1

                                  FOOD AND DRUG ADMINISTRATION

                            CENTER FOR DRUG EVALUATION AND RESEARCH

                                  PULMONARY AND ALLERGY DRUGS
                                       ADVISORY COMMITTEE

                                            Monday,
                                       November 22, 1999

                                 Versailles Ballrooms I and II
                                      Holiday Inn-Bethesda
                                     8120 Wisconsin Avenue
                                       Bethesda, Maryland

                                                                            2

                  IN ATTENDANCE:

                  CURTIS N. SESSLER, M.D., Chairman
                  Professor Medicine
                  Medical College of Virginia
                   at Virginia Commonwealth University
                  Pulmonary and Critical Care Medicine
                  5th Floor, South Wing
                  1200 E. Broad West Hospital
                  Richmond, Virginia  23219

                  IGOR CERNY, Pharm.D., Acting Executive Secretary
                  Advisors and Consultants Staff (HFD-21)
                  Center for Drug Evaluation and Research
                  Food and Drug Administration
                  5600 Fishers Lane
                  Rockville, Maryland  20857

                  Members

                  BRENDA H. CONNER, Consumer Representative
                  c/o Matria Healthcare, Inc.
                  1850 Parkway Place
                  Marietta, Georgia  30067

                  NICHOLAS GROSS, M.D., Ph.D.
                  Professor
                  Department of Molecular and Cellular Biochemistry
                  Stritch School of Medicine
                  Loyola University of Chicago
                  5th and Rossevelt Road
                  Building One, Room A342
                  Hines, Illinois  60141

                  WILLIAM H. KELLY, Pharm.D.
                  Professor of Pharmacy and Pediatrics
                  College of Pharmacy
                  University of New Mexico
                  2502 Marble N.E., Room B-64
                  Albuquerque, New Mexico  87131

                                                                            3

                  IN ATTENDANCE:

                  FDA Consultants

                  ANDREA J. APTER, M.D.
                  Associate Professor
                  Pulmonary, Allergy, and Critical Care Division
                  829 Gates Building
                  Hospital of the University of Pennsylvania
                  Philadelphia, Pennsylvania  19104

                  MARK S. DYKEWICZ, M.D.
                  Associate Professor of Internal Medicine
                  Division of Allergy and Immunology
                  Department of Internal Medicine
                  St. Louis University School of Medicine
                  1402 South Grand Boulevard
                  Doisy R-209
                  St. Louis, Missouri  63104-1028

                  ROBERT J. FINK, M.D.
                  Chairman
                  Department of Pulmonary Medicine
                  Children's National Medical Center
                  111 Michigan Avenue, N.W.
                  Washington, D.C.  20010-2970

                  JESSE JOAD, M.D.
                  Assistant Professor of Pediatrics
                  U.C. Davis Medical Center
                  Department of Pediatrics
                  2516 Stockton Boulevard
                  Sacramento, California  95817

                  MICHAEL S. NIEDERMAN, M.D.
                  Chief
                  Division of Pulmonary and Critical Care Medicine
                  Winthrop-University Hospital
                  Pulmonary and Critical Care Medicine
                  222 Station Plaza North
                  Suite 400
                  Mineola, New York  11501

                                                                            4

                  IN ATTENDANCE:

                  FDA Consultants

                  WILLIAM M. VOLLMER, Ph.D.
                  Senior Investigator
                  Center for Health Research
                  Kaiser Permanente
                  Northwest Division
                  3800 N. Interstate Avenue
                  Portland, Oregon  97227-1110

                  Guest

                  JEAN G. FORD, M.D.
                  Florence Irving Assistant Professor
                  Harlem Hospital Center
                  Columbia University College of Physicians and Surgeons
                  506 Lenox Avenue, MLK 12-106
                  New York, New York  10037

                                                                            5

                                        C O N T E N T S

                                                                         PAGE

                  Call to Order and Welcome

                        Curtis N. Sessler, M.D.
                        PADAC Chairman                                      7

                  Conflict of Interest Statement

                        Igor Cerny, Pharm.D.
                        PADAC Acting Executive Secretary                   10

                  Opening Remarks

                        Robert Meyer, M.D.
                        Director, Division of Pulmonary
                         and Allergy Drug Products, CDER                   12

                        John K. Jenkins, M.D.
                        Director, Office of Drug Evaluation II, CDER       13

                  Ozone Science, the Montreal Protocol,
                  and U.S. Ozone Protection Efforts

                        Erin Birgfeld
                        Essential Use Manager
                        Stratospheric Protection Division
                        Office of Air and Radiation
                        U.S. Environmental Protection Agency               20

                  Review of Past FDA Actions Regarding
                  Ozone-Depleting Substances

                        Robert Meyer, M.D.                                 34

                  Review of the Notice of Proposed
                  Rulemaking (NPR)

                        Leanne Cusumano, J.D.
                        Regulatory Counsel
                        Regulatory Policy Staff, CDER                      50

                                                                            6

                                        C O N T E N T S

                                                                         PAGE

                  Committee Questions on EPA
                  and FDA Presentations                                    59

                  Open Public Hearing

                        Ballard Jamieson, Jr.
                        Secretary and Legal Counsel
                        International Pharmaceutical Aerosol Consortium    98

                        Alfred Munzer, M.D.
                        American Thoracic Society
                        Medical Section of the American Lung Association  104

                        Mary E. Worstell, M.P.H.
                        Executive Director
                        Asthma and Allergy Foundation of America          109

                        Dolores Libera
                        Director of Publications
                        Allergy and Asthma Network/Mothers of Asthmatics  114

                  Committee Discussion on NPR Discussion Points           121

                                                                            7

             1                       P R O C E E D I N G S        (8:15 a.m.)

             2                DR. SESSLER:  Good morning.  I'd like to

             3    welcome everybody to the Pulmonary and Allergy Drugs

             4    Advisory Committee meeting.

             5                My name is Curt Sessler.  I'll be chairing the

             6    meeting.  My principal goals here, I think, are to engender

             7    lively discussion and to keep the meeting on time.

             8                The issue, I'll read, for discussion today from

             9    your agenda.  "The FDA published a notice of proposed

            10    rulemaking on September 1st, 1999, related to the phaseout

            11    of CFCs in metered-dose inhalers.  The committee will

            12    discuss and comment on the NPR and on presentations made

            13    during the public hearing."

            14                The agenda is published, and everybody should

            15    have a copy of that.  In brief, there will be a number of

            16    comments made by Drs. Meyer and Jenkins to start.  There

            17    will be a presentation by Erin Birgfeld, followed by a

            18    formal presentation by Dr. Robert Meyer, then time for

            19    discussion, and a presentation by Leanne Cusumano, and then

            20    a break at 10:30, and then open public hearing from 10:45

            21    till noon.

            22                If the public hearing doesn't extend the full

            23    duration to noon, we'll start the afternoon's agenda at

            24    that time and then break for lunch at 12, and then the

            25    afternoon will be devoted towards committee consideration

                                                                            8

             1    of the discussion points, and you should have copies of

             2    those as well.

             3                I'd like to ask that the committee members and

             4    the members of the FDA and the EPA who are at the head

             5    table introduce themselves, and at this time, I'd also just

             6    remind the committee members and others that this is going

             7    to be recorded, so please speak clearly into the

             8    microphone.  That's for Alan in the corner there, and if

             9    you would, then please introduce yourself and tell us a

            10    little bit about affiliations, and we'll go around the

            11    table and have all the committee and others introduced.

            12                DR. FORD:  I'm Jean Ford.  I'm affiliated with

            13    Columbia University and Harlem Hospital Center in New York,

            14    and I'm a pulmonologist.

            15                DR. VOLLMER:  My name is Bill Vollmer.  I'm a

            16    statistician and epidemiologist with the Kaiser Permanente

            17    Center for Health Research in Portland, Oregon.

            18                DR. APTER:  I'm Andrea Apter, Division of

            19    Pulmonary, Allergy, and Critical Care Medicine, University

            20    of Pennsylvania.  My training is in allergy and immunology.

            21                DR. FINK:  Bob Fink, a pediatric pulmonologist

            22    at Children's National Medical Center, George Washington

            23    University, here in D.C.

            24                DR. GROSS:  I'm Nick Gross.  I'm a

            25    pulmonologist at Loyola University in Chicago.

                                                                            9

             1                DR. JOAD:  I'm Jesse Joad.  I'm at the

             2    University of California at Davis, and I'm a pediatric

             3    allergist and a pediatric pulmonologist.

             4                DR. SESSLER:  I'm Curt Sessler, Pulmonary and

             5    Critical Care at the Medical College of Virginia, Virginia

             6    Commonwealth University in Richmond.

             7                DR. CERNY:  I'm Igor Cerny, Executive

             8    Secretary, of Food and Drug Administration.

             9                DR. KELLY:  Bill Kelly from the University of

            10    New Mexico Health Sciences Center, Professor of Pharmacy

            11    and Pediatrics and Pediatric Clinical Pharmacology.

            12                DR. DYKEWICZ:  Mark Dykewicz.  I'm Associate

            13    Professor of Internal Medicine and Director of the Allergy

            14    and Allergy Training Program at St. Louis University in St.

            15    Louis.

            16                DR. NIEDERMAN:  I'm Mike Niederman from

            17    Winthrop-University Hospital, Mineola, New York, and I'm a

            18    pulmonary and critical care physician and Professor of

            19    Medicine at the State University of New York at Stony

            20    Brook.

            21                MS. CONNER:  I'm Brenda Conner.  I'm a nurse

            22    educator with 22 years pediatric nursing experience, and

            23    I'm the consumer representative to the committee.

            24                MS. CUSUMANO:  I'm Leanne Cusumano.  I'm

            25    regulatory counsel with the Center for Drug Evaluation and

                                                                           10

             1    Research at FDA.

             2                DR. MEYER:  And I'm Bob Meyer, and I'm the

             3    Director of the Division of Pulmonary and Allergy Drug

             4    Products at the FDA.

             5                DR. JENKINS:  I'm John Jenkins.  I'm the

             6    Director of the Office of Drug Evaluation II at the FDA.

             7                MS. BIRGFELD:  Erin Birgfeld, Essential Use

             8    Program Manager at EPA.

             9                MR. COHEN:  Jeff Cohen, U.S. Environmental

            10    Protection Agency.  I'm with the Stratospheric Protection

            11    Division, and we review the substitutes to ozone-depleting

            12    chemicals under the Clean Air Act.

            13                DR. SESSLER:  Thank you.

            14                Dr. Igor Cerny will present the meeting

            15    announcements and conflict of interest statements.

            16                DR. CERNY:  The following announcement

            17    addresses the issue of conflict of interest with regard to

            18    this meeting and is made a part of the record to preclude

            19    even the appearance of such at this meeting.

            20                Based on the submitted agenda for the meeting

            21    and all financial interests reported by the committee

            22    participants, it has been determined that all interested

            23    firms regulated by the Center for Drug Evaluation and

            24    Research present no potential for an appearance of a

            25    conflict of interest at this meeting with the following

                                                                           11

             1    exceptions.

             2                In accordance with 18 U.S.C. 208(b)(3), full

             3    waivers have been granted to Dr. Andrea Apter and Dr.

             4    Michael Niederman.  A copy of the waiver statement may be

             5    obtained by submitting a written request to FDA's Freedom

             6    of Information Office, Room 12A-30 of the Parklawn

             7    Building.

             8                In addition, several of our committee

             9    participants have been involved in activities relating to

            10    the replacement of CFCs that we believe should be

            11    disclosed.  FDA believes it is important to acknowledge

            12    these participants' involvement so that their participation

            13    can be objectively evaluated.

            14                Dr. Curt Sessler has consulted with Hoechst

            15    Marion Roussel regarding asthma management.

            16                Dr. Mike Dykewicz attended a Schering Plough

            17    Speakers Bureau training meeting regarding a product for

            18    asthma.  He also previously participated as a

            19    subinvestigator in an AstraZeneca study of a product for

            20    use in asthma.

            21                In the event that the discussions involve any

            22    other products or firms not already on the agenda for which

            23    an FDA participant has a financial interest, the

            24    participants are aware of the need to exclude themselves

            25    from such involvement, and their exclusion will be noted

                                                                           12

             1    for the record.

             2                With respect to all other participants, we ask

             3    in the interest of fairness that they address any current

             4    or previous financial involvement with any firm whose

             5    products they may wish to comment upon.

             6                DR. SESSLER:  Thank you.

             7                Dr. Robert Meyer will give a welcome.

             8                DR. MEYER:  Thank you.  I wanted to especially

             9    welcome the many new members of the Pulmonary and Allergy

            10    Drugs Advisory Committee.  The FDA is very grateful for

            11    your service, and we look forward to your input on this

            12    important issue and important issues in the future.

            13                I especially want to note that this is a

            14    holiday week, and we especially appreciate your willingness

            15    to travel and attend this meeting today.

            16                I'd also like to thank Dr. Sessler for taking

            17    on the role of chair and look forward to a very productive

            18    time with Dr. Sessler as the chair of this committee.

            19                I also want to note for the record, for the

            20    public and for the returning members, that the division has

            21    a new name that actually puts it more in concert with the

            22    name of the advisory committee.  We've added the title or

            23    the name "Allergy" to our title.  So we're now the Division

            24    of Pulmonary and Allergy Drug Products to reflect our

            25    regulatory purview better, and again it does bring it into

                                                                           13

             1    concert with the name of this advisory committee, and we

             2    also have had changes in jobs within the division.

             3                I've assumed the directorship of the division

             4    since the last meeting of the PADAC, and Dr. Jenkins has

             5    moved upstairs, both literally and figuratively, to the

             6    role of Director of the Office of Drug Evaluation II.  So

             7    he not only oversees the Division of Pulmonary and Allergy

             8    Drug Products, but also the Division of Metabolic and

             9    Endocrine Drug Products and the Division of Anesthesia and

            10    Critical Care Medicine.

            11                I look forward to the committee's discussion of

            12    both the proposed rulemaking that we will take you through

            13    today, and we're not asking for votes today, but we very

            14    much look forward to and will note for the record your

            15    comments and your suggestions about the notice of proposed

            16    rulemaking, and Dr. Jenkins will talk further about that in

            17    a minute.

            18                I think we have a very interesting discussion

            19    on board for tomorrow, quite different from today as well,

            20    and so once again, I'd like to thank the committee for

            21    being here and look forward to the ensuing discussion.

            22                Thank you.

            23                DR. SESSLER:  Thank you.

            24                Dr. Jenkins?

            25                DR. JENKINS:  Thank you, Dr. Sessler.

                                                                           14

             1                I'd like to first add my welcome again to the

             2    new committee members in particular, but to all the

             3    committee members for your willingness to join us here

             4    today for this very important discussion, and a very

             5    personal note of thanks to Dr. Sessler, an old colleague of

             6    mine, for agreeing to take on the position of chair.  I

             7    share Bob's enthusiasm for working with you this year in

             8    your role as chair of the committee.

             9                I wanted to try to start out our discussion

            10    this morning by trying to put this meeting a little bit

            11    into context as far as FDA's activities over the past

            12    decade with regard to the CFC phaseout, and I think this is

            13    important since we have so many new members of the

            14    committee.

            15                I think as I look around the table, the only

            16    member of the committee who was here in April of '97 for

            17    our previous discussion of this topic was Dr. Sessler.  If

            18    I'm wrong, please correct me, but I think this is a new

            19    issue for most of the members of the committee and possibly

            20    for some members of the audience.

            21                So let me give you a little bit of a

            22    perspective on what the FDA has been doing over the past

            23    decade in this regard and where today's meeting fits into

            24    that overall schema.

            25                When it became clear near the end of the '80s

                                                                           15

             1    and the early '90s that the Montreal Protocol was going

             2    into effect and would be banning the use of CFCs in

             3    metered-dose inhalers, the FDA first turned its attention

             4    to working with companies on issues, such as what animal

             5    testing would be needed for the new propellants to make

             6    sure that they were safe for use in humans, and working

             7    with companies on advice regarding development of the new

             8    formulations of the non-CFC-propelled MDIs.

             9                The division also issued a guidance document in

            10    September of 1994.  That guidance was focused on the

            11    clinical development program for these new products.  We

            12    tried to look out for sponsors, the types of studies that

            13    we would expect to see for the new reformulated non-CFC

            14    MDIs or the dry-powder inhalers to try to help sponsors

            15    understand what their development programs should look

            16    like, what questions they should be attempting to answer.

            17                The focus of that guidance was primarily to

            18    encourage sponsors to demonstrate the comparability

            19    clinically of their existing formulation to the new

            20    formulations that they would be developing to get approved.

            21                As the development process continued, and we

            22    started to receive NDAs in the mid-'90s for review of some

            23    of these products, we internally focused some of our

            24    attention toward the issue of how are we going to make a

            25    determination in the future whether the use of CFCs remains

                                                                           16

             1    essential once these new products come into the

             2    marketplace?

             3                That's an essential statutory role that the FDA

             4    has under the Clean Air Act, is in that we determine

             5    whether or not the use of CFCs in medical products is

             6    essential in consultation with the EPA.

             7                So once it became clear that these new products

             8    were starting to be developed and come to fruition as NDAs,

             9    we turned our attention to how will we go about making

            10    those determinations of when a product is no longer

            11    essential and should be taken off the list of essential

            12    products listed in the FDA's regulations?

            13                To accomplish that task, the FDA formed a CFC

            14    work group within the Center for Drug Evaluation to

            15    Research.  Dr. Meyer's currently the chair of that CFC work

            16    group, and the first product of that work group was an

            17    advanced notice of proposed rulemaking which the FDA

            18    published in March of 1997, and that advanced notice was

            19    really designed to seek public comment on various potential

            20    strategies that the FDA could use in making these

            21    determinations of non-essentiality.

            22                That, as I said, was seeking public comment,

            23    and as part of the public comment period for that advanced

            24    notice of proposed rulemaking, we had an advisory committee

            25    meeting in April of 1997 where we sought the input of the

                                                                           17

             1    committee.  There were approximately 25 speakers during the

             2    open public hearing of that meeting, and then during the

             3    subsequent comment period to that advanced notice, we

             4    received approximately 10,000 comments from the public.

             5                So our goal of getting public comment and

             6    public input far exceeded our expectations, and those

             7    public inputs and comments have been very helpful, I think,

             8    in helping us to move on to the next stage, which is where

             9    we are now, in that we have now published a notice of

            10    proposed rulemaking which is basically the second step in

            11    the process towards finalizing FDA regulations about how to

            12    make these essential use determinations in the future.

            13                That proposed rule, as Dr. Sessler noted, was

            14    published at the beginning of September.  We're currently

            15    in the comment period for that proposed rule, and this

            16    meeting today is considered to be part of the public

            17    comment period for the proposed rule.  So the comments from

            18    the committee, the comments from the audience today will be

            19    considered as part of the docket as we go forward with this

            20    process.

            21                As Dr. Meyer said, we're not asking the

            22    committee for votes today.  That's not the nature of the

            23    day's meeting since this is a public comment period for the

            24    proposed rule.  We are asking, though, some very important

            25    questions to help us to further refine the proposed rule as

                                                                           18

             1    we move forward to the final rule as well as we move

             2    forward to actually implementing that final rule in the

             3    future to make determinations that products are no longer

             4    essential.

             5                Many of those questions are engendered in your

             6    talking points that are part of today's agenda.  For

             7    example, we're very interested in hearing your views on

             8    what should we consider to be adequate alternatives to the

             9    CFC-propelled MDIs?

            10                When should the FDA make the determination that

            11    the medical needs of patients who rely on CFC MDIs have

            12    been adequately met by the non-CFC products to determine

            13    that they're no longer essential?

            14                What kind of post-marketing data should the FDA

            15    ask sponsors to develop or should sponsors be developing on

            16    their own for their non-CFC products to help in that

            17    assessment that they meet patient needs?

            18                What are the important subgroups of patients

            19    that we should be thinking about as we're making these

            20    determinations of non-essentiality?

            21                What does the committee think about the FDA's

            22    proposal that the essential use determinations will be made

            23    in the future on a moiety-by-moiety approach?  That's one

            24    of the three possible options that was suggested in the

            25    ANPR in 1997.  So now the agency following public input has

                                                                           19

             1    suggested that the moiety-by-moiety approach is the one we

             2    think would best serve patient needs.

             3                And there's also a proposal in the proposed

             4    rule that we would determine that nasal corticosteroid

             5    products are no longer essential uses of CFCs.  So we'll be

             6    interested in hearing the committee's thoughts on that

             7    issue as well.

             8                Not all the issues that will come up today are

             9    listed in the talking points.  So I encourage you, if we

            10    haven't thought of some things that you want to give us

            11    advice on, to feel free to do that.

            12                With that trying to put the meeting into

            13    context, I want to emphasize that the FDA is not in any way

            14    trying to accelerate the phaseout of CFC MDIs.  That term

            15    became very common in use during the 1997-1998 period when

            16    we were receiving comments on the advanced notice of

            17    proposed rulemaking, and I want to dispel that as being

            18    untrue.  That is not our goal.  That's not what we're

            19    trying to do.

            20                What we are trying to do is to carry out our

            21    statutory mission under the Clean Air Act and the Montreal

            22    Protocol to phase out the use of CFCs in medical products

            23    but only when we're confident that the health and safety of

            24    the patients who rely on those products will be adequately

            25    served by the alternative products.

                                                                           20

             1                The FDA is a Public Health Service agency, and

             2    our primary mission is to protect and promote the public

             3    health.  So that's our primary focus as we try to carry out

             4    this mandate, is to protect the patients who rely on these

             5    products.

             6                With that, I'd like to say that I look forward

             7    to today's discussion, and I hope it will be a very

             8    fruitful input from the committee to the agency as we

             9    continue this process.

            10                Thanks.

            11                DR. SESSLER:  Thank you, Dr. Jenkins.

            12                The first formal presentation will be by Erin

            13    Birgfeld, the Essential Use Manager, Stratospheric

            14    Protection Division, Office of Air and Radiation, U.S.

            15    Environmental Protection Agency.

            16                MS. BIRGFELD:  Well, again, my name is Erin

            17    Birgfeld.  I'm from the Stratospheric Protection Division

            18    at U.S. EPA, and I run the Essential Use Program there.

            19                Really the purpose of my talk today will be

            20    just to highlight the importance of compliance with the

            21    Montreal Protocol and the importance of this FDA rule in

            22    that context.

            23                Okay.  What I'm going to talk about today is

            24    first some brief background, some ozone-depletion science. 

            25    We'll talk about the fact that there really is a problem. 

                                                                           21

             1    Then we'll talk about the effects of increased UVB

             2    radiation hitting our earth's surface, and the effects

             3    specifically on human health and then on ecosystems and the

             4    environment.

             5                Finally, we'll talk about the Montreal

             6    Protocol, just a little bit of background, and then discuss

             7    what are essential uses underneath the Montreal Protocol

             8    and EPA's role in the essential use process as a whole.

             9                Okay.  First, we have this little diagram. 

            10    It's a cartoon of the ozone-depletion process, and when

            11    CFCs were introduced, I believe it was in the 1950s, they

            12    were sort of thought to be a miracle chemical.  They were

            13    low toxicity, were very stable and subsequently found a lot

            14    of uses, both in the industrial sector and in consumer

            15    products, and as we later found out, they also contributed

            16    to stratospheric ozone depletion.

            17                As you can see in this slide, you have CFCs

            18    being released from a bunch of different sources on the

            19    ground, becoming mixed into the troposphere, which is the

            20    area where we live and the lower atmosphere.  These are

            21    mixed and are never broken down.  They don't rain out in

            22    rain, and it takes between two and five years for these

            23    chemicals to get up into the stratosphere.

            24                Once in the stratosphere, they're subjected to

            25    very high levels of UV radiation that does break them down. 

                                                                           22

             1    This releases the chlorine atoms, and it's the chlorine

             2    atoms and also actually bromine atoms that actually do

             3    deplete the ozone layer, and one chlorine atom is capable

             4    of destroying up to a 100,000 ozone atoms.  So this is a

             5    pretty powerful process that's going on.

             6                Subsequent to ozone depletion, there's less

             7    ozone to be soaking up those UVB rays, and we are receiving

             8    more on the earth.

             9                Okay.  Now, this is actual real data, not a

            10    cartoon, of the ozone over Arosa, Switzerland.  This is the

            11    area where we have the most data, going the farthest back,

            12    and as you can see, the ozone layer is not at a steady

            13    state.  I mean, it's really jumping all over the map.

            14                This is the yearly means from 1926 to 1997. 

            15    But as you can see from the 1920s all the way up to the

            16    '70s, overall, it's pretty straight, the line is.  There's

            17    no slope.

            18                However, in the 1970s, after there was a lot of

            19    uses of CFCs, a lot of emissions, you can see a clear

            20    downward trend ending in 1997 where this data ends, and

            21    this is really a problem, and this is why this issue has

            22    come to the fore.

            23                One of the questions that we often get is how

            24    do we know that it's CFCs that are causing these problems? 

            25    Could it be another chlorine-containing chemical?  And as I

                                                                           23

             1    stated before, CFCs are very stable and are mixed pretty

             2    much evenly throughout the troposphere, and it's only once

             3    in the stratosphere you start seeing them decline.  So this

             4    is at CFC-11 declining with increasing altitude in the

             5    stratosphere, and again they're chlorine atoms and causing

             6    ozone depletion.

             7                DR. VOLLMER:  Just a question.  That's

             8    projected now or that's actually --

             9                MS. BIRGFELD:  Yes.  It's the best fit line,

            10    yes.  It's the cartoon, I guess, again.

            11                DR. SESSLER:  I'm sorry to interrupt.  If I

            12    could ask all the committee members and everybody else to

            13    go ahead and speak into the mike, if you would, with

            14    questions, and perhaps if they're not clear for those in

            15    the back, you could repeat the question after the speakers.

            16                MS. BIRGFELD:  Okay.

            17                DR. SESSLER:  Thank you.

            18                MS. BIRGFELD:  Sure.  So the next step is how

            19    does the reduction in stratospheric ozone translate into

            20    increases in UV radiation at the ground level, and here you

            21    can see this is a chart that looks at reduction of ozone in

            22    Antarctica versus the UV increase, and as you can see, it's

            23    quite substantial with 50 percent reduction in ozone, you

            24    get a 100 percent increase in UV radiation.

            25                Okay.  So right now, the ozone layer is at its

                                                                           24

             1    most vulnerable.  The chlorine and bromine loading in the

             2    stratosphere was expected to peak before the year 2000.  So

             3    right now, it's after January 1st, it's supposed to be

             4    declining, and hopefully we'll be on the road to recovery.

             5                However, we haven't seen any increases yet in

             6    1999.  The Antarctica ozone hole was about 25 million

             7    square kilometers big, and in mid-latitudes in the U.S.,

             8    where we're interested, we've seen about a 5 percent total

             9    ozone loss since 1979.  So this is not just a problem in

            10    Antarctica.  This is a problem here as well.

            11                You'll often hear when you're talking about

            12    this issue that ozone recovery is expected by the year

            13    2050, but this date is contingent on full compliance with

            14    the Montreal Protocol, and that's something that's

            15    critical, and I think it just highlights the importance of

            16    this meeting, and just for your interest, everything that's

            17    purple in my little picture of the ozone layer is

            18    considered an ozone hole.  That's ozone with less than 220

            19    dobson units, which is how ozone is measured.

            20                Okay.  So now what are the health effects of

            21    increased UVB?  As you know, skin cancer has been rising in

            22    this country.  It's considered an undeclared epidemic.  As

            23    you know as well, it's associated with UV exposure,

            24    exposure to the sun.

            25                The incidence of melanoma, the most severe form

                                                                           25

             1    of skin cancer, and the one with the highest mortality, in

             2    1935 was only one in 1,500.  In 1998, it was one in 87.  So

             3    that's a clear increase.  In 2000, it's projected the risk

             4    of getting melanoma is one in 75.  And just some more scary

             5    facts.  One American dies of skin cancer every hour, and

             6    over one million new cases are expected in the U.S. this

             7    year alone.  So this is a problem.

             8                Other health effects are cataracts.  Exposure

             9    to UVB has been associated with cataracts.  It's the

            10    leading cause of blindness, and there are 1.3 million

            11    cataract surgeries per year, and it's the greatest single

            12    line item in the Medicare budget.

            13                Another effect of UV on the human population is

            14    immune system suppression.  It's been shown that after

            15    sunburns, the immune system does not react in quite the

            16    same way that it would prior to when the skin is not

            17    sunburned, and this is an area of ongoing research, and

            18    then, finally, the issue of photoaging.  We're all getting

            19    wrinkles a little early, I guess.

            20                Okay.  We're not the only ones on this planet. 

            21    The ecological and environmental effects are also very

            22    important.  Increased UVB has been shown to decrease crop

            23    yields.  It's also been hypothesized to have caused loss of

            24    vulnerable species.

            25                In this country and around the world, there's

                                                                           26

             1    been a dramatic decline in the amphibian populations.  In

             2    addition, there's been deformities found in a lot of

             3    amphibians, and the hypothesis is that the increasing

             4    amounts of UVB may play a role in this problem, and the

             5    worry is that it's sort of like the canary in the coal

             6    mine, you know.  These are the ones that are going to be

             7    hit first.

             8                Next, we have damage to marine ecosystems in

             9    the Antarctica.  Phytoplankton are adversely affected by

            10    increased UVB, and this is the bottom of the food chain. 

            11    So subsequently, it affects the entire food chain.

            12                Finally, this is actually a very interesting

            13    one.  Increased UVB at the ground level actually can cause

            14    an increase of ozone layer in the troposphere.  So the one

            15    that you all are concerned about that causes asthma attacks

            16    and increased hospitalization actually may be increased

            17    with increasing UVB, and then, finally, we have an issue

            18    with materials degradation.  Plastics are falling apart

            19    much quicker than was anticipated.

            20                Okay.  So what do we do about it?  The Montreal

            21    Protocol was the international agreement to address and

            22    solve the problem of stratospheric ozone depletion.  It was

            23    signed by the U.S. in 1987, and subsequently there are over

            24    a 160 countries that are parties to this agreement.

            25                Import and production of CFCs were banned in

                                                                           27

             1    1996 in this country, and, however, of course, as you all

             2    know, the Montreal Protocol and the Clean Air Act do

             3    provide exemptions for some things that are called

             4    "essential uses."

             5                The definition of an essential use is under the

             6    Montreal Protocol is that if it is necessary for health,

             7    safety or is critical for the functioning of society, and

             8    there are no available technically and economically

             9    feasible alternatives.

            10                Here, the essential uses under the Montreal

            11    Protocol were never meant to be permanent exemptions, which

            12    is why all the parties are undertaking the same transition

            13    in their own countries.

            14                FDA's charged with providing the framework. 

            15    FDA is charged by the Clean Air Act with providing the

            16    framework that will ensure safe and predictable transition

            17    to CFC-free inhalers.

            18                It should be noted that metered-dose inhalers

            19    are the only significant commercial product in the U.S. for

            20    which CFCs are still produced.  There's a common

            21    misconception, I think, among the lay public that CFCs are

            22    still used in hair spray.  Those were banned in the 1970s. 

            23    So those have been gone away for a long time.

            24                Other approved essential uses included, beyond

            25    just MDIs, are in the past Class I ozone-depleting

                                                                           28

             1    substances for laboratory and analytical uses.  These are

             2    very small amounts, very pure, high grade, and methyl

             3    chloroform as a solvent for use in the space shuttle and

             4    Titan rockets, and again this is very small amounts.

             5                Okay.  So the process that I manage at the EPA

             6    is the Essential Use Process, and basically what we do is

             7    we receive applications from companies wishing to get CFCs

             8    to produce the MDIs.  We review the data, and then we put

             9    forward the nomination at the meeting of the parties in

            10    Montreal Protocol.

            11                There, the parties discuss whether or not to

            12    approve these CFCs for use in the U.S., and in the past,

            13    the parties have approved the entire U.S. request.

            14                Finally, the last step is that EPA allocates

            15    the CFCs through a notice and comment rulemaking at the end

            16    of the year, and companies are able to order their CFCs and

            17    produce the MDIs, and that's basically all I have.

            18                The issues and topics that I discussed, you can

            19    find in any of these places.  Our home page is

            20    epa.gov/ozone.  It's a good source of information, and then

            21    you can also talk to someone at our hot line if you're

            22    interested.

            23                Thank you for your attention.  I appreciate it.

            24                DR. SESSLER:  Thank you very much.

            25                We have time for questions and comment on Ms.

                                                                           29

             1    Birgfeld's presentation.

             2                DR. FINK:  Do you have any estimate of the

             3    number of pounds or tons of CFCs used in MDIs in the United

             4    States?

             5                MS. BIRGFELD:  Yes.  Actually, the essential

             6    use request for this year is going to be 3,700 metric tons.

             7                DR. FINK:  And how does that relate in terms of

             8    total CFC release into the atmosphere?  Does that rank

             9    Number 1 or 2 or where does it rank?

            10                MS. BIRGFELD:  For this country, it does not. 

            11    For release into the atmosphere, it doesn't.  We're still

            12    dealing with the old CFCs that were produced prior to 1996,

            13    and I guess the issue is that these are newly-produced

            14    CFCs.  So we're adding to the bank of CFCs that are in the

            15    atmosphere.

            16                One interesting thing.  The MDI use for this

            17    year is about one percent of the use from baseline which is

            18    from 1987, but at the same time, this amount of CFCs are

            19    about the same as some developing countries use in total. 

            20    So it's not an insignificant amount.

            21                DR. SESSLER:  Production in the U.S.   How does

            22    that compare to worldwide production?

            23                MS. BIRGFELD:  Of MDIs?

            24                DR. SESSLER:  Yes.  In actually other forms of

            25    ozone-depleting substances.

                                                                           30

             1                MS. BIRGFELD:  Well, actually, to my knowledge,

             2    all the CFCs are actually produced in the Netherlands, and

             3    we import them for use in MDIs.  I'm not entirely sure how

             4    we --

             5                DR. MEYER:  Can I comment?

             6                MS. BIRGFELD:  Yes, that would be great.

             7                DR. MEYER:  Amongst my other hats, I'm actually

             8    on the Aerosols Technical Option Committee for the United

             9    Nations.  So that's the committee that takes the first

            10    crack at the nominations, and Europe had been substantially

            11    higher than us in terms of their need because they not only

            12    produce for internal consumption but export extensively.

            13                The United States does not export extensively

            14    in terms of MDI production.  So Europe had been up in the

            15    5,000 range as far as metric tons in terms of their

            16    requests.  They're now coming down so that their request is

            17    very similar to the United States in recent years, and it's

            18    projected to perhaps even cross in the future.

            19                These nominations are for two years in advance. 

            20    So the 2001 nomination will be considered at this year's

            21    meeting of the parties, and the United States Government is

            22    preparing their nomination for 2002 or will be shortly.

            23                MS. BIRGFELD:  Questions?

            24                DR. FINK:  Since most use of CFCs is

            25    encapsulated or recycled, what proportion of the release

                                                                           31

             1    into the atmosphere on a yearly basis do the MDIs

             2    contribute?

             3                MS. BIRGFELD:  You know what?  I don't know.  I

             4    can get back to you on that.

             5                DR. NIEDERMAN:  Do  you have any estimate as to

             6    what percentage of the total asthma inhaler use has CFCs in

             7    it right now?

             8                MS. BIRGFELD:  I believe there's only one

             9    alternative out there.

            10                DR. NIEDERMAN:  But in terms of percentage of

            11    usage.  In other words, there are some of the dry-powder

            12    inhalers and other devices.

            13                MS. BIRGFELD:  Right.

            14                DR. NIEDERMAN:  Do you know in terms of total

            15    usage what percentage is currently used with CFCs?

            16                MS. BIRGFELD:  I'll let the expert take that

            17    one.

            18                DR. MEYER:  I think that I can give you sort of

            19    rough estimates more than exact answers, but I think the

            20    CFCs are still the large majority of the asthma market as

            21    far as the inhalers go.

            22                I don't really have a good handle for the

            23    recent figures of the dry-powder inhalers, but my

            24    impression is they've been moderately successful, but in

            25    the overall scheme of things remain a fairly small

                                                                           32

             1    percentage, and the approximate market share in terms of

             2    albuterol, of Proventil HFA, has been 8 to 10 percent of

             3    that market, and albuterol's perhaps 50 percent of the

             4    overall CFC use in inhalers in the United States.

             5                DR. NIEDERMAN:  So we could assume that

             6    currently 75 percent plus probably of all asthma therapy

             7    involves CFCs?

             8                DR. MEYER:  At least.  I think that's a very

             9    safe assumption.  It's at least that.

            10                MS. BIRGFELD:  Dr. Fink, I'd like to direct

            11    your question to my supervisor, Jeff Cohen.

            12                MR. COHEN:  I think, if I heard you ask what

            13    the comparison in terms of emission rates between an MDI

            14    and other uses of CFCs, most of the CFCs that are not used

            15    in MDIs are recycled.  Refrigerators, older cars.  Those

            16    emissions are controlled by service personnel and captured

            17    and continued to be recycled.

            18                So theoretically, none of that would be

            19    released.  In practice, some of it ultimately is,

            20    unfortunately, but we know that all of the CFCs when used

            21    as propellant in the MDI is released immediately to the

            22    atmosphere.

            23                I don't know if that answers your question.  I

            24    didn't quite catch all of it.

            25                DR. JOAD:  If CFCs in MDIs were the only source

                                                                           33

             1    of CFCs, what percentage decrease in ozone layer would

             2    occur over what time?

             3                MS. BIRGFELD:  Do you know this?

             4                DR. MEYER:  Well, I think these are interesting

             5    and in some ways important questions, but I think I do need

             6    to emphasize, and I think I put it in the talking points as

             7    well, that the decision by the U.S. Government and the

             8    world community in fact, a 164 other countries besides the

             9    United States, is that all uses of CFCs should be phased

            10    out over time, and that's the international committee

            11    commitment.

            12                You know, if you look at any single use with

            13    perhaps some glaring exceptions, they tend to look fairly

            14    small, but when you've committed to the overall phaseout,

            15    that's the commitment.  So we're not really here to argue

            16    whether that's a good thing or not.  It is the way the

            17    international community and the United States is going to

            18    proceed.  So we're more interested in discussing how to

            19    best get there.

            20                MS. BIRGFELD:  Thank you.

            21                DR. SESSLER:  Thank you very much.

            22                Our next speaker is Dr. Robert Meyer, Director

            23    of Division of Pulmonary and Allergy Drug Products, and he

            24    will be reviewing a number of different facets of this.

            25                Bob?

                                                                           34

             1                DR. MEYER:  I did fail to thank our EPA

             2    colleagues for being here today, and I do thank you both.

             3                I think that this is a collaborative effort

             4    that we're undergoing here.  We're both public health

             5    agencies in some respects, although we do clearly have

             6    different regulatory missions.  But in any case, I think

             7    that this process is best accomplished by what in fact the

             8    EPA's Clean Air Act and their implementing regulations has

             9    required, which is that FDA and EPA move forward with this

            10    process in a consultative and collaborative way.  So thank

            11    you both for being here.

            12                This slide will mainly, I think, be familiar to

            13    federal workers, but we're in a season in the federal cycle

            14    of what's called the Combined Federal Campaign, which is a

            15    way that we get to donate from our paychecks to various

            16    worthy charities and other non-profit organizations, and

            17    it's led to a little bit of alphabet soup.

            18                As you can see, they've got a very nice logo

            19    supporting CFCs, and the reason I put this up is I was

            20    preparing this talk the other morning, and I had gone down

            21    to the cafeteria and was riding up with a woman who had an

            22    Egg McMuffin-type sandwich in a styrofoam box, and on the

            23    top of it, it said, "No CFCs," and she saw the CFC part of

            24    it only.  I guess she didn't see the word "no," and she

            25    said, "You know, they're getting this CFC logo on

                                                                           35

             1    everything."  So she was very impressed with that.  But it

             2    can lead to some confusion.

             3                I did want to just before I talk a little bit

             4    about the FDA history, I did want to talk briefly about why

             5    this is an issue for the FDA because I think some of the

             6    public comments that we received to our advanced notice of

             7    proposed rulemaking reflected some very genuine concern but

             8    some misunderstandings about the role of CFCs in inhalers,

             9    and in fact in other products as well as Erin Birgfeld

            10    mentioned.

            11                Consumer aerosols have not had CFCs in them for

            12    over 20 years.  So we are talking about the last

            13    substantive use of newly-produced CFCs in the United

            14    States, and in fact, it's important to realize for those

            15    who don't know it that the formulation within a CFC-driven

            16    MDI inhaler is almost all, for practical purposes almost

            17    all CFCs.

            18                So the drug substance that we're talking about,

            19    most of them are in the microgram quantities.  So we're

            20    really talking about a spray coming out of these that is 95

            21    percent, if not more, and in some cases more like 99

            22    percent, CFCs, and because one of their good properties is

            23    they're pretty inert, other than how they act up in the

            24    stratosphere, they are rapidly taken in to the lungs

            25    through inspiration and then rapidly excreted or exhaled.

                                                                           36

             1                So in fact, for all intents and purposes,

             2    everything that comes out of a CFC MDI is rapidly released

             3    into the atmosphere.  So one of the, I think, common

             4    misconceptions amongst the public were that either there

             5    was not a lot of CFCs in these inhalers to begin with or

             6    that the body somehow took the CFCs up, and they were not

             7    released into the atmosphere, particularly if you used a

             8    closed-mouth technique.

             9                Well, I think the ozone science was fairly

            10    young when the FDA joined other arms of the government, and

            11    in fact other public interest groups, in recognizing the

            12    dangers that the emerging ozone science represented, and I

            13    think some of the very early work that's subsequently led

            14    to Nobel Prizes was published in the '73-'74 range, and by

            15    1978, the FDA had already published a federal regulation in

            16    final form that stated that CFC-containing products that

            17    FDA regulated in any food, drug, device or cosmetic would

            18    be considered misbranded or adulterated, unless it was

            19    deemed essential.

            20                For the most part, these products that were

            21    deemed essential were products for inhalation for the

            22    treatment of asthma and chronic obstructive pulmonary

            23    diseases and other diseases where bronchospasm is a part of

            24    the pathophysiology, and the determination of essentiality

            25    was based on no technically feasible alternatives, that it

                                                                           37

             1    provided a substantial health benefit, and it actually

             2    allowed for environmental benefit, although I'm not sure I

             3    understand from 20 years on what they meant by that.

             4                But in any case, it provided a substantial

             5    public health benefit, and that the release of CFC were

             6    either small or justified given the public health benefit,

             7    and over the years, there was an original listing under

             8    2.125, Part E, that had the essential use categories, and

             9    over the years, new additions were added through petitions

            10    and notice and comment rulemaking.

            11                In other words, the agency would put out a

            12    proposal that a new classification be added to the

            13    essential uses.  Public comment was received, and then the

            14    agency proceeded accordingly.

            15                The preamble to the final rule to 2.125 back in

            16    1978 made mention to the fact that these essential use

            17    listings were considered to be temporary.  Everybody, I

            18    think, felt that at some point in the future, reasonable

            19    alternatives would exist, so that these products would no

            20    longer meet the essential use criteria by which they were

            21    added to the list.

            22                However, despite that intention that these

            23    listings be temporary, there was no formal removal process

            24    that was put into that regulation, and I think Dr. Jenkins

            25    did a very nice job of bringing people through some of the

                                                                           38

             1    background as it relates to the FDA's role in all this, but

             2    clearly by the mid-1990s, particularly as some of the

             3    alternative products were in the latter stages of testing,

             4    it became clear that FDA needed to take a more active role

             5    in the U.S. transition away from CFC use in medical

             6    products, not perhaps as much -- and again not to get

             7    confused about us accelerating the phaseout, so we were not

             8    taking an active role to accelerate it, but to be

             9    responsive and to fulfill our mandate under both the Clean

            10    Air Act and the Food, Drug and Cosmetic Act.

            11                Basically, as we moved forward, as we

            12    envisioned being a part of this, the U.S. transition away

            13    from CFC use, and in fact ozone-depleting substance use, we

            14    saw a role for the FDA in the overall transition that was

            15    as follows.

            16                We thought as time went on, that we needed to

            17    define acceptable alternatives to CFC-based MDIs.  I think

            18    it's fairly clear that the alternative propelled MDIs, such

            19    as the approved albuterol sulfate using HFAs or

            20    hydrofluoroalkanes, also you'll see those mentioned as

            21    HFCs, hydrofluorocarbons, that those would be, I think, a

            22    pretty neat fit as an alternative product.

            23                They act very much in the similar fashion to

            24    the CFC MDIs.  There are some differences, but obviously

            25    they're a very similar product.

                                                                           39

             1                We at least thought that for some patients, if

             2    not all, that multidose dry-powder inhalers might fulfill

             3    the role of being an alternative in terms of convenience

             4    and effectiveness of the product.

             5                I think we're fully cognizant as are others

             6    that dry-powder inhalers in fact may have some down sides

             7    in some patients, particularly these, by and large, are

             8    patient-driven devices.  So people with very low flow rates

             9    may in fact have problems generating sufficient flow rates

            10    on some devices to allow for full delivery, that being, for

            11    instance, perhaps very young patients or patients with very

            12    severe airways disease.

            13                The other potential problem with dry-powder

            14    inhalers is since many of them contain lactose as carriers,

            15    they tend to be somewhat sensitive to moisture.  So the

            16    manufacturers need to design ways to protect their products

            17    from moisture, and in some cases, once they're taken out of

            18    their overwraps, they can be stable for reasonably short

            19    periods of time compared to alternative propelled MDIs. 

            20    But again the manufacturers are aware of this and

            21    responding to that.

            22                But there are some limitations as far as the

            23    neat fit of multidose dry-powder inhalers to MDIs, and then

            24    there are other products that are in stages of development

            25    that may in fact represent reasonable alternatives to MDIs,

                                                                           40

             1    and I won't spend a lot of time on those, but I think the

             2    agency's fully aware that other products may be coming, and

             3    that other products may in fact serve a very useful role as

             4    alternatives as the technologies are perfected and

             5    approved.

             6                We certainly saw it as the agency's role to

             7    monitor the availability of these alternatives for each

             8    drug product and class as they're developed, and then

             9    clearly to define criteria that would have to be met to

            10    make determinations that products that are already listed

            11    as essential under our regulations and therefore referred

            12    to by the Clean Air Act regulations, a way to remove those

            13    when they were no longer truly essential uses.

            14                To do that, because, as I mentioned, the

            15    original 2.125, our original regulation involving CFCs in

            16    FDA-regulated products, did not have a clear means for

            17    removing essential use listings, we needed to modify our

            18    regulations that confer essentiality on the CFC products to

            19    allow for them to be, if you will, taken off the list as it

            20    is clear that they meet reasonable criteria for being no

            21    longer essential.

            22                Of course, as those products became available

            23    and proved to be medically acceptable, we would then need

            24    to go ahead and modify our essential use listing.

            25                We wanted to do all this in a manner that

                                                                           41

             1    allows adequate time for public input, and certainly

             2    involving the advisory committee where appropriate, such as

             3    today, and again to work with EPA and other interest groups

             4    to coordinate the U.S. efforts.

             5                The overall transition away from ozone-

             6    depleting substances is larger certainly than the FDA, and

             7    I think there is certainly other components of the

             8    government beyond both FDA and EPA that need to be brought

             9    in and other components of the public in fact.

            10                Just for those who don't live and breathe

            11    regulatory processes, I thought I'd take a minute to go

            12    through the rulemaking procedures that FDA and other

            13    regulatory bodies go through.

            14                The FDA is set up and basically has its

            15    authority through the Food, Drug and Cosmetic Act, but

            16    that, as broad as that is and as detailed as it is to read,

            17    it is in fact just a framework for, in many ways, for how

            18    we are supposed to act through our regulations, and it is

            19    through the regulations that we implement that authority in

            20    a way that is binding both on us and on the public.

            21                So the FDA and the CA Act is sort of the

            22    overall umbrella, and the regulations provide a more

            23    detailed manner for which we and the public are meant to

            24    proceed, and the usual pathway for creating a new

            25    regulation is to publish it in the Federal Register in the

                                                                           42

             1    form of a proposed rule which means that we put out some of

             2    our background thinking, and in fact what we call a

             3    codified section, which contains the actual rule itself.

             4                We then allow for a comment period, generally

             5    in the 60-to-90-day range, for the public to respond to it,

             6    and once we get those comments back, it's considered then,

             7    thought about any changes that would need to be made to the

             8    proposed rule.  We then proceed to publish a final rule

             9    which specifically answers the comments received during the

            10    comment period.

            11                Because we anticipated that this was an

            12    important action from the public health standpoint, and

            13    that there might be some controversy to it, and in fact

            14    because we were really just taking our first best effort at

            15    this, the FDA chose the additional step in this case of

            16    what's called an advanced notice of proposed rulemaking,

            17    which in essence kind of repeats the cycle, so that you do

            18    an advanced notice of proposed rulemaking, comment period,

            19    then you put out the proposed rule, another comment period

            20    which we're in now, and then the final rule.

            21                We did this as a way to allow for broad public

            22    input prior to issuing any proposed rule in a manner that

            23    we perceived would be the most fair and equitable.

            24                So again the advanced notice of proposed

            25    rulemaking or what I shall refer to as the ANPR was the

                                                                           43

             1    initial proposal for modifying the FDA regulations to allow

             2    for the removal of the essential use status of products

             3    currently listed in our regulations when appropriate, and

             4    that was published for comment on March 7th, 1997.

             5                To go through it very briefly as far as what

             6    the codified section of that announcement notice of

             7    proposed rulemaking said, we proposed four criteria that we

             8    would need to consider and that would need to be fulfilled

             9    for a CFC product to be no longer considered essential.

            10                We, first of all, wanted there to be adequate

            11    alternatives, and I will get more into this in a minute,

            12    but we thought there would be a variety of ways that one

            13    could state whether there were adequate alternatives and

            14    not moiety-by-moiety, a class approach or a hybrid of the

            15    two.

            16                We certainly would want to know that there are

            17    adequate production capabilities and supplies of the

            18    alternatives to meet the needs of the population that

            19    medically depend on these products.

            20                We'd want to know that there's adequate patient

            21    acceptance.  I think that it is important to realize, and

            22    I'm sure most of you all do, that the drug approval process

            23    does assure that the product is sufficiently safe and

            24    effective for its intended use, but that's rather different

            25    from knowing that in millions of patients, it will provide

                                                                           44

             1    them the same kind of benefit or use as the current CFC MDI

             2    products.

             3                And then, finally, we had proposed in that ANPR

             4    that if those top three criteria were met, that we felt

             5    sure there were adequate alternatives, there were adequate

             6    production capabilities and supplies, and there was

             7    evidence of adequate patient acceptance, that we would

             8    presume that all important subgroups were served, unless we

             9    had evidence to the contrary.

            10                Let me spend a little bit of time talking about

            11    the ways one might define adequate alternatives.  The first

            12    one up here was not in our ANPR.  We did not consider it,

            13    and I'm not sure that it's actually a very viable way to

            14    proceed from the United States' perspective, but that would

            15    be a product-by-product basis.  So that if a particular

            16    product, and I will just use one, like let's say Ventolin

            17    were reformulated, that you would only take away the

            18    essential use listing for the Ventolin CFC if there were a

            19    Ventolin HFA available, and you would not consider any

            20    other drugs containing the same moiety, albuterol, or other

            21    drugs in that therapeutic class.

            22                This seemed to have particular problems in that

            23    it in many ways seemed to reward manufacturers who were not

            24    moving forward with the transition process and would leave

            25    a lot of products on the market for perhaps a longer period

                                                                           45

             1    of time than really justified from a public health

             2    perspective.

             3                It also was quite different from the way the

             4    current regulation listed essential uses.  It didn't list

             5    products, it listed moieties in essence, or in some cases

             6    therapeutic classes.

             7                Then three ways that the ANPR proposed we do go

             8    would be the moiety-by-moiety approach, which means in

             9    essence drug substance-by-drug substance approach.  The

            10    reason we have to use the word "moiety" there is for FDA

            11    purposes.  Albuterol and albuterol sulfate are technically

            12    different drug substances, although they are the same

            13    active moiety, and we do consider albuterol and albuterol

            14    sulfate to be essentially the same for these purposes.  So

            15    I'm going to be using the term "moiety" here, but you can

            16    take that to mean the same as a drug substance.

            17                So that would mean that when there was

            18    sufficient alternatives for any one drug moiety, for

            19    instance beclomethasone, that you would then invoke the

            20    other criteria and then make the determination whether that

            21    use of CFCs was still essential or not, regardless of what

            22    else was going on in that therapeutic class.

            23                So if we were talking about the case of

            24    beclomethasone, you would ignore what was happening with

            25    any of the others, with fluticasone or with triamcinolone,

                                                                           46

             1    any of the other inhaled corticosteroids.

             2                Partly as a response to the way the current

             3    regulations are modified and partly for reasons of feeling

             4    like there can be some crossover use within well-defined

             5    classes, we also proposed that we might take a therapeutic

             6    class approach.

             7                In essence, there were three classes of

             8    therapies listed in our current regulations or there are,

             9    and those would be in more modern wording than was

            10    published in 1978, the inhaled corticosteroids, the

            11    intranasal corticosteroids, and then the bronchodilators or

            12    the adrenergic bronchodilators.

            13                So we thought particularly for the inhaled

            14    corticosteroids and the shorter beta agonists, that one way

            15    to potentially proceed would be to do this on a therapeutic

            16    class approach.

            17                In other words, if you were to take the inhaled

            18    corticosteroids, when you had products representing at

            19    least two of the moieties within that class, where there

            20    were at least three distinct products, two of which had to

            21    be MDIs, we thought that it might be reasonable at that

            22    point to invoke the other criteria, and if those were all

            23    met, then to take away the essential use listing for the

            24    entire class.

            25                One thing that the therapeutic class approach

                                                                           47

             1    does, at least for these two distinct categories, is it

             2    allows for dealing with some products that might have

             3    reasonably small markets and where the manufacturers were

             4    not perhaps interested in reformulating for their own

             5    purposes, for either economic or other considerations.

             6                It would be a way to assure that the -- when it

             7    made sense to remove the essential use listing for the

             8    entire class, that that would happen, and some products,

             9    even if they were not reformulated, might lose their

            10    essential use status.

            11                Finally, laying out the moiety-by-moiety

            12    approach and the therapeutic class approach, it also seemed

            13    reasonable to offer the alternative of what we would call

            14    the hybrid approach, which is to do the moiety-by-moiety

            15    approach on every drug substance that's currently included

            16    in the essential use listing, but when the therapeutic

            17    class criteria was met, we would also act on that.

            18                Again we had the advisory committee meeting

            19    regarding the ANPR on April 11th, 1997.  As Dr. Jenkins

            20    mentioned this morning, we had substantial interest in

            21    public comments at that point.  We had about 24 or 25

            22    people offer their suggestions or comments to the agency as

            23    well as receiving important advisory committee input, and

            24    we also were quite successful in terms of gaining public

            25    comments.  We in fact received over 9,800 or in the range

                                                                           48

             1    of 9,800 comments, which is one of the larger numbers of

             2    comments to the dockets, certainly in the Center for Drugs'

             3    history.  So it was quite a vigorous response.

             4                Many of these were patient-generated comments,

             5    and while reflecting very real concerns on the part of the

             6    patients, they often represented somewhat incomplete

             7    information or understanding of what we were actually

             8    proposing at that point.

             9                In addition to these patient-generated

            10    comments, we also received very broad input from various

            11    professional organizations, from the regulated industry,

            12    patient advocacy groups, environmental groups, and other

            13    important constituencies in this matter.

            14                The advanced notice of proposed rulemaking also

            15    led to several congressional hearings, and we certainly

            16    received input from other components of the government in

            17    terms of considering this.

            18                Once the docket closed, the CFC work group set

            19    about the rather large task of reviewing each and every

            20    comment because we did review each and every comment and

            21    responding accordingly, and we tended to have some baskets

            22    of comments that we thought, like many of the patient

            23    comments, represented very real concerns and things we

            24    should answer because they tended to form themes in a

            25    thematical way, and then we had rather more substantive

                                                                           49

             1    comments that were from again patient advocacy groups,

             2    professional organizations, the industry and so on, and I

             3    think to sum up some of the substantive opposition that we

             4    received, there was substantial concern about our proposal

             5    to operate or to proceed in using a therapeutic class

             6    approach.

             7                I think many people or many commenters saw this

             8    as being too restrictive, as being anticompetitive, and in

             9    fact I think some people saw it as being antipatient, that

            10    if a patient were doing well on something that was not

            11    being reformulated but, you know, other things in the class

            12    had met the criteria, and the criteria in addition were

            13    met, that patient would be subjected to perhaps losing

            14    their inhaler at some future date despite them not being a

            15    direct alternative.

            16                I'm not going to spend a lot of time on this,

            17    but there was some concern about the misbranded and

            18    adulterated provision which exists in the current

            19    regulations, where if a product was no longer considered

            20    essential, it would be considered misbranded and

            21    adulterated under the Food, Drug and Cosmetic Act, which is

            22    sort of the most Draconian wording of the FD&C Act and

            23    basically makes it illegal under FDA law to sell the

            24    product.

            25                I think these commenters felt like perhaps we

                                                                           50

             1    would make the determination better under the Clean Air

             2    Act.

             3                As Dr. Jenkins earlier mentioned, there was

             4    concerns about accelerating the phaseout, and I think, as

             5    Dr. Jenkins said, we certainly want to be responsive to the

             6    changing environment.  Maybe I shouldn't use the word

             7    "environment," but responsive to the transition as it goes

             8    on, but we do certainly see as the FDA, as our primary

             9    mission, protecting the health of the patients who rely on

            10    these products throughout the transition process and not

            11    accelerating the phaseout.

            12                There have been concerns raised about the

            13    patient access and cost concerns as the transition

            14    continues, and, finally, there were concerns about how some

            15    of the rather general criteria that we laid out for

            16    consideration when products were no longer essential, how

            17    those would be specifically evaluated.

            18                I'm going to pause there and turn the

            19    microphone over to Ms. Leanne Cusumano from our Regulatory

            20    Policy staff.  I think we'll save questions as far as

            21    Leanne's presentation and my presentation until after

            22    Leanne's presentation.

            23                MS. CUSUMANO:  I'm Leanne Cusumano.  I'm with

            24    CDER's Regulatory Policy.  I'm a regulatory counsel there,

            25    and for those who've seen the proposed rule, my name's

                                                                           51

             1    listed there in the contact section, and I worked with Dr.

             2    Meyer and the CFC working group to review all of the

             3    comments and to be responsive and to put together the

             4    proposed rule, and Bob brought us to the present and where

             5    we are, and you'll see a little bit of a development of how

             6    we ended up with the proposed rule.

             7                I'm going to talk about three major provisions

             8    of the proposed rule.  First, how we propose to eliminate

             9    essential uses; second, the possibility of adding new

            10    essential uses; and, third, what kind of enforcement will

            11    be taken under the proposed rule.

            12                First, and I put this first because I think

            13    it's what most people are interested in, the question of

            14    how are we going to eliminate essential uses under the

            15    proposed rule, and Bob went through the three alternatives

            16    that we've laid out in the advanced notice of proposed

            17    rulemaking, and based on the comments and based on

            18    consideration of how this would work best, we selected the

            19    moiety-by-moiety approach, which, as Bob had explained, is

            20    drug substance-by-drug substance.  Basically we have a

            21    technical definition in our regulations for moiety.

            22                We talk about supplies, post-marketing data and

            23    how patients are served, and I'm going to step through each

            24    of these step-by-step.

            25                First, in addition to having moiety-by-moiety,

                                                                           52

             1    we are also looking at products delivered by the same route

             2    of administration with the same indication and

             3    approximately the same level of convenience of use.  These

             4    are all factors that patients have expressed as being very

             5    important to them in their ability to use their asthma or

             6    COPD treatments adequately.

             7                In terms of supplies, we want to have supplies

             8    and production capacity that exists or will exist at levels

             9    sufficient to meet patient needs.  It's no good if an

            10    alternative exists, and the patients are not able to get

            11    it.  So we want to make sure the manufacturers are able to

            12    get the product to the patient in adequate levels.

            13                Third, we want to be able to look at at least

            14    one year of United States post-marketing data, and although

            15    we're interested in looking at foreign data, we also want

            16    to see the U.S. data because U.S. populations are

            17    different, our health care system is different, the foreign

            18    data would be supportive, but, in particular, we're

            19    interested in U.S. data, and one of the specific things

            20    that we asked for in the proposed rule was for people to

            21    tell us what kind of post-marketing data we should be

            22    looking at.

            23                We have some general ideas, but we're

            24    interested in hearing what other people think we need to

            25    look at, and, finally, how are patients served?  We want to

                                                                           53

             1    know that patients who medically require the ODS, the

             2    ozone-depleting substance product, the CFC MDI, are

             3    adequately served by available alternatives, and I put the

             4    word "all" in there because we're not looking just at

             5    necessarily the product containing the moiety that's

             6    replacing it but at the whole market of available

             7    alternatives, and again we asked for comments, for people

             8    to tell us how we can make this determination.

             9                Okay.  So we've got that list of things, of

            10    items.  Those four factors are what we're going to look at

            11    in determining whether we're going to eliminate an

            12    essential use.

            13                We also have three other factors that we are

            14    going to look at.  These are ors.  If any one of these four

            15    criteria are met, then we will put out a proposal to remove

            16    an essential use.  We talk about what's going to happen

            17    after January 1st, 2005, what happens if a product is no

            18    longer marketed in a CFC formulation, and then about nasal

            19    steroids, and let me walk through each of those.

            20                January 1st, 2005.  As both Erin and Dr. Meyer

            21    had said, the essential use exemptions were never meant to

            22    be permanent.  So the question is:  when are we going to

            23    accomplish the phaseout?  When is it going to happen? 

            24    Well, we don't know when it's going to happen because it's

            25    really very dependent on what products are in the pipeline,

                                                                           54

             1    but one of the things that we thought is, after a certain

             2    period of time, and in this case, we picked 2005, we would

             3    look at the products that are on the market that are still

             4    unreformulated, and we would say, okay, do we still need

             5    that unreformulated drug, and we would make that

             6    determination by looking at the original essential use

             7    criteria.

             8                Basically does it still meet those criteria,

             9    which are, there's still substantial technical barriers to

            10    reformulation.  Does that still exist?  Does the drug still

            11    provide an important public health benefit?  And is the

            12    release of the CFCs still warranted or not significant?

            13                If the answer to those questions are no, we can

            14    reformulate or there's no important public health benefit

            15    or the release is not warranted, then we would consult with

            16    an advisory committee in an open public meeting and say

            17    should we propose the removal of this product, even though

            18    it hasn't been reformulated?  So that's what the 2005 date

            19    is about, and again I emphasize this is an or.

            20                We can either go by the four criteria I talked

            21    about first, moiety-by-moiety, with the patient service and

            22    all those other things, or after 2005, we can do it this

            23    way.

            24                Now, what about if a drug is no longer

            25    marketed?  In the proposed rule, we are suggesting removal

                                                                           55

             1    of the essential use listings for products no longer

             2    marketed, and there's four products that are listed right

             3    now in our current regulations that are no longer marketed

             4    in a CFC formulation, and they're these four: 

             5    contraceptive vaginal foams, intrarectal hydrocortisone

             6    acetate, and I'm not going to describe polymycin beta

             7    sulfate-bacitracin zinc-neomycin sulfate soluble antibiotic

             8    powder without excipients, metered-dose nitroglycerin human

             9    drugs administered to the oral cavity.

            10                These are all for human use.  So we're

            11    proposing to remove these essential use listings.  The

            12    parties to the Montreal Protocol have not granted use of

            13    CFCs for these products in years, if ever, and they're not

            14    on the market in a CFC formulation.  So there's really no

            15    point in having them in our regulation.

            16                The other proposal that we are making is to

            17    remove the essential use listing for nasal steroids.  Why? 

            18    We're proposing that there are adequate alternatives out

            19    there without the CFC formulations.  Also, that there's

            20    widespread use of those alternatives, sufficient supply. 

            21    The manufacturers have been making them, and the patients

            22    have been able to get them, and again the parties to the

            23    Protocol have not allocated CFC use for these products

            24    ever.  So if they're being manufactured at all, they're

            25    being manufactured with pre-1996 chlorofluorocarbons. 

                                                                           56

             1    There's no new production of CFCs for these products.

             2                In the proposed rule, we asked specifically for

             3    comments on the timing of the removal of the essential use

             4    allocation for nasal steroids, and what we proposed is that

             5    one year from the date we finalized the rule is the date

             6    that the rule would go into effect.

             7                So you know, we're at the proposed rule stage,

             8    in the comment stage.  We have to read the comments, take

             9    them into account, publish a final rule, and one year from

            10    that date would be the date we would remove the essential

            11    use listing for nasal steroids.

            12                So those are the four ways we could remove an

            13    essential use from our regulation.  Either it meets those

            14    four initial criteria under the moiety-by-moiety approach,

            15    it's no longer marketed or after January 1st, 2005, the

            16    total market is sufficient to serve patients or with the

            17    nasal steroids, if they fall in the nasal steroid class.

            18                So how do we add new essential uses?  Well, we

            19    know that addition of a new essential use had better meet

            20    some pretty tough criteria because otherwise, they're not

            21    going to get CFCs for that year from the parties to the

            22    Protocol.

            23                So the criteria we look at, we're proposing to

            24    look at would be that there are substantial technical

            25    barriers to formulating the product in a non-CFC or a non-

                                                                           57

             1    ozone-depleting substance formulation, that this product

             2    provides an unavailable important public health benefit,

             3    that you can't get it from some other non-ODS drug, and

             4    that either the release of the ozone-depleting substance is

             5    not significant or that it's warranted in light of the

             6    public health benefit and kind of the theoretical example

             7    that we toss around is, well, what if we found a cure for

             8    AIDS that could only be formulated in CFC use?  You know,

             9    you'd want to have some kind of mechanism in place for that

            10    kind of eventuality.

            11                So let's say we go ahead and make all these

            12    changes.  We implement the proposed rule.  How's this going

            13    to work?  Right now, in our regulation, we have adulterated

            14    and misbranded provisions, and that's been in that

            15    regulation since the 1970s, like Bob talked about, but the

            16    primary enforcement for this would be under the Clean Air

            17    Act, and EPA regulates products from all around the

            18    country, all kinds of different agencies.

            19                Even though they don't regulate the product

            20    itself because it deals with an environmental issue, they

            21    have the authority under the Clean Air Act to take

            22    enforcement action against the product if it doesn't comply

            23    with the Clean Air Act, and that would be the primary

            24    means.

            25                What does that mean in simple speak?  It means

                                                                           58

             1    that is you're not an essential use in FDA's regs, you

             2    would not be able to market your product in the United

             3    States anymore under the Clean Air Act.

             4                As Bob said, we got quite a number of comments

             5    on the advanced notice of proposed rulemaking, kind of woke

             6    us up and said we need to get more information out there,

             7    so people know what we're doing and have accurate

             8    information.

             9                One of the things we did was develop a web site

            10    at this address.  We've also brought it to the advisory

            11    committee.  We want people to have the opportunity to

            12    comment.  We had a conference call with interest groups on

            13    the date the proposed rule was published, September 1st,

            14    1999, to make sure that they and their constituents know

            15    what we're doing and know accurately what we're doing, and

            16    also we worked with them at their request to help them in

            17    writing articles or in any way that we can in disseminating

            18    accurate information.

            19                So far, and I have to update this because on

            20    Friday, I got one more, we've gotten four comments on the

            21    proposed rule.  Let me tell you the comment period closes

            22    on November 30th, and in my experience, we routinely get

            23    comments on the last day, particularly from big companies

            24    or interest groups, that kind of thing.  So I'm sure we

            25    will be getting more, but so far, we've gotten four.  One,

                                                                           59

             1    parents of an asthmatic, two doctors, and the other one was

             2    from the Service Employees International Union, a branch of

             3    AFL-CIO.

             4                Overall, the comments have been very positive. 

             5    There is still concern about the cost of replacement

             6    products.  A statement that switches can be difficult,

             7    which we all know, and that's part of the reason that we

             8    are so involved in public outreach and public education.

             9                So I'm more than happy to answer any questions. 

            10    I'm sure Bob is, too.

            11                DR. SESSLER:  Questions?

            12                DR. GROSS:  How was the date 2005 arrived at? 

            13    Was that arbitrary?  I'm just wondering is that too far in

            14    the future or maybe not far enough?  Was there a response

            15    reaction by industry?

            16                MS. CUSUMANO:  I haven't heard one yet.  I

            17    think it was pretty arbitrary.  It's not necessarily that

            18    on January 1st, 2005, we will do this, but that we can, and

            19    we won't do it before that.

            20                I think Bob wanted to add to that.  I'm sorry.

            21                DR. MEYER:  Yes, I did want to comment on that

            22    because for folks who are more intimately involved in the

            23    Montreal Protocol process, there's also been some language

            24    through some of their technical and economic assessment

            25    panels and so on about most of the transition being

                                                                           60

             1    complete in developed countries by 2005, and we didn't

             2    choose 2005 to marry to that date, but we were trying to

             3    project from the United States standpoint when might we

             4    have enough products to start thinking about some of these

             5    other products that remain on the essential use listing but

             6    really are not being reformulated, may not be still meeting

             7    the criteria for essentiality, and it happens to coincide

             8    by that date, but it wasn't meant to marry to it because I

             9    think, quite frankly, for the United States, 2005 will be

            10    sort of mid-transition, not late transition.

            11                I think that we'll still have some use of CFCs

            12    at that time point, and again as Leanne said, it's really

            13    important to understand.  From that day onward, we would

            14    have that pathway for us, but it's not like we're going to

            15    be convening this group on January 1st, 2005, to wipe out

            16    the rest of the essential use listings.

            17                DR. GROSS:  But you didn't get a reply from

            18    industry?

            19                DR. MEYER:  We haven't heard any yet.  At least

            20    we've got public comments coming today.

            21                DR. FORD:  One of the criteria for

            22    determination of non-essentiality is the presumption that

            23    all subgroups, including young children and people with

            24    very low air flow, would be served.

            25                Now, what is the process for obtaining the

                                                                           61

             1    evidence that in fact that is the case?  Because I believe

             2    in your presentation, you said unless there's evidence to

             3    the contrary.  How will you obtain the evidence, and how

             4    will you evaluate it?

             5                DR. MEYER:  Yes.  I think that's an important

             6    point because some of what we're proposing here, as Leanne

             7    spoke to and as I alluded to as well, are still fairly

             8    general ideas, and I think the -- particularly what's now

             9    come to be the criteria that patients' needs are met, that

            10    those patients who medically rely on these products, for us

            11    to know that their needs are being met.

            12                We have some ideas on that, but we're not

            13    entirely set on a pathway for us to evaluate that, and

            14    that's actually something we'd be very interested in the

            15    committee's opinion on.

            16                DR. JOAD:  In your original class rules, when

            17    you did it by class, you required that two of the

            18    alternatives be MDIs, but then when you went to the moiety-

            19    by-moiety, you don't have anything about that.

            20                Is there a reason why you didn't include that

            21    or were you thinking of including that in your hybrid? 

            22    What happened with that?

            23                MS. CUSUMANO:  I think that, and we say this in

            24    the proposed rule, that we expect that generally, the ratio

            25    will be MDI for MDI, but technology's progressing, and

                                                                           62

             1    there may be alternatives coming that are better than MDIs

             2    or just as good as MDIs, and we didn't want to lock in to

             3    requiring an MDI when there might be something even better.

             4                DR. NIEDERMAN:  If you take the moiety-by-

             5    moiety approach, does that discourage developing

             6    alternatives for any patented moiety?  In other words,

             7    what's the incentive for somebody who has a patent on a

             8    specific moiety, nobody else can produce it, they have an

             9    MDI?  If the criteria is that there has to be a replacement

            10    for it, what's the incentive to develop that replacement

            11    since there's no competition?

            12                MS. CUSUMANO:  I mean, that's true generally,

            13    that any time you've got --

            14                DR. NIEDERMAN:  And there's pressure to

            15    develop.

            16                MS. CUSUMANO:  I don't know if there is more

            17    pressure in the class approach than there is with this

            18    because people know that the phaseout's coming.  Either

            19    you're going to develop it or eventually --

            20                DR. NIEDERMAN:  But you're allowing -- I mean,

            21    I can conceive that if I have a unique and highly effective

            22    product, I'm going to get the essential exemption, and

            23    there's absolutely no incentive to go through the cost in

            24    developing an alternative, as long as the moiety approach

            25    is used.

                                                                           63

             1                DR. MEYER:  I guess I'd say two things to that. 

             2    I think that it is clear, and it's important, that we

             3    emphasize repeatedly, along with the EPA, that these

             4    essential uses for CFCs are on a year-by-year basis now,

             5    and that they are intended to eventually go away.  So

             6    hopefully at least the manufacturers have that knowledge.

             7                But I guess one thing that we realized about

             8    the moiety-by-moiety approach, although it clearly was --

             9    the message we got was that was the best way to proceed. 

            10    It allows for -- well, it does not allow, I should say, for

            11    sort of a neat cleanup of these products that aren't being

            12    reformulated, particularly sort of the ones that have the

            13    very small market, and there really is not an economic

            14    advantage to a manufacturer to reformulate it, and that's

            15    really why we came up with this approach, that at some date

            16    in the future, we would need to start looking at the market

            17    and all the available treatments and see whether the public

            18    were being served, even if that particular moiety wasn't

            19    being reformulated.

            20                DR. NIEDERMAN:  But I think the danger is if

            21    you have one of these products that has a big market, and

            22    again as long as it's a unique product without competition,

            23    and it has a big market, it's probably even less reason for

            24    them to reformulate it.

            25                DR. MEYER:  Yes.  I think the other thing that

                                                                           64

             1    is difficult in this kind of forum to talk about is that we

             2    are writing this with a fair amount of foreknowledge about

             3    what is being reformulated and what's not.

             4                We know the pipeline pretty well.  So I guess

             5    it's always so uncomfortable as a regulatory body to say

             6    trust us on this, but we did write this with a reasonable

             7    knowledge of what the pipeline is.

             8                DR. SESSLER:  Dr. Vollmer, you were waiting

             9    patiently earlier.

            10                DR. VOLLMER:  I think it's been answered.

            11                DR. SESSLER:  If I may ask, cost is certainly

            12    something that's an important issue and obviously ties into

            13    Dr. Niederman's question.

            14                What are the strategies to address that in

            15    terms of older products that may be reasonable substitutes

            16    and yet optimal, particularly within the next five or six

            17    years?

            18                MS. CUSUMANO:  One of the things that industry

            19    has told us is that for name brand products, they expect

            20    the replacements to be about the same price as other name

            21    brand products.

            22                So if you've got a name brand and a name brand,

            23    you're talking about approximately the same price.  So that

            24    wouldn't be a cost problem.  The only product that has a

            25    generic out there right now is albuterol, and that's a

                                                                           65

             1    question, because the generic is less than the innovator

             2    product.  How is that going to affect the market?  I don't

             3    know if we have a good answer for that yet.

             4                DR. MEYER:  No.  I think another thing that we

             5    would welcome committee thoughts on is how much of a

             6    barrier to access is cost.

             7                DR. SESSLER:  Right.

             8                DR. MEYER:  I think that that's an important

             9    issue for us to consider.  So I'd very much welcome

            10    committee comments on that.

            11                DR. NIEDERMAN:  Is the HFA propellant patented

            12    or is that available widely?

            13                MS. CUSUMANO:  It is patented.

            14                DR. NIEDERMAN:  So again, you could not get

            15    generic albuterol HFA?

            16                MS. CUSUMANO:  Not right now, you can't.  But

            17    there's no barrier to innovation.

            18                DR. GROSS:  Can I ask a question about non-

            19    safety or hazards of alternatives?  It occurs to me that

            20    for the first 20 years or so of CFC use, they were thought

            21    to be ideal agents with no medical problems, and

            22    environmental problems weren't known about at that time.

            23                But what do we know about HFAs or other

            24    alternatives in terms of these long-term possible risks?  I

            25    mean, obviously I understand that right now, they're

                                                                           66

             1    believed to be safe environmentally, unless I'm wrong, but

             2    I mean, how can we be sure that the alternatives that are

             3    being developed don't actually have some worse impact than

             4    CFCs?

             5                I mean, you know, I understand this is very

             6    difficult to predict, but one doesn't want to jump out of

             7    the frying pan and into the fire.

             8                MS. CUSUMANO:  And I can answer part of that,

             9    and maybe I'll ask Bob to answer after, too.

            10                First, part of the development program is we're

            11    using the same moieties that we've been using for years and

            12    years.  So then you're just talking about the interaction

            13    between whatever propellant you're using and the product,

            14    and there has been extensive testing on HFA.

            15                I know IPAC's been involved in it.  We've got

            16    quite a lot of data, much more data than we ever got on

            17    CFCs before we started marketing them is my understanding,

            18    and as far as environmental impacts, I think we know that

            19    HFA has a very small impact, and it's something that's

            20    considered acceptable.

            21                So I think we're at a better knowledge level

            22    than we were with CFCs.

            23                DR. MEYER:  Yes.  Let me pick up on that, and

            24    I'll invite the EPA to comment as well.

            25                As Leanne said, the testing for the HFA was in

                                                                           67

             1    fact very extensive, and in fact, the pre-clinical testing

             2    in terms of the toxicology and so on was as extensive as

             3    what would be done for many new drug products.  In fact,

             4    more extensive than what might be done for some new product

             5    drugs.

             6                I think the FDA felt that was very reasonable

             7    given the type of chronic use that these get, and the fact

             8    that they represent such a large proportion of the

             9    formulation.

            10                As far as the HFAs go, they have no ozone-

            11    depleting potential at all.  So they're very good in that

            12    standpoint.  They do have some global warming potential,

            13    and in fact, HFAs are amongst the gases that are proposed

            14    to be controlled under what's called the Kyoto Protocol or

            15    basically the Greenhouse Gas Protocol.

            16                But there's some important things to bear in

            17    mind there.  One is that the HFAs are actually less potent

            18    global warmers than the CFC alternative or the CFCS they're

            19    meant to replace.  So in fact, from the global warming

            20    standpoint, they're a better trade-off because the CFCs

            21    have more potency.

            22                The other thing is the difference between the

            23    Kyoto Protocol and the Montreal Protocol is quite

            24    substantial in terms of the Kyoto Protocol is talking about

            25    controlling greenhouse gases and not eliminating them, and

                                                                           68

             1    so the Montreal Protocol is talking about the elimination

             2    of ozone-depleting substances.  The Kyoto Protocol is

             3    talking about an overall control, and I should point out

             4    that, to my knowledge, it's not been ratified by the United

             5    States, but the countries have the option of how they sort

             6    of get to their target.

             7                So if we can do that by trading off carbon

             8    dioxide for HFAs, it does allow for sort of a neat

             9    balancing, and so that, as far as I'm aware, is the only

            10    known consequence right now from the environmental

            11    standpoint of HFAs, and I don't see it as a major hurdle

            12    for the future.

            13                I think people realize that this technology,

            14    the HFA MDIs, is very important, that there's been a lot of 

            15    industry outlay of capital to develop them, and I think

            16    that because of the way the Kyoto Protocol's structured,

            17    even if it were ratified, it wouldn't put the MDIs at risk. 

            18    I'd welcome EPA comments on that.

            19                MR. COHEN:  I don't think there's anything that

            20    we can add to what Bob just said.  There was also some

            21    interest in these HFAs or HFCs as a risk in terms of

            22    refrigerant use, and there have been other clinical studies

            23    looking at exposure to folks.  I think they were conducted

            24    in Europe recently, in the Netherlands, and those turned

            25    out to be clean.

                                                                           69

             1                So we're very comfortable with any health risks

             2    associated with these --

             3                DR. GROSS:  Are you going to be monitoring that

             4    in the future?  The risks, possible risks using

             5    alternatives?  I mean, is that something you follow year-

             6    by-year and make sure that there isn't some kind of hazard

             7    that's becoming apparent or having approved an alternative

             8    like HFA, you just say okay, that's it, wait until

             9    something shows up?

            10                DR. MEYER:  Well, I think from the FDA's

            11    standpoint, that we feel quite comfortable with the pre-

            12    clinical testing that we have and in fact the human testing

            13    that we have.

            14                I think sort of in the back of our minds as far

            15    as these formulations overall, including the HFAs, part of

            16    the reason we wouldn't just make a determination that it's

            17    a particular alternatively-propelled MDI as a suitable

            18    alternative the day it's approved is because there are

            19    questions about how patients will react to the formulation

            20    overall, and I think that we will be interested in

            21    monitoring that in total, and I don't think we have a lot

            22    of concerns about the HFA health because we've seen some

            23    very good data about their safety, and they are reasonably

            24    inert compounds.

            25                But we have the overall question about how

                                                                           70

             1    these do in the wider use, and that's at least a small part

             2    of that.

             3                DR. SESSLER:  Did that answer your question,

             4    Dr. Gross?  Did you have EPA implications with your

             5    question as well?

             6                DR. GROSS:  Are there any?

             7                MR. COHEN:  I think, as Bob said, we're pretty

             8    comfortable with the completeness of the data that's been

             9    collected so far.  There have been no reports, no anecdotal

            10    indications that any exposure to HFAs in other uses have

            11    caused any problems.

            12                DR. MEYER:  Actually, let me make one more

            13    point on that just before we turn to the next question, and

            14    that is that, as Leanne said, there was not this level of

            15    testing when CFCs were first used, and in fact, in some of

            16    the head-to-head toxicology testing, HFAs also looked like

            17    they had an advantage over CFCs.  Particularly some of the

            18    CFCs at very high exposure levels caused cardiac

            19    arrhythmias, and the HFAs seem to have less propensity than

            20    at least one of the CFC propellants in terms of that.

            21                DR. FINK:  With at least one product, albuterol

            22    HFA, it's been available for years.  You said it had about

            23    8 to 10 percent of the market.  It seems like voluntary

            24    application of these rules may not be adequate to drive the

            25    market, that there may need to be some sort of tax or

                                                                           71

             1    disincentive on CFC products because if you take the

             2    example of albuterol, where there is an acceptable

             3    reformulated product available, it's not being prescribed

             4    and used, even though studies have shown it may be superior

             5    to the CFC-containing inhalers in terms of clinical

             6    efficacy.

             7                MS. CUSUMANO:  Albuterol's kind of in a unique

             8    situation, and that's kind of the reason that having that

             9    one as the alternative first is maybe not predictive of the

            10    rest of the market just because albuterol does have

            11    generics.

            12                What we've seen in some other countries, in

            13    some of the European countries, where you've got moiety-by-

            14    moiety replacements, is that there's a faster change in

            15    part because the company's not interested in having two

            16    production lines.

            17                So it'll be interesting to see what happens

            18    here, but I'm not sure that albuterol's the model for it.

            19                DR. MEYER:  You know, I think the other thing I

            20    would say to that comment is that the FDA is only part of

            21    the overall U.S. transition process, as is the EPA, and I

            22    think that there are other ways the government has to look

            23    at this and figure out the best way to proceed in terms of

            24    incentives to the transition and accomplishing the

            25    transition.

                                                                           72

             1                So I think we're trying to do our best part

             2    from what we're being called to do, but issues, such as

             3    cost and, you know, the government perhaps stepping in to

             4    facilitate the transition in terms of the payment system

             5    and so on, are really beyond the purview of the FDA.

             6                DR. SESSLER:  Dr. Apter?

             7                DR. APTER:  I was wondering, with albuterol,

             8    there's a propellant that's somewhat comparable to CFCs

             9    with the inhaled steroids and also with the nasal steroids.

            10    The propellants, I believe, for the inhaled steroids, the

            11    propellants are in development.  For nasal steroids,

            12    there's not a comparable propellant on the way.

            13                I think that the delivery system for aqueous

            14    versus gaseous propellants are very different.

            15                DR. MEYER:  There's actually two propellants

            16    that have been developed, being HFA or HFC-134A, which is

            17    in the currently-approved Proventil HFA product.  The other

            18    one that is being put forward as a reasonable

            19    pharmaceutical alternative propellant would be the HFA or

            20    HFC-227EA, and it really is the choice of the manufacturer

            21    as to how to best reformulate.

            22                It's just step back for a second and say it's

            23    been a very technically-challenging process for the

            24    manufacturers because the different solvent capabilities of

            25    the gases that we're talking about, because of different

                                                                           73

             1    vapor pressures and so on, it's really required a

             2    reengineering of the MDI.  It's not just taking out CFC-11

             3    and 12 and putting in HFA-134A or 227EA.  It really

             4    represents reengineering the product substantially, and

             5    that's been a big technical barrier.

             6                But there's no a priori reason why any of the

             7    current MDIs could not be reformulated.  There are some

             8    challenges to doing that, but in one of those two gases,

             9    and I think that we would anticipate that such products

            10    will continue to be developed, both for nasal and oral

            11    inhalant.

            12                MS. CUSUMANO:  This was something I didn't

            13    include in my presentation, but we've got it in the

            14    proposed rule.  There's only three active moieties marketed

            15    as a nasal steroid, beclomethasone, budesonide and

            16    triamcinolone, and beclomethasone and triamcinolone are

            17    also marketed in non-CFC formulations.

            18    So really, it's just budesonide that there's no aqueous

            19    solution for.

            20                DR. MEYER:  Actually, since the proposed rule,

            21    there is now.

            22                MS. CUSUMANO:  There is now?

            23                DR. MEYER:  Yes.

            24                MS. CUSUMANO:  Okay.  So.

            25                DR. SESSLER:  Dr. Kelly, and then Ms. Conner.

                                                                           74

             1                DR. KELLY:  Going by the moiety-moiety

             2    approach, just reflecting back on the albuterol HFA, there

             3    was an attempt, I think, when it was produced to make it

             4    essentially equivalent to the CFC product, but in the

             5    existing approach, it seems like, and I think it's a good

             6    idea, that the new products don't have to be equivalent.

             7                In other words, two puffs equal two puffs, and

             8    so if a new product that's being developed delivers more

             9    drug, for instance, so it could be used as one puff in

            10    replacement of two puffs twice a day or whatever, that that

            11    would be an acceptable alternative, and so the moiety-to-

            12    moiety approach is sort of giving away to the equivalency

            13    approach.

            14                DR. MEYER:  Yes.  I think we have never really

            15    proceeded with an equivalency approach.  I think actually

            16    some other regulatory bodies have used more of sort of a

            17    bioequivalency approach to all this, but I think we've

            18    realized that there may be differences in the products and

            19    maybe by design or maybe by happenstance, but we've allowed

            20    for that, and if you consider the criteria that are in our

            21    notice of proposed rulemaking or were in our ANPR, we never

            22    really called for it being a direct one-to-one switch for

            23    that reason.

            24                We wanted to allow for some either intended or

            25    unintended differences, although certainly in the case of

                                                                           75

             1    unintended differences, we wanted to have enough data to

             2    understand what those differences were before we'd consider

             3    an adequate alternative.

             4                MS. CONNER:  It just seems to me that there's

             5    an overall acceptance that the transition is going to be to

             6    an HFA-type inhaler, and I wondered with this pipeline

             7    knowledge that you have, if you see any other trend towards

             8    different delivery devices.

             9                I know we have dry-powder inhalers and other

            10    type actuated systems that, unfortunately, they are

            11    affected by inspiratory flow, but do you see other

            12    pharmaceutical companies or even some of the generic

            13    companies looking at new delivery mechanisms as opposed to

            14    new propellants?

            15                DR. MEYER:  I think it's clear that this whole

            16    transition process has been a signal to some companies to

            17    think about other ways of delivering the drugs for

            18    inhalation that are as roughly convenient as MDIs but

            19    perhaps don't use a pressurized gas to deliver them, and I

            20    suspect that those products will become available over the

            21    period of this transition.

            22                I think the other thing to bear in mind,

            23    particularly for sort of the broader discussion of what,

            24    you know, when we convene these meetings after the January

            25    1st, 2005, date, of what the market is like, is even if a

                                                                           76

             1    multidose dry-powder inhaler's not perhaps in some people's

             2    opinions a perfect replacement product for an MDI, that

             3    doesn't mean there aren't substantial number of patients

             4    who don't use them and benefit from them.

             5                So if you look at the overall market, they may

             6    substantially help us towards the transition but maybe not

             7    on a direct moiety-by-moiety approach.

             8                DR. SESSLER:  Dr. Dykewicz, and then Dr.

             9    Niederman.

            10                DR. DYKEWICZ:  I'd just have a clarification

            11    I'd like answered.  As proposed by the moiety-by-moiety

            12    approach, I understand that if there were a non-CFC

            13    alternative preparation for that moiety, then the CFC

            14    preparation would be considered non-essential with some

            15    provisions.

            16                To some extent, it gets back to the question of

            17    Dr. Joad about the newer moiety-by-moiety approach would

            18    not specifically consider metered-dose inhalers as a

            19    requirement.

            20                Now, the problem that I could foresee is that

            21    you might have a non-CFC alternative product, the dry-

            22    powder inhaler, that may not meet the needs of all

            23    important subgroups.  For instance, children may not have a

            24    good inspiratory flow.

            25                So if I'm understanding this correctly, even

                                                                           77

             1    though it's not specifically stated, if an assessment is

             2    made by FDA that the alternative DPI product would not meet

             3    all patient subgroups, that would be a reason for

             4    continuing the essential accolade for the CFC MDI?

             5                MS. CUSUMANO:  That's right, and one of the

             6    things that I think it's important to remember is that

             7    moiety-by-moiety includes things like convenience of use,

             8    but it also says for the same indication.

             9                So if you've got the MDI down to six or

            10    younger, and the DPI is only down to 12, you don't have the

            11    same indication.  So you've got a missing product.

            12                The other part of that is, okay, so, we've got

            13    the moiety-by-moiety approach, but one of the or's is after

            14    January 1st, 2005, and this is what Bob was talking about,

            15    do you have not just DPIs out there that are serving 12 and

            16    above, but HFA products or other products, you know, other

            17    types of alternatives that serve that younger population or

            18    the population that can't use the DPI?  If so, then we

            19    would look at removing the essential use for that moiety.

            20                DR. NIEDERMAN:  I was just going to say, I

            21    don't think there's any question that we'll have

            22    alternatives to MDIs and DPIs.  I know I've seen, for

            23    example, a liquid inhaler device that's miniaturized and

            24    portable and probably would work as well.

            25                I think the problem, and I'm not sure how it's

                                                                           78

             1    going to be addressed, and maybe we can't address it, is

             2    the cost issue, and I think as was pointed out with

             3    albuterol HFA, the lack of acceptance has to do, I'm sure,

             4    more than anything with the cheap price of the generics

             5    compared to the much greater price of the HFA, and I think

             6    it is probably a very relevant thing to look at because I

             7    think that the HFA has not been adopted widely probably

             8    because it's just much more expensive, and I think that in

             9    terms of defining essential use as meeting all people's

            10    needs, unless we can find a reasonable way to provide

            11    alternatives that are equal in cost to the current

            12    generics, I think it's going to be very burdensome on

            13    certain populations to make this transition.

            14                MS. CUSUMANO:  Like I said, albuterol is the

            15    exception to the rule because of the generic.

            16                DR. NIEDERMAN:  But it's a good example of, I

            17    think, what's going to happen.  I think it's not an

            18    exception.  I think it's a glimpse into the future of

            19    trying to deal with this issue.

            20                DR. MEYER:  Well, again, I think that, as

            21    Leanne said beforehand, I think it's clear, most clearly

            22    the case with albuterol that there's a generic now, and

            23    that has changed the economics of the market, and I think

            24    that that's why Leanne is saying it most clearly looks like

            25    an exception to us.

                                                                           79

             1                For MDI replacement products, it does appear

             2    from what the industry has said, and in fact Proventil has

             3    held this out, is the price will be essentially the same. 

             4    I believe the Proventil HFA is within a few pennies of the

             5    Proventil CFC.

             6                DR. NIEDERMAN:  But not comparable to the

             7    generics.

             8                DR. MEYER:  Correct.  But, again, albuterol is

             9    the only drug substance right now that has a generic

            10    available.  So presumably if you're talking about Drug X,

            11    and it's an inhaled corticosteroid, and it's reformulated,

            12    it will be reasonably priced, and the other thing, I think,

            13    to bear in mind, now that I'm saying that, this has not

            14    been one of the questions, but these are sort of the way

            15    that we thought we would respond to the transition.

            16                It's entirely within the companies' options,

            17    and in fact some companies have indicated to this, that if

            18    and when they get their alternative approved, they may in

            19    fact want to stop marketing the CFC sooner than we would

            20    perhaps remove the essential use listing.  That is their

            21    prerogative, and although we might have some at least

            22    theoretic concerns about that, that's the way they could

            23    proceed, and obviously CFCs are getting more expensive, and

            24    there's some economic reasons why you wouldn't want to be

            25    running two production lines.

                                                                           80

             1                So I think when we first started the ANPR

             2    process, we really hadn't anticipated the fact that we

             3    might in a lot of cases not even have to invoke this

             4    because the companies may be making a switch on their own

             5    even faster than we might be proposing.

             6                DR. SESSLER:  Dr. Ford?

             7                DR. FORD:  I think that in addition to the cost

             8    issues that Dr. Niederman spoke to, one of the

             9    considerations as a potential determinant of use of the

            10    alternative products is going to be the extent to which

            11    practitioner populations are being reached in terms of

            12    their awareness of what the alternatives are, and I think

            13    that as is mentioned in some of the documents, there has to

            14    be a major effort in terms of making sure that people know

            15    what's available, and I suspect that a lot of that

            16    information is within the specialist population right now,

            17    including the availability and potential benefits of

            18    Proventil HFA, for example.

            19                MS. CUSUMANO:  That's absolutely true, and I

            20    mean that's one of the reasons that we're so involved in

            21    education.  I know Bob participates in NAEPP, National

            22    Association -- National --

            23                DR. MEYER:  National Asthma Education

            24    Prevention Project.

            25                MS. CUSUMANO:  Asthma Education Program.

                                                                           81

             1                DR. MEYER:  As has the CFC work group, and in

             2    fact, the industry itself has, through its consortium

             3    called IPAC, has been producing documents.  We worked with

             4    them and NAEPP and EPA and other professional groups and

             5    patient organizations to produce a document called "Why

             6    Your Inhaler is Changing," and I know there will be other

             7    efforts, both from the NAEPP and, I'm sure, from the

             8    industry, in terms of education.

             9                I think the clear message we're getting from

            10    our colleagues in the U.K. is that education is perhaps

            11    best timed for when the transition's really happening, and

            12    right now, we're sort of in the early phases, but I know

            13    that it's been our experience that Dr. Jenkins and I and

            14    other folks from the FDA have spoken at many public

            15    meetings, such as the AAAAI annual meeting and so on, and

            16    there's been some interest, but, quite frankly, the last

            17    time I spoke at the AAAAI, the room was pretty full, but it

            18    was mostly industry people there, and I think that for a

            19    lot of practitioners, it just hasn't hit yet, that this is

            20    something they need to grapple with now, and so I think

            21    we'll really intensify, we meaning both the FDA and other

            22    components that we interact with, really intensify our

            23    efforts as the transition really starts happening.

            24                DR. SESSLER:  Dr. Kelly?

            25                DR. KELLY:  What are the issues with the

                                                                           82

             1    generics?  I mean, you should know if anybody's trying to

             2    develop any new generics or if there's any drugs available?

             3                If basically it's a moot point, except for

             4    albuterol, then the cost issue is probably not a major

             5    issue.  It would seem hard to develop a generic for, say,

             6    beclomethasone right now.  You're not going to be given the

             7    essentiality based on the fact that it's just a generic

             8    albuterol -- I mean, a generic beclomethasone.

             9                DR. MEYER:  I'd rather not comment on the

            10    specifics of your question.  I will say that the moiety-by-

            11    moiety approach doesn't specify what kind of product it's

            12    in.  So if beclomethasone is considered -- I might even use

            13    beclomethasone -- let's use something else.

            14                DR. KELLY:  Okay.

            15                DR. MEYER:  If Drug X were considered an

            16    essential use of CFCs, that really doesn't discriminate

            17    whether it's a branded or a generic use.

            18                There was something else I wanted to talk to

            19    there in that question, and I'm forgetting -- oh, well, I

            20    was going to say even if it were only albuterol, were only

            21    albuterol, albuterol is such a large product in this

            22    market, that it would make the cost issue very meaningful

            23    in and of itself because it is such a big player in the

            24    asthma market.

            25                DR. SESSLER:  I'd like to bring it back to

                                                                           83

             1    cost, but from a little bit of a different perspective and

             2    perhaps more immediate, and that is really the nasal

             3    corticosteroids.

             4                The proposal seems very reasonable, but I guess

             5    there must be some differences in cost for the various

             6    products that are available currently, and I'm guessing

             7    that perhaps the lower cost items would be CFC rather than

             8    the aqueous.

             9                I guess I'm seeking some information first,

            10    some data on cost comparisons, and then if there is impact

            11    in that area.

            12                DR. MEYER:  Do you have the economic analysis

            13    piece there?

            14                MS. CUSUMANO:  I don't think I have figures

            15    comparing the aqueous versus the CFC part, but I do know

            16    that the four manufacturers marketing five CFC nasal

            17    steroids constitute less than 20 percent of the market. 

            18    So.

            19                DR. MEYER:  I think when we looked at this, it

            20    did not appear to be a substantial barrier.  We did have an

            21    economics analysis as part of this rulemaking process, and

            22    I know that we did look at that issue.  I don't remember

            23    the details offhand, but it did not seem to be a

            24    substantial issue.

            25                The other thing with the nasal corticosteroids

                                                                           84

             1    is that it's a very different part of this than the inhaled

             2    products because they're not considered essential from the

             3    Montreal Protocol standpoint, and I think that we're really

             4    talking more about timing of our action rather than whether

             5    to do it or not.

             6                DR. JENKINS:  If I could just add to that,

             7    Curtis.  All the nasal corticosteroids are branded

             8    products.  They're not generics.

             9                DR. SESSLER:  Right.

            10                DR. JENKINS:  So again, that takes away that

            11    element of the cost comparison.

            12                DR. APTER:  While we're on the subject of the

            13    nasal steroids, which, of course, nasal diseases aren't

            14    usually life-threatening like asthma, and even though you

            15    mentioned those figures about aqueous capturing a large

            16    part of the market, my own clinical experience is there's

            17    not a lot of data comparison, is that some people don't

            18    tolerate the aqueous as well, and that some people don't

            19    get as good delivery with the aqueous versus the aerosol,

            20    and so it may be important to encourage an HFA-like

            21    preparation to come forward.

            22                DR. JOAD:  On average, how much less is the

            23    generic albuterol than the brand name?  Just ball park.

            24                DR. MEYER:  I don't really know the answer as

            25    far as what it costs the patient.  As of months ago, there

                                                                           85

             1    was not a huge difference.  I think that's been expanding

             2    over time at the wholesale level.  So I think that at the

             3    wholesale level, we're probably talking in the mid-20s for

             4    the branded products.  The generic products, I've heard

             5    figures quite low actually, down at least for one of the

             6    so-called generics, and I'll just say so-called generics,

             7    down in the $3 to $4 range at the wholesale level.

             8                I don't have personal knowledge of that, but

             9    that's what I've heard through some of my contacts.  So it

            10    had been much more, sort of $17 to $25 type of comparison,

            11    and I don't know how that translates to what patients

            12    actually pay.

            13                MS. CUSUMANO:  It's one of the issues that

            14    we've struggled with because certainly one of the types of

            15    comments that we heard was about cost, yet there's very

            16    little within our authority that we can do about cost, and

            17    so I mean that's one of the issues that we wanted to bring

            18    here today, to ask what kind of innovations or what kind of

            19    thinking outside the box can we do to address this issue?

            20                DR. NIEDERMAN:  But, again, to put it in

            21    perspective, generic albuterol makes up what percentage of

            22    the albuterol market?  Do you have any guess?

            23                MS. CUSUMANO:  I don't know.

            24                DR. NIEDERMAN:  Of the MDI albuterol market?

            25                MS. CUSUMANO:  Do you know, Bob?

                                                                           86

             1                DR. MEYER:  Taking sort of the non-regulatory

             2    definition of generic, it's a large majority now.  It's, I

             3    think, in the range of about 70 percent, if not more, 80

             4    percent.

             5                DR. NIEDERMAN:  I mean, one obvious focus of

             6    this would be on the managed care companies because I know

             7    in my patient population, they don't want the generics

             8    necessarily.  They're being driven to it by their health

             9    care plans, and certainly a major lobbying effort on behalf

            10    of some of these non-generic new products probably has to

            11    be done at the health care plan level even more so than at

            12    the patient level.

            13                DR. DYKEWICZ:  Revisiting the incentive issue,

            14    that is, the incentive for the manufacturers to develop

            15    alternatives that Dr. Niederman talked about earlier, as I

            16    see this, there's really a two-stage process.

            17                The first stage, moiety-by-moiety, doesn't

            18    really have a major incentive necessarily for the

            19    manufacturer to come up with an alternative, but the second

            20    stage of the proposed regulations is that in 2005, there

            21    would then be the assessment made about whether an agent

            22    were essential, whether a product were essential, and I

            23    could easily foresee, and maybe this is potentially the

            24    intent, even though it's not stipulated, that at that

            25    point, there really would be a therapeutic class assessment

                                                                           87

             1    made, that you have a product for which there are a number

             2    of other alternatives of different moieties, and that on

             3    that basis, the manufacturer would lose its ability to

             4    continue to sell the product because there were

             5    alternatives, and if they didn't ask the manufacturer to

             6    have an alternative preparation that was non-CFC, they

             7    would lose that part of the market.

             8                Essentially, is that correct how that might

             9    play out?

            10                DR. MEYER:  I think in essence that's correct. 

            11    I mean, in some ways, we're, I think, viewing it that

            12    future assessment is being perhaps even broader than just a

            13    class approach in fact, I mean, because you're really

            14    trying to look at the entire market, and what patients'

            15    needs are, and how they're being addressed by the market as

            16    it is at that point.

            17                But in some respects, it does have some

            18    analogies to what the therapeutic class approach we had

            19    previously talked about.  It's just not as restrictive in

            20    some ways.  It's sort of a more broad look at where the

            21    market sits, and at what point does a non-reformulated

            22    product represent such minimal use or not meet the other

            23    criteria that we really can't justify the CFC use in that

            24    product any more?

            25                DR. VOLLMER:  I have a comment relative to the

                                                                           88

             1    presumption that we won't be seeing new CFC generics for

             2    corticosteroids or other products that are going to be

             3    coming off market.

             4                If one makes the case, for instance, that for

             5    albuterol having a low-cost CFC alternative as compelling

             6    reason for not taking it off the essential list, then it

             7    seems to me it opens up the possibility for arguing that

             8    the reason for providing an exemption for being essential

             9    is that we can now roll out a new product which is

            10    substantially cheaper than what you would be getting as a

            11    non-CFC alternative.

            12                I don't know where things stand at FDA and the

            13    government regarding this.  Is this going to be an option

            14    offered to people?  Is this going to be even on the table

            15    for discussion?

            16                DR. MEYER:  I certainly don't want to leave the

            17    impression that we're presuming that there will not be any

            18    further generic CFC products.

            19                From the very strict legal mandate of the FDA,

            20    we do not really have the authority to say there should not

            21    be any more generics.  In fact, it's quite the opposite. 

            22    Really due to the Waxman-Hatch amendments to our Act,

            23    there's a presumption that generics should be approved,

            24    unless some criteria met, and the CFC considerations don't

            25    factor into that.

                                                                           89

             1                Again, I think it's important to realize the

             2    FDA's addressing the transition within the wider

             3    government, and that there may be other components in the

             4    government who might, for instance, feel that even if we

             5    approved it, it should not get essential use allowances.

             6                So just from the FDA's standpoint, if all other

             7    things were met, including being able to show

             8    bioequivalence for a product that was no longer protected

             9    by patent exclusivity or by marketing exclusivity, then if

            10    data were provided to us to show bioequivalence to the

            11    innovative product, we would need to approve that product.

            12                Again, I think it's important to realize there

            13    are discussions outside the FDA, and in fact at the

            14    Montreal Protocol level, about how wise it is to have any

            15    new CFC products approved.  But that's a discussion in many

            16    respects, although we're involved in it, it's a discussion

            17    beyond the FDA.

            18                DR. SESSLER:  Mike?

            19                DR. NIEDERMAN:  I'm sure it would be unwise to

            20    think about putting some sort of tax which would be passed

            21    on to consumers on a product that continued to have CFCs,

            22    but is the reverse possible?

            23                Is there some sort of economic incentive that

            24    can be given to companies that develop non-CFC devices so

            25    that they could bring the costs down and make them more

                                                                           90

             1    competitive with the generics and put pressure on the

             2    generics to do similar types of maneuvers?  Is there any

             3    mechanism for that?

             4                MS. CUSUMANO:  Certainly, there is, but it's

             5    not something FDA could do on its own.  It's something that

             6    would have to be passed by Congress, an amendment to the

             7    Act or an amendment to the Tax Code or something like that.

             8                DR. NIEDERMAN:  So it's not something we can

             9    really reasonably consider.

            10                DR. MEYER:  I think you could make reasonable

            11    comments, but just because FDA doesn't necessarily have its

            12    own authority to do it, I think it's important that we get

            13    all comments.

            14                DR. GROSS:  Can I ask a related question? 

            15    Supposing a drug company came to you with a completely new

            16    entity that they wanted to deliver by inhalation, and they

            17    were proposing to use a CFC propellant for that.  What

            18    would the agency's position be on that?

            19                DR. NIEDERMAN:  Leanne laid out what -- we're

            20    changing our criteria for adding new essential uses to be

            21    even more rigorous than they currently are, and in fact, if

            22    you read what's currently in 2.125, if we were to take a

            23    very, very hard line about that, they're pretty rigorous

            24    already, but these raise the bar even farther, and

            25    basically, unless it was clear that it was a major

                                                                           91

             1    therapeutic advance, we're talking about a new moiety,

             2    major therapeutic advance that was otherwise not available,

             3    that there were technical barriers for it being formulated

             4    in something other than CFCs -- what's the other one?  I'm

             5    sorry.

             6                MS. CUSUMANO:  Substantial technical barrier,

             7    important public health benefit, and the release warranted

             8    in light of the use.

             9                DR. MEYER:  Yes.  That might be the one place

            10    where we and the EPA would engage in a discussion of sort

            11    of environmental risk versus benefit.  Overall in this

            12    process, the risk assessment and the commitment to get rid

            13    of CFCs has been made.  So we're not engaging in that kind

            14    of discussion now, but for new use, we're talking about

            15    potentially doing so.

            16                DR. GROSS:  Sorry.  I didn't understand that. 

            17    When you say non-engaging in that kind of discussion now,

            18    what do you mean?  You won't entertain new submissions that

            19    contain --

            20                DR. MEYER:  No, no, no.  I was actually talking

            21    about -- no, no.  I was talking about we're not, as I said

            22    earlier, here today to debate, you know, how much of an

            23    ozone-depletion risk the current MDI use is and that sort

            24    of thing.

            25                But what I'm saying is in the future new use, I

                                                                           92

             1    think we have to really look at what would be the known

             2    hazard to both the ozone depletion and in fact to the

             3    overall accomplishment of the Montreal Protocol compared to

             4    the public health benefit.

             5                So we're not in this rule or this proposed

             6    rule, we're not closing the door to such circumstances, but

             7    we're, I hope, sending a very clear signal that it's going

             8    to have to be very clear that there's no other alternative

             9    for delivering this moiety, and this moiety is really

            10    providing a benefit that folks won't get otherwise.

            11                DR. GROSS:  Well, I mean, the question really

            12    is what is the incentive for the companies to develop an

            13    alternative propellant form of that, because as was pointed

            14    out earlier, if the drug is patented, and there isn't an

            15    alternative, it's a new entity, what is their incentive

            16    to --

            17                DR. MEYER:  Well, their incentive right now is

            18    if they do not have an approved essential use, they're not

            19    on the current list, they're going to have a very tough

            20    time getting on it.  So if they're in early drug

            21    development, they really should be looking to develop that

            22    in either an alternatively-propelled MDI or some other

            23    alternative device rather than go the CFC route.  I hope

            24    that signal's quite clear.

            25                DR. GROSS:  So essentially what you're saying

                                                                           93

             1    to the company is that we're going to set the bar much

             2    higher for your drug if you're proposing to market it with

             3    a CFC propellant than if you were to use an alternative

             4    environmentally-acceptable one, is that right?

             5                DR. MEYER:  Yes, yes, and in fact, and I would

             6    again invite any comments from the EPA in this regard, but

             7    it's not just us setting that bar higher, but the U.S.

             8    nomination has to be approved by the parties to the

             9    Montreal Protocol.  So it's really the international

            10    community that's raising the bar substantially, too.

            11                DR. SESSLER:  Any comment from EPA?

            12                MR. COHEN:  Again, Bob summed it up pretty

            13    well.  I think it's worth noting that, as Erin said, the

            14    U.S. nomination up till now has been approved year-by-year

            15    since 1996, but there's no guarantee that that will

            16    continue, especially as other countries pursue their own

            17    transition.

            18                DR. SESSLER:  Dr. Vollmer?

            19                DR. VOLLMER:  I must say that I'm generally

            20    very favorably disposed towards the NPR.  I want to echo a

            21    concern that Jean raised earlier.  The one issue in

            22    removing the essential status for a drug, the fourth one,

            23    the special populations, there was a presumption, as was

            24    pointed out, that if the first three criteria are met, then

            25    all needs of special populations are met, and the sort of

                                                                           94

             1    bar for our becoming that is really put back on the

             2    industry to say if you think that's not the case, then give

             3    us evidence of that.

             4                Presumably there would be enough of a -- I

             5    mean, if you can show that there's a market out there, then

             6    there's an economic incentive for them to do that.  On the

             7    other hand, the smaller the market gets, then the less

             8    economic incentive there will be for them to go out and do

             9    whatever analyses they're going to be required to do.

            10                Can you speak a little more to how you see this

            11    working?

            12                MS. CUSUMANO:  First, I'd like to say that the

            13    substantial or the subpopulation that we had in the

            14    advanced notice of proposed rulemaking changed a little to

            15    patients who medically require the ODS are adequately

            16    served by alternatives.  So very similar.

            17                I think what you said still applies, and I

            18    guess the second part of that is we have this idea, and we

            19    understand that there may be patients who can't use the

            20    alternatives, and we're not sure how we're going to figure

            21    that out, and that's one of the questions that we have for

            22    the committee, is how are we going to decide?

            23                A lot of the comments that we had on the

            24    original advanced notice said a subpopulation of one is

            25    very important to that one.  So on the other hand, I know

                                                                           95

             1    sometimes we get comments after a company has removed a

             2    product from the market, you know, on its own that say I

             3    needed that product, what am I going to do without it,

             4    and --

             5                DR. MEYER:  Yes.  I think that, as Leanne said,

             6    we have shifted the language away from a presumption that

             7    these subpopulation needs are being met to really wanting

             8    some level of showing, and it's not necessarily the burden

             9    of the company to do that, but I think this is going to be

            10    a difficult issue and one that we would certainly very much

            11    welcome input on because it is clear that when certain

            12    products have gone away because the manufacturers have

            13    stopped marketing them, you have a vocal minority of

            14    patients who earnestly feel that that's the only product

            15    that can control them, and so we know that will exist.

            16                I guess I could cite my experience during

            17    residency when the VA would switch from one producer of

            18    albuterol to another.  These products were substantially

            19    the same, and at some point in the past, I understand they

            20    might have even come off the same production lines, and

            21    patients would complain bitterly that this one doesn't work

            22    as well as that one.

            23                So we know that because of the variability of

            24    the disease that we're talking about, that being asthma and

            25    chronic obstructive pulmonary disease, that patients tend

                                                                           96

             1    to -- if their disease happens to exacerbate when they

             2    switch inhalers, whether it was due to that inhaler or not,

             3    they may well form the conclusion that it was that inhaler.

             4    So these are some of the difficult things.

             5                I do think it's important, because I don't

             6    think we stressed it earlier, to realize that we are in the

             7    notice of proposed rulemaking as in the ANPR stating that

             8    these removals of essential use listings will be through

             9    further notice and comment rulemaking.

            10                In other words, if we wanted to delist

            11    albuterol at some day in the future, we will need to

            12    publish a proposed rule saying we propose to take albuterol

            13    out, these are the reasons why, and I would suspect,

            14    particularly for some of the drugs like albuterol, that

            15    that will entail bringing this committee back together,

            16    hearing more public commentary and really considering that

            17    as a part of it.

            18                So at least even if we don't have every single

            19    iota of data we need, I think we are envisioning a public

            20    comment process that will allow for other people to bring

            21    in data that will be helpful to us in making the

            22    determinations.

            23                DR. SESSLER:  Thank you.

            24                I'd like to go ahead and take our break now. 

            25    I'd like to thank the committee for their thoughtful

                                                                           97

             1    questions, and the FDA and EPA personnel for their

             2    thoughts.

             3                It was rather free form and covered a lot of

             4    different areas which I hope we will focus in on specific

             5    areas for more complete discussion in the afternoon

             6    session.

             7                Please be back at 10:45.  We'll start promptly

             8    with the opening public hearing.

             9                Thank you.

            10                (Recess.)

            11                DR. SESSLER:  Good morning again.  This will be

            12    the open public hearing component, and we have four listed

            13    speakers.  In addition, we will open it up after those

            14    individuals have spoken to any others who wish to speak

            15    before the committee.

            16                What I'd ask of the speakers is that they tell

            17    who they are and where they are from and who they represent

            18    and also a mention of any disclosure of conflict of

            19    interest.

            20                I would also ask that the comments be limited

            21    to 10 to 15 minutes, please.

            22                Our first speaker is Ballard Jamieson, who is

            23    Secretary and Legal Counsel for the International

            24    Pharmaceutical Aerosol Consortium.

            25                Mr. Jamieson?

                                                                           98

             1                MR. JAMIESON:  Over here?

             2                DR. SESSLER:  Yes, please.

             3                MR. JAMIESON:  Good morning.  My name is Jim

             4    Jamieson.  I'm the Secretary and Legal Counsel to the

             5    International Pharmaceutical Aerosol Consortium, or IPAC,

             6    as it is commonly known.

             7                IPAC is an association of leading manufacturers

             8    of metered-dose inhalers for the treatment of asthma and

             9    chronic obstructive pulmonary disease.  Its members include

            10    AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici,

            11    Glaxo Wellcome, Medeva Americas, Inc., Norton Healthcare,

            12    Ltd., Rhone-Poulenc Rorer, Inc., and 3M Pharmaceuticals.

            13                IPAC was created in response to the mandate of

            14    the Montreal Protocol.  Its goal is to ensure a smooth and

            15    efficient MDI transition that balances public health and

            16    environmental protection.  To this end, IPAC serves as a

            17    source of information and analysis on the MDI industry and

            18    facilitates its participation in the implementation of the

            19    Montreal Protocol worldwide.

            20                Members of IPAC are firmly committed to the MDI

            21    transition.  In 1990, MDI companies undertook an

            22    unprecedented joint testing program to demonstrate the

            23    safety of propellants that would ultimately replace CFCs.

            24                More than 1,400 scientists at 90 laboratories

            25    in 10 countries around the world have been involved in the

                                                                           99

             1    development of non-CFC MDIs.  MDI companies have already

             2    spent $1 billion in this effort and will spend much more to

             3    complete it.

             4                In May 1997, IPAC submitted comments on the

             5    FDA's advanced notice of proposed rulemaking.  On April

             6    11th, 1997, IPAC presented its views on the ANPRM at the

             7    public hearing of this committee.

             8                We appreciate this opportunity to participate

             9    in this hearing today.  Later this month, we will submit

            10    written comments to the FDA on its proposed rule.  I will

            11    now summarize IPAC's comments on the proposed rule.

            12                The proposed rule provides for a moiety-by-

            13    moiety approach.  IPAC supports this approach as the

            14    primary criteria for examining safe and effective non-CFC

            15    alternatives for existing CFC products.  This approach, in

            16    our view, strikes an appropriate balance between ensuring

            17    the availability of vital medications and discontinuing the

            18    use of CFCs.

            19                The proposed rule establishes several criteria

            20    for an alternative to a CFC MDI.  For example, the proposed

            21    rule provides that a non-CFC alternative must feature the

            22    same route of administration.  IPAC supports this

            23    criterion.

            24                Inhalation is the preferred route of

            25    administration for the treatment of respiratory disease. 

                                                                          100

             1    To ensure the continued availability of inhalation therapy,

             2    a CFC MDI should only be replaced by a product with the

             3    same route of administration.

             4                The proposed rule provides that a non-CFC

             5    alternative must feature approximately the same level of

             6    convenience of use.  IPAC supports this criterion, and as

             7    the FDA notes, patients value the compact size and ease of

             8    use of MDIs.  This criterion ensures continuing patient

             9    access to therapy with this same level of convenience.

            10                The proposed rule states that supplies and

            11    production capacity for a non-CFC alternative must exist at

            12    levels sufficient to meet patient need.  IPAC supports this

            13    criterion.  This criterion would safeguard against

            14    interruptions in patient access to vital medications during

            15    the transition to non-CFC MDIs.

            16                In the preamble to the proposed rule, the FDA

            17    states that a non-CFC alternative should be manufactured at

            18    multiple manufacturing sites if the CFC MDI is manufactured

            19    at multiple manufacturing sites.  IPAC believes that the

            20    requirement of multiple manufacturing sites is unnecessary

            21    where an MDI company demonstrates that a single

            22    manufacturing site is sufficient to supply patient need.

            23                MDI companies may consolidate manufacturing

            24    activities at a single site for non-CFC MDIs.  These single

            25    sites will feature supplies, storage and production

                                                                          101

             1    capacities as well as safeguards against disruptions in

             2    manufacture which virtually eliminate risk of product

             3    shortages.

             4                Under the proposed rule, the FDA would require

             5    at least one year of U.S. post-marketing use data for non-

             6    CFC alternatives.  In addition, the FDA would consider

             7    foreign data supportive of U.S. post-marketing use data if

             8    U.S. and foreign formulations, patient populations and

             9    clinical practices were the same or substantially similar.

            10                Finally, the FDA would not require a post-

            11    marketing study if available data, including more

            12    traditional post-marketing surveillance data, are

            13    sufficient to support a finding that the CFC product is no

            14    longer essential.

            15                IPAC supports consideration of post-marketing

            16    data.  IPAC proposes that the requirement for one year of

            17    post-marketing use data in the United States be reduced if

            18    foreign post-marketing use data is sufficient to support a

            19    finding that a CFC MDI is no longer essential.  This

            20    approach would eliminate unnecessary delay in discontinuing

            21    the use of CFCs.

            22                Finally, IPAC believes that existing processes

            23    provide post-marketing use data sufficient to support a

            24    finding that a CFC MDI is no longer essential. 

            25    Accordingly, IPAC believes that Phase IV post-marketing

                                                                          102

             1    studies should not be required for this purpose.

             2                Under the proposed rule, the FDA would

             3    determine whether patients who rely on a particular CFC MDI

             4    would be adequately served by non-CFC alternatives.  In

             5    making this determination, the FDA would consider whether

             6    adequate safety, tolerability, effectiveness and compliance

             7    exists for the indicated populations and other populations

             8    known to medically rely on the CFC MDI product.

             9                IPAC supports this criterion.  This criterion

            10    ensures that vital medications will remain continuously

            11    available for all clinical subpopulations.

            12                Finally, the proposed rule provides that after

            13    January 1, 2005, a CFC MDI will no longer be essential

            14    unless it provides an unavailable important public health

            15    benefit which warrants the release of CFCs into the

            16    atmosphere.

            17                IPAC supports this approach.  A target date for

            18    the review of remaining CFC MDIs would mark the final phase

            19    of the transition to non-CFC alternatives and give

            20    physicians and patients a general sense of the time frame

            21    for its completion.

            22                In sum, IPAC supports many important elements

            23    of the proposed rule.  There are, however, several areas in

            24    need of clarification concerning, for example, the issue of

            25    multiple manufacturing sites and post-marketing studies.

                                                                          103

             1                In addition, IPAC believes that the proposed

             2    rule should require every new CFC MDI product to meet all

             3    essentiality criteria.  In our view, the Clean Air Act

             4    mandates a product-by-product essentiality review for all

             5    new CFC MDIs, if any there be.

             6                We note that leading public health

             7    organizations support this approach.  We will address the

             8    legal aspects of this position in our written comments

             9    submitted later this month.

            10                We appreciate this opportunity to appear before

            11    you today.  As our comments indicate, we are generally

            12    supportive with a few exceptions of the FDA's proposed

            13    rule, a few important exceptions to the rule.

            14                We would like to commend the FDA and its staff

            15    for meeting what we know was a significant challenge in

            16    reviewing, analyzing and responding to the many comments on

            17    the ANPR, and we congratulate them for the effort they have

            18    made.

            19                At this point, we would be pleased to answer

            20    any questions you may have and either now or this afternoon

            21    in the Q&A period.

            22                Thank you.

            23                DR. SESSLER:  We have time for one or two

            24    questions.

            25                DR. VOLLMER:  I'd just like a clarification on

                                                                          104

             1    the -- when you're talking about the post-marketing, and

             2    you were suggesting that you were supporting less than a

             3    one-year post-marketing if there was good European data

             4    available, and then you followed up with a comment about

             5    the lack of a need for Phase IV trials.

             6                Could you just repeat that again because I

             7    missed it?

             8                MR. JAMIESON:  Okay.  Well, our position is

             9    that the Phase IV studies are not necessary because

            10    existing processes are sufficient to make an essentiality

            11    determination.  That's the position.  We will elaborate on

            12    this somewhat more in our comments filed later this month.

            13                DR. SESSLER:  Thank you.

            14                MR. JAMIESON:  Thank you.

            15                DR. SESSLER:  Our second speaker in the open

            16    public hearing component is Alfred Munzer, M.D.,

            17    representing the American Thoracic Society and the Medical

            18    Section of the American Lung Association.

            19                Dr. Munzer?

            20                DR. MUNZER:  My name is Alfred Munzer.  I'm a

            21    physician specializing in lung disease.  I'm a past

            22    president of the American Lung Association, and I have, as

            23    far as disclosure is concerned, to the best of my

            24    knowledge, I have no financial interest in any of the

            25    companies that are affected by this regulation.

                                                                          105

             1                On behalf of the American Lung Association and

             2    its Medical Section, the American Thoracic Society, I want

             3    to thank the FDA Pulmonary and Allergy Drugs Advisory

             4    Committee for the opportunity to present our views.

             5                While many of our concerns with the previous

             6    advanced notice have been addressed in the proposed rule,

             7    there remain many important issues to be resolved.  The

             8    most important issue, in the opinion of the American Lung

             9    Association and the American Thoracic Society, continues to

            10    be the need for broader public education as transition

            11    takes place.

            12                The transition to CFC-free metered-dose

            13    inhalers provides a unique opportunity for the entire

            14    pulmonary-allergy community to refocus attention on the

            15    proper diagnosis and management of asthma and to revitalize

            16    the relationship between physicians and other health care

            17    providers and patients with asthma.

            18                Some people may feel that we have been dealt

            19    some lemons in this whole transition.  What we have failed

            20    to do so far is to make lemonade.

            21                The American Lung Association and the American

            22    Thoracic Society have previously commented regarding the

            23    role of patient and professional education in any

            24    transition strategy.  As noted in the European Union,

            25    education needs reach a critical level when many new

                                                                          106

             1    products are introduced in rapid succession.

             2                We recognize that such education efforts do not

             3    fall within the jurisdiction of the Food and Drug

             4    Administration.  However, we do encourage the FDA to use

             5    its public affairs resources and to explore intraagency

             6    mechanisms to ensure coordination and collaboration with

             7    Federal Government entities having authority for

             8    educational efforts, including the National Asthma

             9    Education and Prevention Program.

            10                Coordination and collaboration among Federal

            11    Government agencies, non-governmental organizations

            12    representing patients and health care providers, including

            13    the pharmaceutical industry and managed care companies,

            14    must occur to ensure a consistent and appropriate level of

            15    effort as reformulated products enter the marketplace.

            16                The American Lung Association and the American

            17    Thoracic Society look to the agency for leadership in this

            18    area.

            19                Let me make some specific comments on the

            20    proposed rule.  First, about the moiety-by-moiety approach. 

            21    The American Lung Association and the American Thoracic

            22    Society concur with the moiety-by-moiety approach detailed

            23    in the proposed rule.  This decision-making structure

            24    should continue to provide a range of treatment options for

            25    physicians and patients as the transition proceeds.

                                                                          107

             1                It is critical that any decision-making scheme

             2    is structured to ensure that physicians remain able to

             3    treat patients effectively following the National Asthma

             4    Education and Prevention Treatment Guidelines.

             5                Second, as to the petitions to add new

             6    essential uses, the American Lung Association and the

             7    American Thoracic Society agree that it is inappropriate to

             8    add new essential uses at a time when developed nations,

             9    including the United States, have committed to the phaseout

            10    of the production and consumption of ozone-depleting

            11    substances.

            12                Third, as to the determination of continued

            13    essentiality, we concur with the decision-making process

            14    outlined in the proposed rule.  In the first instance, the

            15    agency is to be commended for the common sense approach of

            16    removing an active moiety from the essential use list if it

            17    is no longer marketed in an ODS formulation.

            18                Under a second scenario, the agency proposes a

            19    process commencing after January 2005 to review the

            20    essential use status of current active moieties.  We

            21    believe that it is critical to fully engage the patient and

            22    health care provider communities in this process.

            23                A notice and comment period, plus consultations

            24    with an advisory committee, are not sufficient to ensure

            25    input from a well-informed public.  The agency's experience

                                                                          108

             1    with the advanced notice of proposed rulemaking

             2    demonstrates the need for carefully-prepared regulatory

             3    materials, patient, medical professional and public

             4    education and ample opportunity for interaction with agency

             5    advisory board bodies and personnel.

             6                A few additional comments.  First about the

             7    time frame.  The American Lung Association and the American

             8    Thoracic Society are concerned that the proposed decision-

             9    making structures fail to provide a suggested time frame

            10    for non-essential use determinations beyond the market

            11    review after January 1st, 2005.  We note only a time frame

            12    of one year for the collection of post-marketing studies.

            13                The agency must provide patients, health care

            14    providers and the public with detailed time frames,

            15    including an estimation of time, for any anticipated

            16    regulatory proceeding, in addition to the content of

            17    information required.

            18                While there is no consensus at present on what

            19    constitutes an appropriate time frame, the agency should

            20    seek public comment on this important part of the

            21    transition.

            22                The overall monitoring process.  The American

            23    Lung Association and American Thoracic Society previously

            24    commented on the need to establish a mechanism to monitor

            25    the overall transition to non-ozone-depleting substance

                                                                          109

             1    products.

             2                At a minimum, such a mechanism should include

             3    an expert panel appointed to assess baseline information

             4    from which to monitor all aspects of the transition.  Panel

             5    members should include medical experts, other members of

             6    the health care team, including nurse educators,

             7    pharmacists, and respiratory therapists, epidemiologists,

             8    and patients and patient advocates.

             9                Thank you very much.

            10                DR. SESSLER:  We have time for questions.

            11                (No response.)

            12                DR. SESSLER:  Thanks, Dr. Munzer.

            13                DR. MUNZER:  Thank you.

            14                DR. SESSLER:  Our next speaker is Mary E.

            15    Worstell, with a master's of public health, who is

            16    Executive Director of the Asthma and Allergy Foundation of

            17    America.

            18                Ms. Worstell?

            19                MS. WORSTELL:  Good morning.  I'd like to

            20    restate my title as Executive Director of the Asthma and

            21    Allergy Foundation of America.  I'm a health educator by

            22    training.

            23                The AAFA is headquartered in Washington, D.C.,

            24    and I have no known conflict of interests as I present to

            25    you this morning.

                                                                          110

             1                I want to thank the committee for the

             2    opportunity to express our opinion this morning, and I also

             3    want to compliment the FDA in what I believe has been a

             4    very open and inclusive process over the last several years

             5    in seeking patient input on this very critical issue.

             6                The position of the Asthma and Allergy

             7    Foundation of America on this issue has been stated

             8    repeatedly over the last several years in our written

             9    comment to the FDA in 1997, in a number of hearings in

            10    which we have participated on Capitol Hill over the last

            11    several years, and I can tell you that we have not wavered

            12    in our support for the transition to CFC-free metered-dose

            13    inhalers.

            14                We believe that this transition needs to move

            15    forward.  We believe it offers multiple benefits for

            16    patients.  We believe that a plan for transition in this

            17    country is essential, and we would agree with what Dr.

            18    Munzer just presented on the importance of an oversight for

            19    this process as it moves forward.

            20                We believe that the transition to metered-dose

            21    inhalers, CFC-free metered-dose inhalers needs to be

            22    seamless for the patient, and when I talk about seamless,

            23    I'd like to emphasize certain points.

            24                One is we do need to ensure that patients are

            25    educated in this transition, the need for this transition,

                                                                          111

             1    the elements of the transition.

             2                As ALA has just presented, you have multiple

             3    new products that are coming on the market.  We have new

             4    mechanisms in these products for patients.  We are asking

             5    patients to change, and we are all health care consumers,

             6    and we all understand that for us to be active, responsible

             7    participants in our medical care, we need to be educated

             8    and understand what and why we are being asked to make

             9    these changes.  So we will be working in patient education.

            10                We believe strongly that education of the

            11    health care provider is key to this, that health care

            12    providers understand this process, understand the benefits

            13    of the new products, understand the special characteristics

            14    of the new products and can communicate those to their

            15    patients.  There is an integrity of the communication

            16    process between the provider and the patient that we must

            17    use.

            18                In addition, if new information, new technology

            19    is communicated with confidence by the health care provider

            20    to the patient, the patient is steps ahead in terms of a

            21    positive attitude in looking at adopting or adapting to new

            22    characteristics of a product.

            23                As Dr. Munzer said, we believe that there is a

            24    tremendous benefit in this transition to once again focus

            25    on proper diagnosis and management of asthma and to

                                                                          112

             1    revitalize the communication between patients and their

             2    health care provider.  This has been lost, and we need to

             3    go back.  This is critical to overall patient satisfaction

             4    and adequate management of their asthma, and we are

             5    concerned about the cost issue, and that the costs of the

             6    new products be accessible to patients.

             7                The Asthma and Allergy Foundation of America

             8    has a task force of members of our volunteer board of

             9    directors and chapter leaders who have reviewed and

            10    participated in the statement of position of the Asthma and

            11    Allergy Foundation since 1997.

            12                This task force has reviewed the proposed rule,

            13    and there is initial consensus support for this rule.  We

            14    are now in the process of reviewing the stakeholder

            15    consensus comments that we will be presenting to the FDA

            16    later this month, and we will be developing a short

            17    individual statement for the Asthma and Allergy Foundation

            18    congruent with this.

            19                I would really like to say, in addition, that

            20    we will be working with the EPA next year to do some

            21    preliminary market research to reassess where the health

            22    care provider knowledge and attitude focus is on this issue

            23    so that we can better target educational messages to these

            24    critical health care providers as the transition moves

            25    forward.

                                                                          113

             1                We will continue to be an active participant in

             2    this topic and work as we have in the past with other

             3    groups for a consensus position moving forward.

             4                Thank you.

             5                DR. SESSLER:  Questions or comments?

             6                DR. GROSS:  May I ask a question?  I should

             7    know this, but I take it most of the membership of the

             8    foundation consists of patients and their relatives?

             9                MS. WORSTELL:  That's correct.

            10                DR. GROSS:  Have you received any individual

            11    expressions of concern from patients about not being able

            12    to use their regular inhaler because it's not considered

            13    non-essential?

            14                MS. WORSTELL:  I have not received those kinds

            15    of complaints from patients because I'm not sure that the

            16    patients understand the politics behind this transition in

            17    general.

            18                My experience with communication with patients

            19    in principle has been that they have been provided a new

            20    inhaler, different from their old inhaler, without any

            21    advanced notice and without any information about the new

            22    inhalers.

            23                So some of the characteristics have surprised

            24    them and disappointed them, which is why I believe that

            25    education is so important.

                                                                          114

             1                I think that it's simplistic when you just say,

             2    as we heard a couple of years ago, that your metered-dose

             3    inhaler may be changing, and if you don't want that to

             4    change, contact the FDA.  It's very simplistic.  It's much

             5    more complicated, and I believe that when you're looking at

             6    the introduction of new medications or change in

             7    medications, that provider/patient relationship is where

             8    the sense of communication needs to reside.

             9                DR. SESSLER:  Thank you.

            10                Our final scheduled speaker is Dolores Libera,

            11    who is speaking on behalf of Nancy Sander, President, and

            12    Ms. Libera represents the Allergy and Asthma Network and

            13    Mothers of Asthmatics.

            14                MS. LIBERA:  Thank you.

            15                My name is Dolores Libera.  I'm Director of

            16    Publications at the Allergy and Asthma Network/Mothers of

            17    Asthmatics, AANMA.

            18                I'm giving Nancy Sander's presentation.  She

            19    was unable to be here because of illness.  I don't believe

            20    that there are any conflict of interests, and I do want to

            21    thank the committee for allowing us to present.

            22                Our comments will be short and direct.  We

            23    support this version of the NPR because it affords patients

            24    every protection without slowing innovation or transition,

            25    and the stratospheric ozone is not at risk in the process.

                                                                          115

             1                The current NPR addressed the questions that

             2    the first one raised and takes preventive actions that

             3    patients believe are important.  The language of the NPR is

             4    far more direct than the first version, and while there are

             5    areas of additional clarifications, these mostly affect

             6    issues directly impacting the pharmaceutical industry and

             7    do not appear to put patients at risk.

             8                We do not understand, however, the specific

             9    manner in which grandfathered over-the-counter

            10    bronchodilators will be treated.  There seems to be

            11    loopholes through which these products could receive

            12    permanent exemptions.

            13                What actions will the FDA take to ensure that

            14    these medications do not slip through the cracks, that

            15    prescription-only products do not?

            16                Furthermore, AANMA posted notices of the NPR on

            17    our web site and in several other sources.  We did not

            18    undertake a survey as we did with the ANPR because we

            19    learned from the first effort that conducting the survey in

            20    a short period as given is costly and comes at the expense

            21    of other projects within AANMA.

            22                However, we encourage those people who did

            23    visit the FDA web site to read the NPR and forward

            24    questions directly to the FDA and to our office.  We don't

            25    know what the FDA has received in the way of comment, but

                                                                          116

             1    we have received only one letter of concern.

             2                AANMA's questions and concerns as patient

             3    advocates have been responded to thoughtfully.  The NPR

             4    reflects a patient-friendly approach, one in which the best

             5    interests of the patients can be served effectively.

             6                Thank you.

             7                DR. SESSLER:  Dr. Niederman?

             8                DR. NIEDERMAN:  As a representative of the

             9    patient group, is there any concern that's been expressed

            10    on your web site with regard to losing these CFC

            11    propellants?

            12                DR. SESSLER:  Ms. Libera?

            13                MS. LIBERA:  I'm sorry?

            14                DR. SESSLER:  Quite all right.

            15                DR. NIEDERMAN:  I'm trying to find out whether,

            16    from a patient perspective, you've had any comments that

            17    patients are concerned about losing the CFC propellant.

            18                I think this issue was brought up earlier, I

            19    think by Dr. Meyer, that patients frequently complain when

            20    their inhalers are changed, maybe not really based on any

            21    reality, but has there been a concern expressed by any

            22    patients that they're worried about losing their CFC

            23    propellant inhalers?

            24                MS. LIBERA:  I think originally, when this

            25    whole issue began to be publicized, there was a lot more

                                                                          117

             1    concern.  As the transition has occurred, as we've been

             2    able to educate our members through our newsletter and

             3    magazine, and as more products have become available that

             4    do not have CFCs, there seems to be less of a concern.

             5                As I said, apparently we have only received one

             6    letter of concern after it was posted this last time.

             7                DR. GROSS:  To what extent do you think your

             8    members understand the situation?

             9                MS. LIBERA:  Well, I guess I can't speak

            10    definitively, but I think we've gone through a very

            11    extensive process using the materials that have been

            12    available through posters, through specific articles.

            13                We don't receive a lot of phone calls on the

            14    issue at this point.

            15                DR. GROSS:  You have publications, of course?

            16                MS. LIBERA:  We put out a newsletter.

            17                DR. GROSS:  Has there been any coverage of this

            18    subject in your publications?

            19                MS. LIBERA:  I'm sorry?

            20                DR. GROSS:  Has there been any coverage of this

            21    particular subject in your publications?

            22                MS. LIBERA:  We have discussed this

            23    extensively, especially since the original ANPR came out.

            24                MS. CONNER:  I have a question, also, and,

            25    Mary, you may want to address this as well.  Have the

                                                                          118

             1    patients noticed -- and I don't know whether -- maybe the

             2    majority of patients now are covered by pharmacy cards, and

             3    out-of-pocket cash is not as much an issue as it used to

             4    be.

             5                Have you noticed that the change in the devices

             6    or the change in inhalers has increased the costs?  Have

             7    you seen patients complain about that?  Does that appear to

             8    be an issue?  Have they had difficulty with technique or --

             9    I mean, it just seems that there's not the uproar that I

            10    would have expected, and maybe it's because it hasn't

            11    impacted that many patients yet.

            12                MS. LIBERA:  We just have not had the -- when

            13    this originally came up, we had a lot of discussions, but

            14    the transition seems to have been fairly smooth in terms of

            15    bringing attention to the efforts that are available and

            16    assuring that there will be options available.

            17                MS. CONNER:  Right.  I don't doubt that there

            18    will be options.  I just don't know if they are aware of

            19    maybe the financial impact that may be coming, but like I

            20    said, it depends on formularies and what managed care

            21    companies will allow them to have, so that that directly

            22    doesn't come right out of their pockets, but if they're

            23    limited not only in changing what they're familiar with to

            24    maybe something that's not a direct replication of that,

            25    but yet a total different device because of the formulary

                                                                          119

             1    limitations of a managed care company, I just don't know

             2    what -- it seems awfully quiet.  I don't know whether this

             3    is the calm before the storm or --

             4                MS. WORSTELL:  I would have to get more

             5    specific information from our members than I have right

             6    now, but I can tell you anecdotally that the issues of

             7    formulary are real in terms of options.

             8                I have not heard the complaint so much in terms

             9    of cost to date as I have in terms of options, and those

            10    would go back again because, for example, with Proventil

            11    and Proventil HFA a couple of years ago, when it was first

            12    coming on the market, the products, the HFA was made the

            13    only Proventil available in some formularies, and the

            14    switch was made without any kind of education of the

            15    patient, and that was the issue.

            16                I did not hear about costs at that time. 

            17    Certainly, I think there are concerns, particularly, for

            18    example, some of our board members, some of our patient

            19    advocates, because of changes in employment and changes in

            20    health care, they have stayed with their regular physician,

            21    and they don't have the same kind of insurance

            22    reimbursement, and they're paying the costs of their

            23    medication out of their pocket.  Those costs are real to

            24    those patients, and that is an increasing issue, and I

            25    think as we see more products come on the market, the costs

                                                                          120

             1    will become more of a topic.

             2                MS. CONNER:  And I have to commend both of

             3    these organizations.  I don't know if the other committee

             4    members are familiar with them, but it's going to be

             5    organizations like The Asthma and Allergy Foundation and

             6    the Asthma and Allergy Network/Mothers of Asthmatics that

             7    are going to play a pivotal role in this education that's

             8    going to be so necessary in the transition because their

             9    newsletters get to the public and to the population that's

            10    most affected by this type thing, and they are sort of an

            11    unbiased resource of information, and I think they do a

            12    great job.

            13                DR. SESSLER:  Thank you.

            14                Dr. Meyer, the over-the-counter bronchodilator

            15    issue was raised.  I don't know if you would care to speak

            16    to this at this time or later on.

            17                DR. MEYER:  Well, I think I would like to make

            18    one point in that regard right now, and I think perhaps the

            19    committee may choose to raise it again later, and we could

            20    talk further, but I think the main issue I'd want to

            21    clarify is that right now, epinephrine is being treated the

            22    same as every other short-acting bronchodilator, meaning

            23    that it would be considered on a moiety-by-moiety basis,

            24    and we would anticipate that it will have sort of the same

            25    paradigm as the prescription products.

                                                                          121

             1                Obviously it is somewhat of a different issue

             2    in terms of when you get to the broader discussion of the

             3    asthma armamentaria in the 2005 and beyond range.  It has

             4    perhaps a different role from the prescription products

             5    arguably, but there's certainly no -- it's not carved out

             6    as having essentiality forever.

             7                For one thing, the Montreal Protocol doesn't

             8    allow that, and that was not our intent.  Our intent was to

             9    include it in this rule as any other moiety and treat it as

            10    any other moiety.

            11                I gather that some of this question about

            12    whether it's got more protection is because of its market

            13    niche more than anything else, but we're not intending to

            14    treat it differently.

            15                DR. SESSLER:  That concludes our scheduled

            16    speakers for the open public hearing component.  I'd like

            17    to now open the floor, if you will, to any other

            18    individuals who wish to speak before the committee in this

            19    area.

            20                (No response.)

            21                DR. SESSLER:  There appears to be no other

            22    speakers.  So what I'd like to do is we've got about 35

            23    minutes or so left, and what I'd like to go forward with is

            24    really to start the discussion of some of the discussion

            25    points that we are scheduled to address in the afternoon,

                                                                          122

             1    and the first of these, I think, is an important one.

             2                The order that was created by Dr. Meyer and

             3    company, I think, is on target, in that I think some of the

             4    issues that are basic issues, specifically comparison of

             5    the different devices, I think, is a useful starting place,

             6    and particular questions that I have, and what I would like

             7    to do is invite commentary from the committee as well as

             8    from FDA individuals about some of the comparison between

             9    dry-powder inhalers and propellant-driven types of

            10    inhalers, such as the HFA formulation, with the specific

            11    limitations in mind.

            12                In other words, not so much does this meet the

            13    needs of the general population, but really how about some

            14    of the other members of the population, such as children or

            15    the elderly or those who have limited air flow capacity, or

            16    environmental issues, such as excessive moisture in the

            17    environment and things of that nature.

            18                Are these products really comparable?  The

            19    follow-up point within that bulleted point is really what

            20    about novel devices?

            21                So I'd really like to toss it open.  I don't

            22    know, Dr. Meyer, if you want to make any opening comments

            23    in that regard or if there are other individuals here who

            24    have data or established expertise.  We'd be interested in

            25    their comments as well and then open comments by the

                                                                          123

             1    committee.

             2                DR. MEYER:  I think I covered sort of our

             3    concerns on this discussion point earlier.  So unless

             4    people had any questions going into it right now, I'd throw

             5    it open to discussion.

             6                DR. JOAD:  I think my biggest concern about

             7    alternatives is that there should be something in the

             8    regulation that should specifically address anyone who

             9    cannot cooperate in any way with an inhalational device. 

            10    So that's young children who use an MDI with a spacer and a

            11    mask or older people with cerebral palsy.

            12                Anybody who can't actually cooperate in any

            13    way, there should be an alternative for that group, and I

            14    don't think the moiety-by-moiety approach may work for

            15    that.  I'd be happy to have it work that way, but that

            16    might be a place where you needed a class-by-class

            17    suggestion, that at least within each class, there need to

            18    be -- if we don't use the word "MDI," and I understand why

            19    you didn't do that, but there needs to be some sort of

            20    phrase for a type of portable inhalation device that

            21    requires no cooperation.

            22                DR. SESSLER:  Dr. Fink?

            23                DR. FINK:  Yes.  Well, in use of the

            24    alternative devices, such as one, the budesonide

            25    Turbuhaler, I think initially I was concerned about it

                                                                          124

             1    being a pediatrician, and one of the things that had been

             2    very helpful there that I think the FDA could encourage is

             3    the fact that Astra made available a whistle that would

             4    show whether a child could reach adequate air flow to use

             5    the device properly has been very reassuring in introducing

             6    the device as well as reassuring parents, and the only

             7    improvement on it I could see is that if the whistle were

             8    actually built into the actual device, that the dry-powder

             9    inhalers could potentially have incorporated into them some

            10    kind of patient feedback mechanism to ensure that you've

            11    reached adequate peak air flow to deliver the dry powder,

            12    that this would really be helpful.

            13                It's nice to have the whistle separately, but

            14    if it were actually integrated into the device, it would be

            15    even nicer.

            16                DR. NIEDERMAN:  I just want to reiterate a

            17    comment I had made earlier, and that is that we're focusing

            18    a lot on alternative MDIs and on dry-powder inhalers, but

            19    there are other types of devices that are out there.  I've

            20    seen one demonstrated that's a breath-actuated nebulization

            21    in a portable device that's electric and takes liquid and

            22    would be very easily used.

            23                So I think we have to, first of all, hope that

            24    this regulation is going to encourage through the free

            25    market system development of products like that, and,

                                                                          125

             1    secondly, I think if we're going to make a specific

             2    requirement in a moiety-by-moiety analysis, that we have to

             3    have an MDI specifically available that may turn out with

             4    better devices coming to be unnecessary.

             5                We may have devices coming that are easier to

             6    use than MDIs, easier than dry-powder inhalers, and we may

             7    not want to be constrained to specifically require that an

             8    MDI alternative to an existing MDI, if we can find through

             9    the development process that there are better devices out

            10    there.

            11                DR. JOAD:  Just briefly, to really make sure

            12    it's clear that I really don't care if it isn't an MDI, but

            13    I do care that it should be something that requires no,

            14    absolutely no cooperation from the patient, that there be

            15    such a thing for that group of people.

            16                DR. NIEDERMAN:  Or at least that it be not any

            17    more cumbersome than the current MDIs.  I mean, I'm not

            18    sure that you can totally take out cooperation with the

            19    current MDIs even with a spacer device.  I think you need

            20    some cooperation.

            21                So I think the standard has to be that it's no

            22    more patient cooperation-dependent than the current

            23    devices.

            24                DR. JOAD:  I'm talking about a spacer with a

            25    mask.

                                                                          126

             1                DR. GROSS:  I'd like to extend those concerns. 

             2    I think the biggest concern that we should have, one of the

             3    biggest concerns from the patient point of view is that in

             4    five years' time, there are going to be 25 different ways

             5    that patients have available, doctors have available to

             6    prescribe for treating airways diseases, and we don't

             7    really realize how fortunate we are at this particular time

             8    that pretty well everything we want to administer through

             9    the airways, we can do with the same device, and once you

            10    know how to use a device to inhale albuterol, you don't

            11    need to be taught again how to use the same device to

            12    administer some other drug.

            13                But that obviously is all going to go away, and

            14    I have concerns that I'd like to address to the patient

            15    advocates and particularly to the two members that we heard

            16    from this morning that one of the biggest educational tasks

            17    that they're going to be facing is that all of their

            18    membership is going to have to learn how to use not just

            19    one new inhaler but a different new inhaler probably for

            20    every drug they have.

            21                Unless one drug company is fortunate enough to

            22    come up with an idea that's so good, that it simply waves

            23    the other alternative agents away, and everybody wants to

            24    deliver their medication through that one new device, I

            25    don't think that's very likely to happen.

                                                                          127

             1                So I think that we have to get used to the idea

             2    that everybody who wants to use a drug will probably have

             3    to use it through -- every manufacturer who wants to make a

             4    drug available probably will have to do it through a

             5    different agent.  That's really just an aside because I

             6    think it's really a matter for the patient and their family

             7    organizations to arrange to make sure that the education is

             8    there, and obviously the FDA can't do that for you, but you

             9    and your cooperation with other organizations, like the

            10    Thoracic Society, and certainly with the pharmaceutical

            11    industry, who are very interested, I know, in promoting

            12    education and how to use their product well, I'm sure that

            13    will have to be done very quickly.

            14                But I would like to ask the FDA.  Are you

            15    confident that the industry is moving appropriately in

            16    terms of the speed?  Do you think that we will have all the

            17    agents that we need to use by the year 2005 in CFC-free

            18    form?

            19                DR. MEYER:  I think the industry has certainly

            20    been tremendously responsive to this in general.  I think

            21    that it is clear, in fact we've publicly discussed in

            22    congressional testimony and other places, that we're fairly

            23    well aware that there are some products, you might call

            24    them more minor products in the armamentarium, that we do

            25    not have any evidence that they're being considered for

                                                                          128

             1    reformulation.

             2                So we know there are some products that the

             3    sponsors are not attempting to reformulate, and so I guess

             4    in general, it seems like the industry's being very, very

             5    responsive, and there will be perhaps alternatives for most

             6    of the major players.

             7                There clearly will be some that are either

             8    straggling or perhaps not reformulated at all, and they

             9    will present some, I think, challenges in the transition

            10    process.

            11                MS. CUSUMANO:  The only thing I would add to

            12    that is that 2005 is when we might start looking at those

            13    products that haven't been reformulated.  So it's not

            14    necessarily a date when everything that's CFC's going to go

            15    off the market.

            16                DR. SESSLER:  Dr. Kelly?

            17                DR. KELLY:  I guess the question that comes up

            18    is on the approach that Dr. Joad talked about, was what do

            19    you do for the existing non-approved uses of the CFC MDIs?

            20                Dealing in pediatrics, we've been using them

            21    for non-approved uses for a long time, and that has to do

            22    with the face mask and spacer devices, and if you look from

            23    a regulatory point of view at the moiety-for-moiety in just

            24    looking at the approved uses, you might be missing some of

            25    your patient population, and have you thought about how you

                                                                          129

             1    are going to approach it in terms of all the unapproved

             2    uses as well?

             3                DR. MEYER:  Certainly, I think the way the

             4    notice of proposed rulemaking is written, there's sort of

             5    an upfront expectation that we're talking about a product

             6    that has a moiety, a product that has a moiety with the

             7    same indication as the CFC alternative.

             8                But we clearly wrote the rule having in mind

             9    that there are going to be other uses, other than the

            10    approved indications, that we need to consider, and I think

            11    that that will be part of the discussion that occurs at the

            12    time of notice and comment rulemaking or any other approach

            13    that we are taking in the future when we go to delist a

            14    specific moiety.  We will need to consider such uses.

            15                I would add that the agency, through a recent

            16    revision in our Act, has much more authority now to really

            17    upfront expect pediatric trials specifically, and I think

            18    that we are very anxious to even look at some use that we

            19    know is going on, even if it's not approved, in terms of

            20    the safety and efficacy of that, and that could include

            21    things like the use of spacers and masks and so on.

            22                So there's perhaps not a neat answer for that

            23    right now, but I think we're building in ways in our notice

            24    of proposed rulemaking to address this, and the agency also

            25    has other ways that work at least for the pediatric

                                                                          130

             1    population that we're going to be getting such data that

             2    will be helpful for our ultimate assessments.

             3                DR. SESSLER:  One of the questions that I have

             4    relates to the impact of moisture on the dry powder.  That

             5    was mentioned, I think, in the original presentations, and

             6    I guess I don't have a good feel for the magnitude of that.

             7                Is it really a substantial barrier in regions

             8    or locales that have extremely high humidity or what are

             9    the real limitations?  I don't know if you have data or if

            10    a member of the division is an expert on DPI and perhaps

            11    familiar with the European experiences and so on.  If you

            12    could comment.

            13                DR. MEYER:  Well, our chemistry staff is most

            14    intimately involved with these issues, but they require

            15    testing during the development of any of these products,

            16    including the dry-powder inhalers, of exposures to certain

            17    conditions, including high humidity conditions, and I might

            18    add that those high humidity conditions are perhaps even

            19    perhaps a little bit lower humidity than might be

            20    experienced in some regions of the United States.  You

            21    know, Louisiana in the summer, for instance.

            22                DR. SESSLER:  Richmond.

            23                DR. MEYER:  Yes.  Even Washington, D.C.  But I

            24    think the other side of that is the chemistry staff is also

            25    very realistic about wanting to make sure that these

                                                                          131

             1    products hold up under those high humidity conditions, and

             2    really they pay a lot of attention to those sorts of

             3    issues.

             4                But it is the reason why some dry-powder

             5    inhaler products are overwrapped, come in sort of a foil

             6    pouch, or in fact, others have deskins actually in the

             7    device, and it's the reason why some of the ones in the

             8    overwrap, for instance, have an in-use period.

             9                In other words, they have instructions that

            10    after it's been taken out of that pouch for a certain

            11    amount of time, they're no longer considered as within

            12    their expiration date, and because the particle size does

            13    shift over time due to humidity, and so we're fully

            14    confident that when used as directed, that they will

            15    perform safely and effectively.

            16                But I think the industry knows, and we know,

            17    that some of these are susceptible to moisture and that

            18    changes the way they need to be handled.

            19                DR. SESSLER:  I guess as a follow-up, is the

            20    magnitude sufficient that this should be an additional

            21    consideration in terms of -- and I know it has been in a

            22    therapeutic class, that I believe you mentioned the

            23    original proposal included two different approaches to drug

            24    delivery at a minimum.

            25                I don't know if that disappears with the

                                                                          132

             1    moiety-to-moiety approach.  For example, for inhaled

             2    corticosteroids, is it possible that they would all be dry

             3    powder, and is our concern overstated about the moisture

             4    problem or is it something that if we feel confident that

             5    every single delivery system was similar, would that put us

             6    in to difficulty for certain patient populations?

             7                DR. MEYER:  I think for just the issue of an

             8    adequate alternative on a moiety-by-moiety basis, that, for

             9    instance, if there were a dry-powder inhaler approved for a

            10    moiety that was delivered in CFCs, but there was no

            11    alternatively-propelled MDI, if that DPI's approved, then

            12    we are confident that it will perform sufficiently well in

            13    all the circumstances that are likely to occur.

            14                I mean, there's always surprises, and I'll come

            15    back to that in a second, but if it's used correctly in all

            16    regions of the United States, according to the labeling,

            17    that it will perform adequately.

            18                The question is if that means that after it's

            19    taken out of the overwrap, it's only good for three months,

            20    is that an adequate alternative?  I mean, issues of

            21    inspiratory flow aside, is that an adequate alternative,

            22    knowing that perhaps some people keep their CFC inhalers in

            23    their gym locker at the Y for a couple of months, and if

            24    they need it, they go grab it, the gym locker room being a

            25    fairly moist place.

                                                                          133

             1                So I guess that's the question.  We know that

             2    they will perform sufficiently when used as labeled.  I

             3    alluded to there being surprises.  I don't mean from some

             4    sort of a regulatory standpoint.  Patients sometimes will

             5    do things that you can't anticipate to, but that's true of

             6    MDIs as well.

             7                DR. SESSLER:  Dr. Jenkins?

             8                DR. JENKINS:  If I could just follow up on that

             9    as well.  Moisture is not only a problem for dry-powder

            10    inhalers, it can also be a problem for the metered-dose

            11    inhalers.  It seems counterintuitive that moisture can make

            12    its way into those canisters, but I've been surprised to

            13    learn since I've come to the FDA that it can, and it does.

            14                So you may even see in the future some of the

            15    alternatively-propelled metered-dose inhalers may have

            16    protective foil overwraps and may have dating periods after

            17    you've taken them out of the overwrap, how long they might

            18    be in specifications.

            19                So it's a big problem for the dry-powder

            20    inhalers, but it's not unique to the dry-powder inhalers. 

            21    It can affect the metered-dose inhalers as well.  Moisture,

            22    it's everywhere, and it manages to get to wherever you

            23    don't want it to get.

            24                DR. SESSLER:  Thank you.

            25                Any comments from the pediatricians here?  I

                                                                          134

             1    know we've heard already a little bit.  That seems to be

             2    again one of the special populations that we want to be

             3    sure that the device issue is adequately addressed, given

             4    the important differences between kids and adults.

             5                Any further comments from the pediatric folks?

             6                DR. FINK:  Well, what's currently on the market

             7    doesn't meet the needs terribly well, and hopefully there

             8    will be some better novel devices out there.

             9                The spacer/mask combination is usable, but you

            10    don't know how much it's delivering, and it sure is not the

            11    kind of thing you like to do repetitively to an infant. 

            12    It's not usually a good maternal/child interface.

            13                So I think that there's real room there for

            14    something novel.  I mean, something that was a liquid,

            15    electrically operated or battery operated liquid device or

            16    that a dry-powder device that created a cloud.  I mean, I

            17    don't know what people are going to come up with, but

            18    definitely some better devices for the minimally-

            19    cooperative patient would be appreciated and needed.

            20                DR. JOAD:  Well, I just had a concern when you

            21    mentioned that when they reformulate, they may not have to

            22    reformulate in the same doses, and just getting at our use

            23    in very young children, I wouldn't want all of those doses

            24    to be higher than what's presently available.

            25                MS. CUSUMANO:  That's what Bob had referred to,

                                                                          135

             1    to a degree, but with the 1998 pediatric rule.  When a

             2    company files an NDA or a supplement, if there's pediatric

             3    use for the product, they'll have to do a pediatric

             4    assessment, which could include the development of a new

             5    formulation.

             6                DR. JENKINS:  Actually, one of the positive

             7    benefits, if you want to view positive benefits of the

             8    transition, is that it has spurred a lot of innovation.  So

             9    we're no longer in a scenario where everything is just

            10    focused on CFC-based metered-dose inhalers.

            11                There's a tremendous amount of innovation going

            12    on within the pharmaceutical industry, not only for the HFA

            13    MDIs and the multidose dry-powder inhalers, but there's

            14    also a lot of innovation going on on other unique and novel

            15    delivery systems.

            16                So we may get a side benefit from this

            17    transition that we actually get better devices, and in many

            18    ways, they're being stimulated by the need to reformulate

            19    where maybe they would not have been so incentivized in the

            20    past.  So that may be a plus.

            21                DR. SESSLER:  Any other comments related to

            22    delivery devices?

            23                DR. FINK:  Just one comment that has been an

            24    improvement in some of the newer devices, like the Diskus

            25    or the Turbuhaler.  It would also be the opportunity that

                                                                          136

             1    as MDI replacements come along, there has for a long time

             2    been a problem of deciding when it's empty and requiring

             3    manufacturers to have some kind of built-in feature in the

             4    device so that when drug is no longer available, the device

             5    somehow indicates that it's not delivering drug any

             6    further.

             7                DR. SESSLER:  I'm going to move ahead to the

             8    second bulleted point, and this will probably finish up the

             9    morning session.  The question is posed:  how can FDA best

            10    determine the medical needs of patients who previously have

            11    relied on CFC MDIs are being sufficiently met?

            12                So this is kind of, certainly, how can we do

            13    it?  Yes, we need to do it, but the question really is what

            14    suggestions from the committee and others do we have as to

            15    the how?

            16                DR. NIEDERMAN:  I think that this is going to

            17    be a key issue, and we're certainly going to need to rely

            18    on patient reporting and post-marketing surveillance, but I

            19    guess the amount of data that's available now through

            20    insurance companies and Medicare and so forth probably

            21    would allow access to monitoring general admission rates

            22    for asthma, ER visits and so forth, and I think that that's

            23    going to be certainly one important end point to look at.

            24                If we saw an upturn in the amount of emergency

            25    visits for asthma during a transition period, I think that

                                                                          137

             1    would be very important data to have.  So I think there's

             2    going to need to be multiple levels on which this is looked

             3    at, but I would encourage that part of the program involve

             4    some of the larger databases that will be available on a

             5    community-wide level to be looking at general use of

             6    emergency services for asthma.

             7                DR. APTER:  I guess I would most like to see

             8    randomized clinical trials in patients.  Those data are

             9    very useful, but they can also be flawed.  For example,

            10    sometimes outpatient prescriptions by the physician are not

            11    linked to pharmacy bases or not linked to emergency room

            12    visits and hospitalizations.  So it can be useful but very

            13    difficult.

            14                DR. NIEDERMAN:  I think that's good, but --

            15                DR. APTER:  So ideally randomized trials

            16    comparing head-to-head, the old with the new, would be most

            17    ideal.

            18                DR. NIEDERMAN:  But I think if we require that

            19    in order to license a new product, it's going to discourage

            20    some of this innovation and development, and I don't know

            21    how much licensing you're going to require or how much

            22    demonstration of efficacy you're going to require before,

            23    say, a novel device gets licensed for the delivery of, say,

            24    albuterol.

            25                DR. MEYER:  It, I guess, depends a little bit

                                                                          138

             1    on the moiety in question.  If it's an already-accepted

             2    moiety, there undoubtedly would be some streamlining to the

             3    number of trials and the types of trials that might be

             4    required, but we certainly would expect adequate

             5    demonstration of safety and effectiveness in the intended

             6    population and then perhaps, in some respects, a long-term

             7    trial to both look at the safety of the formulation but

             8    also how the new device holds up over time in terms of

             9    performance in patient hands.

            10                DR. NIEDERMAN:  Well, as a matter of just

            11    understanding, when the albuterol HFA was released, what

            12    type of data was needed in order to get approval?

            13                DR. MEYER:  There is some pre-clinical data,

            14    some toxicology data to look specifically at the

            15    reformulation that would be expected for that sort of

            16    product.  There are dose-ranging trials which, for

            17    bronchodilators, generally can be single-dose cross-over

            18    trials to compare it to the CFC product, and then there

            19    generally would be at least one, and I'm forgetting now

            20    that with Proventil HFA, whether it was in fact more than

            21    one 12-week adequate and well-controlled randomized trial

            22    in comparison to the CFC product to see how it performs,

            23    and then the one-year safety study to look at in an open-

            24    label fashion how the patients tolerate it over time.

            25                DR. NIEDERMAN:  So presumably any new product,

                                                                          139

             1    no matter how it's delivered, HFA or novel device, in order

             2    to get approval as a replacement is going to have to go

             3    through a head-to-head comparison with the CFC product?

             4                DR. MEYER:  For a product that's essentially a

             5    new formulation, contains a previously-approved moiety, one

             6    of the paradigms there for the sponsor to do an abbreviated

             7    program is for them to compare it head-to-head to show how

             8    it compares to the prior products, and we can rely on our

             9    previous finding on safety and efficacy to help label the

            10    new product.

            11                They have the option of doing a full new

            12    program and not comparing it head-to-head, but again in an

            13    abbreviated program, we would expect some level of head-to-

            14    head comparison to allow us to rely on our previous

            15    findings.

            16                DR. NIEDERMAN:  And if, hypothetically, an HFA

            17    version of a generic albuterol were to become available,

            18    would that be immediately accepted or would it also have to

            19    be tested and compared since there's a branded albuterol

            20    HFA available?

            21                DR. MEYER:  Well, it would be like any other

            22    approval of a generic, and basically they have to show

            23    bioequivalence.  So it has to be the same in terms of its

            24    pharmaceutics, and then they have to prove bioequivalence,

            25    which, for the albuterol products, basically means doing a

                                                                          140

             1    very rigorous single-dose cross-over comparison to the

             2    innovator product and showing that it acts the same.

             3                So in some ways, that particular study is more

             4    rigorous than we're asking for, like Proventil HFA did not

             5    have to show bioequivalence, but, on the other hand, for a

             6    generic, that's all they have to show.  They have to show

             7    that they're pharmaceutically the same and then

             8    bioequivalent, and then they're done.

             9                DR. NIEDERMAN:  So if those trials aren't

            10    adequate, then I would still think monitoring some sort of

            11    larger databases will give you some general trends, maybe

            12    not accurate but certainly you're going to have these

            13    comparative data, and you're going to want the reassurance

            14    that the asthma field hasn't changed because of the

            15    availability of these new products.

            16                DR. MEYER:  I think clinical trials, well-

            17    controlled clinical trials tell you a lot, but they don't

            18    tell you certainly everything, and particularly they're

            19    very well-groomed patient populations that are taken into

            20    them.  They're the only the patient populations for which

            21    the drug is indicated, and I think we're very much

            22    interested in the post-marketing period about what happens

            23    in the patients who are using it for other indications off-

            24    label or more severe patients than were the clinical trials

            25    or younger or older, so on.

                                                                          141

             1                And then, finally, just due to some of your

             2    statistical limitations, if you have a database of a

             3    thousand patients, you're not likely to pick up a very rare

             4    event.  So if there was some rare reaction to the

             5    formulation, we wouldn't pick that up in clinical trials,

             6    unless we were quite lucky, either.  So.

             7                DR. SESSLER:  Dr. Kelly?

             8                DR. KELLY:  Yes.  Actually, I think the

             9    clinical efficacy and safety trials are the easiest part,

            10    as you alluded to, and it's the clinical effectiveness

            11    studies that we all struggle with on how do you get that,

            12    and I'm not sure large databases from, say, Kaiser or

            13    something like that on emergency room or hospitalization is

            14    even sufficient.

            15                What I'd be more interested in is, you know,

            16    how many school days missed in a patient population because

            17    of less patient acceptance of a particular device, how much

            18    work days are missed.

            19                Can we somehow get to those types of

            20    populations through employer data, and I don't know whether

            21    that's possible or not, but I think you're looking at using

            22    the current things that we use now, you're just looking at

            23    the tip of the iceberg of asthma.

            24                You can define clinical efficacy, but in terms

            25    of the acceptance by the patient population, what you want

                                                                          142

             1    is the effectiveness.

             2                DR. MEYER:  Let me make a statement in that

             3    regard and then invite you to comment back or invite

             4    anybody else to comment back, because I think if we're

             5    effective -- we being the FDA -- in gaining communication

             6    with the patient community, either through their advocacy

             7    groups or otherwise, I think the patient community, perhaps

             8    knowing that they've shifted a product, will be pretty good

             9    about coming forward and saying, you know, since I switched

            10    on this, I don't think I'm doing as well.

            11                I think that we're probably more worried about

            12    specificity than sensitivity from that kind of data.  So I

            13    guess if we do our job in terms of communication with the

            14    patient community, I suspect we may at least get some

            15    handle on important differences.  That's perhaps not the

            16    ideal way to approach it, but I think that that will be one

            17    thing that will be available to us.

            18                So I offer that as a comment and see what you

            19    think.  It's not rigorous, but certainly again I think

            20    patients are quite sensitive to switching products, and if

            21    they do, and they detect a deterioration in their

            22    treatment, as long as there's a way for that to be

            23    transmitted back to us, I think that we'll at least have a

            24    signal there.

            25                DR. SESSLER:  I think one of the important

                                                                          143

             1    questions, also, is availability, moving away a bit from

             2    the specific characteristics of the drug and safety and

             3    efficacy, but availability in particularly the underserved

             4    populations and the risk for them perhaps having less in

             5    the way of asthma control.

             6                Are there ways of coordinating efforts in terms

             7    of epidemiologic studies and funding for those studies with

             8    other government agencies, such as NIH, to look at this not

             9    so much as it relates to a single drug product but really

            10    the care of asthma in transition?  Is there a way of having

            11    our voices heard and the FDA's voices heard as far as

            12    enlisting their financial support and so on for actually

            13    doing good epidemiology?

            14                DR. MEYER:  I'm sure there are ways that that

            15    could be approached outside of the FDA's normal paradigm,

            16    and we do have access to managed care databases and such

            17    for doing some of our post-marketing assessments, and

            18    obviously that's not what you're talking about, and I know

            19    that those populations are of substantial interest to many

            20    groups, including the NAEPP.

            21                So I think there are opportunities for that

            22    kind of partnering.  I think that's something we'll need to

            23    consider as we move ahead.

            24                DR. SESSLER:  Two more comments, and then I

            25    think we'll break for lunch.  Dr. Fink, and Dr. Joad.

                                                                          144

             1                DR. FINK:  I would just be very concerned about

             2    the use of epidemiologic data and large databases because

             3    there are multiple transitions occurring in the care of

             4    asthma.

             5                There's the NAEPP guidelines.  There's the use

             6    of the leukotriene modifiers.  We may soon have interleukin

             7    modifiers and other products that are not traditional CFC-

             8    containing devices that are going to modify the spectrum of

             9    asthma treatment, and these are going to be reflected in

            10    any large database, and I don't know how you're going to

            11    separate out the CFC transition from all of these other

            12    undercurrents in the treatment of asthma that are

            13    occurring.

            14                The fact that we're now getting asthma-friendly

            15    schools is an accepted concept.  I think some of these are

            16    going to have much bigger impacts on what we see nationally

            17    or even locally than the switch or phaseout of CFCs.

            18                DR. SESSLER:  Did you have a comment?

            19                DR. JOAD:  Yes.  In your head-to-head

            20    comparison of the alternatives, are you going to have a

            21    required measurement of convenience to the patient as part

            22    of that?  Did they think of that since that's one of your

            23    criteria?

            24                DR. MEYER:  I don't think we really envisioned

            25    convenience as being something that we would gain a feeling

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             1    for out of the controlled clinical trials because, for one

             2    thing, most of those trials are done in such a manner that

             3    patients are instructed heavily and told how to use it, and

             4    you don't really get a good feel for how convenient they

             5    are.

             6                That being said, there are many manufacturers

             7    that do sort of ask a general questionnaire at the end of

             8    the study of what do you think of this device and often

             9    will present us that kind of data for, say, a dry-powder

            10    inhaler that's a reformulation of a CFC.

            11                But I think we were talking or thinking more in

            12    line of us sort of, from our scientific standpoint, perhaps

            13    using input from the committee, where appropriate, on what

            14    the level of convenience seemed to be, and any signal or

            15    any information that came from the clinical trials would be

            16    additional to that but not the primary way of assessing it.

            17                DR. SESSLER:  Dr. Vollmer?

            18                DR. VOLLMER:  I've been puzzling over the

            19    various issues around this question.  It seems to me that

            20    you're inevitably going to be doing a mix of both clinical

            21    trials certainly in the pre-approval phase as you're

            22    looking at head-to-head comparisons and how things shake

            23    out.

            24                I would concur that taking account of more

            25    patient focused outcomes, such as quality of life and sick

                                                                          146

             1    days and days lost from work for parents, are going to be

             2    relevant outcomes to be looking at, but once the drug is

             3    approved, you're going to have certainly access to it and

             4    an enormous amount of post-marketing data, and even

             5    acknowledging the difficulties that were raised about

             6    secular trends and what else is going on, I think it's

             7    going to provide useful information.

             8                As I thought about the way this talking point

             9    was phrased, how can we best determine the medical needs of

            10    patients who previously relied on the CFC MDIs are being

            11    sufficiently met, it seems to me there's two issues buried

            12    within that.

            13                One is a suggestion that there may be adverse

            14    effects associated with the new devices in particular

            15    populations either because they're not able to use them

            16    properly or whatever, and that's going to have to be looked

            17    at closely, and to the extent that there are anticipated

            18    concerns, I think a lot of the patient advocacy groups in

            19    particular are going to have to be important spokespersons

            20    as these drugs are being brought forth in the development

            21    process so that we take the time to look properly at their

            22    use in those groups.

            23                The second issue is even if there are no

            24    adverse effects from their use, there just may be

            25    populations that are unable to use them, as was pointed

                                                                          147

             1    out, and so that issue about patients being underserved

             2    needs to be looked at and monitored probably in post-

             3    marketing data or whatever of who's really using these, and

             4    that's going to inform the process of dropping the

             5    essential classifications from the CDCs that are currently

             6    being used for this population.

             7                So it seems it happens in two stages.  First,

             8    often the original approval, if there are concerns, you're

             9    going to have specific head-to-head focus comparisons to

            10    look at what happens.  Are there potential adverse effects

            11    or problems in using these medications?

            12                If that doesn't surface, you still have the

            13    opportunity in the post-marketing data to find out whether

            14    certain populations really wind up using them for whatever

            15    reasons, and if not, then it's going to be important to

            16    keep the alternative CFC formulations available for those

            17    populations until something else comes along that does work

            18    for them.  So you have a little bit of both things going

            19    on.

            20                DR. SESSLER:  Thank you.  I'd like to thank

            21    everybody for their comments.

            22                When we start back, we'll be heading right back

            23    into post-marketing.  So it's related, and so if you have

            24    additional comments related to this issue, I think it will

            25    fold in nicely with that.

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             1                We'll meet back here at 1:00 and start on time. 

             2    Thanks.

             3                (Whereupon, at 12:02 p.m., the meeting was

             4    recessed for lunch, to reconvene at 1:00 p.m.)

             5

             6

             7

             8

             9

            10

            11

            12

            13

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                                                                          149

             1                         AFTERNOON SESSION          (1:04 p.m.)

             2                DR. SESSLER:  Good afternoon.  I'd like to go

             3    ahead and bring the afternoon session to order.  I hope

             4    everybody got fuel for a lot of good discussion in the

             5    afternoon and not too much fuel so you fall asleep.

             6                Before we start, Dr. Meyer had something he

             7    wanted to address, I believe.  We'll come back to that, I

             8    guess.

             9                The afternoon is devoted to addressing a number

            10    of the talking points that were raised by FDA for committee

            11    discussion, and we've already gotten well into that with

            12    some good conversation on the first couple of points.

            13                The third point really ties in with the second,

            14    I think, in terms of a nice segue from patients' needs to

            15    post-marketing data, and I think some of the conversations

            16    that we were having just before lunch can easily be carried

            17    right into how this might translate into post-marketing

            18    data discussion as well.

            19                So I'd like to read that and then just toss it

            20    open for comment, and then when Bob gets back, we'll ask

            21    him to make a comment about one of the other points.

            22                What kind of post-marketing data will be most

            23    helpful to ensure patient needs are being met, and that the

            24    product is proving to be reliable and acceptably safe in

            25    broader use?

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             1                I know there has been some discussion already

             2    about post-marketing data with, I guess, differing views to

             3    a certain extent.  I'd like to toss it open for comment

             4    from any committee members.

             5                DR. FORD:  I'd like to concur with some of the

             6    comments that Bill made and the two Bills, Bill Kelly and

             7    Bill Vollmer, about the need for studies that assess

             8    clinical effectiveness, and I would also suggest that

             9    there, it would be appropriate to really look at some

            10    process measures because one of the issues that's going to

            11    really come up is, you know, how good is the education

            12    that's going in, and in interpreting effectiveness data

            13    ultimately, part of what we will have to know is whether or

            14    not the message is breaking down at some point in the

            15    chain, although I would expect that with increasing

            16    experience with a product, that that issue would be

            17    addressed, but it might be worthwhile monitoring whether or

            18    not -- you know, how much confusion there is in practice,

            19    let's say, in terms of the different maneuvers that

            20    patients have to learn to do effectively.

            21                DR. SESSLER:  Anything specific that you or

            22    anybody else would like to add?  I think one of the things

            23    that FDA is always interested in are specific approaches. 

            24    If we have any experience with it or any particular ideas?

            25                DR. FORD:  In studies, just to follow up on

                                                                          151

             1    that, if it were possible to in fact have data about

             2    whether or not, one, providers are communicating properly

             3    to patients in terms of how to use those devices should be

             4    a no-brainer.

             5                I would think these devices are easier to use

             6    than the MDIs, but on the other hand, it's probably

             7    worthwhile to look at that and that's just built-in process

             8    measures in general, and this would be one of them.

             9                DR. NIEDERMAN:  Curt, I guess I'm confused

            10    about one thing.  If there's a new product that becomes

            11    available without a CFC, will the CFC product be available,

            12    say, during the first year while the product is being

            13    trialed or has FDA decided?

            14                DR. SESSLER:  I think the answer is yes, but

            15    Dr. Meyer can comment.

            16                DR. MEYER:  Yes, unless the company chose to do

            17    otherwise.

            18                DR. NIEDERMAN:  Because I think that that

            19    provides an immediate opportunity for post-marketing

            20    studies, to see with different products the ease of

            21    acceptance compared to the CFC and what the usage patterns

            22    are, because I'm not sure how you're going to mandate that.

            23                In other words -- and I'm not sure how you

            24    would regulate that.  I think that may be an important

            25    issue.  If you get an HFA version of an inhaled steroid,

                                                                          152

             1    and you have the CFC version on the market, particularly if

             2    the costs are different, how do you get shifting from one

             3    to the other, and depending on what the answer to that is,

             4    then the monitoring of that shift may be one post-marketing

             5    way to look at the efficacy and the acceptance of that

             6    product.

             7                DR. FINK:  I think if the pharmaceutical

             8    companies are as aware of marketing as they usually are, a

             9    company's going to be faced with the decision that they

            10    either come out with both at the same price or they're

            11    going to price their new product lower because if they

            12    price their new product higher, then they've got to stop

            13    production of the CFC-containing device, and people aren't

            14    going to switch to a new product if it's significantly more

            15    expensive if you leave the low-priced alternative on the

            16    market.

            17                DR. NIEDERMAN:  Yes, but I think the problem

            18    might be if there's a generic version of it or a CFC

            19    alternative to it.  You're right.  For the one company that

            20    does it -- I mean, I think you take the example of

            21    albuterol HFA.  Schering, I guess, eventually stopped

            22    making Proventil in favor of Proventil HFA, but --

            23                DR. FINK:  They still make Proventil, I think.

            24                DR. NIEDERMAN:  I'm not sure.  I'm not sure you

            25    can get it, but you can certainly get the generic

                                                                          153

             1    albuterols with CFCs, and we talked earlier, but I don't

             2    know whether it's the product or it's the price that

             3    accounts for the fact that the uptake was so low.

             4                At least it's something you can monitor.  The

             5    question is, it probably will tell you different things

             6    about different products, depending on what products are

             7    remaining with CFCs in that moiety department or that

             8    class.

             9                DR. SESSLER:  Dr. Fink?

            10                DR. FINK:  One comment that's really not post-

            11    marketing, but as the newer products come out, one thing

            12    that I think would help, particularly for post-marketing

            13    surveillance and for general medical care, is if FDA could

            14    come up with some kind of standardized recognition of

            15    packaging, i.e. that inhaled steroids had to share a blue

            16    stripe, and then they could be any other color, because as

            17    a clinician, I can tell you that if you look at the various

            18    color array of MDIs out there right now, and you talk to a

            19    patient who's using two or three different MDIs, trying to

            20    get a straight history of what they're taking of which drug

            21    is difficult.

            22                I don't know whether it should be moiety-by-

            23    moiety or class-by-class, but using some coloration of

            24    packaging to help physicians identify what kind of drug

            25    you're dealing with would actually potentially be very

                                                                          154

             1    helpful both for the physicians and for the marketing.

             2                DR. SESSLER:  Let me just ask a follow-up to

             3    that.  Are there requirements that have been -- is there

             4    precedent, I guess, for anything like that, either in

             5    pulmonary drugs or in other areas?

             6                DR. MEYER:  I think I may need to defer at

             7    least part of this to Dr. Jenkins from a broader center

             8    perspective because there may be some areas -- it strikes

             9    me that there might be some paradigm like that for some of

            10    the ocular medications, but I'm not entirely sure on that,

            11    and I don't know whether Dr. Jenkins knows either.

            12                But it's not something that we have

            13    historically looked at in the Pulmonary Division.  I know

            14    the U.K. does something very similar to that, where I

            15    believe the short-acting relievers are blue and the

            16    corticosteroids are brown or something like that, make

            17    color coding up tomorrow's product interesting, but --

            18                DR. JENKINS:  I don't think there's been any

            19    effort to do that with pulmonary products.  There have been

            20    efforts in some other parts of the agency.  For example,

            21    there's some standardization of insulin labeling so that

            22    they have the same nomenclature and the same symbols for

            23    regular insulin versus other types of insulin, and I think

            24    there's an international working group that's working on

            25    trying to come up with standardized colors and labeling for

                                                                          155

             1    the various types of insulin, but that's not been something

             2    that's been considered or done in the pulmonary side of

             3    drugs so far.

             4                DR. SESSLER:  Along the lines of post-marketing

             5    surveillance, there's certainly a body of data from Europe

             6    and from other places where some of these products will

             7    have been approved and in use for some period of time, and

             8    this was alluded to by Mr. Jamieson as well.

             9                What is the value of the European data, do you

            10    think, in terms of should it impact on the type or the

            11    amount of post-marketing data that we collect here in the

            12    States?

            13                DR. MEYER:  I think there is certainly value to

            14    non-U.S. data.  That can be somewhat limited by the type of

            15    question we're asking here in terms of what kind of data we

            16    actually can glean because we're asking some questions

            17    different from the usual regulatory questions.

            18                The other thing I think that I should point out

            19    is that the non-U.S. versions of these products are not

            20    necessarily the same product as the U.S. version.  So there

            21    would be, I guess, in theory, instances where the non-U.S.

            22    data clearly would not directly apply to the U.S. product

            23    if the products were different.

            24                DR. JENKINS:  Curt, maybe to stimulate some

            25    discussion, one of the parts of this question that we've

                                                                          156

             1    discussed internally, and I think Mr. Jamieson actually

             2    touched on also, is whether, when we talk about post-

             3    marketing data, should we be happy with the passive

             4    surveillance type of data that we've been talking about

             5    around the table or do you see a role for actual studies

             6    that, you know, have a protocol and have a design, maybe

             7    some sort of large simple trials or real use type of

             8    trials?

             9                There was a trial of that nature that was done

            10    with the Proventil HFA product.  It's actually called

            11    Airomir in the U.K.  There was a post-marketing

            12    surveillance type of prospective study that was done in

            13    general clinical practice, and I guess we're interested in

            14    hearing the committee's thoughts about are those types of

            15    studies worthwhile?  Should they be required?  Should they

            16    be requested?  Where do you see those fitting in to the

            17    overall schema of collecting this post-marketing data,

            18    really getting to the issue of are patients' needs served?

            19                DR. JOAD:  Could you just explain a little bit

            20    more what that is?  What post-marketing large study is?

            21                DR. JENKINS:  Well, if you go back and look,

            22    remember that the pre-approval clinical trials are very

            23    rigorously controlled.  They have very selective entry

            24    criteria.  So you actually generally end up with mild to

            25    moderate asthmatics who are fairly compliant with their

                                                                          157

             1    medications, and they're in a rigorous 12-week clinical

             2    trial with a low of follow-up.

             3                A post-marketing type of study that may be of a

             4    simpler design might be more of a general practice type of

             5    study, where you in some way randomize patients in practice

             6    to one therapy or the other, but you're kind of following

             7    how the drugs are actually used and not proscribing so much

             8    up front about entry criteria, exclusionary criteria,

             9    indications, et cetera.  It's kind of that type of more

            10    simple design, real-world type of experience.

            11                DR. JOAD:  I think it's an excellent idea.  I

            12    think you should have something like that afterwards.

            13                DR. SESSLER:  Actually, why don't we --

            14                DR. JOAD:  Outcome, right.

            15                DR. SESSLER:  Why don't we do something a

            16    little bit differently?  I haven't done this type of thing. 

            17    We've had such good conversations, but I think this may be

            18    a good time to go ahead and we can go around the table and

            19    offer an opinion, because I think it's an interesting way

            20    to get everybody to voice their questions and concerns and

            21    ideas.

            22                Jean?

            23                DR. FORD:  I think large simple trials or other

            24    kinds of approaches to post-marketing studies, but that in

            25    particular would give us a sense of what's going on in the

                                                                          158

             1    real world, and if the studies are designed so that they

             2    can be informative also as to why we get this or that

             3    result in terms of clinical effectiveness, I think that

             4    that would be useful.  So I would think this is a good

             5    approach.

             6                DR. VOLLMER:  I'm biased towards research since

             7    that's what I do as my bread and butter, but I'm trying to

             8    be as objective as possible in looking at this question.

             9                Certainly the kinds of studies that you're

            10    describing would garner a lot more insight into what's

            11    going on.  It sounds like you'd be doing things above and

            12    beyond what you normally do for regular drugs that are

            13    coming through.

            14                Questions that might be of particular interest

            15    to me might be if you have access to a population-based

            16    data set, and you can look at utilization profiles in the

            17    period prior to this coming on board -- I mean, looking at

            18    what's happening, so that would allow you to address on an

            19    individual basis the extent to which their utilization or

            20    compliance with medication seems to be changing for one

            21    medication versus a different medication.  To the extent

            22    that you have different groups, and you can follow them in

            23    parallel over time, you can also look concurrently at that,

            24    but you'd also want to be careful to try to stratify

            25    populations, sort of case mix that analysis, so that you

                                                                          159

             1    can be looking at the more or less severe segments.  You

             2    can try to identify people who may be taking medications

             3    for other co-morbidities that you're particularly

             4    interested in.

             5                So can you identify through these databases

             6    some populations who have other co-existing diseases that

             7    might make them particularly at risk here?  So there's

             8    certainly quite a bit you can learn from it, but to do it

             9    right, it's an expensive undertaking.

            10                DR. APTER:  Well, I think studying post-

            11    marketing drug use will be important, too, and it might be

            12    a way to test educational programs for the new medications

            13    and in different groups with different educational

            14    achievement to see how well various programs are accepted,

            15    to help patients to use the new medications, in addition to

            16    things like quality of life and the other outcomes of

            17    patient satisfaction, plus efficacy, in terms of disease.

            18                DR. FINK:  I guess I'm not as convinced that

            19    post-marketing studies are going to be very valuable.  If

            20    they are global, I think they're going provide too little

            21    control and too little data to really tell us anything.

            22                So I would support potentially targeted post-

            23    marketing studies that are addressing specific questions,

            24    like compliance in three- to six-year-olds or adherence or

            25    medication efficacy in an age group, but I think global

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             1    post-marketing studies are really not going to probably

             2    yield much useful information.

             3                DR. GROSS:  If I understand the question, it's

             4    how are you going to make sure the patients are willing to

             5    use new devices and do actually use them, and obviously

             6    that's a very, very important question, and I don't know

             7    whether it's because it's after lunch, or I'm just

             8    generally losing my creativity, but I really can't think of

             9    a good way to do that, unless you do it in a controlled

            10    clinical trial pre-marketing, or as part of the marketing

            11    process.

            12                I mean, it could take you an awful long time to

            13    get enough data together from kind of casual studies post-

            14    marketing, and I don't have a great deal of confidence in

            15    those studies anyway and the outcomes.

            16                I would think probably what Andrea suggested

            17    this morning is the best way to do it, is just simply to

            18    say we have to do a randomized study where some patients

            19    get the traditional inhaler and other patients get the

            20    innovator, and you follow clinically-relevant outcomes,

            21    number of visits to the ER, number of unscheduled doctor

            22    visits, amount of rescue medication if that's, you know, an

            23    appropriate outcome, and, you know, the usual and

            24    traditional measures, like peak flow, and things like that.

            25                But I guess it's going to take a lot of

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             1    patients, and it will be maybe quite difficult to evaluate

             2    these studies, but I just can't see any other appropriate

             3    way to monitor whether patients are using their new devices

             4    and whether they're actually getting the medication.  I

             5    just don't see any shortcut to getting that information.

             6                DR. JOAD:  I do think it's a good idea to do

             7    that kind of a study.  I understand it won't be as complete

             8    as what you do for the pre-marketing approval, but I think

             9    you'd get a lot of good information, and you do have to get

            10    some sort of sense of how convenient it is and how much

            11    people approve of using it, and from what we've heard, it

            12    doesn't sound like you can count on the market to make a

            13    place for it in such a way that there's a way to evaluate

            14    it.

            15                DR. SESSLER:  I think it's an interesting area

            16    that has a lot of different potential answers to it.  I

            17    don't know if we have an ability to do a more aggressive

            18    passive surveillance, if that's something that would be

            19    useful in terms of reaching out and trying to learn about

            20    populations that are missed with this or that suffer from,

            21    you know, underserved populations and so on, or those who

            22    are having difficulty using the device.

            23                If you're going to do prospective trials, it

            24    seems that they really have to be based on clinically-

            25    meaningful outcomes in terms of missed days of school or

                                                                          162

             1    work or outcomes that are, if possible, directed in that

             2    direction rather than physiologic changes.

             3                It's an important question.  I think it's a

             4    hard one to answer, though.  Some of those things might be

             5    helpful, I think, some of the ideas that have been

             6    presented so far.

             7                Dr. Kelly?

             8                DR. KELLY:  Like the other Bill, because I do

             9    research, yes, I do more research.  That way, I can get

            10    more money.

            11                On the other hand, when you start thinking

            12    about all the things that we've been talking about in terms

            13    of different groups and trying to stratify by those

            14    different groups, those are enormous studies, very large,

            15    cost a lot of money to do, and in order to get enough

            16    patients in some of those groups that we're interested in,

            17    I'm not sure that a prospective trial is capable of

            18    achieving that because even in those post-marketing trials,

            19    you end up with patients that are willing to participate in

            20    a trial, even if it's for a year, and so it's a lot

            21    different than patient population as a whole that we're

            22    interested in.

            23                So unlike everybody else, I have no answers,

            24    just questions.  I think there are databases out there that

            25    can be mined, such as Medicaid DUR databases, databases in

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             1    large HMO populations, that can set up a relatively

             2    rigorous change, and if you could convince a very large HMO

             3    and then some state Medicaid programs, which deal with

             4    different types of populations, and looking at the

             5    introduction of the new devices in those populations, you

             6    might get a better handle of acceptance and utility in

             7    those populations than setting up a prospective trial.

             8                DR. DYKEWICZ:  Well, I've got a few thoughts. 

             9    One is that even with our conventional MDIs, we know that

            10    despite sometimes fairly aggressive efforts at instructing

            11    patients in how to properly use inhalers, if you look a

            12    month or two down the road, the patients really are not

            13    exercising very good technique, and if we're looking at

            14    some of the CFC alternative products that might have a

            15    little bit more complexity to them, to their working, there

            16    might be more of an issue with fall-off of clinical

            17    effectiveness because of problems being consistent with the

            18    device utilization, the technique of utilization.

            19                So I think even though to some extent, this

            20    echoes the points that have been made earlier, that we may

            21    be going above and beyond what is currently required for,

            22    let's say, the CFC-containing MDIs, there is the concern

            23    that unless we do something, we may be seeing some drop-off

            24    in patient effectiveness that had not been anticipated.

            25                The other thing that comes to mind, and I'm not

                                                                          164

             1    sure whether this would be pre-marketing or post-marketing,

             2    but one of the questions, of course, is going to be whether

             3    or not if you introduce an alternative innovative product,

             4    whether all the subgroups are being properly cared for,

             5    could be cared for by using such a device, and I think if

             6    you're looking at large population studies, it's going to

             7    be nearly impossible to glean any meaningful data about

             8    that, and you really are going to have to have some active

             9    studies that will focus on particular subgroups that could

            10    be anticipated to have some problems.

            11                For instance, those patients who have limited

            12    capacity to cooperate with device use, and so I think in

            13    that sort of a more focused way, it really would be

            14    essential to have some active studies, perhaps cross-over

            15    studies, looking to see whether patients that have some

            16    limitations of that sort could be successfully maintained

            17    on the innovative product.

            18                DR. NIEDERMAN:  I would agree that you need

            19    post-marketing data.  You need to see if these drugs are

            20    effective, and you need to see if they're being used.  But

            21    I think that for a number of reasons, I think it would be a

            22    mistake to talk about a prospective randomized control

            23    trial.

            24                First of all, those are being done to get the

            25    drug approved in the first place.  Second of all, if I were

                                                                          165

             1    a patient, I'm not even sure what the motivation for

             2    enrolling in one of those would be, and probably most

             3    importantly, it's not a real-world observation.

             4                I think what you're really asking post-

             5    marketing is does this product work in the real world? 

             6    Will people use it?  You certainly can't answer that

             7    question with a prospective randomized control trial.

             8                I think what you really need to do is you need

             9    to observe what's happening after the product's out there,

            10    and I'm not sure exactly how to best do that.  I think as I

            11    was saying earlier, I think you may have the opportunity,

            12    particularly if the CFC product remains on the market, to

            13    look at the different usage patterns and look at the

            14    outcomes of patients who are using the new products, but as

            15    much as we may criticize databases, and there are

            16    multifactorial issues that may play a role, if we see that

            17    after the introduction of new products, measurable

            18    outcomes, like ER visits and asthma mortality rates or

            19    anything else that we look at, are getting worse, we'd

            20    probably know that there's a problem, and if things are

            21    getting better, whether it's due to the other new medicines

            22    or the inhalers, it probably means that things are

            23    reasonably acceptable.

            24                I think again things like looking at technique

            25    and monitoring that doesn't seem real world to me.  I think

                                                                          166

             1    again the bottom line is even if a patient could

             2    demonstrate to me that they know how to use their inhaler,

             3    that doesn't prove to me that they are using it and that

             4    it's effective, and it's dealing with any of the outcome

             5    issues.

             6                And I think the other issue that to me is very

             7    important here is, I think we have to look specifically at

             8    passive, not active, databases because I think it would be

             9    an unreasonable burden to put on the industry to tell them

            10    that after they've gotten the drug approved, they now have

            11    to fund research to document that that drug's effective.

            12                I think it's going to discourage people from

            13    getting into the field, and I think it's going to further

            14    add to the cost of these new products.  So I think that we

            15    haven't talked about these post-marketing studies and who

            16    would pay for them, but I think that if we ask for

            17    randomized trials, if we ask for detailed studies of

            18    particular populations and how they're using these

            19    products, I think it would discourage a lot of people from

            20    getting involved in this field, and I think it's going to

            21    add to the cost of these new products.

            22                So I think that probably additionally is a

            23    compelling factor for looking at available data that the

            24    agency could pull out of existing databases and trend

            25    specific numbers, but I think it would be a very big burden

                                                                          167

             1    to ask the pharmaceutical industry to develop these

             2    products, do the trials to prove they're effective, and

             3    after they're approved continue to do research to document

             4    that people are using them.

             5                MS. CONNER:  Being last in this list forces one

             6    to be creative with ideas and coming up with things that

             7    haven't been said before.  My tendency as a consumer

             8    representative and as a nurse educator is to think about

             9    not necessarily just efficacy and safety.  I think we have

            10    proven that or it wouldn't be approved by the FDA.  It

            11    wouldn't be out there.

            12                What we need to look at is maybe some type of a

            13    survey or questionnaire before the patient ever gets the

            14    prescription about their usage habits of their current MDI,

            15    their nocturnal wakenings, their absenteeism, their

            16    parents' absenteeism from work, and then maybe a similar

            17    questionnaire six months later, 12 months later, and if

            18    it's on an office visit, you get sometimes a little better

            19    participation than if it's a mail-out questionnaire.

            20                The same thing with technique, and it's not

            21    just patients who have difficulty with technique.  If you

            22    remember the Interiano study, nurses were the worst and

            23    doctors were just above them just a little bit.  Patients

            24    were actually better at technique than some of the

            25    physicians.

                                                                          168

             1                So we need to reevaluate technique, and

             2    especially as we're adding more and more devices with

             3    different techniques, we all need to brush up on that and

             4    stay current with it, but every time the patient comes in,

             5    reevaluate their nocturnal symptoms, their indirect medical

             6    expense, like absenteeism, patient missed days from work,

             7    and it's patients that report data, and some of it's

             8    anecdotal, but it may be a pretty good source of

             9    information.

            10                DR. SESSLER:  Any comments from Dr. Meyer or

            11    Jenkins?

            12                DR. JENKINS:  I think we got a pretty broad

            13    diversity of comments and feedback.

            14                DR. VOLLMER:  Having listened to the group, to

            15    stimulate some further thoughts, I think this was brought

            16    out on several of the comments.  I think the biggest

            17    potential advantage of sort of outcomes research post-

            18    marketing as opposed to a randomized trial is that it does

            19    get at more the real-world situation.  I mean, that's the

            20    big advantage.

            21                Any randomized trial that we do is going to

            22    have a very self-selected population, as was pointed out,

            23    and so the generalizability of that's questionable.  Also,

            24    as was pointed out, you're going to have done any number of

            25    randomized trials to get the drug approved in the first

                                                                          169

             1    place.

             2                So to the extent that you're going to gather, I

             3    think, a lot of new information, other than truly long-term

             4    effects, in a randomized trial, I don't see a lot of merit

             5    requiring those.

             6                I was wondering whether the FDA currently

             7    requires any kind of post-marketing data for newly-approved

             8    drugs.  To the extent that it doesn't now, I would feel

             9    that it wouldn't make sense to require it for these new

            10    medications coming out.

            11                I think that post-marketing studies are going

            12    to be done.  People are going to want them done.  They're

            13    going to want the information, and whether it's the

            14    pharmaceutical industry or NIH or whatever, some of that

            15    work's going to get done, but as to whether it's worth

            16    changing current FDA policies regarding what they require

            17    to be done, I would have a hard time supporting that.

            18                Again, you have plenty of work done up front to

            19    look at the safety and efficacy of this trial, of these

            20    drugs in randomized trials.  So really the issue is what's

            21    happening out there in the real world.

            22                DR. MEYER:  Just to speak to what the FDA

            23    currently requires, I guess it perhaps doesn't help you in

            24    helping us because for sort of the routine drug, where

            25    there's not a particular issue going into the post-

                                                                          170

             1    marketing period, typically we would not require any post-

             2    marketing studies.

             3                However, if there are questions about the

             4    drug's safety or effectiveness in certain subpopulations,

             5    there are certainly many drugs that have Phase IV

             6    commitments that are agreed to by the agency and the

             7    sponsors at the time of approval.

             8                So it's sort of a mixed answer, that both

             9    paradigms exist, and I think one could argue about whether

            10    an HFA reformulation in and of itself would represent such

            11    a level of scientific interest or regulatory interest,

            12    whether you'd require a Phase IV commitment, but I think

            13    when you add on the issue that this may be the product that

            14    leads to a safe and effective product that contains CFCs no

            15    longer being able to market, it may change the balance

            16    some.

            17                DR. VOLLMER:  If that's what you're currently

            18    doing, then I would suggest that much the same is going to

            19    continue to happen.  With the close scrutiny that these

            20    medications are going to get, if there are concerns about

            21    special populations that may not be adequately having their

            22    needs met, you can bet that those are going to get raised,

            23    and therefore if you're requiring post-marketing types of

            24    studies in the past in those conditions, I can't imagine

            25    that you're not going to be also requiring them again in

                                                                          171

             1    these kinds of conditions.

             2                If nobody's raising those concerns, it's

             3    probably a fairly safe bet that there's no large population

             4    out there anyway, you know, a special population that's

             5    likely to be affected because again there's a lot of people

             6    looking very closely at this.

             7                DR. SESSLER:  A number of the comments here

             8    have led right into the next bullet point, which really

             9    deals with subgroups.  What subgroups of asthmatics or COPD

            10    or other respiratory patients need to be specifically

            11    considered in the determination that patients' needs are

            12    being met?

            13                There really has been a fair amount of

            14    discussion surrounding this.  I'd like to see if there are

            15    additional comments.  Michael?

            16                DR. NIEDERMAN:  As I'm listening, I just want

            17    to caution, I guess, that we not try to solve problems that

            18    we can't solve already with these new products.

            19                A lot of the issues that have been brought out

            20    about inability to use inhalers correctly and days lost

            21    from work and quality of life, those are issues now today

            22    with our current technology, and to think that if we can't

            23    solve them now, that somehow that's going to become the

            24    standard by which we ask these new products to meet, it's

            25    very unrealistic.

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             1                I think that there are inherent problems in

             2    asthma that can't be solved by these new medications, and I

             3    think we have to be very careful not to set standards that

             4    try to solve again all of the problems which currently

             5    exist that we're not able to solve, and I think that

             6    particularly when we address special groups, we have to ask

             7    ourselves, if special groups are having problems now,

             8    that's the baseline to which we want to compare our new

             9    technique, and we can't ask reasonably a new device to

            10    solve the problems that special groups have now that can't

            11    be solved with the current technology.

            12                I don't think that's the purview of what we're

            13    trying to address today.

            14                DR. SESSLER:  If I'm interpreting where the FDA

            15    is coming from this is, I think if there is a change in

            16    technique or a change in availability, would that adversely

            17    affect selected subgroups?  Yes?

            18                DR. JENKINS:  I think a point we all need to

            19    keep in mind is that normally, when we are approving new

            20    drugs, whether it be a new molecular entity, a new

            21    formulation of an existing drug, we're approving that

            22    thinking that it's going to go into the market and become

            23    part of the overall armamentarium for the disease.

            24                This is a different paradigm, where these

            25    products are being specifically developed to replace

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             1    existing products.  So when we approve these non-CFC

             2    alternative products, there's an intent through the

             3    Montreal Protocol and the Clean Air Act that if those are

             4    acceptable to patients, they're going to replace the old

             5    products, and part of the question we're trying to get

             6    answers from you are, how can we be certain that we're not

             7    going to make things worse?

             8                We certainly may not be able to address some of

             9    the concerns that are out there now, but I don't think we

            10    want to make things worse by making a determination that

            11    the alternative product meets patient needs, and you

            12    declare the CFC product as no longer essential, and the CFC

            13    product goes off the market, and then you find out that

            14    maybe it really didn't meet patient needs.

            15                So it's a very different paradigm, and that's

            16    why we're asking these difficult questions.

            17                DR. NIEDERMAN:  And I think the opportunity is

            18    presented to you by the intention of having both products

            19    on the market initially together, and I think that that

            20    allows usage studies.  It allows compliance studies.  It

            21    allows outcome studies which can be sorted out by which

            22    type of device patients were using, and I think that -- I

            23    guess that's all that I'm really -- I agree.  I think that

            24    all you really want to document is that you're not making

            25    things worse.  As you said, your intention is to make

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             1    things better.  You're simply coming up with a replacement

             2    product.

             3                DR. JENKINS:  If I could go back, the previous

             4    point that we were discussing about the post-marketing

             5    data, it seems as we went around the room, we got kind of,

             6    you know, several different opinions.  Some people

             7    advocated for asking for post-marketing studies, other

             8    people thought that they weren't all that useful, and some

             9    people said yes, they may be useful, but we're not sure we

            10    should advocate for them.

            11                I think we heard from Mr. Jamieson's

            12    presentation earlier that the industry association, their

            13    position is that the FDA should not be requiring these

            14    studies, and that we should be relying primarily on the

            15    spontaneous reporting system for adverse events and drug

            16    product quality problems as well as any data that can be

            17    garnered essentially passively, and I guess what I'm

            18    interested in hearing from the committee is, how do you

            19    feel about that proposal?

            20                Not specifically point counterpoint with IPAC's

            21    proposal, but to date, we have not required any of the non-

            22    CFC products that have been approved, we have not required

            23    them to do any of these large post-marketing Phase IV

            24    studies designed to help us address this issue.

            25                At the end of the day, when we have the

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             1    alternative, and we start making the determination, is it

             2    meeting patient needs, do you think we're going to be able

             3    to adequately do that by relying on the post-marketing

             4    reporting system that we have, the Medwatch Program, the

             5    quality reporting of product failures, European data, other

             6    foreign data?  Is that going to be enough to address the

             7    issues about meeting patient needs, subpopulations being

             8    adequately served?  I think that's the key point.

             9                DR. KELLY:  Well, I guess a half response to

            10    that, John, is I guess my problem is I don't think a large

            11    post-marketing randomized trial, even though it's not

            12    blinded or anything, just a randomized trial, which a lot

            13    of these post-marketing studies are, is going to answer

            14    that either, and I think I would fall on the side of going

            15    after larger databases along with the self-report system

            16    that we already have in terms of going after those small

            17    entities and groups, and as long as we have the CFC

            18    available until we have that information back, the

            19    community as a whole should feel fairly comfortable.

            20                DR. JOAD:  I think what I was getting at when I

            21    mentioned the market issue is, I think barring some

            22    financial incentive to go to the alternate product, the

            23    people that will use the new products are likely to be, I

            24    would guess, people who are concerned about the

            25    environment, people who are likely to work harder on their

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             1    inhaler technique and are generally more compliant or

             2    adherent, and I think if you really want to see how

             3    something works in the real world, post-marketing, you're

             4    going to need to assign people who are similar to either

             5    get that one or get the alternative or the CFC product, and

             6    maybe a simple questionnaire at the end of a year would be

             7    sufficient or end of six months.

             8                It doesn't have to be so detailed, but

             9    something that looks at real people who are really randomly

            10    assigned to get the alternate product compared with the CFC

            11    product.

            12                DR. SESSLER:  Dr. Apter, and then Dr. Vollmer.

            13                DR. APTER:  Dr. Fink mentioned earlier that

            14    these drugs will be coming on the market when other things

            15    are happening, like other drugs.  Well, there are other

            16    things happening in the health care world while these drugs

            17    are being changed.  Less time to talk with patients, less

            18    time to educate them, and so I think it's very important to

            19    study what's going on, and especially in the high-risk

            20    groups, which are the underserved populations.

            21                It may not be the obligation of the industry

            22    that brings these drugs to market, but I think it's

            23    important.  I think that all types of designs are

            24    important, too.  Looking at big databases tell you some

            25    things and randomized trials and focus groups tells you

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             1    something else, and all would be important, so that these

             2    new drugs don't make things worse.

             3                DR. VOLLMER:  I'll give you an example of a

             4    specific study that I might envision and when I might

             5    envision it, not necessarily as each new drug product comes

             6    out, but when you're at the point of removing the essential

             7    status from a given moiety, at that point, you have one or

             8    other alternative competitors that are out there.  I

             9    believe by your criteria, it has to be at least two.

            10                At that point, you could go out to HMOs or a

            11    variety of other people that have access to large databases

            12    and query them.  Maybe you've got two or three years of

            13    experience with some of these things now, and you've got a

            14    situation where you have both kinds of products on the

            15    formulary because to some extent, if there are unmet needs

            16    in the population, that these aren't working, then they're

            17    going to be demanding some of the other drugs.

            18                So you can go out there and ask who's using

            19    what kinds of drugs, and in particular ask the question of

            20    the people using a given moiety, who's using the CFC

            21    formulation versus the alternative formulation, and you can

            22    take a look to see whether its release to the population --

            23    I would be serving this population.  So I'd try to find out

            24    not only their age, sex, patterns, but their co-morbidities

            25    and actually survey the patients and potentially the

                                                                          178

             1    providers and find out what are the factors that are

             2    causing you to be using this product and not another

             3    product?

             4                Is it just that they just simply refuse to

             5    change in the absence of any effects or can they give you

             6    quantitative reasons why they can't use a product or, I

             7    mean, do you have some unknown reason?

             8                But there's a situation then that you're

             9    several years out, things have sort reached somewhat of a

            10    steady state, particularly if there's multiple different

            11    alternatives for people to be using, and then you can see,

            12    and they may not all be using Drug A, some might be using

            13    Drug B and Drug C, but who's still using the old drugs, and

            14    is that selectively one population?  Is it kids under five

            15    years of age?  Is it individuals over 70 who have cystic

            16    fibrosis or whatever as a co-existing disease?

            17                So you're able to get some insight into who's

            18    still using them and why they're still using them.

            19                DR. SESSLER:  Dr. Fink?

            20                DR. FINK:  I think the other issue with

            21    marketing, there are products out there, and I think,

            22    unfortunately, when you look at post-marketing surveys, and

            23    you're particularly asking the questions you're asking, the

            24    immediate introduction of the drug is when you're going to

            25    get the patients who are either poorly controlled on

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             1    current medications or want to switch, to take up the new

             2    drug.

             3                The group you're asking about is going to be

             4    the last group to take on the use of a new drug which is

             5    going to be to the patients who are well controlled on the

             6    current agent and see no reason to change or those patients

             7    who are wedded to the current agent and don't want to

             8    change, and they're going to be the last group to

             9    transition.

            10                So unless you do your post-marketing studies at

            11    the end of the transition, you're not going to answer the

            12    questions you're asking.

            13                DR. NIEDERMAN:  Yes.  I would just caution

            14    against looking at some of the end points that you've

            15    mentioned because you're presupposing that people are going

            16    to have equal choice about which they use, and I think a

            17    lot of this is going to be driven by cost, and I think that

            18    these new inhalers -- for example, to pick on albuterol

            19    since there's generics, I can't imagine any of the newer

            20    ones are going to be any equal in price to the existing CFC

            21    ones, and I think a lot of this is going to depend on what

            22    type of insurance you have, whether they'll pay for the new

            23    devices, and whether you've got to pay.

            24                DR. VOLLMER:  That's a very good point, yes.

            25                DR. NIEDERMAN:  So I think that you have to at

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             1    least focus on outcomes rather than patient choice because

             2    patient choice may not truly be choice.  It may be driven

             3    by cost.

             4                DR. VOLLMER:  That's an excellent point.  Part

             5    of what you can do with that is you can also look at a

             6    variety of different providers as well as the fee-for-

             7    service sector, but you can go to a variety of different

             8    managed care organizations and see what's on the formulary

             9    and ask them why.  If Drug A is not on their formulary at

            10    all, no CFCs, is it because they've simply said they don't

            11    -- they only choose to go with one drug and that's the way

            12    it's going to be because they don't want to be buying more

            13    than one or what have you.

            14                So gaining insight from a variety of different

            15    providers as to how they're stocking their formularies

            16    would also be -- and what's driving that is also an

            17    important piece.

            18                DR. SESSLER:  Dr. Gross?

            19                DR. GROSS:  Yes.  I want to make the same point

            20    exactly.  I think probably the most potent factor in terms

            21    of willingness to require the inhaler and use it is going

            22    to be cost, there's no question about that, and I don't

            23    think there's going to be any question about the fact that

            24    the new ones are certain to cost a lot more than the

            25    existing ones, and you can get a generic albuterol inhaler

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             1    for a couple dollars, and I can't see any new devices being

             2    able to deliver the same cost per dose at less than

             3    probably between 20 and 30, if that, and so I mean, that's

             4    going to be a hugely potent factor as to whether patients

             5    actually use it.

             6                So in real-world studies, patients will have to

             7    pay for their own medication because it's not real world

             8    otherwise, and the question really is, is the patient going

             9    to pay 10 times as much, and if they do, are they going to

            10    get as satisfactory outcomes as they can get?

            11                So I think one should be prepared for the fact

            12    that asthma control will go down, and I don't see any way

            13    out, and there's a huge subsidy for the medications that we

            14    use right now.

            15                So you have to look at things like emergency

            16    room visits, unscheduled doctor visits, time lost from

            17    work, time lost from school, your real-world type of

            18    outcomes.  Whatever study you're doing, that's what you're

            19    going to be looking at.

            20                But I believe that you can't really get

            21    meaningful data unless you have a control group, you know. 

            22    I mean, I think you have to figure out some way where you

            23    can say, well, is this really meaningful or how does this

            24    compare with what?  You know, it's always a question of

            25    what you're comparing it with, and so I would say pretty

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             1    strongly it has to be some kind of controlled study;

             2    otherwise, you really don't know what the data mean.

             3                I mean, just think how we're still arguing

             4    about whether beta agonists in general are bad for you or

             5    not.  You know, 10 years ago, you had a very same meeting

             6    in this town as to whether beta agonists were safe or not. 

             7    Well, maybe it wasn't 10 years, but it was probably eight

             8    years, and should the FDA institute some additional

             9    controls?  We're still arguing about that.  We don't know

            10    because these are all post-marketing type of questions, and

            11    it's very, very difficult to do it when all these agents

            12    are available, and you're not doing a controlled study. 

            13    You really can't tell exactly what it's due to, what your

            14    outcomes are due to.

            15                So I would think before you make any drastic

            16    steps and make the conventional agent unobtainable anymore,

            17    by which time it's too late to squeeze the toothpaste back

            18    in the tube, you need to do some kind of controlled

            19    studies, looking at real-world types of outcomes rather

            20    than the traditional one, which is FEV1 and peak flows and

            21    so forth.

            22                DR. SESSLER:  I think from my perspective, if

            23    prospective randomized trials in the Phase IV type of

            24    setting were to be undertaken, it probably should be

            25    focused on patient groups for whom there is some perception

                                                                          183

             1    that there might be a problem, perhaps specifically related

             2    to drug delivery, which would translate into long-term drop

             3    in effectiveness and could be measured in terms of real-day

             4    outcomes in terms of ER visits and missed days and things

             5    of that nature.

             6                But, you know, randomized prospective trials

             7    are resource-dependent, and so by focusing perhaps on those

             8    areas that might be highest yield, the ones that are of the

             9    greatest concern, the elderly who may not be able to

            10    generate adequate inspiratory flow for some of the

            11    different instruments, or the pediatric population,

            12    something like that, might be, rather than a global general

            13    population base, make it more specifically focused.

            14                Dr. Ford?

            15                DR. FORD:  After hearing all of the

            16    perspectives presented, including my own, I feel like

            17    saying all of the above.

            18                (Laughter.)

            19                DR. FORD:  And the reason for it is that it

            20    seems to me that we're coming at this looking at different

            21    aspects of the question in terms of what's going to happen

            22    after these drugs are introduced, and certainly if we want

            23    to look at the impact of costs and access on efficacy, a

            24    randomized trial may indeed not be the approach because

            25    most likely it would be providing medications and so forth. 

                                                                          184

             1    So that would not be real world.

             2                So I am favoring now perhaps a targeted

             3    approach, that is, on the one end, that is utilizing

             4    multiple approaches, depending on what the question is. 

             5    If, for example, we want to know what the impact is going

             6    to be on certain more vulnerable populations, well, not

             7    necessarily vulnerable but the very young and patients who

             8    have trouble generating peak inspiratory flow that is

             9    adequate, of course, randomized trials, carefully-designed

            10    studies, with that subgroup of patients might be the

            11    appropriate thing.

            12                But in terms of costs and access and so forth,

            13    I think it may just be appropriate to look at large

            14    databases with the caution that even among the databases,

            15    there is going to be some variability among populations as

            16    to how informative they can be.

            17                I mean, it's really a question of

            18    generalizability, as I think you started to mention here,

            19    because the HMO population in one city may not necessarily

            20    reflect the same kinds of challenges that my patients face

            21    in Harlem, and by the same token, I'm not even sure that

            22    the Medicaid database in New York, which by the way is not

            23    largely an HMO database, you know, our patients are

            24    primarily not in managed care right now, would be

            25    informative.

                                                                          185

             1                So I think what really this is coming at is the

             2    need for, I think, what Dr. Sessler is mentioning

             3    implicitly here, some really hypothesis-driven kinds of

             4    studies, utilizing either databases or clinical trials,

             5    when appropriate, based on issues that we think would have

             6    a foundation, considering what we understand about how

             7    these delivery systems work and the mechanisms by which the

             8    drugs have their effect.

             9                DR. SESSLER:  How was that, John?

            10                DR. JENKINS:  Are you ready to move off the

            11    subgroup issue?

            12                DR. SESSLER:  Yes, yes.

            13                DR. JENKINS:  Because I'd like to really make

            14    you earn your keep today by helping us define what are

            15    subgroups?  We've been using that term a lot today, and

            16    we've talked about some general terms, but what really

            17    constitutes a subgroup?

            18                I know Ms. Cusumano in her presentation talked

            19    about a subgroup of one for some of the patient comments

            20    that came in.  They consider themselves to be a subgroup of

            21    one, and that it was very important to them that they not

            22    lose access to the medication that they felt was the only

            23    one that provided them benefits.

            24                So I'd be interested in any wisdom you have

            25    about how should we define the subgroup, how large is a

                                                                          186

             1    subgroup, and how do you address those issues of single

             2    patient concerns?

             3                DR. SESSLER:  Takers?

             4                DR. JOAD:  I just want to repeat what I said

             5    this morning, that if you include this as a subgroup that

             6    must be served, people who cannot cooperate at all in the

             7    inhalational devices, at least for each class, that you're

             8    not going to leave anyone out, that that would include

             9    young children.  It would include neurologically-abnormal

            10    people.  It would include several different groups that

            11    don't need to particularly be named, except that they can't

            12    cooperate in any sort of breath-activated, put your mouth

            13    around a mouth piece, effort.

            14                DR. GROSS:  I would also state what I guess is

            15    obvious, and that's the elderly, particularly because they

            16    lack manual dexterity.  They lack coordination,

            17    synchronization.  Many times, they can't read very well,

            18    can't see very well, and they're particularly challenged

            19    when it comes to using inhalation devices.

            20                DR. SESSLER:  You know, I might chime in on the

            21    elderly, echoing Dr. Gross's comments, and, in addition, I

            22    think the cost issue is substantial for some of the elderly

            23    in terms of them falling kind of in that gap, and I think

            24    that's true for the working poor as it were, that the

            25    monthly costs of medications is substantial and worthy of

                                                                          187

             1    consideration in terms of -- I don't know if that fits into

             2    a subgroup, but at least it, I think, brings another facet

             3    to the elderly as being a high-risk subgroup, I guess.

             4                DR. NIEDERMAN:  Well, Curt, I would agree that

             5    all these groups make sense, but I would caution again that

             6    these are groups that we have problems with today, and so

             7    if we're going to study them, we have to study them in

             8    comparison to the reality of what we've currently got as

             9    problems and not expect again these products to do better

            10    than we're already doing.

            11                The one group that hasn't been mentioned today,

            12    and at least in my practice is a substantial group, is the

            13    pregnant woman, and I guess we haven't considered whether

            14    there are issues with these new delivery devices that have

            15    to be specifically looked at in pregnancy.

            16                We thought a lot about the individual active

            17    ingredients, but I don't know if the propellants would have

            18    any relevance during pregnancy and whether that needs to be

            19    studied separately.  Certainly asthma's an important

            20    disease in pregnancy.

            21                DR. SESSLER:  Any information to share in that

            22    area, Dr. Meyer?

            23                MS. CUSUMANO:  That was one of the comments

            24    that we had received on the advanced notice of proposed

            25    rulemaking, that I think all but one of the currently-

                                                                          188

             1    approved drugs are Pregnancy Category C, is that right, or

             2    I think all but one are C?  I think there's one in B.

             3                DR. VOLLMER:  What does that mean?  Pregnancy

             4    Category C?

             5                DR. NIEDERMAN:  It means we don't know.

             6                MS. CUSUMANO:  Well, it means different levels

             7    of effect --

             8                DR. NIEDERMAN:  I think C means that there is

             9    not enough convincing data one way or the other.

            10                DR. MEYER:  With some hint in animals that

            11    there may be some teratogenic effects or other pregnancy

            12    effects.  The X is clearly bad.  Thalidomide-type.  A is we

            13    have good data to say to use it.  B is --

            14                DR. NIEDERMAN:  But I guess what I'm asking is

            15    even if you took a component that was Category B now and

            16    put an HFA in it --

            17                DR. MEYER:  Right.

            18                DR. NIEDERMAN:  -- is it still Category B?

            19                DR. MEYER:  Right.

            20                DR. NIEDERMAN:  And what do you have to do to

            21    reach a conclusion about that?

            22                DR. MEYER:  Right.  I think that is an issue

            23    that's been raised before, and one that we certainly need

            24    to grapple with as we move forward.

            25                I think we do have some data about the exposure

                                                                          189

             1    and pharmacokinetics of the HFA, and it's quite minimal as

             2    it is with the CFCs, but I guess there's both that

             3    question, and this, also, I think, in terms of the comments

             4    we got to the ANPR, we're also in the situation where we

             5    can't expect the new products to necessarily leap hurdles

             6    that we haven't gotten information on for the current

             7    products.

             8                In other words, if we don't know enough about

             9    to use albuterol CFC, it doesn't quite seem reasonable to

            10    make the HFA product prove that it's any better or worse.

            11                DR. NIEDERMAN:  I don't think it has to prove

            12    it's better.

            13                DR. MEYER:  Well, or even to prove that it's

            14    not different, if we don't have any reason to believe that,

            15    for instance, the HFA would be particularly risky for that

            16    population.

            17                DR. NIEDERMAN:  Okay.  I guess that's what I'm

            18    asking.  Is that enough to know that -- because there's two

            19    questions in pregnancy.  One is the obvious one of

            20    teratogenicity, but the other one is efficacy, and if

            21    there's an inherent difference in efficacy, that can affect

            22    the outcome in pregnancy as well.

            23                MS. CUSUMANO:  The only other thing I would add

            24    is that the agency as a whole is looking to increase the

            25    information and drugs generally, pregnancy labeling.  So

                                                                          190

             1    we're aware that it's a need, not just in this category.

             2                DR. MEYER:  Yes, and I think the efficacy issue

             3    as it would be for many of these subgroups is somewhat

             4    product specific.  For instance, one could theorize if you

             5    had a large abdominal mass, a fetus or a large baby in your

             6    abdomen, that you might have impaired inspiratory flow and

             7    might not be able to use a DPI quite as effectively as if

             8    you were non-pregnant.

             9                So in other words, I think that there might be

            10    some specific products where we might have more of a

            11    question about whether there'd be sufficient efficacy in

            12    that population in pregnant women as there would be for

            13    other subgroups.  But I think that might very well be

            14    product specific because presumably, although there are

            15    some differences between the way CFC MDIs and HFA MDIs are

            16    likely to perform, I don't think the efficacy in the

            17    pregnant population would be anticipated to be

            18    substantially different.

            19                DR. SESSLER:  Any other comments?  Dr. Ford?

            20                DR. FORD:  Yes.  I think it's been alluded to,

            21    but I also think that perhaps we should introduce it as

            22    clearly as possible as a potential subgroup, that is,

            23    urban, low-income and minority populations, because,

            24    clearly, in terms of who is bearing the brunt of the

            25    epidemic, we all know where areas of asthma, of severe

                                                                          191

             1    health care utilization and so forth and other outcomes for

             2    asthma, where they map out to, and I think that on the one

             3    hand, we would want to be reassured that, you know, we at

             4    least don't do so bad as we are right now overall, but I

             5    think that by the same token, things are so bad right now,

             6    that we don't want to wait to find out that there might be

             7    issues that undermine the effectiveness of asthma therapy

             8    with these new devices.

             9                We wouldn't want to wait too long to find out

            10    about that.  So I think it's really important to look, to

            11    monitor what's going on in those populations.

            12                DR. KELLY:  I would echo that, because I think

            13    the major problem in that population is access or one of

            14    the major problems, and if we're talking about changing

            15    from CFC is going to change access, then that's a

            16    particular population that we might be very interested in.

            17                DR. SESSLER:  Dr. Jenkins?

            18                DR. JENKINS:  I'd like to continue to mine a

            19    little bit with the committee the issue of the subgroup of

            20    one because we do get that type of comment a lot in the

            21    agency, either in response to the ANPR, we got a lot of

            22    comments of individual patients who said for whatever

            23    reason, that they could not be treated with any other drug

            24    than Drug X, and we also get those comments periodically

            25    with a company for whatever reason, either has a temporary

                                                                          192

             1    shortfall of their ability to make a product or they stop

             2    making a product, we get lots of calls from concerned

             3    patients, saying, you know, that's the only product that

             4    works for me.  What am I going to do?

             5                So what I'm really looking for to mine a little

             6    bit with the committee is a lot of the things we've been

             7    talking about so far with regard to subgroups have been

             8    more access-based issues or they've been functionality

             9    issues of can't generate the peak flow, can't understand

            10    how to use the device, and what I'd really to hear you

            11    comment some on, do you believe there are physiologic

            12    differences that would make individual patients respond to

            13    one inhaled corticosteroid and not respond to another

            14    inhaled corticosteroid, regardless of what dose you might

            15    give them, and the same would be true for beta agonists.

            16                We had this discussion some in the 1997 meeting

            17    because at that point, the agency had proposed one option

            18    being the therapeutic class approach, which said that once

            19    you had a couple of options in a therapeutic class, you

            20    could consider the other members of that class to

            21    potentially no longer be essential, and we had some

            22    discussion about whether that was a valid assumption from a

            23    physiologic standpoint.

            24                If you respond to a beta agonist, can you

            25    expect that they will respond to a different beta agonist

                                                                          193

             1    or do you think they're truly patients who only respond to

             2    one molecule?

             3                DR. SESSLER:  Our pharmacologist?

             4                DR. KELLY:  From a clinical pharmacology point

             5    of view, no.  Having been around for 25 years, I think you

             6    get a different perspective, and I have a similar

             7    perspective that Bob had shared about changes in metered-

             8    dose inhalers and, you know, going for metaproterenol to

             9    albuterol.  From patients, you always hear that, and you

            10    always hear of, you know, relatively well-educated

            11    patients.

            12                We had a lawyer that, once we put him on

            13    inhaled steroids --

            14                (Laughter.)

            15                DR. KELLY:  Speaking of subgroups.  Who, even

            16    though we put him on inhaled steroids and better control,

            17    he said, "Every time I get in trouble, I still go get my

            18    Tederol," and so there is that problem, and it's a real

            19    problem from the patient's perspective, and most of the

            20    studies that we've done, that people try to look at and

            21    find those things, you can't find those differences, and so

            22    from my perspective, those N of 1s, I think they're real

            23    problems, but I don't know how to deal with them.

            24                DR. DYKEWICZ:  Well, I'd like to flip the side

            25    of the coin, so to speak, to the, if you will,

                                                                          194

             1    idiosyncratic responses in terms of effectiveness, but then

             2    idiosyncratic responses in terms of side effects, and that

             3    would be an issue.  There might be some people that seem to

             4    get adverse effects from one agent within a class but not

             5    from other agents in the class.

             6                DR. JENKINS:  Right.  That's a valid point, and

             7    I intended, when I made my point, to include that.  There

             8    are documented cases where patients may be responding to an

             9    excipient, for example, an inactive ingredient that's in

            10    one formulation that's not in another formulation.  So I

            11    should have put that in as a caveat, and there's obviously

            12    also physiologic differences between different beta

            13    agonists.  Some have more selective beta adrenergic effects

            14    than others.

            15                So I was trying to target more on efficacy, but

            16    recognizing that there are potential differences and

            17    adverse event profiles because of the molecule or because

            18    of the formulation.

            19                DR. FINK:  From a doctrine of fairness

            20    approach, I'd take a different approach to defining

            21    subgroups and throw out the number 50,000, in that if

            22    50,000 is the number of pediatric individuals who have a

            23    use for a drug to be considered significant and require

            24    pediatric studies, I'm not sure why we shouldn't use a

            25    similar criteria for asthma and say if a subgroup is less

                                                                          195

             1    than 50,000, it doesn't meet the federal criteria of

             2    significance.

             3                DR. SESSLER:  And that's based on --

             4                DR. FINK:  Good pediatric rule, which says that

             5    if a pediatric use of a drug is only considered significant

             6    if there is a group greater than 50,000 who would benefit

             7    from the use of the drug.

             8                DR. SESSLER:  Is that precedent recognized?

             9                MS. CUSUMANO:  I would just say that the flip

            10    side of that rule is it's an or, or provides a meaningful

            11    therapeutic benefit.  So using the number alone maybe

            12    doesn't tell us the whole story.

            13                DR. FINK:  No, but I think the point is we're

            14    splitting down to some of these very small groups that we

            15    would not be giving credence to in development of other

            16    drugs, other classes of drugs, and just because this is a

            17    replacement -- I mean, there's part of me that says this is

            18    a replacement process or a transition process.

            19                There's part of me that says this is no

            20    different than any other transition from injectable

            21    antibiotics to oral antibiotics, QID to oral antibiotics,

            22    BID to oral antibiotics once a day, and we didn't require

            23    post-marketing surveillance to say were people happier with

            24    an antibiotic once a day than an injectable.

            25                You know, there's some people out there who

                                                                          196

             1    would say the injectables work better, and I think maybe

             2    because of sensitivity to the issue, we're almost being

             3    overly responsive to it.

             4                DR. VOLLMER:  Yes.  I don't know what the

             5    number would be, but I think that is just a restatement of

             6    the point that Dr. Niederman's made repeatedly today, which

             7    is that we shouldn't set a standard for these new compounds

             8    that we can't meet for our current compounds.  You're

             9    always going to find individuals now who say they can't

            10    take a medication, they're having trouble, and so it's just

            11    unrealistic to expect that we're going to do better than

            12    what we can currently do now.

            13                DR. SESSLER:  Any other comments?

            14                (No response.)

            15                DR. SESSLER:  Why don't we switch gears in a

            16    pretty major way?  The next couple of bullet points really

            17    deal with the moiety-by-moiety approach.  The first is, is

            18    FDA's proposal to utilize a moiety-by-moiety approach

            19    reasonable, given the special exception for moieties with

            20    more than one product?

            21                The follow-up is, if a moiety-by-moiety

            22    approach -- ever tried saying that? -- is taken, how should

            23    FDA determine when remaining CFC products that are not

            24    being reformulated are no longer needed?

            25                So I'd like to toss that open for commentary.

                                                                          197

             1                MS. CUSUMANO:  If I could just speak for a

             2    moment to the paren there, given the special exception for

             3    moieties with more than one product, this was something I

             4    didn't emphasize in my talk, but under the proposed rule,

             5    we've suggested that for products marketed under more than

             6    one NDA or in more than one distinct strength, there would

             7    have to be at least two replacement products, and that's

             8    what that paren means; whereas, in other cases, it would

             9    just be one.

            10                DR. NIEDERMAN:  Explain what that means for,

            11    say, albuterol.

            12                MS. CUSUMANO:  Albuterol's marketed under

            13    multiple NDAs.  So there would have to be at least two

            14    albuterol replacement products before we would propose

            15    removing the essential use for albuterol.

            16                DR. KELLY:  Well, beclomethasone comes in two

            17    strengths.  So if it comes in two strengths, then it would

            18    require just those two strengths or two replacements period

            19    of any sort?

            20                DR. MEYER:  For sort of regulatory simplicity,

            21    we combine these concepts, but they are somewhat different. 

            22    I think beclomethasone actually has both considerations.

            23                DR. KELLY:  Yes.

            24                DR. MEYER:  Just as there's two different NDAs

            25    for two different strengths.  I think the feeling is that

                                                                          198

             1    for the multistrength products, that it would be hard, I

             2    think, to argue particularly if you were reformulating,

             3    say, the higher strength, that that was an adequate

             4    replacement for a product or a moiety that's available in

             5    two or three strengths because there could be some

             6    populations who specifically need the lower-strength

             7    product.  For instance, pediatric populations.

             8                DR. KELLY:  So what that means is that you

             9    would need replacement for the particular indications or

            10    strengths that are out there, not just that you'd have a

            11    dry-powder inhaler and an HFA inhaler as two replacements?

            12                DR. MEYER:  Right.  And again, that's not

            13    really explicit in the rule, but that's behind our

            14    thinking, that, you know, folded into the other criteria

            15    then would be all the subpopulations that are served, and

            16    if there were two high-strength, one being a DPI, one an

            17    MDI, alternatives available, but there was no alternative

            18    low-strength product, and it was clear that that was needed

            19    for proper treatment of asthma patients who were below the

            20    age of 12, for instance, just as a hypothetical, then we

            21    would not consider that an adequate replacement.

            22                MS. CUSUMANO:  I just wanted to add to that

            23    that it's not necessarily a one-to-one, strength-to-

            24    strength replacement because of the issue that was raised

            25    earlier, that it's possible that, you know, with the

                                                                          199

             1    reformulation, you might only have to take one puff versus

             2    two, something like that, but that if there are particular

             3    populations that need particular strengths, then you would

             4    want to have that available for them.

             5                DR. NIEDERMAN:  I'm not sure how you would

             6    answer that question, but I can see again, as I'm thinking

             7    about it with the moiety-to-moiety approach and the rules

             8    you've made, the following problems.

             9                We talked earlier about how if you happen to

            10    have a CFC product that's unique, and that nobody else can

            11    make, there's virtually no motivation to develop an

            12    alternative because you'll not be declared non-essential

            13    for a long time.

            14                On the other hand, when you take the example of

            15    albuterol, if what you're saying is as soon as there are

            16    two non-CFC alternatives, all the generics are off the

            17    market, there's a great incentive for the HFA makers to

            18    band together, make another product and get the generics

            19    off the market, and the price goes up dramatically again.

            20                So I'm not sure how you're going to deal with

            21    that, but I can see certainly from an industry perspective,

            22    the potential for behavior to optimize profits, which is

            23    what they're in business to do, that can undermine this

            24    whole process.

            25                DR. DYKEWICZ:  Now, as I understand it, the

                                                                          200

             1    second question, of course, was if a moiety-by-moiety

             2    approach is taken, how should the FDA determine what

             3    remaining CFC products that are not being reformulated are

             4    no longer needed?

             5                Now, my understanding about the two-phase

             6    process again is that when we get up to 2005, that would be

             7    the point when that type of an assessment would be

             8    required, whether the remaining products that have not been

             9    reformulated are still deemed to be essential, and earlier

            10    this morning, I was raising the question about whether then

            11    there would be an assessment based upon whether there were

            12    other available drugs within a class which, I think, is a

            13    reasonable type of an approach to make that sort of

            14    assessment.

            15                If you have among, let's say, the inhaled

            16    corticosteroids three or four different other moieties that

            17    have been reformulated into a non-CFC preparation, then you

            18    could make an assessment that, well, you know, the

            19    remaining product or two, they're not to be reformulated

            20    and are no longer essential.

            21                So I think the general thrust of making some

            22    type of a class assessment in 2005, of course, is the year,

            23    you know, time line that starts after that point, but I

            24    think that's a reasonable approach personally to look at

            25    that particular question.

                                                                          201

             1                DR. NIEDERMAN:  But again, you could do it

             2    before 2005.  In other words, am I interpreting you

             3    correctly with albuterol, that if the second HFA product

             4    came out before 2005, all the generics with CFCs would be

             5    declared non-essential?

             6                MS. CUSUMANO:  What would happen is if we had

             7    two acceptable alternatives, we would propose to remove the

             8    essential use for albuterol, and we would go through the

             9    notice and comment rulemaking for removal of that.

            10                DR. NIEDERMAN:  Because, then, again, it's

            11    obvious that the economic incentives are clearly aligned

            12    against the cheaper products, and it's certainly going to

            13    drive up the price dramatically of albuterol if that

            14    happens.

            15                DR. JOAD:  Well, doesn't that bring up

            16    acceptable -- that could include cost, right, or not?

            17                DR. NIEDERMAN:  Again, if you start to think

            18    through the real-world ramifications of all of this stuff,

            19    it gets very, very complex because I see two cost forces,

            20    and neither of which are necessarily looking out for the

            21    patient's best interests.

            22                One of them is the industry where we could

            23    eliminate generics by having two patented non-CFC products. 

            24    On the other hand, if I'm a managed care organization, I

            25    want to have an exemption for cost because I don't want to

                                                                          202

             1    buy these expensive products, and I want to pretend that

             2    I'm interested in low-cost products for patient well-being,

             3    but I'm really interested because I don't want the cost of

             4    my albuterol that I'm paying for to go up tenfold.

             5                So I really don't think these cost issues are

             6    going to be easy to sort out, and I think that there are a

             7    lot of, as I say, economic incentives that you can see

             8    playing out very quickly that don't have patients'

             9    interests in mind.

            10                DR. FORD:  I guess the other side of the

            11    economic question -- and I think these are very important

            12    points.  I haven't thought about this.  The other side of

            13    it also is that once albuterol becomes non-essential, then

            14    there's a huge part of the market that opens up to those

            15    two.  So potentially, there's room for competition and

            16    letting the market sort it out, but I agree.  I wouldn't

            17    take --

            18                DR. NIEDERMAN:  Unless now the non-CFC device

            19    as in the HFA is patented, and it's not open to everybody.

            20                MS. CUSUMANO:  Correct me if I'm wrong, but

            21    you're saying the competition between the two products?

            22                DR. FORD:  Right.  That's what I mean.

            23                PARTICIPANT:  It's still going to be more

            24    expensive.

            25                DR. FINK:  With the example of albuterol, since

                                                                          203

             1    it's focused on a lot since it raises a lot of issues, what

             2    is its legal status?  Because if these products come in as

             3    an MDA, wouldn't they potentially then fall under the

             4    single isomer rule?

             5                DR. JENKINS:  I'm not sure I understand your

             6    question.

             7                DR. FINK:  Well, the FDA guidelines that new

             8    MDAs, if they're single isomers of the product, and it's

             9    known that only one is biologically active, only the

            10    biologically active single isomers should be in the

            11    marketed product?

            12                DR. JENKINS:  That's not really an FDA

            13    position.  I think there's some misunderstanding.  We have

            14    not mandated that racemic mixtures can not be approved.  We

            15    simply have laid out guidance on how you would go about

            16    developing single isomer products.  That's my understanding

            17    of our guidance.

            18                DR. FINK:  Okay.

            19                DR. JENKINS:  And the albuterol products that

            20    we're talking about are racemic mixtures.

            21                DR. FINK:  Right.

            22                DR. JENKINS:  They don't really get into the

            23    issue of single isomer.  There is a single isomer albuterol

            24    product, but that's not where we were focusing today.

            25                DR. SESSLER:  You know, I think the moiety-by-

                                                                          204

             1    moiety approach is on target, but at the same time, there

             2    may be different general classes of drugs that we need to

             3    consider while we're sorting out the details with this.

             4                It seems that albuterol is really quite

             5    different than the situation for inhaled corticosteroids,

             6    primarily because of the generic drug that occupies the

             7    majority of the market right now, and then the third class

             8    is really, I guess, the others in terms of aphatropium

             9    bromide and long-acting beta agonists and so on, that these

            10    are kind of stand-alone drugs to a certain extent.

            11                So we may need to step back a little bit and,

            12    rather than focusing attention on the moiety-by-moiety

            13    approach globally, maybe we need to specifically discuss

            14    inhaled corticosteroids and come to some grips with what

            15    are reasonable alternatives there, and I think coming back

            16    to the idea of 2005 and the class, the therapeutic class

            17    issue, at that point, since we have more than five

            18    different active moieties within that class, and yet the

            19    albuterol issues are, I think, entirely separate and

            20    perhaps trickier in terms of the generic drug and the

            21    potentially underserved population.

            22                So it may be that we need to step back a step

            23    and look at it with that caveat in mind, that there may be

            24    different groups.

            25                Anybody want to talk about inhaled steroids?

                                                                          205

             1                DR. FINK:  Inhaled steroids or albuterol?

             2                DR. SESSLER:  Well, whatever you want.

             3                DR. FINK:  Well, the other approach to

             4    albuterol is to say that if we're looking at the NAEPP

             5    guidelines, it's grossly overused today.  If we bring its

             6    usage down to recommended levels of one to two puffs two to

             7    three times a week, there's not such a great big market for

             8    it, and maybe the problem is that albuterol is just grossly

             9    overutilized today, not that we should be worried about its

            10    costs, because if asthma is treated according to

            11    guidelines, albuterol should actually be used with a

            12    frequency somewhere less than the inhaled steroids or other

            13    controller agents.

            14                DR. SESSLER:  I guess the flip side of that

            15    might be that it's the rescue drug, and that certainly it's

            16    something we want to make sure, of all the drugs, that it's

            17    one that really we don't lose to our underserved

            18    populations that Dr. Ford has spoken to, and we want to be

            19    particularly careful there in terms of not making it more

            20    difficult for the folks who really represent the epidemic

            21    of asthma difficulty from getting drug.

            22                DR. FINK:  And how could you handle the non-

            23    albuterol albuterols, pirbuterol?  Is that a different

            24    moiety, and therefore has its own category, so that it

            25    could stay CFC and cheap?

                                                                          206

             1                DR. MEYER:  In that moiety-by-moiety approach,

             2    the other short-acting beta agonists, such as

             3    metaproterenol and pirbuterol and so on, would be

             4    considered separately.  They'd be considered as their own

             5    moiety.

             6                DR. FINK:  And that potentially is a big

             7    problem in that if an albuterol replacement is more

             8    expensive than the generics, you potentially then are

             9    encouraging more production of the moieties, like

            10    pirbuterol, that are CFC-containing.

            11                DR. DYKEWICZ:  Until 2005.

            12                DR. MEYER:  Yes, I mean, it's certainly a

            13    thought that has crossed our minds, and I think that's part

            14    of the reason why we at least proposed the therapeutic

            15    class approach in the past.

            16                I think that there's some merit to that

            17    approach or I don't think we would have advanced it as a

            18    possibility two years ago, but I think there are some

            19    substantial concerns about it, and I think we acknowledge

            20    and understand those concerns as well.

            21                DR. VOLLMER:  I was compelled, I guess, I mean,

            22    when I read the advanced notice, I liked the recommendation

            23    for therapeutic classes.  It was pretty clear that you got

            24    a lot of feedback to the contrary that came in amongst the

            25    thousands of responses that you got.

                                                                          207

             1                I was impressed today that all the parties that

             2    spoke, both industry and representatives from ATS as well

             3    as our consumer group representatives, all seemed to be

             4    supportive of the moiety-by-moiety approach, and so since

             5    they've had a lot more thought and energy going into it

             6    than I, it seems to me it's probably a way to go.

             7                I'd actually like to get some clarity on an

             8    issue that Mr. Jamieson raised regarding the requirement

             9    that when there's multiple manufacturing sites, that you

            10    have to have a product being apparently produced in

            11    multiple manufacturing sites, and they were proposing -- am

            12    I correct in assuming this is a separate issue than we've

            13    been discussing now?  It's not dosing schemes.  It's actual

            14    different people manufacturing it, and the industry seems

            15    to say that's not a problem for them.  They're actually

            16    happy to have a looser standard.  Have I caught that right?

            17                MS. CUSUMANO:  What Mr. Jamieson's referring to

            18    is actually a statement in the preamble to the actual

            19    proposed rule.  All we say in the proposed rule is that

            20    there must be supplies and production capacity adequate to

            21    provide supplies to patients, and one of the things that we

            22    thought when we wrote that statement is you never know what

            23    might happen to one manufacturing site.

            24                Like Dr. Jenkins was saying earlier, you know,

            25    if you have an earthquake in California, and your

                                                                          208

             1    manufacturing site's in California, and you're put off line

             2    for several months, what are you going to do?  Where's the

             3    patient going to get their drug from?  And it's not

             4    necessarily that in that case that there have to be

             5    multiple sponsors, just that they have to have multiple

             6    manufacturing sites.

             7                DR. JENKINS:  And that's listed in there as a

             8    presumption.  I think it's in language that says that when

             9    FDA is evaluating whether the supplies and production

            10    capacity are adequate, that that might be something we

            11    would take into account.

            12                It's not an absolute requirement.  It's not in

            13    the codified section of the proposed rule.  It's just

            14    trying to explain how the agency would think about those

            15    things when we're evaluating supplies and production

            16    capacity.

            17                There have been instances where natural

            18    disasters have impacted upon the ability of companies to

            19    manufacture inhaled products because they have one location

            20    where they inhaled the product, and the natural disaster

            21    takes that plant off line.

            22                So that's one of the things we were putting in. 

            23    We did not say it was an absolute requirement.  We said it

            24    was something we would probably have a presumption that

            25    that would be better than not having to.

                                                                          209

             1                DR. VOLLMER:  That helps.  Thank you.

             2                DR. JOAD:  I have a comment with regard to my

             3    request of there being a portable device that requires no

             4    cooperation.  In that instance, it seems like it would be

             5    unreasonable to have a moiety-by-moiety approach to that

             6    request, that a class request would be sufficient for that

             7    request.  It wouldn't have to be such a thing for every

             8    single beta agonist out there, but there should be at least

             9    one.

            10                DR. SESSLER:  How about inhaled

            11    corticosteroids?  The reason I bring it up, I think, is a

            12    lot of the discussion and examples really revolve around

            13    albuterol and around the generic question and so on, but

            14    this is, I think, a different kettle of fish in terms of

            15    perhaps the pace of development and some of the impediments

            16    that are different from albuterol.

            17                Is everybody happy with the moiety-by-moiety

            18    approach there with perhaps the 2005 reevaluation of

            19    therapeutic class?  Is that what you all are kind of

            20    thinking about or really am I overstepping, and it's just

            21    moiety-by-moiety?

            22                MS. CUSUMANO:  I'm just kind of hesitant to use

            23    the therapeutic class necessarily, I mean, because what Dr.

            24    Jenkins and Dr. Meyer were saying earlier about, is that

            25    what we're looking at is the market as a whole.  So about

                                                                          210

             1    what was said earlier about progress being made in the

             2    treatment of asthma, so that we're not necessarily looking

             3    at the therapeutic class of corticosteroids, but that if

             4    there have been several reformulated, and in 2005, there

             5    are some that have not been, but there are a number of

             6    other products out there for the treatment of asthma, not

             7    necessarily just corticosteroids, under which people are

             8    well controlled, and they're happy with their asthma, not

             9    missing work, that kind of thing, then looking at the

            10    market as a whole and not just the class necessarily, we

            11    would talk about whether the essential use was still

            12    necessary for a particular product, whether it be a

            13    corticosteroid or a bag.

            14                DR. SESSLER:  Any discussion?

            15                DR. MEYER:  Just as a specific example to sort

            16    of flesh that out a little bit, budesonide is not available

            17    as a CFC inhaler.  It's not really part of this question

            18    about the CFC transition.  But it could very well be that

            19    when you're considering the market, for instance, that the

            20    Pulmicort Turbuhaler could enter into sort of the

            21    consideration of how the asthmatic population in general is

            22    being managed at that time, and, you know, it's quite

            23    conceivable that leukotriene antagonist might play into

            24    that consideration, other agents that have yet to come, as

            25    we are talking about five years hence.

                                                                          211

             1                So we're trying to avoid the therapeutic class

             2    terminology, not just because there were so many comments

             3    about it in the past, but more specifically because we are

             4    proposing something different from that.  It's akin to it,

             5    but it is different from that.

             6                DR. FINK:  For the inhaled steroids, if there

             7    are four or five alternative devices available by 2001,

             8    would you undertake a class review at that point or would

             9    you wait till 2005?  Because it's clear we probably will be

            10    in that situation by the end of next year, I would think,

            11    in terms of having four or five, at least, non-CFC products

            12    available.  And do you wait another four years before you

            13    look at the remainder?

            14                MS. CUSUMANO:  Under the proposed rule, we

            15    would wait another four years.  Now, the flip side of it is

            16    what happens with the Montreal Protocol, because the

            17    parties to the Protocol would look at our requests, and

            18    from that angle, they might not allocate CFCs, but under

            19    the proposed rule, we would not look at it until 2005.

            20                DR. JENKINS:  I think it's also important to

            21    remember the process that is being proposed here because

            22    you can't just focus on the timing at which, say, an

            23    alternative product becomes available because in the

            24    proposed rule, one of the additional criteria was that we

            25    would have at least one year of U.S. post-marketing safety

                                                                          212

             1    data.  So that takes you out at least another year.

             2                Then the agency has to make a determination

             3    that the product adequately meets patient needs and

             4    fulfills those criteria and would issue a proposed rule to

             5    eliminate the use of CFCs in that moiety.

             6                So we're not going to be in the situation a

             7    year from now for the corticosteroids that you were

             8    referencing, Dr. Fink, where we're going to be ready to say

             9    that things are not essential.  This is a process that's

            10    going to take time, and I think everyone needs to

            11    understand the process.

            12                Today, we're talking about a proposed rule

            13    which has no impact until it becomes a final rule, and even

            14    when it becomes a final rule, it simply lays out the

            15    process and the criteria the agency will follow in making

            16    those future determinations.

            17                So this is a multiyear process that we're

            18    talking about here.  Nothing is going to happen overnight.

            19                DR. GROSS:  I'm trying to figure out, if I was

            20    a drug company, why would I have any interest in developing

            21    a non-CFC version of my product until the year 2005? 

            22    Because it's bound to be more expensive, and I'm going to

            23    be paying the development costs anyway, but why not put

            24    them off until the year 2004, and so until I have to

            25    comply, then why would I do so?

                                                                          213

             1                Isn't it sort of like the situation with

             2    automobile air bags and seatbelts?  You know, there was a

             3    time when some people wanted to pay a little bit more, but,

             4    in general, the manufacturers said we don't want to do this

             5    because it's going to add a lot more to the cost, and so

             6    they kicked and screamed about that, but when a deadline

             7    came, lo and behold, everybody had seatbelts in their cars,

             8    and I don't know whether we pay a little bit more for that,

             9    I suppose we do, but it just became an acceptable thing.

            10                So isn't this almost the same situation, where

            11    basically they're not going to do it voluntarily until

            12    there's a deadline that they have to meet?

            13                DR. MEYER:  Well, I think there are various

            14    levels of complexity to answering that, but I think the

            15    message of the international community is clear, that a

            16    date will come when these products can no longer be

            17    marketed, and there is not an absolute deadline, and

            18    certainly we don't want the message coming out of here that

            19    2005 is the absolute deadline in the United States.  So the

            20    companies have that.

            21                There's enough vagaries in being able to

            22    conduct a good, rational and timely development program,

            23    that I'm sure companies would not want to push it off to

            24    the last minute.

            25                Furthermore, I think there's certainly

                                                                          214

             1    increasing problems with getting access to the CFCs.  The

             2    companies do have to go through the essential use process,

             3    and even then, they have to be able to import these and

             4    store them and handle them, and the expense is getting more

             5    to be a consideration, too.

             6                So I think there are some clear incentives for

             7    companies out there, but as we discussed for some products,

             8    I think that some companies have looked at the bottom line,

             9    and for, you know, considering their market, considering

            10    what they see as the future for their market, for their

            11    product, to look at that and say, okay, when the door shut

            12    on us, that's it.

            13                So I think those who want to reformulate,

            14    there's a clear reason why they might want to do that

            15    earlier rather than later.  For those who don't want to

            16    reformulate, I'm sure they'll want to take it out as far as

            17    they can.

            18                DR. JENKINS:  I would add to that that you have

            19    to understand that the development of new drugs is mainly a

            20    global effort these days.  Most of the pharmaceutical

            21    companies that we're talking about who market the CFC-based

            22    inhalers that are the market leaders in the United States

            23    are global companies.  So they're working on developing

            24    these formulations for the global community, and actually

            25    the transition pace may occur more rapidly in other markets

                                                                          215

             1    than it may occur in the United States.

             2                For example, the Australians have already made

             3    a determination that the use of CFCs in albuterol may no

             4    longer be essential in Australia.  So you have to factor in

             5    the global nature of not only the transition and the

             6    Montreal Protocol but also the global nature of how these

             7    companies operate.

             8                The Europeans are, I think, very close to

             9    getting to a point where they may decide that albuterol is

            10    no longer an essential use of CFCs in the European Union. 

            11    So the United States may not be the fastest in the

            12    transition.  So simply looking at it from a U.S.

            13    perspective doesn't give you the total picture that the

            14    companies need to address.

            15                DR. NIEDERMAN:  But again, the economic

            16    incentive is clearly there to develop a non-CFC albuterol

            17    because that will close down the generic market with CFCs,

            18    correct?

            19                DR. JENKINS:  Well, that's one way of looking

            20    at it.  I can say that for the market-leading products in

            21    the United States, those products who have substantial

            22    market share, I've not seen any evidence that there's not

            23    an incentive for those companies to reformulate.  Those

            24    companies have been working very actively, even in

            25    situations where they don't have competition.  They're the

                                                                          216

             1    single source of a molecule.  Companies have been working

             2    activity to reformulate.

             3                DR. NIEDERMAN:  They may do it, as you say,

             4    when they don't have to, but, conversely, specifically in

             5    the albuterol market, there seems to be a strong economic

             6    incentive with your rule of two products to develop a

             7    second product and close down the generic market.

             8                DR. JENKINS:  Right.  That incentive existed

             9    even before we proposed the rule, and I can tell you that

            10    multiple companies are working on albuterol alternative

            11    products, not just one or two and not just necessarily the

            12    ones that currently market albuterol products.

            13                It seems sometimes like every company out there

            14    must be developing an albuterol product because we get the

            15    requests for meetings from them.  So there's no lack of

            16    interest in developing albuterol replacement products.

            17                DR. NIEDERMAN:  So you think that there would

            18    be enough competition of non-CFC albuterol that would not

            19    drive the price up?

            20                DR. JENKINS:  I don't want to get into

            21    speculating about what the market forces of competition may

            22    or may not do because that's way beyond my level of

            23    expertise, but I think we do have the potential that in the

            24    future, there will be multiple albuterol inhalation

            25    products, and I think there will be multiple types of

                                                                          217

             1    devices.

             2                DR. GROSS:  But the criterion of necessity

             3    would be met by having one HFA albuterol and one dry-powder

             4    albuterol?

             5                DR. JENKINS:  That's possible.  It could be two

             6    HFA albuterols.

             7                DR. GROSS:  Right.  But I mean, given that HFA

             8    is a patented substance.

             9                DR. JENKINS:  Well, there are ways around those

            10    patents, and you can enter into licensing agreements, et

            11    cetera.  So.

            12                DR. GROSS:  Yes, but I mean, everybody is

            13    developing dry-powder albuterol right now.  So that, I

            14    mean, is that what you were referring to when you said you

            15    see the new applications coming through?  There's a lot of

            16    applications for dry-powder albuterol.

            17                DR. JENKINS:  There are also applications or

            18    development for HFA albuterols as well.  So there are ways

            19    that companies can address those patent issues.

            20                DR. SESSLER:  Any other comments?

            21                DR. FORD:  I guess following up on the issue

            22    that Dr. Niederman brought up, one practical question that

            23    would come up in the implementation of non-essential status

            24    for albuterol would be whether we would want to wait until

            25    there is sufficient assurance, even as we know what the

                                                                          218

             1    pipeline looks like, that at least albuterol won't become

             2    cost prohibitive even for a period of time, until the

             3    pipeline catches up.

             4                I don't know how much of a concern that is, but

             5    I would imagine that this would be a consideration in the

             6    timing of that determination for albuterol.

             7                DR. SESSLER:  Bob, the next point is really

             8    related to the issues that we've been discussing as it

             9    relates to albuterol, and I believe you wanted to make some

            10    sort of a correction or a statement on that.

            11                DR. MEYER:  Yes.  There's an inaccuracy that I

            12    need to take credit for on that, and that is that the

            13    consortium itself of IPAC has not made this statement, I

            14    think, for understandable reasons.  They don't see

            15    themselves in the position to make statements about drug

            16    pricing because they are a consortium.

            17                So it's actually been member companies not

            18    speaking on behalf of the consortium but on their own

            19    behalf that have stated in various fora that they would see

            20    the replacement products as being priced very comparably to

            21    their CFC-branded counterparts.

            22                So in other words, as I think I mentioned

            23    earlier, Proventil HFA is within pennies of the cost of

            24    Proventil CFC, and other companies have made similar

            25    commitments.  So again not to belabor this point, but I

                                                                          219

             1    think the issue of cost really is perhaps the thorniest for

             2    the products where there's a generic, and right now, the

             3    status of the market is such that's only albuterol.  So

             4    we're really talking about the cost issue being most

             5    important there.

             6                I think I'd even reflect, maybe following up on

             7    what Dr. Ford just said, that I think we have to bear in

             8    mind that three years ago, there were no generic

             9    albuterols, and, you know, for better or for worse, they're

            10    here now, and I think one could argue that perhaps having

            11    cheaper medications is quite a benefit.

            12                But I think we need to bear in mind that up

            13    until three years ago, this was a market without any

            14    generic competition.  So certainly, outside of albuterol,

            15    we're really not talking about costs being -- we anticipate

            16    a major part of this process, but even albuterol, although

            17    I think the issue is important, and we have it here as a

            18    talking point, I'd just like to have everybody bear in mind

            19    that as patients are doing reasonably well compared to how

            20    they're doing today three years ago at a time where

            21    albuterol had a very different pricing structure.

            22                DR. KELLY:  Maybe the low cost of albuterol is

            23    not a good thing.  If we're overusing it, as Dr. Fink has

            24    said, maybe we want to make it costlier so the HMOs would

            25    prefer to give inhaled corticosteroids and not so much

                                                                          220

             1    albuterol.  I mean, there are other ways of looking at

             2    costs.

             3                DR. SESSLER:  Dr. Jenkins?

             4                DR. JENKINS:  Curtis, I get the feeling that

             5    you're getting ready to discuss the specific point on

             6    costs, and before you leave the moiety-by-moiety approach,

             7    I wanted to stimulate a little bit more discussion about --

             8    I tried to highlight a little while ago something that may

             9    be considered to be a positive benefit of the transition,

            10    and that's a lot of innovation and a lot of attention to

            11    new devices.

            12                You could look at another issue related to the

            13    transition that could be viewed as a negative, is it's very

            14    likely at the end of this transition, we will have fewer

            15    moieties by inhalation than we had when we started, and,

            16    for example, some of the very small market share products

            17    that are out there, companies may choose not to reformulate

            18    those products, and it may come that eventually, under this

            19    2005 provision that we've proposed, there will be a

            20    determination that those products are no longer essential,

            21    and I'm wondering how the committee feels about that, the

            22    fact that at the end of the day, as a result of the

            23    transition, there may be fewer moieties available than

            24    there were when we started.

            25                DR. NIEDERMAN:  It seems inevitable, but not

                                                                          221

             1    necessarily bad.  I think some of these, as you said, have

             2    such a small market share, that it's hard to justify either

             3    clinically or pharmacologically that we need as many

             4    different moieties, and there's a lot of historical

             5    perspective as to why some of these products exist.

             6                I think this is probably one issue that's

             7    probably not bad to cut down the number of choices.

             8                DR. JOAD:  I guess it might only be a problem

             9    with inhaled steroids, but we don't know the answer to that

            10    yet.  I mean, we have very little information about

            11    choosing one over another, and when we get that, hopefully

            12    in the next several years, then it could really matter if

            13    one of them is not available, that really does matter to us

            14    more than another.

            15                So that class, I would be more worried about

            16    than, say, the beta agonist class, short-acting beta

            17    agonist class.

            18                DR. JENKINS:  Just to follow up on that, we've

            19    talked a lot today about albuterol, and clearly there's no

            20    secret that albuterol already has an alternative, and we've

            21    talked a lot about other alternatives being developed.

            22                As a hypothetical and not to suggest that this

            23    would be the outcome, how would you feel if, at the end of

            24    the day, when this transition was over, albuterol was the

            25    only short-acting beta agonist that was available?

                                                                          222

             1                DR. GROSS:  I guess I just don't believe

             2    there's a lot of difference between the molecular entities,

             3    but there are other cosmetic things about different

             4    bronchodilators.  There's taste and slight differences

             5    between the devices and so forth.

             6                I mean, I think one needs to have some choices

             7    for non-medical reasons but simply because there is a

             8    preference issue there, and obviously you need it for

             9    competition as well, but I, for one, wouldn't really mind

            10    very much if all the other beta agonists disappeared of the

            11    same duration of action and otherwise similar pharmacologic

            12    properties.

            13                MS. CONNER:  Does anyone else have patient

            14    experience of patients that just absolutely -- if you've

            15    ever tried them on pirbuterol, they won't go back to

            16    albuterol because of the lack of tremor?  They just don't

            17    seem to have -- whether that's real or imagined.  I have

            18    patients that really, really prefer pirbuterol over

            19    albuterol, and it's something that they can detect a

            20    significant difference.

            21                DR. JENKINS:  So you're saying you would be

            22    concerned if there were not a choice?

            23                MS. CONNER:  Yes.  Yes, I would.  At least that

            24    choice.  Some of the others --

            25                DR. GROSS:  Well, that's really hard to justify

                                                                          223

             1    scientifically, because tremor is a beta2 action.

             2                MS. CONNER:  Right.

             3                DR. GROSS:  It's a specific subgroup of one

             4    type of problem.

             5                MS. CONNER:  Of the others, it's the one that

             6    I've seen preferred or asked for.

             7                DR. KELLY:  It's a little less potent than

             8    albuterol, and so you'd expect a little fewer systemic side

             9    effects if you gave the same dosage.

            10                MS. CONNER:  And it may be that they're milder

            11    and use it less frequently when they do use it.

            12                DR. DYKEWICZ:  Hypothetically speaking, let's

            13    say it came to pass that it was found that albuterol had

            14    some unforeseen toxicity in some set of patients.  You

            15    know, we have no evidence, for instance, that it's a

            16    particularly teratogenic agent in pregnancy, but let's say

            17    it played out that in fact that was a problem or that you

            18    got any sort of adverse effect problem, and then you had no

            19    alternative for another drug in the class being available.

            20    Again, we're talking hypothetically, but that might be an

            21    issue.  There would be no alternatives to turn to.

            22                DR. SESSLER:  You know, I think one thing

            23    that's worth bearing in mind, too, is we offer the

            24    prospective of clinicians and the like, and we don't

            25    necessarily represent the patient's perspective, and I

                                                                          224

             1    think Brenda brought that out nicely, that there may be a

             2    much greater outcry from a less scientifically rigorous

             3    look at the comparable drugs, and that we should value that

             4    and pay close attention to it.

             5                So my guess is that choice is better than no

             6    choice for a variety of reasons, although it probably

             7    doesn't need to be quite as broad perhaps as we have

             8    currently.

             9                MS. CONNER:  And I have to admit I'm one of

            10    those patients.

            11                DR. SESSLER:  A personal issue.

            12                MS. CONNER:  It gets right down to it.

            13                DR. SESSLER:  Politics are personal.

            14                DR. GROSS:  Wouldn't market forces suggest that

            15    we will have more than one choice, though, for the same

            16    reason that we have six separate beta2 agonists now?

            17                Once we cross this 2005 hurdle, and for all the

            18    new entities certainly and old entities, with very few

            19    exceptions, have to meet the same standards of the non-CFC,

            20    wouldn't you then have the same comparative pressure to

            21    introduce or bring back a lot of well-known agents, if they

            22    had gone out of production?  Am I missing an economic

            23    factor here?

            24                MS. CUSUMANO:  It might depend on current

            25    market share.

                                                                          225

             1                DR. SESSLER:  You know, another issue that

             2    relates to choice is not so much the molecular entity as it

             3    is the delivery, which is, you know, obvious for the things

             4    in the future, but also you've got the Maxair Autohalers,

             5    something different in terms of a beta2, and you've got

             6    Azmacort with its built-in spacer and convenience of that,

             7    that has played a role at least historically in terms of

             8    drug selection for a lot of patients and doctors, I

             9    suspect.

            10                Some of those, they're separate issues, but at

            11    the same time, from a regulatory standpoint, my

            12    understanding is that they are kind of approved as one

            13    package, that is, the drug and the device, and so that's, I

            14    guess, another wrinkle in to the number of entries into the

            15    market and another factor, I suppose, to be considered with

            16    how many are enough.

            17                DR. JENKINS:  I didn't want it to go unnoticed

            18    that I think Ms. Conner finally answered my question about

            19    what is a subgroup.  I think she defined herself as a

            20    subgroup.

            21                (Laughter.)

            22                DR. SESSLER:  Okay.  Very good.  Any other

            23    moiety-to-moiety -- actually, I brought up the other topic

            24    because we're starting to move into the cost issue or all

            25    day, I guess, we've really been talking about the cost of

                                                                          226

             1    albuterol, but just to get that out there as well.

             2                Anything else from the moiety-to-moiety

             3    approach?  Any last comments on that?

             4                DR. KELLY:  Just a last comment on what Dr.

             5    Jenkins just talked about in terms of albuterol possibly

             6    being the only -- those are market forces which we have no

             7    control over, and they're going to happen probably anyway

             8    in the long run.

             9                If you can't sell pirbuterol Maxair or

            10    whatever, you'll stop making it, even if you don't make the

            11    transition to CFCs, I would think.

            12                DR. SESSLER:  We've touched on it many times,

            13    the cost issue, and Dr. Meyer clarified that second-to-the-

            14    last bullet point there.

            15                I guess the question that was -- there was a

            16    set-up, and then the question was, would price be such a

            17    substantial barrier to access for albuterol that it should

            18    be considered in the determination of essentiality?

            19                So this, I guess, puts the regulatory component

            20    on the question that we've really been talking about for

            21    much of the day.

            22                Michael?

            23                DR. NIEDERMAN:  Well, I think, again, this is

            24    an extremely complex question, and it's not what it appears

            25    on the surface, and I think if you think it through, my

                                                                          227

             1    answer would be that the costs should not be the reason to

             2    make it an exemption from the essential drug list.

             3                I'll tell you the example that I worry about

             4    is, I think about my patient population, and how often I

             5    prescribe the drug that I think is better, and the managed

             6    care prescription plan comes back and asks me to change it

             7    to a cheaper product, and I think that that will end up

             8    being the major lobbying force for a cheaper alternative.

             9                It will not really be as much the underserved

            10    patient, which clearly will benefit from a lower-cost

            11    product, but I think in the marketplace, managed care will

            12    probably be the largest lobbyer for a cheap product rather

            13    than the underserved patient, and I think that they will

            14    work very hard, if cost will be viewed as an exemption.  I

            15    think they will certainly work very hard to maintain low-

            16    cost products that have CFCs because it's a tremendous

            17    economic impact on them with all the inhalers that they're

            18    paying for.

            19                DR. JOAD:  I would just say the transition has

            20    to happen some time, and this will probably always be an

            21    issue.  So that there's probably no perfect time where you

            22    could say cost was an issue now and cost is not an issue

            23    now.  So probably that should not be built into it.

            24                I also realize Dr. Kelly's point about that

            25    maybe it wouldn't be so bad if albuterol weren't quite so

                                                                          228

             1    cheap.

             2                DR. KELLY:  Thank you.

             3                DR. NIEDERMAN:  I think cost is an issue, but I

             4    think, as I say, it's got multiple sides to it.

             5                DR. SESSLER:  I think there are a lot of layers

             6    to this one because you've got your generic albuterol, and

             7    then you've got your albuterol look-alikes that are

             8    separate molecular entities and may hang around for their

             9    five years and be priced more cheaply and impair the

            10    overall transition of the short-acting beta agonist group,

            11    and yet I sure take care of a whole lot of poor folks, and

            12    I'm really concerned about it.

            13                I mean, from the epi standpoint, that's the

            14    area that really we're not winning the battle yet, I don't

            15    think, and, you know, I'd hate for us to look

            16    retrospectively and find that the mortality has gone up in

            17    that subset, you know, that it's gone down for folks who

            18    can afford their meds, and it's gone up for folks who

            19    can't, and so I think even though cost, I think, is

            20    extremely complicated, and I'm not sure how to factor it in

            21    exactly, but that would be my fear, I guess, is if we

            22    ignore it, that that's the consequences that we might pay.

            23                MS. CONNER:  I've also been in a situation at

            24    an asthma camp where we had a large contingency of inner-

            25    city low socioeconomic, lower-income kids, and just in

                                                                          229

             1    dealing with their medications as well as the ones from the

             2    suburbs at all at one time. you can see that availability

             3    and price dictates prescribing patterns.

             4                I mean, these kids would be on generic

             5    theophylline, not even long-acting, but they'd be on

             6    generic theophylline four times a day around the clock

             7    because it was cheaper than a long-acting theophylline, or

             8    they'd be on inhaled nebulized medications, 15-16-year old

             9    kids, because it was cheaper than a metered-dose inhaler.

            10                So I think we can't let their care be impacted

            11    if we limit resources, but by the same token, just like you

            12    said, if it's too cheap or if the lesser-desired product is

            13    cheaper, are we doing them an injustice by making that

            14    available?  I don't know.

            15                DR. FINK:  But, for the children, at least,

            16    Medicaid is done on a state-by-state basis, and all you're

            17    dealing with there really is the state as an HMO because

            18    where there are limitations -- in D.C., there is no

            19    limitation on what I prescribe.  Medicaid is the best payer

            20    for drugs in D.C.  It just depends on how your state

            21    functions as an HMO.  So it's just 50 more HMOs to deal

            22    with, which, if you had another 250 that already exist, I'm

            23    not sure it's terrible.

            24                MS. CONNER:  That in itself is so frightening.

            25                DR. FINK:  But, I don't think it is exclusively

                                                                          230

             1    the underserved that have problems getting their

             2    prescriptions.  They usually have less out-of-pocket

             3    expense for their drugs than other groups, unless the state

             4    has been very aggressive in limiting the choice of

             5    physicians.

             6                DR. FORD:  I think that this is a very complex

             7    issue, and there are multiple layers.  I think there's the

             8    interaction between what providers actually prescribe and

             9    what's available based on cost and so forth, and even if we

            10    were to limit availability of albuterol, I think that there

            11    are other layers of complexity.  You know, if people have

            12    access to other molecules, then they go for the Primatene

            13    Mist a little bit more at that point, and so whatever

            14    intervention we introduce, we're going to have to weigh

            15    very carefully.

            16                I think it's very hard to say categorically do

            17    it this way or the other, and it requires a lot of thought. 

            18    I wish I could be more direct than that.

            19                DR. NIEDERMAN:  I mean, one way to solve the

            20    problem is -- and I don't know how you do this

            21    legislatively, but if there was some way to make it

            22    required, that anybody who needed albuterol would have it

            23    paid for by somebody, then immediately -- I think the

            24    problem is that you create a two-tiered system if you allow

            25    cost to be an issue.

                                                                          231

             1                I think you allow underserved people who have

             2    bad insurance to potentially get inferior products.

             3                DR. FORD:  Precisely.  A lot of our patients,

             4    for example, they are uninsured or they're immigrants who

             5    are outside of any -- they fall off any radar screen.

             6                DR. NIEDERMAN:  I think, again, if this

             7    discussion were being held in Europe, we would realize how

             8    silly our American health care system is, where we're

             9    talking about potentially allowing less than satisfactory

            10    products to stay on the market because we're not providing

            11    coverage for some people with a very serious disease to get

            12    their medications.

            13                So I mean, it's, as has been said repeatedly,

            14    it's complex, but it's complex in the context of the whole

            15    health care system that we work in.

            16                DR. DYKEWICZ:  Another layer of the complexity

            17    may be the reality that really for most patients who are

            18    using albuterol with any frequency, they should be also

            19    obtaining some other controller agent, an inhaled steroid,

            20    for instance, and so what you're really looking at is the

            21    impact on the overall costs for treatment.

            22                On one hand, you could say, well, if they're

            23    going to have to pay a lot more for their albuterol, is

            24    that going to reach a threshold that they aren't going to

            25    be able to afford the controller medication?

                                                                          232

             1                On the other hand, you could make the case that

             2    if they really should be on an inhaled steroid, with very

             3    infrequent use of albuterol, that might be the better way

             4    to kind of drive the utilization or whatever limited

             5    resources there may be.  But, you know, another layer of

             6    the complexity.

             7                DR. SESSLER:  So we need a generic inhaled

             8    corticosteroid?

             9                DR. GROSS:  I think the idea that you're going

            10    to get people to use more steroid by making the albuterol

            11    more expensive is frankly ridiculous.

            12                (Laughter.)

            13                DR. GROSS:  I mean, this is the first-line

            14    treatment for people who have acute attacks.  You can't

            15    simply limit their use certainly by economic forces, and I

            16    can tell you absolutely without any question of being

            17    contradicted, that if you ask a patient, particularly a

            18    poor one, which drug they would rather be able to have easy

            19    access to, albuterol or a steroid, they'd say albuterol

            20    every day of the week.

            21                So I mean, I wish we would stop discussing the

            22    possibility of reducing the use of albuterol by increasing

            23    the price.  I mean, that's gotten flippant, right?

            24                DR. SESSLER:  I hope that helped.

            25                (Laughter.)

                                                                          233

             1                DR. SESSLER:  Any other discussion on the cost

             2    issue?

             3                DR. NIEDERMAN:  But, Curt, I think most people

             4    do agree that costs shouldn't be a way of declaring it an

             5    essential product because it's cheap.  I didn't think

             6    anybody was arguing that we should allow a low-cost CFC

             7    compound to stay on the market simply because it's cheap.

             8                DR. SESSLER:  I think it's a question, to a

             9    certain extent, is that perhaps additional caution should

            10    be undertaken, and that some careful epidemiology work be

            11    done.  If indeed that happens, that to monitor what the

            12    asthma mortality and outcomes are in the groups that we

            13    would target as being at highest risk for having a negative

            14    impact from elimination of that.

            15                I would say that, you know, perhaps it wouldn't

            16    be something that, for my own opinion, would impact the

            17    determination of its essentiality, but I think it would

            18    certainly give us cause to be cautious with our approach.

            19                DR. NIEDERMAN:  But the answer, again, if,

            20    let's say hypothetically, you eliminated the low-cost

            21    alternatives, and in specific populations, they stopped

            22    using the medication because they couldn't get it, and

            23    mortality went up, the answer probably isn't to bring back

            24    the low-cost alternatives, if they're considered

            25    environmentally dangerous and maybe not as good.

                                                                          234

             1                The answer is to find a way to deliver the

             2    drugs to people who can't afford it.

             3                DR. FORD:  So I don't think anybody has a

             4    problem with introducing the new drugs and even taking off

             5    the low-cost alternatives, but I think that for public

             6    health policymakers, there is an obligation that goes along

             7    with this to make sure that at the very least, the level of

             8    access will be comparable to use your standard, and to just

             9    introduce it and think that the marketplace is going to

            10    take care of it, I think, could -- we don't want to wait

            11    for the statistics to tell us that people are going to have

            12    access to albuterol who are having asthma attacks.

            13                DR. SESSLER:  Dr. Meyer?

            14                DR. MEYER:  I was just going to make the

            15    comment, I'm not sure that these kind of data exist in any

            16    rigorous fashion, and this is confounded by secular trends

            17    and so on, but we do have several years now of albuterol

            18    being available as a generic, and I guess we could at least

            19    consider whether there are data to address whether that has

            20    had any impact on asthma morbidity and mortality since it's

            21    been available.

            22                I would hazard a guess that it's probably  not

            23    made any definable dents in either of those statistics, but

            24    I don't know.

            25                DR. KELLY:  Well, the morbidity and mortality

                                                                          235

             1    from asthma is still rising in the last CDC report.  So I

             2    guess we haven't had an impact.

             3                DR. SESSLER:  Well, it's hard to sort out

             4    whether the rate of rise would be steeper, and it would be

             5    flatter in that one.

             6                DR. DYKEWICZ:  Although I believe in our

             7    briefing documents, we received some data which indicated

             8    that the overall number of prescriptions of albuterol

             9    before and after the availability of generics was not

            10    significantly changed, implying that perhaps the access to

            11    albuterol was not that significantly impacted.

            12                DR. MEYER:  Yes.  That is actually true of what

            13    we found with the albuterol data, and it actually tends to

            14    be true of generic drugs in general, and when a drug

            15    becomes available in a generic form, most times, there is

            16    no expansion of the market.  In fact, often, there's a mild

            17    shrinkage of that particular drug being used.

            18                DR. NIEDERMAN:  Which is just saying that the

            19    people who are paying for the drugs are saving more money,

            20    and these days, most of that is probably not the patients.

            21    Most of that is the third party payers.

            22                DR. SESSLER:  Let's move ahead to the final

            23    bullet point here, an entirely different topic.  What are

            24    the merits/problems with a rapid elimination of CFC-based

            25    nasal corticosteroid products, given the availability of

                                                                          236

             1    aqueous products and other alternative treatments?

             2                Bob?

             3                DR. FINK:  I think it's meritorious, and at

             4    least it says that the FDA has taken a stance on the CFC

             5    use, and it sends a message that at least in one product

             6    line, we are phasing it out, and it sends a reality message

             7    to anybody who didn't believe that the eventual phaseout

             8    for the other devices is coming and probably won't cause

             9    any increase in mortality.

            10                DR. SESSLER:  Yes.  Dissenting views?

            11                DR. DYKEWICZ:  I would say that there are some

            12    individual patients, of course, who prefer the non-aqueous

            13    preparations.  I think if you're looking at probably

            14    controlled studies indicating that there's any difference

            15    in efficacy, we really don't have anything that

            16    demonstrates that.

            17                If you're looking at serious adverse effect

            18    profiles, I don't think there's any clear evidence that

            19    there's any difference between that.  You will see the

            20    episodic patient who will say that they just can't tolerate

            21    the drippiness of an aqueous preparation, and they won't in

            22    fact take it as a result, but then, I guess, when you try

            23    to define this in terms of is this, you know, an essential

            24    need to have some non-aqueous preparations available, I'm

            25    not sure if you can make that case, you know, in terms of

                                                                          237

             1    national policymaking or regulatory authority.

             2                DR. SESSLER:  Dr. Meyer, could you give us an

             3    overview on what we currently have available in terms of

             4    both aqueous and CFC products out there, so just to get a

             5    feel for the magnitude of what would change?

             6                DR. MEYER:  Yes.  There are three moieties that

             7    are available and CFC-driven metered-dose inhalers for

             8    nasal corticosteroids, that being triamcinolone,

             9    beclomethasone, and budesonide.

            10                Currently, all of those have aqueous

            11    formulations, either by the same manufacturer or otherwise. 

            12    There's also other aqueous formulations available that are

            13    not available as CFC-driven MDIs, such as fluticasone and

            14    mometasone and momisamide.

            15                I think we are safe to say that, I think, some

            16    of the industry perceives that there is perhaps some

            17    reasons to reformulate the metered-dose nasal products, and

            18    there is some interest in that regard.

            19                So you know, I can't really speculate about the

            20    future, but I'd suspect if there's enough of a patient need

            21    or desire for that, that that will be met.

            22                DR. SESSLER:  Do we have any data as to the

            23    frequency with which intolerance occurs with this?  I mean,

            24    I know there have been some discussion, but again, is that

            25    substantial?

                                                                          238

             1                DR. MEYER:  I think we can pretty safely say

             2    that FDA does not have any good controlled data that would

             3    really answer that question.  It's much more anecdotal, and

             4    even gets to the point -- I know that one of the folks who

             5    serves on the Technical Options Committee with me in the

             6    UNEP is rather prominent in the U.K.'s transition, and he

             7    gets personal calls from people in the EU saying why are

             8    you taking away my nasal inhaler?

             9                So it's anecdotal from him, too, I know, but in

            10    any case, we don't have any good data.

            11                DR. SESSLER:  Can we hear from the allergists

            12    here?  I would like to call on you.

            13                DR. APTER:  I want to second what Dr. Dykewicz

            14    said and reiterate what I said this morning.  For the

            15    patients who have difficult nasal polyps, sometimes topical

            16    nasal steroids won't even get to the right place, and you

            17    require prednisone, but I do have the feeling, and again

            18    there's not head-to-head controlled data, that the

            19    difference in delivery system makes a difference for some

            20    people, some people who have very deviated septa, you know,

            21    very different anatoma, anatomy people with polyps, and so

            22    I think it would be ideal to have a propellant formulation,

            23    but I don't know that it's life-threatening.  I don't know

            24    in weighing the risk of CFC that would be worth delaying

            25    taking the nasal steroid off the market, the propellant off

                                                                          239

             1    the market.

             2                DR. SESSLER:  Other discussion?

             3                (No response.)

             4                DR. SESSLER:  Anything coming down the pike in

             5    terms of non-aqueous agents or is that --

             6                DR. MEYER:  We have seen some gipicard.  I

             7    don't want to be too explicit, but, yes, we have seen some

             8    interest in that.

             9                DR. KELLY:  Is there any marketing data on what

            10    portion of the market the non-aqueous is?

            11                MS. CUSUMANO:  It represents about 20 percent

            12    currently, apparently.  20 percent of the market of the

            13    CFC.

            14                DR. KELLY:  Of the market.  Okay.

            15                DR. APTER:  But my experience is that the

            16    aqueous versions are very heavily marketed at the expense

            17    of the aerosol.  So I'm not sure what that means.

            18                DR. MEYER:  Well, I guess the reason may be

            19    marketing, but at least we know that 80 percent of the

            20    patients at this point seem to be having that as a

            21    satisfactory treatment option.

            22                DR. SESSLER:  Other comments?

            23                (No response.)

            24                DR. SESSLER:  I kind of share the idea that

            25    it's a good starting point, and it sounds like the impact

                                                                          240

             1    would be relatively minimal, especially if there's other

             2    agents that are aqueous alternatives that are coming down

             3    the pike, because I think Dr. Fink stated correctly that

             4    this sends a good message in terms of that it's a

             5    deliberate process, but there's actions being taken as

             6    well.

             7                We certainly have a little bit of time left, if

             8    anybody has any other closing comments as members of the

             9    committee on this process, if anybody would like to offer

            10    anything additional.

            11                Dr. Meyer?

            12                DR. MEYER:  I actually wanted to ask the

            13    committee and the audience a question, because I think one

            14    thing that's clear is that we benefit in trying to come up

            15    with a transition policy that makes sense for patients and

            16    protects patients, and in getting some level of feedback

            17    from patients, and one of the very nice ways that we get

            18    that is through interactions with patient advocacy

            19    organizations.

            20                It has struck me, I certainly have had this

            21    thought before, but it's become much more clear to me, that

            22    the asthma community is rather better organized than some

            23    of the other constituencies, and the one I have in mind

            24    particularly is the chronic obstructive pulmonary disease

            25    community.  Even doing sort of a web search on COPD, it's

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             1    very hard to find many good sort of national organizations

             2    that address that, and I might be missing some resources.

             3                So I'd certainly invite anybody from the

             4    committee or from the audience who really has some contacts

             5    with patient groups, particularly in the chronic

             6    obstructive pulmonary disease community, to share them.

             7                DR. APTER:  I think the place to look is in the

             8    pulmonary rehab community.  There are very active pulmonary

             9    rehab groups.  You can find them meeting at the ATS.

            10                DR. MEYER:  Yes.  I think what I've found, and

            11    this may differ from other people's experience, but what

            12    I've found is they tend to be much more locally or

            13    regionally organized rather than nationally, so that you

            14    have support groups through local ALAs or, you know,

            15    hospital-based programs for rehabilitation or maybe

            16    regional-based programs.

            17                DR. APTER:  But they do meet nationally, too.

            18                DR. NIEDERMAN:  There is the AACVPR, the

            19    American Association of Cardiovascular and Pulmonary Rehab,

            20    but I think that's more of a physician group and not a

            21    patient advocacy group.

            22                DR. GROSS:  And there's the Alpha I community.

            23                DR. MEYER:  Right.  It's quite well organized,

            24    yes.

            25                DR. DYKEWICZ:  I do have one other thought.

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             1                DR. SESSLER:  Please.

             2                DR. DYKEWICZ:  This may not really have any

             3    ultimate impact on how the regulation is being articulated,

             4    but a practical matter, is that if you have a patient who

             5    requires several different classes for treatment of asthma,

             6    so they need their quick-acting beta agonist, they need

             7    their inhaled steroid, and maybe even a third agent,

             8    nedocromil or whatever, the question would be, having some

             9    uniformity of delivery technique so that a patient is not

            10    going to be confused between switching from one preparation

            11    to another, you know.

            12                The problem that immediately has come to mind

            13    in a more restricted way with the introduction of dry-

            14    powdered inhalers has been that the inhalation technique

            15    for those requires a quick, rapid inhalation as opposed to

            16    the MDIs which are more like five-second inhalations, and

            17    then if we're looking ahead at maybe a variety of different

            18    devices, that we'd want to have some type of ideally a

            19    uniformity of technique with drugs of different classes, a

            20    long-acting beta agonist, an inhaled steroid, and a quick-

            21    relief beta agonist, so that a patient wasn't getting

            22    totally confused trying to do a switchover with different

            23    sorts of techniques.

            24                Again, I'm not sure that that's something that

            25    has to be actually put into the whole regulatory proposal,

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             1    but I think it is a practical consideration in real life

             2    with treatment of patients.

             3                DR. MEYER:  I think that it does represent a

             4    part of the educational challenge of the entire transition

             5    because with many new products coming on, it is quite

             6    likely that patients will be on some products that differ

             7    in terms of their technique, and I think that currently, we

             8    know that many patients do not know or cannot use MDIs

             9    correctly sometimes with and sometimes without spacing

            10    devices, or that their practitioners can't instruct them

            11    correctly.

            12                So I think that's an issue that relates to the

            13    transition but perhaps is not directly related but

            14    certainly represents a part of the educational challenges

            15    as we move forward in all this.

            16                DR. SESSLER:  Well, I'd like to thank everyone

            17    for their thoughtful comments.  Thanks.

            18                (Whereupon, at 3:19 p.m., the meeting was

            19    recessed, to reconvene at 7:45 a.m. on Tuesday, November

            20    23, 1999.)

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