1

 

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                       FOOD AND DRUG ADMINISTRATION

 

                 CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

               PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS

 

                            ADVISORY COMMITTEE

 

                   NDA21-645, MT 100, (naproxen sodium

                    and metoclopramide hydrochloride)

                  Tablets, Pozen, Inc. for the proposed

                indication of acute treatment of migraine

                      headache with or without aura

 

 

 

 

 

 

 

 

                         Thursday, August 4, 2004

 

                                8:00 a.m.

 

 

 

 

              Advisors and Consultants Staff Conference Room

                            5630 Fishers Lane

                           Rockville, Maryland

                                                                  2

 

                               PARTICIPANTS

 

       Karl Kieburtz, M.D., MPH, Acting Chair

       Anuja Patel, MPH, Executive Secretary

 

       MEMBERS

 

       Michael D. Hughes, Ph.D.

       Carol L. Koski, M.D.

       Roger J. Porter, M.D., (Industry Rep, Non-Voting)

       Ralph L. Sacco, M.D., M.S.

 

       SPECIAL GOVERNMENT EMPLOYEES (VOTING)

 

       Larry B. Goldstein, M.D.

       Lily K. Jung, M.D., MMM (Acting Consumer Rep)

       Stanley Fahn, M.D.

       Marc E. Lenaerts, M.D.

       K. Michael Welch, M.B., Ch.B., FRCP

       Sheila Weiss-Smith, Ph.D., FISPE

       Mark W. Green, M.D.

 

       FEDERAL GOVERNMENT EMPLOYEE CONSULTANT (Voting)

 

       Dilip V. Jeste, M.D.

 

       FDA

 

       Robert Temple, M.D.

       Russell Katz, M.D.

       Eric Bastings, M.D.

       Mary Ross Southworth, Pharm.D.

                                                                  3

 

                             C O N T E N T S

 

                                                               PAGE

 

       Call to Order and Opening Remarks:

                 Karl Kieburtz, M.D., MPH                         5

                 Anuja Patel, MPH

 

       Conflict of Interest Statement:

                 Mary Ann Killian                                 7

 

       Overview of Issues:

                 Russell Katz, M.D.                              17

 

                 Sponsor Presentation, Pozen Incorporated

 

       Introduction and Summary:

                 Marshall E. Reese, Ph.D.                        24

 

       Overview of Tardive Dyskinesia:

                 A.H.V. (Tony) Schapira, M.D.                    35

 

       Review of MT100 Efficacy:

                 William James Alexander, M.D., MPH, FACP        61

 

       Potential Role of MT100 in Migraine Therapy:

       Balancing Benefits and Risks:

                 David B. Matchar, M.D., FACP                    78

 

       Clinical Considerations on Migraine Treatment:

                 Stephen D. Silberstein, M.D.                    99

 

                             FDA Presentation

 

       FDA Risk/Benefit Considerations:

                 Eric Bastings, M.D.                            108

 

       Overview of Tardive Dyskinesia:

                 Hyder A. Jinnah, M.D., Ph.D.                   127

 

       Post-marketing Review of Movement Disorders

       and Neuroleptic Malignant Syndrome Associated

       with Metoclopramide:

                 Mary Ross Southworth, Pharm.D.                 138

 

       Questions from the Committee to the Sponsor

       and to FDA                                               160

                                                                  4

 

                             C O N T E N T S

 

                                                               PAGE

 

       Open Public Hearing

                 Cynthia McCormick, M.D.                        217

 

       Committee Discussion and Response to FDA Questions       225

                                                                  5

 

                          P R O C E E D I N G S

 

                    Call to Order and Opening Remarks

 

                 DR. KIEBURTZ:  Good morning.  This is the

 

       Peripheral and Central Nervous System Drugs

 

       Advisory Committee.  We here to discuss the New

 

       Drug Application 21-645, proposed trade name of

 

       MT100 Tablets, from Pozen, Incorporated for the

 

       proposed indication of acute treatment of migraine

 

       headache with or without aura.

 

                 I would just also take the opportunity to

 

       refer people to the agenda.  Incorporated in the

 

       agenda are the questions which are posed to this

 

       committee which will be discussing and voting on

 

       today.  We won't be discussing or voting on prior

 

       actions of the FDA including the non-approvable

 

       letter or any issues about a approvability of the

 

       product.  That is not our remit or discussion for

 

       today.

 

                 So I would hope that the presentations are

 

       focused on what the committee will be discussing

 

       and deliberating about today.

 

                 When people speak, please speak into the

                                                                  6

 

       microphone and turn the microphone on.  If you are

 

       interested in speaking, raise your hand or you can

 

       turn the microphone on.  Anuja, the Executive

 

       Secretary, will keep track and will get to people

 

       who want to speak from the committee.

 

                 Just to the committee members, the voting

 

       committee members, please keep in mind that, to

 

       vote, you need to be here.  So there is no leaving

 

       of votes.  Hopefully, there is no leaving until the

 

       meeting is adjourned which is scheduled to be at 5

 

       o'clock.  Please plan your travels accordingly.

 

                 In a second, I am going to introduce Mary

 

       Ann Killian.  There is a new procedure--I think we

 

       are the inaugural run of it--for disclosure of

 

       conflicts of interest where Mary Ann Killian reads

 

       a statement and then each individual member of the

 

       committee reads their conflict statement.  When

 

       that is concluded, Mary Ann has some concluding

 

       remarks and then we will move on with the rest of

 

       the agenda.

 

                 The only individual who does report

 

       conflicts of interest is Dr. Porter as he is the

                                                                  7

 

       industry representative.

 

                 So Mary Ann Killian, the Program Integrity

 

       Advisor from the Ethics and Integrity Staff.

 

                      Conflict of Interest Statement

 

                 MS. KILLIAN:  Thank you very much.  The

 

       FDA is convening today's meeting of the Peripheral

 

       and Central Nervous System Drugs Advisory Committee

 

       under the authority of the Federal Advisory

 

       Committee Act of 1972.  The advisory committee

 

       meeting provides transparency into the agency's

 

       deliberative processes.

 

                 With the exception of the industry

 

       representative, all members of the committee are

 

       special government employees or regular federal

 

       employees from other agencies and are subject to

 

       federal conflict-of-interest laws and regulations.

 

                 Consequently, in the interest of

 

       transparency and the spirit of disclosure, the

 

       following information on the status of this

 

       advisory committee's compliance with federal ethics

 

       and conflict-of-interest laws covered by but not

 

       limited to those found at 18 U.S.C. 208 and 21

                                                                  8

 

       U.S.C. 355(n)(4) is being provided to the

 

       participants in today's meeting and to the public.

 

                 FDA has determined that members of this

 

       advisory committee are in compliance with the

 

       Federal ethics and conflict-of-interest laws

 

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

 

       U.S.C. 355 (n)(4).  Under 18 U.S.C. Section 208,

 

       applicable to all government agencies, and 21

 

       U.S.C. 355(n)(4), applicable to FDA, Congress has

 

       authorized FDA to grant waivers to special

 

       government employees who have limited 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 employer,

 

       spouse, minor child related to the discussions of

                                                                  9

 

       today's meeting.  These interested may include

 

       investments, consulting, expert witness testimony,

 

       contracts/grants/CRADAs, teaching/speaking/writing,

 

       patents and royalties, and primary employment.

 

                 Today's agenda involves a review of New

 

       Drug Application 21-645, proposed trade MT100

 

       Tablets, proposed for acute treatment of migraine

 

       headache with our without aura sponsored by Pozen,

 

       Inc.  MT100 is a combination of two approved drugs,

 

       naproxen sodium, manufactured by the  Albemarle

 

       Corporation, and metoclopramide hydrochloride,

 

       manufactured by Cosam S.p.A, a member of the CFM

 

       group.  This is a particular matters meeting during

 

       which specific matters related to the NDA will be

 

       discussed

 

                 Copies of each acknowledgement and

 

       consent-to-disclosure statement signed by each

 

       participant at today's meeting who received a

 

       conflict-of-interest waiver along with this

 

       statement will be available for review at the

 

       registration table during this meeting and will be

 

       included as part of the official meeting

                                                                 10

 

       transcript.

 

                 A copy of the written conflict-of-interest

 

       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.

 

                 At this time, each member will be asked to

 

       state his or her name for the record and announce

 

       whether his or her participation in this meeting is

 

       based on a conflict-of-interest waiver.

 

                 Please state your name and whether you

 

       have received a waiver from the agency to

 

       participate in today's meeting.  If you have

 

       received a waiver, please describe the details of

 

       the interest or interests for which the waiver has

 

       been granted.  If the agency has reviewed your

 

       reported interest and determined that you do not

 

       require a waiver, please indicate that for the

 

       record.

 

                 I guess we will start with you.

 

                 DR. KIEBURTZ:  I will be the exemplar.  I

 

       am Dr. Karl Kieburtz.  I am a neurologist and on

                                                                 11

 

       the faculty of the University of Rochester in

 

       Rochester, New York.  Based on the agenda for

 

       today's meeting and the information regarding my

 

       financial and other interests required to be

 

       reported to the agency prior to my participation

 

       today as a committee member, I have not received a

 

       conflict-of-interest waiver to participate in

 

       today's meeting.  That means I don't need a waiver.

 

                 Next is Dr. Porter.

 

                 DR. PORTER:  Pass.

 

                 DR. KIEBURTZ:  If you would just introduce

 

       yourself for the record.

 

                 DR. PORTER:  Sure.  I am Roger Porter.  I

 

       am a neurologist twenty years at the NIH, ten years

 

       at Wyeth.  I am now a consultant.

 

                 DR. HUGHES:  I am Michael Hughes.  I am

 

       Professor of Biostatistics from Harvard University.

 

       Based on the agenda for today's meeting and the

 

       information regarding my financial and other

 

       interests required to be reported to the agency

 

       prior to my participation today as a committee

 

       member, I have not received a conflict-of-interest

                                                                 12

 

       waiver to participate in today's meeting.

 

                 DR. KOSKI:  I am Dr. Carol L. Koski.  I am

 

       a Professor of Neurology at the University of

 

       Maryland School of Medicine.  I have received a

 

       waiver for ownership of stock in two competing

 

       firms.  The first is valued between $5,001 and

 

       $25,000.  The second is valued between $25,001 and

 

       $50,000.

 

                 DR. SACCO:  Hi.  Ralph Sacco.  I am a

 

       Professor of Neurology and Epidemiology and

 

       Director of Stroke and Critical Care at Columbia

 

       University.  I have received a waiver for my

 

       service as a consultant for a competing firm.  I

 

       also serve on the Data and Safety Monitoring Board

 

       for a competing firm and I receive less than

 

       $10,001 per year from each firm.

 

                 DR. GOLDSTEIN:  I am Dr. Larry Goldstein.

 

       I am a Professor of Medicine at Duke University and

 

       Director of the Duke Center for Cerebrovascular

 

       Disease.  I have received a waiver for consulting

 

       for four competing firms and I receive less than

 

       $10,001 per firm per year from three of the firms

                                                                 13

 

       and between $10,001 and $50,000 per year from the

 

       fourth firm.  In addition, I serve as a member of

 

       two advisory boards and two steering committees for

 

       competing firms and receive less than $10,001 per

 

       year from each firm.

 

                 DR. JUNG:  Hi.  My name is Lily Jung.  I

 

       am a neurologist with the Seattle Neural Science

 

       Institute and Swedish Medical Center.  I am also a

 

       Clinical Associate Professor at the University of

 

       Washington.  I have received a waiver for ownership

 

       of stock valued from $5,001 to $25,000 in a

 

       competing firm.

 

                 DR. FAHN:  Good morning.  I am Dr. Stanley

 

       Fahn.  I am a Professor of Neurology at Columbia

 

       University subspecializing in the field of movement

 

       disorders.  I have received a waiver for serving on

 

       steering committees for two competing firms.  In

 

       addition, I also serve as a consultant for two

 

       competing firms.  I receive less than $10,001 per

 

       year from each firm.

 

                 DR. LENAERTS:  Good morning.  Marc

 

       Lenaerts, Assistant Professor, University of

                                                                 14

 

       Oklahoma, Department of Neurology, a headache

 

       specialist.  I have received a waiver for serving

 

       on three speakers bureaus.  One is between $10,001

 

       and $50,000, and two are $10,000 or less.

 

                 DR. WELCH:  Good morning.  I am Dr.

 

       Michael Welch.  I am a Professor of Neurology at

 

       Rosalind Franklin University of Medicine and

 

       Science.  I have received a waiver for serving as a

 

       consultant for two competing firms and I am also an

 

       advisory board member for two competing firms and

 

       serve on the steering committee for a competing

 

       firm.  I receive less than $10,001 per year for

 

       each firm.

 

                 DR. SMITH:  Good morning.  I am Professor

 

       Sheila Weiss Smith.  I am an Associate Professor at

 

       the University of Maryland Schools of Pharmacy and

 

       Medicine.  I have not received a

 

       conflict-of-interest waiver to participate in

 

       today's meeting.

 

                 DR. JESTE:  Good morning.  I am Dr. Dilip

 

       Jeste.  I am Professor of Psychiatry and

 

       Neurosciences at the University of California, San

                                                                 15

 

       Diego, and the San Diego V.A. Healthcare System.  I

 

       have received a waiver for advisory board

 

       activities for a competing firm for which I receive

 

       less than $10,001 per year.

 

                 DR. GREEN:  I am Dr. Mark Green.  I am a

 

       Clinical Professor of Neurology at Columbia

 

       University and Director of the Columbia University

 

       Headache Center.  I have received a waiver from my

 

       employer's contracts and grants with three

 

       competing firms.  My employer receives less than

 

       $100,000 from one, between $100,001 and $300,000

 

       from a second and more than $300,000 from a third.

 

                 MS. KILLIAN:  Thank you very much.

 

       Lastly, Dr. Roger Porter is the Industry

 

       Representative on the committee today and he will

 

       be acting on behalf of all related industry.

 

                 In the event that the discussions involve

 

       any other products or firms not already on the

 

       agenda for which an FDA participant may have a

 

       financial interest, all meeting participants are

 

       reminded that they are required by 18 U.S.C. 208 to

 

       exclude themselves from such deliberations and

                                                                 16

 

       announce their exclusion for the record.

 

                 Finally, in the interest of public

 

       transparency, with respect to all other

 

       participants, we ask that they publicly disclose,

 

       prior to making any remarks, any current or

 

       previous financial involvement with any firm whose

 

       products they may wish to comment upon.

 

                 Thank you very much.  This concludes my

 

       statement.

 

                 DR. KIEBURTZ:  Thank you everyone for

 

       doing that.  For an inaugural run, I think that

 

       went pretty well.

 

                 I would just like to point to the agenda

 

       before letting Dr. Katz begin which is, some people

 

       know, the sponsor will have approximately an hour

 

       and fifteen minutes, up until the 9:45 break, to

 

       give their presentation.  We will then break and

 

       then there is a presentation from the FDA.

 

                 There will then be the opportunity for the

 

       committee to ask questions about the content of

 

       those presentations to the presenters.  Then we

 

       will break for lunch.  There will be a public

                                                                 17

 

       hearing after that and then a discussion amongst

 

       the committee members after that.

 

                 During those discussions, the committee

 

       members may ask questions of the presenters

 

       regarding details of their presentation.

 

       Presenters may not interject or contribute to that

 

       discussion voluntarily, just so people know the

 

       rules of the game here.

 

                 If you have questions that arise during

 

       presentations, the FDA's presentation slides are

 

       numbered.  You may want to note them.  You may want

 

       to note the slides of a presenter so that you can

 

       refer back to them with reference when you pose a

 

       question.

 

                 On the FDA side of the table, I would like

 

       to introduce four people.  It looks like it flows

 

       from right to left from my sitting.  Dr. Robert

 

       Temple, Dr. Rusty Katz, Dr. Bastings and Dr.

 

       Southworth.

 

                 Dr. Katz?

 

                            Overview of Issues

 

                 DR. KATZ:  Thanks, Dr. Kieburtz.  I want

                                                                 18

 

       to be very, very brief.  I just have a couple of

 

       points I want to make but, first, I want to add my

 

       welcome to the committee.  Thanks for coming.

 

       Particularly we have several new members.  I would

 

       like to thank them for agreeing to serve on the

 

       committee.

 

                 I would also like to thank Dr. Kieburtz

 

       for agreeing to chair the committee.  It can be a

 

       tough job.  I would also especially like to thank

 

       our invited guests, of whom we have quite a few,

 

       who are experts to help us deal with this

 

       interesting issue.  In particular, I would like to

 

       thank Dr. Jinnah who has graciously agreed to

 

       actually be part of the presentations this morning.

 

       So thanks very much to everybody for coming.

 

                 As you know, we are here to discuss NDA

 

       16-145 submitted by Pozen for the use of MT100

 

       which, as you have heard and which you know, is a

 

       combination of naproxen and metoclopramide for the

 

       treatment of acute migraine.

 

                 Actually, we are asking you today to

 

       address a type of question that is actually fairly

                                                                 19

 

       unusual for the committee to deal with and that is

 

       because many of the questions that we are going to

 

       be asking you to consider are hypothetical in

 

       nature.

 

                 Those of you who have been on the

 

       committee or have seen previous committee meetings

 

       know that, in a typical case, when we bring you a

 

       new drug application, we would ask you whether or

 

       not the application contains sufficient evidence of

 

       safety or effectiveness in order to support

 

       marketing approval.

 

                 But, today, as Dr. Kieburtz has already

 

       stated, we are not primarily interested in the

 

       question of whether or not the sponsor submitted

 

       substantial evidence of effectiveness for the

 

       treatment of acute migraine.  We have already

 

       decided that they have not done so, in particular

 

       because we are unsure that they have presented

 

       sufficient evidence of effectiveness for the

 

       combination, itself, as a treatment for acute

 

       migraine.

 

                 But, perhaps, more importantly for today's

                                                                 20

 

       discussion, we have determined that they have not

 

       demonstrated a contribution of one of the

 

       components to the overall effect of the drug and

 

       that component is metoclopramide.  I think we will

 

       have a lot of discussion about that particular

 

       question today.

 

                 You will, though, of course, hear some

 

       more or less detailed presentations of that

 

       effectiveness data that we have already ruled on in

 

       a sense.  You will hear from the company and you

 

       will hear, to some extent, from us as well, from

 

       Dr. Bastings.  We would hope that you would

 

       primarily consider those data in the context of

 

       helping to inform your answers to the series of

 

       hypothetical questions that we are going to ask

 

       you.

 

                 In particular, we would like you to think

 

       about the previous effectiveness data in the

 

       context of giving us your advice as to whether or

 

       not, if the sponsor does perform an additional

 

       study or additional studies in a particular

 

       population which you will hear about, whether or

                                                                 21

 

       not the results--if the results of these new

 

       studies or new study are more or less of the same

 

       magnitude as what has been seen already, whether or

 

       not you would think that would justify approval of

 

       the combination given the potential risks of the

 

       treatment.

 

                 Of course, the potential risks of the

 

       treatment are the underpinnings for the second

 

       serious of hypothetical questions we want to ask

 

       you.  Specifically, we are interested to know your

 

       views about the likelihood of occurrence and,

 

       perhaps, even estimates of the frequency of

 

       particular adverse events that we are concerned

 

       about which, as you know, are tardive dyskinesia,

 

       primarily, but, in additional, other tardive

 

       movement disorders and possibly neuroleptic

 

       malignant syndrome associated with the chronic

 

       intermittent use of metoclopramide as it would be

 

       presumably used in the treatment of acute migraine.

 

                 This series of questions is hypothetical

 

       because the current data on the risks for these

 

       adverse events associated with metoclopramide, such

                                                                 22

 

       as they are, don't speak directly to the question

 

       of what the frequency of--what they might be when

 

       the drug is given in the regimen that the sponsor

 

       proposes; namely, chronic intermittent use, as is

 

       typical for an acute-migraine treatment.

 

                 As difficult as those questions might be

 

       to answer, we would like you to go even further and

 

       venture an opinion about what sort of possible

 

       dosing recommendations, if any, actually could be

 

       adopted that might reduce the risks to an

 

       acceptable level and then ask you to discuss what

 

       you think that possible result and level of risk

 

       might be.  So these are all, obviously, questions

 

       for which we do not have adequate data.

 

                 That is what makes it difficult.  We know

 

       these are difficult questions, but partly because

 

       they are so difficult, and partly because we think

 

       these questions are very important to try to answer

 

       from the perspective of public health, given the

 

       large prevalence of acute migraine in the

 

       population, that is why we have come to you today.

 

                 So, again, thank you for coming.  I want

                                                                 23

 

       to thank you in advance for all the hard work that

 

       you have done already in reading the documents and

 

       in today's discussion.  So thanks again and I look

 

       forward to an interesting and productive meeting.

 

                 Thanks.

 

                 DR. KIEBURTZ:  Thank you, Dr. Katz.

 

                 Actually, I realize I was a little remiss

 

       in introducing all of you.  Maybe, as we have all

 

       had the chance to introduce ourselves around the

 

       table, Dr. Temple, maybe you could start so that

 

       everyone knows who you all are.

 

                 Also, to follow up on Dr. Katz' comments,

 

       just before you do that, Dr. Temple, these are

 

       difficult questions and they are unusual questions.

 

       I hope the committee members feel comfortable

 

       voicing if they are uncertain about that and I will

 

       be happy, as chair, to direct back to the FDA

 

       questions about clarifying as to whether we are

 

       answering the questions they had in mind and

 

       getting clarity that we are providing them the

 

       advice that they are seeking from us because it is

 

       a little bit unusual.

                                                                 24

 

                 So, if people are a little uncomfortable

 

       about that, that is how we can do that.  We can ask

 

       questions of them to be certain we are addressing

 

       the issues at hand.

 

                 So, Dr. Temple, please.

 

                 DR. TEMPLE:  Good morning.  I am Bob

 

       Temple.  I am the Director of ODE I.  That is

 

       office in which the Division of Neurology Products

 

       lives.  I have not received a waiver.

 

                 DR. KATZ:  I am Russ Katz.  I am the

 

       Director of the Division of Neurology Products.  I,

 

       too, am not allowed to have a conflict of interest.

 

                 DR. BASTINGS:  I am Eric Bastings.  I am a

 

       clinical team leader in the Division of Neurology.

 

                 DR. SOUTHWORTH:  I am Mary Ross

 

       Southworth, a safety evaluator in the Office of

 

       Drug Safety.

 

                 DR. KIEBURTZ:  Next on the agenda is

 

       presentations from the sponsor.

 

                Sponsor Presentation, Pozen, Incorporated

 

                         Introduction and Summary

 

                 DR. REESE:  Good morning and thank you.

                                                                 25

 

                 (Slide CC-1-2)

 

                 Pozen wants to thank the FDA for

 

       assembling the Peripheral and Central Nervous

 

       System Drugs Advisory Committee today to review our

 

       naproxen-metoclopramide combination product called

 

       MT100 for the acute treatment of migraine with and

 

       without aura.

 

                 (Slide CC-3)

 

                 Let me briefly review an outline of

 

       Pozen's presentation for this morning.  Following

 

       my introductory comments, Dr. Schapira, Professor

 

       and Chair of Neurology at the Royal Free and

 

       University College Medical School in London and

 

       Professor of Neurology at Queens Square, will

 

       present an overview of tardive dyskinesia with

 

       metoclopramide use.

 

                 Dr. Alexander, Senior Vice President and

 

       Chief Medical Officer at Pozen, will briefly review

 

       the efficacy data for MT100 as contained in our

 

       NDA.  Dr. Matchar, Professor of Medicine and

 

       Director of the Center for Clinical Health Policy

 

       Research at Duke University, will discuss the

                                                                 26

 

       potential role of MT100 in migraine therapy and the

 

       benefit-to-risk ratio of MT100.

 

                 Dr. Silberstein, Director of Jefferson

 

       Headache Center in Philadelphia and the current

 

       President of the American Headache Society, will

 

       review clinical considerations in migraine

 

       treatments.  Then I will close our presentation of

 

       this morning.

 

                 (Slide CC-4)

 

                 A bit of history.  Pozen filed the IND for

 

       MT100 in 1997 and undertook a preclinical, clinical

 

       and pharmaceutical development program.  There were

 

       several discussions in meetings with the FDA over

 

       the next six years which culminated in the

 

       submission of the NDA in July, 2003.  Pozen

 

       believed that the totality of the data in the NDA

 

       supported approval of the fixed-combination

 

       product.  However, the FDA did not agree with Pozen

 

       and issued a not-approvable letter in May, 2004.

 

                 A critical-path meeting was held in late

 

       October, 2004 with the Division Director, Dr. Katz,

 

       and the Office Director, Dr. Temple.  As a result

                                                                 27

 

       of that meeting, the FDA suggested an

 

       advisory-committee meeting be convened to address

 

       the potential risk of tardive dyskinesia with MT100

 

       before we undertook any additional work.

 

                 (Slide CC-5)

 

                 That brings us to today's meeting which

 

       really revolves around one central question; does

 

       the potential risk of tardive dyskinesia preclude

 

       the ultimate approval of MT100, whether for all

 

       patients or for a readily identifiable group of

 

       patients who receive the maximum benefit.

 

                 (Slide CC-6)

 

                 MT100 is a patented pharmaceutical tablet

 

       formulation which is basically a pill inside a

 

       pill.  The core consists of the 500 milligrams of

 

       naproxen sodium that is sprayed with an insulating

 

       coat followed by a spray coating of 16 milligrams

 

       of metoclopramide hydrochloride,  which is

 

       equivalent to 13-and-a-half milligrams of

 

       metoclopramide base, then followed by a color coat.

 

                 The tablet is designed to release

 

       metoclopramide immediately into the stomach to

                                                                 28

 

       alleviate the gastroparesis often associated with

 

       migraine following the release of the long-acting

 

       drug, naproxen, after it leaves the stomach.

 

       Please note that the doses of both components are

 

       well below the maximum daily doses approved for

 

       these two products for other indications.

 

                 (Slide CC-7)

 

                 In May, 2004, the FDA issued a

 

       not-approvable letter for MT100 citing both

 

       efficacy and safety concerns.  The FDA concluded

 

       that the efficacy data for MT100 provided only

 

       modest benefit over naproxen at 24 hours and that

 

       this benefit, coupled with the possible risk of

 

       metoclopramide-induced tardive dyskinesia, did not

 

       warrant approval of MT100.

 

                 The not-approvable letter also stated that

 

       the data submitted in the NDA did not provide a

 

       significant benefit for all of the

 

       migraine-associated symptoms at two  hours versus

 

       placebo in two well-controlled studies.  The FDA

 

       did agree that one study was considered to have met

 

       all the endpoints necessary for approval.

                                                                 29

 

                 Therefore, the FDA felt that the potential

 

       risk of developing tardive dyskinesia was not

 

       outweighed by the 4 to 6 percent benefit of the

 

       MT100 over the active control, naproxen, at 24

 

       hours.

 

                 (Slide CC-8)

 

                 Now, regarding tardive dyskinesia, the

 

       not-approvable letter states, "The absence of any

 

       detected cases among 300 patients is consistent

 

       with the true rate of TD of about 1 percent, an

 

       unacceptably high risk in the absence of any

 

       advantage of the product."

 

                 The FDA's mathematical calculation of 1

 

       percent is derived from the upper limit of the 95

 

       percent confidence interval around zero which we

 

       believe is based on the 300 subjects in the

 

       long-term safety study.  Any implication that the

 

       true rate approaches 1 percent is unfounded based

 

       on the available scientific data in the literature,

 

       the spontaneous case reports from the U.S. and the

 

       U.K., national safety databases and our own

 

       clinical-trial experience in treating over 3700

                                                                 30

 

       patients with MT100.

 

                 We feel that the risk of tardive

 

       dyskinesia is very low and, certainly, much less

 

       than 1 percent.  While approximately 2700 of these

 

       patients treated only single attacks, our 12-month

 

       safety data that we conducted was actually three

 

       times larger than the FDA had requested.

 

                 This study exposed over 1000 subjects to

 

       MT100 for three months, over 600 subjects for 6

 

       months and over 300 subjects for 12 months treating

 

       over 23,000 individual migraine attacks and there

 

       were no reports of tardive dyskinesia in these

 

       studies.

 

                 (Slide CC-9)

 

                 Now, metoclopramide had been on the market

 

       for over 20 years when Pozen submitted the NDA and

 

       there were never any concerns raised by the FDA as

 

       far as I am aware regarding tardive dyskinesia

 

       during the development of MT100.  Even though we

 

       saw no cases of tardive dyskinesia during the

 

       development program, to be conservative, Pozen

 

       mimicked the current metoclopramide labeling found

                                                                 31

 

       in Reglan, from the Warnings Section of the

 

       approved label, regarding any possible risk of

 

       tardive dyskinesia.

 

                 The Reglan label states, regarding tardive

 

       dyskinesia, that both the risk of developing the

 

       syndrome and the likelihood that it will become

 

       irreversible are believed to increase with the

 

       duration of treatment and the total cumulative

 

       dose.  Less commonly, the syndrome can develop

 

       after a brief treatment period at low doses.  In

 

       these cases, the symptoms appear more likely to be

 

       reversible.

 

                 I would like to stress, again, that the

 

       use of MT100 in the migraine population exposes

 

       patients to both a low dose, 16 milligrams, of

 

       metoclopramide hydrochloride and to an episodic use

 

       of about three to six times per month.

 

                 (Slide CC-10)

 

                 Based on the available scientific

 

       evidence, Pozen submits that the risk of tardive

 

       dyskinesia associated with metoclopramide use is

 

       very low and should be even lower with the episodic

                                                                 32

 

       use of MT100.  The therapeutic dose of

 

       metoclopramide hydrochloride, as I said, in MT100

 

       is only 16 milligrams.  The data from the long-term

 

       safety study indicates that the expected use of

 

       MT100 is only about four doses per month.

 

                 Dr. Schapira will review the spontaneous

 

       national safety databases from both the U.S. and

 

       U.K. and the scientific literature.  There have

 

       been very few cases of tardive dyskinesia reported

 

       from the chronic use of metoclopramide as a single

 

       ingredient over the past 40 years and, to our

 

       knowledge, no cases of tardive dyskinesia have been

 

       reported with the episodic use of metoclopramide.

 

                 As I said, there were no cases of tardive

 

       dyskinesia seen in our clinical-trial program

 

       either.  Therefore, to the best of our knowledge

 

       from the literature, the national safety databases

 

       and experts in the field, the risk of developing

 

       tardive dyskinesia from the episodic use of MT100

 

       should be lower than currently approved

 

       metoclopramide-containing products.  Therefore,

 

       Pozen feels its potential risk of tardive

                                                                 33

 

       dyskinesia should not preclude the ultimate

 

       approval of MT100.

 

                 (Slide CC-11)

 

                 Since MT100 is a fixed-combination

 

       product, it must also satisfy the FDA combination

 

       policy as shown on this slide which simply states

 

       that, "Two or more drugs may be combined in a

 

       single form when each component makes a

 

       contribution to the claimed effects and the dosage

 

       of each component is such that the combination is

 

       safe and effective for a significant patient

 

       population requiring such concurrent therapy as

 

       defined in the labeling."

 

                 We believe MT100 satisfies this policy.

 

                 (Slide CC-12)

 

                 Dr. Alexander will review the efficacy

 

       data for MT100 in a few moments, but I would like

 

       to share a few highlights of what he will show you.

 

                 There was a significant improvement in the

 

       primary endpoint of sustained pain response over 24

 

       hours in five of six studies versus placebo or the

 

       pseudoplacebo metoclopramide.  One study did not

                                                                 34

 

       achieve significance and the p-value was 0.054.

 

                 The data from the two component studies

 

       both demonstrate that each component of

 

       metoclopramide makes a significant contribution to

 

       the claimed effects for all patients but an even

 

       greater effect in a significant patient population

 

       experiencing migraine attacks without nausea.

 

                 In addition to the primary 24-hour

 

       sustained pain endpoint, the FDA requested that we

 

       evaluate migraine efficacy endpoints at two hours

 

       versus placebo.  In all six efficacy studies, MT100

 

       was always significantly better than placebo for

 

       pain at two hours.  We also showed improvement over

 

       the associated symptoms of nausea, photophobia and

 

       phonophobia at two hours.

 

                 Although these studies were not powered to

 

       show a difference in these secondary symptoms, in

 

       most cases, MT100 was numerically, if not

 

       statistically, superior to placebo.

 

                 (Slide CC-13)

 

                 In conclusion, I believe that the

 

       potential risk of tardive dyskinesia should not

                                                                 35

 

       preclude the ultimate approval of MT100.

 

                 (Slide CC-14)

 

                 Next I would like to introduce Dr.

 

       Schapira, Professor and Chair of Neurology at the

 

       Royal Free and University College Medical School in

 

       London and Professor of Neurology at Queens Square,

 

       who will summarize the available information on

 

       tardive dyskinesia associated with metoclopramide

 

       use.

 

                 Thank you.

 

                 DR. KIEBURTZ:  Dr. Reese, before you--does

 

       anybody have just a quick clarification or--okay.

 

       Thank you.

 

                      Overview of Tardive Dyskinesia

 

                 DR. SCHAPIRA:  Thank you, Dr. Reese, and

 

       thank you, Dr. Kieburtz, and thank you to the

 

       committee for the opportunity to come and speak to

 

       you this morning.

 

                 I guess I am coming here wearing two hats.

 

       The first is of a neurologist, a general

 

       neurologist, in the U.K. who, in outpatient clinic,

 

       sees a spectrum of neurological disorders, a

                                                                 36

 

       significant proportion of which, of course,

 

       includes headache and a significant proportion of

 

       that, in turn, includes migraine.

 

                 The second hat is that of a neurologist

 

       with a specific interest in movement disorders.  So

 

       it is with those two hats, if you wish, that I am

 

       going to cover some specific areas this morning.

 

                 (Slide CC-15)

 

                 The first is to address the issue of why

 

       use metoclopramide in migraine and the second is

 

       specifically to address the risk of tardive

 

       dyskinesias, or TD, with metoclopramide use.  I

 

       would like to divide my comments on this into three

 

       areas; the chronic, intermittent and episodic use.

 

       I will come back each of those in turn.

 

                 (Slide CC-16)

 

                 Just to begin with why use metoclopramide

 

       in migraine.

 

                 (Slide CC-17)

 

                 I will cover this only briefly because

 

       others will also comment on this, but we know that

 

       it enhances absorption of orally administered

                                                                 37

 

       analgesics.  It is an anti-nauseant and

 

       anti-emetic.  A meta-analysis indicates that

 

       parenteral metoclopramide seems to have a specific

 

       anti-migraine activity on its own.

 

                 (Slide CC-18)

 

                 The advantages, if you wish, of

 

       metoclopramide in migraine have actually been used

 

       in the U.K. because we have, for 25 years, actually

 

       had access to three drugs, all of which are

 

       metoclopramide analgesic combinations.  The first

 

       is MigraVess.  The second is Paramax, and MigraMax.

 

       MigraVess was available between 1980 and 1999 and

 

       was then withdrawn in favor of Migramax because of

 

       the higher dose of aspirin compound in the latter.

 

                 All of these three compounds, as I say,

 

       contain 10 milligrams of metoclopramide per dose

 

       and the maximum recommended dose in the U.K. is

 

       three dose per 24 hours, so a 30-milligram-per-day

 

       dose of metoclopramide.

 

                 There is no restriction in the U.K. on the

 

       number of times a patient may take this compound

 

       per week, per month, et cetera, so long as they do

                                                                 38

 

       not exceed the three-times-per-day, 24-hour, dose.

 

       I should also point out that, for general use,

 

       metoclopramide has been available in the U.K. since

 

       1964.

 

                 (Slide CC-19)

 

                 The use of these metoclopramide-analgesic

 

       combinations in the U.K. have been found useful.

 

       In fact, they have now been incorporated into the

 

       U.K. Guidelines for the management of acute

 

       migraine.  The first step is a simple analgesic.

 

       The second step is, then, the

 

       metoclopramide-analgesic combinations given orally

 

       or, if necessary, given by suppository.  The third

 

       step is the use of a triptan.

 

                 We have found, in clinical practice in the

 

       U.K., that that middle step, that Step 2, is a very

 

       useful practical intermediate step between the use

 

       of simple analgesics and the use of a triptan.

 

                 (Slide CC-20)

 

                 Now, I would like to come on specifically

 

       to address the issues of tardive dyskinesia.  In

 

       terms of the use, I will focus first on chronic

                                                                 39

 

       use.  This I am going to define, really, as the

 

       most frequent, most common, use in the U.S.,

 

       particularly, of Reglan, or metoclopramide, for its

 

       gastrointestinal uses, and also in the U.K. we have

 

       an equivalent drug which we call Maxolon, again

 

       with the same range of uses for gastrointestinal

 

       disturbances.

 

                 (Slide CC-21)

 

                 Let me, first of all, though, before

 

       moving on to the surveillance data, begin with a

 

       view of tardive dyskinesia.  There are several

 

       different definitions of tardive dyskinesia, so

 

       what I have tried to draw out is some of the

 

       commonalities between them.

 

                 I think we could say that it is a syndrome

 

       consisting of potentially irreversible involuntary

 

       dyskinetic movements which can affect any part of

 

       the body but which predominantly affect the

 

       orolingual-buccal region.  It has traditionally

 

       been associated with chronic, and that is 30 days

 

       or more, use of a dopamine antagonist, generally

 

       speaking, at the higher dose ranges of the those

                                                                 40

 

       antagonists.

 

                 But some definitions of TD also include

 

       daily use for three months, or daily use for one

 

       month if the patient is 60 years or more, onset

 

       during use or, alternatively, onset with four to

 

       eight weeks of cessation.

 

                 The pathogenesis of tardive dyskinesia is

 

       not fully understood but it is thought to include

 

       the development of supersensitivity of the

 

       dopaminergic system.  The prognosis of TD, once it

 

       develops, is variable and, again, the precise

 

       handles on this can vary.  Two studies, for

 

       instance, quoted in the helpful FDA submission,

 

       suggest that 33 percent of patients may resolve

 

       spontaneously in two years and another 29 percent

 

       over six months.

 

                 But, certainly, TD can be irreversible and

 

       can be extremely distressing.

 

                 (Slide CC-22)

 

                 I would like to just now move quickly to

 

       some of the surveillance data that is available on

 

       TD, the first of which, looking at the association

                                                                 41

 

       between TD and metoclopramide came from

 

       Scandinavia.  Between 1977 and 1981, there were

 

       established 11 million doses and they identified 11

 

       cases of TD.

 

                 Then the first of two U.K. studies.  The

 

       first was a retrospective analysis of the Committee

 

       of Safety of Medicines.  This is a yellow-card

 

       system whereby medical practitioners will send in a

 

       yellow card to the CSM when they identify an

 

       adverse drug reaction.

 

                 Looking at the years between 1967 and

 

       1982, so about 15 years, of Maxolon only--so this

 

       is looking at the use of, if you will, the Reglan

 

       equivalent in the U.K.--it established 15.9 million

 

       prescriptions over this 15-year period, so just

 

       over 1 million per year.  They identified four

 

       cases of TD.

 

                 Then there was a prospective study by the

 

       same author looking at a time point in 1986 over a

 

       six-month period where they prospectively looked at

 

       prescriptions, again for Maxolon, the Reglan

 

       equivalent, not for the metoclopramide-analgesic

                                                                 42

 

       combination.  So, for this Reglan equivalent, they

 

       identified just over 2-and-a-half thousand

 

       prescriptions or patients who were given

 

       prescriptions and found 25 extrapyramidal events

 

       with 12 dystonias, eight akathisias, five

 

       drug-induced Parkinsonism but no case of tardive

 

       dyskinesia.

 

                 It might be helpful just for me to set in

 

       context the dosage issues of metoclopramide in the

 

       form of Reglan or Maxolon and that suggested for

 

       MT100.

 

                 (Slide CC-23)

 

                 Reglan, here, I understand, is used at a

 

       recommended dose of 10 to 15 milligrams per day, in

 

       some cases up to 20 milligrams, but the general

 

       recommendation is for 10 to 15, up to four times a

 

       day.  So the maximum dose would be 60 milligrams a

 

       day.  Then the course of the medication varies

 

       according to the indication it is used for, up to

 

       eight weeks or up to 12 weeks.

 

                 If you look at the maximum calculated

 

       recommended exposure for one course, you come to

                                                                 43

 

       just over 5 grams of metoclopramide.  But, if you

 

       take a conservative estimate of usage--let's say if

 

       you half that recommended maximum--you would come

 

       out with, let's say, 10 milligrams four times a day

 

       and for eight weeks rather than 12 weeks.

 

       You come out to about 2.24 grams, so that is 45

 

       percent of the maximum recommended dose on that

 

       schedule.

 

                 Just to put this in context, that

 

       half-exposure, if you wish, half of the maximum

 

       recommended exposure, is the equivalent to treat

 

       166 doses of MT100, 166 migraine attacks, or, if a

 

       patient were to take MT100 at its maximum

 

       recommended dose of 6 tablets per month every

 

       month, they could take 2.3 years of MT100.

 

                 In fact, the median number of doses per

 

       year of MT100 in the 302 study was 22, so if you

 

       translated this into practical MT100 usage, this

 

       would be the equivalent to seven-and-a-half years

 

       of Reglan at half its maximum recommended dose or

 

       15 years of practical use of MT100 at the maximum

 

       exposure of Reglan in one specific course.

                                                                 44

 

                 So that just sets the sort of dosage

 

       issues in context.

 

                 (Slide CC-24)

 

                 I would like to now come to this very

 

       helpful review by Shaffer, Dr. Shaffer, who was--he

 

       and two other colleagues from the FDA and another

 

       from Duke published a paper looking at the U.S.

 

       reporting system for the period 1968 to 2003, so

 

       over 35 years.

 

                 Now, just for the 10-year period between

 

       1994 and 2003, they estimated that there were about

 

       42 million scripts for metoclopramide.  They

 

       identified in their database 87 cases, 40 of which

 

       made that predetermined definition of TD.  But I

 

       will talk about this in a little bit more detail.

 

                 (Slide CC-25)

 

                 This is a 35-year review.  Interestingly,

 

       just when they looked at all the scripts for

 

       patients who were given metoclopramide, 62 percent

 

       of those were intended for women and 24 percent,

 

       almost a quarter, were intended for patients who

 

       were age 70 or over.  The authors actually didn't

                                                                 45

 

       include the use of migraine in their estimations

 

       but I understand from the FDA submission that they

 

       have now calculated that 2 percent of this use was

 

       for migraine and, no doubt, they will address that

 

       issue specifically themselves.

 

                 Now, the predetermined definition of TD

 

       that these authors used to identify their cases was

 

       metoclopramide exposure for 30 days or more and

 

       documented involuntary movements or symptoms.  As I

 

       say, they identified 87 separate reports but 60 of

 

       these had involuntary movements and 53 had duration

 

       of use of 30 days or more.

 

                 In practice, 40 of the 87 met the

 

       predetermined criteria of TD.  I note that, in the

 

       FDA submission, their number is 68 and, again, no

 

       doubt, they will address that separately.

 

                 Of those that did develop TD, the mean age

 

       was 60 with a range of 11 weeks to 95 years, and 65

 

       percent of the TD patients were women which

 

       corresponds, actually, quite well with the 62

 

       percent women that were given the scripts in the

 

       first place.

                                                                 46

 

                 The mean dose was 33 milligrams per day,

 

       the duration 753 days although, again, the FDA

 

       submission, I note, identifies the median as 180

 

       days.  Six of the patients were on anti-psychotics

 

       as well as metoclopramide and 22 of them were

 

       considered to have permanent disability, eight of

 

       whom needed a visit to the emergency department or

 

       hospitalization because of their TD.

 

                 (Slide CC-26)

 

                 I would like to now move from what I have

 

       considered in terms of the Reglan or Maxolon type

 

       usage in the U.K. and the U.S. to the intermittent

 

       or episodic.  Here I would like to draw my own

 

       distinction between these.

 

                 In my understanding, intermittent

 

       pharmacotherapy is a course of treatment separated

 

       by a period of treatment followed by another course

 

       of that same treatment so, over a prolonged period,

 

       intermittent doses with periods in between without

 

       the medication.  I contrast that with episodic PRN

 

       or as in "when required" use such as, for instance,

 

       as used in acute migraine attacks.  That is what I

                                                                 47

 

       am going to refer to as episodic use.

 

                 (Slide CC-27)

 

                 Let me just remind you that, in the U.K.,

 

       we have, for the last 25 years, had access to these

 

       metoclopramide-analgesic combinations for the

 

       treatment, the episodic treatment, of acute

 

       migraine the dosage of which, in any 24 hours, is

 

       30 milligrams.  Looking at the equivalent,

 

       incidently, in MT100, the maximum daily dose is

 

       13.5 milligrams in terms of the base of

 

       metoclopramide which is the equivalent in these

 

       combinations.

 

                 In the U.K., it is estimated almost

 

       100,000 patients receive a total of about 8 million

 

       doses of these combinations per year.  In the

 

       five-year period 1999 to 2003, there were estimated

 

       to be a total of 40 million doses.  So these are

 

       drugs which are used relatively commonly for the

 

       treatment of acute migraine in the U.K.

 

                 (Slide CC-28)

 

                 Now, the ADROIT database is a physician

 

       database.  It records physician-identified and

                                                                 48

 

       reported adverse events to a central, now

 

       computerized, database and it records prescriptions

 

       as well as adverse events, so it is particularly

 

       helpful.

 

                 In the period 1964, when metoclopramide

 

       first became available, to 2005, so about a 40-year

 

       period, they were able to collect data on

 

       metoclopramide.  But what is, I think, of

 

       particular interest this morning is that this

 

       database is able to discriminate between the

 

       Maxolon-Reglan type use in the U.K. and the use of

 

       metoclopramide-analgesic combinations for acute

 

       migraine.  So the database discriminates between

 

       those two uses.

 

                 They found almost 3000 adverse-event

 

       reports by any route of which 156 were related to

 

       the acute-migraine metoclopramide-analgesic

 

       combinations of which 69 were neurological over a

 

       period from 1980 to 2005 which is when these

 

       combinations have been available to us.

 

                 (Slide CC-29)

 

                 Just to look at little bit more closely at

                                                                 49

 

       these 69 neurological events over that 25-year

 

       period reported to this database, there were 26

 

       dystonias or oculogyric crises, eight

 

       extrapyramidal disorders not specified, three

 

       dyskinesias which were not classified as TD--they

 

       were reversible after the patient stopped their

 

       medication--one of Parkinsonism, one of akathisia

 

       but no reports of choreiform movements and no

 

       reports over this 25-year period of tardive

 

       dyskinesias.

 

                 (Slide CC-30)

 

                 There were a collection of other

 

       neurological events; acute extrapyramidal disorders

 

       were numbered 14 and this may well include things

 

       like oculogyric crises, and then a variety of other

 

       neurological features.  So that totals a number of

 

       69 none of which were TD.

 

                 (Slide CC-31)

 

                 Just to make a comparison between acute

 

       episodic use of metoclopramide-analgesic

 

       combinations for acute migraine and the other

 

       general use of metoclopramide, I have listed there

                                                                 50

 

       the adverse events.  You will see that there have

 

       been reports, of course, of a variety of

 

       neurological events including the

 

       dystonia/oculogyric crises with the more chronic

 

       type of metoclopramide use, the sort of

 

       Maxolon-Reglan type use, and 24 cases of tardive

 

       dyskinesia with the non-migraine use of

 

       metoclopramide compared to the zero for the

 

       migraine use.

 

                 (Slide CC-32)

 

                 I would just like to very briefly cover

 

       the MT100 experience; nine phase 3 studies, 3,700

 

       subjects, over 25,000 doses and a study which took

 

       just over a 1,000 patients to follow them up over a

 

       period of up to 12 months.

 

                 In the MT100 studies, there were two

 

       patients that experienced acute dystonic reactions

 

       but no patients that experienced tardive

 

       dyskinesia.

 

                 (Slide CC-33)

 

                 Just looking at the longer-term study,

 

       1,000 patients recruited, 621 were followed over

                                                                 51

 

       six months, 329 over 12 months, treating 23,000

 

       migraine attacks.  As I mentioned before, the

 

       median number of doses per patient over the 12

 

       months was 22 and the mean number of days between

 

       each dose was almost 10.

 

                 (Slide CC-34)

 

                 So just looking at the--one has to accept

 

       somewhat limited MT100 data.  We haven't seen any

 

       cases of TD.  But just looking at the U.K. data

 

       where we have got data now for over 25 years, and

 

       there is that period 1999 to 2003 where

 

       specifically, just for that period, they have

 

       estimated 40 million doses, we haven't had any

 

       reports to the ADROIT database of any cases of

 

       tardive dyskinesia over that period.

 

                 (Slide CC-35)

 

                 I would like to summarize.  I think we

 

       have to accept that the MT100 experience is

 

       insufficient to exclude a small risk of TD with its

 

       usage.  But, moving to the larger U.K. experience,

 

       I think we have had no reports of

 

       analgesic-metoclopramide combinations causing TD

                                                                 52

 

       and that is use for migraine over 25 years and at a

 

       very conservative estimate, over 100,000 million

 

       doses.

 

                 This, remember, is using a dosage and a

 

       frequency for these analgesic-metoclopramide

 

       combinations in the U.K. which is greater than that

 

       which is proposed for MT100.

 

                 (Slide CC-36)

 

                 The FDA briefing documents raised some

 

       important topics and I would just like to address

 

       three of those specifically.  The first is the

 

       question that they asked, is there sufficient

 

       evidence that the chronic intermittent

 

       administration of metoclopramide does not carry the

 

       same risk of TD as the chronic administration.

 

                 I can say that the experience from the

 

       U.K. over the 25 years that we have had them of

 

       these metoclopramide-analgesic preparations, the

 

       answer is yes.  Yes; we do have sufficient evidence

 

       that the chronic intermittent administration of

 

       metoclopramide does not carry the same risk of TD

 

       as the chronic administration.

                                                                 53

 

                 (Slide CC-37)

 

                 So, if the answer is yes, what is the

 

       maximum number of recommended monthly doses to

 

       avoid the risk of TD?  Well, the answer to that is

 

       not known.  But I have to come back to the U.K.

 

       experience just to mention that, over the 25 years,

 

       there have been no cases of TD using the

 

       metoclopramide-analgesic combinations at their

 

       recommended dose and schedule which exceeds that

 

       for MT100.

 

                 (Slide CC-38)

 

                 Finally, this is an issue which will be

 

       addressed by other experts specifically and that is

 

       on medication-overuse headache, but the question is

 

       posed, do you believe that, based on the existing

 

       data on medication-overuse headache, there is

 

       evidence that the proportion of patients prescribed

 

       MT100 will likely take a number of monthly doses

 

       higher than that recommended.

 

                 Well, I can't answer this question

 

       specifically, of course, but I can only say that if

 

       this does happen, even if it does happen with this

                                                                 54

 

       type of combination, the U.K. data don't indicate

 

       that it should lead to TD.

 

                 Thank you very much.

 

                 (Slide CC-39)

 

                 I would like now to pass to Dr. Jim

 

       Alexander who is Pozen's Chief Medical Officer.  He

 

       will review the data on the efficacy of MT100 in

 

       migraine.

 

                 DR. KIEBURTZ:  Same thing.  Anyone have a

 

       point of clarification?

 

                 DR. SMITH:  Could you go over with me, on

 

       Slide CC-21, the definition of tardive dyskinesia,

 

       please--the definition.  My question is, you say

 

       some definitions include the duration of exposure.

 

       When do the definitions include that?  In other

 

       words, is that a common use definition?

 

                 DR. SCHAPIRA:  The definitions vary.  As I

 

       say, some definitions, looking at the case studies

 

       that have been published on TD and metoclopramide

 

       have required that the patient has been taking

 

       metoclopramide continuously for two months, others

 

       for three months.  Some of the other studies like

                                                                 55

 

       the Shaffer review have said that the patient

 

       should be taking it for 30 days or more.

 

                 So there is some variation in how people

 

       define the requirement of metoclopramide exposure

 

       before they will associate it with TD.

 

                 DR. SMITH:  I see.  So, if it doesn't meet

 

       the duration of use, it would be dyskinesia, not

 

       TD?  Is that correct?

 

                 DR. SCHAPIRA:  I think that would depend

 

       on the individual study and the interpretation of

 

       the authors.  For instance, in the Shaffer paper,

 

       they identified that they would use the definition

 

       of 30 days or more.  But they also recognized--for

 

       instance, I think they reported on three juvenile

 

       cases, two infantile and one adolescent case, that

 

       developed tardive dyskinesia, I think the two

 

       infants following an overdose of metoclopramide and

 

       the adolescent also had some other features.

 

                 So I think it depends clearly how strictly

 

       you want to define and whether you will comment on

 

       other cases that fall outside your definition.

 

                 DR. SMITH:  Okay.  Thank you.

                                                                 56

 

                 DR. KIEBURTZ:  Let's hold on that because

 

       we will hear more about definitions.  If the

 

       question is about TD definitions--no?  Go ahead.

 

                 DR. LENAERTS:  Dr. Schapira, in sharing

 

       your U.K. experience, what is your estimate of the

 

       prevalence of specifically migrainers either

 

       overusing metoclopramide-analgesic combinations or

 

       staying frequently or constantly at the maximum

 

       recommended dose, because you mention--

 

                 DR. KIEBURTZ:  Excuse me.  I am just going

 

       to stop.  If you have a clarification on what he

 

       presented, that is one thing.  Additional questions

 

       about something he didn't talk about, not yet.

 

                 DR. LENAERTS:  Thank you.  I will hold.

 

                 DR. KIEBURTZ:  Just clarifications of the

 

       presented material.  Dr. Katz?

 

                 DR. KATZ:  A couple of questions.  On

 

       Slide 22, the second Bateman study, just for

 

       clarification, what the design was.  That was a

 

       prospective study?

 

                 DR. SCHAPIRA:  No; that is a retrospective

 

       study.  The CSM, yellow-card system.

                                                                 57

 

                 DR. KATZ:  The second one is the

 

       yellow-card system.  I thought you said it was a

 

       prospective study.

 

                 DR. SCHAPIRA:  No.  I'm sorry.  The second

 

       Bateman study that you see on the slide there, the

 

       one published in 1989, that was a prospective

 

       study.

 

                 DR. KATZ:  Right; I am talking about the

 

       second study.

 

                 DR. SCHAPIRA:  I'm sorry.  I thought you

 

       said second on the list.

 

                 DR. KATZ:  Oh; I'm sorry.  The second

 

       Bateman study, the 1989.  So that is prospective,

 

       so those patients were followed and their adverse

 

       events were recorded contemporaneous with their

 

       occurrence.

 

                 DR. SCHAPIRA:  Yes.

 

                 DR. KATZ:  It was a true prospective--

 

                 DR. SCHAPIRA:  Yes.

 

                 DR. KATZ:  Okay.  Thanks.  One other

 

       question.  Slide 28, which looks at the reports of

 

       these events over a 40-year period, do you know

                                                                 58

 

       anything about the temporal pattern of those

 

       reports?  In other words, were there more reports

 

       earlier on and then reports started to wane over

 

       time which sort of happens all the time, we think,

 

       with spontaneous reports?  Do you know anything

 

       about that?

 

                 DR. SCHAPIRA:  No; I can't comment on

 

       those.  I can only say that the system has been in

 

       place, of course, for all of that time.  More

 

       recently, over the past years, it has been

 

       computerized.  So the ADROIT system is a fairly

 

       responsive system which is linked to primary-care

 

       computers throughout the U.K.  But I can't tell you

 

       about the pattern of those over the years.

 

                 DR. KATZ:  Just one other, if I can,

 

       question.  The previous slide, 27, which looks at

 

       the combination, the actual acute-migraine

 

       treatments, do we know the actual doses that people

 

       took?  As you say, the maximum dose, I guess, is 30

 

       a day.  Do we know?  I don't know.  Maybe we figure

 

       it out from the numbers, but do we know what people

 

       actually took?

                                                                 59

 

                 DR. SCHAPIRA:  No; we don't know precisely

 

       how many they took, only how many were prescribed.

 

       As I say, it is estimated as an average of 85 per

 

       person, but that doesn't tell you how many they

 

       took in an individual dose.  So I don't have the

 

       data on that.

 

                 DR. KATZ:  Dr. Fahn?

 

                 DR. FAHN:  If we can go back to slide 22,

 

       again, for a clarification, the second Bateman

 

       study, the 1989 study, zero cases of TD, do you

 

       know what definition of TD they used to come to

 

       that number?

 

                 DR. SCHAPIRA:  No.  They did not specify

 

       their definition of TD.

 

                 DR. KIEBURTZ:  Dr. Goldstein?

 

                 DR. GOLDSTEIN:  I am not all that familiar

 

       with your drug-reporting system.  Two questions

 

       about it.  One is how compulsive is the use of

 

       this?  In other words, how often do you think you

 

       are actually getting reports about things that are

 

       actually happening.

 

                 The second question related to it is does

                                                                 60

 

       the system allow for validation somehow of these

 

       reports because, especially with primary-care

 

       physicians, it is not clear to me how accurate

 

       these reports may be about particular types of

 

       problems.

 

                 DR. KIEBURTZ:  It is a little evaluative.

 

       It is a good question.  Can we hold on it because I

 

       am conscious that the sponsor only has a certain

 

       amount of time to present.  I don't want to

 

       infringe on that.

 

                 One last question about the second Bateman

 

       study that you have already had questions about.

 

       Was that only new prescriptions?

 

                 DR. SCHAPIRA:  Yes.

 

                 DR. KIEBURTZ:  Thank you.

 

                 DR. SCHAPIRA:  I'm sorry; can I just

 

       clarify.  That was the number of prescriptions that

 

       were given during that six-month period.  So it

 

       didn't specify whether that was a renewed

 

       prescription for that individual or not.

 

                 DR. KIEBURTZ:  Oh; I see.  Okay.  Thank

 

       you.

                                                                 61

 

                 DR. SCHAPIRA:  Thank you.  I will now hand

 

       over to Dr. Alexander.

 

                         Review of MT100 Efficacy

 

                 DR. ALEXANDER:  Thank you, Dr. Schapira.

 

                 Although the potential risk of tardive

 

       dyskinesia is the primary focus of this meeting,

 

       when Pozen and the FDA discussed the meeting, we

 

       agreed that the committee should have the

 

       opportunity to review data described in the

 

       efficacy of MT100.

 

                 (Slide CC-40)

 

                 My presentation will, therefore, summarize

 

       the results of studies designed to evaluate the

 

       efficacy of MT100 using two different trial designs

 

       which evaluated the acute treatment of single

 

       migraine attacks.

 

                 First, I will show the results from the

 

       phase 3  studies which evaluated MT100 versus

 

       placebo or metoclopramide as a pseudoplacebo.

 

       These studies examined the efficacy of MT100 as a

 

       migraine drug using those endpoints that are

 

       usually required for the approval of new migraine

                                                                 62

 

       therapies.

 

                 Secondly, I will review the data from the

 

       two component controlled trials which I will call

 

       the factorial studies.  These are the trials that

 

       compared MT100 to its two individual components.

 

       Now, as you have heard, the efficacy of naproxen

 

       sodium as a component of MT100 is really not in

 

       question.  So my focus in discussing these data

 

       will be on comparisons between MT100 and naproxen

 

       sodium which directly address the contribution of

 

       metoclopramide as a component of MT100.

 

                 (Slide CC-41)

 

                 The MT100 phase 3 program was quite

 

       extensive and almost 6,000 subjects were enrolled

 

       in six controlled trials treating single migraine

 

       attacks.  Four studies directly compared MT100 with

 

       placebo while, in the two factorial studies shown

 

       below, 301 and 304, metoclopramide was considered a

 

       pseudoplacebo.

 

                 2,355 subjects received single doses of

 

       MT100.  Did these studies provide evidence that

 

       MT100 was an effective migraine drug?  Well, Pozen

                                                                 63

 

       believes that the data clearly showed this.

 

                 (Slide CC-42)

 

                 This table lists the six studies in the

 

       left-hand column.  It is arranged to show the 30

 

       individual different primary and secondary

 

       endpoints in the five columns to the right.  Study

 

       306, which is at the top, is the study that was

 

       accepted by the FDA as demonstrating the efficacy

 

       of MT100.  The two columns on the far left show the

 

       key pain endpoints--that is, sustained pain

 

       response at 24 hours, which was the primary

 

       endpoint in four studies, and the two-hour pain

 

       response in the second column was a key secondary

 

       endpoint in five studies.

 

                 As shown now on the slide, in 11 of 12

 

       comparisons, MT100 was significantly superior to

 

       the comparator for each of these pain endpoints.

 

       In Study 303, which had an unbalanced randomization

 

       with a smaller number of placebo recipients, the

 

       p-value for sustained pain response was 0.054.

 

                 But in all six studies, the efficacy of

 

       MT100 over the comparator for the two-hour pain

                                                                 64

 

       response, shown in the second column, was

 

       significantly superior.  These results provide

 

       clear and compelling evidence that MT100 provides

 

       effective two-hour pain relief, the usual

 

       regulatory endpoint in migraine trials, as well as

 

       providing sustaining pain responses at 24 hours.

 

                 I will provide a better definition of

 

       sustained response in a few minutes.  I want to

 

       mention the efficacy on the associated symptoms.

 

       Efficacy for the associated symptoms of nausea,

 

       photophobia and phonophobia, are also for a

 

       migraine drug.  But, in contrast to pain, these

 

       symptoms are not always present in migraine attacks

 

       and, in fact, none of the Pozen studies were

 

       powered to detect differences for these endpoints

 

       but all were specified as secondary endpoints in

 

       our studies.

 

                 Nevertheless, significant differences in

 

       the incidences of these symptoms were seen among a

 

       number of these studies at two hours after dosing,

 

       as shown now.  In additional comparisons, shown in

 

       yellow, the p-values were between 0.05 and 0.1. 

                                                                 65

 

       The p-values, finally, in orange, are above 0.1.

 

                 As is reviewed in your briefing document,

 

       by three or four hours after dosing, significant

 

       benefits on all of these associated symptoms were

 

       usually present with MT100 treatment.

 

                 So, to summarize, the totality of the

 

       evidence from these six studies clearly shows that

 

       MT100 is an effective acute treatment for migraine.

 

                 (Slide CC-43)

 

                 I will now show the comparisons of MT100

 

       against naproxen sodium.  These comparisons, again,

 

       reflect the direct assessments of the contribution

 

       of metoclopramide within MT100 in order to satisfy

 

       the combination drug rule.

 

                 The two phase 3 factorial studies were

 

       each performed at sites in the U.S.  Subjects were

 

       randomized to treatment with either MT100, naproxen

 

       sodium 500 milligrams, or metoclopramide 16

 

       milligrams, the identical doses of these component

 

       drugs that are contained within MT100.

 

                 Subjects treated a single migraine attack

 

       of moderate of severe pain intensity and symptom

                                                                 66

 

       assessments were performed at baseline and hourly

 

       for 24 hours.  Rescue medication was permitted

 

       after at least two hours had elapsed after dosing.

 

                 (Slide CC-44)

 

                 I would like to take a second and explain

 

       the pain assessments in these trials, the primary

 

       endpoint as well as the secondary endpoints.

 

       Sustained pain response at 24 hours was agreed by

 

       Pozen and the FDA as the appropriate measure to use

 

       to assess the efficacy of MT100 versus each of its

 

       two components.

 

                 Sustained pain response is a composite

 

       measure of efficacy and is defined as pain relief

 

       at two hours--that is, no pain or only mild

 

       pain--and no relapse or moderate or severe pain and

 

       no need for the use of rescue medication over the

 

       next 22 hours after the two-hour assessment.  The

 

       efficacy of this endpoint is judged by how many

 

       subjects meet this definition at 24 hours.

 

                 I would like to stop at this point and

 

       explain why Pozen and the FDA agreed that the use

 

       of the two-hour pain response endpoint would not be

                                                                 67

 

       acceptable for the comparison of MT100 with

 

       naproxen sodium.  This was because both treatment

 

       are active due to the presence of naproxen in each

 

       drug and should, in fact, produce very similar pain

 

       responses at the time point of two hours after

 

       dosing.

 

                 Two-hour pain response was a secondary

 

       endpoint in these studies and was used to evaluate

 

       MT100 versus metoclopramide as a pseudoplacebo, as

 

       I have previously shown.

 

                 In contrast to the sustained pain response

 

       and two-hour response rates which measure the

 

       number of subjects responding, at the bottom of the

 

       slide, you will see three secondary endpoints that

 

       were also evaluated in these trials.  These are the

 

       Pain Intensity Difference score, PID, the Sum of

 

       Pain Intensity Difference scores, SPID, and the

 

       TOTPAR scores, or Total Pain Relief scores, over

 

       time.

 

                 These are the measurements of how much

 

       pain relief is obtained, not of how many subjects

 

       have a specific pain response at a given time. 

                                                                 68

 

       These are the accepted general endpoints for

 

       analgesics within the FDA.  They are recognized as

 

       very sensitive for detecting differences between

 

       individual active analgesic drugs.

 

                 But let's first look at the agreed primary

 

       endpoint and that was sustained pain response from

 

       these two studies.

 

                 (Slide CC-45)

 

                 Shown here are the data from these studies

 

       with a percent of responders plotted.  First, note

 

       that the metoclopramide-alone treatment produced

 

       sustained pain response rates of 19 and 20 percent

 

       which are similar to what might be expected of a

 

       placebo.

 

                 The responses to naproxen sodium alone

 

       were 9 to 10 percent higher than metoclopramide and

 

       the rates were actually 28 percent and 30 percent

 

       in the two trials.  These were significant

 

       differences over metoclopramide. The sustained

 

       response rates for MT100 were 6 percent and 4

 

       percent higher than those for naproxen sodium in

 

       these two studies.

                                                                 69

 

                 I am sure you have noted that Pozen and

 

       the FDA arrived at different p-values for these

 

       comparisons.  But both parties agree that the

 

       absolute differences are 4 and 6 percent for this

 

       endpoint.  Are these differences confirmed by other

 

       analyses?  The secondary endpoints provide support

 

       for these findings.

 

                 (Slide CC-46)

 

                 The mean SPID scores at 24 hours show

 

       significant differences for MT100 versus naproxen

 

       sodium in both studies.  So these analyses of a

 

       secondary endpoint, a valid measure of pain relief,

 

       support the findings of the sustained endpoint. I

 

       would also note, and not shown, but the fact that

 

       the differences were significant in the SPID scores

 

       at two hours after dosing in both studies.

 

                 (Slide CC-47)

 

                 A third dataset, the 24-hour TOTPAR

 

       scores, is also supportive with mean TOTPAR scores

 

       at 24 hours for these two studies showing

 

       significant differences between MT100 and naproxen

 

       sodium.  So these additional analyses, which were

                                                                 70

 

       secondary, support and confirm the results seen

 

       with the sustained pain-response endpoint and

 

       substantiate the contribution of metoclopramide to

 

       the effect of MT100.

 

                 But, even if this were not the case, there

 

       is a subgroup pseudoplacebo that seems to respond

 

       much better to MT100 than the naproxen sodium.

 

       Now, the reason that we can discuss this subgroup

 

       is the following: at the outset of the phase 3

 

       program, Pozen theorized that metoclopramide might

 

       contribute not only to better pain relief but might

 

       also contribute to the relief of nausea that may

 

       accompany migraine attacks.

 

                 (Slide CC-48)

 

                 For this reason, one of the three

 

       pre-planned analyses that were used in all of the

 

       phase 3 studies include analyses of pain endpoints

 

       within two subgroups of migraine attacks--that is,

 

       those with nausea and those without nausea at the

 

       time of treatment.

 

                 (Slide CC-49)

 

                 These are the results for subjects whose

                                                                 71

 

       migraine attacks were not accompanied by nausea.

 

       This type of migraine attack made up one-third of

 

       the attacks treated in Study 304 and one-half of

 

       the attacks treated in Study 301.  The number of

 

       subjects in each study is shown with the figure on

 

       the left being 301, the figure on the right, 304.

 

                 In these subgroups of attacks, the

 

       differences between MT100 and naproxen sodium for

 

       sustained pain responses were essentially doubled

 

       to 9 and 10 percent.  In this instance, the

 

       differences were highly significant, with p-values

 

       less than 0.01 in both studies.  This was seen in

 

       both studies and, therefore, is not likely to be a

 

       chance occurrence.

 

                 Pozen took a further step of providing its

 

       phase 3 data to Drs. Richard Lipton and Ken

 

       Kolodner who conducted independent analyses of

 

       these data and confirmed these findings.  The odds

 

       ratios and the significant p-values are provided in

 

       your briefing document in Table 11.

 

                 (Slide CC-50)

 

                 As additional confirmation, the mean SPID

                                                                 72

 

       scores in these subjects with attacks without

 

       nausea also showed significant differences in these

 

       sensitive measures of pain relief for MT100 versus

 

       naproxen sodium at 24 hours.  When Pozen met with

 

       the FDA in late 2004 and the data for this subgroup

 

       of attacks were presented to the agency, Pozen was

 

       asked if the same effect was seen for MT100 across

 

       the phase 3 studies.

 

                 The answer is definitely yes.  Pozen

 

       performed a pooled analysis of phase 3 trial data

 

       and these results were obtained.

 

                 (Slide CC-51)

 

                 These studies were conducted in the same

 

       time period.  They all treated subjects with

 

       migraine attacks of moderate to severe intensity

 

       and there were similar entry criteria and

 

       evaluation criteria.  The comparators included

 

       placebo, metoclopramide and naproxen sodium.

 

                 As you can see, there was a significant

 

       difference only in the treatment with MT100 for the

 

       comparison of the treatment of attacks with and

 

       without nausea, again, highly significant.

                                                                 73

 

                 So why would these effects be present?

 

       The only plausible explanation is the 16 milligrams

 

       of metoclopramide contained within MT100.

 

                 (Slide CC-52)

 

                 Therefore, the unique contribution of

 

       metoclopramide may be described as counteracting

 

       the gastric stasis associated with migraine,

 

       enhancing the rate of absorption of naproxen,

 

       providing better pain relief in the overall

 

       treatment population and, finally, enabling maximum

 

       benefit to be obtained in migraine attacks without

 

       nausea.

 

                 (Slide CC-53)

 

                 So where does this leave the efficacy of

 

       MT100?  Pozen believes that the data show that

 

       MT100 is an effective migraine treatment, that

 

       MT100 provides an absolute 4 to 6 percent

 

       improvement in sustained pain response over that

 

       for naproxen sodium, that MT100 provides absolute 9

 

       to 10 percent improvements in sustained pain

 

       response over naproxen sodium in migraine attacks

 

       without nausea.

                                                                 74

 

                 Secondary endpoints, SPID and TOTPAR,

 

       confirm the superiority of MT100 over naproxen

 

       sodium.  Finally, the contribution of

 

       metoclopramide to the primary endpoint of sustained

 

       pain response is demonstrated in two studies.

 

                 Thank you for your attention.

 

                 (Slide CC-54)

 

                 I would like now to introduce--it is my

 

       privilege now to introduce Dr. David Matchar,

 

       Professor of Medicine at Duke University School of

 

       Medicine.  Dr. Matchar is Director of the Duke

 

       Center for Clinical Health Policy Research and,

 

       over the past two decades, he has made significant

 

       contributions in the field of evidence-based

 

       decision making in medical care.  In the migraine

 

       area, he has been a member of the U.S. Headache

 

       Consortium and was lead author of the group's

 

       evidence-based guidelines for the treatment of

 

       migraine, a collaboration among eight professional

 

       societies.

 

                 Dr. Matchar was invited by Pozen to

 

       provide his perspective on the potential role of

                                                                 75

 

       MT100 in the treatment of migraine and his view on

 

       the balance of benefits and risks of this

 

       treatment.

 

                 DR. KIEBURTZ:  Just real quickly, any last

 

       clarifying questions?  Dr. Welch?

 

                 DR. WELCH:  The nausea versus the

 

       non-nausea studies.  Was that a prospective nausea

 

       versus non-nausea?

 

                 DR. ALEXANDER:  The studies were both

 

       designed to have a preplanned analysis of the

 

       subgroups of attacks with nausea and without

 

       nausea.

 

                 DR. WELCH:  So you didn't look for

 

       separate populations.

 

                 DR. ALEXANDER:  I'm sorry; I didn't

 

       understand.

 

                 DR. WELCH:  You didn't look for separate

 

       populations.  It was all in the same study.

 

                 DR. ALEXANDER:  Oh; I'm sorry.  It was the

 

       same study.  It was certainly not randomized

 

       between nausea and no nausea.

 

                 DR. WELCH:  Did you look at the time from

                                                                 76

 

       the start of the pain to the onset of the nausea in

 

       the nausea group?

 

                 DR. ALEXANDER:  No; we didn't.

 

                 DR. KIEBURTZ:  Dr. Temple.

 

                 DR. TEMPLE:  Maybe you will think this is

 

       too much discussion, but when you separated out the

 

       nausea people, my assumption always was you thought

 

       the drug would work better in people that had

 

       nausea, not less.

 

                 DR. ALEXANDER:  That is exactly right.  I

 

       mentioned that--I may not have emphasized it enough

 

       because initially Pozen believed that

 

       metoclopramide would have an anti-nausea effect in

 

       migraine.  The thought was, we will look at those

 

       with nausea and those without nausea.

 

                 We did that.  As it turns out, if there is

 

       an anti-nausea effect, it occurs after two hours--

 

                 DR. TEMPLE:  No; I don't even mean that.

 

       You have said that the effect on pain is better in

 

       people with nausea.

 

                 DR. ALEXANDER:  That's correct.

 

                 DR. TEMPLE:  And you did, as you showed,

                                                                 77

 

       have groups with and without nausea separated for

 

       analysis.  But what happened was the opposite of

 

       what you expected.  Maybe that is not a major

 

       point.

 

                 DR. KIEBURTZ:  Dr. Koski?

 

                 DR. KOSKI:  I assume that your patients

 

       within this study had more than one attack of

 

       migraine.

 

                 DR. ALEXANDER:  That's not correct.  This

 

       was a single-attack study.

 

                 DR. KOSKI:  It was single attack.  Thank

 

       you.

 

                 DR. KIEBURTZ:  Dr. Goldstein.

 

                 DR. GOLDSTEIN:  You may also want to defer

 

       this question for later, but the preparations that

 

       you used in these comparator studies, you went

 

       through, or somebody went through, in the beginning

 

       talking about how the MT100 is put together.  You

 

       have a core.  Then it is sprayed and sprayed again,

 

       and then there is another spraying on top of that.

 

                 In these studies, how is the

 

       metoclopramide put together?  Was this done with a

                                                                 78

 

       blind core that was then sprayed in the same way so

 

       that the pharmacokinetics would be the same?

 

                 DR. ALEXANDER:  Yes; they were identical

 

       in visual appearance and the placebo--excuse me;

 

       the comparators were identical and the

 

       metoclopramide was around a core, a blank core.

 

                 DR. GOLDSTEIN:  Thank you.

 

                 DR. KIEBURTZ:  Dr. Katz, did you have

 

       something?

 

                 DR. KATZ:  No.

 

                 DR. KIEBURTZ:  Just to remind the sponsor,

 

       we will stop in half an hour.  Just if you want to

 

       think about your presentations, we will be stopping

 

       at ten of the hour.

 

             Potential Role of the MT100 in Migraine Therapy

 

                       Balancing Benefits and Risks

 

                 DR. MATCHAR:  Good morning.  I think, in

 

       addition to the introduction that Dr. Alexander

 

       gave me, I would just like to comment that I am

 

       also a principal investigator of the three-city

 

       study of headache management that is funded by the

 

       Agency for Healthcare Research and Quality and that

                                                                 79

 

       is in an effort to link the evidence-based

 

       guidelines that have been developed to actual

 

       clinical practice.  So it is in that context that I

 

       will make my remarks this morning.

 

                 I guess, also parenthetically, I should

 

       mention that I am the husband of a migrainer and

 

       the father of a migrainer so I guess I have both a

 

       clinical, a research and also a personal interest

 

       in this topic.

 

                 (Slide CC-55)

 

                 My task that I have been asked to fulfil

 

       today is to talk about the clinical trials and the

 

       safety studies in a clinical-practice context.  In

 

       thinking about this, three questions really arose

 

       in my mind that I felt were particularly salient.

 

                 The first is is there really a role for a

 

       new migraine therapy above and beyond what we have

 

       available.  We have seven triptans that are out

 

       there, for example.  Do we really need something

 

       else?

 

                 The second question is, when we look at

 

       clinical differences in clinical-trial results of 4

                                                                 80

 

       to 6 percent, what, really, does that mean to

 

       patients.  Is that something really worth pursuing?

 

       Then the third question is how should we be

 

       thinking about benefit to risk in the particular

 

       scenario of an acute migraine treatment.

 

                 So, in talking about these three

 

       questions, or in addressing these three questions,

 

       I am going to follow the following outline which is

 

       first describing just some context of the clinical

 

       burden of migraine, efficacy in clinical trials

 

       focusing on the relationship between the measures

 

       and the meaning those measures might have in a

 

       clinical setting, and a little bit about available

 

       oral treatments including something about adverse

 

       effects of available treatments, and then, finally,

 

       talk a little more about this issue of balancing

 

       benefits and risks and a clinically useful

 

       conceptual framework that I have, I use, and I find

 

       useful in thinking about benefit and risk.

 

                 (Slide CC-56)

 

                 Not to really belabor the obvious to a

 

       group of neurologists about headache, headache is

                                                                 81

 

       about pain.  The definition from the International

 

       Headache Society places pain as key.  It is an

 

       episodic disorder lasting 4 to 72 hours with two of

 

       any of the following pain characteristics;

 

       unilateral location, pulsating quality, moderate or

 

       severe intensity and worsened by movement.

 

                 In addition, there are the associated

 

       symptoms which were described earlier, specifically

 

       photophobia and phonophobia together or nausea

 

       and/or vomiting.  So that constitutes a definition.

 

       But, again, the key element from a clinical

 

       perspective, and from the diagnostic perspective,

 

       is pain.

 

                 (Slide CC-57)

 

                 It might go without saying that migraine

 

       is not a homogenous disease.  While pain is nearly

 

       always present, what is less consistent is the

 

       presence of associated symptoms.  Here the

 

       phonophobia or photophobia, the punch line,

 

       basically, is that most people typically do have

 

       these symptoms whereas, in the case of nausea, most

 

       people typically don't have nausea.  So the data

                                                                 82

 

       here is only 38 percent reported nausea or vomiting

 

       in more than half of attacks and only 32 percent

 

       reported nausea in all attacks.  So that is just,

 

       again, the point.  The nausea is not uniformly

 

       present and that migraine really is a syndrome with

 

       a variable syndrome cluster presentation.

 

                 (Slide CC-58)

 

                 The question I am moving on to now is the

 

       issue of the unmet need.  I don't know if anyone

 

       cited the statistic of 25 million people in the

 

       United States having migraine.  That is based on a

 

       very high-quality epidemiologic study done by

 

       Richard Lipton and colleagues.

 

                 Of those 25 million, 53 percent of these

 

       individuals describe a disability, significant

 

       disability, or the need for bed rest.  Now, I think

 

       this is going to be described a bit later, but

 

       there needs to be some understanding of the true

 

       magnitude of a migraine for most migrainers.  These

 

       are very severe headaches.  They are very

 

       disabling.  In fact, a day is sliced out of that

 

       person's life.

                                                                 83

 

                 In addition to there being a lot of

 

       migrainers and the disability being quite severe,

 

       patients tend not to be satisfied with their

 

       treatment.  We will go into that a little bit

 

       later.  I will mention--I will expand a bit on the

 

       issue of adverse effects, in particular, but there

 

       is good evidence that patients are not getting

 

       effective care in their early visits, that

 

       physicians are finding it difficult to take the

 

       medications that are available to them and create a

 

       mix that is useful to a large majority of patients.

 

                 One of the issues at the bottom here that

 

       is cited, and I realize it is not a FDA concern,

 

       per se, but it certainly is a concern for our

 

       patients, is that the medications available are

 

       very expensive and often interfere with patients'

 

       willingness and ability to take them regularly for

 

       their severe attacks.

 

                 (Slide CC-59)

 

                 What do patients need?  What patients

 

       need, effectively, is what they want.  What do they

 

       want?  They want pain relief.  Again, this is from

                                                                 84

 

       a survey done by Dr. Lipton and colleagues.

 

       Patients surveyed with migraine, they say the most

 

       desirable outcomes in an acute migraine therapy are

 

       rapid onset of pain relief, their freedom from pain

 

       and there is no recurrence of pain.  So it is the

 

       notion of a sustained response to pain and

 

       sustained response that goes into the definition of

 

       what patients are asking for from a migraine

 

       therapy.

 

                 (Slide CC-60)

 

                 Do clinical measures, or do measures used

 

       in clinical trials, address what patients want?

 

       Now, the standard measure that is used in clinical

 

       trials is the ordinal rating system in which pain

 

       is rated 3, 2, 1, 0 from severe to none.  It is

 

       important to point out that 3 to 2 is not

 

       especially valuable for patients but going from 2

 

       to 1 is something that patients would clearly

 

       desire and, therefore, the criteria for entry into

 

       clinical studies would be having severe or moderate

 

       pain and the criteria for response is going from

 

       severe or moderate to mild or none.

                                                                 85

 

                 So the measure that is typically used, the

 

       standard measure that has historically been used,

 

       is pain response rate.  It is the proportion of

 

       subjects who achieve mild or pain-free status two

 

       hours after dose when pain was either moderate or

 

       severe at baseline and no rescue medications were

 

       allowed in that period.  But it is a two-hour

 

       measure.

 

                 (Slide CC-61)

 

                 Let's turn to that other issue about

 

       sustainability of the response.  Let's start with

 

       the measure I just mentioned which is a good

 

       measure.  It is a two-hour pain relief.  It is a

 

       good start.  Historically, it is what has been used

 

       as the regulatory endpoint.  Triptans, for example,

 

       were approved on the basis of the two-hour

 

       response.

 

                 But a better response takes into account

 

       this time-course issue that patients care about.

 

       Sustained pain response at 24 hours includes mild

 

       or no pain at two hours, so it is what the

 

       preceding measure includes, but also includes to

                                                                 86

 

       relapse to moderate or severe pain and no use of

 

       rescue medications.  This means you get relief.

 

       You continue to have relief.

 

                 Again, from a clinical perspective, the

 

       notion that you are not going to have a recurrence

 

       is extremely important because the possibility of

 

       having a recurrence is a very ominous concern for

 

       patients.  If you know that there is a good

 

       likelihood that this is going to come back again,

 

       you are not going to be able to experience your day

 

       in a normal way.

 

                 This also raises this concern about, well,

 

       is 5 percent more people having this response

 

       really worthwhile.  I would suggest, well, if we

 

       were only talking about 5 percent of people, or 5

 

       percent of pain, being better, going from 100 to a

 

       95, or going from 95 to a 90, that would not be

 

       particularly worthwhile.

 

                 But what we are talking about is 5 percent

 

       more people, so we are talking about people, in

 

       this case, they get relief and they continue to

 

       have relief.  Again, this is a point of

                                                                 87

 

       differentiation that distinguishes MT100,

 

       potentially, here.

 

                 At the bottom, I have here what would be

 

       considered the best outcome which would be

 

       sustained pain-free at 24 hours.  I think this

 

       constitutes our vision for what we would like to

 

       see in migraine therapy and I think we are moving

 

       towards that as a more standard measure in future

 

       clinical trials.

 

                 (Slide CC-62)

 

                 Briefly, on the issue of associated

 

       symptoms, we talked about the three photophobia,

 

       phonophobia and nausea.  In clinical trials, these

 

       symptoms tend to be more commonly reported than

 

       they are in community samples of migrainers.  But,

 

       again, even in trials, these symptoms are

 

       associated only with a fraction of the patients.

 

                 They are recorded as present or absent so

 

       the all-or-none measure is a relatively crude

 

       measure of response to treatment.  Again, efficacy

 

       is assessed at two hours which has a concern from a

 

       clinical perspective that some of these patients

                                                                 88

 

       who won't have nausea at the outset will start to

 

       have nausea after and will have nausea two hours,

 

       but then might have it relieved at three hours

 

       after their pain is relieved.

 

                 So I think the point here really is that

 

       the measures of associated symptoms--it is not that

 

       associated symptoms aren't important.  They are

 

       important.  But the measures that tend to be used

 

       and are standard in clinical trials are relatively

 

       crude and more so than the measures used for pain.

 

                 (Slide CC-63)

 

                 So what do we have currently for migraine

 

       therapy that is oral and FDA-approved for migraine

 

       indication?  What is currently available includes,

 

       on the left side, the over-the-counters, which are

 

       ibuprofen, which are two products, acetaminophen,

 

       aspirin-caffeine combination.  That is one side.

 

                 On the other side, and I would say,

 

       actually, far on the right side, are, then the

 

       prescription medications.  There are seven triptans

 

       currently FDA-approved for migraine and the point

 

       here is there is a paucity of approved oral drugs. 

                                                                 89

 

       I don't know any clinicians who would say they are

 

       particularly happy with the variety of medications

 

       that are available.

 

                 In light of the fact that most patients

 

       presenting to a doctor have failed over-the-counter

 

       medications for at least their worst headaches,

 

       then there really, truly, is a big gap in what is

 

       available when a patient presents to you.  In

 

       effect, the only thing you have available, as a

 

       migraine-specific therapy in this case, is going to

 

       be the triptans.

 

                 I will mention in a moment that that is

 

       not always a satisfactory solution for patients.

 

       Unfortunately, what happens clinically, when this

 

       gap is not filled with another more useful

 

       medication, physicians are tending to use--continue

 

       to use--narcotics and barbiturates which are

 

       undesirable for lots of reasons, three of which are

 

       that they have not been studied in clinical trials.

 

       They are not FDA-approved, so that is a concern.

 

       And they, obviously, have undesirable adverse

 

       effects.

                                                                 90

 

                 (Slide CC-64)

 

                 This clinical impression that there is a

 

       therapeutic gap is supported by empirical evidence.

 

       This is a couple of studies in which, they point

 

       out, in the real world, half of patients will often

 

       delay treatment with prescribed medications.  They

 

       will have a prescription in hand and 69 percent of

 

       them will wait and see if the headache is really a

 

       migraine.  About half of them will want to take

 

       their medication only if the attack is severe.

 

                 This is not the sign of a very healthy

 

       environment, that people have prescriptions and

 

       they are not wanting to take them even though they

 

       are having, in this case, at least moderate to

 

       severe pain.

 

                 As a consequence, I would presume, that

 

       four out of five migrainers have expressed an

 

       interest, a specific interest, in trying a novel

 

       product with similar efficacy to what they have in

 

       hand, the prescription they have in hand, but has

 

       fewer adverse effects.

 

                 (Slide CC-65)

                                                                 91

 

                 This then turns us to the issue of

 

       bothersome adverse effects.  Why don't migrainers

 

       like what we have available?

 

                 On the right side, you see the non-triptan

 

       products which include the over-the-counters I

 

       mentioned, nonsteroidals, but also include opioids

 

       and barbiturates.  As one would expect, the side

 

       effects are sleepiness, nausea, difficulty

 

       thinking, inability to function, and so on.

 

                 Not too dissimilar, even, are the triptans

 

       on the left side.  But one syndrome which is

 

       particularly bothersome to many of my patients--I

 

       know it is extremely bothersome to my daughter--is

 

       this chest-pressure phenomenon.

 

                 Yes; there are coronary effects of the

 

       triptan.  Some patients--and, indeed, it is

 

       contraindicated with patients with coronary-artery

 

       disease--but, for the vast majority of people who

 

       are having these chest-pressure syndromes, they

 

       have no coronary disease.  These are not coronary

 

       symptoms.  What they are, again, is a bit of

 

       conjecture, but they are extremely frightening and

                                                                 92

 

       most people who experience them find them

 

       sufficiently disturbing that, even if you try to

 

       convince them endlessly that they are not having

 

       cardiac ischemia, they are frightened and they

 

       won't want to take the medication.

 

                 So that is a concern and, as I say, other

 

       symptoms are sufficiently aversive for patients

 

       that they will delay their therapy or not take the

 

       medications prescribed at all.

 

                 (Slide CC-66)

 

                 Now let's turn to the issue of balancing

 

       benefits and risks of acute therapy.  To think

 

       about this, I would like you to imagine, first of

 

       all, another scenario entirely.  This other

 

       scenario entirely is a stroke-preventive

 

       medication.

 

                 A stroke-preventive medication might work

 

       and it might not work.  How do you know that it

 

       doesn't work?  For  the most part, you know it

 

       doesn't work because the patient has a stroke.

 

       Okay; you lose.  And that is how you know that your

 

       drug is a failure.

                                                                 93

 

                 Well, we have a very lucky circumstance

 

       with migraine in that migraine lends itself to

 

       tailoring.  There are multiple episodic attacks

 

       over many years.  You get immediate feedback on the

 

       efficacy of the acute treatment.  Tailoring here,

 

       then, is specifically aimed at maximizing the

 

       chance that the therapy will work for a given

 

       attack.

 

                 The idea, basically, is patients don't

 

       like to take medications that don't work,

 

       especially if they don't have any other effect that

 

       you kind of like.  So an opioid you might take even

 

       if it doesn't really--well, not me, personally, or

 

       you, personally, but, certainly, some people will

 

       take them just because they have another effect

 

       that they like.

 

                 Consequently, with this tailoring

 

       occurring, the benefit-to-risk margin actually

 

       improves over time for each of our individual

 

       patients.

 

                 (Slide CC-67)

 

                 Recognizing that some people don't like

                                                                 94

 

       words as much as they like pictures, I have here a

 

       picture that basically raises this concept as the

 

       filter of clinical experience.  We start out

 

       basically saying, look, from population studies,

 

       from clinical trials, we realize that not all

 

       patients are going to respond.  But we are going to

 

       try it.  We are going to treat all these patients

 

       within some set of characteristics.

 

                 We have some set of characteristics and,

 

       of course, it wouldn't have been approved if we

 

       hadn't considered the benefit-to-risk to be

 

       acceptable.  Now, after some period of time,

 

       patients decide this works under this condition,

 

       this doesn't work under this condition, and they

 

       pick and choose, and what we end up with is

 

       patients taking medications for which they tend to

 

       respond.

 

                 Consequently, the clinical benefit-to-risk

 

       ratio improves over time and is ultimately

 

       maximized.  Again, the point I want to make is that

 

       patients don't take drugs that don't work for the

 

       most park.

                                                                 95

 

                 (Slide CC-68)

 

                 As suggested earlier, from the experience

 

       in the U.K., as Dr. Schapira mentioned as well as

 

       using the components in the United States, the

 

       notion is that MT100 would fill in this gap that is

 

       currently basically being filled with opioids and

 

       barbiturates which is a bad scenario.  The notion,

 

       again, is that, amongst the various options, what

 

       we allow by making this new drug available is to

 

       fill in the gap and to offer an opportunity for

 

       patients to create a mix for themselves that makes

 

       the most sense for them.

 

                 Not all patients, certainly, will respond

 

       to this.  Those who will respond to it will take

 

       it.  The benefit, again, as I mentioned earlier, or

 

       the risks, will only accrue to those people who

 

       achieve benefits.

 

                 (Slide CC-69)

 

                 So, in summary, I am going to just cover

 

       those three questions real quickly.  Is there a

 

       role for a new migraine drug?  I believe the answer

 

       is unequivocally yes.  Migraine is a common

                                                                 96

 

       disorder.  Patients have significant unmet needs.

 

       The available oral medications are very limited

 

       and, unfortunately, the gap that exists is now

 

       being filled by undesirable drugs.

 

                 The second question is what is the meaning

 

       of the clinical-trial difference, this 4 to 6

 

       percent everyone is talking about.  Well, not

 

       quibbling over whether you buy the 4 to 6 percent

 

       statistical significance or not, what does

 

       5 percent mean.  Let's just say 5 percent.  5

 

       percent is not 5 percent of pain.  It is 5 percent

 

       of people.  That is an important point from a

 

       clinical perspective.  That is meaningful.

 

                 Now, the last point, or the last question,

 

       is what is the meaning of a benefit-to-risk ratio

 

       in clinical practice.  I just want to mention again

 

       this concept of tailoring.  Migraine treatment

 

       lends itself to tailoring.  Patients don't take

 

       drugs that don't work and thus, in clinical

 

       practice, we have the lucky circumstance that

 

       benefit-to-risk ratios can be optimized.

 

                 Thank you very much.

                                                                 97

 

                 DR. KIEBURTZ:  Any--Dr. Sacco?.

 

                 DR. SACCO:  Dr. Matchar, just a

 

       clarification, maybe, on Slide 63 for part of your

 

       talk.  I assume most of your talk has been

 

       indicated for acute migraine attacks.  You haven't

 

       dealt with any of the FDA-approved medications for

 

       migraine prevention, of which there are some.

 

                 DR. MATCHAR:  Oh, sure; yes.

 

                 DR. SACCO:  That would just be a

 

       clarification.

 

                 DR. MATCHAR:  Right.  These are oral

 

       products for acute indication, acute migraine.

 

                 DR. KIEBURTZ:  Dr. Lenaerts?

 

                 DR. LENAERTS:  Thank you.  I have a

 

       question regarding Slide 57.  Could you confirm the

 

       38 percent of patients reporting nausea and then 32

 

       percent, actually, reporting in all attacks.  I

 

       have some other information that says up to 90

 

       percent of people have nausea occurring.  So

 

       migrainers have up to 90 percent.

 

                 DR. MATCHAR:  Right.  The point that I am

 

       making here has to do with the patterns, the

                                                                 98

 

       typical patterns, for patients, not the average for

 

       all migraines.  So having nausea is a typical

 

       pattern in a minority of patients.  Actually, Dr.

 

       Silberstein did one of these studies and he might

 

       be able to clarify that later.

 

                 DR. KIEBURTZ:  Dr. Jeste.

 

                 DR. JESTE:  I have a similar question.  If

 

       you look at your Slide 62, you said nausea

 

       incidence is 40 to 70 percent.

 

                 DR. MATCHAR:  Right; and this is in

 

       clinical trials.  So the population you are going

 

       to see in clinical trials is going to be different.

 

       So this says, basically, as a patient enters into

 

       these trials, the presence of nausea is going to be

 

       more likely than it was going to be when you are

 

       asking the question, what is the typical pattern or

 

       cluster of symptoms among migrainers.  So, yes;

 

       patients who are in trials will typically have the

 

       symptoms more commonly.

 

                 DR. KIEBURTZ:  Thank you.

 

                 DR. MATCHAR:  I am going to turn to Dr.

 

       Silberstein.

                                                                 99

 

                 (Slide CC-70)

 

                 Dr. Silberstein is actually a colleague

 

       working on one of the clinical trials that I

 

       mentioned earlier and he is the Director of the

 

       Jefferson Headache Center and the Department of

 

       Neurology and is the President of the American

 

       Headache Society.

 

                 DR. KIEBURTZ:  We see your number of

 

       slides in the book, but just so you are--

 

                 DR. SILBERSTEIN:  I have cut them.

 

                 DR. KIEBURTZ:  Perfect.  Thank you.

 

               Clinical Considerations on Migraine Therapy

 

                 DR. SILBERSTEIN:  I want to thank

 

       everybody for having us here today.  Looking at the

 

       time, I have tried to cut and I will try to talk

 

       reasonably quickly.

 

                 (Slide CC-71)

 

                 I am going to talk a little bit about the

 

       rationale for the use of metoclopramide.  I am

 

       going to briefly talk about attacks without nausea.

 

       I am going to spend most of my time talking about

 

       medication-overuse headache of which I have a

                                                                100

 

       particular interest and then summarize a possible

 

       benefit of MT100.

 

                 (Slide CC-72)

 

                 We learned about metoclopramide and

 

       migraine many years ago from, actually, our

 

       colleagues in London.  Marshall Wilkenson and Nat

 

       Blau who run the City of London Migraine Clinic

 

       made it part of their everyday treatment and it got

 

       introduced, like many things do, on the basis of

 

       anecdote.

 

                 Many of us continue to use it in the

 

       absence of trials until you saw the evidence today.

 

       It is used to prevent nausea.  It enhances the

 

       absorption of nonsteroidals.  Many headache experts

 

       continue to use metoclopramide for those reasons.

 

                 (Slide CC-74)

 

                 I think you have seen the evidence to show

 

       that MT100 is more effective than placebo.  One can

 

       argue about the statistics, but you see in the

 

       evidence that MT100 is more effective than naproxen

 

       sodium and clearly more effective than

 

       metoclopramide.

                                                                101

 

                 (Slide CC-76)

 

                 One of issues is its 4 to 6 percent

 

       response, clinically significant.  I think, in

 

       part, it depends on how seriously you view migraine

 

       as a disorder.  If you had a patient who has had

 

       cancer of the brain and you had a survival rate of

 

       10 percent and you went to 14 percent, nobody would

 

       argue that that is clinically significant.  So take

 

       into context what migraine is to the sufferer and

 

       take into context that migraine is often considered

 

       not a serious disorder.

 

                 One of the ways of looking at it is to

 

       look at all attacks and look at the absolute and

 

       relative differences.  If the 4 to 6 percent really

 

       means in patients getting 14 to 20 percent relative

 

       increase, and if you look at the subset of attacks

 

       without nausea, you are assuming that the data is

 

       correct because the subset analysis was not the

 

       primary endpoint, you are talking about a third

 

       improvement.

 

                 This, to me, is clinically significant.

 

                 (Slide CC-78)

                                                                102

 

                 I would like to spend a little bit of time

 

       talking about the concept of medication-overuse

 

       headache, for that was one of the questions.  What

 

       is it?  First, many patients have chronic daily

 

       headache which, by definition, means nothing more

 

       than headaches occurring more than 15 days a month.

 

                 In the clinic, it is the most common cause

 

       of chronic daily headache.  I was fortunate enough

 

       to be the head of the International Headache

 

       Society Classification Committee on Chronic Daily

 

       Headache.  The criteria we came up with were the

 

       following:  headache has to be there more often

 

       than not greater than or equal to 15 days per

 

       month; regular overuse for more than three months

 

       of acute medication; the headache is actually

 

       developed or worsened coexistent with overuse;

 

       lastly, you stop the overuse medication and the

 

       headache reverts to its previous form.

 

                 (Slide CC-79)

 

                 The next issue is how much medicine.

 

       First, triptans, ergots, opioids or

 

       butalbital-containing analgesics taken on a regular

                                                                103

 

       basis ten or more days per month.  What we don't

 

       mean is ten days in a row.  We mean ten days

 

       divided up.  Two, other analgesics 15 or more days

 

       a month for a total exposure of 15 or more days a

 

       month.  That is the definition of

 

       medication-overuse headache.

 

                 (Slide CC-80)

 

                 The next issue is which are the drugs that

 

       are most likely to produce medication-overuse

 

       headache.  The first caveat is there are absolutely

 

       no placebo-controlled, well-designed clinical

 

       trials of medication-overuse headache in the world,

 

       yet.  High probability based on a series of

 

       anecdotes, opioids or narcotics, ergotamine and

 

       butalbital-containing compounds.

 

                 Chris Diener from Germany said the best

 

       thing he ever did was get butalbital-containing

 

       compounds removed from the market in Germany.  That

 

       is his legacy.

 

                 Caffeine is associated with

 

       medication-overuse headache.  Lower probability;

 

       aspirin, acetaminophen, and triptans.  Unlikely and

                                                                104

 

       controversial, other non-steroidals, DHE or

 

       neuroleptics are even associated with

 

       medication-overuse headache.

 

                 (Slide CC-81)

 

                 In summary, MT100 in migraine therapy.  I

 

       think it could be a primary therapy when simple

 

       analgesics fail.  By the time patients come to the

 

       physician, they have failed simple analgesics and,

 

       as Dr. Matchar showed, there is an area in between.

 

       Triptans can't be used, don't work or are overused.

 

                 The reason for this is, we believe, that

 

       nonsteroidals and neuroleptics, metoclopramide, in

 

       particular, are unlikely to produce

 

       medication-overuse headache.  It is common among

 

       clinicians who are interested in headache--we use

 

       this class of drugs to prevent medication-overuse

 

       headache or to treat medication-overuse headache.

 

       Lastly, we believe it can fill the gap between

 

       simple analgesics and triptans that is now being

 

       filled by opioids and by butalbital-containing

 

       compounds.

 

                 (Slide CC-82)

                                                                105

 

                 I think it is important to realize the

 

       World Health Organization has said that migraine is

 

       one of the four most disabling disorders know to

 

       mankind and that a patient with a severe migraine

 

       attack has the same degree of disability as

 

       somebody who has quadriparesis, dementia or acute

 

       psychosis.

 

                 Thank you.

 

                 DR. KIEBURTZ:  Thank you.

 

                 Any clarification questions?  Dr. Temple?

 

                 DR. TEMPLE:  One of your slides, and a

 

       number of people have shown the same one, was the

 

       attractiveness of oral metoclopramide in migraine.

 

                 DR. SILBERSTEIN:  Correct.

 

                 DR. TEMPLE:  Counteracting gastric stasis.

 

                 DR. SILBERSTEIN:  Correct.

 

                 DR. TEMPLE:  Treating or preventing

 

       nausea, enhancing absorption of NSAIDs and a lot of

 

       people use it.

 

                 DR. SILBERSTEIN:  Right.

 

                 DR. TEMPLE:  I guess what are you saying

 

       about those things?  Are you saying that is part of

                                                                106

 

       the evidence?  Or what?

 

                 DR. SILBERSTEIN:  What I am saying is the

 

       following.  Until these trials were done, we were

 

       doing this on anecdote.  Physicians continue to do

 

       a number of things in the absence of evidence-based

 

       medicine.  I think what you have seen today is

 

       evidence-based medicine.  I think the questions are

 

       going to be, there are a lot of patterns of

 

       behavior.  The pattern of behavior in the United

 

       States today for taking care of most migraine

 

       attacks is to either give a narcotic or opioid or

 

       butalbutal-containing in the absence of scientific

 

       evidence.

 

                 What I am suggesting is this is an

 

       alternative and I think it is the job of this panel

 

       to see whether it is a good or a bad alternative.

 

                 DR. TEMPLE:  Okay.  But you are not

 

       suggesting any of those reasons are the reasons or

 

       true or--

 

                 DR. SILBERSTEIN:  I am suggesting that

 

       this is the anecdotal lure and the basis of why

 

       this compound has been commonly used in the past in

                                                                107

 

       the absence of good scientific evidence.

 

                 DR. TEMPLE:  Okay.

 

                 DR. KIEBURTZ:  Thank you.

 

                 We will break now for fifteen minutes.  I

 

       will just remind the committee members that our

 

       discussions only happen in public.  During the

 

       break, you are not to discuss with other committee

 

       members or, in fact, anybody, the presentations or

 

       your views on things.  The point of having a public

 

       meeting is our discussions are public.  So, just

 

       avoid that in the interim and we will start at

 

       10:05.

 

                 Thank you.

 

                 (Break.)

 

                 DR. KIEBURTZ:  Why don't we get started.

 

       Dr. Bastings will be our first presenter, the

 

       clinical team leader.  We will have, just to

 

       clarify the agenda, about an hour-and-15-minute

 

       presentation from FDA including an invited speaker.

 

       Then we will have time to question, for the

 

       committee to question, both the sponsor and the

 

       FDA.

                                                                108

 

                 Some of the questions I kind of suppressed

 

       earlier about interpretation, context, and so

 

       forth, that is our opportunity to do that.

 

                 So, Dr. Bastings, please.

 

                            FDA Presentations

 

                     FDA Risk/Benefit Considerations

 

                 DR. BASTINGS:  Thank you.  Good morning.

 

                 (Slide 1)

 

                 I will now present you some FDA

 

       risk/benefit considerations for MT100.

 

                 (Slide 2)

 

                 As you know, MT100 is a combination of

 

       naproxen sodium 500 milligrams and metoclopramide

 

       hydrochloride 16 milligrams.  The proposed

 

       indication is the acute treatment of a migraine

 

       headache with or without aura.

 

                 The division issued a not-approvable

 

       action in May, 2004 mostly because the review team

 

       determined that the contribution of both active

 

       drug components to the claimed effects of the

 

       product had not been established.

 

                 (Slide 3)

                                                                109

 

                 According to the FDA Combination Policy,

 

       two or more drugs may be combined in a single

 

       dosage form when each component makes a

 

       contribution to claimed effects and the dosage of

 

       each component is such that the combination is safe

 

       and effective for a significant patient population

 

       regarding such concurrent therapy.

 

                 (Slide 4)

 

                 To address the Combination Policy

 

       requirements, Pozen conducted two factorial studies

 

       of similar design.  These were Study 301 and 304.

 

       In both studies, patients were randomized to MT100,

 

       naproxen or metoclopramide.  The primary endpoint

 

       was sustained pain response.

 

                 (Slide 5)

 

                 Sustained pain response is defined as a

 

       moderate or severe headache at baseline with mild

 

       or no headache at two hours and no relapse and no

 

       use of rescue medication between two and 24 hours.

 

                 (Slide 6)

 

                 This slide shows you the key result of the

 

       two factorial studies.  For Study 301, the

                                                                110

 

       sustained response rate for MT100 was 35.6 percent

 

       as compared to 29.8 percent for naproxen.  So the

 

       contribution of metoclopramide was 5.8 percent and

 

       this was not a statistically significant difference

 

       according to the prespecified analysis plan.

 

                 For Study 304, which was a much larger

 

       study, the sustained response rate for MT100 was

 

       31.8 percent as compared to 27.9 percent for

 

       naproxen.  So the contribution of metoclopramide

 

       was 3.9 percent and this was not a statistically

 

       significant difference according to the

 

       prespecified analysis plan.

 

                 (Slide 7)

 

                 This slide shows you the two-hour

 

       endpoints in the factorial studies.  I must stress

 

       that Pozen was not required to show a contribution

 

       of metoclopramide on these endpoints.  However,

 

       these are highly relevant endpoints in migraine

 

       studies.  These are the ones typically used to

 

       approve migraine drugs.  Since the primary endpoint

 

       did not show a significant contribution of

 

       metoclopramide, it is useful to examine these

                                                                111

 

       typical endpoints.

 

                 What you can see on this slide is that, in

 

       both studies, there was no significant difference

 

       between MT100 and naproxen for the two-hour pain

 

       response, the incidence of nausea at two hours, the

 

       incidence of photophobia at two hours and the

 

       incidence of phonophobia at two hours.

 

                 (Slide 8)

 

                 As you know, sustained pain response is a

 

       composite endpoint.  To better understand the

 

       changes seen with that endpoint, it is useful to

 

       look at the individual components which are the

 

       two-hour pain response and the use of relapse or

 

       rescue medication.

 

                 So, in Study 301, you can see that the

 

       two-hour response for MT100 was 48.1 percent as

 

       compared to 46.6 percent with naproxen.  So the

 

       contribution of metoclopramide at two hours at 1.5

 

       percent.  This was not statistically significant.

 

                 The use of rescue medication or the

 

       relapse of the headache after a response at two

 

       hours was seen in 12.6 percent of MT100 patients

                                                                112

 

       versus 16.8 percent of naproxen patients.  So the

 

       contribution of metoclopramide there was 4.2

 

       percent and this adds up to 5.8 percent of

 

       difference in the sustained response rate.

 

                 (Slide 9)

 

                 In Study 304, you can see a contribution

 

       of metoclopramide for the two-hour pain response of

 

       3.1 percent and you see that the difference in the

 

       relapse or rescue-medication use is less than 1

 

       percent.  This adds up to 3.9 percent of difference

 

       in the sustained response rate.

 

                 (Slide 10)

 

                 Finally, this slide shows the sustained

 

       responses for the associated symptoms.  Sustained

 

       responses here are defined in a similar manner as

 

       for sustained pain response.  For example,

 

       sustained nausea-free means no nausea at two hours

 

       with no relapse of nausea between two and 24 hours

 

       and not use of rescue medication.

 

                 What you can see is that, in both studies,

 

       there was no significant difference between MT100

 

       and naproxen for sustained nausea-free, sustained

                                                                113

 

       photophobia-free, and sustained phonophobia-free.

 

                 (Slide 11)

 

                 Pozen met with the division in October,

 

       2004, and, at that time, they presented these

 

       subgroup analyses which suggested a contribution of

 

       metoclopramide in patients with no nausea at

 

       baseline.  At that time, the division considered to

 

       accept the prospective replication of these

 

       findings to fulfill the Combination Policy

 

       requirements but we assured Pozen that we would

 

       need to bring this to an advisory meeting because

 

       this is an unusual patient population and we need

 

       to make sure the benefits in that population

 

       outweigh the risk related to metoclopramide.

 

                 (Slide 12)

 

                 I will briefly show you these subgroup

 

       analyses that Pozen made.  You already know that,

 

       for the combined patient population, there was no

 

       significant difference between MT100 and naproxen

 

       for sustained pain response and for the two-hour

 

       pain response.

 

                 If you look at the patients who did not

                                                                114

 

       have nausea at baseline, you see about 10 percent

 

       difference between MT100 and naproxen with a low

 

       p-value.  But, if you look at the two-hour pain

 

       response, there was no significant difference

 

       between MT100 and naproxen even in that subgroup.

 

                 For patients who had nausea at baseline,

 

       you can see that there was less than 1 percent

 

       difference between MT100 and naproxen for sustained

 

       pain response.  For the two-hour pain response, the

 

       rate was actually numerically higher for naproxen

 

       but the difference was not statistically

 

       significant with MT100.

 

                 (Slide 13)

 

                 Similar findings for Study 304.  You know

 

       that, for the combined patient populations, there

 

       was no significant difference for sustained pain

 

       response and two-hour pain response.  For patients

 

       with no nausea at baseline, again, there is about a

 

       10 percent difference between MT100 and naproxen.

 

       For the two-hour pain response, there is no

 

       significant difference between MT100 and naproxen

 

       for that subgroup.

                                                                115

 

                 For patients with nausea at baseline,

 

       there was about a 1 percent difference between

 

       MT100 and naproxen for sustained pain response and

 

       the two-hour pain response.  These differences were

 

       not statistically significant.

 

                 (Slide 14)

 

                 I would like to give you some thoughts on

 

       an indication limited to patients with no nausea at

 

       baseline.  In a survey of 500 self-reported

 

       migrainers, nausea occurred in more than 90 percent

 

       of these patients and nearly one-third of these

 

       experienced nausea during every attack.

 

                 Less than 10 percent of patients

 

       consistently had migraine with no nausea at

 

       baseline which is the indication for which MT100

 

       which is being considered today. In line with that

 

       survey, there was a 45 to 69 percent incidence of

 

       nausea at baseline in the MT100 phase e studies.

 

                 (Slide 15)

 

                 Migraine patients, in the majority of

 

       them, may have some attacks with nausea and other

 

       attacks without or nausea may develop during the

                                                                116

 

       attack.  Patients would, therefore, need two

 

       different treatments based on the presence or

 

       absence of nausea or they would treat their attacks

 

       with nausea with a combination product containing

 

       metoclopramide which has no established

 

       contribution for efficacy for the type of attack.

 

       Yet, they would be exposed to the risk of

 

       metoclopramide.

 

                 (Slide 16)

 

                 As you know, our main safety concern is

 

       tardive dyskinesia.  Tardive was originally

 

       intended to emphasize a late appearance during

 

       neuroleptic treatment.  However, there have been a

 

       number of reports that TD may appear early during

 

       the neuroleptic treatment and there seems to be no

 

       fundamental distinction between cases appearing

 

       early and those appearing late.

 

                 (Slide 17)

 

                 In addition, there have been a number of

 

       TD variants described and these include tardive

 

       dystonia, tardive akathisia, tardive myoclonus,

 

       tardive tics, tardive tremor, and it is very much

                                                                117

 

       unclear how well these different variants have been

 

       captured in the post-marketing reporting systems.

 

                 (Slide 18)

 

                 TD is a well-known side effect of

 

       metoclopramide.  Its exact incidence remains

 

       unclear.  There was no case reported in the MT100

 

       database but the database was too small to detect

 

       rare events such as TD.

 

                 (Slide 19)

 

                 The current metoclopramide labeling

 

       includes a warning which I am going to read to you.

 

       "Tardive dyskinesia may develop in patients treated

 

       with metoclopramide.  Although the prevalence of

 

       the syndrome appears to be highest among the

 

       elderly, especially elderly women, it is impossible

 

       to predict which patients are likely to develop the

 

       syndrome.  Both the risk of developing the syndrome

 

       and the likelihood that it will become reversible

 

       are believed to increase with the duration of

 

       treatment and the total cumulative dose.  Less

 

       commonly, the syndrome can develop after relatively

 

       brief treatment periods at low doses.  In these

                                                                118

 

       cases, symptoms appear more likely to be

 

       reversible."

 

                 (Slide 20)

 

                 Because of these safety concerns, the FDA

 

       limited the indication of oral metoclopramide for

 

       short-term therapy for gastroesophageal reflux for

 

       up to 12 weeks and only when conservative treatment

 

       fails for the treatment of diabetic gastroparesis

 

       for up to eight weeks.  The recommended dose is 5

 

       to 15 milligrams up to four times a day.

 

                 (Slide 21)

 

                 As I mentioned earlier, there have been a

 

       number of cases reported in the literature of the

 

       relatively short durations of treatment, sometimes

 

       as short as one or two weeks.  We also asked our

 

       colleagues from the Office of Drug Safety to look

 

       for cases of movement disorders associated to

 

       metoclopramide in the AERS database and you will

 

       hear a presentation with much more detail on that

 

       topic later in the morning.

 

                 In that analysis, the first quartile of

 

       duration of treatment for the cases of TD was 19.5

                                                                119

 

       days.

 

                 (Slide 22)

 

                 This slide show you a breakdown of the

 

       treatment duration.  You can see that there are

 

       quite a few cases with duration of treatment less

 

       than the 90-day definition which has been used in

 

       some of the earlier studies.

 

                 (Slide 23)

 

                 We also asked our colleagues from ODS to

 

       look at the patterns of use of metoclopramide.

 

       Metoclopramide is mostly used for GI indications.

 

       Migraine use, up to now, is quite limited.  It is

 

       less than 2 percent.  13 percent of patients

 

       appeared to have received prescriptions for more

 

       than 90 days and 7 percent of patients for more

 

       than 180 days, so exceeding the labeling

 

       recommendations.

 

                 Over a three-year period, cumulative

 

       therapy was longer than 90 days for almost 20

 

       percent of patients and greater than 180 days for

 

       over 10 percent of patients, again exceeding the

 

       recommendations.

                                                                120

 

                 (Slide 24)

 

                 What about the risk of TD associated with

 

       chronic intermittent use of metoclopramide as has

 

       been proposed in this NDA.  This is very difficult

 

       to evaluate for a variety of reasons which include

 

       that there is no current indication for chronic

 

       intermittent use in the United States and that

 

       there is no specific capture of chronic

 

       intermittent use in the AERS database.

 

                 Some animal data suggests that the

 

       intermittent use of neuroleptics may be no safer,

 

       or even riskier, than continuous use in an animal

 

       model of TD.  In the psychiatric population, the

 

       number of interruptions in chronic treatment--so

 

       this is slightly different from chronic

 

       intermittent but this may be suggestive--the number

 

       of interruptions was the second factor after age in

 

       predicting the occurrence of TD.

 

                 (Slide 25)

 

                 Another concern that we have is the

 

       overuse of acute migraine drugs.

 

       Medication-overuse headache was recently introduced

                                                                121

 

       in the IHS classification.  There is a subcategory

 

       of analgesic-overuse headache.  According to

 

       experts, there is substantial evidence that all

 

       drugs used for the treatment of migraine may cause

 

       medication-overuse headache and the prevalence of

 

       medication-overuse headache in the general

 

       population is around 1 percent.

 

                 The IHS also said that the overuse of

 

       symptomatic migraine drugs is the most common cause

 

       of chronic daily headache.  We are not that much

 

       worried that MT100 could cause chronic daily

 

       headache.  We are just worried that there could be

 

       a similar abuse of the drug as has been seen with

 

       the other approved or non-approved migraine drugs.

 

                 (Slide 26)

 

                 So we have the following questions for the

 

       advisory committee.  The first one; in a recent

 

       submission to the NDA, Pozen estimated an annual

 

       incidence of TD of up to 0.038 percent for

 

       metoclopramide at a daily dose of 30 to 40

 

       milligrams per day for 72 days per year which

 

       corresponds to up to 380 cases of TD per million

                                                                122

 

       patients per year.

 

                 Do you think that this is a reasonable

 

       estimate?  If MT100 were to carry the same risk,

 

       would such a risk level be acceptable if the only

 

       contribution of metoclopramide is a 5 to 10 percent

 

       improvement on sustained headache relief with no

 

       effect onto our endpoints?  Is any risk of TD

 

       acceptable for a migraine population?

 

                 (Slide 27)

 

                 Question 1; is there sufficient evidence

 

       that the chronic intermittent administration of

 

       metoclopramide does not carry a risk of TD?  Is it

 

       possible to define a maximum recommended number of

 

       monthly doses of MT100 to avoid the risk of tardive

 

       dyskinesia?

 

                 (Slide 28)

 

                 Question 3; do you believe that, based on

 

       the existing data on medication-overuse headache,

 

       there is evidence that a proportion of patients

 

       prescribed MT100 will likely take a number of

 

       monthly doses higher than recommended?

 

                 (Slide 29)

                                                                123

 

                 Question 4; all currently approved acute

 

       treatments of migraine are indicated without

 

       restriction regarding the presence of absence of

 

       nausea at baseline.  Given that patients may have

 

       nausea at some attacks and no nausea at others,

 

       does an indication limited to the subpopulation of

 

       migraine patients with no nausea at baseline

 

       represent a clinically meaningful and acceptable

 

       indication?

 

                 (Slide 30)

 

                 The last question; if Pozen shows

 

       prospectively in a new clinical study in migraine

 

       patients with no nausea at baseline a significant

 

       contribution of metoclopramide on sustained

 

       headache pain relief of 5 to 10 percent with no

 

       contribution at two hours and no contribution on

 

       relapse rates or rescue-medication use in the two

 

       to 24 hour period, would the demonstrated benefit

 

       outweigh the risk related to TD?  If not, what

 

       additional data or desired primary outcome, or

 

       desired effect on sustained relief, could provide

 

       evidence of safety and efficacy?

                                                                124

 

                 (Slide 31)

 

                 Finally, I would like to thank the

 

       following FDA colleagues who have contributed to

 

       this presentation .      Thank you for your attention.

 

                 DR. KIEBURTZ:  Thank you.  Same deal.  If

 

       there are some clarifying questions.  Let me just

 

       point out some things about the questions which Dr.

 

       Bastings has presented.  After the public hearing

 

       this afternoon, that will be the time we have to

 

       spend a great deal of time discussing these.

 

                 We can clarify points of these questions

 

       at that time rather than at this time because it

 

       will be immediate to our discussion.

 

                 I would just add at this point my approach

 

       to this, or our approach to this, should be that

 

       there are some assumptions made in here.  We are

 

       not debating whether those assumptions are good

 

       ones or bad ones.  The question to us is, if that

 

       was assumed, how would you think.  This is what Dr.

 

       Katz referred to earlier in terms of this being

 

       somewhat hypothetical.

 

                 I think we could spend a lot of time

                                                                125

 

       arguing about whether the assumptions are good ones

 

       or not.  I don't think that is the meat of the

 

       matter here.  If one assumed those things, then how

 

       would you make decisions about that.  I just want

 

       to put that out there.

 

                 There are some questions that are asked of

 

       us about estimates and whether those are

 

       reasonable.  But, again, much of the clarification

 

       on the questions, I think it would be better to do

 

       at the time we discuss the questions individually

 

       unless you have a burning question about those.

 

       Certainly, they are open to questions about the

 

       rest of Dr. Bastings' presentation.

 

                 Dr. Green.

 

                 DR. GREEN:  I have a regulatory question

 

       about the Combination Policy.  It has to do with

 

       the contribution of each drug and what is

 

       acceptable.  Is one drug increasing the

 

       bioavailability of another?  How would that be

 

       interpreted?

 

                 DR. KIEBURTZ:  Dr. Katz or Dr. Bastings?

 

                 DR. KATZ:  I think the contribution, as

                                                                126

 

       defined in the reg--it is ill-defined in the reg.

 

       It just says "some contribution."  So it could be

 

       in any one of a number of clinical areas, safety,

 

       efficacy.  But, in and of itself, increasing the

 

       bioavailability probably wouldn't be particularly

 

       helpful unless that resulted in some sort of

 

       clinical advantage; faster onset, or more sustained

 

       onset, or fewer side effects.

 

                 So, in and of itself, increasing the

 

       bioavailability in a typical case, at least off the

 

       top of my head, wouldn't be, necessarily,

 

       considered useful.

 

                 DR. TEMPLE:  But you can imagine cases,

 

       and there have been cases, where inhibiting

 

       metabolism might lead to  a more sustained and less

 

       variable blood level.  In some sense, what does

 

       carba dopa do?  So there could be cases.  But, as

 

       Russ says, you would have to weigh the disadvantage

 

       of adding another therapy and, if the alternative

 

       is just tasking 20 percent more, you would probably

 

       find that not worth it.

 

                 DR. KIEBURTZ:  Okay.  Why don't we go on. 

                                                                127

 

       Our next speaker is Dr. Jinnah from Johns Hopkins

 

       Hospital.

 

                      Overview of Tardive Dyskinesia

 

                 DR. JINNAH:  Good morning.

 

                 (Slide)

 

                 Thanks for the invitation to come and

 

       speak here.  I have been asked to give a brief

 

       summary of the clinical condition of tardive

 

       dyskinesia.

 

                 Normally, my presentation on this topic

 

       would be about an hour, but I am going to limit my

 

       comments to ten minutes and, in so doing, I am only

 

       going to be able to touch on the highlights.  I am

 

       going to skip a lot of details but I can certainly

 

       answer questions later if necessary.

 

                 (Slide)

 

                 So, with that, let me just proceed to

 

       review this topic.  The term "dyskinesia" refers to

 

       any abnormal movement and the term "tardive" refers

 

       to late or delayed.  What I would like to do is

 

       first address the nature of the abnormal movements

 

       and then go on to describe when it occurs.

                                                                128

 

                 (Slide)

 

                 The movements vary quite a bit depending

 

       on different patients.  By far the most common

 

       abnormal tardive syndrome is the so-called

 

       buccolingomasticatory syndrome, which is a bit of a

 

       mouthful, but it basically refers to abnormal

 

       movements of the face and tongue.  I will show you

 

       an example of this on videotape in just a second.

 

                 Less common tardive movement disorder

 

       syndromes include the ones listed there including

 

       tardive dystonia, which refers to mainly twisting

 

       and bending movements, tardive chorea, which

 

       resembles dancing, tardive tourettism which

 

       resembles Tourette syndrome, tardive tremor or

 

       myoclonus which, simply put, are shakes and jerks.

 

                 In addition to this group of broader

 

       movement disorders, there are some tardive

 

       syndromes that are not necessarily classified as

 

       abnormal movements but, rather, psychological or

 

       psychiatric manifestations.  These include

 

       akathisia, which is a sense of severe restlessness

 

       that prevents people from sitting still.  It

                                                                129

 

       includes unusual tardive pain syndromes which have

 

       an unusual anatomical distribution that include the

 

       oral or perineal regions, and, finally, respiratory

 

       irregularities referred to as tardive respiratory

 

       dyskinesias.

 

                 Now, most clinicians will recognize the

 

       most common form here and that is the top one, the

 

       face-and-tongue syndrome.  But the less common

 

       forms are far less well appreciated.

 

                 (Video)

 

                 Let me show you an example of two of

 

       these, first the most common one.  This is a

 

       videotape of a man who has two problems.  I hope it

 

       is not too small to see.  If you can see his mouth,

 

       it is in constant motion, jaw, lips and tongue.  He

 

       came complaining that he had trouble talking, he

 

       had trouble eating and he was biting his tongue.

 

                 You can also see his hand.  One of his

 

       hands is shaking.  He has a tremor that resembles

 

       Parkinson's disease.  This man got his condition

 

       after two years of metoclopramide use.  He was,

 

       unfortunately, unaware that he was only supposed to

                                                                130

 

       be taking the medication for three months and his

 

       doctor was unaware that metoclopramide was on the

 

       list of medications that can cause a tardive

 

       syndrome like this.

 

                 (Video)

 

                 Let me show you a second example of the

 

       tardive dystonia.  You can see this man's problem

 

       is much more severe and, perhaps, more disabling.

 

       This is an example of dystonia or the

 

       bending-and-twisting syndrome.  You can see that he

 

       has great difficulty standing up straight because

 

       of extreme arching of his back and backward bending

 

       of his head and neck.

 

                 Here you will see a closer view of the

 

       nature of this problem.  He is like this more than

 

       80 percent of his waking hours, standing or seated.

 

       He gets relief only if he lies down.  He can only

 

       temporarily bring his head to the midline position

 

       voluntarily and then it just goes back and it is

 

       too much effort to keep straight.

 

                 This man got his condition from the use of

 

       a classic neuroleptic agent which is a more common

                                                                131

 

       source of this problem.

 

                 (Slide)

 

                 So what exactly causes these syndromes?

 

       It is widely recognized that they are most commonly

 

       caused by the neuroleptics.  These are the

 

       dopamine-receptor-blocking agents that Dr. Schapira

 

       alluded to in the initial presentation.

 

       Essentially all classes of neuroleptics will cause

 

       this syndrome although some are less likely to

 

       cause it than others.

 

                 These are widely recognized but what is

 

       less well recognized is a much longer list of

 

       agents that also have the potential to cause these

 

       syndromes.  On this list include anti-emetics such

 

       as metoclopramide and prochlorperazine.  Other

 

       medications used in psychiatry such as

 

       anti-depressants and several others of which I have

 

       provided a partial list here.

 

                 (Slide)

 

                 So when do these problems actually arise?

 

       They are referred to as tardive syndromes because

 

       they usually require chronic administration of the

                                                                132

 

       offending drugs.  They occur with a wide range of

 

       prevalence according to different studies from less

 

       than 5 percent to more than 50 percent with an

 

       overall average being somewhere in the 20 percent

 

       range of chronically treated patients.

 

                 These numbers here were not derived

 

       specifically from metoclopramide use but rather

 

       from all neuroleptics and other drugs capable of

 

       causing tardive syndromes.  The incidence is

 

       estimated to be about 5 percent per year during

 

       chronic daily treatment.  The treatment duration is

 

       somewhat arguable and varies from report to report

 

       and definition to definition.  The most

 

       conservative one is that treatment requires at

 

       least three months of constant therapy.

 

                 But, as noted before, there are lots of

 

       cases out there who have developed tardive

 

       syndromes with much shorter durations of action,

 

       sometimes just a few days.  We can then ask whether

 

       or not these disorders should be classified as

 

       tardive syndromes or not, but that is generally not

 

       done in most of the epidemiological reports or

                                                                133

 

       collecting databases.

 

                 There are some known risk factors of

 

       developing this condition.  They include older age,

 

       female gender and several other less

 

       well-understood phenomena such as duration of

 

       treatment, the total cumulative dose of treatment,

 

       prior brain injury or other organic problems,

 

       diabetes, mood disorders and others.

 

                 (Slide)

 

                 How are these treated once they arise?  In

 

       general, these recommendations come from psychiatry

 

       where this problem is most prevalent.  They refer

 

       to all neuroleptics, not specifically to

 

       metoclopramide.  Generally speaking, the

 

       recommendation is to attempt to discontinue the

 

       offending agent if possible.

 

                 If it is not possible, or if

 

       discontinuation does not cause resolution of the

 

       syndrome, as it often does not, there are several

 

       other things that are often tried, but there is

 

       very little evidence supporting a beneficial effect

 

       of any of these.  Individual patients may respond

                                                                134

 

       somewhat to one or another of the items on this

 

       list, but, by no means, can these be considered

 

       reliable treatments.

 

                 Instead, at least in the psychiatry

 

       literature, the belief for the use of neuroleptics

 

       and related offending medications that can cause

 

       tardive syndromes is that prevention should be one

 

       of the key aspects of treatment.

 

                 To prevent the disorder, the general

 

       guidelines are that the neuroleptics should not be

 

       used unless there are no other alternatives.  When

 

       they are used, they should be used at the lowest

 

       dose possible.  Some even recommend intermittent

 

       withdrawal of the neuroleptic to make sure that

 

       ongoing therapy is still needed.  Since this

 

       disorder is quite difficult to treat, prevention is

 

       really quite an important element.

 

                 I believe that is all I have here and if

 

       there are any questions, I could take them.

 

                 DR. KIEBURTZ:  Dr. Jeste.

 

                 DR. JESTE:  One question.  Did you imply

 

       that antidepressants and antibiotics cause tardive

                                                                135

 

       dyskinesia?

 

                 DR. JINNAH:  Causation is difficult to

 

       establish.  If you look in the literature, you will

 

       find many cases of tardive dyskinesia reported that

 

       are due to a whole variety of different

 

       medications.  The frequency of some of these other

 

       medications--for example, antidepressants or

 

       antibiotics, or I should say the frequency of the

 

       reports, is quite low.  We could argue whether or

 

       not the patients who were presented in those

 

       reports really were tardive dyskinesia or not.

 

                 I am not passing judgement on the

 

       diagnosis of those.  But I think it is generally

 

       well-accepted that tardive dyskinesia does not just

 

       come from neuroleptic medications and that was my

 

       point.

 

                 DR. JUNG:  Can you clarify what mood

 

       disorders are associated with the development of

 

       tardive dyskinesia?

 

                 DR. JINNAH:  There appears to be a slight

 

       epidemiological risk associated with affective and

 

       schizo-affective disorders as opposed to, for

                                                                136

 

       example, schizophrenia.

 

                 DR. JUNG:  So that includes just general

 

       depression which is very prevalent in the

 

       population.

 

                 DR. JINNAH:  It does.

 

                 DR. JUNG:  Thank you.

 

                 DR. SMITH:  When a case comes up where

 

       isn't chronic exposure to a drug, is that typically

 

       categorized, then, as a dyskinesia as opposed to a

 

       tardive dyskinesia?

 

                 DR. JINNAH:  It is a very good question.

 

       I think different experts would answer you

 

       differently here.  Some people use a very strict

 

       criteria that it has to be at least 30 days or you

 

       call it something else, dyskinesia and acute

 

       abnormal syndrome.  Some people are a little bit

 

       less strict in their criteria and say, well, if it

 

       looks and behaves like tardive dyskinesia, then,

 

       perhaps, one week exposure is sufficient. But these

 

       are not generally agreed-upon timetables.

 

                 DR. JUNG:  You didn't talk about this on

 

       your slides, but could you discuss a little bit

                                                                137

 

       about the kindling phenomenon with intermittent

 

       use, or is this an appropriate time?

 

                 DR. KIEBURTZ:  Can we hold that one for

 

       the general question session.

 

                 Dr. Sacco?

 

                 DR. SACCO:  On Slide 3, I think it is

 

       Slide 3 of yours, can you clarify what you mean

 

       by--it is actually blurred on my

 

       page--restlessness.

 

                 DR. JINNAH:  Restlessness is exactly what

 

       that sounds like.  These patients report that they

 

       can't sit still.  When you watch them, they often

 

       rock in their chair.  They stand up.  They pace

 

       around.  They just can't sit still and they

 

       describe a severe inner sense of restlessness.

 

                 DR. SACCO:  Thank you.

 

                 DR. KIEBURTZ:  Just a point of

 

       clarification, a follow up on Dr. Jeste's comment.

 

       Linking exposure to a phenomenon or establishing

 

       causation is a long road.  There are various

 

       degrees of that road being established for various

 

       agents in tardive dyskinesia.

                                                                138

 

                 But, if I understood you properly, would

 

       you say that it is generally accepted that

 

       metoclopramide, as an agent, can cause tardive

 

       dyskinesia?

 

                 DR. JINNAH:  I believe most would agree

 

       with that.

 

                 DR. KIEBURTZ:  Thanks.

 

                 Our next speaker is Mary Ross Southworth.

 

                    Post-Marketing Review of Movement

 

                    Disorders and Neuroleptic Syndrome

 

                      Associated with Metoclopramide

 

                 DR. SOUTHWORTH:  Good morning.

 

                 (Slides 1 and 2)

 

                 As we have heard this morning, MT100 is a

 

       combination of metoclopramide and naproxen that is

 

       being evaluated for the treatment of acute

 

       migraine.  The proposed dosing is an a chronic but

 

       intermittent matter based on episodes of migraine.

 

       The proposed dosing of the drug recommends no more

 

       than six tablets be used per month and more than

 

       one tablet used per single migraine episode.

 

                 We were interested in looking at this

                                                                139

 

       chronic intermittent dosing, whether we could look

 

       in our adverse-event database to see whether we

 

       could elucidate the risks associated with this kind

 

       of dosing.

 

                 (Slide 3)

 

                 I think we are pretty clear on the fact

 

       that metoclopramide is well known to cause movement

 

       disorders.  In fact, the program labeling is

 

       specific on several movement disorders including

 

       extrapyramidal symptoms, Parkinsonian symptoms,

 

       tardive dyskinesia and neuroleptic malignant

 

       syndrome.  The labeling for metoclopramide

 

       recommends a daily dose of 5 to 20 milligrams QID

 

       with a duration of therapy not exceeded 12 weeks.

 

                 (Slide 4)

 

                 This slide shows number of prescriptions

 

       dispensed for metoclopramide over about the last

 

       ten years.  You can see that it exceeds 7 million

 

       in the year 2004.  This jump in number of

 

       prescriptions dispensed in 2000 coincides with the

 

       withdrawal of cisipride from the market.

 

                 You have to keep in mind that the numbers

                                                                140

 

       represented here are prescriptions dispensed, not

 

       patients.  Also keep in mind that, although this

 

       usage data slide only extends for ten years, my

 

       adverse-event review will extend farther than that.

 

                 (Slide 5)

 

                 When developing our case series for

 

       metoclopramide-associated movement disorders and

 

       neuroleptic malignant syndrome, we wanted to focus

 

       on several points.  First, could we ascertain what

 

       the reversibility of the reaction was, whether it

 

       be treatment with another pharmacologic agent or

 

       withdrawal of the offending drug.

 

                 We also were very interested in

 

       associating the dose and duration reported in the

 

       adverse-event reports, themselves, to the proposed

 

       dosing for MT100 which, as you have heard, is in a

 

       chronic intermittent manner.  We also wanted to

 

       focus on any associated risk factors that were

 

       apparent in the cases such as concomitant drugs or

 

       concomitant disease states that the patients might

 

       experience.

 

                 (Slide 6)

                                                                141

 

                 So the purpose of our review is to

 

       characterize the cases of some specific adverse

 

       events that were reported in the adverse-event

 

       reporting system, or the AERS database, that were

 

       associated with metoclopramide.

 

                 (Slide 7)

 

                 The AERS database is a computerized

 

       database which contains reports of adverse events

 

       for all U.S. marketed drugs.  It contains over 3

 

       million adverse-event reports.  The reporting in it

 

       is largely spontaneous meaning that healthcare

 

       providers are not compelled to report adverse

 

       events.  However, sponsors, when they become aware

 

       of adverse events through a variety of sources, are

 

       required by regulations to report those to the

 

       agency.

 

                 Consequently, the source of the reports,

 

       for the most part, come from sponsors.  However,

 

       there are a good number that come from healthcare

 

       providers or lay people like consumers, patients,

 

       patient's families or lawyers.

 

                 (Slide 8)

                                                                142

 

                 The left side of the screen shows the

 

       adverse events that were specifically searched for

 

       in our database.  They included neuroleptic

 

       malignant syndrome, acute dystonia, akathisia,

 

       Parkinsonism and tardive dyskinesia.  For each of

 

       these adverse events, we looked at the total number

 

       of case reports with specific focus given to daily

 

       dose of metoclopramide, the duration of treatment,

 

       any risk factors that might be present and the

 

       reversibility of the reaction.

 

                 (Slide 9)

 

                 In order to do this, we ran a search of

 

       the database using each of the movement disorders

 

       and NMS as a search term plus metoclopramide.  We

 

       classified the cases into movement-disorder

 

       categories based on the diagnosis in the case,

 

       itself.  I think it is pretty clear that there is

 

       substantial overlap between some of the reporting

 

       of the different movement disorders and, in order

 

       to keep clarity, we just used the diagnosis that

 

       was used of the case thinking we could capture the

 

       most number of cases that way.

                                                                143

 

                 Some points to remember when reviewing our

 

       case series were there could be what could be

 

       considered case misclassification because some

 

       cases might have reported a movement disorder after

 

       several doses of drug but may have caused the

 

       tardive dyskinesia where it could have possibly

 

       been called an acute dystonia.  But we used the

 

       diagnosis made in the case.

 

                 Another thing to remember is that the way

 

       cases are reported in AERS, we frequently know

 

       dose, duration or frequency of the dose given but

 

       we very rarely know whether the dose was given

 

       continuously or intermittently.

 

                 Obviously, because these are labeled

 

       adverse reactions, there is going to be

 

       under-reporting of adverse events and also because

 

       the drug has been on the market for a long time, we

 

       are not going to get a maximum number of reports of

 

       adverse events.

 

                 The quality of the reports varied, as you

 

       might expect.  There are several data points that

 

       seem to be more inconsistent and some of those

                                                                144

 

       included status of recovery.  Some cases may not

 

       have reported whether the patient recovered or not,

 

       and also time to that recovery.

 

                 (Slide 10)

 

                 This slide shows the number of reports we

 

       retrieved for each of the adverse events we

 

       searched for.  There were 37 cases of NMS, 203

 

       cases of acute dystonia, 57 cases of akathisia, 35

 

       cases of Parkinson's and 68 of tardive dyskinesia.

 

                 (Slide 11)

 

                 Using those reports, we developed our case

 

       series which I will present to you.  The case

 

       series is going to include demographics of the

 

       patients and clinical characteristics including any

 

       information we have on recovery.  I am also going

 

       to spend some time talking about cases that

 

       reported continuing symptoms at the time of

 

       reporting.  I will present some representative

 

       cases and then focus a little bit on cases

 

       associated with short-term metoclopramide therapy.

 

                 (Slide 12)

 

                 The first adverse event that will be

                                                                145

 

       presented is neuroleptic malignant syndrome.  We

 

       had 37 unique cases.  The age represented was a

 

       mean of 49.  The range of daily dose ranged from

 

       7.5 to 80 milligrams with a mean of 33, mostly I.V.

 

       dosing represented here and mostly G.I.-related

 

       indications which will be very common in the next

 

       few slides.  The range of duration of therapy was

 

       from 1 to 196 days with a median of three days.

 

                 (Slide 13)

 

                 In these 37 cases, concomitant medications

 

       that were associated with the development of NMS or

 

       NMS-like symptoms was reported in 20 and they

 

       included anti-depressants, anti-emetics and

 

       anti-psychotics.

 

                 One thing to remember is that not all

 

       cases reported whether there were concomitant

 

       medications or not, so I have just provided

 

       information on the cases that have.

 

                 Drug therapy was used to treat the adverse

 

       event in 18 cases and it largely consisted of what

 

       would be considered standard of care for

 

       neuroleptic malignant syndrome.  The symptoms were

                                                                146

 

       reported or resolved in 11 of the cases.  The

 

       symptom was reported as continuing in one of the

 

       NMS cases but the symptom that was reported as

 

       continuing was more of a dystonic jaw clenching.

 

       In this series, eight patients died.

 

                 (Slide 14)

 

                 To look a little bit closer to the

 

       patients that died, in those eight patients, the

 

       daily dose of metoclopramide ranged from 10 to 40

 

       milligrams with a mean of 32, kind of a mix of oral

 

       and I.V. dosing used, and the duration of therapy

 

       was short and ranged from two days to 15 days.

 

                 (Slide 15)

 

                 The first movement disorder, in our view,

 

       is acute dystonia.  There were 203 unique cases.

 

       Acute dystonia was reported in a younger population

 

       with a mean age of 32.  The range of daily dose was

 

       0.6 to 800 milligrams with a mean of 71 milligrams.

 

       Largely oral dosing reported here.  The range of

 

       therapy from one dose to over 2000 days but a short

 

       median duration of therapy of two days.

 

                 Again, you see mostly G.I. symptoms being

                                                                147

 

       treated here although there were a sizeable number

 

       who were getting pre-treatment for chemotherapy

 

       with metoclopramide.

 

                 (Slide 16)

 

                 For these 203 acute dystonia cases, there

 

       were 64 cases which reported concomitant

 

       medications that were associated with movement

 

       disorders, mostly anti-depressants and

 

       anti-emetics.  Drug therapy was used to treat the

 

       adverse event in 115 cases.  For these acute

 

       dystonia cases, 115 cases reported the symptoms as

 

       improved or resolved.  But symptoms were reported

 

       as continuing in 12 cases.

 

                 (Slide 17)

 

                 In those 12 cases which reported

 

       continuing symptoms, the daily dose ranged from 10

 

       to 40 milligrams with a mean of 25, mostly oral

 

       dosing, and duration of therapy ranged from one day

 

       to over 2000 days with a median of 2.5 days.

 

                 (Slide 18)

 

                 We have 57 unique cases of akathisia.  The

 

       mean age seen in this case series was 45.  The

                                                                148

 

       daily dose ranged from 5 to 200 milligrams with a

 

       mean of 42, mostly oral dosing again.  Duration of

 

       therapy ranged from one over 2500 days with a

 

       median duration of 17 days.  Again, mostly G.I.

 

       indications.

 

                 (Slide 19)

 

                 For these 57 cases akathisia, concomitant

 

       medications associated with movement disorders was

 

       reported in 23.  Drug therapy was used to treat

 

       akathisia in 29 cases.  Symptoms were reported as

 

       improved or resolved in 31 cases but symptoms were

 

       reported as continuing in nine cases.

 

                 (Slide 20)

 

                 In the nine cases that reported continuing

 

       symptoms, the daily dose ranged from 8.6 to 40

 

       milligrams with a mean of 25 milligrams, mostly

 

       oral dosing.  Duration of therapy ranged from 17 to

 

       over 2500 days with a median duration of 119 days.

 

                 (Slide 21)

 

                 We reviewed 35 unique cases of

 

       Parkinson's.  This was in an older population with

 

       a mean age of 60.  Daily dose ranged from 10 to 80

                                                                149

 

       milligrams with a mean dose of 36 milligrams per

 

       day, mostly oral dosing.  The duration of therapy

 

       ranged from one to over 1400 days with a median of

 

       60 days.

 

                 (Slide 22)

 

                 In these 35 cases of Parkinson's, there

 

       were 13 cases which reported concomitant

 

       medications that were associated with movement

 

       disorders.  Drug therapy was used to treat the

 

       adverse event in 18 cases.

 

                 Symptoms were reported as improved or

 

       resolved in 15 of the cases but symptoms were

 

       reported as continuing in eight cases.

 

                 (Slide 23)

 

                 In those eight cases that reported

 

       continuing symptoms of Parkinson's, the daily dose

 

       ranged from 20 to 40 milligrams with a mean of 32,

 

       mostly oral dosing, and the duration of therapy

 

       ranged from one day to 203 days with a median

 

       duration of 81.

 

                 (Slide 24)

 

                 There were 67 cases of tardive dyskinesia.

                                                                150

 

       The mean age was 57.  The daily dose ranged from 5

 

       to 80 milligrams with a mean of 35, mostly oral

 

       dosing again.  Duration of therapy ranged from one

 

       to over 4700 days with a median of 180 days, again

 

       G.I. indications for the metoclopramide.

 

                 (Slide 25)

 

                 25 cases reported that the patient was

 

       taking concomitant medications associated with

 

       movement disorders and drug therapy was used to

 

       treat the adverse event in 19 cases.  In 12 of

 

       these cases, symptoms were reported as improved or

 

       resolved.  In 20 cases, symptoms were reported as

 

       continuing.

 

                 (Slide 26)

 

                 In those 20 cases with continuing

 

       symptoms, the daily dose ranged from 5 to 80

 

       milligrams with a mean of 53, mostly oral dosing

 

       and a duration of therapy from one to over 4700

 

       days with a median of 165 days.

 

                 (Slide 27)

 

                 After we developed our case series, we

 

       wanted to look at a more focused group of these

                                                                151

 

       cases to see if we could approximate the dosing

 

       seen in the MT100.  So we looked at two further

 

       subgroups of our case series.  One, we looked at

 

       characteristics of cases that specifically reported

 

       symptoms as continuing at the time of reporting.

 

       Then we also looked at cases with the diagnosis of

 

       tardive dyskinesia that were related to short-term

 

       metoclopramide therapy.

 

                 (Slide 28)

 

                 There were 50 cases out of 400, over 400,

 

       that reported continuing symptoms.  They were

 

       represented by eight Parkinson's, 20 tardives, nine

 

       akathisias, 12 acute dystonias and one NMS which

 

       was actually likely a dystonic reaction.  A little

 

       over half of the cases with continuing symptoms

 

       reported a duration of therapy of greater than 30

 

       days.

 

                 (Slide 29)

 

                 So 15 cases in our series reported

 

       continuing symptoms with a duration of therapy of

 

       less than 31 days.  Eight of those cases reported

 

       continuing symptoms with a duration of therapy of

                                                                152

 

       less than three days, what we would call very short

 

       durations of therapy.  That included one

 

       Parkinsonism case, two tardive cases, four acute

 

       dystonias and one NMS.  Most of those eight cases

 

       occurred after at least three doses of

 

       metoclopramide.

 

                 (Slide 30)

 

                 I have a few representative cases to

 

       describe to you.  The first one is a 49-year-old

 

       female who received two doses of metoclopramide, 20

 

       milligrams orally, over two days for treatment of

 

       gastric reflux.  Concomitant therapy included

 

       cimetidine.  On Day 2 of therapy, she developed

 

       dystonic reactions consisting of torticollis and

 

       trismus.  Her dystonic reaction was reversed by

 

       diphenhydramine.  However, she subsequently

 

       complained of left-sided weakness and temporary

 

       loosing of the teeth.

 

                 (Slide 31)

 

                 The second case is a 34-year-old female

 

       with nausea who received metoclopramide, 10

 

       milligrams, orally three times a day for three

                                                                153

 

       doses and experienced difficulty breathing,

 

       extremity shaking, head and neck jerking back.  She

 

       went to the E.D. where she was treated with

 

       benztropine, after which she started to relax.

 

                 However, symptoms still occurred.  She was

 

       subsequently treated with lorazepam and paroxetine

 

       which did not completely relieve the symptoms.  She

 

       was seen in the E.C. and by neurologists several

 

       times for reactions milder than the first reaction.

 

       Approximately three months later, she still suffers

 

       from head pain, dizziness, tingling, pressure,

 

       fatigue, agitation, involuntary shaking, muscle

 

       spasm and neck pain among other symptoms.

 

                 (Slide 32)

 

                 The third case, a 27-year-old male

 

       received three doses of metoclopramide, 10

 

       milligrams orally, over two days for diabetic

 

       gastroparesis.  He experienced a dystonic reaction

 

       with psychotic tendencies, agitation and agitation

 

       with suicidal tendencies on the second day of

 

       therapy.

 

                 He was treated in the E.D. with

                                                                154

 

       diphenhydramine and lorazepam.  Once discharged, he

 

       continued to have symptoms of inability to

 

       concentrate, slowed mental processing, difficulty

 

       focusing, eye strain, vertigo, loss of equilibrium,

 

       fatigue, dizziness and hallucinations.

 

                 (Slide 33)

 

                 The second subgroup analysis of our case

 

       series that we did looked at specific cases with

 

       the diagnosis of tardive dyskinesia that were

 

       associated with short-term therapy of

 

       metoclopramide of less than 30 days.  What we were

 

       trying to look at here was trying to approximate

 

       what kind of dosing regimen would be seen with

 

       chronic overusers of migraine therapy because there

 

       is a certain population of migrainers who might use

 

       this drug prophylactically in a manner similar to

 

       other migraine therapies.

 

                 We chose tardive dyskinesia as our adverse

 

       event because the diagnosis of tardive dyskinesia

 

       infers a long-term or permanent adverse event.  We

 

       also noted that about 25 percent of our cases had a

 

       duration of therapy of less than 30 days.

                                                                155

 

                 (Slide 35)

 

                 You have seen this slide before, but you

 

       can see that this is the distribution of our cases

 

       based on the duration of therapy of metoclopramide.

 

       The large number are reported with durations of

 

       therapy of less than 90 days, but there is a

 

       significant number with durations of therapy of

 

       less than 30.  Actually, there are 15 such cases of

 

       tardive dyskinesia with a duration of therapy of

 

       less than 31 days.

 

                 Of these 15 cases, the status of recovery

 

       was not reported in nine of them.  Symptoms were

 

       reported as resolved in one case but continuing

 

       symptoms were reported in five of these cases.

 

       Some of the characteristics of these cases include

 

       two out of the five cases reported symptoms as

 

       continuing but improved.  Two out of the five cases

 

       reported I.V. dosing and four out of five cases

 

       reported daily doses of 40 milligrams.

 

                 The important thing to remember is, again,

 

       we are not really able to discern, because of the

 

       AERS data, whether this was chronic intermittent

                                                                156

 

       use of metoclopramide or chronic continuous use of

 

       metoclopramide in these cases.

 

                 (Slide 36)

 

                 In fact, we found no cases in AERS that

 

       specifically linked intermittent use of

 

       metoclopramide with any movement disorders.  There

 

       are maybe several reasons for this.  First, and

 

       probably most likely, is that AERS--the way data is

 

       reported in AERS does not make the distinction

 

       about intermittent dosing so it just wasn't clearly

 

       described in the report.

 

                 It could be that intermittent dosing is

 

       not commonly used or the adverse events seen with

 

       intermittent dose are not commonly reported or that

 

       there may be few movement-disorder-related adverse

 

       events with intermittent dosing.

 

                 (Slide 37)

 

                 So, in conclusion, most of the reports

 

       that we saw with continuing symptoms of the adverse

 

       event involved long-term therapy of greater than 30

 

       days with the caveat, again, that we didn't know

 

       whether it was intermittent or continuous therapy.

                                                                157

 

                 There were eight cases which reported

 

       continuing symptoms with very short-term therapy.

 

       There were five cases of tardive dyskinesia that

 

       were associated with therapy of less than 30 days.

 

       Concomitant medications associated with movement

 

       disorders were frequently present in the cases and

 

       there were two out of eight deaths from neuroleptic

 

       malignancy syndrome that occurred after less than

 

       three days of therapy.

 

                 (Slide 38)

 

                 That's it.

 

                 DR. KIEBURTZ:  Thank you.

 

                 Questions or clarifications for our last

 

       speaker?

 

                 DR. KIEBURTZ:  Dr. Jeste.

 

                 DR. JESTE:  In these cases of acute

 

       dystonia and neuroleptic malignant syndrome, some

 

       of the patients have some concomitant therapy as

 

       shown, in these cases, the side effects occur after

 

       metoclopramide therapy.

 

                 DR. MATCHAR:  Right; they were temporarily

 

       associated with metoclopramide.  Yes.

                                                                158

 

                 DR. KIEBURTZ:  Dr. Porter.

 

                 DR. PORTER:  Metoclopramide is not widely

 

       used in the U.S.  You didn't spend a lot of time on

 

       the primary diagnosis.  I presume that you found no

 

       migraine-related movement disorders in this search.

 

                 DR. MATCHAR:  There were very, very few

 

       cases that reported adverse events related to

 

       migraine.  As you saw from the indications, they

 

       were mostly G.I.-related indications.

 

                 DR. KIEBURTZ:  Dr. Welch.

 

                 DR. WELCH:  Were there any different

 

       characteristics of the patients who had the T.D.

 

       after the short-term as opposed to the long-term?

 

       It is almost like a biphasic population response

 

       there.

 

                 DR. MATCHAR:  No; it was a very

 

       heterogeneous population.  There were different

 

       presentations, different durations of therapy, so I

 

       am not really sure whether you could say those that

 

       experienced it earlier had similar characteristics

 

       than those that presented after 90 days of therapy.

 

                 DR. KIEBURTZ:  Dr. Katz.

                                                                159

 

                 DR. KATZ:  Just one point of clarification

 

       which I think is true.  Maybe you said it and I

 

       missed it, but, obviously, we focused on the

 

       patients with continuing symptoms, at least in

 

       part.  As a general matter, I think, for these

 

       reports, and correct me if I am wrong, what we

 

       don't have which would be nice to have in terms of

 

       information about those cases is sort of the

 

       latency between the onset of the event, the

 

       movement disorder, and the time of the report.

 

                 So it could be that an event happened on

 

       Day 1 and the report is made on Day 2, in which

 

       case, it might be continuing.  But if the report

 

       had been made on Day 47, after the drug had been

 

       discontinued, for example, it might be that they

 

       were discontinued.  So I think, as a general

 

       matter, we don't know this duration of continuation

 

       of symptoms because we don't know the link between

 

       when the event happened or stopped and the time of

 

       the reporting.

 

                 There were a few cases, I think, where we

 

       do have that but I think, in many cases, we don't.

                                                                160

 

                 DR. MATCHAR:  Right.

 

                 DR. KIEBURTZ:  Dr. Hughes.

 

                 DR. HUGHES:  You mentioned under-reporting

 

       in the AERS database, a well-known problem.  But

 

       when you have an adverse event which is labeled,

 

       what sort of characterizes the types of adverse

 

       events that might then be reported?  We are looking

 

       at a very peculiar set here.

 

                 DR. MATCHAR:  Probably.  There were a lot

 

       of reports from lawyers.  I mean, that is one.

 

       Looking at other case series that I have done, it

 

       seemed like there were a lot of reports from

 

       lawyers.  But we looked at, actually, quarters of

 

       years, the reports, and there really didn't seem to

 

       be any change, like an increase in reporting after

 

       cisipride came off.  It seemed to be fairly steady

 

       so I am not sure that I could say that there was

 

       one specific thing.

 

                 DR. KIEBURTZ:  Good.  Thank you.

 

           Questions from the Committee to the Sponsor and FDA

 

                 Now, we have time to ask questions of the

 

       presenters without me suppressing you about them to

                                                                161

 

       be about clarifications.  We have about an hour to

 

       do that.  I suggest we start principally with

 

       questions to the sponsor and immediately with those

 

       individuals who I suppressed.

 

                 I recall stopping Dr. Goldstein when you

 

       were asking Dr. Schapira a question about the U.K.

 

       reporting database, I believe, and Dr. Lenaerts, I

 

       stopped you in the middle of a question, too, but I

 

       can't remember the context.

 

                 DR. LENAERTS:  It was in the same context.

 

                 DR. KIEBURTZ:  Dr. Goldstein, would

 

       you--and you can draw anyone from the sponsor or

 

       from the FDA if you would like to them to repeat or

 

       present material again.

 

                 DR. GOLDSTEIN:  I guess what I was

 

       actually asking for was clarification about the

 

       validity and accuracy and reporting rates in the

 

       U.K. system, especially now as contrasted to the

 

       last presentation we had from data here in the

 

       United States which is a similar sort of reporting

 

       system, but the numbers seem to be quite different.

 

                 DR. SCHAPIRA:  Thank you.  The U.K.

                                                                162

 

       reporting system to the Committee of the Safety of

 

       Medicines, the so-called yellow-card system, is a

 

       system by which physicians send in to the CSM

 

       documentation of an adverse event.  So it is

 

       physician-led.  It is not spontaneous in terms of

 

       including patients.  But it is spontaneous in the

 

       sense that physicians have to send in the yellow

 

       card.

 

                 Those that do send in yellow cards often

 

       get a response back from the CSM asking for further

 

       clarification if all the relevant information is

 

       not included in the original yellow form that they

 

       have submitted.

 

                 As for a proportion of reporting to all

 

       potential cases, of course, I can't comment on

 

       that.  I don't know the data.  Obviously, that is

 

       not possible to obtain.

 

                 DR. GOLDSTEIN:  The second part of that

 

       question--it was sort of a two-parter--was, in

 

       terms of validating the conditions that are being

 

       reported, we have this clear problem with

 

       categorizing a lot of these movement disorders. 

                                                                163

 

       There is this point of definition about how much

 

       exposure is enough exposure to be categorized as a

 

       given type of condition.  Are these validated in

 

       any way, or is it just based on individual

 

       reporting.

 

                 DR. SCHAPIRA:  It is predominantly based

 

       on physician reporting.

 

                 DR. KIEBURTZ:  It sounds analogous to what

 

       we heard from Dr. Southworth.  Dr. Bastings.

 

                 DR. BASTINGS:  I have a comment regarding

 

       the U.K. reporting system.  We have a fair idea of

 

       the incidence of acute dystonic reactions with

 

       metoclopramide.  In the Pozen study, it was 0.05

 

       percent.  I find it surprising to see that only 26

 

       cases were reported with migraine product, if you

 

       consider the exposure, to have so few cases and it

 

       suggests that there was a vast under-reporting of

 

       these adverse reactions.

 

                 Do you have any comment on that?

 

                 DR. SCHAPIRA:  This, remember, was the

 

       number of reported cases with migraine preparations

 

       as opposed to those with all metoclopramide

                                                                164

 

       preparations.  Do you have the slide number from

 

       which that is taken?

 

                 DR. BASTINGS:  Yes; it is Slide 31, CC-31.

 

                 DR. SCHAPIRA:  Just looking at all

 

       metoclopramide preparations, that is to say the

 

       non-migraine ones, there were 478 of those.  I

 

       don't know how that compares to the U.S. data.

 

                 DR. SOUTHWORTH:  There were 203 unique

 

       dystonia cases.

 

                 DR. SCHAPIRA:  In the U.S. data.

 

                 DR. SOUTHWORTH:  Over about the early

 

       '80's to present.

 

                 DR. SCHAPIRA:  So this is actually twice

 

       the number here in the U.K.

 

                 DR. KIEBURTZ:  Over a longer period.

 

                 DR. SCHAPIRA:  Over a period of 64 to 45.

 

       So this is 40 years and the U.S. data was over 35

 

       years, I think.  Is that right?

 

                 DR. SOUTHWORTH:  The earliest reports we

 

       have are from the early '80's.

 

                 DR. SCHAPIRA:  So about 25 years.

 

                 DR. KATZ:  I think the point is that we

                                                                165

 

       have a good--an estimate, anyway, from the Pozen

 

       control trials of a particular adverse event

 

       associated with the acute use of the product.  It

 

       is 0.05 percent or maybe it is 0.1 percent,

 

       depending--we have seen those numbers vary.

 

                 DR. SCHAPIRA:  Yes.

 

                 DR. KATZ:  But, when you look at, for

 

       example, over the 40-year period in the U.K., and

 

       if you look at dystonia with episodic use of the

 

       combination products, which are the migraine

 

       products, there are 26 reports.  So I don't know

 

       what the percentage of use that is, but it is

 

       probably less than 0.1 percent.

 

                 I think that is the point from the

 

       controlled trials, which are the best way to get an

 

       estimate of these events, you see some finite risk.

 

       It is relatively low but finite that the reporting

 

       rate seems to be, perhaps, orders of magnitudes

 

       less than that, the point being that

 

       under-reporting may be a sizeable--there may be

 

       sizeable under-reporting for these events which are

 

       known to be associated with these treatments.

                                                                166

 

                 DR. SCHAPIRA:  Yes; I agree entirely.  It

 

       was just the comparison between the U.S. and the

 

       U.K. reporting system.  It seems that there isn't a

 

       difference between them here.

 

                 DR. KIEBURTZ:  Dr. Hughes, did you have a

 

       comment?

 

                 DR. HUGHES:  A related question.  I think

 

       you mentioned there were no cases of tardive

 

       dyskinesia amongst the combination users.  I think

 

       you mentioned something like 100 million doses had

 

       been prescribed.  That was an estimate.

 

                 DR. SCHAPIRA:  That was an estimate.

 

                 DR. HUGHES:  But 24 cases amongst those on

 

       chronic use.

 

                 DR. SCHAPIRA:  Yes.

 

                 DR. HUGHES:  Do you have an idea of how

 

       many doses have been prescribed for chronic use?  I

 

       am trying to get some sense of--

 

                 DR. SCHAPIRA:  Right.  Of course, I am

 

       going to have to speculate on this, but the

 

       proportion of use of metoclopramide in the U.K. for

 

       migraine as a precaution for all of its other uses

                                                                167

 

       is about 20 to 25 percent of metoclopramide

 

       prescriptions are for migraine, approximately.  So

 

       I suppose that one could extrapolate from that.

 

                 DR. KIEBURTZ:  Dr. Temple.

 

                 DR. TEMPLE:  Just a comment on reporting

 

       rates and spontaneous reporting systems.  We spend

 

       endless hours and months agonizing about this.  It

 

       is very clear the rates are different for different

 

       kinds of reactions.  There is something called the

 

       Weber curve that was derived mostly from British

 

       data that says reports of any given reaction

 

       decline after the first three years because people

 

       all know about it.  It is in the label.

 

                 You can easily imagine that people

 

       wouldn't report very much of something like a

 

       dystonic reaction which everybody knows about.  You

 

       would hope that they would be more likely to report

 

       TD because it is not as clear that everybody knows

 

       about it.  But there is just no way to know these

 

       things and it is a constant source of difficulty.

 

                 The other thing that is going on, in the

 

       United States, in the '80s, there were maybe 20,000

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       reports to us a year.  You probably have the

 

       number.  We are now up over 400,000 a year.  So we

 

       have a belief that reporting of all things is going

 

       up.  It is very impossible to reach conclusions

 

       that are valid, however.

 

                 DR. KIEBURTZ:  Dr. Jung.

 

                 DR. JUNG:  I will pass.

 

                 DR. KIEBURTZ:  Dr. Fahn.

 

                 DR. FAHN:  Regarding Slide 31 and then 22,

 

       where there is no tardive dyskinesia being

 

       reported, Slide 22, the Bateman second article

 

       there, the Bateman 1989, the second of the Bateman

 

       articles, fortunately, and I must congratulate the

 

       sponsor because we do have the reprints of these

 

       articles so I was looking at that because that came

 

       as a big surprise where there were zero TD cases.

 

                 But, actually, what this survey was is

 

       that they wrote to the physicians who prescribed

 

       the drug Maxolon for migraine--I assume it is all

 

       for migraine--and got the responses back.  But they

 

       grouped the responses.  They didn't list tardive

 

       dyskinesia as one of the responses.  They just said

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       dystonia-dyskinesias and they grouped all that

 

       together.  So they are listed here in your table as

 

       12 dystonias.  But a lot of them--and some of these

 

       are older people.  It is very likely that a lot of

 

       these were persistent dyskinesias and not just

 

       acute dystonic reactions or something that this

 

       table may imply.

 

                 So I just wanted to say that, looking at

 

       this, you can't really clearly say how many--there

 

       was no zero TD cases.  So that was one comment.

 

                 DR. SCHAPIRA:  Yes; they classified

 

       patients as dystonia-dyskinesia which, if you look

 

       back at the first Bateman paper here, they also

 

       used that classification and separated out from

 

       tardive dyskinesia.  So, in the first paper they

 

       did, they did clearly separate dystonia-dyskinesia

 

       and tardive dyskinesia.  In the dystonia-dyskinesia

 

       they noted that--I think the dyskinesia resolved

 

       and made the comment--and this is with respect to

 

       their paper in 1985--that this was more likely an

 

       acute type reaction.

 

                 DR. FAHN:  But the other thing on this

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       table, too, in the second Bateman article, they

 

       have 46 other events.  So, perhaps, within that,

 

       there might be TD.  That is what I am saying.  From

 

       this paper, you can't really say there was no TD

 

       because they specifically failed to talk about TD.

 

       That is the problem.

 

                 If I can also make a comment at this time.

 

       The definitions of TD, that is another thing that

 

       can confuse people.  If you are going to use the

 

       definition of TD that you have to be on the drug

 

       for 30 days or more or three months, as some

 

       definitions have used, I am not sure any

 

       neurologist used that kind of definition.  We

 

       tended to look at tardive dyskinesia as persistent

 

       dyskinesia.

 

                 The name tardive was given because it

 

       wasn't seen until later on after the neuroleptic

 

       drugs had been on the market for a while.  That is

 

       when tardive came on.  But, with more experience

 

       with this, recognizing what the syndromes are, we

 

       sort of consider, now, tardive dyskinesia really

 

       should have been properly named persistent

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       dyskinesia, meaning that it lasts longer than 30

 

       days.

 

                 It doesn't matter how long they have been

 

       on it for.  They can be on it for one day and still

 

       have persistent dyskinesia.  To us, that is what we

 

       now refer to as tardive dyskinesia.  So we don't

 

       give up the name tardive dyskinesia.  We use the

 

       definition differently than what was stated here.

 

       I just wanted to make sure the concern I would

 

       have, as a neurologist, who treats tardive

 

       dyskinesia as meaning persistent dyskinesia, that

 

       these can be irreversible.

 

                 When I heard the comment about how

 

       devastating migraine is, and I agree it can

 

       be--severe pains can be very bad for people,

 

       devastating, but so can severe akathisia including

 

       tardive akathisia, I consider that equally as bad.

 

       If you ever induce this for a drug you might not

 

       have needed, then that is a concern for us that we