1

 

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

                 CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

                         PULMONARY-ALLERGY DRUGS

 

                            ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                         Wednesday, July 13, 2005

 

                                8:00 a.m.

 

 

 

 

 

 

                           Gaithersburg Hilton

                              The Ballrooms

                            620 Perry Parkway

                          Gaithersburg Maryland

                                                                  2

 

                               PARTICIPANTS

 

          Erik R. Swenson, MD, Chairman

          Teresa Watkins, R.Ph., Executive Secretary

 

          MEMBERS:

 

          Mark L. Brantly, M.D.

          Steven E. Gay, M.D., M.S.

          Carolyn M. Kercsmar, M.D.

          Fernando D. Martinez, M.D.

          I. Marc Moss, M.D.

          Lee S. Newman, M.D.

          Calman P. Prussin, M.D.

          Michael Schatz, M.D.

          David A. Schoenfeld, Ph.D.

 

          CONSULTANTS AND GUESTS (VOTING):

 

          Karen Schell, RRT, Consumer Representative

          Jacqueline S. Gardner

          Nancy J. Sander, Patient Representative

 

          GUEST SPEAKER (NON-VOTING):

 

          Christine Sorkness, Pharm.D.

 

          FDA STAFF:

 

          Robert Meyer, M.D.

          Badrul Chowdhury, M.D.

          Ann Trontell, M.D., M.P.H.

          Sally Seymour, M.D.

          J. Harry Gunkel, M.D.

          Eugene J. Sullivan, M.D., FCCP

                                                                  3

 

                             C O N T E N T S

                                                               PAGE

       Call to Order

                  Erik R. Swenson, M.D., Chairman                 5

 

       Introductions                                              6

 

       Conflict of Interest Statement

                 Maryanne Killian                                 8

 

       FDA Introductory Remarks

                 Badrul Chowdhury, M.D., Division of

                   Pulmonary-Allergy Drug Products               14

 

       Guest Speaker Presentation:

 

          An Overview of Long-Acting Beta Agonists

                 Christine Sorkness, Pharm.D.,

                   University of Wisconsin                       21

 

       Questions by the Speaker                                  68

 

       GlaxoSmithKline Presentation:

 

          Opening Remarks

                 C. Elaine Jones, Ph.D.                          82

 

          Salmeterol Review

                 Katharine Knobil, M.D.                          87

 

          Closing Remarks

                 C. Elaine Jones, Ph.D.                         115

 

       Questions by the Committee                               116

 

       Novartis Presentation:

 

          Introduction

                 Eric A. Floyd, M.S., M.B.A.                    136

 

          Efficacy and Safety of Foradil

                 Gregory P. Geba, M.D.                          139

 

          Clinical Implications

                 James F. Donohue, M.D., Chief, Pulmonary

                   Division, University of North Carolina       155

                                                                  4

 

                       C O N T E N T S (Continued)

 

                                                               PAGE

 

       Questions by the Committee                               168

 

       FDA Presentation:

 

          Salmeterol

                 Sally Seymour, M.D., Division of

                   Pulmonary-Allergy Drugs                      183

 

          Formoterol

                 J. Harry Gunkel, M.D., Division of

                   Pulmonary-Allergy Drugs                      207

 

       Questions by the Speakers                                224

 

       Opening Public Hearing:

 

                 Chris Ward, Asthma and Allergy

                   Foundation of America                        233

 

       Committee Discussion                                     238

                                                                  5

 

                          P R O C E E D I N G S

 

                 DR. SWENSON:  Good morning, everyone.  I

 

       am Dr. Erik Swenson.  I am the Chairman of this

 

       Pulmonary-Allergy Drug Advisory Committee meeting,

 

       meeting today here to discuss the implications of

 

       recently available information and data related to

 

       the safety of long-acting beta agonist

 

       bronchodilators.

 

                 Before we go around and introduce the

 

       members of the panel, I would like to ask them to

 

       remember that we have microphones here that have

 

       dual functions.  One is to show that you wish to

 

       raise a question.  That is the "request" option

 

       there; then to speak is on the right-hand side.

 

       So, in raising questions, would you please first

 

       hit the "request" button.  We will be monitoring

 

       and call you in turn.  Please do remember to use

 

       the "speak" button when you do speak since

 

       transcribers will need to hear you on the tapes.

 

                 With that having been said, I would like

 

       to have members of the panel here go around and

 

       introduce themslves.  We will start with Bob Meyer

                                                                  6

 

       and have you introduce yourself in turn.

 

                              Introductions

 

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

 

       Director of the Office of Drug Evaluation II in the

 

       Center for Drugs.

 

                 DR. CHOWDHURY:  I am Badrul Chowdhury, the

 

       Division Director, Division of Pulmonary and

 

       Allergy Drug Products.

 

                 DR. TRONTELL:  Ann Trontell, the Deputy

 

       Director of the Office of Drug Safety.

 

                 DR. SULLIVAN:  My name is Gene Sullivan.

 

       I am the Deputy Director of the Division of

 

       Pulmonary and Allergy Drug Products.

 

                 DR. SEYMOUR:  I am Sally Seymour, medical

 

       officer in the Division of Pulmonary and Allergy

 

       Drug Products.

 

                 DR. GUNKEL:  Harry Gunkel, medical officer

 

       in the Division of Pulmonary and Allergy Drug

 

       Products.

 

                 MS. SANDER:  Nancy Sander, President,

 

       Allergy and Asthma Network, Mothers of Asthmatics.

 

                 DR. GARDNER:  Jacqueline Gardner,

                                                                  7

 

       Professor of Pharmacy at the University of

 

       Washington, and a member of the Drug Safety and

 

       Risk Management Advisory Committee to FDA.

 

                 DR. SCHATZ:  Michael Schatz.  I am an

 

       allergist/immunologist from Kaiser Permanente San

 

       Diego.

 

                 MS. WATKINS:  I am Teresa Watkins,

 

       executive secretary for this committee.

 

                 DR. GAY:  I am Steven Gay.  I am medical

 

       director of critical care support services,

 

       assistant professor at the University of Michigan.

 

                 DR. MOSS:  Marc Moss, associate professor

 

       of medicine, Emory University in Atlanta.

 

                 DR. NEWMAN:  Lee Newman, professor of

 

       medicine, National Jewish Medical and Research

 

       Center and University of Colorado Denver.

 

                 DR. BRANTLY:  Mark Brantly, professor of

 

       medicine, University of Florida.

 

                 DR. MARTINEZ:  I am Fernando Martinez,

 

       professor of pediatrics at the University of

 

       Arizona.

 

                 DR. KERCSMAR:  Carolyn Kercsmar, professor

                                                                  8

 

       of pediatrics, Rainbow Babies and Children's

 

       Hospital, Cleveland, Ohio.

 

                 MS. SCHELL:  I am Karen Schell.  I am the

 

       consumer representative.  I am a respiratory

 

       therapist from Emporia, Kansas.

 

                 DR. PRUSSIN:  Calman Prussin.  I am senior

 

       clinical investigator in the Laboratory of Allergic

 

       Diseases, NIAID, NIH.

 

                 DR. SCHOENFELD:  David Schoenfeld,

 

       professor of medicine at the Harvard Medical School

 

       and professor of statistics at the Harvard School

 

       of Public Health.

 

                 DR. SWENSON:  Thank you.  I would like now

 

       to call Maryanne Killian, of the FDA.  She has a

 

       statement on conflict of interest to read.

 

                      Conflict of Interest Statement

 

                 MS. KILLIAN:  Good morning, everybody.

 

       The Food and Drug Administration is convening

 

       today's meeting of the Pulmonary-Allergy Drugs

 

       Advisory Committee under the authority of the

 

       Federal Advisory Committee Act.  With the exception

 

       of the industry representative, all members of this

                                                                  9

 

       committee are special government employees or

 

       regular federal employees from either agencies,

 

       subject to the conflict of interest laws and

 

       regulations.

 

                 FDA has determined that the members of

 

       this advisory committee are in compliance with

 

       federal ethics and conflict of interest laws,

 

       including but not limited to 18 USC Section 208 and

 

       21 USC Section 355(n)(4) which applies to FDA

 

       people.  Congress has authorized FDA to grant

 

       waivers to special government employees who have

 

       financial conflicts when it is determined that the

 

       agency's need for a particular individual's

 

       services outweighs his or her potential financial

 

       conflict of interest.

 

                 Members who are special government

 

       employees at today's meeting, including special

 

       government employees appointed as temporary voting

 

       members, have been screened for potential financial

 

       conflicts of interest of their own, as well as

 

       those imputed to them including those of their

 

       employers, spouse or minor child related to the

                                                                 10

 

       discussions on July 13, 2005 regarding implications

 

       of recently available data related to the safety of

 

       long-acting beta agonist bronchodilators, and on

 

       July 14, 2005 regarding the continued need for the

 

       essential use designation of prescription drugs for

 

       the treatment of asthma and chronic obstructive

 

       pulmonary disease under 21 CFR 2.125.  These

 

       interests may include investments, consulting,

 

       expert witness testimony, contracts, grants,

 

       CREDAs, teaching, speaking, writing, patents and

 

       royalties and primary employment.

 

                 In accordance with 18 USC Section

 

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

 

       following participants.  Please note that all

 

       interests are in firms that could be potentially

 

       affected by the committee's deliberations.  With

 

       regard to the July 13th meeting, Dr. Carolyn

 

       Kercsmar for activities on a speaker's bureau.  She

 

       receives less than $10,001 per year for a grant

 

       which is valued at less than $100,000 per year, and

 

       for a grant for which the firm supplies products

 

       worth approximately less than $100,000 per year;

                                                                 11

 

       Ms. Nancy Sander for ownership of stock currently

 

       valued at between $25,001 and $50,000, and for

 

       unrelated advisory board activities for which she

 

       receives less than $10,001 per year; Dr. Steven Gay

 

       for speaker bureau activities with four firms, from

 

       three of which he receives less than $10,001 per

 

       firm per year, and one for which he receives from

 

       between $10,001 to $50,000 per firm per year.  We

 

       would also like to disclose that Dr. Erik Swenson

 

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

 

       USC 208(b)(3) is not required because the de

 

       minimis exemption under 5 CFR 2640.202 applies.

 

                 With regard to the July 14th discussions,

 

       Dr. Carolyn Kercsmar for activities on a speakers

 

       bureau.  She receives less than $10,001 per year

 

       for two grants which are valued at less than

 

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

 

       firm supplies products worth approximately less

 

       than $100,000 per year.  She also owns stock less

 

       than $5,001.  A waiver under the USC 208(b)(3) is

 

       not required because the de minimis exemption under

 

       5 CFR 2640.202 applies.  Dr. Fernando Martinez for

                                                                 12

 

       his membership on a speakers bureau.  He has not

 

       lectured or received remuneration in the past 12

 

       months, and for membership on a related advisory

 

       board.  He has not participated or received any

 

       remuneration to date.  Dr. Michael Schatz for his

 

       activities on a speakers bureau.  He receives less

 

       than $10,001 per year, and for a grant for which

 

       the firm supplies product worth approximately less

 

       than $100,000 per year.  Miss Nancy Sander for

 

       ownership of stock currently valued between $25,001

 

       and $50,000, and for unrelated advisory board

 

       activities for which she receives less than $10,001

 

       per year.  Miss Sander also owns stock worth less

 

       than $5,001, again a de minimis waiver is not

 

       required because 5 CFR 2640.202 applies.  Dr.

 

       Steven Gay for speakers bureau activities with five

 

       firms, from three of which he receives less than

 

       $10,001 per year, and two of which he receives from

 

       $10,001 to $50,000 per firm per year.

 

                 We would also like to disclose that Dr.

 

       Marc Moss' spouse owns stock less than $5,001.  A

 

       waiver under 18 USC 208(b)(3) is not required

                                                                 13

 

       because the de minimis exemption under 5 CFR

 

       2640.202 applies.

 

                 A copy of the written waiver statements

 

       may be obtained by submitting a written request to

 

       the agency's Freedom of Information Office, Room

 

       12A-30 of the Parklawn Building, 5600 Fishers Lane,

 

       Rockville, Maryland.

 

                 In addition, Dr. Christine Sorkness is

 

       participating as FDA's invited guest speaker on

 

       July 13th.  She would like to disclose that she is

 

       a researcher with regards to GlaxoSmithKline's

 

       Advair and Novartis' formoterol.  She also lectures

 

       for GlaxoSmithKline concerning Advair and receives

 

       less than $10,000 per year.

 

                  Lastly, Dr. Theodore Reiss is the

 

       industry representative on the committee at the

 

       meeting.  He is acting on behalf of all related

 

       industry.  He is employed by Merck.  Thank you.  I

 

       am done.

 

                 DR. SWENSON:  Thank you, Miss Killian.  I

 

       would like now to turn the microphone over to Dr.

 

       Robert Meyer of the FDA.

                                                                 14

 

                 DR. MEYER:  Thank you.  Prior to more

 

       formal introduction by Dr. Chowdhury, I wanted to,

 

       first off, thank the advisory committee in advance

 

       for your attendance today and for what I am sure

 

       will be a very careful deliberation.

 

                 One of the things I wanted to mention was

 

       that there was some speculation in the trade press

 

       yesterday that there was a very specific purpose

 

       and outcome hoped for by the agency in holding this

 

       meeting today.  I just wanted to be clear that the

 

       FDA looks forward to a very open discussion of the

 

       data available on the safety experience with the

 

       long-acting beta agonists and any potential future

 

       regulatory actions that might be recommended coming

 

       out of this committee.  So, thank you very much for

 

       your attendance today.

 

                 DR. SWENSON:  Thank you, Dr. Meyer.  Now

 

       Dr. Chowdhury, from the FDA, is going to give us

 

       some introductory remarks pertinent to our

 

       discussion today.

 

                         FDA Introductory Remarks

 

                 DR. CHOWDHURY:  Good morning.  Honorable

                                                                 15

 

       Chairperson, members of the Pulmonary-Allergy Drugs

 

       Advisory Committee, representatives from GSK and

 

       Novartis and others in the audience, I welcome you

 

       to this meeting.

 

                 In this brief presentation I will

 

       introduce you to the subject matter of this

 

       advisory committee meeting.  Members of the

 

       committee, the objective of this meeting is to

 

       discuss the implications of the available data

 

       related to the safety of long-acting beta agonist

 

       bronchodilators.  There are two long-acting

 

       bronchodilators marketed in the United States that

 

       will be discussed in this meeting.  These are

 

       salmeterol from GSK and formoterol from Novartis.

 

       Products containing salmeterol and formoterol are

 

       indicated for use as bronchodilators in patients

 

       with asthma and COPD as maintenance treatments.

 

                 These are effective drugs and form

 

       important components of the treatment options

 

       available for patients with asthma and COPD.  But

 

       an important array of adverse effects that has been

 

       observed with these drugs is the occurrence of

                                                                 16

 

       severe asthma exacerbation.  The intent of this

 

       advisory committee meeting is to discuss this

 

       specific finding of severe asthma exacerbation

 

       related to these two drugs.  Since the available

 

       data pertain to asthma, the focus of this meeting

 

       is on asthma and not COPD.

 

                 Surrogates of short-acting beta agonist

 

       bronchodilators, such as albuterol, is not a

 

       subject of this meeting.  As you discuss and

 

       deliberate on the safety of thee two drugs, keep in

 

       mind the well-established efficacy of these drugs

 

       because the use of these drugs, like any other

 

       drug, is dependent on the risk/benefit ratio.

 

                 As you can see in the agenda, the first

 

       presentation will be by Dr. Christine Sorkness.

 

       Dr. Sorkness is a professor of pharmacy and

 

       medicine in the University of Wisconsin.  She will

 

       give an overview of long-acting beta agonist

 

       bronchodilators.  We are very fortunate that Dr.

 

       Sorkness, and expert in pharmacological drugs used

 

       in the treatment of asthma, has agreed to speak at

 

       this meeting.  I thank her on behalf of the agency.

                                                                 17

 

                 Following Dr. Sorkness, GSK and Novartis

 

       will make presentations on salmeterol and

 

       formoterol respectively, followed by FDA

 

       presentations on these two drugs.  This will be

 

       followed by an open public hearing and committee

 

       discussion.

 

                 As you hear these presentations you will

 

       note that the safety signal of severe asthma

 

       exacerbation with salmeterol was seen in

 

       postmarketing studies, specifically the recently

 

       halted large controlled study called the salmeterol

 

       multicenter asthma research trial, acronym SMART,

 

       conducted by GSK.  In contrast, the safety signal

 

       of severe asthma exacerbation with formoterol was

 

       seen in the studies conducted by Novartis to

 

       support registration of formoterol in the United

 

       States.  Novartis also conducted a Phase 4 study

 

       with formoterol that did not show a clear signal of

 

       severe asthma exacerbation, but the formoterol

 

       Phase 4 study was much smaller compared to the

 

       SMART study.

 

                 We are choosing to have this meeting now

                                                                 18

 

       because all pertinent data on salmeterol and

 

       formoterol have only become recently available.  We

 

       also decided that it would be fruitful to discuss

 

       these two related drugs together in one meeting.

 

       Although salmeterol has been approved for marketing

 

       in the United States since 1994, the study relevant

 

       to this meeting, the SMART study, was halted by GSK

 

       in January of 2003 and the data has been recently

 

       fully analyzed.

 

                 Formoterol was approved for marketing in

 

       the United States in 2001.  The Phase 4 study for

 

       formoterol was completed in March, 2004 and the

 

       data from the study also has been recently

 

       analyzed.

 

                 The significant regulatory actions that

 

       the FDA has taken so far pertaining to these two

 

       drugs, based on the available data, are in

 

       cooperation of the results of the SMART study in

 

       all salmeterol-containing product labels, including

 

       the addition of a boxed warning, and not approving

 

       formoterol 25 mcg twice daily dose for marketing in

 

       the United States.  Formoterol is currently

                                                                 19

 

       approved at a dose of 12 mcg twice daily.  Please

 

       note that the formoterol drug label does not

 

       currently have warnings similar to salmeterol

 

       because of lack of specific data related to the

 

       marketed formoterol 12 mcg twice daily dose.

 

                 In the presentations from the industry and

 

       the FDA you will see the data that led to the

 

       agency regulatory actions.  As you hear the

 

       presentations, I request that you keep in mind the

 

       questions that are in the FDA briefing book and

 

       also attached to the agenda since you will discuss

 

       and deliberate on these questions later in the day.

 

                 Here are the four questions that you will

 

       be asked to discuss and deliberate later in the day

 

       today.  Question one, the product labels of

 

       salmeterol-containing products have been modified

 

       to include warnings related outcome the SMART

 

       study.  Based on currently available information,

 

       what further actions, if any, do you recommend that

 

       the agency take to communicate or otherwise manage

 

       the risks of severe asthma exacerbations seen in

 

       the SMART study?

                                                                 20

 

                 Based on the currently available

 

       information, do you agree that salmeterol should

 

       continue to be marketed in the United States?

 

                 Question two, the label of the

 

       formoterol-containing product does not include

 

       warnings comparable to the warnings that are

 

       present in the salmeterol-containing products.

 

       Based on the currently available information,

 

       should the label of formoterol-containing products

 

       include warnings similar to those in the salmeterol

 

       label?

 

                 Based on the currently available

 

       information, do you agree that formoterol should

 

       continue to be marketed in the United States?

 

                 Question three, what further

 

       investigation, if any, do you recommend to be

 

       performed by GSK that can improve the understanding

 

       of the nature and magnitude of the risk of

 

       salmeterol?

 

                 Question four, what further investigation,

 

       if any, do you recommend to be performed by

 

       Novartis that can improve the understanding of the

                                                                 21

 

       nature and magnitude of the risk of formoterol?

 

                 These are the four questions.  We look

 

       forward to an interesting meeting and, again, I

 

       thank you for your time, effort and commitment to

 

       this important public health service.  Thank you.

 

                 DR. SWENSON:  Thank you, Dr. Chowdhury.

 

       At this point we would like to invite Dr. Christine

 

       Sorkness who was just introduced.  She has been

 

       kind enough to give us a broad overview of these

 

       drugs and I would like to turn the podium over to

 

       her.

 

                 An Overview of Long-Acting Beta Agonists

 

                 DR. SORKNESS:  Good morning.  I would

 

       first like to thank Dr. Chowdhury and Dr. Sullivan

 

       for inviting me to speak this morning, and most of

 

       all, for gathering this group of both clinicians,

 

       researchers, industry colleagues and the committee

 

       to review what I believe to be an incredibly

 

       important topic.  The risk versus benefit

 

       considerations for the long-acting beta agonists

 

       are the topic at hand and the committee has been

 

       asked to discuss the implications of the available

                                                                 22

 

       data related to the safety of long-acting beta

 

       agonists, as Dr. Chowdhury articulated.

 

                 It is a little bit awesome to review this

 

       topic because of its breadth and depth, and also

 

       because I know many of the committee members and

 

       would acknowledge that they probably know more than

 

       I do about this particular topic.  So with that

 

       caveat, I am going to indicate that I am just going

 

       to review and try to set a tone for the discussions

 

       and in particular anchor some of the available

 

       data, at least as I see it as a researcher and a

 

       clinician, that you might use to answer the

 

       questions that you have been charged with.

 

                 The specific objectives that I have been

 

       asked to address are to provide an overview of the

 

       clinical pharmacology of the long-acting beta

 

       agonists; to discuss the selection of therapeutic

 

       outcomes which I believe are relevant for the

 

       assessment of risks versus benefits of the

 

       long-acting beta agonists; to review selected

 

       clinical trials, selected because there are so many

 

       which provide insight into the risk/benefit of the 

                                                                 23

 

       long-acting beta agonists; and to outline the

 

       controversies and the remaining questions which I

 

       believe are related to the role.

 

                 First an overview of the clinical

 

       pharmacology of albuterol, salmeterol and

 

       formoterol.  We have come a long way from ephedra

 

       from China and its pharmacologic properties many,

 

       many years ago to, certainly ephedrine and

 

       epinephrine and isoproterenol.  The three major

 

       drugs that we use in our therapeutic armamentarium

 

       for asthma right now are albuterol, salmeterol and

 

       formoterol.  You can see in common that they all

 

       have a simple catecholamine ring, and there has

 

       been great novelty from the industry of adding a

 

       variety of different side chains to these products

 

       to affect their oral versus inhalation efficacy

 

       and, in particular, if you look at salmeterol and

 

       formoterol you see that there are very large side

 

       chains that have been attached to the basic

 

       molecule of albuterol.  This has allowed these two

 

       products to have an extended duration of action.

 

                 Both salmeterol and formoterol are highly

                                                                 24

 

       lipophilic products, which may explain some of

 

       their long duration of action, salmeterol more than

 

       formoterol.  We know that salmeterol binds within

 

       the ligand binding cleft of the receptor which

 

       probably allows sensitivity stimulation of the

 

       receptor and its long duration, and there are other

 

       speculated mechanisms of action for the long

 

       duration of formoterol.  Formoterol is a raceme and

 

       only the RR and N tumor is active.

 

                 If you were to compare very globally the

 

       beta adrenergic agents, this table is probably

 

       relevant.  Most of the pharmacologic studies relate

 

       molar potency of these products to isoproterenol,

 

       which is designated as a potency of 1.  You can see

 

       that both formoterol and salmeterol are more potent

 

       products than isoproterenol.  The pharmacologic

 

       profile of the drugs is illustrated, with

 

       isoproterenol an formoterol classified as full

 

       agonists and albuterol and salmeterol as partial

 

       agonists.

 

                 You can see that in comparison to

 

       isoproterenol as its comparator, albuterol,

                                                                 25

 

       formoterol and salmeterol all have the luxury or

 

       beta2 selectivity which is acknowledged to allow

 

       these drugs to have primarily effects on the lung

 

       versus the cardioselective effects that we see

 

       primarily with activation of the beta                                    

                                                         1 receptors.

 

       The duration of action clearly is different in

 

       these agents and, because of the long side chains

 

       and mechanisms of action of formoterol and

 

       salmeterol, we have known that these are the

 

       longest acting inhaled bronchodilators on the

 

       market today, with durations of action of at least

 

       12 hours after a dose, and the bronchoprotective

 

       effects, which specifically in this slide refer to

 

       the prevention of bronchoconstriction induced by

 

       exercise or non-specific bronchial challenges such

 

       as methacholine, have, indeed, a long

 

       bronchoprotective effect.

 

                 If you were to look at a more direct

 

       clinical comparison of formoterol and salmeterol

 

       based specifically on information in the package

 

       inserts, it is believed that equipotent

 

       bronchodilating doses of formoterol and salmeterol

                                                                 26

 

       are listed as above, based specifically on the

 

       dosage form by which they are delivered.  So we

 

       believe, at least in clinical practice, that 12 mcg

 

       of Foradil aerolizer is clinically bronchodilating

 

       equipotent to 50 mcg delivered by Serevent Diskus.

 

       In order to deliver these equipotent doses, the

 

       recommended inspiratory flow rate is acknowledged

 

       to be about 60 L/min for both products over a time

 

       course of 2-3 seconds.  As you might expect,

 

       particularly because these drugs have been FDA

 

       approved for individuals with much more severe

 

       broncho-obstruction such as in COPD, probably an

 

       inspiratory flow rate much below that can get

 

       adequate delivery of drugs.

 

                 Both of these drugs are classified as

 

       pregnancy category C and, indeed, enjoy the same

 

       FDA approved indications based on the package of

 

       information submitted to the FDA, the only

 

       distinction being that salmeterol is approved for

 

       the treatment of asthma and prevention of

 

       bronchospasm for children over 4 years of age and 5

 

       years on formoterol.  Both of these agents have

                                                                 27

 

       been approved for EIB prevention and for

 

       maintenance treatment of COPD, which is not part of

 

       the agenda today.

 

                 Now, the differentiation of formoterol and

 

       salmeterol, by and large, comes down to its

 

       acknowledged difference in onset of action.  You

 

       can find many, many studies that would classify

 

       different pharmacologic profiles.  In summary,

 

       formoterol probably achieves 80 percent of the

 

       maximum bronchodilation within 5-10 minutes.  It is

 

       thought to have an onset of action quite comparable

 

       to albuterol and acts within 3 minutes.  For

 

       salmeterol most of the data suggests that 90

 

       percent maximum bronchodilation occurs after one

 

       hour, with a median time to significant

 

       bronchodilation of 30-40 minutes, and an onset

 

       certainly at a time point of about 10 minutes.

 

                 This is a simple cartoon that segues to

 

       the issue of the long-acting beta agonists

 

       themselves in combination with clucocorticoids.

 

       This is a cartoon that suggests the proposed

 

       molecular interaction between the long-acting beta

                                                                 28

 

       agonists and the inhaled corticosteroids.  The

 

       long-acting beta agonist, through their activation

 

       of the beta adrenergic receptor with adenylyl

 

       cyclase, cyclic AMP, protein kinase A and mitogen

 

       activated protein kinase may actually prime the

 

       glucocorticoid receptor for greater nuclear

 

       translocation and affinity for the binding to the

 

       glucocorticoid regulatory element, which is

 

       designated in this slide as GRE.  Therefore, it has

 

       been speculated by a variety of pharmacologic

 

       models--Ikleburg[?] and others who have done very

 

       elegant work--that actually the anti-inflammatory

 

       effect of glucocorticoids can be enhanced with the

 

       combination of long-acting beta agonist and,

 

       clearly, that is certainly the rationale that

 

       brought the combination products to the

 

       marketplace.

 

                 Now, when we talk about risks versus

 

       benefits of any agent, it is best to talk about the

 

       outcomes of interest.  I am going to preface my

 

       remarks by the fact that I think the medical

 

       community and patients have all been led to hope

                                                                 29

 

       for a 100 percent active and effective drug with

 

       absolutely no side effects.  I quite honestly

 

       believe that to not be realistic.  Therefore, when

 

       we talk about risk/benefits we need to put in

 

       perspective and weigh those issues, and I think it

 

       is important to recognize that we may have very

 

       safe medications that really have very poor

 

       clinical efficacy, and I would suggest that they

 

       have a distinct risk in their own right by their

 

       inability to treat the disease at hand.

 

                 So, I am going to try to illustrate some

 

       issues about what I believe to be important

 

       outcomes and talk about some of the clinical trials

 

       to date that teach us lessons about this as

 

       applying this drug class to asthma.

 

                 We traditionally have used lung function

 

       measures for management of asthma, both from the

 

       perspective of clinical decision-making and

 

       clinical research.  There are many longitudinal

 

       studies of lung health that have been enhanced by

 

       measurements of lung function, particularly FEV                         

                                                                                

   1

 

       and FEV                                           1/FEC ratio.  Clearly,

it has been

                                                                 30

 

       acknowledged that the gold standard for trial entry

 

       for the pivotal trials reviewed by the FDA have

 

       been traditional FEV                                                    

           1's of 60-80 percent predicted

 

       with 15 percent reversibility.  Therefore, there

 

       have been very uniform population groups that have

 

       been studied in our clinical trials.  I would

 

       actually conjecture now, and will come back to it,

 

       that we may need to broaden that a bit to capture a

 

       more generalizable population.

 

                 Clearly, lung function measures have been

 

       primary outcomes to measure efficacy because we can

 

       standardize those procedures both on site and with

 

       home measurements, and we have grown to believe

 

       that we can minimize variability around the

 

       measurements and can really get a handle and our

 

       arms around what outcomes are important.  Please

 

       recognize as I talk about different outcomes in

 

       asthma, I am not dispelling at all the value of

 

       lung function measurements.  I think they are still

 

       critical but I don't believe that they are enough.

 

                 Let's start talking about what I believe

 

       to be illustrative studies.  This is a study

                                                                 31

 

       published by the Asthma Clinical Research Network

 

       in which I am one of the investigators, and it was

 

       affectionately called the SOCS trial.  This is a

 

       study that was intended to ask the question that in

 

       a patient who was well stabilized on an inhaled

 

       steroid and representative triamcinolone, and that

 

       had pretty stable FEV                                                   

             1's and peak flow variability,

 

       could this patient basically be transferred to

 

       placebo and do equally well; be converted to a

 

       salmeterol product and do equally well; or did they

 

       need to maintain continuance on an inhaled steroid

 

       as represented by triamcinolone?

 

                 This is a study that enrolled individuals

 

       whose mean FEV1 was 93 percent predicted, had very

 

       low peak variability of about 10 percent, and

 

       during the run-in period showed very good asthma

 

       stability.  The primary outcome of this study was

 

       morning peak flow.  That was selected because of

 

       experience that the Asthma Clinical Research

 

       Network had with what we believe to be an effect

 

       size that we could power our study of a difference

 

       of about 25 L/min, and because that effect size

                                                                 32

 

       correlated with other more clinically robust

 

       endpoints in a variety of trials.

 

                 I think you can see that if you look at

 

       the primary outcome of this trial of AM peak flow

 

       you wee in the run-in period that all of the

 

       patients in ultimately the three arms improved

 

       during the run-in with triamcinolone, as you would

 

       expect.  You see the placebo group, once it was

 

       randomized at six weeks, had deterioration in that

 

       outcome; whereas, the triamcinolone and salmeterol

 

       groups both had maintenance and actually

 

       improvement in the primary outcome of peak flow,

 

       and there was not statistically significant

 

       difference between those two arms in this

 

       particular outcome.

 

                 Now, there was obviously a variety of

 

       secondary outcomes in this trial.  You can see that

 

       on the basis, in particular, of some markers of

 

       inflammation that there was both a clinically and

 

       statistically significant difference in favor of

 

       the inhaled corticosteroids.  Because of the

 

       multiple comparisons used by the statistician, a p

                                                                 33

 

       value of 0.016 was that which was deemed to be of

 

       statistical significance.

 

                 This is important in that it translates to

 

       another very important secondary outcome of this

 

       trial, that being defined as treatment failure

 

       rates, on the left, and asthma exacerbation rates,

 

       on the right.  First, asthma exacerbation rates

 

       were defined as increases in albuterol use,

 

       decrease in peak flow, and the need for oral

 

       corticosteroids.  You can see with this particular

 

       outcome that triamcinolone is the only one by the

 

       Kaplan-Meier survival curve that, in essence, did

 

       not have significant asthma exacerbations.  Very

 

       similarly, if you looked at treatment failure

 

       rates, which was defined as an FEV1 less than 50

 

       percent predicted, at least one course of

 

       prednisone, the occurrence of emergency room or

 

       urgent care visits or hospitalization, the same

 

       trend could be seen.  The triamcinolone was very

 

       effective in preventing treatment failure rates but

 

       salmeterol was quite comparable to placebo.

 

                 The summary for the ACRN investigators was

                                                                 34

 

       that patients with persistent asthma, well

 

       controlled by low doses of an inhaled steroid

 

       cannot be switched to salmeterol monotherapy

 

       without risk of clinically significant loss of

 

       asthma control.  I think this is one of the studies

 

       that clearly the asthma community has endorsed to

 

       support the fact that long-acting beta agonists in

 

       asthma should not be used as monotherapy, and I

 

       don't believe that there is particular debate on

 

       this issue and I think there are many studies that

 

       illustrate similar outcomes.

 

                 This study is also important in that it

 

       shows clear disparity between lung function

 

       measures and other outcome measures, and leads us

 

       to the conclusion from this study that multiple

 

       measurements and dimensions of control are needed

 

       to adequately assess therapies.

 

                 Therefore, I think, whether we broach

 

       studies that are industry sponsored or NIH

 

       sponsored, we are beginning to endorse more

 

       composite measures of asthma control.  This would

 

       include days of asthma control; treatment failure

                                                                 35

 

       and asthma exacerbation criteria, as I have shown

 

       in this study and many others.  I would make as a

 

       caveat that it becomes oftentimes very difficult to

 

       compare trials because the specific definitions for

 

       treatment failure versus asthma exacerbations and

 

       mild, moderate and severe exacerbations may be a

 

       little bit different.  So, it is important for us

 

       to anchor the definitions when we evaluate.

 

                 Other composite measurements have actually

 

       been improvements or shifts in NAEEP defined NAEEP

 

       defined asthma severity classification; the

 

       achievement of total control or well controlled

 

       status, as defined by GINA and applied to the GOAL

 

       study; and certainly a variety of more patient

 

       specific surveys of asthma control and quality of

 

       life that have become important secondary outcomes

 

       in our clinical trials.

 

                 Now, in reflecting upon the issue of more

 

       composite clinical outcomes, the question needs to

 

       be raised in applying an appropriate risk/benefit

 

       relationship and assessment of how much benefit can

 

       actually be achieved by the combination of inhaled

                                                                 36

 

       steroids and long-acting beta agonists.  I am going

 

       to focus my remarks on the combination because I

 

       have told you that at least my belief is that

 

       asthma is best treated by combination and,

 

       therefore, the relevant studies are those that use

 

       that.

 

                 A fairly early study that began to address

 

       the role of inhaled steroids and long-acting beta

 

       agonists in combination is the OPTIMA trial,

 

       entitled, low dose inhaled budesonide as a

 

       representative inhaled steroid an formoterol as a

 

       representative long-acting beta agonist.

 

                 This study had both a group A and a group

 

       B.  I am going to focus on group A as a

 

       representative trial of taking patients naive to

 

       being on inhaled steroids and ultimately, after a

 

       one-month run-in in which they were qualified to be

 

       in this trial, were then continued on placebo,

 

       Pulmicort or Oxis, as formoterol is called.

 

       Therefore, they continued on beta agonists alone

 

       versus being randomized to Pulmicort 100 mcg BID

 

       and Oxis placebo or Pulmicort 100 mcg BID and

                                                                 37

 

       active Oxis 4.5 mcg BID.

 

                 The primary outcome of this trial was

 

       severe exacerbation, designated by the arrow.  This

 

       was defined as the need for oral corticosteroids or

 

       admission to a hospital or an emergency room visit

 

       or substantial decrease in peak flow.  This study

 

       group enrolled patients who were 12 years of age

 

       and older, not on inhaled steroids, who had to have

 

       an FEV                                         1 of at least 80 percent

predicted post

 

       bronchodilator, and actually enrolled a pre

 

       bronchodilator mean FEV                                                  

                   1 group of about 90 percent.

 

                 These are the two primary outcomes of this

 

       particular study.  If you look on the left-hand

 

       side in panel A, this is the Kaplan-Meier survival

 

       curve and you can see that both the budesonide

 

       alone versus the budesonide in combination win

 

       formoterol did much better in preventing the time

 

       to the first severe asthma exacerbation as compared

 

       to the placebo group, which is the last curve that

 

       you see on the slide.  When you plot this, on the

 

       right-hand side of the slide you see that actually

 

       the two active treatments were, indeed, better than

                                                                 38

 

       placebo but were quite comparable to each other.

 

       However, if you look at the other important outcome

 

       of pulmonary function test, the morning peak

 

       expiratory flow, you see in the top curve that the

 

       combination product is superior to both budesonide

 

       and placebo.  So, whereas by one outcome the

 

       exacerbation rates of the two active products were

 

       not statistically significant, when you add in

 

       another important secondary outcome the

 

       combination, indeed, showed better outcomes.

 

                 Now, this same issue of looking at

 

       prevention of asthma exacerbations has been

 

       published by many, many authors.  This is just a

 

       representative study which looked at an analysis of

 

       asthma exacerbations, looking at available studies

 

       of higher dose fluticasone versus the addition of

 

       salmeterol to low dow fluticasone.

 

                 If you look at this particular slide,

 

       which is the probability of the time to the first

 

       exacerbation, you see that the top curve, in green,

 

       is salmeterol and, in red, the combination, and the

 

       combination was clearly superior in the outcome of

                                                                 39

 

       time to first asthma exacerbation compared to the

 

       long-acting beta agonist alone.

 

                 The analysis in this study group culled

 

       out the different Ns of the spectrum of pulmonary

 

       function impairment at baseline.  As I mentioned,

 

       typically the pivotal trials enroll patients that

 

       have baseline FEV                                                       

   1's pre bronchodilator between

 

       40-85 percent predicted.  That is what you see on

 

       the left-hand side of all-comers that enrolled in

 

       those pivotal trials.  If you, instead, break down

 

       patients who present with less bronchoconstriction

 

       at baseline, for example, 60-85 percent predicted

 

       versus 40-60 percent, you see that the trends are

 

       not different and that either way, depending upon

 

       the severity of obstruction in these patients, the

 

       trend of the benefit of combination certainly could

 

       be seen.

 

                 Now, the FACET trial also showed I think a

 

       very important lesson about looking at the outcome

 

       of severe exacerbations and relationships of

 

       dose-response curves with inhaled steroids, as well

 

       as the benefit of long-acting beta agonists.  This

                                                                 40

 

       goes back to budesonide and formoterol as the

 

       representative drugs in this study, and in this

 

       study severe exacerbations were defined as a need

 

       for oral steroids or a decrease in peak flow to

 

       more than 30 percent baseline.  So, severe

 

       exacerbations here are predominantly due to the

 

       need for oral beta agonists.

 

                 This is a large trial that randomized

 

       individuals to one of four arms.  If you look at

 

       the far left, in green is the budesonide 200 mcg or

 

       low dose inhaled steroid group; the purple bar is

 

       budesonide 200 mcg a day plus formoterol; in

 

       yellow, a higher dose of budesonide alone versus,

 

       in the orange bar, the addition to formoterol.  I

 

       think what you can see is the very logical

 

       dose-response curve that 800 mcg of budesonide

 

       fared better than 200 mcg of budesonide but, very

 

       importantly, you can see that the prevention of

 

       severe exacerbations in both groups could be

 

       enhanced by the addition of formoterol.  So, again,

 

       another study that suggests to us that combination

 

       therapy can achieve the prevention of asthma

                                                                 41

 

       exacerbations.

 

                 Now, in brevity, rather than showing you

 

       the individual studies of exacerbations to date

 

       published, I am going to take advantage of a

 

       meta-analysis, published by Sinn and others in

 

       JAMA, in 2004 that looked at a systematic review

 

       and meta-analysis of a variety of pharmacologic

 

       therapies to reduce exacerbations.

 

                 This study clearly reviewed all of the

 

       drugs that we know that are on the marketplace but

 

       I am specifically going to look at two of the

 

       analyses.  This is the effect of long-acting beta

 

       agonists alone on exacerbations and the distinct

 

       trials that the meta-analysis chose.  You can see

 

       that the majority of these studies favored a

 

       long-acting beta agonist over placebo, and a pooled

 

       analysis showing a relative risk and confidence

 

       interval that favors the long-acting beta agonists.

 

                 This is the analysis that looks at many of

 

       what I believe to be the paradigm shifting trials

 

       that showed the addition of long-acting beta

 

       agonists to be better than either doubling or more

                                                                 42

 

       than doubling the inhaled steroids, and includes

 

       the Matz and O'Byrne studies and Pauwels studies

 

       that I shared with you earlier.  I think you can

 

       see that we have at least somewhat mixed results

 

       here.  Certainly the majority of trials favor the

 

       combination of inhaled steroids and long-acting

 

       beta agonists together versus favoring the high

 

       doses of steroids.  Some of them are right on the

 

       line.  The pooled summary obviously, here by this

 

       graph, favors the steroids and the long-acting beta

 

       agonists.

 

                 I would suggest that certainly some of the

 

       differences are certainly on the basis of study

 

       design, size of study, construct, and so forth but,

 

       again, I think the meta-analysis supports the

 

       individual trials as far as evidence that suggests

 

       benefit of the combination.

 

                 Now, in switching gears, besides asthma

 

       exacerbations, I think that the issue of the

 

       capture of asthma control, as has been defined by

 

       GINA and the NAEEP, is a very important outcome

 

       that we have begun to carefully think about and to

                                                                 43

 

       posture in our individual trials.  The GOAL trial

 

       asked a very simple but important question, is GINA

 

       NIH guideline based control achievable, and in what

 

       proportion of patients with a

 

       salmeterol-fluticasone combination compared with

 

       fluticasone alone?

 

                 So, this is going beyond the issue of just

 

       looking at exacerbations but overall asthma control

 

       as defined by the guidelines.  You can read this.

 

       There is both total control and well controlled,

 

       and it basically reflects what we, as clinicians,

 

       hope to achieve for our asthma patients.  And, the

 

       question is can this be achieved by the therapies

 

       that we have at hand?

 

                 The GOAL study design was very complex.

 

       It was a year study of three strata of patients

 

       based on whether they were either corticosteroid

 

       naive or free for six months; whether they were on

 

       a modest dose of a baclomethasone equivalent or

 

       higher dose of a beclomethasone equivalent.  These

 

       were individuals that had to be at least 12, not

 

       well controlled in the run-in period, and showed

                                                                 44

 

       reversibility of 15 percent.  They were randomized

 

       to either the salmeterol-fluticasone combination or

 

       fluticasone alone via diskus, with a dose based on

 

       the stratum.

 

                 During this complex design in phase 1, the

 

       doses were either stepped up every 12 weeks until

 

       total control was achieved or a maximum dose was

 

       reached.  In study phase 2 a dose of total control

 

       or a maximum study dose was continued for 52 weeks.

 

                 It is important to recognize that all the

 

       patients in this trial deserved to be on control

 

       therapy.  Their FEV                                                     

        1's were about 75-80 percent

 

       predicted.  They had very, very obvious

 

       bronchodilator reversibility, averaging about 20

 

       percent, and what I would call were young adults.

 

       So, whatever the stratum, these individuals

 

       deserved to be stepped up with the therapies that

 

       were used.

 

                 These are the patients who achieved well

 

       controlled status.  The triangles in dark are the

 

       combination; the open circles are fluticasone

 

       alone.  You can see the run-in phase versus phase 1

                                                                 45

 

       versus phase 2 on this graph.  You can see that

 

       both study groups had a fairly brisk improvement in

 

       achievement of well-controlled status.  This

 

       continued through the 52 weeks of the trial and was

 

       achieved by both study arms, but was achieved to a

 

       statistically significant greater extent with the

 

       combination therapy.

 

                 Also importantly is exacerbation rates as

 

       were studied in this trial as a secondary outcome.

 

       This exacerbation was defined in this study as

 

       either a burst of steroids or an ER or

 

       hospitalization.  You can see whether it was

 

       steroid naive, the low dose inhaled steroid or the

 

       moderate dose inhaled steroid stratum.  Clearly,

 

       all groups showed the trend that the combination

 

       therapy was better at achieving prevention of

 

       exacerbation rates as defined by the GOAL

 

       investigators.

 

                 The results of GOAL are very important in

 

       that significantly more patients achieved control

 

       with combination versus fluticasone in each stratum

 

       and in each stratum the time to achieve the first

                                                                 46

 

       individual week of well-controlled asthma was

 

       significantly lower with combination than

 

       fluticasone alone.  More patients achieved control

 

       at the same or lower dose of inhaled steroid in

 

       each stratum for combination again verifying what

 

       had been previously published on the inhaled

 

       steroid-sparing effect.

 

                 I think very importantly in looking at

 

       outcomes, we know that the majority of patients who

 

       achieved well-controlled asthma in phase 1

 

       maintained the status when assessed in the last 8

 

       weeks of the study.  But, also, there were some

 

       patients that, additionally, were able to gain

 

       control with sustained therapy.  So, there may be,

 

       very importantly, subjects who initially are able

 

       to gain control but others that require longer

 

       exposure to achieve this particular outcome.

 

                 Now I am going to switch gears a little

 

       bit and talk briefly about a pediatric trial.  One

 

       of the things, at least in my mind, is that most of

 

       the data that we have in looking at inhaled

 

       steroids and long-acting beta agonists, whether

                                                                 47

 

       they be as entry therapy or as add-on therapy in

 

       preventing the addition of inhaled steroids, has

 

       predominantly been done in adults.  Even those

 

       studies which have enrolled individuals greater

 

       than 12 years in age and up in general have not had

 

       a sizeable enough cohort of the 12-18 population

 

       that really have led to what I believe is a

 

       substantive subanalysis.  So, most of what we have

 

       I believe is in adult studies, and I think we will

 

       see more pediatric studies in the future.

 

                 This is a study that was recently

 

       presented at the American Thoracic Society meeting

 

       this summer, and was conducted by the CARE network

 

       of the NHLBI-sponsored network.  It is a one-year

 

       prospective comparison of three control or

 

       medications for the treatment of mild or moderate

 

       persistent asthma in children.

 

                 In brief, the study schematic is a proof

 

       of study concept.  All children were in a one- or

 

       two-week run-in period and then were either

 

       randomized to an inhaled steroid alone, an inhaled

 

       steroid at half the dose in combination with a

                                                                 48

 

       long-acting beta agonist in comparison to a

 

       leukotriene receptor antagonist.  In order to

 

       achieve this particular proof of concept, the ICS

 

       group received fluticasone by morning and evening

 

       diskus and an evening capsule placebo.  The middles

 

       group of combination, and what I am going to call

 

       combination in the future, received an Advair

 

       diskus in the morning, a salmeterol diskus in the

 

       evening and a placebo capsule, and the leukotriene

 

       regimen active arm received montelukast at night

 

       and two placebos.

 

                 Because this study has not been published

 

       and there are responsibilities to editors, I am not

 

       going to be able to share with you in slide form

 

       all of the data, but I would like to summarize it

 

       for you as I did at the ATS.

 

                 Inclusion criteria for this study were

 

       children 6-14 years of age who had acknowledged

 

       mild to moderate persistent asthma, as defined by

 

       symptoms or beta agonist rescue use of peak flows

 

       in the yellow zone.  They needed to demonstrate

 

       asthma by a PC20 methacholine less than 12.5 mg/ml. 

                                                                 49

 

       Bronchodilator reversibility was collected but it

 

       was not an entry criterion because we believed it

 

       would bias the outcomes because one of the study

 

       arms contained a long-acting beta agonist.  These

 

       were individuals who were naive to controller

 

       medications.  The issue was to look at whether

 

       these three arms and how asthma control was

 

       achieved in individuals with mild or moderate

 

       asthma.

 

                 The percent of asthma control days during

 

       the study period of 12 months was asthma control

 

       days defined as a day without albuterol rescue,

 

       without the use of non-study asthma medications, no

 

       daytime or evening asthma symptoms, unscheduled

 

       provider visits of school absenteeism, so a day in

 

       which a parent and a physician both would be happy

 

       that the asthma was well controlled and that was

 

       the defining outcome for this trial.

 

                 In summary, I am going to focus

 

       predominantly on the two outcomes related to the

 

       full dose inhaled steroid arm and the combination

 

       arm of the half dose fluticasone in combination

                                                                 50

 

       with salmeterol.  Both of those study arms achieved

 

       improvement in the percent of asthma control days.

 

       At baseline this group of children had about 27

 

       percent of the days that were asthma

 

       controlled--so, very, very few.  This actually

 

       almost doubled or tripled during the active they

 

       and the fluticasone group gained asthma control

 

       days of 64 percent versus the combination of 60

 

       percent.  So, both groups adequately achieved

 

       asthma control and these were not statistically

 

       different.

 

                 Treatment failure was also a secondary

 

       outcome in this trial, defined by either the third

 

       burst of prednisone or a hospitalization or ER

 

       visit due to asthma.  There were only five

 

       treatment failures in the fluticasone arm and eight

 

       treatment failures in the combination arm.  That

 

       was not statistically significant.  Of that, there

 

       were no hospitalizations due to asthma in the

 

       fluticasone group and two hospitalizations with the

 

       combination group.

 

                 Overall, the comparison of the two groups

                                                                 51

 

       showed in many outcomes that the inhaled steroid

 

       alone versus the inhaled steroid at half dose in

 

       combination with salmeterol were comparable, as I

 

       mentioned, in asthma control days; the time to

 

       prednisone bursts and treatment failure status.

 

                 There were some important differences in

 

       that if you looked at secondary outcomes such as

 

       change in PC                                                   20, the

improvement and ENO as a marker

 

       of inflammation, and actually changes in maximum

 

       bronchodilator response, the full dose of inhaled

 

       steroid was actually statistically better.

 

                 I mention this study from the point of

 

       view of one study looking at children that will,

 

       hopefully, soon be published and gives us some

 

       experience, I believe, with at least efficacy and

 

       safety in a pediatric population.

 

                 Now, let's switch gears to potential

 

       safety concerns that have been raised by the use of

 

       beta agonists.  That is what the committee has been

 

       asked to really put in perspective today.  It has

 

       not been just in the last few years that safety

 

       concerns with beta agonists have been raised. 

                                                                 52

 

       Studies in the early '90s suggested that the

 

       regular use of a particular beta agonist,

 

       fenoterol, might produce adverse effects.  This is

 

       the number of subjects without exacerbation as a

 

       Kaplan-Meier curve and you can see those

 

       individuals treated with a regular dose of

 

       fenoterol had more asthma exacerbations than as

 

       needed.  This study, by Taylor and others, raised

 

       the specter of regular use of short to intermediate

 

       beta agonists producing adverse effects.

 

                 As you well know, fenoterol never made it

 

       to the U.S. market and albuterol has become clearly

 

       the drug of choice as the intermediate rescue beta

 

       agonist.  Therefore, Jeff Drazen and the Asthma

 

       Clinical Research Network felt it important as one

 

       of its missions to try to answer the question of,

 

       given that albuterol was the primary beta agonist

 

       used in the marketplace, did it matter whether

 

       patients were treated with regular beta agonists

 

       versus as needed beta agonists.  To achieve this

 

       trial, patients either received two puffs of

 

       albuterol four times a day plus extra as needed, or

                                                                 53

 

       placebo inhaler two puffs four times a day and as

 

       needed, thus, sufficing the regularly scheduled

 

       versus as needed paradigm.  The study had a run-in,

 

       a 16-week treatment trial and then a run-out of 4

 

       weeks.

 

                 Now, whereas this group today is not here

 

       to debate the issues of safety of short and

 

       intermediate beta agonists, this trial basically

 

       has led to many of the questions that we have asked

 

       about long-acting beta agonists, and has led to

 

       what I believe is a series of trials that are in

 

       construct and will build on.

 

                 The summary from this particular study,

 

       using again peak flow as the primary outcome and

 

       power to find a difference of 25 L/min in the two

 

       study arms, suggested that whether you are on as

 

       needed albuterol or regular albuterol it really

 

       didn't make a difference in this outcome and,

 

       therefore, there was nothing evil about the use of

 

       regular beta agonists.  But the authors

 

       acknowledged that clearly based on the way the

 

       asthma community was moving, PRN beta agonists was

                                                                 54

 

       the more rational approach.

 

                 Whereas this was a prospective trial, at

 

       the same time that this study was in the midst of

 

       being carried out, Steve Liggett's group at

 

       Cincinnati and others were working on cloning the

 

       beta receptor.  This is the beta receptor as a

 

       G-coupled protein.  As you well know there has been

 

       a lot of interest in single nucleotide

 

       polymorphisms at both the 27 position and the 16

 

       position in a variety of both in vitro and in vivo

 

       studies, looking at acute bronchodilator responses

 

       as well as a variety of other asthma outcomes.

 

                 So, when this was cloned, the Asthma

 

       Clinical Research investigators went back to the

 

       BAGS trial that was still ongoing and were able to

 

       get most of the participants to come back and be

 

       genotyped.  In that regard, the analysis showed

 

       that there was no effect in this primary outcome at

 

       the B27 locus.  There was no effect in the B16

 

       heterozygotes.  However, there was a signal.  When

 

       the B16 Arg/Arg patients were compared to the B16

 

       Gly/Gly patients, with a difference found in the

                                                                 55

 

       primary outcome variable.

 

                 So, this is a retrospective look at the

 

       BAGS data that shows that if you were a group of

 

       patients who received regular albuterol and you

 

       were Arg/Arg, in yellow, your AM peak flow

 

       deteriorated during the course of the trial, in

 

       contrast to whether you received as needed beta

 

       agonists and were Arg/Arg, in red, or whether you

 

       received regular albuterol and were Gly/Gly.  This

 

       retrospective analysis was believed by the ACRN to

 

       be hypothesis generating, not definitive and,

 

       therefore, led to another study which I will share

 

       with you.

 

                 At the same time, Robin Taylor reported on

 

       the influence of beta adrenergic receptor

 

       polymorphisms in some studies he had done looking

 

       at, again, asthma exacerbations in this context.

 

       If you look at the far right of all-comers in this

 

       trial, you see that albuterol and salmeterol are

 

       comparable and superior to placebo in preventing

 

       exacerbations.  If you look at the Gly/Gly and the

 

       Gly/Arg groups, there were really no significant

                                                                 56

 

       differences.  However, in those individuals that

 

       were Arg/Arg at the B16 locus, you can see that

 

       there were more exacerbations with those treated

 

       with albuterol but this was not seen with the

 

       salmeterol therapy.

 

                 So, we began to see in the asthma

 

       community some signals, some subtle signals in

 

       retrospective data about the issue of the potential

 

       relevance of polymorphisms at the beta receptor.

 

       Therefore, I told you that the Drazen trial,

 

       retrospective, was hypothesis generating to allow

 

       us to go forward to actually create a prospective,

 

       randomized, placebo-controlled, double-blind trial

 

       of regular versus minimal albuterol in each

 

       genotype.  This has affectionately been called the

 

       BARGE trial.

 

                 In this trial, in order to minimize beta

 

       agonist use, patients were provided with

 

       ipratropium for rescue as a primary inhaler and

 

       then had a backup to use albuterol of symptoms were

 

       not relieved by ipratropium.

 

                 This is a fairly complex study design but

                                                                 57

 

       which we believed was important to answer the

 

       question.  First, individuals between the ages of

 

       18 and 55 years of age who had an FEV                                    

                                                         1 of at least

 

       70 percent predicted, and naive to inhaled

 

       steroids, were screened and genotyped.  If they

 

       were either found to be Arg/Arg or Gly/Gly at the

 

       B16 they were matched on the basis of FEV                               

                                                                   1,

 

       enrolled in the trial, went in a 6-week run-in

 

       period in which individuals were all on placebo

 

       with just rescue therapy.  They were then

 

       randomized to receive 16 weeks of active treatment

 

       or placebo; then had an 8-week run-out; were

 

       crossed over to the opposite trial; and then a

 

       following run-out arm.

 

                 So, a complex study design that allowed

 

       each patient to serve as their own control of being

 

       on scheduled albuterol versus placebo and using the

 

       backup rescue.  These are individuals who were

 

       about 31 years of age, had fairly normal FEV1's of

 

       about 90 percent predicted and were matched in

 

       pairs on the basis of the genotype of interest.

 

                 This is the data as published in Lancet. 

                                                                 58

 

       This shows the curves of either the albuterol

 

       modeled or raw means data versus the placebo

 

       modeled and raw means data.  In particular, if you

 

       can look at the left-hand side of the slide, this

 

       is the Arg/Arg group.  The right-hand side is the

 

       Gly/Gly group.

 

                 Let's look at the Gly/Gly group first.  If

 

       you look at the Gly/Gly patients in the orange line

 

       on the top, you can see that, as you would expect,

 

       those patients on albuterol scheduled therapy

 

       improved by their morning peak flow during the

 

       course of the study.  In contrast, during the time

 

       they received placebo, in green, they really showed

 

       no improvement in their peak expiratory flow.  In

 

       contrast, the Arg/Arg patients behaved differently.

 

       In green is the placebo and you can see the Arg/Arg

 

       patients on placebo actually improved and those

 

       Arg/Arg patients on albuterol, in orange, failed to

 

       improve their peak flow during the course of the

 

       trial.

 

                 The primary analysis with this study was

 

       to look at the treatment differences and the mean

                                                                 59

 

       change in AM peak flow by genotype at week 16.  You

 

       can see that the albuterol versus placebo Arg/Arg

 

       patients had a difference in their mean peak flow

 

       of 10 L/min; the albuterol versus placebo Gly/Gly

 

       comparison, a difference of about 14.  Therefore,

 

       the treatment difference of the mean Arg/Arg minus

 

       the Gly/Gly was a difference of about 25 L/min,

 

       which is what this study was powered to find and

 

       what we had used in other studies to power it.  So,

 

       this was determined to be statistically

 

       significant.

 

                 There were other outcomes that paralleled

 

       the change in peak flow.  This is looking at the

 

       difference between regular versus placebo changes

 

       in FEV                                         1 over the 16 weeks.  You

can see that the

 

       Gly/Gly subjects had an improvement in their FEV                        

                                                                                

     1,

 

       whereas the Arg/Arg patients had a deterioration in

 

       FEV                                    1.  The same thing could be seen with

morning

 

       symptoms of an increase in the Arg/Arg patients

 

       versus a decrease in the Gly/Gly patients, and a

 

       complementary pattern of seeing a difference in

 

       inhaler use in the different groups, whether it be

                                                                 60

 

       ipratropium as first-line rescue versus albuterol.

 

                 In summary, the BARGE data concluded that

 

       morning and evening peak flow, FEV1's, symptoms and

 

       rescue inhaler use improved significantly in

 

       Arg/Arg patients with asthma when beta agonists

 

       were withdrawn, and when ipratropium was

 

       substituted, as compared with regular albuterol

 

       used.  The pattern was reversed in the Gly/Gly

 

       patients who actually improved with regular beta

 

       agonist use.  The authors suggested that Arg/Arg

 

       patients, who are known to be one-sixth of

 

       asthmatics, may actually benefit from minimizing

 

       short-acting beta agonist use.

 

                 I included this study also because of the

 

       important caveats from the investigators and their

 

       conclusions.  They emphasized that this study was

 

       conducted in only individuals with mild disease,

 

       not patients with concomitant inhaled steroid doses

 

       and, therefore, whether this data can be

 

       extrapolated to more severe disease or to those

 

       patients who are on concomitant inhaled steroid

 

       doses just could not be answered by this particular

                                                                 61

 

       trial, suggesting that both issues need to be

 

       studied more in the asthma community.

 

                 Obviously, the million dollar question is,

 

       indeed, do similar effects occur with long-acting

 

       beta2 agonists, and what is the impact of

 

       concurrent use of inhaled steroids?  Obviously, Dr.

 

       Chowdhury addressed the committee to really

 

       deliberate today to answer those questions.  I

 

       don't have the answers for you and, fortunately, I

 

       am not charged to do that.  That is your tough job

 

       today.

 

                 I would have some comments on what I

 

       believe to be future studies that may help you to

 

       answer those questions.  Much as the BAGS trial was

 

       hypothesis generating for BARGE, the SOCS and SLIC

 

       trial from the ACRN did retrospectively look at

 

       their two studies of long-acting beta agonists

 

       alone.  That was the SOCS trial that I shared with

 

       you, and the SLIC trial which looked at combination

 

       of inhaled steroid and long-acting beta agonists

 

       and the tapering of such.

 

                 The data from these two retrospective

                                                                 62

 

       studies has been presented at meetings, suggesting

 

       that there was a signal of a same pattern of a

 

       difference in morning peak flow based on whether

 

       you were Arg/Arg or Gly/Gly at the 16 locus, and

 

       that the pattern with salmeterol, with or without

 

       the inhaled steroid, seems to be the same.

 

                 I carefully indicated that, indeed, these

 

       are retrospective studies, very small in design

 

       and, clearly, will be hypothesis generating for

 

       more robust, longer-term studies that the ACRN, and

 

       I believe the industry, will conduct.  Therefore,

 

       the ACRN now has a study called LARGE that is in

 

       the middle of operation that is very similar to the

 

       BARGE study but will look at an inhaled steroid,

 

       with or without the addition of a long-acting beta

 

       agonist, to answer the question of whether the same

 

       patterns in a prospective, carefully designed study

 

       can be extrapolated.

 

                 Now, we do have some data to answer the

 

       question on a safety issue about does regular use

 

       of long-acting beta agonists delay awareness of

 

       asthma progression or effect from recovery?  We

                                                                 63

 

       have been concerned that if patients are so well

 

       controlled with symptoms with their long-acting

 

       beta agonists will they be aware that they are

 

       having an asthma exacerbation, or will they fail to

 

       recover from an exacerbation in the way that they

 

       expected to?

 

                 This is one representative study that I

 

       think illustrates the point.  This is the Matz

 

       article I showed you earlier of an accumulation of

 

       data from earlier published studies.  At the arrow,

 

       the day of diagnosis is the point in time at which

 

       the patient had an asthma exacerbation as defined

 

       by these authors.  You can see that if you look at

 

       the change in asthma symptom score about four days

 

       or so before the actual diagnosis of an

 

       exacerbation these individuals began to have an

 

       increase in symptoms, were treated in completion of

 

       an exacerbation satisfactorily, and you see that

 

       their symptoms decreased after the exacerbation.

 

       In this particular trial you actually see that

 

       there is a change in the asthma symptom score that

 

       was different in the two different study groups.

                                                                 64

 

                 Now, one of the things that this provides

 

       I think is some reassuring issues that on the basis

 

       of symptoms patients are well able to detect a

 

       difference in their symptoms, and to know whether

 

       they are having an asthma exacerbation, and they

 

       recover as we expect.  There seems to be no adverse

 

       effect of the addition of salmeterol.  In fact,

 

       these patients seem, by symptoms, to recover even

 

       quicker.

 

                 We did the same analysis with the PACT

 

       pediatric trial that I shared with you just for

 

       interest, to do the same pattern looking at

 

       symptoms, the issue of albuterol use and the issue

 

       of peak flow.  We plotted the three arms of the

 

       study to look at whether the patterns were any

 

       different.  In relevance to you today, the patients

 

       who were on combination therapy as compared to

 

       inhaled steroid alone had no difference in their

 

       pattern.  So, all three groups were equally able to

 

       perceive symptoms of an exacerbation and to

 

       adequately recover in the same kind of a pattern.

 

       So, we are beginning to, I think, have more data

                                                                 65

 

       that resolves this concern that has been raised.

 

                 Now, why we are here today in particular

 

       is to discuss the evidence for increased severe

 

       asthma exacerbations with long-acting beta

 

       agonists.  Indeed, for these studies, as Dr.

 

       Chowdhury outlined for you, the major issue at hand

 

       is, indeed, severe asthma exacerbations as has been

 

       defined by these trials.  I am not going to review

 

       them for you as you clearly have received

 

       preliminary information and I suspect you will have

 

       other members of the audience that will provide far

 

       better detail of these than I can do.  Suffice it

 

       to say that these are studies that have raised

 

       questions in the asthma community about the role of

 

       long-acting beta agonists, and my own particular

 

       comment on these is the fact that, whereas they are

 

       compelling for a signal and certainly warrant a

 

       very careful review of the trials of what they can

 

       tell us and what they cannot tell us, it is very

 

       difficult from these trials to discern whether

 

       these individuals were, indeed, using concurrent

 

       inhaled steroids during the course of the trial. 

                                                                 66

 

       Therefore, it makes it certainly somewhat difficult

 

       to do a full analysis and, therefore, no questions

 

       are easily answered.

 

                 In summary, I think the committee today

 

       has a very important job of reconciling what I

 

       believe to be a very crucial question.  How do we

 

       all reconcile the finding of these very rare

 

       severe, life-threatening episodes that are reported

 

       in the SMART an formoterol trials with what I hope

 

       to have shown you is obviously the far more global

 

       evidence that the use of long-acting beta agonists,

 

       particularly in combination with inhaled steroids,

 

       results in a decrease of overall asthma

 

       exacerbations?  You all are faced with the data

 

       that I believe show that there is very strong

 

       evidence of the ability of inhaled steroids and

 

       long-acting beta agonists to both achieve asthma

 

       control and to reduce overall asthma exacerbations,

 

       as defined by the trials that I have shown you and

 

       others.  So, that piece of data needs to be kept in

 

       context.

 

                 I would comment that there clearly is more

                                                                 67

 

       evidence in adults than children so most of the

 

       decisions made are based on adult data.  I believe

 

       that the remaining concerns about safety have to

 

       ask the question about whether, indeed, there is an

 

       influence of genotypic predictors, as has been

 

       picked up as the signal with the intermediate beta

 

       agonists.  I believe that we have to look at

 

       phenotypic predictors.

 

                 I think the era of treating all patients

 

       equally for asthma is gone and we need to gain

 

       insight about phenotypic predictors of responses to

 

       all our therapy.  I think this needs to include

 

       age, severity of disease, bronchodilator

 

       reversibility status, ethnicity and a variety of

 

       others.  Clearly, we have had some signals that

 

       there may be ethnic differences in responses to

 

       albuterol based on whether you happen to be Puerto

 

       Rican or Mexican-American.  So, we need to get more

 

       information.

 

                 We need to have larger and longer trials

 

       which incorporate multiple outcomes, including the

 

       concurrent use of inhaled steroids, and we need to

                                                                 68

 

       be able to ultimately answer questions of whether

 

       this is a class effect of a dose effect.

 

                 I don't envy the committee.  I know that

 

       you will deliberate carefully.  And, I appreciate

 

       you allowing me to provide you an overview in

 

       anchoring your thoughts for your deliberation.

 

       Thank you very much.

 

                 DR. SWENSON:  Dr. Sorkness, I want to

 

       thank you for a very fine talk.  Since you are

 

       going to be leaving before the day is out, I wanted

 

       to particularly leave some time for members of the

 

       panel to ask you questions at this moment.  So, we

 

       will take questions from the panel on the talk or

 

       issues around it.

 

                        Questions for the Speaker

 

                 DR. MARTINEZ:  Thank you so much for that

 

       very, very nice presentation.  During your

 

       presentation you said that in the PACT trial you

 

       were the principal investigator within the CARE

 

       network.  The decision was made, you said, to use

 

       methacholine responsiveness as a criterion for

 

       inclusion into the trial and not reversibility.  I

                                                                 69

 

       am trying to quote you as best as I can, because

 

       this could have introduced bias into the results,

 

       unquote.

 

                 DR. SORKNESS:  Yes.

 

                 DR. MARTINEZ:  Are you suggesting that

 

       some of the results of the studies that you have

 

       shown to us, including the GOAL study in which

 

       exacerbation was shown to be less in combination

 

       than in use of inhaled corticosteroids alone, may

 

       be explained by bias introduced by the fact that,

 

       for example, in the GOAL study 15 percent

 

       reversibility was a criterion for inclusion?

 

                 Or, a second question, has anybody tried

 

       to separate the studies in this meta-analysis that

 

       you presented to us between those that demanded 15

 

       percent reversibility and those which did not?

 

                 DR. SORKNESS:  It is a great question,

 

       Fernando, and I think it allows me to clarify my

 

       intent of saying that.  Clearly, because of a

 

       variety of reasons, whether it be historical of our

 

       belief that bronchodilator reversibility convinces

 

       us that this is, indeed, reversibly asthma and,

                                                                 70

 

       therefore, the documentation of such allows

 

       enrollment into a clinical trial, or it convinces

 

       us that reversibility allows other drugs to show

 

       comparability.  The majority of trials, whether

 

       they be industry sponsored or not, clearly have

 

       used bronchodilator reversibility as entry

 

       criteria, and clearly most of that which I shared

 

       with you is that.  That has historically been the

 

       context.

 

                 My point in this the fact that I believe

 

       that there are a much broader group of asthmatics

 

       in the world today that don't have that much

 

       bronchodilator reversibility or may have very

 

       little and truly have asthma.  So, our assumptions

 

       of our outcomes in the therapies are predicated on

 

       the fact that we tend to enroll a fairly defined

 

       population.

 

                 I think, second to that, there is

 

       certainly some data from ACRN and other groups that

 

       bronchodilator reversibility as a phenotype clearly

 

       may be more predictive of response to long-acting

 

       beta agonists or for inhaled steroids, for that

                                                                 71

 

       matter.  So, we have isolated a particular

 

       phenotype and enrolled them in our trials.

 

                 The ACRN, because of that and I think

 

       because of our mission of trying to more globally

 

       answer questions in a broader asthma population, in

 

       general have suggested that people can be in these

 

       studies whether you have a bronchodilator response

 

       or PC                                       20 as evidence of having asthma.

Both issues

 

       are collected by entry is not predicated on having

 

       simply a bronchodilator effect.

 

                 In the PACT trial I wanted to emphasize

 

       that I think, because of at least some concerns

 

       about the generalizability of the PACT results, we

 

       felt that PC                                                   20

predominantly was the right entry

 

       criteria.  Bronchodilator reversibility was

 

       collected.  And, clearly, the PACT data will have

 

       the capability of looking at both genotypic and

 

       phenotypic predictors of responses.  I can say that

 

       about the PACT data.  I haven't, Fernando, really

 

       been privy to know whether many of these other

 

       studies teased out bronchodilator responsiveness.

 

       So, that is my answer to the question.

                                                                 72

 

                 DR. SWENSON:  Just for the record, that

 

       was Dr. Martinez that posed that question.  Dr.

 

       Sorkness, to what extent are the exacerbations, as

 

       they are detected in these multiple studies, based

 

       on the criteria of increased use of a short-acting

 

       beta agonist or the rescue use?  Because that seems

 

       pertinent to the question of whether long-acting

 

       beta agonists simply just, for a while, reduce the

 

       need for short-acting and so allow whatever

 

       underlying process toward exacerbation to go

 

       further without recognition.

 

                 DR. SORKNESS:  As a very general comment

 

       to this, it is a difficult question to answer

 

       simply because whether it be asthma exacerbations

 

       or treatment failure there is clearly, in my mind,

 

       not a uniform definition of either in the trials

 

       that have been described.  I think, in fairness,

 

       the vast majority of at least the mild and leading

 

       on to the use of prednisone exacerbations in

 

       general have been anchored by asthma action plans

 

       that have been a combination of symptoms, albuterol

 

       use and, on some occasions, peak flows below some

                                                                 73

 

       safety criteria.  So, many of these studies have at

 

       least incorporated an asthma action plan of

 

       albuterol symptoms and peak flow leading to the use

 

       of prednisone.  So, I think it becomes kind of a

 

       composite decision that the patient makes in

 

       concert with the physician for those studies.

 

                 Having said that, the vast majority of the

 

       studies, at least in my mind, that have used the

 

       term asthma exacerbation in general have been

 

       defined by the need for prednisone, with or without

 

       in some cases either an ER visit or a

 

       hospitalization, but certainly the asthma

 

       exacerbation in many of the studies could have been

 

       achieved simply by the issue of prednisone by that

 

       action plan.  But the definitions are very variable

 

       and I think that does make it harder to bring all

 

       of these together to get the best insight.

 

                 DR. SWENSON:  Miss Sander?

 

                 MS. SANDER:  Thank you.  I need a little

 

       bit more information on what you just said.

 

       Whenever there is the term "rescue" medications

 

       used, that is any and all reasons not just rescue

                                                                 74

 

       examples?

 

                 DR. SORKNESS:  I am not sure I understand,

 

       Miss Sander.

 

                 MS. SANDER:  So, rescue would imply that

 

       they had an emergency need for that medication.

 

       Would it include all uses such as early

 

       intervention, prevention of exercise?

 

                 DR. SORKNESS:  In my mind, most of the

 

       studies have in their action plans specified that

 

       the use of albuterol to relieve symptoms and/or to

 

       treat a peak flow at a certain safety level were

 

       used in the definition of an action plan of going

 

       on to treat the exacerbation.  Most of the action

 

       plans in these trials, or at least the ones

 

       certainly from the ACRN and CARE, did not

 

       incorporate pre-exercise intended scheduled

 

       albuterol use in that paradigm.  It was strictly

 

       albuterol use for relief of those symptoms or

 

       relief of a drop in a peak flow to make it return

 

       to some baseline safety level.

 

                 MS. SANDER:  Thank you.  Also one other

 

       question, were there any expectant mothers in any

                                                                 75

 

       of these?

 

                 DR. SORKNESS:  I can't say this with

 

       absolute confidence but I would be highly suspect

 

       that any of the trials were conducted that did not

 

       have a safety pregnancy test at entry and did not

 

       have some appropriate monitoring of pregnancy

 

       status during the trial.  The vast majority of

 

       studies that have been privy to even mandate that

 

       if a methacholine challenge procedure is being done

 

       at a study visit a pregnancy test be done.  There

 

       is a series of questions that coordinators and

 

       investigators ask about the chance of a pregnancy

 

       to make decisions as far as people continuing in

 

       trials.  So, I would be very surprised if

 

       individuals were enrolled being pregnant.

 

       Unfortunately, life is not perfect and I think that

 

       there are certainly trials where a woman became

 

       pregnant during the trial.  Most of the studies I

 

       know of, that actually required a mandated

 

       withdrawal because of the potential influence of

 

       pregnancy on stability of asthma.  So, I don't

 

       think there is much we can gain in insight, quite

                                                                 76

 

       honestly, if that is some of what you are driving

 

       at.  I just don't think it exists in these trials.

 

                 DR. SWENSON:  Dr. Newman?

 

                 DR. NEWMAN:  Yes, thank you for what was a

 

       very clear presentation.  I wonder if you might

 

       comment about, from the benefit side, any

 

       differences in these trials based on race.

 

                 DR. SORKNESS:  That is a tremendous

 

       question.  I think the fairness of answering the

 

       question is that most of the trials that I am aware

 

       of--and I say this carefully because I don't know

 

       the literature in its extreme--probably did not

 

       have the ability to have a satisfactory subset of a

 

       particular racial or ethnic group to be able to

 

       cull out to do a reasonable racial analysis.  In

 

       the beta agonist trial by Drazen, et al., I know

 

       for a fact that because of NIH NHLBI guidelines of

 

       enrollment of at least a third of minority

 

       participants, that we did do a statistical analysis

 

       in that trial and it showed that the minority

 

       ethnic group did not do differently on any of the

 

       outcomes versus Caucasians, negative or benefit. 

                                                                 77

 

       They had equal responses, as did actually a gender

 

       analysis.

 

                 I really do not know of any other trial

 

       that could answer your question explicitly but I

 

       think it is very important, especially given some

 

       of what we are learning about the potential role of

 

       ethnicity, and that mandates that we all make a far

 

       more serious effort for doing trials big enough

 

       with groups to answer the question.

 

                 DR. SWENSON:  Dr. Brantly?

 

                 DR. BRANTLY:  Dr. Sorkness, as I recall

 

       there were a number of bronchial biopsy studies

 

       using ICSs.  I don't recall any regarding using

 

       either long-acting beta agonists or short-acting

 

       beta agonists.  Do they exist?

 

                 DR. SORKNESS:  I am not sure I can answer

 

       that with comfort.  I actually do believe that

 

       there are bronchial biopsy studies in individuals

 

       on long-acting beta agonists alone and certainly on

 

       combination.  That is not clearly my area of

 

       expertise and I really think I would be remiss in

 

       trying to answer the question of what I know about

                                                                 78

 

       those studies.  I am a clinical researcher.

 

       Certainly, some of my partners do those kinds of

 

       studies but that is clearly not an expertise that I

 

       would feel comfortable answering.  And, there may

 

       be somebody else on the committee that clearly

 

       knows that data far more than I.

 

                 DR. SWENSON:  Dr. Prussin?

 

                 DR. PRUSSIN:  Chris, on your last slide

 

       you have a note that says, "need for larger and

 

       longer trials which incorporate multiple outcomes."

 

       My question is, you know, clearly long-acting beta

 

       agonists decrease exacerbations and, yet, we have

 

       very good data that severe pulmonary events and

 

       death are increased.  So, you can't use a trial

 

       that is looking at exacerbations to answer the

 

       outcome that we are interested in here.  Since I

 

       work more in a smaller frame in terms of allergic

 

       disease, not large clinical trials, can you give me

 

       more of an idea of what you think a large clinical

 

       trial and multiple outcomes that we should be

 

       looking at for these endpoints of death,

 

       intubation, severe pulmonary outcomes?

                                                                 79

 

                 DR. SORKNESS:  Cal, I think it is

 

       difficult and I will try to answer as best I can.

 

       I do believe we are in an era where the most

 

       important studies are not monotherapy in asthma

 

       with long-acting beta agonists but with

 

       combination.  So, that is the first issue.

 

                 I believe that whereas the SMART trial and

 

       some of the formoterol pivotal trials and others

 

       that have raised the signal of concern are helpful

 

       and we need to take that under consideration.  I

 

       find that the way that those studies were

 

       constructed leave me wanting more.  The methods by

 

       which patients were accrued; the issue of whether

 

       you really knew whether people were on inhaled

 

       steroids concurrently and were adherent with such;

 

       that you took into account and balanced severity of

 

       disease at the beginning; that you truly looked at

 

       what we believe clinically as the best that we can

 

       ask of this array of overall asthma exacerbations

 

       and control of disease; a year long study to deal

 

       with seasonality, especially in kids; looking at

 

       some markers of inflammation.

                                                                 80

 

                 I think that we are at a stage that we

 

       would feel better and have more confidence in the

 

       risk/benefit relationship if we had those kinds of

 

       trials done both in adults and children, and

 

       particularly were able to answer in our own minds

 

       whether the combination together--adherence, people

 

       taking them, being on them, controlling for the

 

       issues--that we really knew what we were doing with

 

       those particular trials.  And, I think that is the

 

       best that we can do.

 

                 DR. PRUSSIN:  Let me just follow that up.

 

       The SMART trial was stopped because of difficulties

 

       with accrual and slow accrual.  Again, we are

 

       talking about a huge clinical trial.  In your

 

       estimation, since this is what you do, is it

 

       possible to do that large a trial and get the

 

       information in a much more rigorous way, as you are

 

       proposing?  I mean in terms of accrual.  Is this a

 

       feasible endeavor to go into?  Because we have been

 

       told that SMART simply became impossible to carry

 

       forward.

 

                 DR. SORKNESS:  Yes, I think the reality is

                                                                 81

 

       such that it is I believe, and I am investigator so

 

       I am asked to do these things--I think it is

 

       impossible in this day and age to recruit large

 

       enough subjects even in a multicenter study that

 

       are naive to either inhaled steroids or long-acting

 

       beta agonists at entry so that you are bringing in

 

       this naive population to answer the question.  I

 

       don't think those patients are out there anymore

 

       because we have done such a good job with

 

       guidelines and because all these trials showing

 

       that when you give people good medicines, by golly,

 

       they get better.

 

                 So, I think that if you, indeed, enroll a

 

       far broader population of phenotypes, of patients

 

       that have certain entry criteria, and then you

 

       randomized them to an inhaled steroid with and

 

       without a long-acting beta agonist, and followed

 

       them for long enough, I think those studies can be

 

       constructed.  And, I think that is one of the

 

       challenges to do and I suspect that they will be

 

       done.

 

                 DR. SWENSON:  Well, thank you, Dr.

                                                                 82

 

       Sorkness.  We appreciate very much that fine talk

 

       and discussion.  At this point we will turn the

 

       program now over to GlaxoSmithKline and, to do so

 

       and to introduce her colleagues, Elaine Jones will

 

       take over.

 

                       GlaxoSmithKline Presentation

 

                             Opening Remarks

 

                 DR. JONES:  Good morning.  My name is

 

       Elaine Jones and I am Vice President of Regulatory

 

       Affairs at GlaxoSmithKline.  On behalf of

 

       GlaxoSmithKline, I would like to thank the agency

 

       and the advisory committee for this opportunity to

 

       review data pertinent to the discussion of the

 

       safety of long-acting beta                                              

                           2 agonists in the

 

       treatment of asthma.

 

                 Our presentation today will focus on our

 

       data with the inhaled long-acting beta                                  

                                                           2 agonist

 

       salmeterol.  As we begin the presentation today, I

 

       would like to set the stage by speaking first about

 

       the burden of asthma.  As the committee members are

 

       well aware, asthma is a chronic disease associated

 

       with significant morbidity and mortality.  In the

                                                                 83

 

       United States alone asthma affects approximately 20

 

       million patients.  Asthma exerts a tremendous

 

       societal burden as evidenced by the half million

 

       hospitalizations and over 4,000 deaths in the U.S.

 

       in 2002.

 

                 There are many risk factors that have been

 

       identified that put patients at risk for an

 

       asthma-related death.  Some of these include

 

       excessive reliance on rescue medications and use of

 

       inhaled corticosteroids, disease severity and a

 

       delay in seeking care.  Ethnic origin is also an

 

       important risk factor, demonstrated by the fact

 

       that the rate of asthma deaths in African Americans

 

       is approximately 2.5-fold higher than that of

 

       Caucasians.

 

                 The tremendous burden of asthma has fueled

 

       a continual development of new medications to treat

 

       this disease and GSK has a long history in the

 

       development of respiratory medicines.  Salmeterol

 

       was the first inhaled long-acting bronchodilator,

 

       and its approval in the United Kingdom over a

 

       decade and a half ago represented an important

                                                                 84

 

       advance in the management of asthma.

 

                 To date, regulatory authorities have

 

       granted approval to market salmeterol in over 100

 

       countries.  In the United States there are three

 

       salmeterol-containing products that have been

 

       approved for marketing.  These are Serevent

 

       inhalation aerosol, Serevent diskus and Advair

 

       diskus which contain salmeterol as one of its

 

       components.  Each one of these products has been

 

       approved for use in patients with asthma or COPD,

 

       and each of these approvals required a full

 

       clinical development program.

 

                 It should be noted that the inhalation

 

       aerosol formulation, which contained

 

       chlorofluorocarbons, has been discontinued by GSK

 

       as part of the phase-out of CFC-containing products

 

       consistent with the Montreal protocol.

 

                 Worldwide approvals by regulatory

 

       authorities have led to a great deal of clinical

 

       experience with salmeterol.  Over the last 15 years

 

       the exposure to salmeterol is the result of the use

 

       of salmeterol formulated as a single agent and the

                                                                 85

 

       use of salmeterol formulated with fluticasone

 

       propionate in a single device.  In total the

 

       worldwide exposure is now estimated at 45.2 million

 

       patient-years.

 

                 Based on extensive clinical experience and

 

       a systematic review of numerous clinical trials,

 

       evidence-based guidelines from the National Heart,

 

       Lung and Blood Institute's expert panel report

 

       recognize the pivotal role of long-acting beta

 

       agonists in the treatment of asthma.  While the

 

       safety of long-acting beta                                              

                           2 agonists is the topic

 

       of today's meeting, it is important to consider the

 

       safety of these medications in the context of their

 

       overall benefit/risk profile.  Part of the context

 

       is provided by current asthma treatment guidelines

 

       which position the use of inhaled long-acting beta

 

       agonists with inhaled corticosteroids as the

 

       preferred treatment option for patients with

 

       moderate to severe persistent asthma.

 

                 Asthma is a serious disease with

 

       significant morbidity and mortality and salmeterol

 

       has become a well-established pharmacological

                                                                 86

 

       therapy in the management of this disease.  As you

 

       know, no medication is without risk and today's

 

       meeting provides an important opportunity to review

 

       safety data for inhaled long-acting beta agonists.

 

       We look forward to discussing the safety of

 

       salmeterol with the committee.

 

                 Salmeterol has been shown to be highly

 

       effective in the treatment of asthma and, since its

 

       approval 15 years ago, clinicians have accrued

 

       considerable experience with its use.  Based on the

 

       extensive body of evidence in patients with asthma,

 

       including 64 studies in approximately 45,000

 

       patients in the U.S. alone, GSK believes that

 

       salmeterol continues to exhibit a favorable benefit

 

       to risk profile.

 

                 Dr. Kate Knobil will now provide a brief

 

       overview of the efficacy of salmeterol, followed by

 

       a discussion of safety data.  Following Dr.

 

       Knobil's presentation, I will return to the podium

 

       to introduce the experts here with us today and

 

       then we will take questions from the committee.

 

                            Salmeterol Review

                                                                 87

 

                 DR. KNOBIL:  Good morning, everyone.  For

 

       my presentation today I will first present a brief

 

       overview of the benefits of salmeterol for the

 

       treatment of asthma, followed by a review of the

 

       salmeterol safety data.  My review of the safety

 

       data will focus on the postmarketing safety

 

       surveillance studies, SNS and SMART, and the

 

       results from epidemiology studies of salmeterol.

 

       In addition, I will describe the ongoing studies

 

       currently being conducted by GSK to further

 

       evaluate the efficacy and safety of salmeterol.

 

       Finally, I will close with an overall assessment of

 

       salmeterol for the treatment of patients with

 

       asthma.  Given time limitations, I will not be able

 

       to cover all of the information that is in your

 

       briefing document.  However, any questions you may

 

       have may be addressed during the Q&A.

 

                 For several decades beta agonists have

 

       been widely used to treat bronchoconstriction.

 

       This slide shows the structures of albuterol and

 

       salmeterol, and you have seen these already today,

 

       and highlights the long lipophilic tail that helps

                                                                 88

 

       anchor salmeterol in the beta adrenergic receptor.

 

       Albuterol is highly selective for beta                                  

                                                           2 receptor,

 

       thus having fewer cardiovascular effects than

 

       earlier less selective beta agonists.  Short-acting

 

       beta agonists are very effective but are limited by

 

       their relatively short duration of action of 4-6

 

       hours.

 

                 This limitation was largely overcome by

 

       the development of selective long-acting beta                           

                                                                              2

 

       agonists, such as salmeterol, which are effective

 

       for at least 12 hours.  In addition to having a

 

       longer duration of action, in vitro studies have

 

       shown salmeterol to be at least 50 times more

 

       selective for the airway beta                                           

                                   2 receptor than

 

       albuterol.

 

                 The benefit of the longer duration of

 

       action of salmeterol can be seen in the data pooled

 

       from the two registration studies for salmeterol

 

       metered dose inhaler.  At the time that these

 

       studies were conducted regular albuterol use was a

 

       common treatment for asthma and so was included as

 

       an active comparator.  For salmeterol, shown in

                                                                 89

 

       green, a single dose results in a clinically

 

       significant improvement in FEV                                          

                                      1 within 30 minutes,

 

       with maintenance of effect for at least 12 hours.

 

       This is in contrast to albuterol, shown in grey,

 

       which has a more rapid onset of effect but the

 

       bronchodilator effect lasts only 4-6 hours.

 

       Additionally, as shown on the right, the

 

       bronchodilator effect of salmeterol was maintained

 

       after 12 weeks of treatment with no diminution of

 

       FEV                                    1 response over time.

 

                 Studies of up to one year in duration have

 

       confirmed that the bronchodilator properties of

 

       salmeterol are maintained with long-term use.  In

 

       this study, 12-hour FEV                                                 

                   1 area under the curve, or

 

       AUC, was obtained after the first dose and

 

       following 8, 20 and 48 weeks of treatment.  For

 

       salmeterol the mean FEV                                                 

                   1 AUC was similar at all

 

       time points, and in all cases was significantly

 

       greater than placebo, demonstrating maintenance of

 

       bronchodilator effect.   In addition to important

 

       bronchodilator effects, salmeterol is very

 

       effectiveness at reducing the symptoms of asthma. 

                                                                 90

 

       The data shown here are from the same two studies

 

       for salmeterol MDI that I showed previously.  Over

 

       12 weeks treatment with salmeterol resulted in a

 

       significant reduction in asthma symptoms scores for

 

       chest tightness, shortness of breath, wheezing and

 

       cough compared with placebo and albuterol given 4

 

       times daily.  Although not shown here, in these and

 

       other studies salmeterol also reduced nocturnal

 

       symptoms associated with asthma.

 

                 Salmeterol has also been shown to be an

 

       important treatment option for patients with asthma

 

       who are not adequately controlled on inhaled

 

       corticosteroids.  This landmark study by Greening

 

       and colleagues examined the effect of adding

 

       salmeterol to inhaled corticosteroid therapy, in

 

       this case beclomethasone, as compared to increasing

 

       the dose of inhaled steroids.  The addition of

 

       salmeterol to a low dose of inhaled corticosteroid

 

       was shown to result in a greater improvement in

 

       lung function, as shown by peak expiratory flow,

 

       then when compared to the higher dose of inhaled

 

       steroids.  In addition to the improvements in lung

                                                                 91

 

       function, the use of salmeterol resulted in greater

 

       improvements in symptoms and rescue albuterol use.

 

                 The addition of salmeterol to a low to

 

       medium dose of inhaled steroid has also been shown

 

       to reduce the recurrence of asthma exacerbations.

 

       Shown here again is the study by Matz and

 

       colleagues, and was of similar design to the study

 

       that I showed previously.  When compared to

 

       increasing the dose of fluticasone propionate, or

 

       FP, the addition of salmeterol to the low dose of

 

       FP significantly increased the time to the first

 

       asthma exacerbation requiring oral corticosteroids.

 

       Further, significantly fewer salmeterol-treated

 

       patients experienced one or more exacerbations, 8.8

 

       percent compared to the increased dose of FP at

 

       13.8 percent of patients.

 

                 Another means of evaluating the patient

 

       benefit of a medication is to assess the impact on

 

       quality of life.  In this 12-week study that was

 

       designed to assess asthma-specific quality of life,

 

       patients with asthma were randomized to either

 

       salmeterol or placebo, with all patients receiving

                                                                 92

 

       albuterol as needed to use for symptoms.

 

       Salmeterol MDI was shown to significantly improve

 

       quality of life compared with placebo, and the

 

       minimally clinically important difference of 0.5

 

       was achieved for each domain as well as the global

 

       score.

 

                 To summarize, the benefits of salmeterol

 

       have been well established and salmeterol has been

 

       accepted as having an integral role in the

 

       treatment of asthma.

 

                 I will now move on to the safety portion

 

       of the presentation, beginning first with the

 

       postmarketing surveillance studies for salmeterol.

 

       These studies are of interest because at the time

 

       of launch of salmeterol in both the U.K. and in the

 

       U.S. there was concern that the regular use of beta

 

       agonists may lead to deterioration of asthma

 

       control.  This was based primarily on studies of

 

       short-acting beta agonists, particularly fenoterol,

 

       that suggested worsening of asthma with scheduled

 

       use.  These studies could not determine a cause and

 

       effect relationship, however, they did bring

                                                                 93

 

       significant attention to the appropriate use of

 

       this class of medications.

 

                 The first study that I will discuss is the

 

       Serevent Nationwide Surveillance Study, or SNS,

 

       which was performed in the U.K. between 1990 and

 

       1992.  This 16-week randomized, double-blind study

 

       evaluated over 25,000 patients with moderate to

 

       severe asthma.  The study compared salmeterol MDI

 

       to albuterol given 4 times daily in patients 12

 

       years of age and older.  Both treatments were added

 

       to the patient's current asthma therapy.

 

                 At visit 1 patients were randomized in a

 

       2:1 fashion to either salmeterol or albuterol.  The

 

       primary endpoint for SNS was combined serious

 

       adverse events and all medical and non-medical

 

       withdrawals.  This very broad endpoint was not

 

       restricted to respiratory events.  For this

 

       endpoint the percentage of events was similar for

 

       the salmeterol and albuterol groups.  Additional

 

       endpoints of interest included asthma-related

 

       deaths, hospitalizations and withdrawals.  Based on

 

       national health statistics in the U.K. and on the

                                                                 94

 

       2:1 randomization, 10 and 5 asthma-related deaths

 

       were predicted in the salmeterol group and

 

       albuterol group respectively.

 

                 In this study, 14 asthma-related deaths

 

       occurred, with 12 in the salmeterol group and 2 in

 

       the albuterol group, resulting in a relative risk

 

       of 3.  This difference was not statistically

 

       significant but did raise concern.  The results for

 

       asthma-related deaths were not consistent with the

 

       data for asthma-related hospitalizations.  As you

 

       can see here, the data for this endpoint did not

 

       indicate an increase in risk with salmeterol.  The

 

       only statistically significant difference between

 

       the groups was seen for the percentage of

 

       withdrawals due to worsening asthma, with a lower

 

       percent observed in the salmeterol group compared

 

       with albuterol.

 

                 In light of the results of SNS, including

 

       the asthma-related deaths and spontaneous reports,

 

       GSK, in conjunction with the FDA, designed the

 

       Salmeterol Multicenter Asthma Research Trial, or

 

       SMART.  The study was initiated in 1996.  SMART was

                                                                 95

 

       a randomized, double-blind surveillance study of 28

 

       weeks duration that was conducted at over 6,000

 

       sites in the United States.  Patients with asthma

 

       who were 12 years of age or older, with no previous

 

       use of inhaled long-acting beta agonists, were

 

       included.  All other asthma medications were

 

       allowed during the study.

 

                 SMART consisted of a single clinic visit

 

       at which patients were assessed for eligibility and

 

       then randomized to receive either salmeterol or

 

       placebo which was added to their usual asthma care.

 

       Subjects were given a 28-week supply of study

 

       medication and were not required to return for

 

       clinic visits.  Instead, patients were contacted

 

       every 4 weeks by phone primarily to collect

 

       information on serious adverse events, including

 

       respiratory-related events.

 

                 The combined endpoint of

 

       respiratory-related deaths or life-threatening

 

       experiences was chosen as the primary endpoint.

 

       Asthma-related death was also of interest but

 

       because this is a rare event the sample size

                                                                 96

 

       required for this to be the primary endpoint was

 

       too large to be feasible.  Even with the broader

 

       combined endpoint, it was determined that a sample

 

       size of 30,000 patients would be required.

 

       However, after 15,000 patients were enrolled in the

 

       study the actual rate of primary events was found

 

       to be approximately half of what was expected and

 

       the target sample size was increased to 60,000

 

       patients.

 

                 Key secondary endpoints were

 

       respiratory-related deaths, combined asthma-related

 

       deaths or life-threatening experiences, and

 

       asthma-related deaths, all of which were subsets of

 

       the primary endpoint.

 

                 Two independent review committees were

 

       involved with SMART.  They were the mortality and

 

       morbidity review committee, or MMRC, and the data

 

       safety monitoring board, or DSMB.  Each serious

 

       adverse event was adjudicated in a blinded fashion

 

       by the MMRC to determine if it was respiratory

 

       related and, if so, whether it was asthma related.

 

       The categories for this adjudication were

                                                                 97

 

       unrelated, unlikely related, possibly related or

 

       almost certainly related.  Only respiratory- and

 

       asthma-related events considered possibly related

 

       or almost certainly related comprised the primary

 

       and secondary endpoints.  The DSMB met regularly to

 

       evaluate blinded aggregate data which included the

 

       cases adjudicated by the MMRC.

 

                 An interim analysis was planned when

 

       approximately one-half of the patients had been

 

       enrolled.  At the interim analysis the study did

 

       not reach predetermined stopping criteria, however,

 

       there was a suggestion of worse outcomes in

 

       salmeterol-treated patients, especially African

 

       Americans.  For this reason, the DSMB recommended

 

       that ideally the study should be completed within 2

 

       years or, if that was not possible, the study

 

       should be terminated and the results disseminated.

 

       Following discussions with the DSMB, GSK made the

 

       decision to stop the study due to difficulties in

 

       enrollment and the findings in African Americans.

 

                 I will now move on to the results of

 

       SMART.  Overall, the baseline characteristics of

                                                                 98

 

       age, sex, ethnic origin and baseline peak

 

       expiratory flow were well matched between the

 

       treatment groups.  Approximately 70 percent of the

 

       population was Caucasian and 18 percent was African

 

       American.  For reference, approximately 15 percent

 

       of the patients with asthma in the United States

 

       are African American.

 

                 Asthma medications were reported at

 

       baseline and were similar between the treatment

 

       groups.  The most commonly reported asthma

 

       medications were inhaled or oral beta agonists

 

       which were reported in over 90 percent of patients.

 

       Forty-seven of the patients reported use of inhaled

 

       corticosteroids at baseline.

 

                 While baseline characteristics were

 

       similar between the treatments for the total

 

       population, this was not the case when comparing

 

       baseline characteristics between Caucasians and

 

       African Americans.  The baseline characteristics

 

       indicate that African Americans had more severe

 

       asthma as measured by peak expiratory flow,

 

       nocturnal symptoms, and history of hospitalizations

                                                                 99

 

       and intubations.  For example, the proportion of

 

       African Americans reporting a hospitalization for

 

       asthma during the previous 12 months was more than

 

       twice the percentage reported for intubation for

 

       asthma in their lifetime.  In addition to these

 

       markers of increased severity in African Americans,

 

       the reported use of an ICS at baseline was lower

 

       than that in Caucasians.

 

                 The results for the primary and key

 

       secondary endpoints will be shown on this slide.

 

       Due to the amount of information, I will take a few

 

       moments to summarize the data.  These figures are

 

       also available in your briefing document for

 

       reference.

 

                 First let me orient you to the slide.  The

 

       relative risk point estimate and corresponding 95

 

       percent confidence intervals for the primary and

 

       secondary endpoints will be displayed graphically.

 

       The values that correspond with these data will be

 

       shown on the right side of the slide.  The total

 

       population will be represented in yellow, the

 

       Caucasian subgroup in green, and the African

                                                                100

 

       American subgroup in orange.

 

                 I will start by showing the results for

 

       the total population as this was the primary

 

       analysis.  Then I will show the results for

 

       Caucasians and African Americans as this post hoc

 

       analysis was requested by the DSMB at the time of

 

       the interim analysis.

 

                 The number of primary events, combined

 

       respiratory-related death or life-threatening

 

       experiences, was approximately two-thirds of what

 

       was expected.  The primary endpoint for the total

 

       population, as shown here on the slide, was not

 

       statistically significantly different between

 

       treatment groups as the confidence interval

 

       includes 1.  As I review the key secondary

 

       endpoints for the total population, which are

 

       respiratory-related deaths, combined asthma-related

 

       deaths or life-threatening experiences and

 

       asthma-related deaths, it is important to remember

 

       that each is a subset of the primary endpoint.

 

                 For the secondary endpoints, statistically

 

       significant differences were observed between

                                                                101

 

       treatment groups for the total population,

 

       including asthma-related death which I will discuss

 

       in more detail in a moment.  The numbers of primary

 

       events in the Caucasian subgroup, shown in green,

 

       were similar between the treatment groups.

 

       However, in the African American population, shown

 

       here in orange, a significantly greater number of

 

       primary events occurred in the salmeterol treatment

 

       group.

 

                 For the key secondary endpoints the

 

       relative risk of events was higher in African

 

       Americans compared with Caucasians.  In particular,

 

       a significantly greater number of combined

 

       asthma-related deaths or life-threatening

 

       experiences occurred in the salmeterol group in the

 

       African American population, while there was no

 

       difference between treatment groups in the

 

       Caucasian population.

 

                 The number of asthma deaths in SMART was

 

       approximately half of what was expected.  There was

 

       a significantly higher number of asthma-related

 

       deaths seen in the overall population for patients

                                                                102

 

       receiving salmeterol compared with placebo and the

 

       same pattern was seen in the ethnic subgroups.

 

       While the relative risk of asthma deaths appears

 

       similar between ethnic groups, note that there were

 

       approximately 4 times as many Caucasians in this

 

       study than African Americans.  Therefore, the rates

 

       for all asthma-related endpoints were much higher

 

       in the African American population.

 

                 The effect of inhaled corticosteroids was

 

       also of particular interest to the DSMB at the time

 

       of the interim analysis.  A post hoc analysis was

 

       conducted to explore the association of baseline

 

       use of ICS with the primary and key secondary

 

       outcomes.  As I mentioned previously, 47 percent of

 

       the patients reported using inhaled steroids at

 

       baseline.  The results for the total population are

 

       shown here, again in yellow, for reference.

 

       Results for subjects reporting inhaled

 

       corticosteroid use at baseline will be shown in

 

       blue, and those not reporting ICS use at baseline

 

       will be shown in white.

 

                 For subjects reporting ICSs at baseline

                                                                103

 

       there were not statistically significant

 

       differences between the treatment groups for the

 

       primary and secondary outcomes.  Patients receiving

 

       salmeterol who did not report the use of inhaled

 

       corticosteroids at baseline, here in white,

 

       experienced significantly more combined

 

       asthma-related events than those receiving placebo.

 

       The number of deaths in those patients not

 

       reporting inhaled corticosteroid use at baseline

 

       was 9 in the salmeterol group versus zero in the

 

       placebo group so direct calculation of relative

 

       risk cannot be performed.  In the patients

 

       reporting corticosteroid use at baseline the

 

       numbers were 4 and 3 respectively.

 

                 Although SMART was not designed to assess

 

       the effects on inhaled corticosteroid use, these

 

       data suggests that ICS may have had a beneficial

 

       effect on asthma outcomes in SMART.

 

                 Finally, the data were analyzed by both

 

       ethnicity and inhaled corticosteroid use reported

 

       at baseline.  Caucasians are shown, again, in green

 

       and African Americans in orange.  Patients

                                                                104

 

       receiving inhaled corticosteroids are represented

 

       by solid lines while dotted lines represent

 

       patients not reporting inhaled corticosteroid use

 

       at baseline.  The relative risk for the primary

 

       endpoint was higher in African Americans than

 

       Caucasians, and those not reporting inhaled

 

       corticosteroids at baseline had higher relative

 

       risks within those populations.

 

                 Similar to the primary endpoint, the

 

       relative risk for combined asthma-related events

 

       was higher in the groups that did not report

 

       inhaled corticosteroids at baseline independent of

 

       ethnicity.

 

                 If we focus specifically on the number of

 

       asthma-related deaths, shown here at the bottom of

 

       the slide, it is evident that these events were

 

       rare.  There were more asthma-related deaths in

 

       patients receiving salmeterol who did not report

 

       ICS use at baseline in both Caucasians and African

 

       Americans.  Again, direct calculation of relative

 

       risk cannot be performed for asthma-related deaths

 

       for patients not reporting inhaled corticosteroids

                                                                105

 

       at baseline since there were no deaths in the

 

       placebo group for this endpoint.

 

                 SMART was not designed to determine the

 

       effect of inhaled corticosteroids and ethnicity on

 

       these endpoints, and the number of events in each

 

       subgroup is quite small.  Therefore, these data

 

       should be interpreted carefully.

 

                 In summary, there were more events,

 

       including asthma-related deaths, reported in the

 

       patients receiving salmeterol.  There was also a

 

       suggestion that both African Americans and patients

 

       who did not report using inhaled corticosteroids at

 

       baseline had a higher risk of asthma-related

 

       events.  However, the number of events in SMART was

 

       lower than expected, preventing definitive

 

       conclusions from the data.

 

                 A careful review of the data did not

 

       reveal any clear explanation of the results.

 

       Possible explanations include a direct

 

       pharmacologic effect of salmeterol; the presence of

 

       polymorphisms in the beta receptor gene; or

 

       patient-related factors, including a delay in

                                                                106

 

       seeking medical care.  It is well accepted that the

 

       prevalence of patient-related risk factors is not

 

       equally distributed across ethnic groups so the

 

       differences in outcomes seen between the ethnic

 

       groups in SMART may be associated with disparities

 

       in access to medical care and asthma management and

 

       may not reflect biological differences between the

 

       groups.  Unfortunately, none of these hypotheses

 

       can be confirmed or refuted by the data from SMART.

 

       While there are no clear explanations for the data,

 

       the findings were communicated to physicians to

 

       allow for informed treatment decisions.

 

                 In collaboration with the FDA, a number of

 

       activities were undertaken to communicate the

 

       results in order to inform physicians about SMART.

 

       On the day the study was stopped a "dear healthcare

 

       professional letter" was delivered by overnight

 

       mail to the 229,000 healthcare professionals in the

 

       United States who had prescribed salmeterol or

 

       salmeterol-containing products within the previous

 

       year.  Simultaneously, notices on both the FDA and

 

       GSK web sites were posted.

                                                                107

 

                 A second letter was sent out to health

 

       professionals when the prescribing information for

 

       Serevent and Advair was changed to include the

 

       preliminary results of the interim analysis of

 

       SMART.  The information was elevated to the highest

 

       level of prominence in the form of a boxed warning.

 

       When the final results were obtained the labeling

 

       for both products was updated.

 

                 This is the boxed warning that was added

 

       to the prescribing information for Serevent and

 

       Advair.  It describes the final results of the

 

       interim analysis of SMART.  For your reference, the

 

       full label, including the boxed warning, is

 

       available in your briefing package.

 

                 The results of the interim analysis were

 

       presented at the American College of Chest

 

       Physicians meeting as a late-breaking abstract.

 

       This was the first available national meeting with

 

       high attendance of respiratory physicians.  The

 

       manuscript is now in press at Chest, the journal of

 

       the American College of Chest Physicians.

 

                 Epidemiology studies offer an additional

                                                                108

 

       method to investigate associations between drug

 

       exposure and serious outcomes.  The major advantage

 

       of these studies is the utilization of

 

       comprehensive medical and pharmacy databases.

 

       These databases allow identification of a greater

 

       number of events than can be achieved in

 

       traditional randomized clinical trials.  The

 

       primary limitation of observational studies is the

 

       fact that assignment of treatment is not random and

 

       treatment effects may be confounded by differences

 

       in baseline characteristics, including co-morbid

 

       disease, differences in asthma severity and

 

       selective prescribing.  Since many more events can

 

       be evaluated in an observational design, this may

 

       be a more informative way to assess treatment

 

       effects on the rare endpoint of asthma-related

 

       death.

 

                 This figure displays the relative risks

 

       from all large published cohort and case-control

 

       studies that evaluated whether salmeterol use was

 

       associated with the occurrence of severe

 

       respiratory and asthma-related outcomes.  The

                                                                109

 

       dotted line represents a relative risk of 1.

 

                 The first study determine the relative

 

       risk of respiratory-related death among patients

 

       with asthma receiving salmeterol compared with

 

       those receiving theophylline on the left side of

 

       the highlighted area, or those receiving

 

       ipratropium, which is on the right side of the

 

       highlighted area.

 

                 The second study, which was conducted in

 

       the United States, evaluated three endpoints,

 

       asthma-related emergency room visits,

 

       hospitalizations and ICU admissions, comparing

 

       salmeterol with theophylline recipients.

 

                 The last two were separate case-control

 

       studies that evaluated the relative risk of

 

       asthma-related ICU admission or asthma-related

 

       death associated with salmeterol use relative to no

 

       use.

 

                 This last and most recent study, shown

 

       here on the far right, included 532 pairs of asthma

 

       deaths and matched controls and is the largest

 

       case-controlled study evaluating asthma-related

                                                                110

 

       death ever conducted.  Notably, none of these

 

       studies showed a significant increase in the

 

       relative risk of these serious outcomes for

 

       salmeterol.

 

                 GSK is committed to a comprehensive

 

       research plan to further evaluate the safety and

 

       efficacy of salmeterol.  We believe that these

 

       currently ongoing studies will provide valuable

 

       information regarding the safety and efficacy of

 

       salmeterol in patients with either asthma or COPD.

 

       In order to address some of the issues raised by

 

       SMART, two studies are under way.

 

                 The first is a year long clinical study

 

       evaluating the incidence of asthma exacerbations in

 

       460 African American subjects.  Results are

 

       expected in 2007.  The second is an epidemiology

 

       study utilizing data from 7 Medicaid plans to

 

       examine racial variation and association of

 

       asthma-related prescription medication use with

 

       asthma morbidity and mortality.  The results are

 

       expected in 2006.

 

                 Studies have suggested that response to

                                                                111

 

       short-acting beta agonists may be affected by

 

       genetic polymorphisms in the beta                                       

                                              2 receptor.

 

       However, there is one study that has suggested

 

       there is no similar association with salmeterol and

 

       clinical outcomes including exacerbations.  This

 

       was the Taylor study that Dr. Sorkness showed

 

       earlier.  Since there were no genetic samples

 

       collected in SMART we are conducting two studies to

 

       address whether clinical outcomes in patients

 

       receiving salmeterol are affected by genotype.

 

                 The first study is a 38-week clinical

 

       trial evaluating response by beta                                       

                                              2 receptor

 

       genotype in 540 subjects with asthma.  The results

 

       are expected in 2007.  The second study will

 

       evaluate polymorphisms in beta                                          

                                      2 adrenergic

 

       glucocorticoid pathways with respect to clinical

 

       response in approximately 1,000 subjects from

 

       completed GSK clinical trials.

 

                 Finally, while asthma has been the focus

 

       of today's discussion, there are ongoing studies in

 

       patients with COPD that will help address whether

 

       the results of SMART are relevant for patients with

                                                                112

 

       COPD.  The first is a 3-year study of all-cause

 

       mortality in approximately 6,200 subjects with

 

       COPD.  Results from this study are expected in

 

       2006.  In addition, we are conducting 2 year-long

 

       replicate studies examining the rate of moderate to

 

       severe COPD exacerbations, with results expected in

 

       2007.

 

                 Asthma is a serious chronic disease with

 

       significant morbidity and mortality.  Salmeterol is

 

       one of the most thoroughly studied medications for

 

       asthma and has been shown to provide substantial

 

       therapeutic benefit, including improvements in lung

 

       function, and asthma-related quality of life, and

 

       reduction in symptoms, rescue medication and asthma

 

       exacerbations.

 

                 The extensive clinical trials have led

 

       evidence-based asthma treatment guidelines to

 

       recommend long-acting beta agonists with ICS as the

 

       preferred option for patients with moderate,

 

       persistent asthma.  There are conflicting data for

 

       salmeterol.  SMART and SNS suggest that salmeterol

 

       may be associated with an increased risk of rare

                                                                113

 

       serious asthma-related events including

 

       asthma-related death.  But when large cohorts of

 

       patients are evaluated in epidemiology studies this

 

       association is not observed.  The low number of

 

       serious asthma events in SNS and SMART does not

 

       allow for definitive conclusions, and the fact that

 

       the events of concern are also those that are

 

       experienced by patients with asthma, regardless of

 

       treatment, makes assessment of cause and effect

 

       relationships difficult.

 

                 Ultimately, what are the implications of

 

       the data for patients with asthma?  Well, specific

 

       treatment decisions for an individual patient can

 

       only be made by their physician.  It is our

 

       responsibility to provide the complete information

 

       so that the physician can make well-informed

 

       treatment decisions.  We have done this in the

 

       prescribing information for products containing

 

       salmeterol.

 

                 From the time that salmeterol was

 

       introduced in the United States in 1994 the

 

       prescribing information has provided specific and

                                                                114

 

       appropriate guidance on its use.  This includes

 

       that salmeterol should not be used to treat acute

 

       symptoms.  It is not a substitute for inhaled or

 

       oral corticosteroids, and consideration should be

 

       given to adding anti-inflammatory agents, for

 

       example corticosteroids.

 

                 In 1995 further information was added,

 

       including a warning that salmeterol should not be

 

       initiated in patients with significantly worsening

 

       or acutely deteriorating asthma.  As I have already

 

       mentioned, detailed information on the rare

 

       asthma-related events seen in SNS and SMART had

 

       been incorporated in the prescribing information so

 

       that informed treatment decisions can be made.

 

       This includes the boxed warning, as well as other

 

       language to address the inconclusive nature of the

 

       results and the potential for a class effect of

 

       inhaled long-acting beta agonists.

 

                 In conclusion and based on the weight of

 

       evidence, we firmly believe that salmeterol remains

 

       a valuable medication that has improved the level

 

       of care for patients with asthma and COPD. 

                                                                115

 

       Additionally, GSK is committed to further research

 

       that will not only help better characterize the

 

       efficacy and safety of salmeterol but will also

 

       help better understand asthma in general.  There is

 

       a large volume of data from clinical trials of

 

       salmeterol, as well as extensive clinical

 

       experience with this medication.  Taken together,

 

       these continue to support a favorable benefit to

 

       risk profile and, therefore, salmeterol should

 

       remain available to physicians and patients.

 

                 I thank you for your time and I will now

 

       turn the podium back over to Dr. Jones.

 

                             Closing Remarks

 

                 DR. JONES:  I would like to introduce

 

       three additional experts here with us today.  Prof.

 

       Richard Beasley is the director of the Medical

 

       Research Institute of New Zealand.  He is also an

 

       international expert on beta agonist safety and

 

       asthma epidemiology.  Dr. Eugene Bleecker is

 

       professor and section head, Pulmonary, Critical

 

       Care, Allergy and Immunologic Diseases at Wake

 

       forest University Health Sciences.  Dr. Bleecker is

                                                                116

 

       also the co-director of the Center for Human

 

       Genomics, and was a member of the MMRC for SMART.

 

       Finally, Dr. George O'Connor is professor of

 

       medicine in the Division of Pulmonary and Critical

 

       Care Medicine at Boston University School of

 

       Medicine, and is director of the Adult Asthma

 

       program at Boston Medical Center.  In addition, he

 

       was the chairman of the DSMB for SMART.

 

                 We would be happy to address any points of

 

       clarification and questions.  Thank you.

 

                        Questions by the Committee

 

                 DR. SWENSON:  Dr. Schatz?

 

                 DR. SCHATZ:  I think one possible

 

       hypothesis based on the SNS study, where there was

 

       increased withdrawal due to asthma in the placebo

 

       patients, is the possibility that there ended up

 

       being an imbalance in severity by the end of the

 

       study due to disproportionate withdrawal of more

 

       severe patients from the placebo group.  That is

 

       obviously not so easy to tease out but I would

 

       question whether, in fact, one looked at baseline

 

       severity in those who withdrew versus those who

                                                                117

 

       didn't in both groups but particularly in the

 

       placebo group.

 

                 DR. KNOBIL:  For SNS we don't have that

 

       cut of the data to provide for you, but it would

 

       probably make a lot of sense that the patients who

 

       withdrew were more severe.

 

                 DR. SCHATZ:  But for SMART data--

 

                 DR. KNOBIL:  Oh, for SMART we saw the same

 

       thing in that there was greater withdrawal in the

 

       placebo group than in the salmeterol group but,

 

       again, we don't have that cut of the data for you

 

       today.

 

                 DR. SWENSON:  Dr. Gardner?

 

                 DR. GARDNER:  I have two questions, one

 

       related to measures of adherence within or between

 

       the groups and whether anything has been done with

 

       that.  The second is would you give us the status

 

       of the ongoing studies at this time?  You have

 

       listed four with expected results.  Can you tell us

 

       the enrollment at this time; how far along you are?

 

       I understand the word "commitment" but can we see

 

       something about progress at this time and status?

                                                                118

 

                 DR. KNOBIL:  All of the studies that I

 

       mentioned to you are right now currently enrolling.

 

       As you might imagine, enrolling limited populations

 

       of only African Americans takes a little bit longer

 

       than general populations.  As well, in the genetic

 

       studies we are making sure that we have balanced

 

       groups with the different genotypes.  So, that does

 

       take some time.  So, what I can tell you is that

 

       they are enrolling but I can't tell you when they

 

       will be done enrolling.

 

                 DR. GARDNER:  And adherence?

 

                 DR. KNOBIL:  Oh, I am sorry.  During the

 

       monthly telephone contacts we did ask the

 

       question--if you could show the slide, please?  On

 

       a scale of 0-10, with zero meaning you missed all

 

       of your doses and 10 means you took all of your

 

       doses, what number represents how well you followed

 

       the study physician's instructions?  In the study

 

       the mean response, patient reported response was 8

 

       for each group.  Again, this is patient reported

 

       and patients did not return to the clinic so we

 

       cannot verify this.  We did not ask them to bring

                                                                119

 

       their cans in.  We did not weigh canisters and we

 

       didn't have a chronolog.  But I think from studies

 

       of chronolog, we know that patients sometimes

 

       report taking more medication than they actually

 

       do.  So, I can't really verify the actual

 

       compliance of the patients.

 

                 DR. GARDNER:  As far as you can tell, was

 

       there similar adherence between the African

 

       American subjects and the Caucasian subjects?

 

                 DR. KNOBIL:  Yes, as far as can tell there

 

       was no difference between any specific group.

 

                 DR. GARDNER:  Finally, on the Medicaid

 

       study, that doesn't require enrollment.  Can you

 

       tell me where that is being done and how far along

 

       that one is?

 

                 DR. KNOBIL:  Yes, that one is being done

 

       in seven states.  What we are doing right now is

 

       the first phase of the study, which is to see if we

 

       can identify enough patients with high enough

 

       proportion of African Americans to make an analysis

 

       feasible.  So, that is where that study is right

 

       now.

                                                                120

 

                 DR. SWENSON:  Dr. Moss?

 

                 DR. MOSS:  I have two separate questions.

 

       The first one has to do with the dissemination of

 

       the information in your letters and the labeling

 

       revisions.  I think the goal of this meeting is to

 

       disseminate information properly to the physicians

 

       and the community.  The question I have is when you

 

       sent out those letters and put on the box labels,

 

       do you know if that changed the prescription

 

       practices for the physicians that received those

 

       letters or for the general community in terms of

 

       the prescription of your medication?

 

                 DR. KNOBIL:  I don't know if that

 

       information changed the way physicians prescribe

 

       the medications.  We don't have any specific data

 

       to that effect.

 

                 DR. MOSS:  Did overall use of your

 

       compound decline after those letters were sent out?

 

                 DR. KNOBIL:  The rate of use did not

 

       change after those letters were sent out.  But, you

 

       know, we can't guess what would have happened; all

 

       we saw was no change.

                                                                121

 

                 DR. MOSS:  You saw no change.  I think

 

       that raises a concern about, you know, we are

 

       trying to disseminate information and are we doing

 

       that in the proper way?

 

                 The next question I have may be answered

 

       by you but might also be answered by either Dr.

 

       Bleecker or O'Connor.  I think it is really hard to

 

       figure out why someone died.  Taking care of people

 

       I see this.  It is really hard to define

 

       specifically what a cause of death is.  I was just

 

       wondering if you can give us some insight into how

 

       you define respiratory versus asthma deaths in the

 

       SMART study.

 

                 DR. KNOBIL:  Dr. Bleecker, would you like

 

       to address that?

 

                 DR. WEAN:  While Dr. Bleecker is coming

 

       up, I want to get back to the earlier question you

 

       raised.  I am David WEAN, Senior Vice President of

 

       Regulatory Affairs at GlaxoSmithKline.  I don't

 

       think it appropriate to say that because we can't

 

       posit a change in prescribing habits because of the

 

       letters and the label that they were not effective.

                                                                122

 

       The important thing is that the information was

 

       disseminated in a very large way to prescribers

 

       and, thereby, to patients.  To expect that you

 

       would see a drop-off in use of these drugs that

 

       have therapeutic benefit because of that

 

       communication I think would be an inappropriate

 

       assessment about the effectiveness of that

 

       communication.

 

                 DR. MOSS:  But I think one thing we have

 

       learned is that publishing articles and papers does

 

       not get information out to the people that need the

 

       information to be received.  In the same way, I am

 

       not sure that sending letters out to physicians who

 

       get a lot of mail is an effective way of

 

       communicating information.

 

                 DR. SWENSON:  Dr. Bleecker?

 

                 DR. BLEECKER:  I was asked to talk a

 

       little bit, and George O'Connor could complement on

 

       how the mortality review committee in SMART

 

       adjudicated cases.  I agree, it is often very

 

       difficult, and as we did this we probably all

 

       learned.  I joined the mortality review committee

                                                                123

 

       after about a third of the cases had been done.

 

       The members of the committee before that had been

 

       Roland Ingrham who was professor of medicine at

 

       Emory.  He had retired.  The chairman of the

 

       committee was Hal Nelson who is a professor of

 

       medicine at Colorado, and the third member was

 

       Scott Weiss who is professor at Brigham and

 

       Williams and also head of their pulmonary and

 

       respiratory epidemiology program.

 

                 We had data on most patients available

 

       both from death certificates and from the medical

 

       monitors who worked with Covance.  We used that to

 

       answer questions which were related to the cause of

 

       death; was this respiratory related; and you heard

 

       before the likelihood or unlikelihood of that

 

       during Kate Knobil's presentation; and then was it

 

       asthma related.  All three of us adjudicated this

 

       independently.  If we agreed on all of these

 

       characteristics the case was not discussed further.

 

       All of the cases in which there was any

 

       disagreement, ranging even between "unrelated" and

 

       "unlikely" were discussed in detail in timely

                                                                124

 

       conference calls.  I think at times we did the best

 

       we could on relating to that.

 

                 The least amount of information was

 

       available on deaths toward the end of the study

 

       that were picked up from the national death

 

       registry.  On those deaths we had to rely on death

 

       certificates or more limited information.

 

                 DR. MOSS:  Can I just follow-up on that?

 

       Can you explain a little bit how you differentiate

 

       asthma from respiratory deaths?  A respiratory

 

       death that is not asthma, is that pneumonia?  What

 

       were criteria to differentiate those specific

 

       things?

 

                 DR. BLEECKER:  Well, often asthma entered

 

       into those deaths.  Let me give you an example of

 

       respiratory death.  Because someone during an auto

 

       accident had trauma to the chest--and this did

 

       occur in some of the younger individuals--and died,

 

       and that clearly was related to an automobile

 

       accident and because of the nature of the event and

 

       other things was not related to asthma.  It was

 

       more difficult if someone entered the hospital with

                                                                125

 

       pneumonia, was intubated and in an intensive care

 

       unit.  I think under those circumstances, some of

 

       those deaths were adjudicated depending on the

 

       course on the ventilator or those serious events as

 

       possibly related to asthma.  So, at times it is

 

       very hard to distinguish that from the records.

 

       Again, I think the fact that they were performed

 

       independently and you needed to look for

 

       concurrence and discussion, I think a reasonable

 

       approach was performed.

 

                 DR. SWENSON:  Dr. Gay?

 

                 DR. GAY:  Based on the appropriate

 

       emphasis that you have begun to make on genetic

 

       testing, as we have seen based on the information

 

       that Dr. Sorkness elegantly presented before, do

 

       you have any preliminary estimates of what you feel

 

       would be the prevalence of Arg/Arg gene

 

       presentation in patients with greater severity of

 

       asthma or based on ethnic differences?

 

                 DR. KNOBIL:  Yes, I would not be able to

 

       predict the different prevalences of those genetic

 

       subtypes and I would ask Dr. Bleecker to comment on

                                                                126

 

       that.  The one thing I would add is that in the one

 

       genetic study we are making sure that there are

 

       equal numbers of each genetic subtype so that we

 

       don't have a predominance of one and very few of

 

       another.  Dr. Bleecker?

 

                 DR. BLEECKER:  I would like to add a few

 

       comments to that because I think there are some

 

       important aspects of this.  First of all, we have

 

       centered on basically one variation within the

 

       beta2  adrenergic gene.  Looking at that gene more

 

       carefully--and there have been published studies on

 

       this, especially from the Liggett group as well as

 

       some work from our laboratory which has been

 

       presented at last year's ATS and Academy of Allergy

 

       meetings--there is a good deal more variation in

 

       that gene, and there are relationships between the

 

       arginine genotype and some of that other variation.

 

       Some of that may be very important in trying to

 

       sort out the hypothesis of whether variation in

 

       this gene affects therapeutic response and

 

       potentially affects outcome.

 

                 The second important issue is there is

                                                                127

 

       more variation, and African Americans have a higher

 

       prevalence of the Arg/Arg genotype, about 22

 

       percent, and that is what was seen during the

 

       screening for the ACRN BARGE trial versus about

 

       12-14 percent in Caucasians.  The implications of

 

       that on outcome are difficult, and I think it is

 

       very important that the studies that were outlined

 

       by Dr. Knobil on studying specifically an African

 

       American cohort in which they are going to look at

 

       outcome such as exacerbations and genotype are

 

       critical because those kinds of studies are not

 

       being done because of the limitations in

 

       recruitment by the NIH NHLBI asthma clinical

 

       network.

 

                 DR. SWENSON:  Dr Prussin?

 

                 DR. PRUSSIN:  I have a similar question

 

       that I raised before with Dr. Sorkness.  You have

 

       some very nice studies that are undergoing, but do

 

       you think they are going to address the question at

 

       hand in terms of asthma deaths or severe pulmonary

 

       endpoints?  They are fairly small studies relative

 

       to the SMART study and, when all is said and done

                                                                128

 

       in three or four years, it is not clear to me at

 

       least that you are going to have any kind of handle

 

       on asthma death.  Could you comment on that?

 

                 DR. KNOBIL:  Yes, as I mentioned, it is

 

       very difficult to prospectively study

 

       asthma-related death because the rate is relatively

 

       low and you need a very large N to get conclusive

 

       results.  The one study that will help us get there

 

       though, I believe, is the Medicaid study in that we

 

       can get information from the 7 Medicaid plans and

 

       look at the different racial subgroups, look and

 

       see what medications they were on and see what

 

       contributed to those patient's deaths, whether it

 

       is a long-acting bronchodilator, short-acting

 

       bronchodilator or some other related medication.

 

       So, I do believe that in that observational design

 

       we will be able to get some more information about

 

       asthma-related death.  The other studies are mainly

 

       going to address asthma exacerbations and other

 

       responses such as lung function, rescue albuterol

 

       use, and we will be able to look at those in

 

       relationship to genetic makeup as well.

                                                                129

 

                 DR. PRUSSIN:  The difficulty I have with

 

       that though is that there is a lot of data showing

 

       that salmeterol improved asthma exacerbations.  You

 

       have shown that.  Clearly, the more severe

 

       endpoints of death are tracking differently.  So,

 

       you are thinking of it as the tip of the iceberg,

 

       that however exacerbations are going to track

 

       asthma deaths are going to track and clearly they

 

       are behaving differently.  So, just because you

 

       have certain data on asthma exacerbations in

 

       certain subgroups, that may not be proportional or

 

       relate to asthma.  We don't have any prospective

 

       studies ongoing or planned to really address the

 

       endpoint that I think this committee has been asked

 

       to address, which is asthma death.  So, it could

 

       very well be a different phenomenon than what is

 

       causing asthma exacerbations.

 

                 DR. KNOBIL:  That is true, and there are

 

       other factors beyond asthma treatment that may be

 

       contributing to asthma-related death as well,

 

       including access to care or how a patient's asthma

 

       is managed.  We don't know the answers to that

                                                                130

 

       either.  So, that is why in order to actually even

 

       look at asthma-related death an observational

 

       design is probably going to provide more

 

       information more quickly.

 

                 I take your point that it seems that a

 

       prospective study would be the gold standard.  The

 

       issue there is that if the rate of asthma-related

 

       death was similar to what we saw in SMART, in order

 

       to see an effect you might have to have a study as

 

       large as 800,000 patients.  As you can see, that

 

       would be very difficult to do.  So, yes, it would

 

       be nice to be able to do it prospectively but it is

 

       going to be more difficult than doing it in an

 

       observational design.

 

                 DR. JONES:  Actually, I think Dr. Beasley

 

       wanted to make a comment.

 

                 DR. BEASLEY:  Yes, in response to that I

 

       would like to caution in terms of considering a

 

       prospective clinical trial as being the gold

 

       standard when you are looking at a rare outcome

 

       such as mortality.  I think we saw that in the

 

       SMART study, where it was required to study

                                                                131

 

       approaching 30,000 subjects to obtain around 35

 

       respiratory-related deaths, and there was a real

 

       compromise in terms of design of the study to

 

       actually achieve that and individuals were given 7

 

       canisters at the beginning of the study without any

 

       formal clinical follow-up, which is something which

 

       would not be done on label in terms of salmeterol

 

       therapy. In terms of the other issues of the label,

 

       many of the subjects had asthma severity where

 

       salmeterol would be inappropriate as sole therapy.

 

                 So, I think that when you try a

 

       prospective controlled trial to look at a rare

 

       outcome such as death you often have to incorporate

 

       a methodology that clearly is outside the spectrum

 

       of what is recommended clinical practice.  That

 

       clearly happened with the SMART study so that we

 

       have to consider the SMART study results not

 

       applicable to what would be considered good

 

       clinical practice, and the alternative is actually

 

       to increase the number of deaths through

 

       case-control methodology and that was the method we

 

       used in New Zealand to identify the risks

                                                                132

 

       associated with fenoterol.

 

                 In that regard, I think that the Anderson

 

       study in the BMJ is considerably more powerful in

 

       terms of looking at the role of bronchodilator

 

       therapy and the rare outcome of asthma mortality.

 

       They were able to look at over 500 deaths, match

 

       them with subjects who came from the same

 

       proportion of the population of patients in terms

 

       of severity, who were subjects with a previous

 

       hospital admission, and then they were able to

 

       stratify their analysis by looking at an even more

 

       severe subgroup.  When they did that there was

 

       actually no increased risk associated with the use

 

       of salmeterol therapy.

 

                 So, I think that in terms of the

 

       epidemiological approach to a rare outcome of

 

       asthma mortality looking at the role of medication

 

       use, the epidemiological view is very clearly that

 

       the case-control methodology is more powerful and

 

       more accurate than a prospective clinical trial.  I

 

       think in some respects almost the learning point

 

       from the experience with the SMART study was the

                                                                133

 

       compromise that had to be obtained in terms of

 

       clinical practice to achieve a study which, even

 

       with 30,000 people, did not have sufficient power.

 

                 DR. SWENSON:  Dr. Schoenfeld?

 

                 DR. SCHOENFELD:  Do you have a tabulation

 

       for the whole group and for each of these subgroups

 

       and for each of the endpoints  of the absolute risk

 

       or the attributable risk?  Because from a

 

       risk/benefit point of view the relative risk isn't

 

       very informative because, of course, you can have a

 

       3-fold relative risk of a very, very rare event and

 

       that may be important if you are judging something

 

       like an environmental pollutant that you can remove

 

       but is not really important when you are judging a

 

       very effective drug which improves people's quality

 

       of life.  So, I wonder if you have that tabulated.

 

       I have done some back-of-the-envelope calculations

 

       but it would be helpful to have the actual numbers

 

       where we looked at the percent of deaths per

 

       patient-year or number of deaths per 1,000

 

       patient-years, or something of that sort that would

 

       be attributable, assuming that there is some

                                                                134

 

       attributable risk to the use of the drug, or even

 

       just the total risk among asthma patients per 1,000

 

       patient-years or 10,000 patient-years, or whatever.

 

                 DR. KNOBIL:  Unfortunately, we don't have

 

       those data.  We have not done those calculations.

 

                 DR. SWENSON:  Dr. Martinez?

 

                 DR. MARTINEZ:  Would you please clarify

 

       what the entry criteria were for both studies, the

 

       British one and the one done in the United States?

 

       How was asthma defined?  Were any of the usual

 

       parameters--response to beta                                            

                                2 agonists or

 

       methacholine used to define asthma in these two

 

       studies?

 

                 DR. KNOBIL:  These studies were a little

 

       different than normal clinical trials, say, to

 

       register a medication for asthma.  It was the

 

       opinion of the investigator if the patient have

 

       asthma.  They did not have to show reversibility.

 

       There was no smoking criterion.  In this case they

 

       had to be 12 years of age or older.  In SNS they

 

       had to have moderate to severe asthma and in SMART

 

       they were not allowed to have concomitant

                                                                135

 

       administration of beta blockers.  That is about

 

       all.

 

                 DR. MARTINEZ:  Was response to

 

       bronchodilators measured?

 

                 DR. KNOBIL:  It was not measured.

 

                 DR. SWENSON:  Miss Sander?

 

                 MS. SANDER:  Yes, when we are looking at

 

       possible causes of death, are you able to know if

 

       patients who died were using salmeterol as if it

 

       was an acute bronchodilator?

 

                 DR. KNOBIL:  In SMART the only question we

 

       asked was if the patient was using the medication

 

       as the physician told them to.  That is the data

 

       that I showed you earlier.  We do not have any data

 

       on whether they were using it as a rescue

 

       medication.

 

                 DR. SWENSON:  I realize that there are

 

       more questions to be posed to GSK but we need to

 

       take a break at this point.  We have a general

 

       question session in the afternoon and the rest of

 

       these questions should be addressed at that time.

 

       We will be back again in 15 minutes.

                                                                136

 

                 [Brief recess]

 

                 DR. SWENSON:  We will resume the meeting

 

       with Dr. Eric Floyd, from Novartis, to discuss

 

       formoterol and its place in this controversy.

 

                          Novartis Presentation

 

                               Introduction

 

                 DR. FLOYD:  Good morning.  Dr. Swenson,

 

       members of the FDA advisory committee, Dr.

 

       Chowdhury, members of the Food and Drug

 

       Administration and guests, my name is Eric Floyd.

 

       I am Vice President and Global Head of Drug

 

       Regulatory Affairs for the therapeutic areas of

 

       dermatology, respiratory and infectious diseases.

 

       On behalf of Novartis Pharmaceuticals Corporation,

 

       I thank you for the opportunity to review the

 

       current safety experience today for a long-acting

 

       beta agonist, Foradil.

 

                 There have been numerous safety concerns

 

       expressed publicly regarding use of long-acting

 

       beta agonists.  The purpose of our presentation

 

       today is to discuss implications of recently

 

       available data related to the safety profile of

                                                                137

 

       long-acting beta agonists.  This morning Novartis

 

       would like to present to you the results and

 

       conclusions of our review of available safety data

 

       for Foradil.  Based upon our review of clinical

 

       trial data and postmarketing experience, we would

 

       like to demonstrate that formoterol exhibits a

 

       favorable risk/benefit profile.

 

                 To provide a brief regulatory overview,

 

       Foradil was first approved for marketing in France

 

       in 1990, and subsequently approved in other

 

       European countries.  Foradil received FDA approval

 

       to market in the United States in 2001.  Foradil is

 

       currently approved in over 80 countries worldwide

 

       and to date, we currently have over 13 million

 

       person-years of exposure.

 

                 Foradil Aerolizer was marketed as a dry

 

       powder capsule for oral inhalation and was approved

 

       in 2001 for a dosage regime of 12 mcg twice daily

 

       for maintenance therapy for individuals with asthma

 

       5 years of age and above for the following

 

       indications, acute prevention of exercise-induced

 

       bronchospasm in individuals 5 years of age and

                                                                138

 

       older when administered on an occasional as needed

 

       basis, and for chronic obstructive pulmonary

 

       disease, including chronic bronchitis and

 

       emphysema.

 

                 Outside of the United States, Foradil is

 

       approved at 12-24 mcg twice daily and is a highly

 

       prescribed bronchodilator, and is also indicated

 

       for the maintenance therapy of asthma specifically

 

       in adults and children 5 years of age and older;

 

       for the prophylaxis and treatment of

 

       bronchoconstriction in patients with asthma;

 

       prophylaxis of bronchospasm induced by inhaled

 

       allergens, cold air or exercise; prophylaxis and

 

       treatment of bronchoconstriction in patients with

 

       reversible or irreversible COPD, including chronic

 

       bronchitis and emphysema.  In some countries it is

 

       also approved as metered dose inhaler and

 

       multi-dose dry powder inhaler, 10 mcg, Certihaler.

 

                 In order to provide a more detailed review

 

       of our current data to date, I would like to

 

       introduce our speakers today.  Dr. Gregory Geba,

 

       who is the Vice President and U.S. Head,

                                                                139

 

       Respiratory, Dermatology and Infectious Diseases,

 

       Clinical Development and Medical Affairs for

 

       Novartis Pharmaceuticals, will present the safety

 

       profile of Foradil.

 

                 He will be followed by Dr. James Donohue,

 

       who is Professor of Medicine, Chief of Pulmonary

 

       Division, University of North Carolina, Chapel

 

       Hill, who will present the clinical implications.

 

                 In addition to the key speakers, we also

 

       have additional advisors available to address any

 

       specific questions you may have.  Specifically from

 

       a statistical perspective we have Dr. Gary Koch,

 

       Professor of Biostatistics, School of Public

 

       Health, University of North Carolina, Chapel Hill.

 

       I would now like to turn the podium over to Dr.

 

       Geba.

 

                      Efficacy and Safety of Foradil

 

                 DR. GEBA:  Thank you, Dr. Floyd.  Dr.

 

       Swenson, committee members, members of the FDA and

 

       interested attendees from the community, it is my

 

       role to review with you all of the clinical data

 

       and postmarketing data we have available for

                                                                140

 

       Foradil, the other long-acting beta agonist being

 

       discussed today.  We firmly believe that Foradil is

 

       a drug that provides clinical benefit with a

 

       favorable benefit/risk profile.

 

                 As indicated in the previous presentation

 

       by Dr. Floyd, and later on in this presentation by

 

       Dr. Donohue, the clinical features of Foradil have

 

       led to its inclusion in both U.S. and international

 

       guidelines in the treatment of moderate to severe

 

       persistent asthma.

 

                 These are the key points of the

 

       presentation.  We will describe pharmacologic

 

       differences that exist between formoterol and

 

       salmeterol, which may or may not have clinical

 

       impact; a Phase 4 trial, 2307, which examined

 

       asthma-related serious adverse events in

 

       adolescents and adults; our integrated Foradil

 

       clinical database; and postmarketing adverse event

 

       data.  The totality of the evidence does not

 

       elevate concern for a safety signal for Foradil

 

       which continues to support its favorable

 

       benefit/risk profile.

                                                                141

 

                 These are the chemical structures of

 

       formoterol on top and salmeterol on the bottom.

 

       Please note that at the end of the molecule that

 

       interacts with the beta receptor, the catechol end

 

       of the molecule, the molecules are actually similar

 

       in having a hydroxyl group at position 5.  However,

 

       they are different at positions 6 where you see

 

       different side chains.  Most importantly, at

 

       position formoterol has a much longer allophanic

 

       chain, as previously shown.  Thus, although both

 

       molecules bind to the beta                                              

                           2  receptor, differences

 

       in structure allow salmeterol to bind to an

 

       additional site within the beta                                          

                                        2  receptor termed

 

       an exosite.  Prolonged salmeterol activity depends

 

       on binding with the exosite when formoterol's

 

       activity is independent of an exosite.  In

 

       addition, mutation of the exosite region could

 

       affect the duration of action of salmeterol.  One

 

       of the consequences of structural differences is

 

       that formoterol is a full agonist at the beta                           

                                                                              2

 

       adrenergic receptor, whereas salmeterol is a

 

       partial agonist.

                                                                142

 

                 Typical experiments illustrating this

 

       point are performed with human bronchial explants

 

       which show that the bronchodilatory effects of

 

       isoprenaline are decreased by prior incubation of

 

       tissues with salmeterol but not formoterol.  The

 

       potential clinical implication of this difference

 

       is that in the setting of beta                                          

                                      2  receptor

 

       down-regulation the effect of rescue

 

       bronchodilators may be greater for full agonists

 

       than for partial agonists.

 

                 I would like to now move on to a

 

       discussion of the Phase 4 trial 2307.  This trial

 

       was recently completed and is detailed in your

 

       briefing book.  Why was this study done?  Protocols

 

       040, 041 and 049 were 3 pivotal studies conducted

 

       to support registration of Foradil in the United

 

       Sates and 040 and 041 were 12 weeks in duration and

 

       were conducted in adolescents and adults; 049 was

 

       conducted for one year in children ages 5-12.

 

                 Trial participants were randomized to

 

       receive Foradil 12 mcg BID, 24 mcg BID or placebo.

 

       In 040 and 041 there was also a comparison to

                                                                143

 

       regular doses of albuterol 180 mcg QID.  Please

 

       note that all groups were allowed to take

 

       additional doses of albuterol as needed for

 

       residual symptoms and all groups were allowed

 

       anti-inflammatory agents.

 

                 Shown here are the proportion of patients

 

       with asthma-related serious adverse events.  These

 

       studies showed more serious asthma-related serious

 

       adverse events in the higher don formoterol arms

 

       compared to the lower doses or the approved

 

       formoterol arm as well as the placebo arm.

 

                 In light of these findings, the agency did

 

       not approve the higher dose of Foradil.  After

 

       discussing this observation with the agency and

 

       with their guideline, we pursued a safety study

 

       whose primary endpoint was asthma-related SAEs.

 

       The inclusion and exclusion criteria for protocol

 

       2307 were identical to protocols 040 and 041 which

 

       were our pivotal trials.  Indeed, the resulting

 

       population studied in protocol 2307 was similar to

 

       that of the pivotal trials in adolescents and

 

       adults, which was the population studied and

                                                                144

 

       requested, as shown in this slide.

 

                 Apart from the trial duration which is

 

       different, age differences were pretty similar.

 

       FEV                                    1 at baseline was fairly similar.

Please note

 

       that the proportion of black patients in this trial

 

       mimicked the proportion of patients in the U.S.

 

       population.  There are some subtle differences in

 

       terms of ICS use and reversibility.  Actual

 

       reversibility for 2307 was slightly less than 040

 

       and 041 but otherwise the study populations were

 

       very, very similar.

 

                 The design of this safety study is shown

 

       here.  Using identical entry criteria--again, these

 

       are identical entry criteria to those employed in

 

       our pivotal studies--after a 2-week run period,

 

       shown here, patients were randomized to receive, in

 

       a double-blind fashion, one of the following

 

       treatments, either formoterol 12 mcg BID formoterol

 

       24 mcg BID--again, 12 mcg BID was the approved

 

       dose; 24 mcg was the higher dose.  They received

 

       either of those two doses or placebo in another

 

       group or, in an open-label group, received

                                                                145

 

       formoterol 12 mcg BID plus an additional up to 2

 

       rescue doses of formoterol 12 mcg BID, which

 

       constituted the intermediate dose arm.

 

                 Please note that to increase the rigor of

 

       this study, after 16 weeks of treatment we planned

 

       to contact all patients, including those who

 

       discontinued, to record all adverse events.  This

 

       assured that all patients would be evaluated for

 

       AEs irrespective of treatment efficacy and trial

 

       persistence.

 

                 Results of the study are shown here.

 

       Please note that there was a correction made to the

 

       briefing book provided by the agency.  The lower

 

       dose arm had a somewhat higher number of patients

 

       who reported serious asthma-related AEs.  However,

 

       after review of the specifics of these cases, the

 

       agency excluded 2 of these events in the Foradil 12

 

       mcg arm, reducing that number from 5 to 3.  Thus,

 

       the final event rates were 0.2 percent in the

 

       placebo group; 0.6 percent in the low dose group;

 

       0.2 percent in the intermediate dose group; and 0.4

 

       percent in the high dose group.  Overall, there

                                                                146

 

       were far fewer events than expected based on the

 

       pivotal trials.

 

                 Displayed on this slide are the point

 

       estimates and 95 percent confidence

 

       intervals--which I hope you can see as red on a

 

       blue background--for the proportion of patients

 

       experiencing asthma-related SAEs in each treatment

 

       group.  As previously mentioned, the rates are low

 

       for all treatment groups.  The 95 percent

 

       confidence interval for all Foradil doses combined

 

       overlaps the 95 percent confidence interval for

 

       placebo and excludes 1 percent.  These data reflect

 

       the revised rates after an FDA adjudication.

 

                 In conclusion, the observed rate of

 

       adverse events was far lower than we expected from

 

       our pivotal trials despite demographics that were

 

       similar to protocols 040 and 041.  Absolute

 

       differences between groups were very small.  Higher

 

       SAE rates in the higher dose of Foradil arm,

 

       previously observed in adolescents and adults in

 

       protocols 040 and 041, were not observed in this

 

       larger, specifically designed safety study.

                                                                147

 

                 Now I would like to review with you a

 

       comprehensive safety analysis of our clinical trial

 

       database.  We performed an extensive review of

 

       safety based on our clinical trial database which

 

       focused on deaths and asthma-related adverse

 

       events.  In terms of deaths, we examined all

 

       controlled and uncontrolled trials in the Aerolizer

 

       and Certihaler databases.  All studies irrespective

 

       of trial duration were examined to assure that the

 

       very rare case of sudden paradoxical asthma,

 

       culminating in the demise of a patient, was

 

       captured.

 

                 For the analysis of asthma-related adverse

 

       events we focused on controlled trials of greater

 

       than or equal to 4 weeks duration so as not to

 

       dilute the denominator for adverse events in trials

 

       of longer duration with very short trials,

 

       sometimes as short as 24 hours, which were

 

       performed to assess short-term changes in lung

 

       function.

 

                 For controlled trials the database

 

       included nearly 6,000 patients on Foradil, shown

                                                                148

 

       here; for uncontrolled trials over 2,700.  For

 

       trials of 4 weeks or greater in duration the number

 

       was over 5,000 on Foradil, whereas the

 

       placebo-controlled trial database was comprised of

 

       over 3,700 patients who had been randomized to

 

       Foradil.

 

                 Looking at our controlled trials, there

 

       were 3 deaths overall, one death in the Foradil

 

       group, representing over 1,600 patient-years of

 

       experience; one death in the albuterol group,

 

       representing 241 patient-years of experience; and

 

       one death in the placebo group, representing nearly

 

       600 patient-years of experience.  The rates of

 

       death, therefore, was 0.41, 0.17 and 0.06 in the

 

       albuterol, placebo and Foradil arms respectively.

 

       The Foradil death was asthma related, shown here,

 

       representing a rate of 0.06 asthma deaths per 100

 

       patient-years of exposure.  So, here we are

 

       expressing it as a rate per years of exposure to

 

       the drug, which represents less than one asthma

 

       death per 1,000 years of treatment.

 

                 In reviewing the uncontrolled clinical

                                                                149

 

       database, it is important to note that these

 

       studies were those that did not incorporate

 

       comparator arms.  They were all open-label and

 

       included trials conducted as part of compassionate

 

       use programs.  In addition, patients tended to be

 

       older, with a high proportion of elderly subjects;

 

       had more severe asthma; used more beta agonists at

 

       baseline; and exhibited noon-asthma-related

 

       mortality at a higher rate, indicating a higher

 

       degree of general medical morbidity compared to the

 

       control database.  There were 5 deaths overall, 3

 

       of which came from one study in France which

 

       allowed entry of severely ill patients.

 

                 Now I would like to move on to address

 

       significant asthma exacerbations.  This term

 

       includes asthma-related adverse events which were

 

       meaningful enough to prompt patient discontinuation

 

       whether severe or not and, to get to Dr. Schatz'

 

       point, included asthma-related adverse events

 

       reported as serious whether or not they caused a

 

       discontinuation.  So, we are looking at patients

 

       that dropped out of the trial due to an

                                                                150

 

       asthma-related event that was meaningful enough to

 

       stop therapy.

 

                 Displayed are the discontinuation rates

 

       due to an asthma-related adverse event in multiple

 

       dose, placebo-controlled trials of greater than or

 

       equal to 4 weeks in discontinuation.  These are the

 

       discontinuation rates.  Please note that there were

 

       fewer asthma-related discontinuations in the

 

       Foradil arms compared to the placebo arm or to

 

       albuterol.  So, the rate overall for an formoterol

 

       doses was 7.1; for placebo it was 10.7; for

 

       albuterol 8.1.  Please note that this was

 

       especially notable for the approved dose of

 

       Foradil, 5.6 versus 10.7.

 

                 A reverse pattern was observed for

 

       asthma-related serious adverse events.  Foradil

 

       patients experienced more events than placebo.

 

       Here the imbalance was greater for the higher

 

       Foradil dose.  The numbers are shown here, 3.5 for

 

       the approved dose versus 3.1 for albuterol, 0.9 for

 

       placebo and a higher rate for the albuterol 48 mcg

 

       dose.  Again, this dose is the approved dose in the

                                                                151

 

       U.S.

 

                 When both types of events are taken into

 

       consideration, the rate of significant asthma

 

       exacerbations, that is, asthma-related AEs

 

       meaningful enough to cause the patient to

 

       discontinue and asthma-related events that were

 

       labeled as serious whether or not they caused

 

       discontinuation, was actually lower for Foradil at

 

       its approved dose than the rate for placebo or for

 

       albuterol.  Note that at the highest dose of

 

       Foradil that rate was similar to the placebo rate.

 

       But for Foradil at its approved dose the rate was

 

       7.1 versus a placebo rate of 10.9.

 

                 In summary, based on this analysis of our

 

       clinical trial database for asthma-related adverse

 

       events, we observed a rate of significant asthma

 

       exacerbations for the approved Foradil dose that

 

       was lower than placebo rates.

 

                 I would like to now move on to a review of

 

       postmarketing data.  In order to explore the

 

       adverse event profile of Foradil on the market and

 

       to provide some estimates as to how it might

                                                                152

 

       compare to other drugs in its class, we performed

 

       an analysis of postmarketing data based on FDA AERS

 

       database, that is the FDA's adverse events

 

       reporting system.

 

                 We must recognize that this type of

 

       postmarketing analysis has its limitations.

 

       Although spontaneous reporting of ADRs remains the

 

       most common method used for monitoring the safety

 

       of marketed drugs and is useful for detecting

 

       safety signals, it is limited by the fact that a

 

       substantial percentage of ADRs are not reported.

 

       The reporting rate also tends to be lower the

 

       longer a drug is on the market.  This is a

 

       well-known phenomenon and is known as the Weber

 

       effect.  In addition, targeting drugs to lower or

 

       higher risk patients may alter apparent ADR

 

       occurrence, and notoriety associated with a drug or

 

       class may alter reporting rates.  A final concern

 

       is that the ADR that is being reported in this

 

       instance is the disease itself,  It is a

 

       manifestation of the disease itself.

 

                 We examined FDA adverse reports for death

                                                                153

 

       or outcome of death and found that rates were

 

       highest in the first years after launch and

 

       declined each year thereafter.  This analysis is

 

       shown in your briefing book.

 

                 We will now review the reporting rates for

 

       these and other events of interest.  Please note

 

       that reporting rates are reports with case

 

       definition on the drug of interest divided by the

 

       exposure worldwide since the drug was marketed in

 

       the U.S. per 100,000 patient-years.

 

                 Relative rates of reporting can also be

 

       assessed by simply calculating the percentage of

 

       reports at case definition by the total number of

 

       adverse events reported.  This does not take into

 

       consideration the exposure to the drug of interest

 

       and may inflate the Weber effect if there is a

 

       difference of time on the market.  Shown here are

 

       the reporting proportions, on the left, and the

 

       reporting rates per 100,000 patient-years, on the

 

       right, for Foradil and salmeterol.

 

                 As you can see, the reporting proportion

 

       for formoterol, a drug that was established on the

                                                                154

 

       U.S. market in 2001, compared to salmeterol, which

 

       was on the market since 1994, is somewhat higher.

 

       However, one must adjust for the exposure to the

 

       drug which was far greater for salmeterol.  When

 

       adjusting for this higher number of exposures for

 

       salmeterol the result ratio flips.  That is, when

 

       we adjust for actual exposure to the drug we note

 

       that the rate for Foradil was somewhat lower than

 

       that of salmeterol.

 

                 In conclusion, well-described

 

       pharmacologic differences exist between formoterol

 

       and salmeterol although the clinical relevance is

 

       not known.  In pivotal trials conducted for U.S.

 

       registration, a potential safety signal emerged in

 

       the Foradil high dose group, leading only to the

 

       approval of the 12 mcg dose, that is 12 mcg BID,

 

       and the request for postmarketing asthma safety

 

       study 2307.  Study 2307 examined asthma-related

 

       serious adverse events in adolescents and adults

 

       and did not provide evidence of a safety signal for

 

       Foradil at any dose.

 

                 An analysis of the pooled Foradil clinical

                                                                155

 

       trial database and a review of postmarketing

 

       adverse event data, with its limitations, do not

 

       provide evidence of a safety signal for Foradil.

 

       The totality of the evidence, therefore, does not

 

       elevate concern for a safety signal and continues

 

       to support the favorable benefit/risk profile of

 

       Foradil in the treatment of asthma.

 

                 Thank you for your attention.  Dr. James

 

       Donohue will now present the clinical implications.

 

                          Clinical Implications

 

                 DR. DONOHUE:  Thank you, Dr. Geba.  Dr.

 

       Swenson, members of the advisory committee, Dr.

 

       Chowdhury and Dr. Meyer and members of the FDA,

 

       ladies and gentlemen, I am here today as a

 

       clinician investigator to talk about the clinical

 

       implications of the long-acting beta agonist class.

 

       As an older physician, I can talk a little bit

 

       about life before the introduction of the

 

       long-acting beta agonist class into our clinical

 

       practices.  While the alternatives were

 

       short-acting beta agonists, theophylline, various

 

       epinephrine agents, oral beta agonists, each of

                                                                156

 

       these treatments had different benefit/risk ratios

 

       or profiles from the long-acting beta agonist

 

       class.  I would like to discuss a little bit the

 

       implication of the roller-coaster effect on our

 

       patients with asthma's lives, the lack of nocturnal

 

       coverage with most of these shorter-acting agents

 

       and issues with compliance.  There have always been

 

       issues with the short-acting beta agonists for the

 

       need to frequently dose; special issues with our

 

       children and whether or not they could be dosed in

 

       the schools; the difficulty in our blue-collar

 

       workers, of course, who need frequent dosing of

 

       their medications.

 

                 The short-acting beta agonists have, as I

 

       say, benefits and risks.  Overdosing of the

 

       short-acting beta agonists was associated with

 

       tremor, particularly with the peak.  There were

 

       changes in metabolism, hypokalemia and changes in

 

       glucose metabolism which may or may not be

 

       clinically significant but could be under certain

 

       circumstances.  There was also tachycardia

 

       associated with people using some higher doses or

                                                                157

 

       people who had more co-morbidity issues.  Then

 

       also, to inform us, we had very useful data from

 

       Saskatchewan looking at thee use of short-acting

 

       beta agonists in Canada.  These are combined data

 

       for formoterol and albuterol.

 

                 These are the deaths per 100,000 per year

 

       and the number of canisters.  We can see that as we

 

       start getting up in the number of canisters,

 

       especially win formoterol, one sees an increase in

 

       deaths due tot he short-acting beta agonists or

 

       associated--not necessarily due to but associated

 

       with the short-acting beta agonist class.  So this

 

       was, of course, a concern to all of us and is part

 

       of the recommendations presently in the guidelines.

 

                 We also had different side effect profiles

 

       of other medications available to us before the

 

       long-acting beta agonists and drugs we would have

 

       to consider today as substitutes.  First and

 

       foremost, theophylline, particularly the

 

       longer-acting forms.  Their safety profile is

 

       important to look at.  There was a narrow

 

       therapeutic window, as everyone knows, with these

                                                                158

 

       drugs.  There were very, very important drug

 

       interactions.  In fact, if we look at our elderly

 

       asthmatic population, commonly these patients would

 

       enter the hospital with use of an antibiotic or a

 

       medication for reflux causing a drug-drug

 

       interaction and making the patient theophylline

 

       toxic.  Furthermore, if we look at drug

 

       interactions in the hospital, there is a huge

 

       safety concern about medication errors, and

 

       what-have-you, and theophylline were always at the

 

       top of the list.

 

                 Other medications we had were oral beta

 

       agonists, both short-acting and long-acting and,

 

       again, much less of an efficacy profile as compared

 

       to the long-acting inhaled agents and a much

 

       greater safety risk with tachycardia, tremor and

 

       reflux.  Oral corticosteroids have to be used more

 

       and more when patients have more and more

 

       exacerbations and I don't have to review the

 

       laundry list of side effects that are well-known to

 

       everyone in the room.

 

                 Now, throughout the world we have--I have

                                                                159

 

       outlined in yellow here the G8 nations because of

 

       last week's meeting, but we can see the variation

 

       in prevalence of asthma symptoms as we get more

 

       industrialized societies.  We see a very large

 

       increase in the number of patients who suffer with

 

       airways disease.

 

                 On the other hand, there are facts that I

 

       find very, very consoling and comforting.  This is

 

       the death rate due to asthma in the United States

 

       going back to 1960 up to 2002.  These are the

 

       deaths per 100,000 so we can sort of get the rate

 

       that you are asking for.  Then we have the African

 

       Americans here and the Caucasian population here.

 

                 Short-acting beta agonists were introduced

 

       in the 1970s.  We had the inhaled corticosteroids

 

       introduced in the 1980s.  There have been enormous

 

       efforts in patient education, efforts by the expert

 

       panels of the National Institute of Health for

 

       guidelines and just generalized education programs,

 

       along with the introduction of effective controller

 

       medicines along with the long-acting beta agonists

 

       that seems to have led to a decline, although still

                                                                160

 

       very high, relatively higher in the African

 

       American population, but to the general United

 

       States population, from 5,400 to a little bit above

 

       4,000.  So, we are clearly doing something right.

 

       What the attribution would be here to the various

 

       things introduced is, of course, beyond my ability

 

       to say but, clearly, all these things together have

 

       helped us to improve the lives of our patients.

 

                 Now, what about the long-acting beta

 

       agonists?  Just briefly, you have seen an awful lot

 

       of this data this morning and, at the risk of being

 

       a little bit redundant, the first benefit, of

 

       course, is in patient symptoms.  These are better

 

       bronchodilators.  I think we would all agree that

 

       the data are overwhelming on this.  There is a

 

       reduction in the roller-coaster effect, and I will

 

       come back to that in a minute; better control

 

       because of the longer duration of effect and

 

       nocturnal symptoms.  Because of the control, we

 

       have less use of rescue medications.  We have

 

       improved morning lung function and also less

 

       diurnal lung function variability.  It doesn't

                                                                161

 

       completely eradicate it but it does minimize to

 

       some extent some of the early morning dipping that

 

       leads to waking up or even worse outcomes.  Also,

 

       equal important perhaps, it gives us protection

 

       against exercise-induced bronchospasm and that is

 

       the exercise of normal daily activities in normal

 

       life, and it is nice to have that kind of

 

       protection on board so you don't have to

 

       continuously dose yourself.

 

                 Looking at the formoterol data, Dr. Geba

 

       has shown us the safety data.  We saw that there

 

       are 3 pivotal trials that you have in your briefing

 

       documents.  There is superior improvement in the

 

       FEV                                    1 over placebo over the course of

12 hours.

 

       This duration of action is sustained for 12 weeks

 

       so there doesn't appear to be a signal that there

 

       is any tolerance or reduced efficacy.  There is a

 

       reduced need for nighttime rescue medicine, and the

 

       onset of action is similar to albuterol, as has

 

       been outlined.

 

                 Just again showing the similar 12-hour

 

       studies, this is the 040 and the 041 that you have

                                                                162

 

       seen a moment ago.  This is at week 12.  Here we

 

       see the 12-hour curve and this is the mean change

 

       in baseline FEV                                                        1.

Here is the short-acting

 

       albuterol and placebo, and here is the sustained

 

       effect of the long-acting beta agonist, in this

 

       case formoterol.  First of all, let me draw your

 

       attention to the pre-dose or trough.  Often we

 

       power clinical trials on long-acting beta agonists

 

       and this changes well over 10 percent here, around

 

       12 percent, and that usually can be transferred to

 

       as meaningful clinical improvements such as

 

       symptoms in the morning and what-have-you.  Over

 

       the course of the day you see the roller-coaster.

 

       That in itself means nothing but what this means

 

       here is that as these drugs flow off here our

 

       patients become symptomatic and have to disrupt

 

       their daily activity to take rescue albuterol.

 

                 Also one other thing I would like to show

 

       here is the peak effect.  Patients perceive change

 

       and when you have a nice plateau effect a lot of

 

       side effects such as tremor are much less

 

       perceptible to a patient.

                                                                163

 

                 Other outcomes besides bronchodilator is

 

       rescue medication.  These again are from 040 and

 

       041, the run-in for the 3 arms, formoterol,

 

       albuterol and placebo.  We see over the course of

 

       4, 8 and 12 weeks a nice decline in the rescue

 

       albuterol.  These parameters are less rigorously

 

       defined but we think the minimal clinical

 

       improvement in that parameter is 0.8 puffs per day

 

       ranging to 1.  So, it appears to be in the ballpark

 

       of something that means something to a patient and

 

       we could quantitate that.

 

                 Simply, formoterol reduces nocturnal

 

       symptom scores.  I am showing 040 and 041 which I

 

       believe are the adult studies run-in and over 12

 

       weeks and the companion study here.  We see a nice

 

       decline from about 0.5 to 0.1 in the nocturnal

 

       asthma symptom score parameter.

 

                 To end up, one of the studies that I take

 

       consolation from as a physician is the FACET study.

 

       Again, points are well taken here today, we are

 

       talking about deaths.  It is very difficult in

 

       asthma studies though to power our studies, as

                                                                164

 

       everyone in the room has heard over and over again,

 

       on death as the outcome.  Exacerbations are

 

       extremely important and the reason that I take a

 

       lot of comfort from this study is that it is a

 

       one-year study.  Also, the exacerbations are

 

       precisely defined, as Dr. Sorkness mentioned this

 

       morning.

 

                 In this study we see--again in the

 

       mechanical function, 835 patients, 12 months--a

 

       marked improvement after the run-in.  The patients

 

       were in the run-in symptomatic on inhaled

 

       corticosteroids.  But this study gives us some look

 

       at what is the added value of adding a long-acting

 

       beta agonist--added clinical value--to inhaled

 

       corticosteroids.

 

                 Here are the two budesonide arms.  I think

 

       there is no surprise that on the mechanical

 

       function we do see a change of 7 or 8 percent.  But

 

       I think one takes a better message away from

 

       looking at exacerbations.  First of all, if

 

       inflammation is ongoing and not being checked the

 

       patient is going to know that they are going to

                                                                165

 

       breakthrough with an exacerbation.  This is our

 

       best clinical surrogate for the so-called masking

 

       of inflammation, that is, the breakthrough of

 

       exacerbations.  In a study of one-year duration we

 

       have adequate duration to bring this signal out.

 

                 So, in this study, as Chris Sorkness

 

       pointed out this morning, we have an arm with 100

 

       BID of budesonide and with formoterol.  Then, the

 

       second arm is 400 BID with the addition of

 

       formoterol.  And, the exacerbations were described

 

       as mild with an increase in terbutaline, the rescue

 

       medicine, and severe, defined by a 30 percent

 

       change in peak flow and oral prednisone.  The

 

       decline in mild exacerbations was about 29 percent

 

       and 40 percent with the combination.  But with the

 

       higher dose, high dose budesonide reduced the

 

       exacerbation rate by 49 percent.  When one adds

 

       formoterol to it it went to 62 percent.  So, there

 

       is a net gain there and the actual clinical

 

       implication of that is that it appears to be

 

       significant.  We really haven't put a number on

 

       that yet but that, in my mind, is a very reassuring

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       piece of evidence that supports the use of this

 

       class of drug.

 

                 Using the best evidence that one has, the

 

       expert panels--many of the members of which are in

 

       the room here--have come together, and you have

 

       seen this before over and over again, and have

 

       concluded that inhaled steroids and long-acting

 

       beta agonists have a complementary effect.  One can

 

       lower the dose of inhaled corticosteroids by using

 

       the combination, and not everyone responds to

 

       inhaled corticosteroids although a great majority

 

       do.

 

                 For more severe patients we would be using

 

       higher doses of inhaled corticosteroids and

 

       long-acting inhaled beta agonists and, hopefully,

 

       we will be able to avoid the use of prednisone and

 

       its very difficult side effect profile.

 

                 So to summarize, long-acting beta agonists

 

       have really become an established part of the

 

       current standard of asthma treatment in the United

 

       States and also internationally.  It is an integral

 

       part of internationally established guidelines

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       using the best evidence that we have at our

 

       disposal at the present time.  It is well

 

       established that long-acting beta agonists have a

 

       place in the treatment regimen for asthma but must

 

       be conjunction with inhaled corticosteroids for

 

       those with moderate and severe persistent asthma.

 

                 Again, I don't think at the present time

 

       there is an alternative inhaled controller

 

       bronchodilator or one on the immediate horizon that

 

       is suitable for asthma.  So the LABAs, the

 

       long-acting beta agonists, have provided documented

 

       improvement in symptoms, airway function and

 

       quality of life and you have heard a great deal

 

       about that today.  For whatever reason, since the

 

       introduction of long-acting beta agonists,

 

       controllers and a national effort in education and

 

       guidelines, asthma hospitalizations and mortality

 

       have decreased, which is very reassuring at least

 

       to me and I think to many others.  Long-acting beta

 

       agonists in conjunction with inhaled steroids

 

       represent a medication category critical for

 

       optimal care of patients with moderate to severe

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       asthma.  Thank you very much.

 

                        Questions by the Committee

 

                 DR. SWENSON:  The time now is open for

 

       questions to Novartis.  Dr. Schatz?

 

                 DR. SCHATZ:  Some of the things we are

 

       hearing suggest a possible disconnect between

 

       exacerbations, as has been studied and defined

 

       usually to include oral steroids and emergency

 

       departments or hospitalizations, and then death or

 

       near death.  So, I guess my question has to do with

 

       2307.  How were SAEs defined?  However, were

 

       asthma-related SAEs defined?

 

                 DR. FLOYD:  Dr. Geba?

 

                 DR. GEBA:  To answer this question I would

 

       like to bring up a slide that gives the definition

 

       of asthma-related and the definition of serious.

 

                 We used predefined asthma terms, MedDRA

 

       terms, MedDRA preferred terms.  Asthma-related AEs

 

       were defined as asthma, dyspnea, bronchospasm and

 

       chest discomfort, cough, wheezing, etc., acute

 

       respiratory failure and hypoxia.  For the

 

       definition of SAEs it was one of the above plus one

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       of the following, death, life-threatening

 

       hospitalization, disability, congenital

 

       abnormalities--this is regulatory definition, and

 

       required intervention to prevent further

 

       impairment--standard definition.

 

                 DR. SCHATZ:  Just to follow-up,

 

       intervention could mean oral corticosteroids?

 

                 DR. GEBA:  Yes, it could be.  It could be