FOOD AND DRUG ADMINISTRATION










                            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





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

       Anuja Patel, MPH, Executive Secretary




       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.




       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.




       Dilip V. Jeste, M.D.




       Robert Temple, M.D.

       Russell Katz, M.D.

       Eric Bastings, M.D.

       Mary Ross Southworth, Pharm.D.



                             C O N T E N T S




       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



                             C O N T E N T S




       Open Public Hearing

                 Cynthia McCormick, M.D.                        217


       Committee Discussion and Response to FDA Questions       225



                          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




                 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



       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



       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



       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



       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




                 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





                 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




                 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




                 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



       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



       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




                 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



       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



       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



       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



       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




                 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



       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




                 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.




                 Dr. Katz?


                            Overview of Issues


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



       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




                 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



       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




                 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




                 But, perhaps, more importantly for today's



       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




                 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



       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




                 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



       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



       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.




                 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.



                 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.



                 (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



       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



       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



       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.



                 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




                 (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



       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




                 (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



       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




                 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



       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



       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



       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



       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




                 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



       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



       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



       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




                 (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



       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




                 (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





                 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



       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



       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




                 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




                 (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



       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




                 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.



                 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



       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.



                 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



       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




                 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



       reported adverse events to a central, now


       computerized, database and it records prescriptions


       as well as adverse events, so it is particularly




                 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



       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




                 (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



       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




                 (Slide CC-33)


                 Just looking at the longer-term study,


       1,000 patients recruited, 621 were followed over



       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



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


       very conservative estimate, over 100,000 million




                 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.



                 (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



       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




                 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



       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.



                 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.



                 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




                 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




                 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



       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?



                 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



       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




                 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





                 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





                 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




                 2,355 subjects received single doses of


       MT100.  Did these studies provide evidence that


       MT100 was an effective migraine drug?  Well, Pozen



       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



       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. 



       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



       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



       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




                 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




                 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. 



       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




                 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.



                 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



       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



       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



       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.



                 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




                 (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.



                 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




                 Dr. Matchar was invited by Pozen to


       provide his perspective on the potential role of



       MT100 in the treatment of migraine and his view on


       the balance of benefits and risks of this




                 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




                 DR. WELCH:  So you didn't look for


       separate populations.


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




                 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



       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,



       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




                 DR. KIEBURTZ:  Dr. Koski?


                 DR. KOSKI:  I assume that your patients


       within this study had more than one attack of




                 DR. ALEXANDER:  That's not correct.  This


       was a single-attack study.


                 DR. KOSKI:  It was single attack.  Thank




                 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



       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




                 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



       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




                 The second question is, when we look at


       clinical differences in clinical-trial results of 4



       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



       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



       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.



                 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



       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




                 (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.



                 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




                 (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




                 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



       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



       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



       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. 



       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





                 (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)



                 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



       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




                 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.



                 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




                 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




                 (Slide CC-67)


                 Recognizing that some people don't like



       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




                 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.



                 (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



       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.



                 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




                 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



       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.





                 (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



       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




                 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





                 (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




                 This, to me, is clinically significant.


                 (Slide CC-78)



                 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



       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



       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




                 (Slide CC-82)



                 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




                 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



       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




                 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



       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




                 Thank you.




                 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





                 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)



                 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



       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



       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



       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



       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



       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.



                 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



       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




                 (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



       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



       cases, symptoms appear more likely to be




                 (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





                 (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




                 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





                 (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



       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



       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




                 (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)



                 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




                 (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?



                 (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



       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




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


                 DR. KATZ:  I think the contribution, as



       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. 



       Our next speaker is Dr. Jinnah from Johns Hopkins




                      Overview of Tardive Dyskinesia


                 DR. JINNAH:  Good morning.




                 Thanks for the invitation to come and


       speak here.  I have been asked to give a brief


       summary of the clinical condition of tardive




                 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.




                 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.





                 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



       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




                 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.




                 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



       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.




                 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



       source of this problem.




                 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.




                 So when do these problems actually arise?


       They are referred to as tardive syndromes because


       they usually require chronic administration of the



       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



       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.




                 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



       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





                 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




                 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



       example, schizophrenia.


                 DR. JUNG:  So that includes just general


       depression which is very prevalent in the




                 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



       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




                 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.



                 But, if I understood you properly, would


       you say that it is generally accepted that


       metoclopramide, as an agent, can cause tardive




                 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



       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



       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




                 (Slide 6)



                 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




                 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)



                 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.



                 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



       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



       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




                 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



       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



       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



       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.




                 (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



       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.



       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




                 (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



       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




                 (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



       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




                 (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



       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




                 He was treated in the E.D. with



       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.



                 (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



       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.



                 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




                 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.



                 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




                 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.



                 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.



                 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



       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.



       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




                 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. 



       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




                 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



       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



       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.



                 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




                 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



       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



       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



       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



       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




                 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



       dyskinesia, meaning that it lasts longer than 30




                 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