, by and
large, going
to be easier and more natural with some
of the
other products. We have already seen, as I have
pointed out in one of my slides, a fair
amount of
transition occurs already.
Albuterol is the only MDI for
which
generics are available. To date, it appears that
the HFA alternatives are priced quite
comparably to
the branded products that they
replace. I guess in
the case of QVAR, it might even be
somewhat lower
than the branded products.
So, where there is not generic
competition, where there is sort of
one-on-one
replacement by the same companies and so
on, a lot
of these issues go away. There will still be
occasions where we will come back to this
committee
282
for products that are not being
reformulated, as
mentioned this morning, and I suspect
epinephrine
will be a particularly interesting
discussion in
the not-too-distant future.
But, for the purposes of today,
I thank
you. I thank Dr. Chinchilli for serving as our
Acting Chair today and look forward to
future
discussions with the committee. Thank you.
MS. JAIN: Before the meeting is adjourned
and the committee members leave, if
anyone would
like to have their background information
mailed to
them, please just leave them at your
seats with
your name tag. We are happy to do that for you.
Thanks again to all of the open
public
hearing participants and the time that
they took to
do their detailed research, present and
submit
written and Powerpoint
presentations. Thank you.
DR. CHINCHILLI: Thank you, everyone. We
are adjourned.
(Whereupon, at 3:38 p.m., the
meeting was
adjourned.)
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