FOOD AND DRUG ADMINISTRATION










                         PULMONARY-ALLERGY DRUGS


                            ADVISORY COMMITTEE


















                         Thursday, July 14, 2005


                                8:10 a.m.







                           Gaithersberg Hilton

                              The Ballrooms

                            620 Perry Parkway

                          Gaithersburg, Maryland





       Erik R. Swenson, M.D., Chairman

       Teresa Watkins, R.Ph., Executive Secretary




       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.




       Karen Schell, RRT




       Nancy J. Sander, Virginia




       Robert Meyer, M.D.

       Badrul Chowdhury, M.D.

       Eugene J. Sullivan, M.D., FCCP



                             C O N T E N T S




       Call to Order and Opening Remarks

                 Erik R. Swenson, M.D.                            4


       Introduction of Committee                                  4


       Conflict of Interest Statement

                 Teresa A. Watkins, R.Ph.                         6


       FDA Introductory Remarks


          Plaque Presentation

                 Robert Meyer, M.D.                              11


       FDA Presentation:


          The Montreal Protocol and the Status

            of Essential Use Process (21 CFR 2.125)

                 Robert Meyer, M.D.                              12


       Clarifying Questions                                      43


       Open Public Hearing                                       64


       Clarifying Questions                                      79


       Committee Discussion                                      85



                          P R O C E E D I N G S


                    Call to Order and Opening Remarks


                 DR. SWENSON:  Good morning, everyone.  I


       am Erik Swenson, Professor of Medicine at the


       University of Washington, and chairman of this


       meeting of the Pulmonary-Allergy Drugs Advisory




                 We are meeting today to discuss the


       continued need for essential use designations of


       several prescription drugs for the treatment of


       asthma and chronic obstructive pulmonary disease


       under 21 CFR 2.125.  This is an issue surrounding


       the use of CFC propellants in inhaled drugs for the


       treatment of lung disease.


                 To begin with, I would like the members of


       the panel to go around and introduce themselves and


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


                        Introduction of Committee


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


       Director of the Office of Drug Evaluation II in the


       Center for Drugs, FDA.


                 DR. CHOWDHURY:   I am Badrul Chowdhury,



       Director, Division of Pulmonary and Allergy Drug


       Products, FDA.


                 DR. SULLIVAN:  My name is Gene Sullivan.


       I am the Deputy Director of the Division of


       Pulmonary and Allergy Drug Products.


                 DR. SCHOENFELD:  David Schoenfeld.  I am a


       member of the Committee.  I am a Professor of


       Medicine and Biostatistics at Harvard.


                 MS. SANDER:  I am Nancy Sander.  I am


       President and founder of the Allergy and Asthma


       Network, Mothers of Asthmatics.  I am here as a


       patient advocate.


                 DR. PRUSSIN:  I am Calman Prussin,


       Clinical Investigator, Laboratory of Allergic


       Diseases, National Institutes of Health.


                 DR. SCHATZ:  Michael Schatz, an


       allergist/immunologist from Kaiser Permanente, San




                 MS. WATKINS:  I am Teresa Watkins, the


       Executive Secretary for this committee.


                 DR. GAY:  Steven Gay, Assistant Professor


       and Medical Director of Critical Care Support



       Services, University of Michigan.


                 DR. MOSS:  Marc Moss, Associate Professor


       of Medicine, Emory University, Atlanta.


                 DR. NEWMAN:  Lee Newman, Professor of


       Medicine and Preventive Medicine Biometrics,


       National Jewish Medical and Research Center, and


       University of Colorado School of Medicine, Denver,




                 DR. BRANTLY:  Mark Brantly, Professor of


       Medicine, University of Florida.


                 DR. MARTINEZ:  Fernando Martinez,


       Professor of Pediatrics, University of Arizona in




                 DR. KERCSMAR:  Carolyn Kercsmar, Professor


       of Pediatrics, Rainbow Babies and Children's


       Hospital, Case Medical School in Cleveland.


                 MS. SCHELL:  Karen Schell.  I am a


       consumer representative.  I am a respiratory


       therapist from Emporia, Kansas.


                      Conflict of Interest Statement


                 MS. WATKINS:  I will now read the Conflict


       of Interest Statement.



                 The Food and Drug Administration is


       convening today's meeting of the Pulmonary-Allergy


       Drugs Advisory Committee under the authority of


       Federal Advisory Committee Act of 1972.  With the


       exception of the industry rep, all members of the


       Committee are special government employees or


       regular federal employees from other agencies


       subject to federal conflict of interest laws and




                 FDA has determined that all members of


       this advisory committee are in compliance with


       federal ethics and conflict of interest laws


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


       U.S.C. 355, Subsection (n)(4).


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


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


       applicable to FDA, Congress has authorized FDA to


       grant waivers to special government employees who


       have financial conflicts when it is determined that


       the agency's need for a particular individual's


       services outweighs his or her potential financial


       conflict of interest.



                 Members who are special government


       employees at today's meeting, including special


       government employees appointed as temporary voting


       members, have been screened for potential conflicts


       of interest of their own, as well as those imputed


       to them including those of their employer, spouse,


       or minor child related to the discussions regarding


       the continued need for the essential use


       designations of prescription drugs for the


       treatment of asthma and chronic obstructive


       pulmonary disease under 21 CFR 2.125.


                 These interests may include investments,


       consulting, expert witness testimony, contracts,


       grants, credos, teaching, speaking, writing,


       patents and royalties, and primary employment.


                 In accordance with 18 U.S.C. Section


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


       following participants.  Please note that all


       interests are in firms that could be potentially


       affected by today's discussion.


                 Dr. Carolyn Kercsmar, for activities on a


       speakers bureau.  She receives less than $10,001



       per year for two grants which are valued at less


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


       the firm supplies products worth approximately less


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


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


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


       minimus exemption under 5 CFR 2640.202 applies.


                 Dr. Fernando Martinez, for his membership


       on a speakers bureau.  He has not lectured or


       received remuneration for membership on the related


       advisory board. He has not participated or received


       any remuneration to date.


                 Dr. Michael Schatz, for activities on a


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


       year, and for a grant for which the firm supplies


       the product worth approximately less than $100,000


       per year.


                 Ms. Nancy Sander, for ownership of stock


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


       for unrelated advisory board activities for which


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


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



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


       because the de minimus exemption under 5 CFR


       2640.202 applies.


                 Dr. Steven Gay, for speakers bureau


       activities with five firms, three of which he


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


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


       per firm per year.


                 We would also like to disclose that Dr.


       Marc Moss' spouse owns stock worth less than


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


       required because the de minimus exemption under 5


       CFR 2640.202 applies.


                 A copy of the written waiver statements


       may be obtained by submitting a written request to


       the agency's Freedom of Information Office, Room


       12A-30 of the Parklawn Building.


                 Lastly, the industry representative Dr.


       Theodore Reiss was invited, but due to a family


       emergency he was unable to attend today.


                 DR. SWENSON:  Dr. Robert Meyer of the FDA


       will give us some introductory remarks.



                         FDA Introductory Remarks


                           Plaque Presentation


                 DR. MEYER:  Thank you very much.


                 Before proceeding with the formal part of


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


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


       Schell, Karen Schell, has served our committee now


       for four years, actually officially from November


       2001 through May 2005.  We have continued to call


       on her services in a special government employee


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


       few weeks ago, as well.


                 But she has served for these four years as


       the consumer representative, which is a very


       important role to these committees, where she


       brings the patient perspective, which I think she


       has done admirably.


                 Her background is, as she said earlier, as


       a respiratory therapist in Emporia, Kansas, and she


       has got a very broad background in respiratory


       therapy including being a registered


       polysomnographist and also has certification in



       disease management of asthma, so she is very well


       qualified for representing the concerns of


       patients, and we have really benefited from having


       her on the committee.


                 In recognition of that, we would like to


       present her with this plaque and I will walk over


       and do so.




                             FDA Presentation


                 The Montreal Protocol and the Status of


                   Essential Use Process (21 CFR 2.125)


                 DR. MEYER:  I would like to extend my


       thanks again in advance to the committee for being


       here.  This will be a very different session from


       yesterday and, indeed, a very different session I


       think from most every advisory committee I have


       ever been involved in, because this is not really


       asking you your opinion of data, but it is really


       calling on your expertise as practitioners to let


       us know whether some of the remaining medicines


       that are listed as essential uses are indeed


       essential uses under certain criteria that I will



       discuss shortly.




                 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




                 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




                 So, during this talk, I would like to


       briefly touch on some ozone science.  I am not an


       ozone scientist, but I will briefly touch on that


       as a prelude to talking about the Montreal


       Protocol, which is the international treaty that is


       in place to deal with the preservation of the ozone


       layer and hopefully, the restoration of the ozone


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



       laws pertaining to these.  This will all serve as


       background to the discussion that we hope will


       ensue from that.


                 Just to start off with the general


       background on the ozone science, the ozone layer,


       as it is called, is actually a region of relatively


       higher ozone concentration in the stratosphere.


                 On this graphic that is depicted here, we


       have ozone amounts in parts, I think it is actually


       in pressure, milliPascals, and on the y axis we


       have altitude in kilometers.  You can see other


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


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


       in the troposphere where we live.  Otherwise, the


       ozone is fairly limited in terms of its


       representation in the environment until you get to


       the stratosphere, which begins at about 15


       kilometers high and reaches a peak just at about 24


       kilometers or about 16 miles up.




                 This layer, as it is called, reduces the


       amount of ultraviolet radiation, UV-B in



       particular, reaching the surface of the earth from




                 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




                 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






                 Now, because the development of the U.S.



       laws, FDA regulations, and indeed the Montreal


       Protocol itself have proceeded in overlapping


       timeframes, when I continue this talk, I will


       overlap these discussions and go back and forth to


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




                 In 1974, there was a paper published in


       Nature by Molina and Rowland that was the first


       paper to tie the depletion of ozone, which had been


       recently detected and defined, to stratospheric


       chlorine from degraded CFCs, so these are the first


       scientists to put together the fact that the


       emission of CFCs could lead to this phenomenon.


                 At that time, CFCs were very widespread in


       use in the United States.  They were used, for


       instance, in refrigerators, both in terms of the


       coolant itself, as well as the foam insulation in


       air conditioners in cars and homes, and other


       chillers, foams, and in many consumer and medical


       aerosol products.  So, they were ubiquitous in use


       at that time.


                 CFCs have many wonderful properties.  They



       are incredibly inert and very stable, which in some


       respects is their downfall in the ozone, because as


       they migrate up to the stratosphere, their


       half-life up in the stratosphere is measured in






                 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




                 So, since 1978, consumer aerosols, such as


       hairsprays and spray paint, and other such


       aerosols, bug sprays, have not contained CFCs, so


       they have actually been gone from such products for


       nearly 30 years.


                 At that same time period, FDA first


       published our regulation, which is 21 CFR, this is



       our chapter of the Code of Federal Regulations, and


       the specific citation for that is 2.125, and that


       also banned the use of CFCs in FDA regulated


       products including drug products, but did allow for


       essential exemptions.




                 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.





                 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




                 Now, it is important to point out, though,


       that while there is a lot of attention paid to this


       ozone hole over the Antarctic, the depletion is


       prominent over a lot of the southern hemisphere,


       Australia, for instance, is quite affected by this


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


       in Australia now that schoolchildren on recess need


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


       the depletion besides being prominent in the



       southern hemisphere, is global.


                 The other thing I should point out that


       although we are here to talk about


       chlorofluorocarbons because of their role as


       propellants in many important asthma and COPD


       medications, the Montreal Protocol controls many


       ozone-depleting substances, and there are many


       others other than CFCs, such as halons, HCFCs,


       methyl bromide, and carbon tetrachloride.




                 With regard to CFCs, however, as of


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


       industrialized countries and is targeted for this


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


       2010, so just in another five years.


                 MDIs for asthma and COPD currently--and I


       underline that for a reason--are exempted from


       essential use processes.  There has been an


       essential use process in place since January 1,


       1996, but it was always the intent of the Montreal


       Protocol that this be a temporary process and that


       all such uses would be phased out over time.



                 Nominations for essential uses in


       medications are reviewed annually and generally,


       they are reviewed two years in advance, so, in


       other words, in 2005, the parties would ordinarily


       be reviewing 2007 nominations.  In fact they are. I


       put the word "ordinarily" in there because there


       are some issues with that this year, that are not


       germane to today's discussion, but we are doing


       everything really in anticipation of two years down


       the road, and that is to allow the countries that


       make these nominations to go through their own


       processes of then taking what is allotted to them


       and allocating it out and making sure it gets to


       the products that they have deemed essential.




                 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





                 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




                 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






                 Decision XII/2 stated that any product



       approved after December 2000 must individually meet


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


       this really took it from the macroscopic to the


       microscopic, so any new product at that point must


       meet the criteria of having no technically or


       economically feasible alternatives to have that


       essential role in the treatment of society or in




                 This product-centered determination of


       essentiality really precluded new CFC generics or


       other new CFC products because of this high hurdle.




                 Decision XV/5 stated that essential use


       nominations are now specific.  In the past, a


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


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


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


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


       instance, and those numbers are not meant to be


       accurate, they are just meant to be representative


       or used as an example.


                 This decision also said no quantity of



       essential use CFCs will be authorized for albuterol


       specifically beginning with 2005's meeting of the


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


       of albuterol and submitted to the Open-Ended


       Working Group.  This is an earlier working meeting


       of the parties by the summer of 2005.


                 I would just point out that the FDA final


       rule published earlier this year on the phase-out


       of albuterol, which stated that we will consider


       albuterol no longer to be essential in the United


       States after December 31st, 2008.  We regard this


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




                 In response to the Montreal Protocol and


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


       '80s, the Clean Air Act Amendments included changes


       to the Clean Air Act that essentially implemented


       the Montreal Protocol into U.S. law.


                 The EPA regulations that then implemented


       the amendment to the Clean Air Act refer to the


       Health and Human Services and FDA through citing


       our specific regulation of essentiality for



       determining medical essentiality.  Again, this


       rule, 2.125 was published before the Montreal


       Protocol and, in fact, before we really had much


       experience with the phase-out or even the prospects


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




                 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.




                 Importantly, that rule, when it was


       promulgated, had no mechanism to determine when


       uses were no longer essential, so it had ways to


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



       when products were no longer essential and then to


       take them off the essential use list.


                 The other thing that was notable about it


       is most important drugs were not listed as separate


       entities, but they were actually listed in very


       broad classes, such as there was a class of


       adrenergic bronchodilators for human use that


       included albuterol, pirbuterol, salmeterol, and so


       on, so things were not individually listed.


       Although there was some individual listing, many


       things were put into broad therapeutic classes.


                 So, to deal with both of these issues, in


       1996, FDA published an Advanced Notice of Proposed


       Rulemaking, so the very early stages or rulemaking


       to revise 2.125.




                 That publication led to a very large


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


       public comments, which to folks not perhaps


       involved in regulations may not have sort of a


       goalpost to measure it by, but this is a large


       number of comments.  Many of these were sparked by



       lobbying efforts of concerned entities.


                 In 1999, taking several years to consider


       carefully all the comments that we received and the


       changes in the Montreal Protocol and other factors,


       FDA published a Notice of Proposed Rulemaking,


       which is the first formal step in rulemaking.


                 That Notice resulted in far fewer


       substantive comments and much less controversy than


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


       complete a final rule, revising 2.125, in July of


       2002, and that rule went into effect in 2003.




                 Just to highlight some of the revisions,


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


       listed individual moieties as essential uses rather


       than classes, so, for instance, I had mentioned


       earlier that albuterol was under the class of


       adrenergic bronchodilators for human use, was taken


       out and listed separately within the essential use


       list under Part (e) here of 2.125.


                 One of the reasons we did this was because


       in 1996, when we published the Advanced Notice of



       Proposed Rulemaking, one of the things we said was


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


       float the idea that you could do this two ways.


                 You could say, okay, albuterol will only


       be considered in and of itself, and after there are


       adequate alternatives, then, we could say albuterol


       CFC is no longer essential.


                 On the other hand, you could do what is


       called a therapeutic class determination and say if


       you took the inhaled corticosteroids, for instance,


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


       corticosteroids with adequate alternatives, we


       might say all the rest are no longer essential, and


       that would a therapeutic class approach.


                 The attraction to such an approach is that


       it allows products that are not being reformulated


       to be dealt with if they are in that therapeutic


       class, but the public comments were very strong


       against the therapeutic class approach, and in


       response to that, we no longer had a therapeutic


       class approach as 2.125 came to finalization.


                 So, it was important then to list every



       moiety separately, and I will get back to the


       implications of the lack of a therapeutic class


       approach in a second.


                 These revisions also added a higher hurdle


       for new IND use or investigational new drug use of


       ozone depleting substances.  I guess I should also


       pause here and say we changed the terminology here


       to be consistent with the Montreal Protocol, and


       what we are essentially talking about for the


       purposes of this meeting remain CFCs, but because


       the Montreal Protocol talks about ozone depleting


       substances, we have changed that to be consistent


       with that and the Clean Air Act.


                 Besides adding a higher hurdle for new IND


       use, it also raised the bar for new listings of


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


       has been any new essential list listings certainly


       since the time of this publication.




                 Importantly, then, the changes to 2.125


       listed criteria for determining when individual


       uses would no longer be essential and the moiety



       would come out of the essential use list that is


       contained in 2.125(e).


                 Let me just go over those criteria


       quickly.  The non-essentiality criteria essentially


       stated that at least one non-ozone depleting


       substance product with the same activity moiety,


       the same indication, the same route of


       administration, and about the same level of


       convenience would need to be available.


                 In addition to that, we would need


       adequate post-marketing data to be available for


       the non-ODS product.


                 We would need to be assured that


       production capabilities and supplies were adequate


       or would be adequate at the time the de-listing


       becomes final, and finally, there was a requirement


       to be assured that patients who require the CFC


       product are adequately served by the alternative.


                 Now, there is an asterisk here stating


       that this is for products with only one marketed


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


       1 here.  For products with more than one strength



       available, such as fluticasone, for instance, is a


       product with numerous strengths, or for products


       where there is more than one NDA or more than one


       source of that product, such as albuterol, which


       had not only two branded products, but numerous


       generic products.


                 We stated that there would have to be at


       least two non-ozone depleting products with the


       same active moiety, the same indication, route of


       administration.  So, all the other criteria were


       the same, but the difference here was that there


       would have to be at least two.




                 Now, as I mentioned earlier, one of the


       advantages to a therapeutic class approach is that


       it can help to deal with products that are not


       being reformulated, but because of important and


       well-taken public input, we did not include a


       therapeutic class approach in the finalization of


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


       dealing with products that are remaining on the


       market, and not represented by any kind of



       alternatives in the marketplace, and we stated in


       that rule that FDA has therefore revised


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


       evaluation of all ozone depleting products after


       January 1, 2005, not just those products without a


       non-ODS replacement.




                 So, what this means is that beginning in


       2005, beginning now, FDA can convene public


       meetings, that is, an advisory committee meeting,


       such as today, to discuss those products still


       listed as essential to determine if changes in the


       medical practice and availability of alternatives


       render these products as no longer essential.


                 Under the revised 2.125, kind of harkening


       back to earlier language, that essential is based


       on there being no technically feasible


       alternatives, provides substantial health, public,


       or environmental benefit, and release of CFC small,


       or justified given that benefit.


                 These reason this is in yellow and I have


       got some things grayed out here is because this



       bullet is really what we are here to discuss.  This


       is your expertise.  I think we are not asking you


       to justify CFC amounts and we are not asking you


       about technically feasible alternatives because


       that expertise I think lies elsewhere, but your


       expertise lies in this bullet, providing do the


       products that remain on the market and do not have


       available direct alternatives with that same


       moiety, do those continue to provide substantial


       health benefit considering the practice of medicine


       and the availability of other products.




                 Please note that as we go through this


       discussion, and we will discuss a list of the


       moieties that are involved, that if you recommend


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


       process that would play out from here.


                 If FDA were to follow the advice, we would


       need to publish a Notice of Proposed Rulemaking


       stating that we had preliminarily determined that


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


       would cite as our basis for doing that the



       recommendations coming out of this meeting.


                 But what that means is that the public


       would then have a chance to comment on that


       proposed rule and we would consider those public


       comments prior to going to final regulatory action.


                 So, your recommendation would not


       precipitously lead to any of these products


       disappearing.  They would lead to a process being


       played out where we would get further public






                 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




                 So, at that time that the revisions to


       2.125 occurred, we had this kind of universe of


       products listed as essential uses, and those that



       are in red here are already no longer essential, so


       that includes things like isoethrane,


       isoproterenol, nasal steroids, contraceptive foams,


       rectal foams, polymyxin, nitroglycerine.  Those


       products have either been discontinued, some of


       them have been reformulated in non-pressurized




                 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






                 The products in yellow here are


       potentially or could be de-listed soon, many of


       these because they are no longer marketed.  For


       instance, as GlaxoSmithKline spoke to yesterday,


       they chose to discontinue the marketing of



       salmeterol inhalation aerosol, marking instead


       their dry powder inhaler, because of their own


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


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


       that shortly.  The same thing with beclomethasone.


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


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


       in the agenda, but in the handout of my slides


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


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


       on the back of the slides that were being handed


       out today.  I am not sure that the Advisory


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


       the actual agenda that I had.




                 This is the List B.  There are available


       non-CFC inhaled respiratory medications, and I


       would note that I did not try to include


       nebulization products here.


                 So, for albuterol, we now have Proventil


       HFA approved since 1996, Ventolin HFA approved I


       believe since the year 2000, and IVAX's albuterol



       sulfate HFA was approved last year.


                 Levalbuterol was more recently approved,


       Xopenex HFA in an MDI.  We also have salmeterol,


       which I just mentioned is being marketed as a dry


       powder inhaler, a multi-dose dry powder inhaler


       called Serevent Diskus, and formoterol is


       available, as we also heard yesterday, in a dry


       powder inhalation, single capsule at a time form


       called Foradil Aerolizer.


                 We have numerous choices with regard to


       inhaled corticosteroids.  We have budesonide, which


       is Pulmicort Turbuhaler, fluticasone, which is


       available in a diskus or approved in a discus


       formation, and Flovent HFA, which is a marketed HFA


       alternative to Flovent MDI.


                 Recently approved was mometasone, which is


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


       inhaler, and finally, beclomethasone, which is


       known as QVAR, which actually is approved in two


       different dosage strengths, unlike the MDI that was


       formerly available in the United States.





                 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.




                 So, that gets us to what I believe is


       designated as List A in your background documents,


       which is the moieties currently listed as essential


       for which there is no current reformulated or


       direct alternative product approved or marketed.


                 Under the beta-agonist classification, we


       have metaproterenol or Alupent.  We have pirbuterol


       or Maxair. One thing I would point out with Maxair



       is Maxair is approved both as a press and breathe,


       although I prefer to say breathe and press, a


       metered dose inhaler, and as an autohaler device or


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


       actuates the spray.


                 Under the inhaled corticosteroids, we have


       two products that are in that classification,


       flunisolide marketed as Aerobid, and triamcinolone


       marketed as Azmacort.


                 For the cromones, we have cromolyn or


       Intal, and nedocromil or Tilade.


                 Finally, there is a combination product of


       beta agonists and anticholinergic that while


       available as a nebulizer, which would not have the


       same level of convenience as an MDI, is not


       available in a sort of portable, hand-held device


       at this point, and that, of course, is


       albuterol/ipratropium also called Combivent.


                 Note here, too, I am not sure how legible


       this is, but I have not included epinephrine in the


       discussion of the beta agonists.  We will need to


       have a separate discussion of epinephrine at a



       later Advisory Committee meeting, because it is


       important, since that is an over-the-counter


       medicine, to include colleagues from the


       Non-Prescription Drug Advisory Committee, as well,


       so folks can look forward to a future timely


       discussion of epinephrine.




                 Well, bringing this all back towards the


       Montreal Protocol process, what has been the


       history to date of the Montreal Protocol?


                 Although this say global, I believe this


       is actually restricted to the developing countries,


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


       in inhalers, but this is the pattern of the amount


       asked for from the Montreal Protocol parties, the


       amount actually used, and the amount in stockpiles


       within the developing countries.


                 You can see that in the early years of the


       essential use nominations, about 14,000 tons,


       metric tons of CFCs total were requested.  At their


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


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



       4,000 range, and will continue to fall.


                 I would just state as sort of an


       educational point that the stockpiles are closely


       matched here to the amount used and that is by


       design.  The Montreal Protocol, it is felt that


       because of uncertainties in the supply of CFCs, it


       is to the countries and companies within those


       countries' advantage to keep stockpiles that would


       allow for one year's worth of production.




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


       Government moved proactively to address the issue


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


       role in the implementation and the conduct of the


       Montreal Protocol.


                 The Montreal Protocol is a successful


       treaty and it has led to important reductions in


       CFCs and other ozone-depleting substances, and,


       indeed, there is evidence now that the destruction


       of the ozone has leveled off and it is hoped and


       projected that under the current provisions of the


       Montreal Protocol, that the ozone layer will



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


       the mid-part of this century.


                 The Montreal Protocol is increasingly


       moving towards control in specific essential uses,


       notably albuterol, and the U.S. has acted






                 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.




                 So, your charge today will be as per the



       revisions of 2.125, we are convening this meeting


       to discuss the products listed as essential to


       determine if changes in the medical practice and


       availability of alternatives render these products


       as no longer essential.


                 Remember that that definition of


       "essential" is that there are no technically


       feasible alternatives, that the drug provides


       substantial health, public, or environmental


       benefit, and that the release of CFCs is small or


       justified given the benefit.  Again, I think your


       particular expertise lies in that second bullet.




                 Yet another depiction of the ozone layer,


       this being picture from 1983 and a similar vantage


       point in 1993 showing, indeed, the expansion and


       the further depletion of the ozone particularly


       over the Antarctic region.


                 With that, I will stop and than you for


       your attention.


                           Clarifying Questions


                 DR. SWENSON:  At this point in the



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


       planned following Dr. Meyer's presentation, but I


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


       move into the next session denoted by clarifying


       questions and take a break after that.


                 So, at this point, if there is no problem


       with proceeding, I would like to start with that


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


       ask for clarifications.


                 Dr. Schatz.


                 DR. SCHATZ:  Just one relatively simple


       one.  I was not under the impression that


       nedocromil was still being marketed, I mean it is


       still available, but I gather it is.


                 DR. MEYER:  I actually tried to go on


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


       available, so to the best of my knowledge.


                 DR. SWENSON:  Dr. Brantly.


                 DR. BRANTLY:  Dr. Meyer, in your


       consideration, I didn't see consideration of the


       economics.  Is that also a dimension that we should


       consider particularly in the context that



       oftentimes patients are on multiple respiratory


       medications and some of them can be quite




                 DR. MEYER:  It is certainly a factor that


       we think about in terms of the more formal


       moiety-by-moiety approach when we say patients are


       adequately served.  We included the consideration


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


       certainly welcome your thoughts in that regard as


       you discuss the moieties today.


                 DR. SWENSON:  Ms. Schell.


                 MS. SCHELL:  I have a question about


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


       enough to fill in the gap from the other companies


       that already produce it?


                 DR. MEYER:  I think the important thing


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


       whatever recommendation is taken today, if there is


       a recommendation that a product is no longer


       essential, we will go through a notice and comment


       rulemaking which will not only allow for public


       comment, but will allow other manufacturers perhaps



       of other products that might have to increase their


       supply to do so.


                 So, I think that this changeover would not


       be precipitous, it would be planned and it would


       allow for the other products that might need to


       increase their supply to do so.


                 MS. SCHELL:  I have just one more


       question.  With the Montreal Protocol, what other


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


       are they completely caught up with it, or are we




                 DR. MEYER:  It depends on how you define


       behind. Our albuterol process is slower than some


       other countries, notably, Canada, Australia, many


       countries within the EU, for instance.


                 On the other hand, the EU has certain


       provisions that make, for instance, the de-listing


       of beclomethasone tougher for them, because they


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


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


       have a CFC product available.  We will be able to


       shortly de-list beclomethasone.



                 So, I think that in some measures, we


       might be behind and in some measures we are not,


       but it is sort of a different healthcare system,


       different mix of considerations at this point, but


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


       earlier of the alternatives available, we have made


       substantial progress in the transition at this




                 DR. SWENSON:  Dr. Schatz.


                 DR. SCHATZ:  I guess I have two questions.


       One is by taking away some medications on this


       list, do we improve the chances of getting what we


       want for the drugs that we really do think are


       essential.  My understanding of our relationship


       with the parties is that we go request and they are


       in a position to approve.


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


       improving the chances that the stuff we really


       think we need we are going to get?


                 DR. MEYER:  You have to understand that I


       will only be able to answer that from personal


       opinion, because I certainly don't speak for the



       parties, but I think to the degree that we are


       showing successful transition, that helps our


       requests for any remaining essential uses.  I think


       that is true.


                 DR. SCHATZ:  My second question is, all of


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


       personal prescribing practices, but I am wondering


       whether there is any information available as to


       how many patients are using these drugs current,


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


       least how many patients think they are useful or




                 DR. MEYER:  We do not have those data


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


                 DR. SWENSON:  Dr. Gay.


                 DR. GAY:  Thank you.  Will the FDA have


       available to us data concerning progression of


       development, for example, whether or not companies


       have made a good-faith attempt to begin to develop


       MDIs, if they are well along the pipeline and very


       close to approval, or if there is no significant


       information that they have even started



       development?  Will the FDA have that information


       available to us today?


                 DR. MEYER:  Since this is an open public


       meeting, some of that information cannot be


       discussed in this meeting.  To the degree that some


       of this has been acknowledged and perhaps might


       even be spoken about in the open public sessions by


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


                 DR. SWENSON:  Dr. Martinez.


                 DR. MARTINEZ:  Dr. Meyer, one of the


       criteria for non-essentiality is that patients who


       require CFC product are adequately served.  I


       assume that that criterion is valid.  We had a


       similar discussion a year ago regarding albuterol.


                 If we decide to declare some of these


       products nonessential, will there be potential


       increase the minimal possible costs for patients of


       inadequate means or do not have insurance, that


       would make them require paying more for available


       products, and thus, perhaps because of means, not


       have the products available for treatment?


                 DR. MEYER:  I think that will have to be



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


       if you are talking about a patient on a brand name


       corticosteroid where there are many alternatives


       available with a variety of presentations, a


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


       that patient will be significantly impacted by




                 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




                 I would say that for the direct switches


       to date, in other words, the pricing of Ventolin


       HFA versus Ventolin CFC, so the brand name, the


       price of other products that have been directly



       switched, where they are branded products, they


       have been basically on parity, they have been the




                 The companies have actually publicly


       committed to that kind of pricing policy.


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


       are you then suggesting that a decision in this


       case will probably not cause a significant change


       in potential cost of the medicine for the public in


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


       the inhaled corticosteroids that are in the list


       that we are going to make a decision about, are


       discontinued, none of them is of such a low cost


       that would have allowed a patient to receive


       inhaled corticosteroids, but now will not because


       of an issue of cost?


                 DR. MEYER:  I am not necessarily


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


       that as a broad generalization for this.  So,


       again, on an individual discussion, if you get to


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


       priced aggressively, it is cheaper than any of



       these other ones, I think again we would welcome


       the input of the committee if they feel like that


       would have an important implication on the patients


       being affected.


                 DR. MARTINEZ:  Are costs available as


       information for us at this meeting?


                 DR. MEYER:  They are not available at this




                 DR. SWENSON:  Dr. Kercsmar.


                 DR. KERCSMAR:  Are all the inhalers that


       are on this B list manufactured in the United


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


       usage, the country that manufactures them or the


       country to which they are being sold or imported?


                 DR. MEYER:  The products that we are


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


       use process, so they are produced in the United


       States.  There are other products that have already


       been dealt with, albuterol is a notable one where


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


       these products are all produced within the U.S.


                 DR. SWENSON:  Dr. Schoenfeld.



                 DR. SCHOENFELD:  Is there a well-defined


       procedure for developing reformulating these


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


       them have any effect on these companies' abilities


       to develop non-CFC formulations?


                 DR. MEYER:  That is a good question.


       Actually, with regard to the first part of your


       question, it is a very difficult task to


       reformulate.  I think early on, the thought process


       by any, I think even including those in the


       industry who are directly involved was that this


       would not be so difficult a task, but the chemical


       and physical properties of the non-CFC propellants,


       the HFAs, are such that it is required a


       reengineering of the valves, many of the gaskets,


       the cans themselves, so they are really entirely


       new products that are being developed, and it has


       been challenging.


                 In fact, some products have not been


       successfully reformulated because of those




                 With regard to if a product were to be



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


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


       should have any effect on that with the possible


       exception of one of the things we have liked to see


       with these replacement products is a comparison in


       a study against the product it is replacing when it


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


       need to have study medication available.


                 But these products have all been approved


       under new separate drug applications, so it is not


       like one of them going away would affect the path


       forward for the other.   DR. SCHOENFELD:  Does that


       basically mean that if they reformulated, they


       would have to get approval of the new formulation,


       not on the bioequivalence grounds, but actually on


       efficacy grounds, and that would be true today


       before they de-listed, and also true after they


       were de-listed?


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


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


       that bioequivalence in terms of an inhaled drug


       that is locally acting is very, very difficult, if



       not impossible, to establish under currently


       available science, but the other issue is that


       there are other things introduced by having such


       different formulations in terms of tolerability and


       safety that we feel need exploration in studies


       beyond the small, rather defined pharmacokinetics


       type studies.


                 DR. SWENSON:  Dr. Newman.


                 DR. NEWMAN:  I just want to make sure in


       light of some of the questions here today, I want


       to make sure I understand exactly what you are


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


       asking us whether the essential question is provide


       substantial health benefit, that's a little


       different than asking us whether it provides


       substantial public benefit.


                 This question of economics, for example,


       comes in if we are thinking about this in terms of


       public benefit, and it sounds like we are not here


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


       perspective on the health aspect and then you


       decide whether to--and then those other issues will



       be raised subsequently.  Just help clarify that for




                 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




                 DR. SWENSON:  With respect to some of the


       drugs for which there are no obvious replacements,


       the cromones in particular, but this may apply to


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


       as to when the patents expire and if any generic


       options are in the pipeline?


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



       could probably get that in fairly short order, but


       I would not be surprised, particularly for the


       Intal, cromolyn, for instance, it that were already




                 The challenge to the developing a generic


       alternative to a cromone or to a corticosteroid is


       establishing bioequivalence, and part of the


       reasons that there are not further generics outside


       of albuterol is because of there not being a


       methodology for establishing bioequivalence in a


       reliable fashion.


                 DR. SWENSON:  Ms. Schell.


                 MS. SCHELL:  I have a question about the


       Montreal Protocol as far as deadlines or


       compliance.  Is the United States in compliance


       with the Montreal Protocol, and is there a date


       where they have to have this totally met, and is


       there a consequence if not?


                 DR. MEYER:  We are in compliance with the


       Montreal Protocol.  There is no firm date that has


       been established.  Back in the late nineties when I


       first started my involvement with this process,



       many pointed to the year 2005 for the developed


       countries being totally out of the use of CFCs and


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


       for the United States or many of the other


       developed countries.


                 That said, I think that as I stated during


       my talk, it has been envisioned that the essential


       use process would be a temporary process, not


       permanent, and clearly, there is increasing


       interest on the parts of the countries involved


       with the Montreal Protocol to effect these


       transitions in a timely fashion.


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


       move forward responsibly, and when I say


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


       health benefits of the environmental side of this


       treaty, as well as protecting the public through


       assuring that medicines are available to patients


       who need them.


                 DR. SWENSON:  Dr. Schatz.


                 DR. SCHATZ:  Two questions again.  Tell me


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



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


       we think that we and our colleagues can adequately


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


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


       and our colleagues can adequately care for patients


       without it?


                 DR. MEYER:  I think that would be a fair


       way to pose the question.


                 DR. SCHATZ:  Okay.  Then, my second


       question is that you mentioned this would be the


       beginning of a process. How long would you


       estimate, if possible, between a decision today


       that a drug is no longer essential and when, in


       fact, it would no longer be available based on that




                 DR. MEYER:  It is hard to say with


       certainty what that would be, but it is very common


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


       I mean if, for instance, you took the albuterol


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


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


       until 2002.  There was a lot of controversy and



       considerations in that.


                 In a more focused rulemaking, it might be


       considerably quicker than that, but it is not


       uncommon for it to take a year or two to complete


       rulemakings, to go from notice and comment, or


       opening up with a Notice of Proposed Rulemaking to


       the point where it is finalized.


                 Then, once it is finalized, it doesn't


       necessarily become effective the day that it's


       published.  It may be published with an effective


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


       might do that is to allow patients to sort of


       acclimate to the new realities, as well as to allow


       the other manufacturers who make products that


       might increase in sales to account for this gap in


       the marketplace, to plan accordingly and increase


       their production.


                 DR. SWENSON:  Dr. Schoenfeld.


                 DR. SCHOENFELD:  I have never actually


       designed or ran a clinical trial of an inhaled


       asthma medication, so I was just wondering how


       difficult would it be for these things to go back



       on the market in new formulations in terms of the


       clinical trials required.  Does the fact that the


       chemical was previously approved make a difference?


       Are we talking about clinical trials with thousands


       of patients or clinical trials with tens of


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


       difficult these drugs are to develop.


                 DR. MEYER:  Yes, these have typically been


       relatively streamlined development programs,


       because we do understand a lot about the moieties,


       so the purpose of the trials is really to


       understand the specifics of the product that is


       delivering that moiety.


                 Commonly, you might have a short-term


       trial that looks at pharmacodynamic measures if


       they are available, say, for a bronchodilator, and


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


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


                 Then, you might also, depending on how


       different the formulation is, have a longer term


       extension of that, an open-label extension of maybe


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



       for instance.


                 So, they are much smaller than for a new


       molecular entity, but it is not trivial either.


                 DR. SWENSON:  Dr. Kercsmar.


                 DR. KERCSMAR:  I was wondering if you


       could clarify the reason that products that are


       available that are equivalent or the same drug for


       nebulization have been excluded, is it really


       thought that the convenience factor is so


       overwhelming for those nebulization products that


       should we not consider the availability of those in


       these deliberations?


                 DR. MEYER:  Well, for the direct


       de-listing, we did not include the nebulization


       products because of the level of convenience,


       because one of the criterion was that it had to


       have approximately the same level of convenience,


       and clearly, standard nebulization treatment does


       not have the same level of convenience of an MDI,


       for instance.


                 For the purposes of today, I think that


       you are free to consider the entire therapeutic



       armamentarium available in terms of making a


       determination, that Dr. Schatz said, you know,


       would my patient suffer if this product were to be




                 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.





                 DR. SWENSON:  We will begin this next


       portion of the meeting, if I could ask all members


       to return to their seats.


                           Open Public Hearing


                 DR. SWENSON:  We will now begin the open


       public hearing portion of this meeting.  Before


       that, I will read this particular statement


       relevant to presentations.


                 Both the Food and Drug Administration and


       the public believe in a transparent process for


       information gathering and decisionmaking.  To


       ensure such transparency at the open public hearing


       session of the Advisory Committee meeting, the FDA


       believes that it is important to understand the


       context of an individual's presentation.


                 For this reason, FDA encourages you, the


       open public hearing speaker, at the beginning of


       your written or oral statement to advise the


       committee of any known financial relationship that


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


       known, its direct competitors.



                 For example, this financial information


       may include the sponsor's payment of your travel,


       lodging, or other expenses in connection with your


       attendance at the meeting.


                 Likewise, the FDA encourages you at the


       beginning of your statement to advise the committee


       if you do not have any such financial


       relationships.  If you choose not to address this


       issue of financial relationships at the beginning


       of your statement, it will not preclude you from




                 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




                 IPAC is an association of leading


       manufacturers of metered dose inhalers for the


       treatment of asthma and COPD.  Its current members


       are AstraZeneca, Boehringer Ingelheim, Chiesi,


       GlaxoSmithKline, and INEX.



                 IPAC is firmly committed to the MDI


       transition as evidenced by the extraordinary


       investments and R&D efforts that its members have


       taken.  IPAC companies' use of CFCs has declined


       substantially over the past decade as they have


       launched CFC alternatives and phased out CFC MDIs,


       and one of our members has phase out all use of


       CFCs in the United States.


                 IPAC is grateful for the opportunity to


       speak today and has always supported an open and


       transparent process that allows for input from all


       interested stakeholders.


                 IPAC strongly believes that any


       consideration of the continued need for CFCs under


       FDA's essential use exemption and under


       corresponding EPA regulations in which FDA has a


       statutory role should take into account the


       uncertain future access to CFCs.


                 As FDA itself noted at the June 2004 PADAC


       hearing, each year the Montreal Protocol parties


       are more reluctant to grant CFCs to the United


       States.  Last month's protocol meeting only



       confirmed this point.


                 This potential reduction is exacerbated by


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


       date for albuterol non-essentiality.  As a result


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


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


       year for the next three years if the protocol


       allows it.


                 This could result in shortages for


       non-albuterol products for which there is as yet no


       CFC-free replacement. Therefore, it is critically


       important that CFCs only be used for truly


       essential products.  To better ensure that this


       occurs, IPAC believes there are two key actions


       that FDA should take.


                 First, CFCs should be allocated only for


       MDIs that do not have a corresponding CFC-free


       alternative and where the manufacturer is


       diligently undertaking meaningful efforts to


       research and develop a CFC-free alternative.


                 Given future CFC uncertainty, it is


       imprudent for FDA and EPA to allocate annual CFC



       volumes to companies for a CFC product where there


       are already adequate CFC-free alternatives on the


       market.  This is particularly true when the company


       has in its power to phase out sale of its CFC


       products and to transition its own market.


                 IPAC companies have done this, so we know


       it can be accomplished, but some companies that


       have CFC-free alternatives are still major users of


       CFCs, so action by FDA is needed.


                 FDA should address this in two


       complementary ways:  (a) by eliminating the


       essentiality designations for such products in 21


       CFR Section 2.125 via a notice and comment


       rulemaking; and (b) by informing EPA that essential


       use CFC allocations are not necessary for such




                 Secondly, FDA should advise EPA not to


       allocate CFCs to companies that are holding


       excessive CFC stockpiles. The protocol's expert


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


       and other medical experts, has carefully reviewed


       the issue of CFC stockpiles and concluded that a



       one-year CFC reserve is adequate.


                 IPAC companies, based on decades of


       experience manufacturing MDIs, fully concur with


       the protocol panel's assessment.  FDA should


       therefore advise EPA that it is only necessary to


       allocate a license for new CFC production in an


       amount such that the receiving company's stockpile


       does not exceed a one-year reserve.


                 In conclusion, IPAC urges FDA to


       proactively implement the July 24, 2002, final rule


       and to be proactive in exercising its joint


       responsibility with EPA for allocating essential


       use volumes by taking the actions we recommended




                 Doing so will facilitate a timely and


       effective conclusion to the transition and minimize


       the continued need to CFCs to that which is truly


       necessary to meet patient need.


                 IPAC would be pleased to serve as a


       resource during this process and would be happy to


       provide further, more detailed information relevant


       to the transition of non-albuterol MDIs as the



       issues evolve.


                 Thank you.


                 DR. SWENSON:  Thank you, Ms. Hardwick.


                 Our next presentation will be by Dr. Kirk




                 DR. SHEPARD:  Good morning, Mr. Chairman,


       members of the Advisory Committee, FDA


       participants, ladies and gentlemen.  My name is


       Kirk Shepard.  I am Vice President of Clinical and


       Scientific Affairs at Boehringer Ingelheim


       Pharmaceuticals in Ridgefield, Connecticut.


                 Boehringer Ingelheim appreciates the


       opportunity to appear before the FDA


       Pulmonary-Allergy Drug Advisory Committee and share


       the company's extensive respiratory drug research


       and development efforts that bear directly on the


       discussions of this meeting.


                 In the United States, these efforts have


       yielded a number of effective products for the


       treatment of COPD including Spiriva, HandiHaler


       (tiotropium bromide inhalation powder), Atrovent


       (ipratropium bromide), and Combivent (ipratropium



       bromide and albuterol sulfate) inhalation aerosols.


                 Atrovent and Combivent inhalation aerosols


       contain CFCs and are identified as essential uses


       in 21 CFR 2.125.  We hope that our comments today


       assist the committee in advancing the public


       discourse on the CFC MDI transition in a manner


       that will be benefit patients and the environment.


                 Boehringer Ingelheim is committed to


       improving respiratory care through the development


       of safe, effective, and environmentally responsible


       therapies.  For over 40 years, Boehringer Ingelheim


       has been a world leader in the research,


       development, and the manufacture of drug products


       for the management of respiratory disease.


                 Over 8 million patients worldwide with


       COPD and asthma rely on our medications.


       Recognizing that no single drug delivery system can


       meet all patients' needs, the company has


       developed, or is developing, a variety of products


       that included metered dose inhalation (MDIs), dry


       powder inhalers (DPIs), solutions for nebulization,


       and propellant-free inhalers.  Boehringer Ingelheim



       strongly endorses a smooth, timely and effective


       transition of our CFC-containing aerosol products


       that protects patients.


                 Protection of the environment and public


       health are an integral part of future planning at


       Boehringer Ingelheim, as we are dedicated to the


       research and development of CFC-free respiratory




                 The company has taken a leading role in


       the global CFC transition by investing nearly $400


       million in the development of HFA-based MDIs and


       propellant-free inhalers. Our CFC-free development


       programs involve the reformulation of more products


       than any other MDI manufacturer.  We have deployed


       over 200 scientists in 35 laboratories around the


       world and enrolled 10,000 patients in clinical


       trials to date.


                 Worldwide, 13 BI products have been


       reformulated or are in the process of being


       reformulated to 4 HFA MDIs and 2 propellant-free


       inhalers.  Our CFC-free alternatives have been


       introduced in nearly 50 countries that are parties



       to the Montreal Protocol.


                 In the United States, Boehringer Ingelheim


       research programs have yielded CFC-free products


       for the treatment of COPD, including Spiriva,


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


       recently introduced Atrovent HFA metered dose




                 Atrovent HFA, approved by the FDA in


       November 2004 and introduced in May of 2005, is the


       result of over a decade of Boehringer Ingelheim


       research into CFC-free alternatives.  During these


       early months after Atrovent HFA introduction,


       Atrovent inhalation aerosol continues to be


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


       a seamless and orderly transition to CFC-free


       anticholinergic therapies such as Spiriva or


       Atrovent HFA.


                 Mindful of our commitment to the


       environment and global transition and after


       consultations with the FDA, Boehringer Ingelheim


       has decided to voluntarily discontinue the


       marketing and distribution of the CFC-containing



       Atrovent inhalation aerosol in the United States as


       of January 1, 2006.


                 Accordingly, we have notified the U.S. EPA


       to reduce our 2006 CFC production rights to account


       for the removal of Atrovent inhalation aerosol from


       the market.


                 Combivent inhalation aerosol is an


       important product for the management of COPD.


       Clinical studies have demonstrated that maintenance


       bronchodilation of COPD patients is improved with


       Combivent compared to each of its agents alone.


                 There are many COPD patients whose


       symptoms cannot be controlled with just one inhaled


       bronchodilator therapy, thus making combivent


       patient population significant.  In 2004,


       Boehringer Ingelheim distributed over 3.5 million


       combivent MDIs, serving over 2 million patients in


       the U.S.


                 Noncompliance is a significant barrier to


       improving patient health.  The rapid onset of the


       benefit perceived by the patients in taking a


       short-acting beta-agonist in combination with the



       long-acting ipratropium bromide increases both the


       convenience and patient satisfaction, two important


       factors in improving patient compliance.


                 Published results of several clinical


       trials provide evidence that regular treatment with


       anticholinergics may reduce the severity of COPD


       exacerbations in COPD patients with moderate to


       severe disease.


                 In short, combining of these two widely


       prescribed bronchodilators for COPD into one


       product has afforded these patient benefits while


       at the same time achieving a 50 percent reduction


       in CFC emissions that would have resulted from the


       use of the two, single-agent CFC products.


                 As with Atrovent, Boehringer Ingelheim has


       pursued a multi-year research and development


       program into a CFC-free alternative for Combivent.


       The company has applied extensive resources to


       reformulating Combivent, exploring both alternative


       HFA propellant and propellant-free inhalation


       devices as alternatives.


                 As a combination of a suspension and a



       solution formulated with an HFA propellant,


       Combivent has posed technical complexities that


       have challenged our best reformulation efforts.


                 However, we remain optimistic that we will


       overcome these challenges.  Our research and


       development is ongoing and Boehringer Ingelheim


       reaffirms its commitment to continue this effort to


       find a CRC-free alternative for Combivent.


                 We share FDA's high standards for products


       and until a CFC-free alternative to Combivent that


       meets those high standards is available, Combivent


       inhalation aerosol must continue to be designated


       as an essential use under 21 CFR 2.125.


                 Thank you for the opportunity to address


       the committee and for your time and attention.


                 DR. SWENSON:  Thank you, Dr. Shepard.


                 Our next speaker is Mr. Alan Krueger.


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


       an Associate Director of Regulatory Affairs at Kos




                 Kos acquired the U.S. marketing rights to


       Azmacort, both CFC and HFA, in April 2004 from



       Aventis Pharmaceuticals.  Azmacort CFC, available


       commercially for over 20 years, continues to be


       actively prescribed by physicians.


                 Since this product was acquired by Kos,


       new and total prescriptions have increased.  In May


       2005, combined total prescriptions were 92,000.


       New prescriptions accounted for nearly half of this


       number of 92,000.


                 Kos is committed to conversion to HFA.


       Final approval for Azmacort HFA is being actively


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


       a December 2004 meeting with FDA, further


       development and approval plans for this product


       were discussed.  Commercialization is anticipated


       in approximately 2008.


                 Other Kos aerosol R&D projects are also


       underway. Four projects, including two for


       asthma/COPD, one undisclosed for a systemic


       disease, and the last for inhaled insulin, are at


       various stages of development.


                 Thank you.


                 DR. SWENSON:  Thank you, Mr. Krueger.



                 Our last speaker is Dr. Leslie Hendeles.


       I am a clinical pharmacist in the Pediatric


       Pulmonary Clinic at the University of Florida, and


       I am here as an independent person interested in


       the topic, and I have no conflict of interest with


       a beta-agonist manufacturer.


                 I just wanted to point out to the panel


       members who don't take care of children that the


       breath-actuated device called the autohaler has


       some unique properties for kids.  It enables them


       to get a quick relief medicine without having to


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


       your deliberations, not only the drug is an issue,


       but the delivery device might be an issue, too,


       that I ask that you consider.


                 Thank you.


                 DR. SWENSON:  Thank you.


                 At this point, then, I think we can move


       then into the formal discussion with each of the


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


       further points to be raised, this is the moment.


                 Dr. Meyer.



                           Clarifying Questions


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


       to clarify something with respect to a question


       that Dr. Gay asked earlier about how much we would


       be able to say about things under development.


                 I wanted to clarify for the purposes of


       the discussion, I would like you to speak about the


       transition as it is today, in other words, whether


       a product is being actively reformulated or not


       really shouldn't factor into your recommendations


       to us.  It should be given the current medical


       practice and given the current available


       alternatives, do these products on this list in the


       Charge to the Committee remain essential




                 DR. SWENSON:  Dr. Moss.


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


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


       experience a year ago with the albuterol


       discussion.  It seems to me that after the


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


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



       compounds for albuterol.


                 Do you anticipate, if we make similar


       decisions on these agents, what the lag time would


       be after the decisions are made for these




                 DR. MEYER:  That time frame was very


       specific to the considerations with regard to


       albuterol and actually reflected some of the advice


       given by some of the members participating in that


       committee that they had concerns particularly about


       the impact of balancing cost considerations versus


       availability of medications, and so on.


                 So, that was very specific to albuterol


       and again was responsive to some of the advice that


       we got.  I think this would depend whether any of


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


       you folks, would have any kind of lag period


       afterwards would be highly individual, but would be


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


       might be quite a bit quicker than that.


                 DR. SWENSON:  Dr. Schoenfeld.


                 DR. SCHOENFELD:  Maybe this would occur at



       the public hearing, at the subsequent public


       hearing, but I am a little concerned about the


       process here in that it seems that a regulatory


       decision is made without really relying on


       evidence-based medicine in the same way that, for


       instance, regulatory decisions were made yesterday.


                 That is, it would seem a better process


       would be to ask each of these companies that make


       these products to marshal the scientific evidence


       in the form of maybe what they initially submitted


       to gain approval for these products plus subsequent


       papers in the medical literature that would argue


       that these products are essential, and then have


       these documents just as they are in new drug


       applications reviewed by your staff and a report


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


       decisions based on the usual level of evidence that


       we are used to seeing in making important decisions


       like this.


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


       beginning, this is a very different advisory


       committee than the usual.  Unfortunately, I think



       there would be a paucity of direct data of the kind


       of substantial evidence that we normally discuss in


       these kind of settings because of the relative lack


       of comparative data that exist.


                 But I would point out that in the


       subsequent rulemaking process, I suspect that any


       affected company would, in fact, marshal whatever


       kind of data that do exist to address their


       argument should they choose to say that they think


       they continue to be essential.


                 So, I think we would have that kind of


       discussion or that kind of presentation to us at


       that stage.


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


       reiterate, then, our charge is to give you some


       early guidance as to prioritizing these individual


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


       that type of adding weight to then your decision as


       to whether to bring these forward at separate




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


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



       just the first step of the process, so this


       wouldn't be a definitive, if you folks


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


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


       longer essential, there is a process that goes on


       from there, too, more fully in a public comment




                 DR. SWENSON:  So, for each of these


       agents, then, there would be a fair hearing to




                 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




                 DR. SWENSON:  Any further general


       questions?  Dr. Moss.



                 DR. MOSS:  I had a general question again


       for Dr. Meyer.  I think I am assuming correctly


       that the companies that make these compounds were


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


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


       the open public forum?


                 DR. MEYER:  Yes, I just was conferring


       with one of our regulatory legal staff, and, in


       fact, just in answer to the question of a moment


       ago, all subsequent actions, all subsequent


       rulemaking would engender an open public hearing,


       would require of us an open public hearing, so it


       would not just be in written form, there would be


       an open public hearing.


                 Yes, there would be opportunities at that


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


       it would be in the open public hearing session or


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


       that meeting.


                 DR. MOSS:  But all of the companies were


       informed of this meeting, so if they had


       information that they wanted to relay, they could



       have come to this meeting for the other compounds?


                 DR. MEYER:  This meeting was publicly


       announced in the Federal Register as per usual, and


       I believe companies are very good at surveying the


       Federal Register for notices that affect them.


                           Committee Discussion


                 DR. SWENSON:  If there are no further


       general questions, I think we should move then to


       the specifics, and the first will be the


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


       and I think we should start with metaproterenol and


       ask if there are any specific comments about


       metaproterenol from any of the panel members.


                 Dr. Schatz.


                 DR. SCHATZ:  Just a point.  Are we going


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


       these, or is it not that sort of decisionmaking?


                 DR. MEYER:  I don't think we were


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


       were envisioning much more of a discussion and


       allowing folks to make individual recommendations,


       but not a formal vote.



                 DR. SCHATZ:  Since my microphone is on, I


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


       patients without the availability of




                 DR. SWENSON:  Any other thoughts by panel




       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




                 DR. SWENSON:  That is fair enough since we


       are talking about two drugs here of very similar



       action and basically the same position, so what I


       might do is recommend in behalf of the panel that


       both of these not be considered for special


       exemption and ask if any members wish to disagree


       with that assessment.


                 MS. SANDER:  I have a couple of questions.


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


       of Boehringer Ingelheim to discontinue this product


       anyway, do you know?


                 DR. MEYER:  We had a spokesperson from


       Boehringer Ingelheim speak just a few moments ago.


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




                 DR. SHEPARD:  We do not plan to


       reformulate the decision as far as when it would be


       discontinued, which it probably would be, has not


       been made yet.


                 MS. SANDER:  How many patients do you have


       using that right now?


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


       specifics on that.


                 MS. SANDER:  Okay.  With regard to Maxair,



       do we have anyone from 3M?


                 DR. MEYER:  I do not believe that I saw


       anybody from 3M.


                 MS. SANDER:  I agree with the panel with


       regard to Alupent.  With regard to Maxair, I think


       we would need to do a little more examination about


       its use in pediatric populations.  I don't have


       enough information in that area, because it is a


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


       amount of people using it.


                 DR. SWENSON:  Could we ask our two


       pediatricians to comment to Ms. Sander?


                 DR. KERCSMAR:  The device in question


       certainly confers benefit in ease of use, and while


       it certainly may be relevant to pediatric patients,


       I would still say that probably a minority of our


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


       argue that it is not just for kids and that anybody


       who has difficulty with an MDI device certainly


       would benefit from an autohaler, and that could


       include any adult, and certainly elderly patients


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



       just restricted to children.


                 I think that the other thing that would be


       important to know is whether that device can be


       adapted to non-CFC-containing inhalers.


                 DR. SWENSON:  Dr. Martinez.


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


       anything to add.


                 DR. SWENSON:  Dr. Newman.


                 DR. NEWMAN:  I guess that given the scope


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


       agree that what you are all saying about the


       potential use of that delivery device is


       potentially important, I think there is a step


       beyond this for addressing how important that is


       and what the alternatives could be to that, and


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




                 I would again stress I think the


       importance of setting the ball in motion on both of


       these products in order to let that be aired.


                 DR. MEYER:  I have perhaps changed my


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



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


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


       think it might be helpful just to poll each person


       on the individual moiety after you have had your


       discussion about it.


                 I know that your comment, Dr. Swenson, was


       about perhaps the committee could regard these


       together, but I would like to individually poll on


       both of them.


                 DR. SWENSON:  Before we start that poll,


       any further questions, comments?


                 Okay.  Ms. Schell, would you offer your




                 MS. SCHELL:  On we are just using Alupent?


                 DR. SWENSON:  On metaproterenol only.


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


       essential drug.


                 DR. KERCSMAR:  I would agree.  I can take


       care of my patients without that drug.


                 DR. MARTINEZ:  Nonessential.


                 DR. BRANTLY:  Nonessential.


                 DR. NEWMAN:  Nonessential.



                 DR. MOSS:  Nonessential.


                 DR. GAY:  Nonessential.


                 DR. SWENSON:  Nonessential.


                 DR. SCHATZ:  Nonessential.


                 DR. PRUSSIN:  Nonessential.


                 MS. SANDER:  Nonessential.


                 DR. SCHOENFELD:  I will have to abstain


       since this is not my level of expertise.  If


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


                 DR. SWENSON:  All right.  We will proceed


       then with pirbuterol or Maxair, and we have already


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


       further points to make?


                 Dr. Schoenfeld, I will let you start.  I


       suspect maybe it's the same.


                 DR. SCHOENFELD:  The same.


                 DR. SWENSON:  Abstention.


                 Ms. Sander.


                 MS. SANDER:  There is part of me that


       realizes that CFCs are going away and that there is


       holding chambers and other devices, and maybe I


       should abstain.



                 DR. PRUSSIN:  Nonessential.


                 DR. SCHATZ:  Nonessential.


                 DR. SWENSON:  Nonessential.


                 DR. GAY:  Nonessential.


                 DR. MOSS:  Nonessential.


                 DR. NEWMAN:  Nonessential.


                 DR. BRANTLY:  Nonessential.


                 DR. MARTINEZ:  Nonessential.


                 DR. KERCSMAR:  Nonessential.


                 MS. SCHELL:  Nonessential.


                 DR. SWENSON:  We will move then to the


       category of inhaled corticosteroids.  Let's begin


       just then with the opportunity for any general


       comments or questions of either of the two agents,


       flunisolide or triamcinolone.


                 Dr. Martinez.


                 DR. MARTINEZ:  As I requested before,


       information about potential costs, cost


       consequences of the decision we are going to make,


       I would like to comment about this.


                 I think that as has been well said by the


       FDA representatives, this is I think not an issue



       in this case. There is a situation with respect to


       inhaled corticosteroids which are as essential for


       the treatment of asthma as albuterol is, and it has


       to do with our previous discussion.


                 The situation for inhaled corticosteroids


       is not the same as that for albuterol.  The


       discontinuation of the medicines that are in this


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


       capacity of patients given their economic means to


       have access to these medicines.


                 So, with a sense of fairness with respect


       to the type of discussion we had the last time


       about albuterol, I think in this case, this does


       not apply.  This not applying the issue of the


       atmosphere in relation to CFC exposure becomes




                 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? 





                 We will begin then with flunisolide.  Ms.




                 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




                 Dr. Schoenfeld, you abstain?  All right.


                 Ms. Sander.


                 MS. SANDER:  Nonessential.


                 DR. PRUSSIN:  Nonessential.


                 DR. SCHATZ:  Nonessential.



                 DR. SWENSON:  Nonessential.


                 DR. GAY:  Nonessential.


                 DR. MOSS:  Nonessential.


                 DR. NEWMAN:  Nonessential.


                 DR. BRANTLY:  Nonessential.


                 DR. MARTINEZ:  Nonessential.


                 DR. KERCSMAR:  Nonessential.


                 MS. SCHELL:  Nonessential.


                 DR. SWENSON:  We move now to the third


       category, the cromones, cromolyn or Intal, and


       nedocromil or Tilade, and specific comments related


       to the class or to individual compounds?  Dr.




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


       of circumstances where I think it has a unique


       role.  One is in exercise-induced bronchospasm for


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


       other is prevention of a specific allergy-induced


       episode of asthma, patients going to visit where


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


       prevent those symptoms.


                 So, in this case, I actually would like to



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


       with it available.


                 DR. SWENSON:  Any further comments?  Ms.




                 MS. SANDER:  We don't have anyone here


       from the company that manufactures this, do we?


                 DR. SWENSON:  No representatives applied


       for the public hearing.


                 Dr. Newman.


                 DR. NEWMAN:  Could I make two comments?


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


       imply to me that maybe they have nothing to say on


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


                 But the other thing I wanted to say is


       that Dr. Schatz, your comment I think is well


       taken, but I think of alternatives in other classes


       that I can use that allow me to get around whether


       a cromolyn type compound is available.


                 It is true that it seems to hold kind of a


       small place still in the armamentarium, but from my


       perspective, I think one can work without it just


       in my own practice.



                 DR. SWENSON:  Dr. Prussin.


                 DR. PRUSSIN:  I would concur with that.  I


       mean you are right, there are uses of these drugs


       that are unique and I am sure there are patients


       who really prize them, but they are relatively


       ineffective drugs in terms of clinical trials in


       asthma, they track more or less with placebo, and


       when you compare cromones to inhaled steroids, they


       are much less active.


                 Now, again, I think you are right, there


       are specific patients who get benefit from them,


       but I guess the question is how many of those are


       there and are there really no other alternatives.


       I just put that out there for the group.


                 DR. SWENSON:  Dr. Schatz.


                 DR. SCHATZ:  I actually think this is a


       situation where it isn't so patient specific, as


       much as it is circumstance specific.  I think the


       data are quite good for the two circumstances that


       I mentioned, and I actually don't think there


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


       think there are better alternatives for the patient



       who is sensitive to beta-agonists taking something


       right ahead of time for exercise, and the patients,


       I don't think there are any other alternatives that


       do the same thing prior to a specific allergen




                 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




                 DR. SWENSON:  I want to echo some of that


       in that as we discussed albuterol in the last


       meeting, that total amount relative to the vast


       amount of CFCs that were being used for all the


       commercial and industrial and cosmetic purposes


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



       an essentiality to these compounds, this represents


       an even smaller, vanishingly small total amount of


       CFC, and again for the individual patient for whom,


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


       certain drug works wonderfully, I think possibly


       given there are no alternatives, and this


       represents possibly a very, very small amount of


       the total, small amount being used for inhaled


       therapy, I would think that maybe we should


       consider an essentiality continuation.


                 Ms. Sander.


                 MS. SANDER:  The request for CFCs for this


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


       amount, is it a small amount?


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


       characterize that.  Dr. Swenson just referred to


       that albuterol certainly accounts for approximately


       half of all the CFCs requested by the United


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


       which are not on this list because they have direct


       alternatives, such as the Atrovent HFA, account for


       the other half.



                 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



       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




                 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



       committed to changing over to proper inhalation




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


       information from these companies before we make a




                 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



       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




                 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



       strictures that I read at the start of this open




                 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




                 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,



       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




                 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



       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



       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




                 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.



                 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



       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




                 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



       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




                 DR. SWENSON:  Ms. Sander, do you have


       anything further?


                 MS. SANDER:  No.



                 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



       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



       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




                 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.



                 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




                 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.



                 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.



                 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



       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




                 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




                 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,



       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



       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




                 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



       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. 



       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



       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




                 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



       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



       depending on how much time you have available to


       develop those efforts.


                 It is just an opinion, not a definitive




                 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.



                 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.



                 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.



                 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



       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,



       patients who are currently tethered to oxygen or to


       their homes, and really do see this as a necessary




                 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



       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




                 DR. SWENSON:  We will go ahead and begin


       our poll.


                 Ms. Schell.



                 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




                 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.



                 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




                                  - - -