FOOD AND DRUG ADMINISTRATION





































                        Thursday, June 10, 2004


                               8:03 a.m.








                        Holiday Inn Gaithersburg

                              The Ballroom

                     Two Montgomery Village Avenue

                         Gaithersburg, Maryland




      Vernon Chinchilli, Ph.D., Acting Chair

      Shalini Jain, PA-C, MBA, Executive Secretary




                Carolyn M. Kercsmar, M.D.

                Fernando D. Martinez, M.D.

                Theodore F. Reiss, M.D. (Industry Rep)

                Michael Schatz M.D., M.S.

                Karen S. Schell, RRT, (Consumer Rep)

                Erik R. Swenson, M.D.




                T. Prescott Atkinson, M.D., Ph.D.

                I. Marc Moss, M.D.

                Wayne Mitchell, M.D.



                            C O N T E N T S




      Call to Order and Opening Remarks:

                Vernon Chinchilli, Ph.D.                         5


      Introductions                                              6


      Conflict of Interest Statement:

                Shalini Jain, PA-C, MBA                          7


      Opening Remarks:

                Robert Meyer, M.D.                              10


      History of the Montreal Protocol and 21 CFR 2.125         13


      Medical Considerations:

                Eugene Sullivan, M.D.                           40


      Economic Considerations:

                Randall Lutter, Ph.D.                           60


      Questions from the Committee to the Speakers              76


      Open Public Hearing (1)

                Pamela Wexler, U.S. Stakeholders Group          93

                Elaine Jones, Ph.D. GlaxoSmithKline            104

                Ron Garutti, M.D., Schering-Plough             119


      Open Public Hearing (2)

                Ballard Jamieson, Jr., International           143

                  Pharmaceutical Aerosol Consortium

                Neil Flanzraich, IVAX Corporation              149

                Richard Rozek, Ph.D., National Economic        162

                  Research Associates

                David Doniger, Natural Resources               172

                  Defense Council

                Joseph Rau, M.D., American Association         181

                  for Respiratory Care

                Jodi Finder, Asthma Therapy Coalition          183

                Steven Bernhardt, M.D.,                        190

                  Honeywell Chemicals



                      C O N T E N T S (Continued)


      Open Public Hearing (2) (Continued)

                Nancy Sander, Allergy and Asthma Network       193

                  Mothers of Asthmatics

                Anthony Marinelli, M.D., American              198

                  Thoracic Society

                Ira Finegold, M.D., College of Allergy,        203

                  Asthma and Immunology

                Spenser Atwater, M.D., Joint Council on        207

                  Allergy, Asthma and Immunology

                 (statement read by Ms. Jain)


      Committee Discussion                                     211


      Adjournement                                             282




                         P R O C E E D I N G S


                   Call to Order and Opening Remarks


                DR. CHINCHILLI:  Good morning, everyone.


      This is a meeting of the Pulmonary-Allergy Drugs


      Advisory Committee.  We are here today to discuss


      whether the use of chorofluorocarbons as


      propellants in albuterol-metered dose inhalers in


      no longer an essential use under the criteria as


      set forth in the Code of Federal Regulations 12 CFR




                My name is Vern Chinchilli.  I am the


      Acting Chair today for the committee.  So we will


      have some opening remarks.  The first thing I


      usually do is introduce--I will ask each committee


      member--we will go around the table--to introduce


      themselves.  Please make sure you hit the


      microphone button so it is on.


                Why don't we start with Dr. Reiss.  Oh; he


      is not here?  Dr. Atkinson?


                DR. ATKINSON:  I am Prescott Atkinson,


      Allergy and Immunology at University of Alabama in






                DR. SCHELL:  Karen Schell, Consumer


      Representative from Kansas.


                DR. MARTINEZ:  I am Fernando Martinez from


      the Arizona Respiratory Center, University of




                DR. SCHATZ:  I am Michael Schatz, Allergy


      and Immunology, Kaiser Permanent, San Diego.


                DR. KERCSMAR:  Carolyn Kercsmar, pediatric


      pulmonology, Rainbow Babies and Children's Hospital


      in Cleveland.


                DR. MOSS:  Mark Moss, Pulmonary and


      Critical Care, Emory University in Atlanta,




                DR. CHINCHILLI:  Vern Chinchilli.  I am a


      biostatistician from the Penn State Hershey Medical




                MS. JAIN:  Shalini Jain, Exec Sec, Acting,


      and, at this point, for this meeting for the


      Pulmonary-Allergy Drugs Advisory Committee.


                DR. SWENSON:  Erik Swenson, Pulmonary and


      Critical Care Medicine at the University of


      Washington in Seattle.




                DR. LUTTER:  Randy Lutter, Economics, with


      the Office of the Commissioner in FDA.


                DR. MITCHELL:  Wayne Mitchell, Office of


      Regulatory Policy in the Center for Drug Evaluation


      and Research.  I am the draftsman on the rule.


                DR. SULLIVAN:  I am Gene Sullivan.  I am


      the Deputy Director of the Division of Pulmonary


      and Allergy Drug Products at FDA.


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


      Director of the Office of Drug Evaluation II in the


      Center for Drugs at FDA.


                DR. CHINCHILLI:  Thank you, everyone, for




                Next, Shalini Jain will talk about the


      Conflict of Interest Statement.


                     Conflict of Interest Statement


                MS. JAIN:  The following statement


      addresses the issue of conflict of interest with


      respect to this meeting and is made part of the


      record to preclude even the appearance of such at


      this meeting.


                Based on the agenda, it has been




      determined that the topics of today's meeting are


      issues of broad applicability and there are no


      products being approved at this meeting.  Unlike


      issues before a committee in which a particular


      product is discussed, issues of broader


      applicability involve many industrial sponsors and


      academic institutions.  All special government


      employees have been screened for their financial


      interests as they may apply to the general topic at




                Because there has been reported interest


      in pharmaceutical companies, the Food and Drug


      Administration has granted general-matters waivers


      to the special government employees who require a


      waiver under Title 18, United States Code Section


      208 which permits them to participate in today's




                A copy of the waiver statement may be


      obtained by submitting a written request to the


      agency's Freedom of Information Office, Room 12A-30


      of the Parklawn Building.  Because general topics


      impact so many entities, it is not prudent to




      recite all potential conflicts of interest as they


      apply to each member, consultant and guest speaker.


                FDA acknowledges that there may be


      potential conflicts of interest but, because of the


      general nature of the discussion before the


      committee, the potential conflicts are mitigated.


      With respect to FDA's invited industry


      representative, we would like to disclose that Dr.


      Theodore Reiss is participating in this meeting as


      an industry representative acting on behalf of


      regulated industry.  Dr. Reiss is employed by




                In the event that the discussion involves


      any other products or firms not already on the


      agenda for which an FDA participant has a financial


      interest, the participants are aware of the need to


      exclude themselves from such involvement and their


      exclusion will be noted for the record.


                With respect to all other participants, we


      ask, in the interest of fairness, that they address


      any current or previous financial involvement with


      any firm whose products they may wish to comment






                Thank you.


                DR. CHINCHILLI:  Thank you, Ms. Jain.


                We are ready to start the regular part of


      the agenda.  Dr. Meyer, the Director of the Office


      of Drug Evaluation II, will have some opening




                            Opening Remarks


                DR. MEYER:  Good morning.  Although I


      service Director of the Office of Drug Evaluation


      II in the Center for Drugs, I, for many years,


      served for the Center Lead on issues related to the


      Montreal protocol and phase-out of CFCs from


      FDA-regulated medical products, specifically MDIs


      for asthma and COPD.


                So, on behalf of the FDA, I wish to


      welcome all the participants in today's meeting of


      the Pulmonary and Allergy Drugs Advisory Committee.


      I want to thank you in advance for your time and


      your efforts and your thoughtfulness in your


      discussions and advice.


                When we were originally planning this




      meeting, we had hoped the meeting would coincide


      with the open public comment period of a proposed


      rule to delist albuterol as an essential use of


      ozone-depleting substances, specifically CFCs.


      This is now, indeed, the case although the rule


      just went on display at the Federal Register and,


      subsequently, on our web page yesterday afternoon.


      I believe you have been provided copies.


                I would point out that, although the


      proposed rule  is posted on these sites, it is not


      officially published until June 16 so what you have


      in hand is a pre-publication version that means


      some dates are missing and the pagination will


      change when it is officially published in the


      Federal Register.


                I would also point out that the six-day


      comment period starts on the day of official


      publication which will be June 16 although,


      clearly, the discussions today will be considered


      as part of the docket for us to consider in coming


      to the final rule.


                We particularly look foreword today to




      input from the public in our public hearing portion


      of the meeting and I thank those individuals and


      organizations who are presenting or have otherwise


      submitted materials for the record.


                All of the presentations, submissions and


      the deliberations of the committee and advice given


      today will be entered into the docket, as I said,


      and will help us to move forward towards finalizing


      this rule with a target of Summer of 2005.


                I would note to the committee that we are


      not seeking any formal votes today on a particular


      question but do, very much, seek your counsel on


      the matter at hand whether the use of CFCs in


      albuterol metered-dose inhalers remains an


      essential use under the provisions of our




                We will have three speakers from the FDA


      today.  I will first speak, giving a history of the


      Montreal Protocol and FDA's regulations regarding


      essential use of CFCs.  Dr. Eugene Sullivan, from


      the Division of Pulmonary and Allergy Drug


      Products, will then follow with considerations




      related to the current situation with albuterol and


      its essentiality as well as some related issues.


                To close FDA's presentations, Randy


      Lutter, who is FDA's Chief Economist in the Office


      of Planning, will speak on economic considerations


      related to the potential for delisting albuterol as


      an essential use.


                Again, we would like to thank you for your


      time in being here and look forward to today's




                DR. CHINCHILLI:  Thank you, Dr. Meyer.


                I believe you are on the agenda next for


      your presentation.


           History of the Montreal Protocol and 21 CFR 1.125


                DR. MEYER:  Good morning, again, from this


      venue.  When I arrived at the agency about ten


      years ago this July, I can assure you that I never


      envisioned I would be standing here representing


      the FDA on the issue of ozone protections.  As a


      pulmonologist, it was not something that entered my


      mind at that point.


                But life is full of happy occurrences. 




      This picture on my title slide is from NASA's web


      page and shows the largest recorded ozone hole over


      the Antarctic which actually was shot last


      September of 2003.  This serves as a fitting


      graphic to start a talk on the history of the


      Montreal Protocol as well as the FDA regulations


      that related to chlorofluorocarbons and


      ozone-depleting substances.


                The stratosphere is a region of the


      earth's atmosphere that begins roughly ten to


      fifteen kilometers above the earth's surface,


      depending on the particular part of the earth one


      is focused on, and extends up to 50 kilometers.


      Most of the ozone, over 90 percent of the ozone, in


      the atmosphere is in this stratosphere where it


      acts, in part, to filter ultraviolet B radiation by


      absorbing this band of wave length from sunlight.


                Increases in UV-B reaching the earth's


      surface are detrimental to human health in a number


      of ways as well as to other life forms and to


      synthetic materials.  The human consequences of


      most note are increases in skin cancer as well as




      cataracts and alterations in immunity.  Those skin


      cancers are both of the melanoma type as well as




                This, then, is the background as to why


      there is a worry about protecting the ozone layer.


      Also, by way of background, since we are talking


      about regulations, I would like to explain how


      rules are made.  The FDA operates under laws or


      statutes, most notably the Food, Drug and Cosmetic


      Act, as well as other statutes.


                However, no matter how well written or


      detailed a law may be, it cannot provide sufficient


      detail to inform the specific process of


      regulation.  This is accomplished by the writing of


      rules which, when finalized, have the force of law


      behind them as it represents the agency's


      implementation of the respective law that we are


      operating under.


                The usual pathway for reaching a final


      regulation or rule is by what is called Notice and


      Comment Rulemaking.  Formally, that involves the


      FDA publishing a Notice of Proposed Rulemaking, or




      NPR, in the Federal Register such as will shortly


      occur for albuterol.


                An NPR typically has a comment period


      between 60 and 90 days--again, that, for the rule


      at hand is 60 days beginning on June 16--during


      which time comments from the public, including the


      regulated industry, are solicited.  These comments


      are then individually considered and addressed in


      reaching a final rule.  Rulemaking is an integral


      part of the CFC non-essentiality determinations.  I


      will speak more on this later.


                The purpose of my talk, then, this


      morning, is to give a history and background of the


      Montreal Protocol and to FDA's regulations with


      regard to ozone protection.  The timeframes for


      these, as they developed, overlap and, obviously,


      the efforts intersect.  So I will interweave the


      two topics in my talk.


                Back in the mid-1970s, two scientists


      operating out of trial University of California at


      Irvine posited that chlorofluorocarbons were


      reaching the stratosphere were UV radiation slowly




      would cleave off the chloride atoms that, in turn,


      catalyze the destruction of ozone.  This work was


      by Molina and Rowland, who later was awarded the


      Nobel Prize.


                At the time that this article came out,


      chlorofluorocarbons, or CFCs, were ubiquitous in


      use in multiple applications.  They became


      widespread for a number of reasons.  Amongst these


      were that CFCs are quite non-toxic which,


      parenthetically, makes them excellent for use in


      inhalers, very stable and had physical-chemical


      properties that were advantageous for use in


      refrigerant systems, air conditioners and aerosols.


                The stability of these gasses is, in part,


      why they are so devastating to the stratosphere.


      They have a very long half-life when they reach the


      stratosphere and, therefore, damage the ozone layer


      for many, many years.


                In 1978, really in a fairly remarkably


      short time after the seminal publication by Rowland


      and Molina, the U.S. Government acted to address


      the issue of CFCs and to place a general ban on the




      use of CFCs as propellants in consumer aerosol


      products.  This was accompanied by a rule from FDA


      in the relevant chapter of the Code of Federal


      Regulations or what we call the CFR, and that, for


      the FDA, is the 21st Chapter, banning the use of


      CFCs in all regulate products except for those


      deemed as essential uses.


                This rule is now called 2.125 because that


      is the citation where it is published.  That is how


      we will be referring to it throughout much of the


      day.  Notably exempt  at that time were broad


      classes of asthma and allergy products such as a


      nasal steroids, the inhaled steroids, and


      adrenergic bronchodilators.


                In 1987, as the science of ozone depletion


      advanced and as there was further evidence


      accumulated about ozone reductions, a global treaty


      known as the Montreal Protocol on substances that


      deplete the ozone layer was initiated.  At that


      time, 27 nations, including the USA, were




                I would note, just to make this topical to




      sort of current events, that this was during the


      latter years of the Reagan Administration.  The


      original protocol now has at least 184 signatory


      countries.  As of the time that I queried the web


      page for the Secretariat of the Ozone Efforts about


      a month, it was 184 countries.  Countries are also


      called parties under the terms of the protocol.


                This is widely considered a successful


      example of global, environmental cooperation.


      Indeed, there is evidence that the chloride levels


      in the stratosphere have stabilized in recent years


      and it is expected that the stratospheric ozone


      layer will slowly recover to levels that were seen


      in the early 1980s by the middle part of this


      current century.


                The original phase-out of CFCs was slated


      for the Year 2000.  That was taken in London in


      1990.  This was moved up, however, by meeting of


      the parties in Copenhagen which occurred in 1992.


      It was moved up to 1995, at the end of '95, because


      of increasing evidence of marked ozone depletion,


      particularly over the extreme southern hemisphere,




      as you saw in my first slide.


                This phenomenon is commonly called an


      ozone hole.  It is not really a true hole but an


      area of extreme depletion.  I should point out


      that, although it is a depletion that is


      particularly prominent over the southern


      hemisphere, it has occurred globally.


                I should also point out that, while we are


      focussing on CFCs today because that is the


      relevant topic for the FDA, the protocol, itself,


      has controls on many other ozone-depleting


      substances such as halons, HCFCs, methylbromide,


      carbon tetrachloride and other substances.


                So, while the CFCs are an important issue


      to FDA and, indeed, to the Montreal Protocol, I do


      want to be clear that the protocol is a much


      broader effort in scope than simply the




                In accordance with the Copenhagen


      Amendment to the protocol, the production and


      importation of CFCs became illegal in economically


      developed countries including the United States as




      of January 1, 1996.  The rest of the world is


      expected to have phased out new CFCs by 2010.


      Metered-dose inhalers, or MDIs, for asthma and COPD


      are currently considered as potentially acceptable


      essential uses of CFCs.  I say potentially


      acceptable because there is a nomination process


      that parties undergo if they want to produce or


      import CFCs for use in MDIs.


                These nominations have to be done annually


      and the process generally begins nearly two years


      prior to the year in question.  So, for instance,


      the U.S. had to submit its nomination for 2006 in


      early 2004.


                I would also point out that nominations


      are historically approved by consensus of the


      parties to the Montreal Protocol but, actually, if


      the consensus process fails, there is a mechanism


      within the protocol to default to a two-thirds


      majority decision.


                I wanted to go through sort of how the


      protocol has evolved over time  This is a decision


      of the parties from the Copenhagen meeting. 




      Decision IV, or this IV, means that it was from the


      fourth meeting of the parties and it was the 25th


      decision taken at that meeting.  This was the


      definition at the time that they decided the


      phase-out would begin on January 1, 1996, or the


      ban on CFCs, that stated that, "All essential uses


      of CFCs would have to be based on products being


      necessary for public health and that there were not


      adequate alternatives."  The failure to have


      adequate alternatives could either be based on


      technical problems or economical problems.


                But this was macroscopic in terms of both


      this determination as well as the general use.  In


      other words, it was widely accepted at that point


      in general that the uses of CFCs and MDIs for


      asthma and COPD could be considered an essential




                However, over time, the protocol evolved


      so that, as the phase-out progressed, as


      alternatives became available, this sort of more


      generally and broad interpretation of what was an


      essential use became narrower and narrower in






                In Beijing, at the twelve meeting of the


      parties in the Year 2000, another decision was


      taken that said that any product approved after


      December, 2000, must individually meet these


      criteria for essentiality under Decision IV-25.


      So, in other words, it is not just a general


      consensus any longer that the use of CFCs for


      asthma and COPD was acceptable but, in this case,


      any new product would have to individually meet




                So this was a product-centered


      determination of essentiality that essentially


      precluded new CFC generics and, actually, many


      other new CFC products.  It essentially was


      shutting the door, for all intents and purposes,


      except under extraordinary circumstances for any


      new CFC MDIs.


                This past year, in Nairobi, a further


      decision was taken by the parties that became even


      more narrow and specific in scope.  It stated that


      essential-use nominations from parties which, in




      the past, had been lumped and general and not


      parsed out for the purposes of the protocol's


      evaluation, or the Montreal Protocol evaluation.


                Now it stated that essential-use


      nominations have to be specific; for example, a


      country might say they need some


      undetermined--well, they would have to give a


      specific number, but some number of tons for


      albuterol.  No quantity of essential-use CFCs would


      be authorized for albuterol.  This is, I think,


      particularly germane today--that no quantity of


      essential uses of CFCs would be authorized,


      period--actually, this is a little bit of a


      misstatement in the way this is terms--if a country


      does not submit to the meetings of the


      party--beginning of the open-ended working group,


      excuse me, in the summer of 2005--a clear plan for


      when albuterol, specifically, would no longer be




                Let me go through that again, because this


      is key.  Countries who request essential uses,


      including the United States, will have to submit to




      the Ozone Secretariat of the Open-Ended Working


      Group in the summer of 2005 a plan or a


      date-certain for when albuterol will no longer be


      considered essential. If parties fail to do that,


      including the U.S., we will not receive and


      essential-use allocation at all.


                Now, turning a little bit from the


      evolution of the Montreal Protocol back to our


      rules and regulations, the Clean Air Act Amendments


      of 1990 codified the Montreal Protocol into U.S.


      law.  The implementing EPA regulations specifically


      call for FDA to define what is an essential medical


      use and refers to our 2.125 as the source of the


      listing of those essential products.


                I remind you, however, that 1.125 was


      finalized before the Montreal Protocol existed and


      before the Clean Air Act Amendments.


                The rule, as promulgated in 1978, stated


      that a  CFC-containing product regulated by FDA was


      misbranded or adulterated under the FD&C Act; that


      is, it would be illegal under our authority unless


      deemed essential and listed in 2.125.  The




      definition of essential was that there would be no


      technically feasible alternatives; that the use of


      CFCs in that particular product provided


      substantial health, public or environmental


      benefit; and that the release of the CFC was small


      or justified given the public-health benefit.


                Notably, the FDA rule had no mechanism to


      determine when things were no longer essential and,


      therefore, to delist them.  It did have ways to add


      new classes of drugs to the list and, in fact, that


      was done over the years.  But it had no specified


      way for delisting things.


                Another important feature of the rule that


      needed to be correct is that many drugs, including


      albuterol, were not specifically mentioned as


      essential uses but, rather, there were broad


      definitions of drug classes, if you will, such as


      albuterol and other beta-agonists being under the


      general term of adrenergic bronchodilators for


      human use.


                So, realizing that we needed to correct


      some things about this rule that was written prior




      to the Montreal Protocol and the Clean Air Act, and


      specifically to develop a mechanism for delisting


      things that were no longer essential, FDA, in 1996,


      undertook revisions.  Because of wanting to do


      these revisions in the very most public and


      informed manner, the FDA took an additional step to


      the steps that I gave you earlier for the


      publication of a rule, doing something called an


      Advance Notice of Proposed Rulemaking which,


      actually, starts with another cycle of notice and




                This effort proved very successful if


      measured by the number of comments.  We got close


      to 10,000 comments to this Advance Notice of


      Proposed Rulemaking, many of which, I would point


      out, were actually patient-based comments sparked


      by lobbying efforts.


                We then took all 10,000 comments and


      reviewed them and responded to them.  I would note


      that there were many fewer substantive comments but


      still all of the comments were carefully reviewed


      and considered.  That resulted in the publication




      of a Notice of Proposed Rulemaking in 1999.


                That proved to be less controversial in


      many ways and it received many fewer substantive


      comments and comments overall and, as I said, had


      seemingly much less controversy.  So FDA moved


      forward with amending 2.125 in July of 2002 and


      this went into effect six months later.


                The 2002 revisions did a number of things.


      First of all, it listed essential uses as


      individual moieties.  I would point out that, to


      coincide more correctly with the Montreal Protocol,


      it no longer referred simply to chlorofluorocarbons


      but to ozone-depleting substances.  But, for the


      purposes of today and for all intents and purposes,


      most of FDA's activities, you can consider ODS, or


      ozone-depleting substances, as being synonymous


      with CFCs in terms of this discussion.


                So, for instance, albuterol is now


      separately listed rather than there just being a


      broad class without any citation of individual




                The revisions also added a higher hurdle




      for investigational new drugs to be developed with


      CFCs and it raised the bar for new listings of


      essential uses as well.  There was also a list of


      criteria, importantly for today, for determining


      when individual uses were no longer considered




                One other revision I would point out that


      is not on this slide was that we shifted the rule,


      because of the re-write of the Clean Air Act, to


      state that if something was no longer essential, it


      would be considered illegal to market it under the


      Clean Air Act and not under the Food, Drug and


      Cosmetic Act.


                Let me go through these important


      nonessentiality criteria.  I would point out that


      Dr. Sullivan will revisit these in his talk


      specific to albuterol, but I think they are worth


      hearing a couple of times.


                For a specific moiety to be considered


      nonessential, there would have to be at least one


      non-ozone-depleting-substance product--in other


      words, a non-CFC product--with that same active




      moiety, and here I am only talking about a moiety


      where there is only one marketed-brand product or


      one marketing strength, so, at least one active


      moiety with the same indications, same route of


      administration--in other words, oral albuterol


      would not be considered an alternative under these


      criteria--and about the same level of convenience.


                We stated in the preamble to the final


      rule that, although dry-powdered inhalers might fit


      this description, we felt that MDIs would most


      neatly do so and, I think, most logically do so.


                In addition to this, these alternatives


      would have to have adequate postmarketing data to


      prove that they are not only safe and effective for


      approval purposes but will serve as an adequate


      alternative in the marketplace.  Importantly, there


      would have to be production capabilities and


      supplies that are adequate to meet the needs of


      patients who depend on the use of this moiety for


      the treatment of their asthma or COPD and patients


      who require the CFC product are adequately served.


                I would state, and I am sure that Gene




      will bring this up as well, that, under the


      considerations for adequately served, is the issue


      of price in that--not so much whether there will be


      any impact on the price to the patients but will


      patients be disaffected or unable to get the


      medicine if there is a price differential.


                We didn't build that in as an explicit


      consideration, the cost issue, but it was mentioned


      in the preamble because many of the comments to the


      ANPR and to the PR as we developed this re-write of


      2.125, brought up the issue of affordability.


                Now, specific to albuterol which


      has--actually, this should say one branded product


      available and three generics marketed--for moieties


      with more than one available product or strength


      such as albuterol, you would need at least two


      non-ozone-depleting-substance products with the


      same active moiety, the same indication, route of


      administration, about the same level of


      convenience, and the other criteria were the same.


                So, in other words, if the moiety was


      represented in the marketplace by different




      strengths or different numbers of products from


      different manufacturers, we felt it important that


      there be sort of at least--if not a full match to


      the range, at least alternatives that represented


      some choice.


                Let me just show you, to wrap up this


      background, where all this has led over time.  This


      is a graph of the global situation for CFC


      essential uses.  Let me go through the two lines


      here.  This is 1996.  The open space is actually


      the year, not the hatch mark, so we go from 1996


      out to 2006 on the X axis.  On the Y axis, we are


      talking about metric tons.  A metric ton is 2200


      pounds, so these are metric tons of total CFC used


      for essential-use allowances in these developed




                The red line is the amount that was


      exempted--in other words, the amount that was


      nominated and approved by the parties.  The blue


      line is the amount that was actually used over


      time.  The green line is the stockpiles.  So these


      are the amounts held by the countries that don't




      represent new production.


                You can see that the peak of the use


      worldwide, or at least in these developed countries


      that were putting in essential uses, was just about


      9,000 metric tons occurring in the 1997-1998 range.


      This has fallen by 2003 down to just a little bit


      over 4,000 tons.  One would project from the amount


      nominated, which generally has been historically


      higher than the amounts actually used, that this


      will further fall in the coming two years rather


      dramatically.  So the amounts nominated in 2006 are


      down below 3,000 metric tons.


                I apologize for this being a little harder


      to see.  I could not manipulate this as easily as


      the last one.  But this is the situation for the


      United States, itself.  Again, this is metric tons


      per year on the Y axis, years on the X axis.  I


      know that will be very difficult for people in the


      audience to see but the main point here is this is


      the blue line, which is the amount used for


      metered-dose inhalers in the United States.


                You can see, for the most part, that it




      has been reasonable stable from the


      pre-Montreal-Protocol years through the time period


      of the Montreal Protocol, although there was a


      rather substantial fall in the last couple of


      years--this goes out to 2002--at which time the


      total use was just a little bit over 1500 metric


      tons in the United States.  I would point out that


      the use for albuterol is a substantial portion of


      the United States nomination.


                Let me also now talk about the transition


      within the United States, itself.  What we have


      here is a slide that attempts to display the


      original listings under the 2.125 and then the


      specific listings under 2.125, and then to display


      changes over time.


                So, originally, 2.125 had the broad class


      of beta-adrenergic agents: inhaled corticosteroids;


      nasal steroids; the cromones--cromolyn and


      nedocromil were actually separately listed;


      ipratropium; atropine, which was actually approved


      for use in Desert Storm; a combination product,


      albuterol and ipratropium.




                I think it is important for me to point


      out, if Dr. Sullivan does not and if it is


      repeated, I think it is still and important thing;


      we are not talking about a combination product


      today.  We are only talking about those products


      that solely contain albuterol as their active


      ingredient; and then a number of other products,


      many of which were actually, as you can see, not


      MDIs.  So we had talc, contraceptive foams, rectal


      foams, ergotamine MDIs, polymxin, anesthetic drugs


      including those that directly use CFCs, and




                When the re-write of 2.125 was finalized


      in 2002, those products listed in red were taken


      out, many of these because they either did not meet


      the criteria any longer or  were not considered


      essential under the Montreal Protocol, or they were


      no longer marketed.


                So, at the time of the finalization,


      isoetharine, isoproterenol, the nasal steroids as a


      class, contraceptive foams, rectal foams, polymyxin


      and nitroglycerine all came out and were not




      separately listed in 2.125.


                The products in yellow could be considered


      as potential for delisting soon, these because they


      are no longer available, marketed as CFC products.


      One of the things in 2.125 re-write that was said


      was that, if a product was not marketed for a


      substantial period of time, one could consider it


      to be not essential.  Those would include


      bitolterol, salmeterol, which was discontinued by


      the manufacturer, dexamethasone, talc, ergotamine


      MDIs and anesthetic drugs.


                Beclomethasone is no longer marketed, the


      MDIs, at least not newly produced MDIs, and there


      are alternatives.  So that is another potential


      delisting.  Albuterol, I guess I did not put in


      yellow here because that is what we are here to


      discuss today is whether that has met the criteria


      that we laid out in the revisions of 2.125.


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


      Government moved proactively to address the issue


      of ozone depletion shortly after the development of


      the ozone science, and the U.S. Government had a




      key role in the formation and the conduct of the


      Montreal Protocol.  The Montreal Protocol is


      considered a successful treaty that has led to


      important reductions in CFCs and other


      ozone-depleting substances and, as I mentioned,


      there are data to suggest that the recovery of the


      stratospheric ozone layer is in the early stages.


                Now, the Montreal Protocol, as I pointed


      out from the evolution of some of the decisions


      taken, is increasingly moving towards control in


      its specific essential uses, notable amongst those


      would be albuterol.


                Just as a transition slide, I chose


      another picture off the NASA web page of the ozone


      depletion.  Remember that I said we would recover


      to the early '80's levels by the mid part of this


      century.  This shows the Antarctic region in 1983


      and the Antarctic region in 1993.  You can see the


      difference where the white is the thicker ozone.


      You can see the difference in the ozone layer in


      that decade.


                So, thank you very much.




                DR. CHINCHILLI:  Thank you, Dr. Meyer.


                You finished a few minutes early so let's


      see if there are any questions from our committee


      members.   I have one, Dr. Meyer.  What was the


      rationale behind the decision about not pursuing


      this with the--not considering the dry-powdered


      inhalers as a similar moiety?


                DR. MEYER:  What we said was that we


      thought they could serve as an alternative but it


      would not be as automatic as an MDI.  So, in fact,


      I think if there were an albuterol dry-powdered


      inhaler that met those criteria otherwise, we would


      consider it.


                I think, at the time we were writing it,


      we had considerations such as, at that point,


      albuterol was available in a capsule, an individual


      capsule, rotohaler-type device where one would


      place it in, turn it and breathe.  We did not feel


      that that had sort of the same level of convenience


      and portability and so on as an MDI.  So I think we


      wanted to not exclude all dry-powdered inhalers out


      of hand but say that they would have to meet




      certain levels of convenience and patient




                Again, the presumption in the preamble to


      rule was that the MDIs would most neatly do that


      because they are very much similar.


                DR. CHINCHILLI:  Dr. Martinez?


                DR. MARTINEZ:  Dr. Meyer, in your


      multicolored slide, there was some products in


      white.  I presume those will continue to be


      available by way of CFCs and includes epinephrine,


      for example; is that correct?


                DR. MEYER:  Some of those products in


      white are, in fact, under development in that are


      alternatives being developed.  Some are not.  One


      of the provisions in the rule that I didn't bring


      up today because it wasn't fully germane but I


      would be happy to answer as a part of your question


      is the fact that, beginning next year, we will have


      the ability to call this body into meetings, have


      the advisory committee come to meetings, to discuss


      those products that remain on the list that are not


      being reformulated and whether they remain






                I think, just parenthetically, epinephrine


      will be something that will be important for us to


      discuss at some time in the future.


                DR. CHINCHILLI:  Any other questions from


      the committee?  If not, thank you, again, Dr.




                I guess we will move forward with Dr.


      Sullivan, the Deputy Director of the Division of


      Pulmonary Drug Products.


                         Medical Considerations


                DR. SULLIVAN:  Good morning.  I am Gene


      Sullivan.  I am a pulmonologist.  I am also the


      Deputy Director of the Division of Pulmonary and


      Allergy Drug Products at FDA.  For the next twenty


      or thirty minutes, I am going to be discussing some


      of the medical considerations in regard to this


      proposal to remove albuterol from the list of drug


      substances that are considered essential uses for




                Following my talk, you will hear from Dr.


      Lutter, as Dr. Meyer mentioned.  Dr. Lutter will go




      into more depth in regard to the economic aspects


      of this question.  Then, following that, you will


      hear some very important information from


      interested parties who will be speaking during the


      open public hearing.


                So this slide provides a background


      overview of my talk.  Dr. Meyer has just given a


      very nice background on the overarching issues


      about the Montreal Protocol and the FDA Regulation


      2.125, so my background remarks will be brief.


      Then, also, briefly, I will review the currently


      marketed albuterol MDI products.  But the bulk of


      my talk will be in this section specifically


      looking at the criteria that Dr. Meyer mentioned


      that are included in the Amended 2.125, so the


      currently existing regulation, and specifically


      examining those criteria in regard to how they


      apply in the case of albuterol.


                Then, finally, I will touch on a couple of


      other issues which, although they are not directly


      responsive to the criteria laid out in 2.125, I


      think are clearly important issues to consider when




      deciding on a path forward with regard to




                So, again, Dr. Meyer has provided very


      nice background on the Montreal Protocol and on the


      FDA regulation concerning the essential-use


      determinations, that being 21 CFR 2.125 and, as Dr.


      Meyer mentioned, I will be referring to it as 2.125


      from now on.


                As you know, the agency is currently


      considering whether albuterol, in fact, has met the


      criteria that are listed in 2.125 for removal from


      the list of essential uses.  This process that we


      are embarking on is in keeping with the goals of


      the Montreal Protocol, specifically, the goal of


      phasing out production and importation of


      ozone-depleting substances including




                I think the step forward with albuterol is


      an important step in that direction particularly


      because approximately half of the annual


      essential-use CFC allocation in the U.S. is for


      albuterol.  We are moving forward in this direction




      in light of the fact that there now exist two


      alternative, non-CFC albuterol metered-dose


      inhalers on the market in the U.S., that being


      Proventil HFA and Ventolin HFA.


                In addition, in 2003, the American Lung


      Association submitted a citizen petition on behalf


      of a group of organizations, collectively referred


      to as the U.S. Stakeholders Group.  That petition


      requested that the agency move forward with this


      rulemaking process in order to remove albuterol


      from this list.


                That citizen petition is included in your


      background materials.  Your background materials


      also include other communications we received from


      the Stakeholder's Group as well as the submissions


      to the public docket that were submitted by various


      interested parties and organizations in response of


      the citizen petition.


                So what are the currently marketed


      albuterol metered-dose inhalers?  Obviously, they


      can be divided into those that contain CFCs, which


      are ozone-depleting substances, and those that




      don't contain CFCs.  In terms of the CFC MDIs,


      there are several.  First of all, there is the


      branded product, Proventil, marketed by


      Schering-Plough.  This was approved in 1981.  In


      addition, there is a product marketed under a


      Warrick label which is marketed under the same NDA.


                Then there are several generic versions.


      Actually, four have been approved.  The first of


      these was approved in 1995.  Currently, three of


      these are being marketed.  As you may know, in


      1981, there were actually two branded albuterol CFC


      MDIs that were approved, the other one being


      Ventolin.  That is not listed here because it is no


      longer marketed within the U.S.


                Now moving to the non-CFC MDIs or, and I


      will use the shorthand, as alternatives, these


      don't use CFCs.  Rather they use HFA 134A which is


      a substance that does not affect the ozone layer.


      There are two of these HFA products; Proventil HFA,


      which was approved and initially marketed in 1996


      and, more recently, Ventolin HFA, which was


      approved in 2001 and was marketed in 2002.




                So this is the regulation, obviously, that


      is at the heart of today's discussion, 2.125,


      called the Use of Ozone Depleting Substances in


      Food, Drugs, Devices or Cosmetics.  Among a number


      of thing, one of the things that it does is it


      lists specific drug moieties for which the use of


      CFCs is considered essential.


                In addition, as Dr. Meyer mentioned, it


      sets forth criteria.  There are four such criteria


      that must be met in order to remove a drug moiety


      from the list of essential uses.


                I will run through these again.  Dr. Meyer


      has been through them.  I will run through again,


      though, because I think they are the heart of


      today's discussion.  First of all, and here I am


      referring to active moieties represented by two or


      more NDAs which is the case, as I mentioned, with




                The first criterion for removing a drug


      from the list of essential uses would be that at


      least two non-ozone-depleting-substance products


      that contain the same active moiety are being




      marketed with the same route of delivery for the


      same indication with approximately the same level


      of convenience as the ozone-depleting product.


                The second criterion is that supplies and


      production capacity for the alterative must exist


      or be expected to exist at levels that would be


      sufficient to meet patient need.


                The third criterion is that adequate


      postmarketing-use data should be available for the


      non-ozone-depleting products.  Again, as Dr. Meyer


      mentioned, that is to provide some reasonable


      assurance that no unanticipated limitation of the


      alternative product emerges during the


      postmarketing, so real-world experience that was


      not detected prior to approval.


                Then, finally, the fourth criterion is


      that patients who medically require the product


      would be adequately served by non-ozone-depleting


      products containing the same active moiety and


      other available products.


                So now I am going to walk through each of


      these criteria and look at how they apply to




      albuterol.  The first criterion; again, at least


      two products containing the same active moiety, the


      same route of delivery, the same indication and


      approximately the same convenience of use.  So,


      clearly, the alternatives that we are discussing,


      Ventolin HFA and Proventil HFA, both have the same


      active moiety, albuterol.  Both are delivered by


      the same route of delivery, oral inhalation, and


      carry the same indication, prevention and relief of


      bronchospasm and patients with reversible


      obstructive airway disease and prevention of


      exercise-induced bronchospasm.


                I should point out the initial NDA,


      Proventil, was approved down to the age of 12 and


      Ventolin was approved down to the age of four.


      Both of the alternative products are approved down


      to the age of four.


                Finishing up with the first criterion, the


      final bit of it is the same level of convenience.


      Now, when we looked at the same level of


      convenience, we described, in the Preamble, various


      aspects of what we might mean by that.  We looked




      at things like portability, preparation before use


      and the physical effort of manual dexterity that


      might  be needed to administer the drug.


                The CFC and HFA MDIs are quite similar and


      so have very similar portability and require


      similar degrees of physical effort and dexterity to


      use.  I should mention, in regard to preparation


      before use, that, in the early experience with the


      first HFA that was approved, the Proventil HFA, we


      became aware that there were occasional instances


      of clogging of the actuator if they were not


      cleaned properly.


                Now, the CFC and the HFA inhalers have


      actually very similar cleaning instructions.  It is


      just evident that patients using the HFA inhalers


      need to pay more attention to the cleaning


      instructions that are already in the label for both




                The second criterion is a little bit more


      difficult to definitively establish at this point.


      This is the criterion that states that supplies and


      production capacity for the alternatives need to be




      at levels that would be sufficient to meet patient


      needs.  At least in part, because of the price


      differential between the generics and the currently


      marketed FHA products, the market share for the HFA


      products, at this point in time, is much smaller in


      comparison than the market share of the CFC




                So, if the CFC products were to become


      unavailable suddenly today, the current supplies


      and production capacity of the HFA alternatives are


      not sufficient to meet patient need.  That is


      because, simply, that the manufacturers would need


      time to ramp up production.  However,


      GlaxoSmithKline, in its statement in response to


      the citizen petition submitted to the docket and


      included in your background package has stated that


      it is confident that additional internal and


      external capacity can be installed to insure


      adequate supplied and production capacity for


      Ventolin HFA and that this could be accomplished


      within twelve to eighteen months.


                In addition to this statement in the




      docket, GlaxoSmithKline and, also, Schering-Plough,


      will be speaking today and I expect that at least a


      portion of their comments may address specifically


      this criterion.


                The third criterion that we are applying


      is that adequate U.S. postmarketing data be


      available for the alternatives, again, looking for


      unexpected real-world problems with the


      alternatives.  At this point in time, we have


      Proventil HFA which has been marketed for seven


      years and Ventolin HFA which has been marketed for


      two years.


                Apart from the early reports of actuator


      clogging that I mentioned, the available


      postmarketing use data does not suggest any


      problems in terms of safety, efficacy, tolerability


      or patient acceptance of these two alternatives.


                Perhaps the most difficult of the criteria


      to address is the fourth.  This is the criterion


      that states that patients who medically require the


      ODS are adequately served by the alternative.  This


      term, "adequately served," is fairly broad and it




      encompasses a number of things.


                Clearly, the most important is that the


      available data on the alternatives must demonstrate


      sufficient efficacy and safety and tolerability and


      so forth such that the alternatives could be


      considered reasonable replacements for the CFC


      MDIs.  This type of data was submitted with the NDA


      and has accumulated in a postmarketing period and


      seems to imply that the alternatives do meet these




                But there is a further subtlety to the


      adequately served phrase here and that is cost.  As


      Dr. Meyer mentioned, during the process of the ANPR


      and the proposed rule, there were comments about


      the effect of this rule on the price of


      medications.  In the Preamble, in the Federal


      Register, the Preamble to the 2002 Amendment where


      these criteria were established, the FDA clearly


      stated that it will consider cost in determining


      whether the alternatives meet patient needs.


                So I am going to take a couple more slides


      to just look at this cost issue a little bit in




      more depth.  As with most drugs, branded CFC


      products cost more than their generic counterparts.


      As it turns out, in this very complicated


      healthcare system that we have in the U.S. in which


      the specific price of a medication varies according


      to a number of factors including who is paying, it


      is somewhat difficult to arrive at "the" price of a




                Therefore, it is somewhat difficult to


      arrive at a clear statement of the differential


      between the cost of a branded product and a generic


      product.  Dr. Lutter will go into this in a little


      bit more depth and talk about the various sources


      of data that are available for the price of a


      medication and how complicated that issue is.


                I have provided on this slide some data


      from an FDA website that highlights the cost


      savings to a patient that can be achieved with


      generic products.  The web address is in your


      handouts.  On this site, data on the average


      national retail price, which was data from IMS


      Health, were used to generate this information so




      that the retail cost per day for an asthmatic


      patient who used Ventolin would be $1.44 whereas


      the CFC generic would be 69 cents per day.


                Of course, this is a comparison between a


      CFC generic and a CFC branded, so it is important


      to note the branded HFAs, in general, are priced


      comparably to the branded CFC products although not


      exactly the same price.


                The other element to this is that there


      are a number of existing patents and, due to these


      patents, there are currently no generic HFA


      products available.  These patents are listed to


      expire, the first one in 2010 and the final patent


      in 2015.  So, given the current realities, the


      removal of the essential-use status of albuterol


      would result in an increase in the price of


      albuterol MDIs.


                The public-health consequences of such an


      increase in price are not known and are, in fact,


      very difficult to predict.  One possibility would


      be that patients who are prescribed albuterol


      metered-dose inhalers may be either unable or




      unwilling to pay for that and so may not purchase


      the albuterol inhalers.


                It is also possible that an increase in


      the price of an albuterol MDI, which is an


      acute-reliever drug from which patients, as you


      know, perceive an immediate benefit, might result


      in them forgoing filling prescriptions of other


      medications such as asthma-controller drugs from


      which they don't receive the same immediate


      feedback.  But, as you know, controller drugs are


      quite important in the appropriate management of




                So, as I mentioned, Dr. Lutter will


      discuss in greater depth these economic aspects


      including descriptions of the various sources of


      price data that are available and means for


      estimating how changes in the price of albuterol


      MDI might affect the utilization.


                As I mentioned, that is a difficult task


      in and of itself, how will an increase in price of


      an MDI translate into a change in utilization of


      albuterol and, even if we were able to establish




      that firmly, the next question that begs answering


      would be how does the change in utilization


      translate into important health outcomes.  Of


      course, that is an open question as well.


                So, before I close, as I mentioned, I want


      to bring up a couple of other issues that are not


      directly responsive to the criteria in 2.125 but,


      nonetheless, may be quite important in


      considerations regarding a path forward on


      albuterol.  Both of these issues relate to the


      future availability of chlorofluorocarbons.


                The first issue has to do with production


      facilities.  Currently, the only source of


      pharmaceutical-grade CFC 11 and 12 for use in the


      U.S. is Honeywell's plant in the Netherlands.  CFC


      11 and 12 are the particular chlorofluorocarbons


      that are contained in the albuterol CFC MDIs.


                The Dutch Government has informed


      Honeywell that CFC production at that factory will


      no longer be permitted after 2005.  So that might


      jeopardize the supply of CFCs that are necessary


      for the manufacture of albuterol MDIs but also all




      of the other MDIs that use pharmaceutical-grade


      CFCs.  However, Honeywell has stated in its


      submission to the docket in response to the citizen


      petition that it will begin production of


      pharmaceutical-grade CFC 11 and 12 at a U.S. plant


      and will be able to supply CFCs beyond 2005.


      Honeywell will also be speaking during the open


      public hearing session today.


                The second issue that touches on the


      future availability of the CFCs refers to potential


      actions that might be taken by the parties to the


      Montreal Protocol.  So, as Dr. Meyer mentioned,


      each year the U.S. and other countries who request


      to manufacture CFC MDIs, go through a nomination


      process whereby specific quantities of CFCs are


      requested of the parties.


                Thus far, the parties have respected the


      U.S. determination that albuterol is, in fact,


      essential and have granted the volumes requested by


      the U.S.  However, more recently, the parties have


      very pointed noted the availability of two non-CFC


      alternatives within the U.S. and some have




      questioned the continued need for


      chlorofluorocarbons for this purpose.  It is not at


      all clear how long the parties will continue to


      grant CFC requests for use in albuterol MDIs.


                So, with that, I will close.  I have


      listed on this slide the questions or topics for


      discussion that have  been provided to you in a


      handout format.  Essentially, the agency is asking


      you to discuss the extent to which you believe the


      criteria that are established in the 2.125 for


      removal of a drug substance from the list of


      essential uses of CFCs have been met in the case of


      albuterol.  Beyond that, we are open to hearing


      from you any suggestions of additional data,


      additional information or other issues you think


      should be considered as we move forward in this


      process of determining the essential-use status of




                With that, I will close.


                DR. CHINCHILLI:  Thank you, Dr. Sullivan.


      Again, we are ahead of schedule so we can take some


      questions from committee members if there are any




      questions.  Yes, Dr. Atkinson?


                DR. ATKINSON:  Can you comment on whether


      the existence of the patents on the new HFA devices


      are going to preclude the development of any


      generics until that time period?  Are there any


      pending applications for generic devices?


                DR. SULLIVAN:  Of course, we can't comment


      on any pending applications.  The analysis of


      patents is a complex issue that the FDA doesn't


      really directly do.  Companies claim they have


      patents which protect them.  If a generic firm


      wants to challenge that patent, they can.  I think,


      beyond that, perhaps I will invite Wayne Mitchell


      to comment more specifically, if he can.


                MR. MITCHELL:  I really can't say much


      more.  We don't have any institutional expertise on


      patent law.  Patents are listed in our Orange Book.


      The patents are listed through 2015.  That is about


      all we really can say.


                DR. CHINCHILLI:  Any other questions?  Dr.


      Sullivan, I have a question.  In one of your


      slides, when you talked about Proventil HFA, you




      said that early reports of actuator clogging were


      available.  Does that imply that there are no


      longer reports of this problem?  Were there


      modifications to the device?  I just was confused


      by the word "early" reports of actuator clogging.


                DR. SULLIVAN:  That refers to the fact


      that when the product first went on the market--and


      it is not unusual to get more reports on a


      particular drug when it first hits the market, but


      the agency became aware that patients were having


      problems with the clogging of the actuator and an


      effort was made to better publicize the necessity


      of cleaning these products because, although the


      cleaning instructions were included in the CFC


      versions, they may not have been followed by




                It was determined that if the instructions


      are actually followed, there are fewer reports.  I


      believe that the number of such reports has


      declined.  That was sort of an early phenomenon.


                DR. CHINCHILLI:  Thank you.  Any other


      questions?  Okay; if not, then we will move on to




      Dr. Lutter.


                        Economic Considerations


                DR. LUTTER:  My name is Randy Lutter.  I


      manage a small economics group within the Office of


      Policy and Planning, Office of the Commissioner at


      FDA.  It is my pleasure to be here.


                I would like to talk to you today about


      the question of whether or not delisting albuterol


      will have effects on--whether the patients will be


      adequately served by delisting albuterol.


                Let me begin by giving you an overview.


      The key conclusion is that delisting albuterol CFCs


      will deter the use of a number of prescribed MDIs


      that is large in absolute terms but small relative


      to the market.  Our analysis is ignoring an


      announced giveaway by GlaxoSmithKline of 2 million


      MDIs per year because we lack a basis to evaluate


      that quantitatively.  We also find that the effects


      on public health are too uncertain to quantify.


                Let me give you some brief institutional


      background of how an economist ends up in the


      position of speaking before a group of esteemed




      pulmonary and allergy advisors to FDA.  There is an


      executive order, 12866, signed by President Clinton


      in '93 and it actually follows one signed by


      President Reagan in '81.  It directs the agencies


      to assess the costs and benefits of all regulatory


      actions developed through the notice and comment


      rulemaking that Dr. Meyer described earlier.


                The office that I had at FDA develops the


      economic analyses required by that executive order.


      The method of economic analysis that we developed


      follows the constraints of OMB Circular A-IV which


      is the latest in a series of circulars developed by


      the Federal Office of Management and Budget


      directing agencies on how to conduct economic




                The executive order directs agencies to


      assess the cost and the benefits and to take


      regulatory actions which are cost-effective but


      economics also is reflected in the decisions of the


      Montreal Protocol.  Drs. Meyer and Sullivan have


      mentioned the term "essential," and "essential


      use," turns on whether there are available




      technically and economically feasible alternatives


      or substitutes that are acceptable from the


      standpoint of environment and health and that is in


      Decision IV-25.  Section 2.125 uses the phrase


      "adequately served."  As described by Dr. Meyer,


      that has economic content.


                So there are actually three institutional


      reasons why economics matters for the current




                A brief discussion of economic


      fundamentals.  The issue here is that delisting


      would remove albuterol MDIs with CFCs.  Those are


      currently the only generic albuterol MDIs on the


      market.  Therefore, one would anticipate on that


      basis an increase in the price.  So the broad


      question is whether or not that increase in price


      has effects on whether or not patients are


      adequately served.


                To comply with the executive order, we


      need to assess the benefits of delisting and, in


      particularly, a relatively earlier delisting as


      opposed to a later one, and also the costs of




      earlier delisting.


                The benefits come in four separable


      categories.  The first is a controlled transition.


      You have already heard presentations about the


      nature of the international cooperation and the way


      that that might affect the availability of CFCs by


      offering a relatively--by proceeding with this


      rulemaking, FDA hopes to establish an opportunity


      for a controlled transition to CFC-free MDIs.


                The second category of benefits is clearly


      the environmental ones that Dr. Meyer has


      described.  Reduced emissions would lead to


      reductions in skin cancers, cataracts and


      UVB-related ecological benefits.  For this, our


      proposal, FDA has not been able to quantify the


      benefits in terms of skin cancers, cataracts or


      UVB-related ecological benefits.


                Some analysis in quantitative terms has


      been conducted previously by other federal agencies


      including the EPA.  The difficulty that we face is


      in translating their estimates of aggregate


      benefits to the benefits from the much smaller




      reductions of CFC emissions that might be achieved


      from this rulemaking, and we haven't been able to


      do that for this proposal.


                A fourth category of benefits pertains to


      international cooperation.  Dr. Meyer did not


      understate in any way the importance of the


      Montreal Protocol.  It is a flagship treaty for


      successful international environmental protection


      and it enjoys wide respect and esteem for that




                A final category of benefits is that this


      rulemaking may encourage innovation in


      environmental safe technologies.


                In terms of the costs, I would like not to


      focus on the increased spending associated with a


      higher price of MDIs but, instead, focus on a


      related question of whether or not the increased


      prices may deter appropriate usage.  I think that


      is the appropriate issue for this panel and that is


      the one that I am going to devote the rest of my


      time to.


                Also, by way of background in economics, a




      key notion is what are we comparing the world to


      when we do our analysis.  We need to describe what


      is the baseline relative to which we are assessing


      the effects of delisting.  The baseline in this


      instance is the continued availability of generic


      CFC albuterol.  So the analysis that we are


      conducting is relative to a world in which the CFC


      albuterols continue to be available and, therefore,


      the generic CFCs also continue to be available.


                What I am going to focus on is a


      relatively standard and conventional economist


      approach to estimating the response to higher


      prices.  It really focuses, in particular, on the


      estimated quantity of metered-dose inhalers that


      may not be consumed as a result of the increased


      price.    It interprets this as the


      product, really, of three things.  One is the price


      increase in percentage terms.  The other one is a


      measure of the consumer sensitivity to the price


      increase, a measure the economists typically


      describe using the word "elasticity," and, lastly,


      the MDIs sold in the baseline to price-sensitive




      consumers.  So these are three parameters that I


      will draw your attention to.


                With respect to the price increase, the


      prices are, of course, variable in a particular


      way.  The vary with market conditions and they vary


      also in response to the marketing decisions made by


      the different companies marketing the products.  As


      a result, the assessments of the price are


      difficult not only because of the data deficiencies


      but also because, ideally, we need to be looking


      forward to what the price difference might be


      between a world where the albuterol CFCs are


      delisting and a world where they would continue to


      be available.


                That forward-looking approach requires and


      association of these prices that takes the


      variability into account.  For the purposes of our


      analysis, that is too complicated and we are,


      instead, going to take the current price


      differences as a measure of the price increases


      from the delisting.  The merits of this approach


      are simplicity, transparency and also consistency




      with an announced policy of GSK that it would


      freeze wholesale prices through December, 2007.


                Where does one go for information on


      prices?  In the modern day, Google comes to mind as


      a source of all information.  If you go to Google


      and look for prices, you come to drugstore.com.  It


      listed generic MDIs with albuterol on the 24th of


      March for $14.  HFA at drugstore.com sold a


      Proventil.  The Proventil HFA was sold at $39.61


      and Ventolin HFA sold at $38.99.  Those prices I


      have checked twice and they were relatively


      unchanged in the recent period.


                That gives an increase of about 180


      percent just comparing the generics to the HFA.


      But these web-based prices are really


      unrepresentative.  They neglect the


      brick-and-mortar outlets.  They neglect shipping


      costs.  Ideally, what one would want are average


      retail market prices for the cash-paying customers


      who would be sensitive to price increases.


                We have not acquired these idea data for


      the analysis that we have conducted for this




      proposal.  So, instead, I am going to talk to you


      about data we have acquired which are the best


      available proxies at this moment.


                The Medical Expenditure Panel Survey of


      the Agency for Healthcare Research and Quality


      provides some information on prices.  This survey


      assesses expenditures by the noninstitutionalized


      people age less than 65 in the non-Medicare


      population.  It provides information on the average


      retail prices among all payer types, the insured


      and the uninsured alike, for CFC albuterol inhaler


      prescriptions 2000 to 2001.


                The information is that the generics are a


      little bit less than $25.  I also report here the


      standard error.  The brand is $39.  You have heard


      Professor Sullivan mention that the branded price


      of the CFC tends to be close to the branded price


      of the HFA.  In this instance, the data on the HFA


      prices are too rare to report.


                We also looked using the MEPS survey at a


      sensitive population that lacks insurance or has


      only private non-group insurance which, in the




      judgment of experts at ARC would typically exclude


      coverage for drugs.  We looked among this group at


      people with incomes less than 400 percent of the


      federal poverty level.  This was a convenient


      cutoff, given the data constraints of MEPS.


                Within this group, the estimated average


      retail prices were $22 for the generic inhalers


      and, again, in this instance, the data on the


      branded inhaler prices were too rare to be


      reportable.  This group had about 2.8 million


      albuterol prescriptions annually.


                A second source of data on prices that we


      consulted is proprietary information from IMS


      Health, their national prescription audit for the


      first quarter of 2004.  Note the distinction in


      dates.  The MEPS is 2000-2001 and this is 2004.


      There is no more recent information on MEPS.  For


      the IMS price information, we have prices measured


      using the average pharmacy's revenues from


      uninsured customers, insured customer and Medicaid


      beneficiaries alike.  So this is basically across


      all payer types.




                This includes chain, independent,


      food-store pharmacies.  It excludes the Internet.


      It excludes mail-order and long-term-care




                Information on prices from IMS suggests


      that the median price for the generic albuterol


      MDIs is $19.70 and for the albuterol HFA MDIs, the


      price is $43.00, the price difference of about


      $23.00.  This suggests an increase of about 120




                It is important to view these data as


      approximate for a variety of reasons.  I have


      acknowledged the proxies for the conceptually


      correct measure.  In addition, the HFA prices have


      been changing.  The MDI data suggests that there


      has been an increase of about 18 percent over the


      twelve months preceding the sample of the first


      quarter in 2004.  Again, these prices reflect the


      full price for the insured and the uninsured alike.


                The next part of the puzzle is to assess


      the response to the increase in price that one


      might expect among consumers.  In general, there is




      an extensive economics literature that reports


      small effects of price increases on consumption.


      It rarely distinguishes, however, among drugs.


      There is a very recent article by Dana Goldman of


      Rand in JAMA that surveys more than a half million


      people in 52 health plans over four years.


                interestingly, it reports responses to


      increases in co-pay among different categories of


      medicines.  With respect to anti-asthmatics, as the


      average co-pay for anti-asthmatics doubles, the


      average number of days of treatment supplied fell


      by more than 30 percent.  The authors report that


      albuterol was the most common anti-asthmatic


      including albuterol sulfate.


                They also assess the effects on public


      health.  Let me back up a moment.  They also assess


      for drugs with no OTC substitutes, the set that


      presumably includes albuterol MDIs.  The response


      in utilization described as I just did in the


      average number of days of treatment supplied is


      0.15.  So there is substantial uncertainty about


      what would be the relevant number.




                With respect to average co-pay for


      anti-asthmatics as a group, the response is 0.3.


      But, if one then looks at drugs with no OTC


      substitutes which would also include albuterol, the


      effect is 0.15.


                The authors go on to talk about the effect


      of these increases in co-pay on ER visits and on


      hospital days for the class of drugs diabetes,


      asthma and gastric-acid disorder together, ER


      visits grew by 17 percent and hospital days by 10


      percent when co-pays doubled.  The authors


      acknowledge that these results are "not definitive"


      for reasons of data limitations.


                As a result, we are unable to quantify any


      effects on public health because of the nature of


      the limitations to the data.


                Let me offer a summary of what we know


      about the response to a price increase.  I have


      mentioned that an analysis would have, really,


      three parts.  With respect to the MDIs sold to a


      price-sensitive population, MEPS suggests that


      there are 2.8 million MDI albuterol prescriptions




      going to the uninsured patients with incomes of


      less than 400 percent of the poverty line who are


      not Medicare eligible and under age 65.


                If one takes, instead, data from the


      National Health Interview survey and combines that


      with data on the distribution of MDIs as described


      in the proposal, one ends up with a larger number


      of MDIs that would be used by the price-sensitive




                With respect to the price increase, we


      really have two estimates.  One is 120 percent


      increase.  That is from the IMS National


      Prescription Audit reflecting average prices for


      all payer types including those that are insured.


      We also have the 180 percent which reflects the


      Internet information.


                A key question pertaining to the analysis


      is the estimated elasticity, or the nature of the


      consumer response.  JAMA, as I mentioned, reports


      two numbers that may be plausible.  I think the


      0.15 is one that we focus on.  That reflects their


      estimate of the response to increases in co-pay for




      drugs with no OTC substitutes.  I think that is


      also consistent with other economics literature.


                The next question pertains to the


      interpretation of these.  The JAMA paper really


      focuses on consumer response for insured patients


      to higher co-pays.  They report an average co-pay


      of a little bit more than $12.  So that co-pay and


      the increase are roughly the same order of


      magnitude as the price and the price increase that


      one would anticipate for uninsured patients.


                So, if one applies that increase in price


      implicit in both the IMS data and in the Internet


      data and the consumer response implicit in the JAMA


      paper to the MDIs sold in the price-sensitive


      population, then it is reasonable to infer a


      quantity response among the uninsured population in


      the high hundreds of thousands.  It is very


      difficult to be more precise.  This is a daunting


      exercise with data that are imperfect, as we have


      acknowledged.  But the numbers that we have


      presented in particular are 0.4 million to 1


      million.  These are clearly approximate.




                Let me offer some empirical caveats.  I


      have neglected the response of insured patients to


      any increases in co-pays.  The JAMA paper measured


      these and we know that the co-pays for branded


      products are much higher than co-pays for generics.


      But this delisting of albuterols would have no


      direct effect on the co-pays.  The co-pays may


      change only in response to the changes of the


      insurance companies.  We, therefore, believe these


      are too uncertain for us to quantify at this time.


                Let me reiterate that the estimates of the


      price-sensitive population of the price increase


      and the consumer response, or the elasticity, are


      all relatively uncertain.


                There is another caveat with respect to


      the interpretation of these estimates.


      GlaxoSmithKline wrote to FDA on May 3 of 2004


      stating that 2 million complementary samples of


      Ventolin would be made available each year to


      physicians who may choose to reserve these inhalers


      for their lower-income patients.


                We are unable to assess quantitatively




      what this might do for any reductions in


      utilization because of the uncertainty associated


      with how they might actually be distributed in


      physicians' offices.  The GSK letter also said that


      it would freeze wholesale acquisition costs or


      prices thereby suggesting that the eventual HFA


      prices at the retail level would also be relatively


      constant.  As I have mentioned, that is an


      assumption that we maintain.


                The giveaway, in general, may


      significantly offset the loss of canisters provided


      it is well targeted to the most price-sensitive




                Thank you for the opportunity to talk.  I


      would be happy to take questions.


                DR. CHINCHILLI:  Thank you, Dr. Lutter.


      Are there any questions from the committee?  Dr.




              Questions from the Committee to the Speakers


                DR. SCHATZ:  My question is the


      relationship between elasticity and


      over-the-counter substitutes.  I gather that, with




      more over-the-counter substitutes, then elasticity


      is theoretically increased?


                DR. LUTTER:  Yes.


                DR. SCHATZ:  Then I would submit that


      there may be an over-the-counter substitute which


      is Primotine so that I think that, in


      consideration, one might have the higher elasticity


      and that patients doing that might be not as well




                DR. LUTTER:  Lacking your medical


      expertise, I will leave the judgment and the


      discussion about the substitutability of the OTC to


      you.  Let me simply say that the availability of


      OTC substitutes would affect the response in that




                DR. SCHATZ:  And it could make the higher


      value that they found more relevant than the lower


      value potentially.


                DR. LUTTER:  Yes.


                DR. CHINCHILLI:  Dr. Martinez?


                DR. MARTINEZ:  Certainly with the caveat


      which we may discuss later, but Primotine is not




      albuterol and, thus, a potential consequence that


      has not been thought of is that individuals who


      cannot afford albuterol anymore will start using


      over-the-counter Primotine which is associated with


      a completely different set of side effects which


      need to be seriously considered.


                DR. CHINCHILLI:  Ms. Schell, you had a




                MS. SCHELL:  Yes, thank you.  I just have


      a question about the shift of production of the CFC


      to the United States from the Netherlands in 2005.


      Do you project an increase in the CFC MDIs' cost


      with that shift of production coming to the U.S.?


                DR. LUTTER:  That is not something we have


      taken into account in the analysis.  We have no


      information on which to assess that question.


                MS. SCHELL:  Thank you.


                DR. CHINCHILLI:  Do any of the FDA


      representatives want to respond to that or the


      previous question?


                DR. MEYER:  I think, as far as that


      question--I don't think we have data that could say




      one way or the other.  Not the least of the


      considerations there is how much in the price does


      the actual cost of CFCs play, and I don't think we


      know that.


                As far as the earlier question and point,


      I think it is something we can certainly consider


      as we consider all the input from today.


                DR. CHINCHILLI:  Dr. Swenson, you had a




                DR. SWENSON:  Yes.  Regarding that JAMA


      article, did you pursue at all the cost


      implications of this greater ER and hospitalization


      rate that might arise from some of these shifts


      that you have postulated?


                DR. LUTTER:  No, largely because of the


      uncertainty in quantifying those increases.  As I


      mentioned, there were three categories of


      therapeutic classes that they grouped together only


      one of which was asthma.  Albuterol is only one


      treatment for asthma and, therefore, we thought


      that inferring--that the judgment of the


      applicability of those estimates to this delisting




      appeared to--is that we have no basis to accept


      those estimates to predict quantitative reductions,


      quantifiable reductions, in the ER visits or days


      in the hospital.  So, therefore, we don't really


      want to estimate either the cost of reductions or


      increases associated with those either.


                DR. CHINCHILLI:  Dr. Moss?


                DR. MOSS:  I work at Grady Memorial


      Hospital which serves an indigent-care patient


      population.  About 40 percent of the patients there


      are self-pay which means they don't have insurance.


      It is nice way of saying that.  One of the big


      problems in the hospital is the in-hospital


      pharmacy costs.  Do you have any information or is


      there a way to figure out how the changing cost of


      inhalers would affect operating at a hospital that


      serves indigent-care patients or is there a way to


      figure that out?


                DR. LUTTER:  There probably is a way to


      figure it out.  It is not something we have done.


                DR. CHINCHILLI:  Dr. Kercsmar?


                DR. KERCSMAR:  The transition to HFA




      inhalers has been made in a number of other


      developed and industrialized countries.  Are there


      any data that are comparable to that that has been


      published in the JAMA article?  You referenced that


      might give other insight into the elasticity


      problem, changes in morbidity, lack of prescription


      refills or, because of the difference in economic


      structure and drug reimbursement in these


      countries, are there no data available?  Are there


      lessons to be learned from countries that have


      already made the transition?


                DR. LUTTER:  It is a good question.  We


      thought of that.  Other countries lack the


      uninsured population that exists in the United


      States and generally control prices.  In


      particular, the price discrepancy that I have


      described here is unusual if not unique.


                DR. CHINCHILLI:  Any other questions by


      the committee members for Dr. Lutter?


                MR. MITCHELL:  Just before the break there


      is something I would like to say.


                DR. CHINCHILLI:  Yes; please go ahead.




                MR. MITCHELL:  This is addressed to the


      people who are watching this procedure through the


      webcast.  The proposed rule that we have been


      discussing is available on FDA's website if you go


      to www.fda.gov.  In the middle column, you should


      see FDA advanced display.  If you click on that,


      you should be able to see another link which goes


      to advanced publication display.  Click on that and


      you should see something about a special filing,


      publishing, on June 16, 2004.  That should get you


      to the Notice of Proposed Rulemaking.


                Thank you, Mr. Chairman.


                DR. CHINCHILLI:  Thank you, Dr. Mitchell.


      Yes; Ms. Schell?


                MS. SCHELL:  I am not sure who to direct


      this question to, but I have a question.  Several


      of you talked about what the ozone depletion does


      in cataracts, skin cancer and that, but no one has


      mentioned how it affects asthmatics of COPD


      patients, the depletion of the ozone layer and how


      that would increase, if we didn't do something now,


      how the ozone depletion would affect asthmatics in




      the future.  Would we be causing more asthmatics to


      have problems with their breathing?


                Thank you.


                DR. MEYER:  I will try to answer that.  I


      think it is unclear to us that asthma or COPD


      patients would be differentially affected in terms


      of the environmental consequences of ozone


      depletion.  You were not asking this, but, for the


      public, I think it is hard for them to understand


      that ozone in the lower regions of the atmosphere


      is bad for asthmatics, particularly, and probably


      for COPD as well.  But ozone in the stratosphere


      probably has no bearing on the development of


      asthma and COPD that we know of.


                So we would assume that the consequences


      to the asthmatic and COPD population would be the


      same as to consequences to other populations.  One


      could perhaps try to parse that out more closely in


      that it is potential that inhaled corticosteroids,


      for instance, may somewhat increase the


      predisposition to cataracts.  Whether that would be


      even more the case in the circumstances of a




      thinned ozone layer, who knows.  But, again, we


      have no basis at this point to believe that there


      would be a differential effect on those patients.


                DR. CHINCHILLI:  Any other questions from


      committee members for our FDA representatives?




                DR. MEYER:  I just wanted to make the


      point--I realize that the people sitting around


      this table probably are fairly well versed in this


      but, for the purposes of the public, I realize that


      we didn't really sort of step back and make this


      point.  But albuterol has really become a prime


      drug for both the treatment of asthma, in


      particular, but also for COPD in a way that, even


      when we began the advanced notice of proposed


      making in '96, I don't think we have fully




                It is now clear that approximately 50


      million or more canisters of albuterol are


      necessary to treat patients with asthma and COPD in


      the United States.  It is, again, by far and away


      the bronchodilator or short-acting reliever of




      choice in patients with asthma and COPD.


                Again, I think the people around the table


      know this but, for the matter of the public record,


      I just wanted to get on the table the kind of


      numbers we are talking about.  This is a very


      important drug that is sold widely and is really


      critical in the asthma armamentarium and very


      important in the COPD armamentarium as well.


                DR. CHINCHILLI:  Thank you, Dr. Meyer.


      Dr. Martinez?


                DR. MARTINEZ:  I have one question


      regarding worldwide distribution of sales.  What is


      the situation in the underdeveloped world?  Which


      are the products that are sold there and what are


      the projected consequences of this regulation in


      that particular market?


                DR. MEYER:  From the FDA perspective, I


      don't think we have a lot of information on that.


      I also am involved in the Montreal Protocol on a


      working group on aerosols, medical aerosols.  I can


      say that the United States actually exports


      relatively few of its MDIs as opposed to the EU




      where much of their production is exported.


                So most of what we are talking about here


      is for domestic consumption and will not really


      have much bearing on the rest of the world.  I


      would parenthetically note that there is a lot of


      attention paid in the Montreal Protocol about how


      this phase-out in the developed world will affect


      that in the developing world because it is a very


      important issue.


                Unfortunately, in much of the developing


      world, the use of MDIs is not very common because


      they are--although they are cheap per dose, to


      actually buy one requires you to buy a certain


      number of doses as opposed to oral medications


      which may be more expensive per dose but cheaper


      where you can just buy a few.


                So there is probably undertreatment in the


      developing world in general and specifically there


      is not a lot of use of MDIs relative to the


      developed world.


                DR. CHINCHILLI:  Before we proceed with


      other questions, I would like to welcome Dr. Reiss




      to the committee.  Would you turn on your


      microphone and introduce yourself to everyone?


                DR. REISS:  Sure.  I apologize for being


      late this morning.  I am Ted Reiss from Merck


      Research Labs.  I am the industry non-voting


      representative on the committee.


                DR. CHINCHILLI:  Thank you.  Any other


      questions?  Yes; Dr. Swenson?


                DR. SWENSON:  Dr. Meyer, a couple


      questions.  I didn't see anywhere in the data,


      either in the background information, if you could


      go back to the initial signing of the protocol.  At


      that point, how much CFC was being produced and


      now, of that amount, what does the present use of


      CFC in albuterol represent in a percentage term or


      absolute amount?


                DR. MEYER:  I am sorry that I don't


      actually have those particular figures available.


      I can say that the use of CFCs for MDIs when the


      protocol was signed was a relatively small


      proportion of the CFC use because CFCs were then


      used in refrigerators, auto air conditioners, home




      air conditioners, foams and so on.


                Now that the provisions of the Copenhagen


      Amendments went into place, the use of CFCs for


      MDIs in the developed world is the large majority


      of these CFCs but it is still a small fraction


      compared to what was the total in 1987.


                Albuterol in both the United States and in


      the rest of the world has been a prominent use of


      CFCs.  As I mentioned, for the United States, it


      amounted to about half, or does amount to about


      half, of our essential-use denomination.  So I am


      not giving you specific numbers, but I hope I am


      sort of giving you a qualitative feel.


                DR. SWENSON:  Okay.  The next question I


      have then is, on Slide 24 or one of the similar


      slides that you had in your talk, was the projected


      return, or this idea of a projected return, of


      normal stratospheric ozone levels by mid-century


      based on the present use right now which includes


      our use of CFCs or was that based on complete


      elimination of CFCs?


                DR. MEYER:  Those projections, and just to




      be clear, they are actually projecting the recovery


      to early 1980s levels which was still not normal


      but a recovery nonetheless, are based on the


      successful conduct of the Montreal Protocol.  So it


      is based on the Montreal Protocol as currently


      amended being successfully carried out into the




                DR. CHINCHILLI:  Ms. Schell?


                MS. SCHELL:  I am sorry.  I would like one


      more question on the 50 million uses of Ventolin or


      albuterol.  Have you looked at the overuse of


      albuterol and the underuse of the


      anti-inflammatory?  Is there any look at overuse?


      As we know, asthmatics, a lot of the time, don't


      have the proper education in the use of the


      anti-inflammatory so they overuse their albuterol.


      Are there any numbers reflecting that?


                Thank you.


                DR. MEYER:  We do not have such numbers.


      It is certainly something that we considered.  As


      Dr. Lutter said, there are a lot of things we would


      wish to consider in an ideal analysis.  One of the




      complications of projecting a public-health


      consequence of some drop in the number of albuterol


      MDIs distributed or used relates to these


      questions, relates to the possibility that when


      beta-adrenergic bronchodilators are overused that


      that might, itself, have detrimental effects.


                But these things, although clearly we


      think about them, are not something we can


      reasonably quantitate.  So we have not.


                DR. CHINCHILLI:  Any other questions from


      the committee?  If not, I want to thank the FDA for


      enlightening us on these issues.  We are scheduled


      for a break at 10:00.  We are about eight minutes


      before that, so we will take the break early.  But


      I would like to reconvene at 10:10.


                Thank you.




                DR. CHINCHILLI:  I do have one


      announcement and that is if you have a cell phone


      and it must be on, it would be preferable if you


      put it on vibrating mode and then, if it does go


      off, that you take your call outside the room. 




      Thank you.


                Before we go on to the open public


      hearing, the first session that we will have this


      morning, I just want to make sure that the


      committee members don't have any other questions


      for the FDA representatives.  Are there any other


      questions from the committee?  Any final comments


      from the FDA?


                If not, then we are going to move into the


      open public hearing.


                    Open Public Hearing (Session 1)


                DR. CHINCHILLI:  One other announcement I


      am supposed to make.  Both the Food and Drug


      Administration and the public believe in a


      transparent process for information gathering and


      decision making.  To ensure such transparency at


      the open public hearing session of the advisory


      committee meeting, the FDA believes that it is


      important to understand the context of an


      individual's presentation.


                For this reason, the FDA encourages you,


      the open public hearing speaker, at the beginning




      of your written or oral statement, to advise the


      committee of any financial relationship that you


      may have with any company or any group that is


      likely to be impacted by the topic of this meeting.


                For example, the financial information may


      include a company's or a group's payment of your


      travel, lodging or other expenses in connection


      with your attendance at the meeting.  Likewise, the


      FDA encourages you, at the beginning of your


      statement, to advise the committee if you do not


      have any such financial relationships.


                If you choose not to address this issue of


      financial relationships at the beginning of your


      statement, it will not preclude you from speaking.


                So that is important for our open public


      hearing speakers to recognize that and to make


      acknowledgments.  I probably will repeat this


      statement when we start the afternoon session as




                We are ready for our first speaker during


      the open public hearing.  Please be sure to


      introduce yourself and pay attention to the




      statement I just made.


                MS. WEXLER:  Good morning.  I am Pamela


      Wexler.  Since 1997, I have served as attorney and


      advisor to the U.S. Stakeholders Group on MDI


      transition.  I have no financial interest in any of


      the companies or participants today.


                I would like to start by telling you a


      little bit about the U.S. Stakeholders Group.  It


      is a consortium of nine leading patient and medical


      professional organizations.  Members of the


      organizations include patients with asthma, chronic


      obstructive pulmonary disease and other respiratory


      diseases.  Collectively, the member organizations


      represent and reach 25 million Americans who suffer


      from asthma and other respiratory diseases and they


      include organizations that educate and advocate for


      individual patients and their families through


      local chapters.


                Members of the Stakeholders Group also


      include physicians, respiratory therapists and


      other healthcare professionals who specialize in


      respiratory care and they are recognized leaders




      among the healthcare community.  The stakeholders,


      as a group, and its member organizations


      individually collaborate with various other


      interested organizations in the U.S. and around the




                In the eight years since the Stakeholders


      Group has acted formally, neither its membership


      nor its procedures have changed.  The American Lung


      Association convenes the U.S. Stakeholders Group.


      The member organizations elect representatives to


      the stakeholders process and these individuals


      meet, in person, once or twice a year and


      communicate regularly.


                Oftentimes, the leadership of these


      organizations attends stakeholder meetings and


      participates in the deliberations.  Other times,


      the government and the private sector are invited


      to attend as well and make presentations.  Any


      action taken under the name of the stakeholders is


      approved by each member organization.


                Now, I would like to turn to our petition.


      Eighteen months ago, we petitioned FDA to consider




      albuterol essentiality.  The petition was not


      precipitous.  It, in fact, was requesting the


      agency merely consider essentiality.  It was FDA,


      itself, in a rulemaking process that started in


      1997 and lasted five years that set up these


      essentiality criteria, the conditions under which


      any drug substance would be delisted and no further


      CFCs would be available.


                The stakeholders petition asserted that


      the criteria had been met or, with the case of


      manufacturing capacity, that the criteria could be


      met or that information could be ascertained and,


      hence, it was time for FDA to consider removing the


      essential-use designation.


                Now, there are a number of reasons why the


      stakeholders petitioned FDA.  I will just take a


      moment to touch on them.  First and foremost is the


      environmental imperative.  I won't spend too much


      time on this because I think that the importance of


      repairing the ozone layer is well established, both


      by the Montreal Protocol and the U.S. Clean Air Act


      on which, by the way, the U.S. has been a leader




      since the beginning on the international process.


      FDA, in its July, 2002 Final Rule establishing the


      essentiality criteria actually offered a very


      concise and clear explanation of why every use of


      CFCs must be eliminated, even seemingly small


      amounts like those used in MDIs.


                I won't spend too much time on the second


      sub-bullet either because a physician from one of


      our member organizations in the next session, later


      this afternoon, will present more on the


      opportunity to improve disease management.  But let


      me just say that, from its inception, the


      stakeholders position on the potential of


      transition has not changed and that is that we


      understand the potential of a switch in medication


      and we have worked, and we hope to continue to


      work, to ensure that that experience provides an


      opportunity to improve patient care.


                On the third and the last, and probably


      the most pressing, issue for patients and


      physicians is the issue of CFC supply and how it


      might affect the availability of medications.  As I




      am sure you will hear more about today, the future


      of CFCs to make MDIs is uncertain and fundamentally


      the stakeholders want FDA to sufficiently plan for


      that and for CFC-free medications to be available


      and widely accepted before CFC supply can have any


      impact on product availability or price.


                Since the petition was filed, in the


      eighteen months since the stakeholders filed the


      petition to consider albuterol essentiality, a lot


      has changed and we have learned a lot more.  As to


      supply, anyone who follows this knows that, in the


      past three to five years, there has been a lot of


      new and often conflicting information about where


      PhRMA-grade CFCs were going to come from after


      December 31, 2005.


                Remember, that is an issue simply for the


      U.S. market because, for the most part, developed


      countries will not need these chemicals after that


      date.  They are on pace to phase out the use of


      CFCs in MDIs.


                The stakeholders have never had full


      information on the future of CFC supply.  We heard




      originally, maybe two years ago, there were going


      to be two plans, one in Europe and one here.  They


      we heard that that wasn't going to happen.  Then


      the issue of certification was raised, that plants


      had to be certified, the CFCs produced had to be


      certified, and that the production that would


      replace the production that is going to be lost in


      Europe would be a different kind of production and


      that different specifications would be required.


                We heard, now, recently, despite a letter


      from Honeywell indicating its stated intent to


      supply CFCs at a plant in Baton Rouge, Louisiana,


      that we still had questions about certification as


      that was not mentioned in the letter and we have


      never heard anything further about FDA on what,


      exactly, that requires.


                So the stakeholders, themselves, have


      limited information on which they could base a


      conclusion that the CFC supply would be without


      problems.  Recently, a non-governmental


      organization, NRDC, wrote the EPA suggesting that


      it would be illegal to produce CFCs in Baton Rouge.




      So, again, we are faced with not a lot of clear


      information on how we will go forward.


                As to the second sub-bullet, even if the


      Baton Rouge plant is not a problem, we certainly


      see an increase in pressure on the part of the


      international community to limit future supply of


      CFCs especially where there are alternatives as in


      the case of albuterol.  We heard recently that the


      U.S. request that was recently put into the parties


      was approved but with the strong suggestion that


      the U.S. come back to the parties after this


      rulemaking was complete since it wasn't clear that


      those quantities would be needed.


                So it is obvious that the parties are


      signalling the intent to stop authorizing new CFC


      production for MDIs, again, in the case of a drug


      like albuterol where there are safe alternatives.


                Also, since the petition was filed, we


      have, in the FDA docket, an independent analysis


      conducted by National Economic Research Associates,


      NERA, that provided us a much better picture of the


      albuterol market.  I expect that we will hear more




      about the NERA analysis this afternoon, but it gave


      us a very good picture of how the market is


      supplied, how patients who rely on albuterol pay


      for their drugs.


                It estimates the price and what the market


      might look like once HFA alternatives are


      introduced.  More importantly, NERA projects how


      the increased costs might be distributed and


      allocated among the different classes of patients,


      managed care and other payers including Medicare


      and Medicaid.


                Now, you know, the stakeholders are


      medical and patient advocates, medical


      professionals and patient advocates.  We are not


      economists.  So we aren't here to speak to the


      specific numbers in the NEAR report but we do


      believe that the general thrust of the report


      comports with what we have always believed about


      the albuterol market and our understanding of how


      increases, not just in medications but in all sorts


      of other medical procedures and services rise and


      are absorbed in the healthcare system.




                Now, there is no mistake about the need to


      ensure patient access to medication.  In our


      petition to FDA, we were clear that FDA needed to


      take into account price and how it would affect


      patients and their ability to obtain medication and


      comply with their treatment regimens.  But we think


      that, between the manufacturers, the stakeholders


      and FDA, collective, we can adequately protect the


      potentially at-risk subgroups and we can do it in a


      variety of ways.


                On the part of the manufacturers, we have


      one submission already in the docket from an HFA


      manufacturer outlining what it intends to do.  We


      would hope that we would see similar commitments


      from other manufacturers as we move forward about


      increasing the number of samples and enhancing


      patient-assistance programs.


                On the part of the stakeholders, our


      member organizations are committed to working with


      the agency and the manufacturers to develop an


      educational strategy for communicating the


      availability of free and discounted albuterol.  We




      can work with our member organizations and our


      network to deploy these messages in advance of


      transition to patients, to specialty, general


      physicians and the rest of the healthcare




                As for FDA, we think that there also might


      be mechanisms that the agency can consider to


      protect, again, these potentially at-risk


      populations.  One thing we have discussed within


      stakeholder meetings is for FDA to monitor the


      patient compliance or access to HFA albuterol and


      reserve the right to allow a certain number of CFC


      MDIs to be sold in the case of a real emergency so,


      if you will, a phase-down process that allows the


      potential--and that is the potential in both CFC


      supply and manufacturing capacity to not be gone


      before we are out of transition, so a phase-down


      period that protects that at-risk population.


                I think that if FDA acts in a relevant


      timeframe, there would still be enough stockpile to


      be able to incorporate such a mechanism.


                Last, I would like to turn to the timing




      of transition.  There has been a lot of talk about


      when the right time is.  Now, it is no secret that


      the stakeholders have long supported December 31,


      2005 as the effective date for removing CFC


      albuterol from sale in the U.S.  As early as 1996,


      in fact, before we had ever heard the word "TEFA"


      or "WEERT," we embraced the idea of a target date.


                We embraced the eventuality that these


      chemicals as slated for elimination.  We understood


      that it was useful to have a target date so that


      manufacturing capacity could be put into place.


      That idea of an aim, a target, a goal, has proven


      successful as is evidenced by the fact that the


      rest of the world or the rest of the developed


      countries also adopted that date and or on pace to


      meet it.


                We saw transition as an opportunity to


      educate physicians and patients about the learning


      that has been done, especially in the last decade,


      regarding asthma treatment and management.


                But, in 1996, we saw December 2005 as a


      goal, not an imperative.  Eight years later, we now




      know that WEERT will close.  We know there are


      additional uncertainties regarding the Baton Rouge


      facility.  We know that there are two alternatives


      ready to go and a third on the way.  Given that,


      December 31, 2005 makes a lot of sense.


                Again, I just want to go back to


      mechanisms for actually proceeding through


      transition.  Ending at December 31 is sensible and


      it is achievable and, most importantly, it is


      near-term enough that any problems with HFA


      production, any problems with patient access, any


      problems with affordability, compliance, any


      unforeseen consequences, can be discovered and


      addressed before CFCs are unavailable and before


      the capacity to produce additional CFC products is




                Thanks very much.


                DR. CHINCHILLI:  Thank you very much.


                We will move on now to our second speaker.


                DR. JONES:  Good morning.  My name is


      Elaine Jones and I am Vice President of U.S.


      Regulatory Affairs at GlaxoSmithKline.  On behalf




      of GlaxoSmithKline, I would like to thank the


      advisory committee and the agency for opportunity


      to present our commitment to the transition from


      albuterol CFC-free metered-dose inhalers, or MDIs,


      which are ozone-depleting to albuterol HFA MDIs,


      which are non-ozone-depleting.


                Principally, during this presentation, I


      will address the two questions that have been posed


      to us by the agency that relate to the FDA's


      criteria for transition.


                The first question concerns our


      manufacturing capacity for Ventolin HFA and the


      second, what GSK programs are, or will be put in


      place to help ensure that patients are adequately


      served during the transition from albuterol CFC to


      albuterol HFA and thereafter.


                To set the stage for discussion of the two


      principle questions, I would like to review the


      timing of Ventolin HFA development in relation to


      implementation of the Montreal Protocol.


      Development of Ventolin HFA started before the


      Montreal Protocol was ratified and resulted in




      submission of a new drug application in 1998.


      Filing of this NDA was the result of over ten years


      of research and development including a technically


      challenging reformulation effort under


      comprehensive clinical program.


                After gaining FDA approval, GSK launched


      Ventolin HFA in 2002 and stopped the sale of


      Ventolin CFC.  Currently, GSK sells Ventolin HFA in


      165 countries around the world which has resulted


      in over 20 million patient years of experience.


      Also, in 2002, FDA published its final rule


      outlining the criteria for transition from CFC


      MDIs, which was the culmination of a lengthy


      process that took five years to complete.


                Quoted on this slide is one of the


      criteria for transition from the 2002 Final Rule.


      FDA has asked us, as one of the manufacturers of


      the replacement products for albuterol CFC MDIs to


      address this criterion which relates to the issue


      of adequate supply and production capacity.


      Specifically, the question is, can GSK, in


      conjunction with other manufacturers of the




      replacement albuterol product, manufacture


      sufficient quantities to satisfy patient demand


      after the CFC products are no longer available.


                To help answer this question, here is a


      graphical representation of GSK's manufacturing


      capacity over time in relation to the overall


      albuterol market.  Other manufacturers can be


      expected to contribute to the supply as well.  At


      present, patient need for albuterol MDIs is about


      50 million per year, as shown by the yellow shading


      in this graph.  This demand has remained fairly


      constant over the past five years and is expected


      to remain constant into the future.


                The blue shaded portions of the graph


      represent two distinct components of GSK's ability


      GSK's ability to contribute to meeting this demand


      with CFC-free MDIs.  The darker shaded blue area


      reflects currently installed capacity and the


      lighter shaded blue area reflects expansion


      capacity.  The sum total of both components is


      about 30 million MDIs per year, or about 60 percent


      of the expected market.




                Now, I would like to discuss in detail our


      current capacity.  GSK manufacturers Ventolin HFA


      at a facility in Zebulon, North Carolina, which has


      a long history of manufacturing MDIs including the


      now discontinued Ventolin CFC.  At this facility,


      we already have installed the capacity to


      manufacture 15 million Ventolin HFA MDIs.  At


      present, since transition has yet to take place, we


      are utilizing only 2 percent of our installed




                Production of up to 5 million MDIs could


      be achieved immediately and this could be


      progressively increased to the full 15 million MDIs


      within six to twelve months.  To achieve this


      capacity is a relatively straightforward process.


      We would need to hire additional staff and


      reconfigure existing space.


                As illustrated on the graph I presented


      earlier, GSK is prepared to increase production


      capacity by an additional 15 to 18 million MDIs.


      This would entail significant capital investigation


      on the part of GSK, would take approximately twelve




      to eighteen months to complete and would require


      the installation of additional manufacturing


      equipment and securing of MDI components.


                This could be undertaken simultaneously


      with a previous increase in production.  This


      expansion, in addition to our current capacity,


      would deliver a total of approximately 30 million




                I would now like to address the second


      question posed to us by the agency which concerns


      another one of the criteria in the 2002 Final Rule


      on Essential Use Determinations and is reflected on


      this slide.  The issue is whether a high-priced,


      non-ODS, product is effectively unavailable to a


      portion of the patient population because they


      cannot afford to buy the product.


                Payers, and the healthcare system overall,


      may experience higher costs as the market


      transitions to CFC-free albuterol.  But the


      relevant question under FDA's 2002 Final Rule is


      how individual patients will be impacted by this


      transition, specifically whether they will have




      adequate access to CFC-free formulations of




                The larger policy questions regarding a


      balancing of societal cost against environmental


      benefits have already been resolved by the Montreal




                In order to assess the economic impacts of


      an albuterol transition, GSK commissioned a study


      by the National Economic Research Associates.  The


      analysis proceeded on the basis of data collected


      from a variety of sources as shown on this slide.


      Although the economic report examined impacts on


      payers as well as patients, our focus today is on


      the impact a transition will have on the access to


      albuterol HFA MDIs for individual patients.


                To understand the impact on patients, one


      must appreciate that albuterol is dispensed to


      patients in different settings including retail


      pharmacies, hospital pharmacies, clinics and


      federal healthcare facilities.  As represented by


      the large green slices of pie chart, 84 percent of


      dispensing takes place at retail pharmacies.  The




      remaining 16 percent takes place in other settings;


      for example, a Veterans Administration Hospital


      where financial impacts on patients, of changes in


      drug prices, are likely to be quite limited.


                The pie chart on the right reflects a


      further breakdown of the retail-pharmacy segment.


      Within the retail portion, 72 percent of MDIs are


      covered by private drug insurance and 15 percent


      are covered by Medicaid.  About 13 percent of


      albuterol MDIs dispensed by retail pharmacies go to


      patients who pay cash.  GSK recognizes that it is


      within this group of patients that the greatest


      concern exists regarding access to albuterol MDIs


      after a transition.


                As we consider the patients who pay cash


      for their prescriptions, it is important for us to


      emphasize our long-standing dedication to helping


      those in need obtain access to our medicines.  For


      over two decades, GSK and its Heritage Companies


      have been committed to helping patients without


      public or private drug insurance to get the


      medicines that they need.  To this end, we have had




      in place various patient assistant programs.


                I will now describe Bridges to Access, the


      GSK program which is directed at patients of all


      ages who require financial assistance.  For those


      who qualify, GSK offers its medicines, including


      Ventolin HFA, at no cost or at a minimal


      retail-pharmacy dispensing fee.


                Individuals with annual incomes up to


      $25,000 or families at or below 250 percent of the


      federal poverty level are eligible for Bridges to


      Access.  Patients who enroll can receive their


      medication the same day that it is prescribed.


      This program also includes a spend-down option that


      allows patients to deduct medical bills from their


      income for purposes of determining eligibility




                Patients are not required to be U.S.


      citizens to qualify for Bridges to Access.


      Patients who apply also receive assistance in


      finding additional healthcare programs for which


      they qualify such as Medicaid, AIDS drug-assistance


      programs, state children's health insurance and




      state elderly drug-assistance programs.


                In this visual illustration, we use the


      federal poverty level as a baseline to compare the


      income eligibility levels for Medicaid and Bridges


      to Access.  The yellow line represents the federal


      poverty level income for households of different


      sizes ranging from one to four members.  The blue


      lines represent the average income eligibility


      ceiling for Medicaid which is 135 percent of the


      federal poverty level.


                Each orange bar represents the maximum


      qualifying income under Bridges to Access for a


      household of that size.  This maximum qualifying


      income level is $25,000 for households with one


      individual or 250 percent of the federal poverty


      level for households with more than one individual.


                I might add that certain patients who do


      not meet   Medicaid's eligibility requirements


      despite meeting the income requirements could


      potentially qualify for Bridges to Access.  For


      lower-income patients who do not have public or


      private drug insurance, for whatever reason,




      Bridges to Access is, thus, a valuable resource.


                GSK's experience with Bridges to Access


      for Ventolin HFA from June 2003 to May 2004


      illustrates the program benefits for patients.  We


      have distributed nearly $3 million worth of product


      representing approximately 100,000 inhalers to


      nearly 14,000 patients.  During this period of


      time, the total amount of Ventolin HFA distributed


      was approximately 400,000 MDIs which means that one


      out of four Ventolin HFA MDIs went to a Bridges to


      Access patient.


                GSK has generated awareness of this


      program through various avenues including half a


      million letters sent to advocates at the launch of


      the program, training for healthcare providers and


      partnerships with public agencies and professional


      associations.  In addition, we maintain a public


      website with extensive information about our


      program including application forms.


                These activities represent some of the


      significant efforts GSK has made to raise awareness


      of the program and we look forward to continuing




      our outreach efforts.  We are committed to provide


      Ventolin HFA to all eligible patients in the event


      of an increased need at the time of transition.  In


      order to show more clearly the estimated financial


      impact of a transition to CFC-free albuterol on


      individuals, I would like to now illustrate how a


      lower-income patient might fare in a transition


      both with and without the benefit of Bridges to




                Our hypothetical patient is an individual


      who makes less than $25,000 a year and, thus,


      qualifies for Bridges to Access and who also uses


      four albuterol inhalers.  To make this calculation,


      we compared the current average wholesale price of


      Ventolin HFA to the mean of the average wholesale


      prices for the three top selling generic albuterol




                Average wholesale price, or AWP, is


      commonly used as a pricing reference point for


      distributors and payers in the healthcare system


      and is calculated and reported by commercial data


      vendors.  GSK does not set an AWP for its products




      or sell its products according to AWP and we


      recognize published AWPs are different from actual


      prices paid in the marketplace.


                Based on the AWP comparison, the current


      difference in price between Ventolin HFA and


      generic albuterol is $9.49.  Therefore, in our


      example, if the patient did not enroll in Bridges


      to Access, the extra cost per month would be $3.16


      or $37.96 a year.


                With assistance from Bridges to Access,


      the cost of Ventolin HFA would be limited to a


      one-time charge of $10.00 for the patient's first


      60-day retail pharmacy fill.  The patient would


      then experience no added cost for further


      prescription.  In fact, the medicine would be


      entirely free from that time forward.


                Keep in mind that this hypothetical


      patient, if not enrolled in Bridges to Access prior


      to the transition, would previously have been


      paying out of pocket for that generic albuterol.


                For seniors or disabled persons, in


      addition to Bridges to Access, GSK offers the




      saving programs, Orange Card and Together Rx to


      help make GSK medicines more affordable.  The GSK


      Orange Card was the first of its kind.  It is


      available for Medicare beneficiaries without any


      prescription-drug insurance and incomes of up to


      $30,000 for an individual and up to $40,000 for a


      married couple.


                Orange Card offers savings on GSK products


      including Ventolin HFA to eligible Medicare


      beneficiaries of up to 40 percent depending on a


      pharmacy's usual and customary price for the


      medicine.  The program, Together Rx,  is a


      multi-company savings program and, as such,


      provides access to a larger number of medicines.


      This program was modeled after the GSK Orange Card


      and has similar eligibility criteria.


                Although the arrival of a Medicare drug


      benefit in January 2006 should substantially lessen


      the need for assistance of this kind, GSK's


      commitment to helping patients access our medicines


      will remain.


                In addition, GSK has committed to provide




      at least 2 million professional samples of Ventolin


      HFA each year beginning a transition.  Although


      samples are distributed to physicians with no


      conditions attached, we understand, anecdotally,


      that many physicians do take medication-access


      considerations into account in allocating samples


      among their patients.  Furthermore, GSK has


      committed to freeze the price of Ventolin HFA from


      November 5, 2003 until December 31, 2007.


                In summary, GSK is committed to and has


      global experience in transition to ozone-friendly


      formulations.  GSK has currently installed


      production capacity to produce 15 million Ventolin


      HFA MDIs per year.  We are prepared to expand the


      total capacity to approximately 30 million MDIs per




                GSK has demonstrated an abiding commitment


      to helping patients gain access to our medicines


      and, towards this end, has patient-assistance


      programs in place to help ensure access to Ventolin


      HFA at transition.  Finally, GSK has committed to


      provide professional samples and freeze the price




      of Ventolin HFA.


                We expect that the criteria for


      transition, as outlined in the 2002 Final Rule,


      will be met with the support of all currently


      approved albuterol HFA suppliers.  Therefore, GSK


      supports a transition date of December 31, 2005


      which would allow for a smooth and orderly


      transition for patients.


                I would like to conclude by, once again,


      thanking the advisory committee and the agency for


      allowing GlaxoSmithKline the opportunity to present




                Thank you.


                DR. CHINCHILLI:  Thank you, Dr. Jones.


                Let's have our third speaker for this




                DR. GARUTTI:  Members of the committee,


      Food and Drug Administration, invited guests,


      ladies and gentlemen, good morning.  My name is Dr.


      Ron Garutti.  I am a pediatrician and I am Group


      Vice President of Global Regulatory Affairs at


      Schering-Plough Research Institute.




                On behalf of Schering-Plough Corporation,


      I want to thank the FDA for the opportunity to


      address the advisory committee today.


                Let me say, at the outset, that our


      company firmly supports the principles of the


      January 29, 2003 petition of the U.S. Stakeholders,


      which you have heard about, which requests an end


      to the exemption for albuterol CFC-based in


      inhalers.  As pointed out, this exemption, after


      all, was never intended to be permanent.


                Now, I will not devote any of my


      discussion today to the rationale for removing CFCs


      from albuterol inhalers as I believe that that


      rationale is well understood and accepted by most


      interested parties as the right and necessary thing


      to do.


                In so removing CFCs, the United States


      would be accomplishing the transition to a non-CFC


      environment that has already successfully been


      implemented by most of the European Union, Canada,


      Australia, Japan and other countries.


                So the important question, then, today,




      for the committee is not if the transition should


      be done but when.  It can be done as soon as FDA,


      in conjunction with the healthcare community and


      the industry, is prepared to initiate the




                It has been pointed out that in July,


      2002, the FDA issued a final rule which set forth


      the conditions that would have to be met before an


      essential-use designation for albuterol inhalers


      could be removed.  Both Drs. Meyer and Sullivan


      have noted them.  Schering believes that all of the


      necessary elements to remove the essential-use


      designation can be met as early as December 31,




                We acknowledge the proposed rule


      distributed today and we are pleased to learn that


      FDA plans to publish this on June 16.  We are


      hopeful that today's discussion will lead to the


      establishment of a firm date.


                As a company with more than twenty years


      of respiratory experience and the first with our


      partner 3M to introduce an HFA inhaler to the




      United States, Schering understands that we, in


      conjunction with all of you and other members of


      the professional asthma community, will be asking


      millions of patients to change their behavior.


                We recognize the significance of this


      transition to patients and providers alike and we


      are sensitive to the fact that ongoing


      communication efforts will be essential elements to


      ensuring that the transition is smooth and




                To accomplish this effectively, however,


      it is critical that FDA establish a clear timeline


      to end the exemption because we believe that only


      in doing so will there be the necessary stimulus to


      drive the kind of provider and patient-behavior


      change that will be required.  Schering's


      contribution, as well as that of others, to


      effecting a successful transition hinges on


      implementing the various elements of the transition


      at the right time in relation to the effective




                In the absence of such a date, it will be




      difficult to manage these various aspects


      efficiently.  For example, patients may not be


      receptive to targeted communication efforts until a


      fixed date has been established.  It has been


      pointed out, in addition, that significant planning


      decisions and resource commitments required to


      increase current production capacity need to be


      made and, for us, we need about eighteen months in


      advance of a known effective date.


                That being said, Schering is poised to


      play a part in a planned orderly transition and we


      could be ready for an HFA-only environment as early


      as the end of next year.  We believe that for the


      FDA to remove the exemption, certain assurances are


      required.  These are that safe and effective


      alternatives are available, that patients and


      providers are knowledgeable about and comfortable


      with the use of the inhalers and that industry can


      adequately meet the demand.


                In the next few minutes, I will point out


      that we do have safe and effective alternatives


      right now and Schering will have educational




      programs ready so that patients and providers will


      be knowledgeable about and comfortable with their


      HFA alternatives and that we can have an adequate


      supply and production capacity of Proventil HFA


      available again as early as December 31, 2005 or


      within eighteen months of an established transition




                Now, regarding the safe and effective


      alternatives, following the issuance of the


      Montreal Protocol in 1987 and after years of


      research and development, Schering was the first


      company to market, in collaboration with our


      partner 3M, a non-CFC inhaler in the United States


      in 1997.


                Industry researchers had created HFAs that


      were more environmentally friendly than CFCs.


      These HFAs were then extensively tested to ensure


      that they possessed the desired characteristics of


      an MDI propellent.  A wide range of toxicology


      studies, comparable in scope to that for a new


      molecular entity and consisting of acute, chronic


      reproductive genetic and carcinogenicity




      evaluations, established that certain HFA molecules


      were, in fact, suitable candidates to replace CFCs


      in inhaled delivery systems.


                The new technology was then applied to


      Proventil and, after a comprehensive clinical


      program established that Proventil HFA was both


      safe and effective, the FDA approved the product


      for marketing clearance in 1996.  In addition to


      the clinical studies that were included in the NDA,


      3M also conducted a robust observational


      postmarketing program which studied more than 6,000




                In the nearly eight years of postmarketing


      patient experience to date, more than 17 million


      prescriptions for Proventil HFA have been written.


      Spontaneously reported adverse events, as you have


      heard, have been consistent with the product's


      labeling and similar in nature to that of its CFC




                Taken together, available data clearly


      support the established safety profile of Proventil


      HFA and so, yes, we do have safe and effective




      non-CFC alternatives available right now and, in


      fact, with Glaxo's HFA product, there are, as said,


      two such products available.


                Let's turn now to another assurance


      required before removing the exemption, that


      relating to education and communication.  Schering


      is committed to playing its part in communicating


      important information around the transition to both


      patients and providers.  Including in that


      important information is reiteration of the message


      that HFA inhalers are as safe and effective as the


      CFC inhalers to which most patients are accustomed.


      The HFA inhalers are also similar in size and shape


      and as convenient to use.


                Now, we all recognize, especially those


      who treat asthma patients, that there can be a


      significant psychological and emotional component


      to asthma and its treatment.  Asthma patients come


      to rely on their inhalers and expect a certain type


      of experience in using them.  They tend to


      associate activity of the drug and subsequent


      relief with the forceful sensation of the spray




      from a CFC inhaler has on the back of the throat.


                I would point out that, with an HFA


      inhaler, however, there is a softer spray and less


      sensation although, of course, the active drug is


      still effectively delivered to the lung.  This fact


      must this communicated to patients to ensure the


      appropriate use of the product.  Patients will also


      need to be comfortable with the fact the drug from


      an HFA inhaler may taste and smell slightly


      different than that from a CFC inhaler.


                Schering has always had educational


      programs in support of our respiratory-care


      business and messages such as those I have just


      noted will be included in our developing multipoint


      communication and awareness programs intended to


      facilitate a safe and orderly transition.


                Educational information will be accessible


      via many channels including informational websites,


      written materials available in physician's offices


      and through our professional sales representatives.


      Schering has traditionally had strong collaborative


      working relationships with relevant national




      medical associations including both the American


      Academy and the American College of Allergy, Asthma


      and Immunology, the Academy of Family of


      Physicians.  We will continue to work with these


      associations and others to develop appropriate


      educational materials for patients and providers.


                We especially appreciate the efforts of


      organizations such as the allergy and asthma


      network Mothers of Asthmatics in their own


      commitments to educating and supporting the needs


      of asthma patients.


                Schering is also one of the founding


      sponsors of the National Patient Safety Foundation


      and has held a seat on its board of directors since


      1997.  This group is dedicated to improving patient


      safety through educational programs and initiatives


      and Schering will continue to provide input and


      leadership on issues related to safe medication




                As I stated in my introduction, the impact


      of an expanded successful patient and provider


      education campaign will be highly dependent on




      implementing the various elements at the right time


      in relation to a proposed effective date.  These


      programs, to be maximally effective, will need to


      be timed in coordination with the transition date


      established by FDA so that the asthma community can


      be optimally prepared.


                On other point related to the transition,


      it is, unfortunately, a fact and well known that


      many asthma patients do not regularly visit their


      healthcare provider.  Schering believes, in


      agreement with the U.S. Stakeholders, that the


      transition will offer a good opportunity for


      physicians and patients to increase their general


      dialogue about asthma management.


                A visit to the healthcare provider,


      prompted by the switch to an HFA inhaler, will


      allow for a reassessment of the patient's condition


      and adjustment of treatment if deemed appropriate.


      It will be especially useful for those patients who


      may not have seen a physician for some time.


                A third assurance required before removing


      the exemption is that an adequate supply and




      production capacity of the HFA alternative will


      exist.  FDA has stated, and you have heard several


      times today, that over 50 million albuterol


      canisters are sold or distributed in the U.S. each


      year.  Schering currently supplies approximately


      30 million units annually.


                Our manufacturing partner, 3M, stands


      ready to expand production in its facilities to


      manufacture this amount of Proventil HFA and


      Schering and 3M both have confidence that the


      necessary capacity can be in place to meet our


      share of the expected demand.


                While much of the preparatory work to


      expand capacity is well underway, advanced planning


      activities and significant resource commitments


      necessary to formally initiate this process require


      some assurance of the timing of the transition.


      The overall lead time to execute these steps,


      including scale-up to current market demand, is


      approximately eighteen months, again, thus, making


      a fixed transition date established by FDA critical


      for us and our partner.




                In conclusion, the time to set a


      transition date is now.  Schering is confident that


      we can meet our share of the demand and ensure that


      asthma patients who need Proventil HFA are


      adequately served.  The focus throughout the


      transition from CFC to HFA inhalers must be on


      education and communication efforts towards


      patients and providers.  Schering is committed to


      playing its part in effecting a successful


      transition and supports the removal of the CFC




                The first step requires that a proposed


      final rule be published and a clear date


      communicated so that all asthma stakeholders can


      act together.  Finally, Schering believes the U.S.


      can join the group of countries who have already


      undergone a successful removal of the exemption


      because we do have safe and effective FDA


      alternatives now.  We will be educating patients


      and providers and ensure their comfort level with


      the transition and industry can adequately meet the


      supply and demand.




                Thank you.


                DR. CHINCHILLI:  Thank you, Dr. Garutti.


      Do the committee members have any questions of our


      three open presenters this morning?  Dr. Schatz?


                DR. SCHATZ:  I guess a question for the


      stakeholders.  The presentation talked, actually,


      about two aspects of concern.  One was CFC


      availability, itself, and then, obviously, the


      detrimental aspects.  But I was trying to get some


      sense as to what the relative concerns were and if,


      in fact, if CFC availability were assured, would


      that change the thinking in terms of a time line?


                MS. WEXLER:  If CFC availability was--


                DR. SCHATZ:  A fair amount has been


      emphasized about the concern as to whether CFCs


      will continue to be available in terms of the


      production as a rationale for the December 2005


      date.  My question was to what extent that one


      factor is important and if CFC availability were


      assured, if the production were not an issue, would


      that affect your thinking in terms of a transition






                MS. WEXLER:  No.  I think that they work


      together to signal that these chemicals are being


      eliminated.  There is a reason that Honeywell has


      been asked to shut the manufacturing plant in the


      Netherlands and that is because the Dutch


      government does not want CFCs produced on its soil.


      It is a political statement about getting out of


      these chemicals.


                To answer your question specifically, if


      Baton Rouge were able to produce, it is not clear


      that the international community would continue to


      authorize those quantities and that would put the


      stakeholders in the position of suggesting that we


      don't care about international commitments.


                The U.S., the government, has made a


      commitment to comply with the Montreal Protocol and


      so producing in Baton Rouge is only part of the


      equation.  It is that gets us the potential to use


      them.  But the right to use them legally needs to


      be granted by the parties to the protocol.  So they


      have to work together in order for us to be able to


      go forward.




                I think what, in some ways, you are asking


      is would we support renouncing the protocol?


                DR. SCHATZ:  No.  It is a matter of would


      the date, would your date, change.  I was trying to


      get the sensitivity of your position to CFC


      availability versus other considerations relative


      to the date you suggest.


                MS. WEXLER:  Again, I think that they work


      together.  Given what we know about the timeline,


      the U.S.--forgive me; I want to make sure it is


      clear.  We ask to use CFCs, wherever we get them


      from.  Regardless of where they are produced, each


      country must ask the international process sort of


      at the beginning of the year.  We just put in our


      request and those requests are two years in




                So the request that the U.S. recently


      submitted was for 2006 quantities.  That request


      was not welcomed completely.  It was suggested that


      the U.S. might want to reconsider that nomination


      in light of this rulemaking or the rule that is go






                So even if supply weren't necessarily an


      issue, I think that it would be foolish for us to


      believe that the international community is going


      to continue to provide authorization to use those


      CFCs indefinitely.  So we are talking about a


      2005-2006 timeframe for getting out of this and not


      worrying about either of those conditions, of CFC


      supply or the international community not granting




                I think that, as we have heard, the


      process of transitioning, making sure that the


      HFA-installed capacity is there, making sure we


      don't do anything precipitous and have a problem


      and then have no CFC production capability and the


      stockpiles of the CFCs that are available sort of


      suggest that we want to kind of look towards the


      sooner rather than later so that we buy ourselves


      some time.


                In other words, I don't think the protocol


      parties will look kindly at a nomination for 2007


      or 2008 regardless of whether Baton Rouge actually


      ends up coming on line in a legal way.




                DR. CHINCHILLI:  Thank you.   Dr.




                DR. ATKINSON:  I sort of get the


      impression that one of the big concerns among the


      committee members and the FDA also is the


      possibility that a small percentage of asthma


      patients might be unable to purchase the HFA units


      that they need.  GSK has a program, or described a


      program, that was going to assist with that.  I


      wanted to ask Dr. Garutti if Schering had any such


      program and if they were considering creating one


      if they don't have one now.


                DR. GARUTTI:  Let me say this is a patient


      group and a provider group that we care very deeply


      about.  We are committed to the respiratory


      business.  We have been in it a long time and we


      are going to do whatever is necessary to serve our


      patient population.


                First and foremost there is to make sure


      that there is Proventil HFA available when we do


      transition to the HFA-only environment.  Currently,


      as I have pointed out, that will entail a




      significant ramp-up and a significant expenditure


      of cost to get there.  And we are confident we will


      get there.


                In fact, Schering-Plough does have a


      patient assistance program.  It is called SP Cares.


      We have had it since, I believe, the mid-1990s.  It


      has similar eligibility requirements to those of


      Glaxo's program, not entirely the same but similar.


      Last year along we provided free drug of our


      primary-care products including Proventil HFA to


      some 75,000 low-income uninsured patients.


                Periodically, we review the elements of


      this program and criteria and we are committed to


      continuing this program.


                DR. CHINCHILLI:  Thank you.  Dr. Moss; you


      had a question?


                DR. MOSS:  I was going to ask something


      along the same lines.  Maybe the people from GSK


      and Schering can talk about how they are going to


      market those programs for the uninsured, if they


      have any plans for how to make physicians aware of


      these programs.




                MS. WEXLER:  I wanted to point out that,


      in anticipation of this move, the stakeholders, on


      our website which is at inhalertransition.org, has


      listed all of the patient-assistance programs and


      has link to them so that our member organizations


      can now start to disseminate that information.  So


      we also will work with the companies to promote




                DR. JONES:  Yes.  Bridges to Access,


      actually, at the moment, has 435,000 patients in


      its program.  We have done a lot and will endeavor


      to meet and strive towards this end.  We have put a


      lot of programs in place in order to be able to


      reach as many people as possible and we will


      continue to have these outreach efforts in place to


      allow physicians and their associates to actually


      be aware of these programs.


                But, as I say, we have 435,000 at the


      moment in the Bridges to Access program.


                DR. CHINCHILLI:  Thank you.   Dr. Garutti?


                DR. GARUTTI:  I am not sure there is much


      more we can add.  As we have indicated, we are




      developing many aspects of our communication


      program.  This is one element of them, the


      awareness of the SP Cares program and we are going


      to be working with various organizations that we


      mentioned to make sure that it is more widely


      communicated now as we transfer to an HFA-only




                DR. CHINCHILLI:  Any other questions from


      committee members?  If not, we are going to break


      for lunch.  I'm sorry; Dr. Meyer.  I didn't see




                DR. MEYER:  Sorry; not to delay lunch.  I


      did want to make a clarification on an issue that


      was left open from Ms. Wexler's talk earlier about


      how the CFC sources is handled by the FDA because I


      think she left that as kind of an open question.


                Without getting into the details of the


      Baton Rouge situation, what I would say is that the


      FDA does not approve a CFC source, per se.  What we


      have done is we set standards for the purity that


      is acceptable for CFCs when used in metered-dose


      inhalers.  It is the expectation that the sponsor




      of a product that uses those CFCs will provide us


      evidence, both from the manufacturer as well as


      their own testing, that the CFCs meet those


      specifications and, if they do, then, in fact, they


      can be used in that product.


                DR. CHINCHILLI:  Thank you for the


      clarification.  Let me make sure nobody else has


      anything.  Okay.  We will break for lunch.  We plan