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

                                                                  2

 

                               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

                                                                  3

 

                             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

                                                                  4

 

                          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,

                                                                  5

 

       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

                                                                  6

 

       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.

                                                                  7

 

                 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.

                                                                  8

 

                 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

                                                                  9

 

       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

                                                                 10

 

       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.

                                                                 11

 

                         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

                                                                 12

 

       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

                                                                 13

 

       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.

                                                                 14

 

       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

                                                                 15

 

       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.

                                                                 16

 

       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

                                                                 17

 

       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

                                                                 18

 

       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.

                                                                 19

 

                 [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

                                                                 20

 

       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.

                                                                 21

 

                 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.

                                                                 22

 

                 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

                                                                 23

 

       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

                                                                 24

 

       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

                                                                 25

 

       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

                                                                 26

 

       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

                                                                 27

 

       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

                                                                 28

 

       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

                                                                 29

 

       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

                                                                 30

 

       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

                                                                 31

 

       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

                                                                 32

 

       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

                                                                 33

 

       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

                                                                 34

 

       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

                                                                 35

 

       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

                                                                 36

 

       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

                                                                 37

 

       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.]

                                                                 38

 

                 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

                                                                 39

 

       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

                                                                 40

 

       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

                                                                 41

 

       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

                                                                 42

 

       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

                                                                 43

 

       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

                                                                 44

 

       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

                                                                 45

 

       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

                                                                 46

 

       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.

                                                                 47

 

                 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

                                                                 48

 

       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

                                                                 49

 

       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

                                                                 50

 

       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

                                                                 51

 

       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

                                                                 52

 

       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.

                                                                 53

 

                 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

                                                                 54

 

       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

                                                                 55

 

       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

                                                                 56

 

       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

                                                                 57

 

       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,

                                                                 58

 

       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,

                                                                 59

 

       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

                                                                 60

 

       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

                                                                 61

 

       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,

                                                                 62

 

       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

                                                                 63

 

       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.

                                                                 64

 

                 [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.

                                                                 65

 

                 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.

                                                                 66

 

                 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

                                                                 67

 

       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

                                                                 68

 

       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

                                                                 69

 

       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

                                                                 70

 

       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

                                                                 71

 

       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

                                                                 72

 

       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

                                                                 73

 

       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

                                                                 74

 

       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

                                                                 75

 

       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

                                                                 76

 

       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

                                                                 77

 

       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.

                                                                 78

 

                 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.

                                                                 79

 

                           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

                                                                 80

 

       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

                                                                 81

 

       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

                                                                 82

 

       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

                                                                 83

 

       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.

                                                                 84

 

                 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

                                                                 85

 

       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.

                                                                 86

 

                 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

                                                                 87

 

       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,

                                                                 88

 

       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

                                                                 89

 

       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

                                                                 90

 

       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.

                                                                 91

 

                 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.

                                                                 92

 

                 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

                                                                 93

 

       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? 

                                                                 94

 

       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.

                                                                 95

 

                 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

                                                                 96

 

       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.

                                                                 97

 

                 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

                                                                 98

 

       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

                                                                 99

 

       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.

                                                                100

 

                 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

                                                                101

 

       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

                                                                102

 

       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

                                                                103

 

       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

                                                                104

 

       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

                                                                106

 

       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

                                                                112

 

       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

                                                                113

 

       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.

                                                                131

 

                 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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