1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PULMONARY-ALLERGY DRUGS

ADVISORY COMMITTEE

Thursday, July 14, 2005

8:10 a.m.

Gaithersberg Hilton

The Ballrooms

620 Perry Parkway

Gaithersburg, Maryland

PARTICIPANTS

Erik R. Swenson, M.D., Chairman

Teresa Watkins, R.Ph., Executive Secretary

COMMITTEE MEMBERS

Mark L. Brantly, M.D.

Steven E. Gay, M.D., M.S.

Carolyn M. Kercsmar, M.D.

Fernando D. Martinez, M.D.

I. Marc Moss, M.D.

Lee S. Newman, M.D.

Calman P. Prussin, M.D.

Michael Schatz, M.D.

David A. Schoenfeld, Ph.D.

SGE CONSULTANTS (VOTING)

Karen Schell, RRT

SGE PATIENT REPRESENTATIVE (VOTING)

Nancy J. Sander, Virginia

FDA

Robert Meyer, M.D.

Badrul Chowdhury, M.D.

Eugene J. Sullivan, M.D., FCCP

C O N T E N T S

PAGE

Call to Order and Opening Remarks

Erik R. Swenson, M.D. 4

Introduction of Committee 4

Conflict of Interest Statement

Teresa A. Watkins, R.Ph. 6

FDA Introductory Remarks

Plaque Presentation

Robert Meyer, M.D. 11

FDA Presentation:

The Montreal Protocol and the Status

of Essential Use Process (21 CFR 2.125)

Robert Meyer, M.D. 12

Clarifying Questions 43

Open Public Hearing 64

Clarifying Questions 79

Committee Discussion 85

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. SWENSON: Good morning, everyone. I

am Erik Swenson, Professor of Medicine at the

University of Washington, and chairman of this

meeting of the Pulmonary-Allergy Drugs Advisory

Committee.

We are meeting today to discuss the

continued need for essential use designations of

several prescription drugs for the treatment of

asthma and chronic obstructive pulmonary disease

under 21 CFR 2.125. This is an issue surrounding

the use of CFC propellants in inhaled drugs for the

treatment of lung disease.

To begin with, I would like the members of

the panel to go around and introduce themselves and

where they are from. We will start with Dr. Meyer.

Introduction of Committee

DR. MEYER: Dr. Bob Meyer. I am the

Director of the Office of Drug Evaluation II in the

Center for Drugs, FDA.

DR. CHOWDHURY: I am Badrul Chowdhury,

Director, Division of Pulmonary and Allergy Drug

Products, FDA.

DR. SULLIVAN: My name is Gene Sullivan.

I am the Deputy Director of the Division of

Pulmonary and Allergy Drug Products.

DR. SCHOENFELD: David Schoenfeld. I am a

member of the Committee. I am a Professor of

Medicine and Biostatistics at Harvard.

MS. SANDER: I am Nancy Sander. I am

President and founder of the Allergy and Asthma

Network, Mothers of Asthmatics. I am here as a

patient advocate.

DR. PRUSSIN: I am Calman Prussin,

Clinical Investigator, Laboratory of Allergic

Diseases, National Institutes of Health.

DR. SCHATZ: Michael Schatz, an

allergist/immunologist from Kaiser Permanente, San

Diego.

MS. WATKINS: I am Teresa Watkins, the

Executive Secretary for this committee.

DR. GAY: Steven Gay, Assistant Professor

and Medical Director of Critical Care Support

Services, University of Michigan.

DR. MOSS: Marc Moss, Associate Professor

of Medicine, Emory University, Atlanta.

DR. NEWMAN: Lee Newman, Professor of

Medicine and Preventive Medicine Biometrics,

National Jewish Medical and Research Center, and

University of Colorado School of Medicine, Denver,

Colorado.

DR. BRANTLY: Mark Brantly, Professor of

Medicine, University of Florida.

DR. MARTINEZ: Fernando Martinez,

Professor of Pediatrics, University of Arizona in

Tucson.

DR. KERCSMAR: Carolyn Kercsmar, Professor

of Pediatrics, Rainbow Babies and Children's

Hospital, Case Medical School in Cleveland.

MS. SCHELL: Karen Schell. I am a

consumer representative. I am a respiratory

therapist from Emporia, Kansas.

Conflict of Interest Statement

MS. WATKINS: I will now read the Conflict

of Interest Statement.

The Food and Drug Administration is

convening today's meeting of the Pulmonary-Allergy

Drugs Advisory Committee under the authority of

Federal Advisory Committee Act of 1972. With the

exception of the industry rep, all members of the

Committee are special government employees or

regular federal employees from other agencies

subject to federal conflict of interest laws and

regulations.

FDA has determined that all members of

this advisory committee are in compliance with

federal ethics and conflict of interest laws

including, but not limited to, 18 U.S.C. 208 and 21

U.S.C. 355, Subsection (n)(4).

Under 18 U.S.C. Section 208, applicable to

all government agencies and 21 U.S.C. 355(n)(4)

applicable to FDA, Congress has authorized FDA to

grant waivers to special government employees who

have financial conflicts when it is determined that

the agency's need for a particular individual's

services outweighs his or her potential financial

conflict of interest.

Members who are special government

employees at today's meeting, including special

government employees appointed as temporary voting

members, have been screened for potential conflicts

of interest of their own, as well as those imputed

to them including those of their employer, spouse,

or minor child related to the discussions regarding

the continued need for the essential use

designations of prescription drugs for the

treatment of asthma and chronic obstructive

pulmonary disease under 21 CFR 2.125.

These interests may include investments,

consulting, expert witness testimony, contracts,

grants, credos, teaching, speaking, writing,

patents and royalties, and primary employment.

In accordance with 18 U.S.C. Section

208(b)(3), full waivers have been granted to the

following participants. Please note that all

interests are in firms that could be potentially

affected by today's discussion.

Dr. Carolyn Kercsmar, for activities on a

speakers bureau. She receives less than $10,001

per year for two grants which are valued at less

than $100,000 per year, and for a grant for which

the firm supplies products worth approximately less

than $100,000 per year. Dr. Kercsmar also owns

stock worth less than $5,001. A waiver under 18

U.S.C. 208(b)(3) is not required because the de

minimus exemption under 5 CFR 2640.202 applies.

Dr. Fernando Martinez, for his membership

on a speakers bureau. He has not lectured or

received remuneration for membership on the related

advisory board. He has not participated or received

any remuneration to date.

Dr. Michael Schatz, for activities on a

speakers bureau. He receives less than $10,001 per

year, and for a grant for which the firm supplies

the product worth approximately less than $100,000

per year.

Ms. Nancy Sander, for ownership of stock

currently valued between $25,001 and $50,000, and

for unrelated advisory board activities for which

she received less than $10,001 per year. Ms.

Sander also owns stock worth less than $5,001. A

waiver under 18 U.S.C. 203(b)(3) is not required

because the de minimus exemption under 5 CFR

2640.202 applies.

Dr. Steven Gay, for speakers bureau

activities with five firms, three of which he

receives less than $10,001 per firm per year, and

two of which he receives from $10,001 to $50,000

per firm per year.

We would also like to disclose that Dr.

Marc Moss' spouse owns stock worth less than

$5,001. A waiver under 18 U.S.C. 208(b)(3) is not

required because the de minimus exemption under 5

CFR 2640.202 applies.

A copy of the written waiver statements

may be obtained by submitting a written request to

the agency's Freedom of Information Office, Room

12A-30 of the Parklawn Building.

Lastly, the industry representative Dr.

Theodore Reiss was invited, but due to a family

emergency he was unable to attend today.

DR. SWENSON: Dr. Robert Meyer of the FDA

will give us some introductory remarks.

FDA Introductory Remarks

Plaque Presentation

DR. MEYER: Thank you very much.

Before proceeding with the formal part of

today's agenda, I did want to take a moment out for

I think a very nice activity, which was that Ms.

Schell, Karen Schell, has served our committee now

for four years, actually officially from November

2001 through May 2005. We have continued to call

on her services in a special government employee

role for this meeting, and I think a meeting just a

few weeks ago, as well.

But she has served for these four years as

the consumer representative, which is a very

important role to these committees, where she

brings the patient perspective, which I think she

has done admirably.

Her background is, as she said earlier, as

a respiratory therapist in Emporia, Kansas, and she

has got a very broad background in respiratory

therapy including being a registered

polysomnographist and also has certification in

disease management of asthma, so she is very well

qualified for representing the concerns of

patients, and we have really benefited from having

her on the committee.

In recognition of that, we would like to

present her with this plaque and I will walk over

and do so.

[Applause.]

FDA Presentation

The Montreal Protocol and the Status of

Essential Use Process (21 CFR 2.125)

DR. MEYER: I would like to extend my

thanks again in advance to the committee for being

here. This will be a very different session from

yesterday and, indeed, a very different session I

think from most every advisory committee I have

ever been involved in, because this is not really

asking you your opinion of data, but it is really

calling on your expertise as practitioners to let

us know whether some of the remaining medicines

that are listed as essential uses are indeed

essential uses under certain criteria that I will

discuss shortly.

[Slide.]

I realized in black and white that this

depiction of the earth's ozone layer over the

Antarctic was a little bit of a Rorschach test.

People were asking me why I was placing a picture

of eyeballs or tracheas or other things in the

document, but that is indeed the ozone hole over

the Antarctic taken by one of NASA's environmental

satellites.

I think it serves as background to the

reason we are here today, which is the very serious

environmental issue of the thinning of the ozone

layer.

So, during this talk, I would like to

briefly touch on some ozone science. I am not an

ozone scientist, but I will briefly touch on that

as a prelude to talking about the Montreal

Protocol, which is the international treaty that is

in place to deal with the preservation of the ozone

layer and hopefully, the restoration of the ozone

layer, and also the FDA regulations and the U.S.

laws pertaining to these. This will all serve as

background to the discussion that we hope will

ensue from that.

Just to start off with the general

background on the ozone science, the ozone layer,

as it is called, is actually a region of relatively

higher ozone concentration in the stratosphere.

On this graphic that is depicted here, we

have ozone amounts in parts, I think it is actually

in pressure, milliPascals, and on the y axis we

have altitude in kilometers. You can see other

than a blip in what is really a smog ozone, which

is, as asthma doctors well know, a bad thing down

in the troposphere where we live. Otherwise, the

ozone is fairly limited in terms of its

representation in the environment until you get to

the stratosphere, which begins at about 15

kilometers high and reaches a peak just at about 24

kilometers or about 16 miles up.

[Slide.]

This layer, as it is called, reduces the

amount of ultraviolet radiation, UV-B in

particular, reaching the surface of the earth from

sunlight.

As a result of loss of ozone from this

layer in recent times, there has been an increase

in the UV-B radiation that reaches the earth, and

that has resulted in numerous health consequences,

perhaps the most important of which are skin

cancers, both melanoma and non-melanoma types, as

well as other consequences, such as increase in

cataracts. There is actually data that show that

this increase in UV-B can lead to impaired

immunity.

Besides the human consequences, there are

other deleterious effects on the environment, as

well, on animals, on flora and fauna of all types,

and actually, on non-biologic materials, as well,

like plastics in dashboards, and so on.

So, this protection from the UV-B

radiation that the ozone layer affords us is

important.

[Slide.]

Now, because the development of the U.S.

laws, FDA regulations, and indeed the Montreal

Protocol itself have proceeded in overlapping

timeframes, when I continue this talk, I will

overlap these discussions and go back and forth to

do this in as time-related fashion as I can.

[Slide.]

In 1974, there was a paper published in

Nature by Molina and Rowland that was the first

paper to tie the depletion of ozone, which had been

recently detected and defined, to stratospheric

chlorine from degraded CFCs, so these are the first

scientists to put together the fact that the

emission of CFCs could lead to this phenomenon.

At that time, CFCs were very widespread in

use in the United States. They were used, for

instance, in refrigerators, both in terms of the

coolant itself, as well as the foam insulation in

air conditioners in cars and homes, and other

chillers, foams, and in many consumer and medical

aerosol products. So, they were ubiquitous in use

at that time.

CFCs have many wonderful properties. They

are incredibly inert and very stable, which in some

respects is their downfall in the ozone, because as

they migrate up to the stratosphere, their

half-life up in the stratosphere is measured in

decades.

[Slide.]

Now, very shortly in government time,

after the science was published by Rowland and

Molina--which I forgot to mention did receive a

subsequent Nobel Prize--very shortly after that

work was published, in response to the growing

evidence of CFCs harming the ozone layer, CFCs were

generally banned in spray cans and aerosols by the

U.S. Government. That was through actions of the

EPA.

So, since 1978, consumer aerosols, such as

hairsprays and spray paint, and other such

aerosols, bug sprays, have not contained CFCs, so

they have actually been gone from such products for

nearly 30 years.

At that same time period, FDA first

published our regulation, which is 21 CFR, this is

our chapter of the Code of Federal Regulations, and

the specific citation for that is 2.125, and that

also banned the use of CFCs in FDA regulated

products including drug products, but did allow for

essential exemptions.

[Slide.]

Now, we skip forward to 1987, and at that

time 27 nations, including the United States,

initiated a global ozone treaty in Montreal,

Canada, and that has subsequently been known as the

"Montreal Protocol on Substances that Deplete the

Ozone Layer," and I will call it from now on in the

talk as the "MP."

That original protocol has grown in terms

of the number of signatory parties, and it now has

well over 180 signatory parties to the original

protocol and is regarded as one of the role models

or models of successful environmental treaties.

There have been some recent bumps in the

road, but this has really been a very successful

effort and has led to the near elimination of CFCs

from the developed world.

[Slide.]

When original written, the phase-out of

CFCs was slated for 2000. It was actually decided

in London in 1990, but that was moved up to the end

of 1995, so that phase-out in the developed

countries was targeted for January of 1996 at a

meeting in Copenhagen, because there was increasing

evidence at that time of ozone depletion,

particularly over the Antarctic, as I showed you in

the opening slide. This has been known ever since

as the ozone "hole," but it is really a relatively

dramatic thinning of that ozone layer in the

stratosphere.

Now, it is important to point out, though,

that while there is a lot of attention paid to this

ozone hole over the Antarctic, the depletion is

prominent over a lot of the southern hemisphere,

Australia, for instance, is quite affected by this

ozone hole, and, in fact, I believe there is a law

in Australia now that schoolchildren on recess need

to wear hats, so this is not a trivial issue, and

the depletion besides being prominent in the

southern hemisphere, is global.

The other thing I should point out that

although we are here to talk about

chlorofluorocarbons because of their role as

propellants in many important asthma and COPD

medications, the Montreal Protocol controls many

ozone-depleting substances, and there are many

others other than CFCs, such as halons, HCFCs,

methyl bromide, and carbon tetrachloride.

[Slide.]

With regard to CFCs, however, as of

January 1, 1996, all use of CFCs has been banned in

industrialized countries and is targeted for this

ban to go into place in the rest of the world in

2010, so just in another five years.

MDIs for asthma and COPD currently--and I

underline that for a reason--are exempted from

essential use processes. There has been an

essential use process in place since January 1,

1996, but it was always the intent of the Montreal

Protocol that this be a temporary process and that

all such uses would be phased out over time.

Nominations for essential uses in

medications are reviewed annually and generally,

they are reviewed two years in advance, so, in

other words, in 2005, the parties would ordinarily

be reviewing 2007 nominations. In fact they are. I

put the word "ordinarily" in there because there

are some issues with that this year, that are not

germane to today's discussion, but we are doing

everything really in anticipation of two years down

the road, and that is to allow the countries that

make these nominations to go through their own

processes of then taking what is allotted to them

and allocating it out and making sure it gets to

the products that they have deemed essential.

[Slide.]

Now, the Montreal Protocol has a number of

stipulations that are worth me highlighting for

you, and let me just talk a little bit about the

designation here. When it says Decision IV/25, the

IV refers to the fourth meeting of the parties, and

the 25 means that it was the 25th decision taken

there.

To draw an analogy, if the Montreal

Protocol was a law, these decisions would be like a

regulation, so they don't really amend the

protocol, but they basically help interpret the

protocol.

So, the Decision IV/25 stated that all

essential uses of CFCs should be based on products

being necessary for public health without adequate

alternatives, and they defined adequate as either

technically adequate or economically adequate.

This determination at that time was really

viewed macroscopically, in other words, you could

make the determination here that all CFCs and MDIs

for asthma and COPD could be considered essential.

You weren't saying albuterol versus beclomethasone,

and so on. It was that the use of CFCs broadly in

MDIs for asthma and COPD were considered essential.

But again that was fairly early on in the Montreal

Protocol being at the fourth meeting of the

parties.

[Slide.]

Decision XII/2 stated that any product

approved after December 2000 must individually meet

these criteria under IV/25, so, in other words,

this really took it from the macroscopic to the

microscopic, so any new product at that point must

meet the criteria of having no technically or

economically feasible alternatives to have that

essential role in the treatment of society or in

society.

This product-centered determination of

essentiality really precluded new CFC generics or

other new CFC products because of this high hurdle.

[Slide.]

Decision XV/5 stated that essential use

nominations are now specific. In the past, a

party, such as the United States, would go and say

we need 2,000 tons for our essential uses. Now, we

have to say we need 2,000 tons and of that 2,000

tons, 1,000 tons will be for albuterol, for

instance, and those numbers are not meant to be

accurate, they are just meant to be representative

or used as an example.

This decision also said no quantity of

essential use CFCs will be authorized for albuterol

specifically beginning with 2005's meeting of the

party unless a plan was in place for the phase-out

of albuterol and submitted to the Open-Ended

Working Group. This is an earlier working meeting

of the parties by the summer of 2005.

I would just point out that the FDA final

rule published earlier this year on the phase-out

of albuterol, which stated that we will consider

albuterol no longer to be essential in the United

States after December 31st, 2008. We regard this

final rule as meeting this stipulation for the U.S.

[Slide.]

In response to the Montreal Protocol and

the U.S. signing of that protocol back in the late

'80s, the Clean Air Act Amendments included changes

to the Clean Air Act that essentially implemented

the Montreal Protocol into U.S. law.

The EPA regulations that then implemented

the amendment to the Clean Air Act refer to the

Health and Human Services and FDA through citing

our specific regulation of essentiality for

determining medical essentiality. Again, this

rule, 2.125 was published before the Montreal

Protocol and, in fact, before we really had much

experience with the phase-out or even the prospects

of the phase-out since it was published in 1978.

[Slide.]

Now, at the time that that rule was

published, it stated that CFC-containing products

would be misbranded or adulterated, in other words,

illegal under the Food, Drug, and Cosmetic Act

unless deemed essential, and the determination for

"essential" use under that rule was that there was

there was not technically feasible alternatives

available, that the product provided substantial

benefit, be it health, public, or environmental,

and that the release of CFCs from the product was

small or justified given this important benefit.

[Slide.]

Importantly, that rule, when it was

promulgated, had no mechanism to determine when

uses were no longer essential, so it had ways to

add to the list, but it had no way to determine

when products were no longer essential and then to

take them off the essential use list.

The other thing that was notable about it

is most important drugs were not listed as separate

entities, but they were actually listed in very

broad classes, such as there was a class of

adrenergic bronchodilators for human use that

included albuterol, pirbuterol, salmeterol, and so

on, so things were not individually listed.

Although there was some individual listing, many

things were put into broad therapeutic classes.

So, to deal with both of these issues, in

1996, FDA published an Advanced Notice of Proposed

Rulemaking, so the very early stages or rulemaking

to revise 2.125.

[Slide.]

That publication led to a very large

number of public comments. We had close to 10,000

public comments, which to folks not perhaps

involved in regulations may not have sort of a

goalpost to measure it by, but this is a large

number of comments. Many of these were sparked by

lobbying efforts of concerned entities.

In 1999, taking several years to consider

carefully all the comments that we received and the

changes in the Montreal Protocol and other factors,

FDA published a Notice of Proposed Rulemaking,

which is the first formal step in rulemaking.

That Notice resulted in far fewer

substantive comments and much less controversy than

the original action in 1996. So, we were able to

complete a final rule, revising 2.125, in July of

2002, and that rule went into effect in 2003.

[Slide.]

Just to highlight some of the revisions,

then, one of the things that this rule did was it

listed individual moieties as essential uses rather

than classes, so, for instance, I had mentioned

earlier that albuterol was under the class of

adrenergic bronchodilators for human use, was taken

out and listed separately within the essential use

list under Part (e) here of 2.125.

One of the reasons we did this was because

in 1996, when we published the Advanced Notice of

Proposed Rulemaking, one of the things we said was

that it made sense to us, or at least we wanted to

float the idea that you could do this two ways.

You could say, okay, albuterol will only

be considered in and of itself, and after there are

adequate alternatives, then, we could say albuterol

CFC is no longer essential.

On the other hand, you could do what is

called a therapeutic class determination and say if

you took the inhaled corticosteroids, for instance,

you could say, well, if we had two or three inhaled

corticosteroids with adequate alternatives, we

might say all the rest are no longer essential, and

that would a therapeutic class approach.

The attraction to such an approach is that

it allows products that are not being reformulated

to be dealt with if they are in that therapeutic

class, but the public comments were very strong

against the therapeutic class approach, and in

response to that, we no longer had a therapeutic

class approach as 2.125 came to finalization.

So, it was important then to list every

moiety separately, and I will get back to the

implications of the lack of a therapeutic class

approach in a second.

These revisions also added a higher hurdle

for new IND use or investigational new drug use of

ozone depleting substances. I guess I should also

pause here and say we changed the terminology here

to be consistent with the Montreal Protocol, and

what we are essentially talking about for the

purposes of this meeting remain CFCs, but because

the Montreal Protocol talks about ozone depleting

substances, we have changed that to be consistent

with that and the Clean Air Act.

Besides adding a higher hurdle for new IND

use, it also raised the bar for new listings of

essential uses, and, indeed, I do not believe there

has been any new essential list listings certainly

since the time of this publication.

[Slide.]

Importantly, then, the changes to 2.125

listed criteria for determining when individual

uses would no longer be essential and the moiety

would come out of the essential use list that is

contained in 2.125(e).

Let me just go over those criteria

quickly. The non-essentiality criteria essentially

stated that at least one non-ozone depleting

substance product with the same activity moiety,

the same indication, the same route of

administration, and about the same level of

convenience would need to be available.

In addition to that, we would need

adequate post-marketing data to be available for

the non-ODS product.

We would need to be assured that

production capabilities and supplies were adequate

or would be adequate at the time the de-listing

becomes final, and finally, there was a requirement

to be assured that patients who require the CFC

product are adequately served by the alternative.

Now, there is an asterisk here stating

that this is for products with only one marketed

brand or strength, so there would be sort of a 1 to

1 here. For products with more than one strength

available, such as fluticasone, for instance, is a

product with numerous strengths, or for products

where there is more than one NDA or more than one

source of that product, such as albuterol, which

had not only two branded products, but numerous

generic products.

We stated that there would have to be at

least two non-ozone depleting products with the

same active moiety, the same indication, route of

administration. So, all the other criteria were

the same, but the difference here was that there

would have to be at least two.

[Slide.]

Now, as I mentioned earlier, one of the

advantages to a therapeutic class approach is that

it can help to deal with products that are not

being reformulated, but because of important and

well-taken public input, we did not include a

therapeutic class approach in the finalization of

the revised 2.125, but we did put in a pathway for

dealing with products that are remaining on the

market, and not represented by any kind of

alternatives in the marketplace, and we stated in

that rule that FDA has therefore revised

2.125(g)(2) to permit the agency to undertake an

evaluation of all ozone depleting products after

January 1, 2005, not just those products without a

non-ODS replacement.

[Slide.]

So, what this means is that beginning in

2005, beginning now, FDA can convene public

meetings, that is, an advisory committee meeting,

such as today, to discuss those products still

listed as essential to determine if changes in the

medical practice and availability of alternatives

render these products as no longer essential.

Under the revised 2.125, kind of harkening

back to earlier language, that essential is based

on there being no technically feasible

alternatives, provides substantial health, public,

or environmental benefit, and release of CFC small,

or justified given that benefit.

These reason this is in yellow and I have

got some things grayed out here is because this

bullet is really what we are here to discuss. This

is your expertise. I think we are not asking you

to justify CFC amounts and we are not asking you

about technically feasible alternatives because

that expertise I think lies elsewhere, but your

expertise lies in this bullet, providing do the

products that remain on the market and do not have

available direct alternatives with that same

moiety, do those continue to provide substantial

health benefit considering the practice of medicine

and the availability of other products.

[Slide.]

Please note that as we go through this

discussion, and we will discuss a list of the

moieties that are involved, that if you recommend

that Drug X is no longer essential, there is then a

process that would play out from here.

If FDA were to follow the advice, we would

need to publish a Notice of Proposed Rulemaking

stating that we had preliminarily determined that

Drug X was no longer essential, and I am sure we

would cite as our basis for doing that the

recommendations coming out of this meeting.

But what that means is that the public

would then have a chance to comment on that

proposed rule and we would consider those public

comments prior to going to final regulatory action.

So, your recommendation would not

precipitously lead to any of these products

disappearing. They would lead to a process being

played out where we would get further public

comments.

[Slide.]

Now, I have got a couple of slides that

really get to the same thing. This one is a little

busy, so I spend a little time on it, but then I

will get to a cleaned up version, but what I wanted

to show is that these are the original

classifications that were included, some of these

implicitly, in 2.125 back in 1978 and added

subsequently.

So, at that time that the revisions to

2.125 occurred, we had this kind of universe of

products listed as essential uses, and those that

are in red here are already no longer essential, so

that includes things like isoethrane,

isoproterenol, nasal steroids, contraceptive foams,

rectal foams, polymyxin, nitroglycerine. Those

products have either been discontinued, some of

them have been reformulated in non-pressurized

sprays.

In the case of nasal corticosteroids,

those products were not considered essential under

the Montreal Protocol and therefore no new CFCs

could be obtained for the production of those, and

besides that aspect, we had the aqueous

formulations, the pump sprays that we thought were

adequate alternatives. Indeed, now, we have some

HFA products which have been approved as MDI nasal

steroids.

[Slide.]

The products in yellow here are

potentially or could be de-listed soon, many of

these because they are no longer marketed. For

instance, as GlaxoSmithKline spoke to yesterday,

they chose to discontinue the marketing of

salmeterol inhalation aerosol, marking instead

their dry powder inhaler, because of their own

initiatives with regard to the CFCs phase-out. So,

since that is no longer marketed, we could de-list

that shortly. The same thing with beclomethasone.

So, what I would like to do here, and I

believe in the handout today, I am not sure it is

in the agenda, but in the handout of my slides

today, there is a List B. This is that list. So,

if you need the List B, and you don't have it, it's

on the back of the slides that were being handed

out today. I am not sure that the Advisory

Committee folks have it or not, but it was not on

the actual agenda that I had.

[Slide.]

This is the List B. There are available

non-CFC inhaled respiratory medications, and I

would note that I did not try to include

nebulization products here.

So, for albuterol, we now have Proventil

HFA approved since 1996, Ventolin HFA approved I

believe since the year 2000, and IVAX's albuterol

sulfate HFA was approved last year.

Levalbuterol was more recently approved,

Xopenex HFA in an MDI. We also have salmeterol,

which I just mentioned is being marketed as a dry

powder inhaler, a multi-dose dry powder inhaler

called Serevent Diskus, and formoterol is

available, as we also heard yesterday, in a dry

powder inhalation, single capsule at a time form

called Foradil Aerolizer.

We have numerous choices with regard to

inhaled corticosteroids. We have budesonide, which

is Pulmicort Turbuhaler, fluticasone, which is

available in a diskus or approved in a discus

formation, and Flovent HFA, which is a marketed HFA

alternative to Flovent MDI.

Recently approved was mometasone, which is

known as Asmanex. It is a multi-dose dry powder

inhaler, and finally, beclomethasone, which is

known as QVAR, which actually is approved in two

different dosage strengths, unlike the MDI that was

formerly available in the United States.

[Slide.]

For the cromones, we actually have no

alternatives approved at this point no direct

alternatives certainly in that classification.

The anticholinergics, ipratropium has been

approved as an HFA metered dose inhalers known as

Atrovent, and there is a dry powder inhaler also a

single capsule at a time device known as Spiriva.

That did not, of course, have an MDI predecessor.

Finally, I think as you are all well

aware, too, there is long-acting beta-agonist

corticosteroid combination known as Advair Diskus

that is available in several dosage strengths,

also, that had no MDI predecessor.

[Slide.]

So, that gets us to what I believe is

designated as List A in your background documents,

which is the moieties currently listed as essential

for which there is no current reformulated or

direct alternative product approved or marketed.

Under the beta-agonist classification, we

have metaproterenol or Alupent. We have pirbuterol

or Maxair. One thing I would point out with Maxair

is Maxair is approved both as a press and breathe,

although I prefer to say breathe and press, a

metered dose inhaler, and as an autohaler device or

a device where, in essence, the patient's breath

actuates the spray.

Under the inhaled corticosteroids, we have

two products that are in that classification,

flunisolide marketed as Aerobid, and triamcinolone

marketed as Azmacort.

For the cromones, we have cromolyn or

Intal, and nedocromil or Tilade.

Finally, there is a combination product of

beta agonists and anticholinergic that while

available as a nebulizer, which would not have the

same level of convenience as an MDI, is not

available in a sort of portable, hand-held device

at this point, and that, of course, is

albuterol/ipratropium also called Combivent.

Note here, too, I am not sure how legible

this is, but I have not included epinephrine in the

discussion of the beta agonists. We will need to

have a separate discussion of epinephrine at a

later Advisory Committee meeting, because it is

important, since that is an over-the-counter

medicine, to include colleagues from the

Non-Prescription Drug Advisory Committee, as well,

so folks can look forward to a future timely

discussion of epinephrine.

[Slide.]

Well, bringing this all back towards the

Montreal Protocol process, what has been the

history to date of the Montreal Protocol?

Although this say global, I believe this

is actually restricted to the developing countries,

which, of course, count for most of the use of CFCs

in inhalers, but this is the pattern of the amount

asked for from the Montreal Protocol parties, the

amount actually used, and the amount in stockpiles

within the developing countries.

You can see that in the early years of the

essential use nominations, about 14,000 tons,

metric tons of CFCs total were requested. At their

height, about 9,000 metric tons were used, and that

is now down, as far as this graph goes, down in the

4,000 range, and will continue to fall.

I would just state as sort of an

educational point that the stockpiles are closely

matched here to the amount used and that is by

design. The Montreal Protocol, it is felt that

because of uncertainties in the supply of CFCs, it

is to the countries and companies within those

countries' advantage to keep stockpiles that would

allow for one year's worth of production.

[Slide.]

So, to conclude my talk, the U.S.

Government moved proactively to address the issue

of ozone depletion, and, in fact, has had a key

role in the implementation and the conduct of the

Montreal Protocol.

The Montreal Protocol is a successful

treaty and it has led to important reductions in

CFCs and other ozone-depleting substances, and,

indeed, there is evidence now that the destruction

of the ozone has leveled off and it is hoped and

projected that under the current provisions of the

Montreal Protocol, that the ozone layer will

recover to pre-1990 levels or mid-1980 levels by

the mid-part of this century.

The Montreal Protocol is increasingly

moving towards control in specific essential uses,

notably albuterol, and the U.S. has acted

accordingly.

[Slide.]

I think you can also see from the List B

that I provided, that the U.S. is progressing in

the CFC transition, and there are many non-CFC

products available and in common use now. In fact,

many of the CFC products that were formerly listed

even at the time of the revision of 2.125 are no

longer marketed.

However, some CFC products and moieties

remain on the market and have no currently approved

or marketed alternatives. So, the question for the

day, and the question for you folks to ponder and

to give us advice on is do these products

individually remain essential.

[Slide.]

So, your charge today will be as per the

revisions of 2.125, we are convening this meeting

to discuss the products listed as essential to

determine if changes in the medical practice and

availability of alternatives render these products

as no longer essential.

Remember that that definition of

"essential" is that there are no technically

feasible alternatives, that the drug provides

substantial health, public, or environmental

benefit, and that the release of CFCs is small or

justified given the benefit. Again, I think your

particular expertise lies in that second bullet.

[Slide.]

Yet another depiction of the ozone layer,

this being picture from 1983 and a similar vantage

point in 1993 showing, indeed, the expansion and

the further depletion of the ozone particularly

over the Antarctic region.

With that, I will stop and than you for

your attention.

Clarifying Questions

DR. SWENSON: At this point in the

meeting, we are ahead of schedule. We had a break

planned following Dr. Meyer's presentation, but I

think, given as early as it is already, we might

move into the next session denoted by clarifying

questions and take a break after that.

So, at this point, if there is no problem

with proceeding, I would like to start with that

and open it up to any members of the panel here to

ask for clarifications.

Dr. Schatz.

DR. SCHATZ: Just one relatively simple

one. I was not under the impression that

nedocromil was still being marketed, I mean it is

still available, but I gather it is.

DR. MEYER: I actually tried to go on

drugstore.com and confirm these, and I did find it

available, so to the best of my knowledge.

DR. SWENSON: Dr. Brantly.

DR. BRANTLY: Dr. Meyer, in your

consideration, I didn't see consideration of the

economics. Is that also a dimension that we should

consider particularly in the context that

oftentimes patients are on multiple respiratory

medications and some of them can be quite

expensive?

DR. MEYER: It is certainly a factor that

we think about in terms of the more formal

moiety-by-moiety approach when we say patients are

adequately served. We included the consideration

of economics in that. So, I think that we would

certainly welcome your thoughts in that regard as

you discuss the moieties today.

DR. SWENSON: Ms. Schell.

MS. SCHELL: I have a question about

supply. If we take one drug out, will there be

enough to fill in the gap from the other companies

that already produce it?

DR. MEYER: I think the important thing

with regard to that is that we do, as I said,

whatever recommendation is taken today, if there is

a recommendation that a product is no longer

essential, we will go through a notice and comment

rulemaking which will not only allow for public

comment, but will allow other manufacturers perhaps

of other products that might have to increase their

supply to do so.

So, I think that this changeover would not

be precipitous, it would be planned and it would

allow for the other products that might need to

increase their supply to do so.

MS. SCHELL: I have just one more

question. With the Montreal Protocol, what other

countries, are they still in use of this way, or

are they completely caught up with it, or are we

behind?

DR. MEYER: It depends on how you define

behind. Our albuterol process is slower than some

other countries, notably, Canada, Australia, many

countries within the EU, for instance.

On the other hand, the EU has certain

provisions that make, for instance, the de-listing

of beclomethasone tougher for them, because they

need to have two products to do that, and in some

of the EU countries they do not. We don't even

have a CFC product available. We will be able to

shortly de-list beclomethasone.

So, I think that in some measures, we

might be behind and in some measures we are not,

but it is sort of a different healthcare system,

different mix of considerations at this point, but

clearly, as I said, in the List B that I pointed to

earlier of the alternatives available, we have made

substantial progress in the transition at this

point.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I guess I have two questions.

One is by taking away some medications on this

list, do we improve the chances of getting what we

want for the drugs that we really do think are

essential. My understanding of our relationship

with the parties is that we go request and they are

in a position to approve.

So, my question is, by doing this, are we

improving the chances that the stuff we really

think we need we are going to get?

DR. MEYER: You have to understand that I

will only be able to answer that from personal

opinion, because I certainly don't speak for the

parties, but I think to the degree that we are

showing successful transition, that helps our

requests for any remaining essential uses. I think

that is true.

DR. SCHATZ: My second question is, all of

us I am sure will have some views based on our own

personal prescribing practices, but I am wondering

whether there is any information available as to

how many patients are using these drugs current,

that would I think help us get some sense as to at

least how many patients think they are useful or

essential.

DR. MEYER: We do not have those data

available for you today. I am sorry that we don't.

DR. SWENSON: Dr. Gay.

DR. GAY: Thank you. Will the FDA have

available to us data concerning progression of

development, for example, whether or not companies

have made a good-faith attempt to begin to develop

MDIs, if they are well along the pipeline and very

close to approval, or if there is no significant

information that they have even started

development? Will the FDA have that information

available to us today?

DR. MEYER: Since this is an open public

meeting, some of that information cannot be

discussed in this meeting. To the degree that some

of this has been acknowledged and perhaps might

even be spoken about in the open public sessions by

some of the manufacturers, then, yes, so not fully.

DR. SWENSON: Dr. Martinez.

DR. MARTINEZ: Dr. Meyer, one of the

criteria for non-essentiality is that patients who

require CFC product are adequately served. I

assume that that criterion is valid. We had a

similar discussion a year ago regarding albuterol.

If we decide to declare some of these

products nonessential, will there be potential

increase the minimal possible costs for patients of

inadequate means or do not have insurance, that

would make them require paying more for available

products, and thus, perhaps because of means, not

have the products available for treatment?

DR. MEYER: I think that will have to be

considered on a case-by-case basis. For instance,

if you are talking about a patient on a brand name

corticosteroid where there are many alternatives

available with a variety of presentations, a

variety of costs, I think it is hard to say whether

that patient will be significantly impacted by

this.

It is clearly a different situation from

albuterol, because albuterol had a generic. There

are no generic MDIs available for any other product

except epinephrine, and we are not discussing

epinephrine today, so while there might be

differences in pricing, I don't think it is of the

magnitude certainly that we are talking about with

albuterol, but since these are not direct

replacements, it is a little bit harder to say

broadly that we could say that there is no cost

impact.

I would say that for the direct switches

to date, in other words, the pricing of Ventolin

HFA versus Ventolin CFC, so the brand name, the

price of other products that have been directly

switched, where they are branded products, they

have been basically on parity, they have been the

same.

The companies have actually publicly

committed to that kind of pricing policy.

DR. MARTINEZ: So, as a follow-up then,

are you then suggesting that a decision in this

case will probably not cause a significant change

in potential cost of the medicine for the public in

terms of, for example, if we determine that some of

the inhaled corticosteroids that are in the list

that we are going to make a decision about, are

discontinued, none of them is of such a low cost

that would have allowed a patient to receive

inhaled corticosteroids, but now will not because

of an issue of cost?

DR. MEYER: I am not necessarily

suggesting that. I am just suggesting I can't say

that as a broad generalization for this. So,

again, on an individual discussion, if you get to

Drug X and the discussion is, well, Drug X is

priced aggressively, it is cheaper than any of

these other ones, I think again we would welcome

the input of the committee if they feel like that

would have an important implication on the patients

being affected.

DR. MARTINEZ: Are costs available as

information for us at this meeting?

DR. MEYER: They are not available at this

point.

DR. SWENSON: Dr. Kercsmar.

DR. KERCSMAR: Are all the inhalers that

are on this B list manufactured in the United

States, and if not, who gets charged for the CFC

usage, the country that manufactures them or the

country to which they are being sold or imported?

DR. MEYER: The products that we are

talking about today are part of the U.S. essential

use process, so they are produced in the United

States. There are other products that have already

been dealt with, albuterol is a notable one where

some of the production was outside the U.S., but

these products are all produced within the U.S.

DR. SWENSON: Dr. Schoenfeld.

DR. SCHOENFELD: Is there a well-defined

procedure for developing reformulating these

products to a non-CFC method, and does de-listing

them have any effect on these companies' abilities

to develop non-CFC formulations?

DR. MEYER: That is a good question.

Actually, with regard to the first part of your

question, it is a very difficult task to

reformulate. I think early on, the thought process

by any, I think even including those in the

industry who are directly involved was that this

would not be so difficult a task, but the chemical

and physical properties of the non-CFC propellants,

the HFAs, are such that it is required a

reengineering of the valves, many of the gaskets,

the cans themselves, so they are really entirely

new products that are being developed, and it has

been challenging.

In fact, some products have not been

successfully reformulated because of those

challenges.

With regard to if a product were to be

de-listed, would it make it more difficult for the

new product to come forward, I don't think it

should have any effect on that with the possible

exception of one of the things we have liked to see

with these replacement products is a comparison in

a study against the product it is replacing when it

is a direct one-to-one replacement. So, you would

need to have study medication available.

But these products have all been approved

under new separate drug applications, so it is not

like one of them going away would affect the path

forward for the other. DR. SCHOENFELD: Does that

basically mean that if they reformulated, they

would have to get approval of the new formulation,

not on the bioequivalence grounds, but actually on

efficacy grounds, and that would be true today

before they de-listed, and also true after they

were de-listed?

DR. MEYER: That is true. That is true,

and there is a couple of reasons for that. One is

that bioequivalence in terms of an inhaled drug

that is locally acting is very, very difficult, if

not impossible, to establish under currently

available science, but the other issue is that

there are other things introduced by having such

different formulations in terms of tolerability and

safety that we feel need exploration in studies

beyond the small, rather defined pharmacokinetics

type studies.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I just want to make sure in

light of some of the questions here today, I want

to make sure I understand exactly what you are

asking of us today, because I think that if you are

asking us whether the essential question is provide

substantial health benefit, that's a little

different than asking us whether it provides

substantial public benefit.

This question of economics, for example,

comes in if we are thinking about this in terms of

public benefit, and it sounds like we are not here

today to really debate that, but just to give you a

perspective on the health aspect and then you

decide whether to--and then those other issues will

be raised subsequently. Just help clarify that for

me.

DR. MEYER: Yes, I think that is a good

way to put it. Clearly, your expertise is in

making recommendations or observations about the

specifics of the health benefit. I think we would

welcome also other considerations from you. It is

not like we are focusing in and will only accept

recommendations or comments based on health alone,

but to the degree that the economics are not things

that we were planning to get into or answer today,

I think if you raise concerns about that, we will

duly note those, but those would be better dealt

with in the notice and comment rulemaking

subsequently.

DR. SWENSON: With respect to some of the

drugs for which there are no obvious replacements,

the cromones in particular, but this may apply to

some of the others, as well, do you have any data

as to when the patents expire and if any generic

options are in the pipeline?

DR. MEYER: I don't have data on those. I

could probably get that in fairly short order, but

I would not be surprised, particularly for the

Intal, cromolyn, for instance, it that were already

past.

The challenge to the developing a generic

alternative to a cromone or to a corticosteroid is

establishing bioequivalence, and part of the

reasons that there are not further generics outside

of albuterol is because of there not being a

methodology for establishing bioequivalence in a

reliable fashion.

DR. SWENSON: Ms. Schell.

MS. SCHELL: I have a question about the

Montreal Protocol as far as deadlines or

compliance. Is the United States in compliance

with the Montreal Protocol, and is there a date

where they have to have this totally met, and is

there a consequence if not?

DR. MEYER: We are in compliance with the

Montreal Protocol. There is no firm date that has

been established. Back in the late nineties when I

first started my involvement with this process,

many pointed to the year 2005 for the developed

countries being totally out of the use of CFCs and

MDIs, and that has proven not to be the case either

for the United States or many of the other

developed countries.

That said, I think that as I stated during

my talk, it has been envisioned that the essential

use process would be a temporary process, not

permanent, and clearly, there is increasing

interest on the parts of the countries involved

with the Montreal Protocol to effect these

transitions in a timely fashion.

So, I think that the U.S. does need to

move forward responsibly, and when I say

"responsibly," I mean both in terms of the public

health benefits of the environmental side of this

treaty, as well as protecting the public through

assuring that medicines are available to patients

who need them.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: Two questions again. Tell me

if this is fair, to try to answer the question,

because I think it's answerable, is the question do

we think that we and our colleagues can adequately

care for our patients if a drug is gone, in other

words, a drug is nonessential, if we think that we

and our colleagues can adequately care for patients

without it?

DR. MEYER: I think that would be a fair

way to pose the question.

DR. SCHATZ: Okay. Then, my second

question is that you mentioned this would be the

beginning of a process. How long would you

estimate, if possible, between a decision today

that a drug is no longer essential and when, in

fact, it would no longer be available based on that

ruling?

DR. MEYER: It is hard to say with

certainty what that would be, but it is very common

for a rulemaking to take a year or two to play out.

I mean if, for instance, you took the albuterol

rule, actually, the early process began in '96, the

late process began in '99, and it wasn't finalized

until 2002. There was a lot of controversy and

considerations in that.

In a more focused rulemaking, it might be

considerably quicker than that, but it is not

uncommon for it to take a year or two to complete

rulemakings, to go from notice and comment, or

opening up with a Notice of Proposed Rulemaking to

the point where it is finalized.

Then, once it is finalized, it doesn't

necessarily become effective the day that it's

published. It may be published with an effective

date of six months or longer. One of the reason you

might do that is to allow patients to sort of

acclimate to the new realities, as well as to allow

the other manufacturers who make products that

might increase in sales to account for this gap in

the marketplace, to plan accordingly and increase

their production.

DR. SWENSON: Dr. Schoenfeld.

DR. SCHOENFELD: I have never actually

designed or ran a clinical trial of an inhaled

asthma medication, so I was just wondering how

difficult would it be for these things to go back

on the market in new formulations in terms of the

clinical trials required. Does the fact that the

chemical was previously approved make a difference?

Are we talking about clinical trials with thousands

of patients or clinical trials with tens of

patients? I don't have a good sense of how

difficult these drugs are to develop.

DR. MEYER: Yes, these have typically been

relatively streamlined development programs,

because we do understand a lot about the moieties,

so the purpose of the trials is really to

understand the specifics of the product that is

delivering that moiety.

Commonly, you might have a short-term

trial that looks at pharmacodynamic measures if

they are available, say, for a bronchodilator, and

then you might have a 4- to 12-week treatment trial

which may have, say, 70 to 80 patients per arm.

Then, you might also, depending on how

different the formulation is, have a longer term

extension of that, an open-label extension of maybe

100 to 200 patients out to six months to a year,

for instance.

So, they are much smaller than for a new

molecular entity, but it is not trivial either.

DR. SWENSON: Dr. Kercsmar.

DR. KERCSMAR: I was wondering if you

could clarify the reason that products that are

available that are equivalent or the same drug for

nebulization have been excluded, is it really

thought that the convenience factor is so

overwhelming for those nebulization products that

should we not consider the availability of those in

these deliberations?

DR. MEYER: Well, for the direct

de-listing, we did not include the nebulization

products because of the level of convenience,

because one of the criterion was that it had to

have approximately the same level of convenience,

and clearly, standard nebulization treatment does

not have the same level of convenience of an MDI,

for instance.

For the purposes of today, I think that

you are free to consider the entire therapeutic

armamentarium available in terms of making a

determination, that Dr. Schatz said, you know,

would my patient suffer if this product were to be

removed.

DR. SWENSON: There being no further

questions, Ms. Watkins is going to read a statement

regarding our open public hearing.

MS. WATKINS: Actually, it will be in

relationship to communication with the press.

I would like to remind the committee that

in the spirit of the Federal Advisory Committee Act

and the Sunshine Amendment, that discussions about

today's topic should take place in the form of this

meeting only, and not occur during lunch, breaks,

or in private discussions.

We ask that the press honor the

obligations of the committee members, as well.

The open public hearing speakers, if you

would please come see me during break, I would

appreciate it.

DR. SWENSON: We will break and reconvene

in 15 minutes.

[Break.]

DR. SWENSON: We will begin this next

portion of the meeting, if I could ask all members

to return to their seats.

Open Public Hearing

DR. SWENSON: We will now begin the open

public hearing portion of this meeting. Before

that, I will read this particular statement

relevant to presentations.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. 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, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any known financial relationship that

you may have with a sponsor, its product, and, if

known, its direct competitors.

For example, this financial information

may include the sponsor'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.

Our first presentation then will be by Ms.

Maureen Hardwick.

MS. HARDWICK: Good morning. My name is

Maureen Hardwick and I am here today on behalf of

IPAC, the International Pharmaceutical Aerosol

Consortium.

IPAC is an association of leading

manufacturers of metered dose inhalers for the

treatment of asthma and COPD. Its current members

are AstraZeneca, Boehringer Ingelheim, Chiesi,

GlaxoSmithKline, and INEX.

IPAC is firmly committed to the MDI

transition as evidenced by the extraordinary

investments and R&D efforts that its members have

taken. IPAC companies' use of CFCs has declined

substantially over the past decade as they have

launched CFC alternatives and phased out CFC MDIs,

and one of our members has phase out all use of

CFCs in the United States.

IPAC is grateful for the opportunity to

speak today and has always supported an open and

transparent process that allows for input from all

interested stakeholders.

IPAC strongly believes that any

consideration of the continued need for CFCs under

FDA's essential use exemption and under

corresponding EPA regulations in which FDA has a

statutory role should take into account the

uncertain future access to CFCs.

As FDA itself noted at the June 2004 PADAC

hearing, each year the Montreal Protocol parties

are more reluctant to grant CFCs to the United

States. Last month's protocol meeting only

confirmed this point.

This potential reduction is exacerbated by

FDA's choice of a December 31st, 2008, effective

date for albuterol non-essentiality. As a result

of this decision, the U.S. albuterol market could

continue to use over 1,000 metric tons of CFC per

year for the next three years if the protocol

allows it.

This could result in shortages for

non-albuterol products for which there is as yet no

CFC-free replacement. Therefore, it is critically

important that CFCs only be used for truly

essential products. To better ensure that this

occurs, IPAC believes there are two key actions

that FDA should take.

First, CFCs should be allocated only for

MDIs that do not have a corresponding CFC-free

alternative and where the manufacturer is

diligently undertaking meaningful efforts to

research and develop a CFC-free alternative.

Given future CFC uncertainty, it is

imprudent for FDA and EPA to allocate annual CFC

volumes to companies for a CFC product where there

are already adequate CFC-free alternatives on the

market. This is particularly true when the company

has in its power to phase out sale of its CFC

products and to transition its own market.

IPAC companies have done this, so we know

it can be accomplished, but some companies that

have CFC-free alternatives are still major users of

CFCs, so action by FDA is needed.

FDA should address this in two

complementary ways: (a) by eliminating the

essentiality designations for such products in 21

CFR Section 2.125 via a notice and comment

rulemaking; and (b) by informing EPA that essential

use CFC allocations are not necessary for such

products.

Secondly, FDA should advise EPA not to

allocate CFCs to companies that are holding

excessive CFC stockpiles. The protocol's expert

panel, which includes an FDA physician, Dr. Meyer,

and other medical experts, has carefully reviewed

the issue of CFC stockpiles and concluded that a

one-year CFC reserve is adequate.

IPAC companies, based on decades of

experience manufacturing MDIs, fully concur with

the protocol panel's assessment. FDA should

therefore advise EPA that it is only necessary to

allocate a license for new CFC production in an

amount such that the receiving company's stockpile

does not exceed a one-year reserve.

In conclusion, IPAC urges FDA to

proactively implement the July 24, 2002, final rule

and to be proactive in exercising its joint

responsibility with EPA for allocating essential

use volumes by taking the actions we recommended

today.

Doing so will facilitate a timely and

effective conclusion to the transition and minimize

the continued need to CFCs to that which is truly

necessary to meet patient need.

IPAC would be pleased to serve as a

resource during this process and would be happy to

provide further, more detailed information relevant

to the transition of non-albuterol MDIs as the

issues evolve.

Thank you.

DR. SWENSON: Thank you, Ms. Hardwick.

Our next presentation will be by Dr. Kirk

Shepard.

DR. SHEPARD: Good morning, Mr. Chairman,

members of the Advisory Committee, FDA

participants, ladies and gentlemen. My name is

Kirk Shepard. I am Vice President of Clinical and

Scientific Affairs at Boehringer Ingelheim

Pharmaceuticals in Ridgefield, Connecticut.

Boehringer Ingelheim appreciates the

opportunity to appear before the FDA

Pulmonary-Allergy Drug Advisory Committee and share

the company's extensive respiratory drug research

and development efforts that bear directly on the

discussions of this meeting.

In the United States, these efforts have

yielded a number of effective products for the

treatment of COPD including Spiriva, HandiHaler

(tiotropium bromide inhalation powder), Atrovent

(ipratropium bromide), and Combivent (ipratropium

bromide and albuterol sulfate) inhalation aerosols.

Atrovent and Combivent inhalation aerosols

contain CFCs and are identified as essential uses

in 21 CFR 2.125. We hope that our comments today

assist the committee in advancing the public

discourse on the CFC MDI transition in a manner

that will be benefit patients and the environment.

Boehringer Ingelheim is committed to

improving respiratory care through the development

of safe, effective, and environmentally responsible

therapies. For over 40 years, Boehringer Ingelheim

has been a world leader in the research,

development, and the manufacture of drug products

for the management of respiratory disease.

Over 8 million patients worldwide with

COPD and asthma rely on our medications.

Recognizing that no single drug delivery system can

meet all patients' needs, the company has

developed, or is developing, a variety of products

that included metered dose inhalation (MDIs), dry

powder inhalers (DPIs), solutions for nebulization,

and propellant-free inhalers. Boehringer Ingelheim

strongly endorses a smooth, timely and effective

transition of our CFC-containing aerosol products

that protects patients.

Protection of the environment and public

health are an integral part of future planning at

Boehringer Ingelheim, as we are dedicated to the

research and development of CFC-free respiratory

products.

The company has taken a leading role in

the global CFC transition by investing nearly $400

million in the development of HFA-based MDIs and

propellant-free inhalers. Our CFC-free development

programs involve the reformulation of more products

than any other MDI manufacturer. We have deployed

over 200 scientists in 35 laboratories around the

world and enrolled 10,000 patients in clinical

trials to date.

Worldwide, 13 BI products have been

reformulated or are in the process of being

reformulated to 4 HFA MDIs and 2 propellant-free

inhalers. Our CFC-free alternatives have been

introduced in nearly 50 countries that are parties

to the Montreal Protocol.

In the United States, Boehringer Ingelheim

research programs have yielded CFC-free products

for the treatment of COPD, including Spiriva,

HandiHaler introduced in the U.S. in 2004 and the

recently introduced Atrovent HFA metered dose

inhaler.

Atrovent HFA, approved by the FDA in

November 2004 and introduced in May of 2005, is the

result of over a decade of Boehringer Ingelheim

research into CFC-free alternatives. During these

early months after Atrovent HFA introduction,

Atrovent inhalation aerosol continues to be

available in the U.S. to allow for patients to make

a seamless and orderly transition to CFC-free

anticholinergic therapies such as Spiriva or

Atrovent HFA.

Mindful of our commitment to the

environment and global transition and after

consultations with the FDA, Boehringer Ingelheim

has decided to voluntarily discontinue the

marketing and distribution of the CFC-containing

Atrovent inhalation aerosol in the United States as

of January 1, 2006.

Accordingly, we have notified the U.S. EPA

to reduce our 2006 CFC production rights to account

for the removal of Atrovent inhalation aerosol from

the market.

Combivent inhalation aerosol is an

important product for the management of COPD.

Clinical studies have demonstrated that maintenance

bronchodilation of COPD patients is improved with

Combivent compared to each of its agents alone.

There are many COPD patients whose

symptoms cannot be controlled with just one inhaled

bronchodilator therapy, thus making combivent

patient population significant. In 2004,

Boehringer Ingelheim distributed over 3.5 million

combivent MDIs, serving over 2 million patients in

the U.S.

Noncompliance is a significant barrier to

improving patient health. The rapid onset of the

benefit perceived by the patients in taking a

short-acting beta-agonist in combination with the

long-acting ipratropium bromide increases both the

convenience and patient satisfaction, two important

factors in improving patient compliance.

Published results of several clinical

trials provide evidence that regular treatment with

anticholinergics may reduce the severity of COPD

exacerbations in COPD patients with moderate to

severe disease.

In short, combining of these two widely

prescribed bronchodilators for COPD into one

product has afforded these patient benefits while

at the same time achieving a 50 percent reduction

in CFC emissions that would have resulted from the

use of the two, single-agent CFC products.

As with Atrovent, Boehringer Ingelheim has

pursued a multi-year research and development

program into a CFC-free alternative for Combivent.

The company has applied extensive resources to

reformulating Combivent, exploring both alternative

HFA propellant and propellant-free inhalation

devices as alternatives.

As a combination of a suspension and a

solution formulated with an HFA propellant,

Combivent has posed technical complexities that

have challenged our best reformulation efforts.

However, we remain optimistic that we will

overcome these challenges. Our research and

development is ongoing and Boehringer Ingelheim

reaffirms its commitment to continue this effort to

find a CRC-free alternative for Combivent.

We share FDA's high standards for products

and until a CFC-free alternative to Combivent that

meets those high standards is available, Combivent

inhalation aerosol must continue to be designated

as an essential use under 21 CFR 2.125.

Thank you for the opportunity to address

the committee and for your time and attention.

DR. SWENSON: Thank you, Dr. Shepard.

Our next speaker is Mr. Alan Krueger.

MR. KRUEGER: My name is Al Krueger. I am

an Associate Director of Regulatory Affairs at Kos

Pharmaceuticals.

Kos acquired the U.S. marketing rights to

Azmacort, both CFC and HFA, in April 2004 from

Aventis Pharmaceuticals. Azmacort CFC, available

commercially for over 20 years, continues to be

actively prescribed by physicians.

Since this product was acquired by Kos,

new and total prescriptions have increased. In May

2005, combined total prescriptions were 92,000.

New prescriptions accounted for nearly half of this

number of 92,000.

Kos is committed to conversion to HFA.

Final approval for Azmacort HFA is being actively

pursued by Kos, an IPACT-1 and IPACT-RS member. In

a December 2004 meeting with FDA, further

development and approval plans for this product

were discussed. Commercialization is anticipated

in approximately 2008.

Other Kos aerosol R&D projects are also

underway. Four projects, including two for

asthma/COPD, one undisclosed for a systemic

disease, and the last for inhaled insulin, are at

various stages of development.

Thank you.

DR. SWENSON: Thank you, Mr. Krueger.

Our last speaker is Dr. Leslie Hendeles.

I am a clinical pharmacist in the Pediatric

Pulmonary Clinic at the University of Florida, and

I am here as an independent person interested in

the topic, and I have no conflict of interest with

a beta-agonist manufacturer.

I just wanted to point out to the panel

members who don't take care of children that the

breath-actuated device called the autohaler has

some unique properties for kids. It enables them

to get a quick relief medicine without having to

use a valve-holding chamber or spacer device, so in

your deliberations, not only the drug is an issue,

but the delivery device might be an issue, too,

that I ask that you consider.

Thank you.

DR. SWENSON: Thank you.

At this point, then, I think we can move

then into the formal discussion with each of the

specific agents, but before we do so, if there are

further points to be raised, this is the moment.

Dr. Meyer.

Clarifying Questions

DR. MEYER: Yes, I want to just take time

to clarify something with respect to a question

that Dr. Gay asked earlier about how much we would

be able to say about things under development.

I wanted to clarify for the purposes of

the discussion, I would like you to speak about the

transition as it is today, in other words, whether

a product is being actively reformulated or not

really shouldn't factor into your recommendations

to us. It should be given the current medical

practice and given the current available

alternatives, do these products on this list in the

Charge to the Committee remain essential

individually.

DR. SWENSON: Dr. Moss.

DR. MOSS: I had a question for Dr. Meyer.

Maybe we can benefit a little bit from the panel's

experience a year ago with the albuterol

discussion. It seems to me that after the

discussion a year ago, there is a lag time of about

I guess 3 1/2 years before there will be no CFC

compounds for albuterol.

Do you anticipate, if we make similar

decisions on these agents, what the lag time would

be after the decisions are made for these

companies?

DR. MEYER: That time frame was very

specific to the considerations with regard to

albuterol and actually reflected some of the advice

given by some of the members participating in that

committee that they had concerns particularly about

the impact of balancing cost considerations versus

availability of medications, and so on.

So, that was very specific to albuterol

and again was responsive to some of the advice that

we got. I think this would depend whether any of

these, if they were recommended to be de-listed by

you folks, would have any kind of lag period

afterwards would be highly individual, but would be

unlikely to always be in the 3-year time frame. It

might be quite a bit quicker than that.

DR. SWENSON: Dr. Schoenfeld.

DR. SCHOENFELD: Maybe this would occur at

the public hearing, at the subsequent public

hearing, but I am a little concerned about the

process here in that it seems that a regulatory

decision is made without really relying on

evidence-based medicine in the same way that, for

instance, regulatory decisions were made yesterday.

That is, it would seem a better process

would be to ask each of these companies that make

these products to marshal the scientific evidence

in the form of maybe what they initially submitted

to gain approval for these products plus subsequent

papers in the medical literature that would argue

that these products are essential, and then have

these documents just as they are in new drug

applications reviewed by your staff and a report

written, and in that case, we would be making these

decisions based on the usual level of evidence that

we are used to seeing in making important decisions

like this.

DR. MEYER: Point noted. As I said at the

beginning, this is a very different advisory

committee than the usual. Unfortunately, I think

there would be a paucity of direct data of the kind

of substantial evidence that we normally discuss in

these kind of settings because of the relative lack

of comparative data that exist.

But I would point out that in the

subsequent rulemaking process, I suspect that any

affected company would, in fact, marshal whatever

kind of data that do exist to address their

argument should they choose to say that they think

they continue to be essential.

So, I think we would have that kind of

discussion or that kind of presentation to us at

that stage.

DR. SWENSON: So, Dr. Meyer, just to

reiterate, then, our charge is to give you some

early guidance as to prioritizing these individual

decisions, that you would take a yes or a no with

that type of adding weight to then your decision as

to whether to bring these forward at separate

discussions.

DR. MEYER: I might say it's a little bit

more than early guidance, but yes, I mean it is

just the first step of the process, so this

wouldn't be a definitive, if you folks

recommend--and I don't refer to one of these by

name--but if you recommended that Drug X was no

longer essential, there is a process that goes on

from there, too, more fully in a public comment

manner.

DR. SWENSON: So, for each of these

agents, then, there would be a fair hearing to

follow.

DR. MEYER: Yes, any advice from you folks

that one or more of these was no longer essential

would lead to rulemaking on our part that would

lead to subsequent public discussion.

DR. SCHOENFELD: Possibly meaning coming

back to us.

DR. MEYER: Possibly. In some

circumstances, it might be in written form, in some

circumstances, it might actually come back to the

committee.

DR. SWENSON: Any further general

questions? Dr. Moss.

DR. MOSS: I had a general question again

for Dr. Meyer. I think I am assuming correctly

that the companies that make these compounds were

all told about this meeting, and if they wanted to,

like two of them did, they could come and talk at

the open public forum?

DR. MEYER: Yes, I just was conferring

with one of our regulatory legal staff, and, in

fact, just in answer to the question of a moment

ago, all subsequent actions, all subsequent

rulemaking would engender an open public hearing,

would require of us an open public hearing, so it

would not just be in written form, there would be

an open public hearing.

Yes, there would be opportunities at that

for the companies to either--I don't know whether

it would be in the open public hearing session or

might even be a sponsor's presentation as a part of

that meeting.

DR. MOSS: But all of the companies were

informed of this meeting, so if they had

information that they wanted to relay, they could

have come to this meeting for the other compounds?

DR. MEYER: This meeting was publicly

announced in the Federal Register as per usual, and

I believe companies are very good at surveying the

Federal Register for notices that affect them.

Committee Discussion

DR. SWENSON: If there are no further

general questions, I think we should move then to

the specifics, and the first will be the

beta-agonist. This will be on your List A page,

and I think we should start with metaproterenol and

ask if there are any specific comments about

metaproterenol from any of the panel members.

Dr. Schatz.

DR. SCHATZ: Just a point. Are we going

to actually vote, do we want to vote on each of

these, or is it not that sort of decisionmaking?

DR. MEYER: I don't think we were

envisioning a formal vote on these. So, I think we

were envisioning much more of a discussion and

allowing folks to make individual recommendations,

but not a formal vote.

DR. SCHATZ: Since my microphone is on, I

will just say that I do believe I could care for my

patients without the availability of

metaproterenol.

DR. SWENSON: Any other thoughts by panel

members?

Dr. Brantly.

DR. BRANTLY: I agree.

DR. SWENSON: Dr. Moss?

DR. MOSS: I would agree also.

DR. SWENSON: I will go ahead and agree,

as well.

DR. GAY: I will agree, as well.

DR. NEWMAN: I would agree, as well, and

just add that given the circumstance that we are in

here, and what we are being asked to do here today,

and that there is going to be a public process that

follows, I don't actually know why we wouldn't want

to start the ball in motion for everything on this

list.

DR. SWENSON: That is fair enough since we

are talking about two drugs here of very similar

action and basically the same position, so what I

might do is recommend in behalf of the panel that

both of these not be considered for special

exemption and ask if any members wish to disagree

with that assessment.

MS. SANDER: I have a couple of questions.

With the Alupent, I don't see--are there any plans

of Boehringer Ingelheim to discontinue this product

anyway, do you know?

DR. MEYER: We had a spokesperson from

Boehringer Ingelheim speak just a few moments ago.

I don't know whether he would like to address that

question.

DR. SHEPARD: We do not plan to

reformulate the decision as far as when it would be

discontinued, which it probably would be, has not

been made yet.

MS. SANDER: How many patients do you have

using that right now?

DR. SHEPARD: I am sorry, I don't have the

specifics on that.

MS. SANDER: Okay. With regard to Maxair,

do we have anyone from 3M?

DR. MEYER: I do not believe that I saw

anybody from 3M.

MS. SANDER: I agree with the panel with

regard to Alupent. With regard to Maxair, I think

we would need to do a little more examination about

its use in pediatric populations. I don't have

enough information in that area, because it is a

breath-activated inhaler, but I don't know the

amount of people using it.

DR. SWENSON: Could we ask our two

pediatricians to comment to Ms. Sander?

DR. KERCSMAR: The device in question

certainly confers benefit in ease of use, and while

it certainly may be relevant to pediatric patients,

I would still say that probably a minority of our

patients use it, but on the other hand, I would

argue that it is not just for kids and that anybody

who has difficulty with an MDI device certainly

would benefit from an autohaler, and that could

include any adult, and certainly elderly patients

perhaps as well, so I don't think it's an issue

just restricted to children.

I think that the other thing that would be

important to know is whether that device can be

adapted to non-CFC-containing inhalers.

DR. SWENSON: Dr. Martinez.

DR. MARTINEZ: I agree. I don't have

anything to add.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I guess that given the scope

of what we are being asked to do here, I would

agree that what you are all saying about the

potential use of that delivery device is

potentially important, I think there is a step

beyond this for addressing how important that is

and what the alternatives could be to that, and

whether there is a way of making it CFC-free, et

cetera.

I would again stress I think the

importance of setting the ball in motion on both of

these products in order to let that be aired.

DR. MEYER: I have perhaps changed my

request to the panel. What I would like to do is

actually--let's call it a poll, because I don't

want it to have the formality of a vote, but I

think it might be helpful just to poll each person

on the individual moiety after you have had your

discussion about it.

I know that your comment, Dr. Swenson, was

about perhaps the committee could regard these

together, but I would like to individually poll on

both of them.

DR. SWENSON: Before we start that poll,

any further questions, comments?

Okay. Ms. Schell, would you offer your

advice?

MS. SCHELL: On we are just using Alupent?

DR. SWENSON: On metaproterenol only.

MS. SCHELL: I don't qualify it as an

essential drug.

DR. KERCSMAR: I would agree. I can take

care of my patients without that drug.

DR. MARTINEZ: Nonessential.

DR. BRANTLY: Nonessential.

DR. NEWMAN: Nonessential.

DR. MOSS: Nonessential.

DR. GAY: Nonessential.

DR. SWENSON: Nonessential.

DR. SCHATZ: Nonessential.

DR. PRUSSIN: Nonessential.

MS. SANDER: Nonessential.

DR. SCHOENFELD: I will have to abstain

since this is not my level of expertise. If

somebody has data, I will be glad to look at it.

DR. SWENSON: All right. We will proceed

then with pirbuterol or Maxair, and we have already

had some comments, but before we do this poll, any

further points to make?

Dr. Schoenfeld, I will let you start. I

suspect maybe it's the same.

DR. SCHOENFELD: The same.

DR. SWENSON: Abstention.

Ms. Sander.

MS. SANDER: There is part of me that

realizes that CFCs are going away and that there is

holding chambers and other devices, and maybe I

should abstain.

DR. PRUSSIN: Nonessential.

DR. SCHATZ: Nonessential.

DR. SWENSON: Nonessential.

DR. GAY: Nonessential.

DR. MOSS: Nonessential.

DR. NEWMAN: Nonessential.

DR. BRANTLY: Nonessential.

DR. MARTINEZ: Nonessential.

DR. KERCSMAR: Nonessential.

MS. SCHELL: Nonessential.

DR. SWENSON: We will move then to the

category of inhaled corticosteroids. Let's begin

just then with the opportunity for any general

comments or questions of either of the two agents,

flunisolide or triamcinolone.

Dr. Martinez.

DR. MARTINEZ: As I requested before,

information about potential costs, cost

consequences of the decision we are going to make,

I would like to comment about this.

I think that as has been well said by the

FDA representatives, this is I think not an issue

in this case. There is a situation with respect to

inhaled corticosteroids which are as essential for

the treatment of asthma as albuterol is, and it has

to do with our previous discussion.

The situation for inhaled corticosteroids

is not the same as that for albuterol. The

discontinuation of the medicines that are in this

list, I don't think will have an effect on the

capacity of patients given their economic means to

have access to these medicines.

So, with a sense of fairness with respect

to the type of discussion we had the last time

about albuterol, I think in this case, this does

not apply. This not applying the issue of the

atmosphere in relation to CFC exposure becomes

essential.

Therefore, I think that that needs to be

considered, and since there are other medicines

that are equally or more effective than the ones

that are on this list, I think that should be the

essential consideration in this case.

DR. SWENSON: Any further questions?

Comments?

We will begin then with flunisolide. Ms.

Schell.

MS. SCHELL: Nonessential.

DR. KERCSMAR: Nonessential.

DR. MARTINEZ: Nonessential.

DR. BRANTLY: Nonessential.

DR. NEWMAN: Nonessential.

DR. MOSS: Nonessential.

DR. GAY: Nonessential.

DR. SWENSON: Nonessential.

DR. SCHATZ: Nonessential.

DR. PRUSSIN: Nonessential.

MS. SANDER: Nonessential.

DR. SCHOENFELD: I will abstain.

DR. SWENSON: We will move to

triamcinolone.

Dr. Schoenfeld, you abstain? All right.

Ms. Sander.

MS. SANDER: Nonessential.

DR. PRUSSIN: Nonessential.

DR. SCHATZ: Nonessential.

DR. SWENSON: Nonessential.

DR. GAY: Nonessential.

DR. MOSS: Nonessential.

DR. NEWMAN: Nonessential.

DR. BRANTLY: Nonessential.

DR. MARTINEZ: Nonessential.

DR. KERCSMAR: Nonessential.

MS. SCHELL: Nonessential.

DR. SWENSON: We move now to the third

category, the cromones, cromolyn or Intal, and

nedocromil or Tilade, and specific comments related

to the class or to individual compounds? Dr.

Schatz.

DR. SCHATZ: Here, I can think of a couple

of circumstances where I think it has a unique

role. One is in exercise-induced bronchospasm for

people who don't tolerate beta-agonists, and the

other is prevention of a specific allergy-induced

episode of asthma, patients going to visit where

there is a cat in the house, it really does seem to

prevent those symptoms.

So, in this case, I actually would like to

still--I feel I can take care of my patients better

with it available.

DR. SWENSON: Any further comments? Ms.

Sander.

MS. SANDER: We don't have anyone here

from the company that manufactures this, do we?

DR. SWENSON: No representatives applied

for the public hearing.

Dr. Newman.

DR. NEWMAN: Could I make two comments?

One is if they aren't here, that would sort of

imply to me that maybe they have nothing to say on

it, but we obviously don't know that for sure.

But the other thing I wanted to say is

that Dr. Schatz, your comment I think is well

taken, but I think of alternatives in other classes

that I can use that allow me to get around whether

a cromolyn type compound is available.

It is true that it seems to hold kind of a

small place still in the armamentarium, but from my

perspective, I think one can work without it just

in my own practice.

DR. SWENSON: Dr. Prussin.

DR. PRUSSIN: I would concur with that. I

mean you are right, there are uses of these drugs

that are unique and I am sure there are patients

who really prize them, but they are relatively

ineffective drugs in terms of clinical trials in

asthma, they track more or less with placebo, and

when you compare cromones to inhaled steroids, they

are much less active.

Now, again, I think you are right, there

are specific patients who get benefit from them,

but I guess the question is how many of those are

there and are there really no other alternatives.

I just put that out there for the group.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I actually think this is a

situation where it isn't so patient specific, as

much as it is circumstance specific. I think the

data are quite good for the two circumstances that

I mentioned, and I actually don't think there

are--I mean there are alternatives--but I don't

think there are better alternatives for the patient

who is sensitive to beta-agonists taking something

right ahead of time for exercise, and the patients,

I don't think there are any other alternatives that

do the same thing prior to a specific allergen

exposure.

I would also say that if, in fact, it is

limited to those uses, which certainly in my

practice it is, I don't use it instead of inhaled

steroids in any other circumstances, the amount of

total use would not contribute a lot of CFCs, but I

do believe the benefit to those patients in that

category of patients would be worth it.

I still, in my sense, and by my

definition, this would help me differently. I

certainly understand the other views that are being

expressed.

DR. SWENSON: I want to echo some of that

in that as we discussed albuterol in the last

meeting, that total amount relative to the vast

amount of CFCs that were being used for all the

commercial and industrial and cosmetic purposes

that you outlined, Dr. Meyer, if we decide to keep

an essentiality to these compounds, this represents

an even smaller, vanishingly small total amount of

CFC, and again for the individual patient for whom,

for reasons that we can't put our finger on, a

certain drug works wonderfully, I think possibly

given there are no alternatives, and this

represents possibly a very, very small amount of

the total, small amount being used for inhaled

therapy, I would think that maybe we should

consider an essentiality continuation.

Ms. Sander.

MS. SANDER: The request for CFCs for this

product, Dr. Meyer, can you tell us is it a large

amount, is it a small amount?

DR. MEYER: I don't think I can properly

characterize that. Dr. Swenson just referred to

that albuterol certainly accounts for approximately

half of all the CFCs requested by the United

States, so all the rest of these products, some of

which are not on this list because they have direct

alternatives, such as the Atrovent HFA, account for

the other half.

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So, I think you could sort of work from

there. If each of these was equally distributed,

you could sort of guess what that might be, but I

can't really quantitate that for you.

MS. SANDER: So, CFCs are going to go away

totally at some point in time in the future, right?

DR. MEYER: Yes, that's the expectation of

the Montreal Protocol.

MS. SANDER: Right. So, patients who are

currently using drugs that contain CFCs really need

to be thinking about, and working with their

doctor, on alternatives now as opposed to waiting

until later on, is that right?

DR. MEYER: Well, I think that would

depend on your point of view, but I think that that

is a valid way to view things.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I think absent knowing how

small this contribution in and not really knowing

how appropriately confined the practice use

patterns are for these drugs, I don't know why we

wouldn't want to go ahead and have there be a

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public airing and let the cromone enthusiasts speak

and map out how large or small this contribution

is, and let this again be brought forward for

public discussion.

I would be in favor of there being public

discussion around it.

DR. SWENSON: Dr. Moss.

DR. MOSS: I would agree with what Dr.

Newman was saying. I think it is important to find

out why the companies that makes these cromolyn

medications have not proceeded through the process

of converting from CFC compounds to non-CFC

inhalers.

The Montreal Protocol has been around for

a while. If the other companies have done a very

job of converting over, you know, it would be nice

to hear from the company side why they haven't made

the effort to convert their medication over.

Maybe they are not as committed to the

medication as we are, and if that is an important

point, then, it sort of doesn't matter in the sense

if we think it is essential or not, if they are not

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committed to changing over to proper inhalation

compounds.

So, I agree, it would be nice to get more

information from these companies before we make a

decision.

DR. SWENSON: Dr. Kercsmar.

DR. KERCSMAR: I also agree with Dr.

Newman. The cromones are still going to be

available in nebulized form and certainly while the

convenience isn't great, the efficacy will be the

same for the patient with a planned known exposure,

nebulization could certainly serve as an

alternative for the small group of patients that

have no choice.

I think there probably are other

alternatives for exercise, but I think the bigger

issue, the market I am sure is still very small,

and this is other data that we would need to make a

cogent decision.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I would say a couple of

things. I think as we all know, the difference in

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convenience between a metered dose inhaler and a

nebulizer are substantial, so that wouldn't make me

feel better if it weren't there.

I also don't think it is our decision, I

don't think it's our role to try to figure out why

the company isn't here or be concerned that they

are not here. I think we could conjecture that the

total market, as was mentioned, for cromolyn is

small, and therefore it doesn't make a difference

to them, that's a conjecture, but that doesn't

matter, I think, to my determination that I would

like to have it available in that niche that it

serves.

So, I guess those are my two responses.

DR. SWENSON: At this moment, and in an

attempt to be totally fair, we have one more person

that wishes to express a statement in the spirit of

an open public forum, so I will ask that individual

to stand.

Would you please introduce yourself,

because we have no information about you, would you

identify your affiliation and abide by all of the

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strictures that I read at the start of this open

forum.

MR. DABREZZI: My name is Carl Dabrezzi.

I am with 3M. I am coming up partially because of

your question of the manufacturer for Intal. That

is 3M. This also goes back to the comment back on

pirbuterol, and I guess the only comment I would

like to make is that do not assume, the committee

should not assume that activities are not going on

with these molecules simply because presentations

weren't here.

We are aware the public comment period

will be made available to us at the time of the

rulemaking process. So, I stepped up only as a

manufacturer of the Intal as you were asking. So,

thank you.

DR. SWENSON: Thank you.

If there are no further discussions to be

made--

DR. SCHOENFELD: I am a little confused

about the sort of level of proof here in this kind

of meeting, which is a little bit--in other words,

105

is the idea that sort of anything that has a

suspicion of being nonessential should go through

to the next step, or is it that we should be fairly

sure that it is nonessential to go to the next

step?

I mean this is not for me to make the

decision, but for the rest of the committee, I am

not sure what--this is a question of the FDA, at

what level of feeling, what level would--I mean in

a way, the purpose of this meeting is to sort of

save a lot of trouble because once things to on to

the next step, it is going to cost the companies a

lot of money, and it is going to cost the taxpayer

a lot of money to go to the next step, so I am not

sure what kind of burden is for our voting.

DR. MEYER: Fair enough. I would like to

introduce Mr. Wayne Mitchell, who is a lawyer in

the regulatory policy staff of the Center for

Drugs, who has been very involved with these issues

for a number of years. I would like to introduce

him and allow him to speak to this.

MR. MITCHELL: The first thing is the next

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step is a Notice of Proposed Rulemaking, and in

that, our conclusions are very tentative or can be

very tentative.

The other thing we can do in that, and I

am certainly listening to the discussions on

pirbuterol and the cromones, is we can ask specific

questions, ask for specific comments on what sort

of niche market a particular drug has, whether the

Maxair mechanism presents special advantages for

pediatric patients. We can ask for specific

comments on these sorts of things.

That is one of the things I am trying to

derive from not so much the polling, but from the

discussion that precedes the polling, or what sort

of comments should we be looking for, which we

would be asking for.

I mean there is a certain inclination, at

least on my part, to want to go ahead with the

Notice of Proposed Rulemaking on as many drugs as

possible. If I hear from the committee, no, that's

totally wrong, that is absolutely an essential use,

well, that is a different situation, but if it's an

107

open question, then, I would like to go ahead with

this, just because it is a long, complicated

administrative process.

We have this meeting. We have the Notice

of Proposed Rulemaking. We have a comment period.

During that comment period, we will have an open

public hearing. Then, finally we have to have a

final rule. We will also be consulting with other

agencies - EPA, State, OMB, so it is a very long

process.

So, if we can get the process started,

even if during that process we are not 100 percent

sure and we are still asking questions, then, I

think that is probably the best way to go here.

DR. SWENSON: We will poll then with each

of these drugs, and I think we will allow people to

offer any further points to the needs that you

foresee in any new rule policymaking.

Ms. Schell, will you begin for us then

with cromolyn?

MS. SCHELL: Nonessential.

DR. KERCSMAR: Nonessential.

108

DR. MARTINEZ: Essential.

DR. BRANTLY: Nonessential.

DR. NEWMAN: Nonessential.

DR. MOSS: I am going to abstain.

DR. GAY: Essential.

DR. SWENSON: Essential.

DR. SCHATZ: Essential.

DR. PRUSSIN: Essential.

MS. SANDER: Essential.

DR. SCHOENFELD: I will abstain.

DR. SWENSON: Okay.

Dr. Schoenfeld, I will start you off.

DR. SCHOENFELD: I will abstain.

DR. SWENSON: For Tilade. We are talking

about nedocromil.

Ms. Sander.

MS. SANDER: Are we going to have any

discussion around Tilade?

DR. SWENSON: We can, certainly. This is

the point. If you wish to make comments, go ahead.

MS. SANDER: I would just like to hear

from people around the table a little bit of

109

discussion about this, about Tilade, what they see.

DR. SWENSON: Could you help us by at

least asking a few questions as to why you think

maybe it's different from what we have done with

cromolyn, what separates them?

MS. SANDER: Well, actually, the very

first question, is Tilade really still even around.

It know it's not on this list, and the way this

list was done, we contacted manufacturers.

DR. MEYER: It is still on the essential

use list. It was probably several months ago that

I looked on line to see, but I could not state with

surety that it is marketed at this point, but let's

assume for the purposes of discussion that it is,

because if it's not marketed, we actually have a

mechanism in our essential use rules right now to

remove it without any recommendations of the

committee.

MS. SANDER: I feel it's nonessential.

DR. SWENSON: Does anybody wish to say

anything, so that your opinions might inform the

other members of the panel, or should we continue

110

with the poll?

Dr. Schatz, go ahead.

DR. SCHATZ: As a champion for cromolyn, I

don't feel the same way from clinical experience or

from the data that exists in terms of the

differences between nedocromil and cromolyn, and I

know I can live without it because I have assumed

it has been unavailable and have not been

prescribing it for a long time.

So I feel that it is not the same as

cromolyn in terms of its essentiality, and I think

the comparative data that do exist, by and large,

support that. So, particularly if cromolyn were

available, I don't see nedocromil would have to be.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I can't think of the last

time I picked up a pen and wrote a prescription for

that particular medication, so I would underscore

that.

DR. SWENSON: Ms. Sander, do you have

anything further?

MS. SANDER: No.

111

DR. SWENSON: Let's start again then just

in light of these comments.

Dr. Schoenfeld.

DR. SCHOENFELD: I will abstain.

DR. SWENSON: Ms. Sander.

MS. SANDER: Nonessential.

DR. PRUSSIN: Nonessential.

DR. SCHATZ: Nonessential.

DR. SWENSON: Nonessential.

DR. GAY: Nonessential.

DR. MOSS: Nonessential.

DR. NEWMAN: Nonessential.

DR. BRANTLY: Nonessential.

DR. MARTINEZ: Nonessential.

DR. KERCSMAR: Nonessential.

MS. SCHELL: Nonessential.

DR. SWENSON: We will move to our last

agent, the combined product of albuterol and

ipratropium, Combivent. I think we should just

begin first with any general comments that panel

members wish to make.

DR. PRUSSIN: I have a question for the

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pulmonologists. How much Combivent, how often is

it being used rather than, let's say, as a

combination inhaler rather than somebody, let's

say, being on Advair and then using ipratropium as

a separate inhaler? Is this really a mainstay of

COPD therapy?

DR. BRANTLY: It remains a mainstay. It

is used quite frequently by many physicians at the

present time.

DR. SWENSON: I would concur with that.

It represents probably about 50 percent for me

vis-a-vis the separate agents.

Dr. Gay.

DR. GAY: Indeed, it remains quite

popular. The concern is whether or not its

popularity will begin to progressively wane with

the increasing popularity of Spiriva. The two

drugs cannot be used together because of the

interactions between the short-acting

anticholinergic and the long-acting

anticholinergic, so what you may see with time is

if patients triage to the newer medication, the

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Spiriva (tiotropium), clearly, the usage of

Combivent is going to have to decrease.

DR. SWENSON: Dr. Moss.

DR. MOSS: I work at a hospital that has a

very limited budget, and we do not have Combivent

on our formulary. Patients are required or have to

use each medication individually, and I think it is

just important to point out that these medications

are available individually, people can get these

drugs.

It is easier if they use it in one

inhaler, but if we are thinking about whether

something is essential or not, I am not sure we can

say it's essential if the two drugs are available

independently in non-CFC compounds.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I believe there were some

recent COPD guidelines, at least I heard a

presentation about that, and I don't take care of

COPD, so I am not as up to date, but where does

this combination fit in terms of those guidelines?

DR. SWENSON: Dr. Gay.

114

DR. GAY: It fits in the guidelines with

the short-acting bronchodilator, so for patients

with mild disease, at this time, that is where it

falls. It has been used upon occasion as a rescue

type inhaler, as well, not only in COPD, but in

asthma, as well, but its utility, its frequency of

use in that asthma population tends to be

considerably low.

But at this point, it's a short-acting PRN

or a short-acting inhaler for patients with mild

disease.

DR. SWENSON: Dr. Kercsmar.

DR. KERCSMAR: I just have a question to

clarify also. We don't take care of a lot of COPD

in pediatrics. So, is what you are saying in the

guidelines, is what is recommended the fixed dose,

metered dose inhaler, or the two drugs given

separately or simultaneously?

DR. GAY: No, you are very correct, and I

thank you. It is not specifically this inhaler,

but the two drugs, the two drugs.

DR. SWENSON: Ms. Schell.

115

MS. SCHELL: I am not sure if this is a

consideration, but compliance factor of the patient

taking the medication, taking the Combivent

compared to taking the two inhalers, is that

something that would play into this when we are

looking at essential or not, because I know, as a

practitioner, with patients, that I can get them to

take a Combivent easier than I can get them to take

two different inhalers. So, is that a factor that

we look at when we are looking at if it's

essential, its compliance?

DR. MEYER: I just wanted to make a

comment in that regard. I think it's an important

question. Both albuterol and the ipratropium in

the setting of COPD are primarily aimed at symptom

reduction, and not disease modification.

Compliance would be a particularly

important consideration in a disease modification

therapy, and a therapy aimed at treating symptoms

and driven by, particularly if it's prescribed at a

PRN manner by symptoms occurring, I don't think

compliance is quite the issue.

116

So, I would just raise that perspective.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I would still say that I

think it should be an issue. I think that if the

guidelines recommend the combination, there is just

no question that the fact that they are available

separately, I think we serve patients better by

keeping the combination available.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I think a clarification. I

don't think that there is a guideline that I am

aware of that requires you to be on both of these

medicines simultaneously. Dr. Gay, maybe you want

to comment on that.

DR. GAY: To clarify this, each of these

medications separately falls under the guideline of

a short-acting bronchodilator, which is recommended

for the treatment across the board for use in COPD.

There is no place in the guideline

specifically for the physical moiety of Combivent.

There is clearly use of beta-agonists in

combination with anticholinergics as part of

117

symptom reduction, both as short acting and long

acting agents, but no, there is not a specific

place in any of the guidelines that says that

Combivent alone is appropriate therapy, although

there are places in the guidelines where they do

clearly talk about the combination of the different

bronchodilators.

DR. SWENSON: Dr. Moss.

DR. MOSS: I think if we are going to talk

about compliance issues that Ms. Schell brought up,

which I think are very important, I agree if you

have one inhaler, it is easier to use that than if

you have two, and the compliance will be better,

but I think that needs to be balanced by the cost

of the medication as Combivent together is more

than each individual inhaler alone, at least in our

practice.

So, when you are talking about compliance,

there is the other side of cost that needs to be

balanced with the ease of use. So, I just wanted

to make that statement.

DR. MEYER: Can I follow up on that,

118

because that is probably true now. When albuterol

is no longer available as a generic inhaler, which

will happen as of December 31st, 2008, that may

well not be the case any longer.

So, just to put that in perspective.

DR. SWENSON: Ms. Sander.

MS. SANDER: I have a couple of questions

for Boehringer Ingelheim. Can I ask them directly?

DR. SWENSON: I think that is fair.

MS. SANDER: In your presentation, you

said over 8 million patients worldwide use

Combivent, or excuse me, use your medications. How

many of them use Combivent?

DR. SHEPARD: We quoted that 2 million

patients in the U.S. use Combivent. As far as the

worldwide figure, I am sorry, I am not sure, but

it's 2 million in the U.S. with over 13 million

prescriptions also in the U.S.

MS. SANDER: With 13 million prescriptions

did you say?

DR. SHEPARD: Correct.

MS. SANDER: In your testimony, you said

119

you strongly endorse a smooth, timely, and

effective transition that protects patients. How

would you describe that for Combivent, taking place

for Combivent?

DR. SHEPARD: In other words, protecting

the patient?

MS. SANDER: Right, well, in terms of you

making your company strategy, to make the

transition from CFC to--you know, I know that you

are working on your HFA.

DR. SHEPARD: Atrovent HFA was approved.

It was a comment relating to that as far as making

sure the transition occurred smoothly, having the

offering of both, and then the discontinuation of

that product which we thought was a reasonable time

for the patient and the physician to make that

transition.

Did I answer your question?

MS. SANDER: Yes. So, your conclusion is

that right now, in order for you to serve patients'

needs here in the United States, Combivent must

continue to be designated as an essential use, is

120

that right?

DR. SHEPARD: Correct.

MS. SANDER: Thank you.

DR. SHEPARD: I guess I shouldn't comment

anymore if I wasn't asked a question about it, but

when we are talking about patient care also, we are

also saying that we have made available, somebody

else said Spiriva in an alternative form, we now

have Atrovent, but there is a stronghold of

patients--that is where we gave the numbers--that

still use this product, and are very loyal to it.

MS. SANDER: We see in our dealings with

patients that a lot of them are using Combivent.

DR. SWENSON: Dr. Prussin.

DR. PRUSSIN: A very simple and direct

point, but the word here is essential, and I think

all these uses we are talking about are preferable,

but not essential uses of a drug.

DR. SWENSON: Dr. Martinez.

DR. MARTINEZ: The arguments that have

been given convince me that we cannot consider this

an essential medication in the sense described.

121

The patients will have available the two other

products. I completely agree with Dr. Meyer that

this does not meet the requirement for compliance

because here, it should be considered more relief

type medication, and individuals who take this

medication, one would suspect feel the relief and

thus will have the stimulus to do so, which is

different for a controller.

I think here we have to take into account

what Dr. Meyer told us with respect to the

commitments of the United States to the protection

of the environment. I mean that sense and given

also the fact that the company has told us

explicitly that they remain optimistic that they

will overcome these challenges to product this

combined product.

I think by declaring nonessential will

stimulate the company to pursue this even further

and more aggressively because by 2008, which is

when the albuterol will become perhaps more

expensive, if they do so, I think we should expect

that this product will be available in the form of

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an HFA.

So, for those reasons, I think we cannot

consider this an essential product.

DR. SWENSON: Ms. Schell.

MS. SCHELL: I have a question. If we

consider this nonessential, will there be enough

Atrovent available? I mean is there enough drug

available to replace the 13 1/2 million? Do you

see what I am saying? Will the drug be available

if we don't have Combivent available, will there be

enough Atrovent available?

DR. MEYER: Again, I think the important

point there is that there is a process that would

play out from here that would allow time, and if,

in fact, we were convinced that there were not

adequate alternatives available in terms of supply,

we could effect a date such that it would allow for

that.

I did want to make one comment with regard

to Dr. Martinez's points, which is I don't think we

can infer that the lack of Combivent alternative

product now represents any lack of commitment on

123

the part of BI, and therefore, I don't think we can

infer that if we said that Combivent was

nonessential, that it would spur their development

to be better than it is now, you know, to be fair

to the company.

I think your points are well taken, but I

just wanted to make that point that I think the

challenges to reformulation, particularly for

products with very low microgram strength, such as

the ipratropium component of this product, are

high, they are very high, and I don't think you

could take the lack of a product being available at

this point as a lack of commitment on the part of

the sponsor.

DR. MARTINEZ: I am sorry, I didn't intend

to infer that. I just said that--I am not talking

about the past--I am talking about the future. It

is obvious to me as a matter of logic that the fact

that now perhaps this product would be on the list

of products that would be declared nonessential,

could stimulate even further efforts, because the

amount of efforts that can be put may differ

124

depending on how much time you have available to

develop those efforts.

It is just an opinion, not a definitive

issue.

DR. MEYER: Understood. I just wanted to

make a defense of the company, that I think that

there are significant challenges, and I don't think

we can infer or imply that, in fact, the fact that

it is not on the market right now means they are

not fully committed and working quite hard in terms

of reformulation.

DR. MARTINEZ: Point well taken.

DR. SWENSON: Dr. Schatz.

DR. SCHATZ: I come back to these

guidelines which I think I am remembering better.

It was my understanding that these international

guidelines started with beta-agonists, and granted

for the milder ones, that when that wasn't

adequate, then, a second inhaled bronchodilator was

recommended, and that would either be then

albuterol plus ipratropium, or it would be

albuterol plus tiotropium.

125

Then, the next level up was inhaled

steroids. So, for that group, if I am correct

about that, for that group that we want to add that

second bronchodilator, if they don't tolerate

tiotropium, then, if we take away the combination,

then again we are forcing these two different

products, and I do come back to the fact that one

product in that recommended category for patients

is easier than the other.

So, I do believe that this has an

important role for a substantial number of

patients, and so I am still advocating for its

essential use.

DR. SWENSON: Dr. Gay.

DR. GAY: Yes, I should clarify the

guideline once again. No, the initial portion of

the guideline is not beta-agonist. It is clearly

written as short-acting bronchodilator, and that

bronchodilator can be either the short-acting

beta-agonist or a short-acting anticholinergic.

DR. SCHATZ: Right, and the next level is

two bronchodilators.

126

DR. GAY: That is correct.

DR. SWENSON: Dr. Newman.

DR. NEWMAN: I think at the end of the day

I ask myself can I practice good medicine without

this particular combination drug, and the answer is

yes. Do I think that Marc Moss' patients get

inferior care because this hospital doesn't have

Combivent on its formulary, I think the answer is

no, they can get good care.

If a patient came to me and said, Dr.

Newman, I must have Combivent, and I didn't have it

available, I would say we can take care of your

needs with other medications. I think for me, at

the end of the day, that makes it nonessential in

my view, you know, with all the caveats about yes,

it is more convenient, and in the short term I

think it is admirable that it's a drug that, by

combining it, reducing the CFCs by 50 percent, and

all the energy that BI is putting into trying to

reformulate, all that being taken into account,

when you ask the question is this essential, I

would say no, it isn't in my practice.

127

DR. SWENSON: Dr. Brantly.

DR. BRANTLY: I would go back to the

studies that have shown that the combination of

ipratropium bromide and albuterol versus the two

separate is superior in several of the studies that

have been done, and I think that from that

standpoint, I think it is--it has been shown in the

past to be more effective primarily because of

patient compliance.

I just want to remind you again that there

are probably 2 million patients that are taking

this, and they are taking it for a good reason. At

least in my practice of medicine, I prescribe this

widely, and it is used, and the patients ask for it

on a regular basis also.

I believe that in the context that this

company has been moving forward in transferring, I

think leaving it as an essential drug for the

present time is a reasonable approach.

DR. SWENSON: Ms. Sander.

MS. SANDER: What happens if the

manufacturer for Drug X is making all these great

128

strides forward with an HFA formulation, but, you

know, there is challenges that they just ultimately

don't meet, they can't meet in the new formulation?

If we decide something today is not

essential, how does that affect what patients are

going to wind up with if a company is unable to get

something through the NDA process? That is part

one of my question.

DR. MEYER: Okay. Again, I think for

purposes of today's discussion, you should not

regard the reformulation effort. So, you should

assume that if you were to recommend that Drug X is

not essential, that you are envisioning a future

where Drug X may not be available to your patients

in any formulation.

MS. SANDER: Thank you. With that, then,

I would have to say as a patient advocate and from

the patient perspective, you know, I do see this as

a drug that needs to remain essential at least for

the time being, because of the severe anxiety and

unnecessary anxiety that many families and

patients, more importantly, would go through,

129

patients who are currently tethered to oxygen or to

their homes, and really do see this as a necessary

medication.

DR. SWENSON: Dr. Moss.

DR. MOSS: I have sort of a question and a

comment. It gets back to the timing issue.

Correct me if I am wrong, Dr. Meyer, but it is not,

you know, when something is decided to be

nonessential, the amount of time that the company

has to try to convert over is not a uniform thing,

and it would be something that the FDA could work

with the company to help with that transition

process, is that correct?

DR. MEYER: I think if we were aware of an

impending approval, for instance, we might take

that into consideration, but again, we have to some

degree divorce these to some degree.

DR. MOSS: The other think I wanted to say

is if we start talking about compliance issues,

which are clearly important, and we combine an

anticholinergic agent with a beta-agonist, and

Combivent, and say that is essential, it sort of to

130

me raises the issue which I don't think we want to

raise, well, what if you combine a beta-agonist

with an inhaled corticosteroid, are those all of a

sudden now essential medications because it is

easier to use those two combined them, one

separately, so I think it raises another issue that

if you think about it that way, I am not sure we

would sit there and now say that Advair is an

essential medication, and they could go back to

using it that way.

DR. SWENSON: All right. There being no

further questions, one last chance. I think people

have expressed some opinion.

DR. MEYER: I just wanted to respond to

Dr. Moss' comment. I understand your comment, but

I don't think the committee should really be

thinking that way either. Just focus on this

particular matter and don't think about the

present.

DR. SWENSON: We will go ahead and begin

our poll.

Ms. Schell.

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MS. SCHELL: Essential.

DR. KERCSMAR: I am going to abstain.

DR. MARTINEZ: Nonessential.

DR. BRANTLY: Essential.

DR. NEWMAN: Nonessential.

DR. MOSS: Nonessential.

DR. GAY: Essential.

DR. SWENSON: Nonessential.

DR. SCHATZ: Essential.

DR. PRUSSIN: Nonessential.

MS. SANDER: Essential.

DR. SCHOENFELD: Abstain.

DR. SWENSON: Okay. I believe we have

concluded business, but, Dr. Meyer, any other

points?

DR. MEYER: Just again I know I started

off by thanking the committee in advance, and now I

would like to thank you in retrospect actually for

both days. I think this has been very different

considerations on day one versus day two, but I

think this has been a very, very helpful discussion

on both days.

132

I am very grateful to the talented and

very intelligent folks who are serving on our

committee, and thank you for your attendance. I am

glad to have you dismissed a little early.

DR. SWENSON: And we thank you, the FDA,

for all the work that you have put together for

this and to everyone.

We are formally adjourned.

[Whereupon, at 11:00 a.m., the meeting was

adjourned.]

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