1

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

                       FOOD AND DRUG ADMINISTRATION

                 CENTER FOR DRUG EVALUATION AND RESEARCH











               PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS

                            ADVISORY COMMITTEE
















                         Wednesday, June 6, 2001

                                8:15 a.m.












                               Holiday Inn
                            Bethesda, Maryland 
                                                                  2


                               PARTICIPANTS

       Claudia H. Kawas, M.D., Consultant and Acting
       Chairman
       Sandra Titus, Ph.D., Executive Secretary

       MEMBERS:

       Ella P. Lacey, Ph.D., Consumer Representative,
       LaRoy P. Penix, M.D.
       Richard D. Penn, M.D.
       Gerald Van Belle, Ph.D.

       CONSULTANTS:

       Gustavo C. Roman, M.D.
       Jerry S. Wolinsky M.D.

       XYREM CONSULTANTS:

       VOTING:

       Pippa Simpson, Ph.D.
       Carol Falkowski, Ph.D.

       NON-VOTING:

       Christine A. Sannerud, Ph.D.
       Jerry Frankenheim, Ph.D.
       Jo-Ellen Dyer, Ph.D.

       ON PONE-LINK - NON-VOTING:

       Ronald Chervin, M.D.
       Christian Guilleminault, M.D.

       FDA:

       Robert Temple, M.D.
       Russell Katz, M.D.
       Ranjit Mani, M.D.
       John Feeney, M.D.
       Deborah B. Leiderman, M.D. 
                                                                  3

                             C O N T E N T S

       Call to Order and Introductions                            4

       Conflict of Interest                                       6

       FDA Overview, Russell Katz, M.D.                           8

       Orphan Medical Presentation:
          Introduction, David Reardan, Ph.D.                     19
          Medical Need, Emmanuel Mignot, M.D.                    25
          Efficacy, William Houghton, M.D.                       36
          Polysomnographic Effects of Xyrem,
             Jed Black, M.D.                                     55
          Safety and Summary of Risk/Benefit Assessment,
             William Houghton, M.D.                              61

       FDA Response to the Presentation,
          Ranjit Mani, M.D.                                      84
       Committee Discussion and Deliberations                    89

       FDA Invited Speakers on Risk Management Issues:
          Epidemiology of GHB Abuse Issues,
          Carol Falkowski                                       131
          Adverse Medical Effects with GHB,
          Jo Ellen Dyer                                         148

       Sponsor Presentation on Risk Management and Abuse                     
Liability, Bob Balster, Ph.D.                         162
       Risk Management, Patti Engel, R.N., BSN                  176

       Open Public Hearing:

          Sharon Fitzgerald, Littleton, Colorado                187
          Richard L. Gelulla, MSW, National Sleep
            Foundation                                          191
          Abbey S. Meyers, National Organization
             for Rare Disorders, Inc.                           197             
        Robert L. Cloud, Narcolepsy Network                   200
          Cindy Pekarick                                        204
          Eric C. Strain, M.D., College on Problems of
            Drug Dependence                                     208
          Deborah Zvorsec, Ph.D., Hennepin County
             Medical Center                                     213
          Trinka Porrata, LAPD                                  218
          Matt Speakman                                         223
          Charles F. Cichon, National Association of Drug
             Diversion Investigators                            227             
        Debbie Alumbaugh, Michael's Message
             Foundation, Inc.                                   230
          Brian A. Hunter, Young Adults with Narcolepsy         233
          Joe Spillane, Pharm.D., ABAT                          237
          Mali Einen                                            241
          Sandra Jones                                          246

       Continued Committee Discussion and Deliberations         249 
                                                                  4

   1                      P R O C E E D I N G S

   2                 Call to Order and Introductions

   3             DR. KAWAS:  Good morning, everyone, and

   4   welcome to the Wednesday, June 6, 2001 meeting of

   5   the Peripheral and Central Nervous System Advisory

   6   Committee.  My name is Claudia Kawas, and I think

   7   we can begin with introductions, please, perhaps

   8   over by Dr. Temple's side.

   9             DR. TEMPLE:  Bob Temple, I am the Office

  10   Director.

  11             DR. KATZ:  Russ Katz, Division of

  12   Neuropharmacological Drug Products, FDA.

  13             DR. FEENEY:  John Feeney, neurology team

  14   leader, FDA.

  15             DR. MANI:  Ranjit Mani, medical reviewer,

  16   Neuropharm., FDA.

  17             DR. LEIDERMAN:  Deborah Leiderman,

  18   Director, Controlled Substance Staff, FDA.

  19             DR. SIMPSON:  Pippa Simpson, University of

  20   Arkansas Medical Sciences, biostatistician.

  21             DR. FALKOWSKI:  Carol Falkowski, drug

  22   abuse researcher, Hazelden Foundation.

  23             DR. ROMAN:  Gustavo Roman, Professor of

  24   Neurology at the University of Texas, San Antonio.

  25             DR. WOLINSKY:  Jerry Wolinsky, Professor 
                                                                  5

   1   of Neurology, University of Texas, Houston.

   2             DR. TITUS:  Sandy Titus, FDA, the

   3   administrator of the Peripheral and Central Nervous

   4   System Committee.

   5             DR. PENN:  Richard Penn, neurosurgeon at

   6   the University of Chicago.

   7             DR. LACEY:  Ella Lacey, professor emerita,

   8   Illinois University, Carbondale, Illinois.

   9             DR. VAN BELLE:  Gerald Van Belle,

  10   Department of Biostatistics, from the University of

  11   Washington.

  12             DR. PENIX:  LaRoy Penix, Associate

  13   Professor of Neurology at Moorehouse School of

  14   Medicine.

  15             DR. SANNERUD:  Christina Sannerud, Drug

  16   and Chemical Evaluation Section, Drug Enforcement

  17   Administration.

  18             DR. DYER:  I am Jo Dyer, with the

  19   University of California, San Francisco and the San

  20   Francisco Poison Control System, California.

  21             DR. FRANKENHEIM:  Jerry Frankenheim,

  22   pharmacologist, National Institute on Drug Abuse.

  23             DR. KAWAS:  Today we have met to discuss

  24   the consideration of Xyrem, proposed to reduce the

  25   incidence of cataplexy and to improve the symptom 
                                                                  6

   1   of daytime sleepiness for persons with narcolepsy.

   2   The main focus of the deliberations will also be on

   3   risk management issues.

   4             If we could ask Dr. Titus to begin with

   5   the conflict of interest statement?

   6                  Conflict of Interest Statement

   7             DR. TITUS:  Before I begin the conflict of

   8   interest statement, I just want to announce that we

   9   have two people on line with us, Dr. Chervin and

  10   Dr. Guilleminault.  They are both in a room

  11   listening to us and will participate with us on the

  12   mikes.

  13             The following announcement addresses the

  14   issue of conflict of interest with regard to this

  15   meeting and is made a part of the record to

  16   preclude even the appearance of such at this

  17   meeting.

  18             The special government employees

  19   participating in today's meeting have been screened

  20   for interests in Orphan Medical's Xyrem and for

  21   interests in the products and sponsors deemed by

  22   the agency to be competing.  Based on the agency's

  23   review of each participant's response to the

  24   conflict of interest screening, it has been

  25   determined that there is no potential for a 
                                                                  7

   1   conflict of interest with regard to this meeting.

   2             With respect to FDA's invited guests,

   3   there are reported affiliations which we believe

   4   should be made public to allow the participants to

   5   objectively evaluate their comments.

   6             Dr. Ronald Chervin would like to disclose

   7   for the record that he has a contract with Cephalon

   8   to study Provigil, but not for use in narcolepsy.

   9   He is the principal investigator, however, no funds

  10   from Cephalon, present or past, have contributed to

  11   his personal salary and none have been made

  12   available for his non-research related use.

  13   Further, in previous years Dr. Chervin was a

  14   co-investigator with Cephalon in a narcolepsy

  15   clinical trial.

  16             Christian Guilleminault has been the

  17   administrator of the Sleep Disorder Clinic in Palo

  18   Alto, California, where the study of Xyrem was

  19   performed by a team of researchers.

  20             In the event that the discussions involve

  21   any other products or firms not already on the

  22   agenda for which an FDA participant has a financial

  23   interest, the participants are aware of the need to

  24   exclude themselves from such involvement and their

  25   exclusion will be noted for the record. 
                                                                  8

   1             With respect to all other participants, we

   2   ask in the interest of fairness that they address

   3   any current or previous involvement with any firm

   4   whose products they may wish to comment upon.

   5   Thank you.

   6             DR. KAWAS:  Thank you very much, Dr.

   7   Titus.  We will begin with Dr. Russell Katz, of the

   8   FDA, who will give us the FDA overview of the

   9   issues.  I want to point out to the committee

  10   members that they have much of the materials that

  11   they will be seeing during this meeting in front of

  12   them.

  13                           FDA Overview

  14             DR. KATZ:  Thanks, Claudia.  First, I

  15   would like to welcome the committee back.  You were

  16   here just a few months ago so I appreciate your

  17   coming back so soon.

  18             We have a number of invited guests who are

  19   augmenting the committee today, and many of them

  20   are experts in the evaluation of issues related to

  21   drug abuse, and I would just like to welcome them,

  22   in particular Drs. Simpson, Sannerud and

  23   Frankenheim.

  24             We have two other experts who will

  25   actually be speakers later this morning.  Dr. Dyer 
                                                                  9

   1   will speak on her experience with GHB use and

   2   misuse in cases she has seen, and Dr. Falkowski

   3   will talk about the epidemiology of GHB abuse in

   4   the United States.

   5             Finally, as Dr. Titus mentioned, we have

   6   two acknowledged experts in sleep disorders who are

   7   attending the annual sleep meetings in Chicago, but

   8   who have agreed to sit in a hotel room for however

   9   long this takes and participate by phone.  So, Drs.

  10   Guilleminault and Chervin, wherever you are, thank

  11   you.  Thanks for being here.

  12             As you know and as you have heard, today

  13   we will ask you to discuss NDA 21-196, which was

  14   submitted by Orphan Medical for the use of Xyrem,

  15   gamma hydroxybutyrate or better known as GHB, for

  16   the treatment of cataplexy and excessive daytime

  17   sleepiness in patients with narcolepsy.

  18             GHB is a simple molecule and it is

  19   ubiquitous in mammalian tissues, its function

  20   though is not really well known.  Its relevant

  21   regulatory history goes back to about 1990, and

  22   prior to that date it was freely available in

  23   health food stores.  But in 1990 the agency began

  24   to receive reports of widespread recreational use

  25   in a number of different types of folks, for a 
                                                                 10

   1   number of different types of reasons, or GHB and

   2   began to get numerous reports of serious adverse

   3   events associated with its misuse.

   4             It was not entirely clear that all of

   5   these events were necessarily related to GHB.  It

   6   was difficult to interpret some of these reports

   7   because there were concomitant medications that

   8   were unreported and it wasn't entirely clear

   9   whether or how much GHB was in a particular

  10   preparation that someone had taken.  Those sorts of

  11   issues made it difficult to completely interpret

  12   the reports, but many of the reports were of events

  13   that were known to be consistent with GHB's effect

  14   as a potent CNS depressant, including things like

  15   respiratory depression, coma and other decreased

  16   levels of consciousness.  So, it was reasonable to

  17   believe that GHB was at least in part responsible

  18   for some of these reports.

  19             As a result of these reports, the agency

  20   withdrew GHB from health food shelves and made it

  21   illegal to use.  However, illicit use continued and

  22   continues to this day, not only with GHB but with

  23   two related drugs which are precursors, GBL and

  24   1,4-butanediol, and there have been similar reports

  25   of serious adverse events associated with the use 
                                                                 11

   1   of those products.

   2             So, against this background of use, the

   3   investigation of GHB as a treatment for cataplexy

   4   began.  Based on the results of a single trial

   5   performed by the sponsor and their commitment to

   6   perform additional trials, the sponsor was granted

   7   a treatment IND in December of 1998.  For those of

   8   you unfamiliar with a treatment IND, it is

   9   basically a mechanism to permit use of an

  10   investigational drug outside the context of a

  11   controlled trial for a serious disease for which

  12   there aren't other available treatments.  It is

  13   usually granted relatively late in the development

  14   of a drug so that by the time you grant it you have

  15   some reasonable idea, based on controlled data,

  16   that the drug is probably effective and reasonably

  17   well tolerated.

  18             Just another relevant piece of history, in

  19   2000 Congress passed a law which placed GHB in

  20   Schedule I and also placed it into Schedule III for

  21   any approved uses that may be granted.

  22             The NDA that we are discussing today was

  23   submitted in September of 2000 by the company, and

  24   it contains the results of four controlled trials

  25   which the sponsor believes establish substantial 
                                                                 12

   1   evidence of effectiveness for cataplexy and

   2   excessive daytime sleepiness in patients with

   3   narcolepsy.  It also contains, obviously, safety

   4   experience.

   5             I just want to talk about the safety

   6   experience for just a little bit.  As you know from

   7   the briefing documents, much of the safety data in

   8   the application was not generated by the company

   9   but by an individual investigator under his own

  10   individual investigator IND.  This is Dr. Scharf,

  11   and he is an acknowledged expert in the use of GHB

  12   and he has been treating patients under his IND for

  13   about 16 years.  His data comprise almost 30

  14   percent of the patient safety database in the NDA.

  15   If one looks at patient time, his experience

  16   constitutes about 70 percent of the total patient

  17   exposure.

  18             As part of a routine investigation of the

  19   NDA to look at source documents, the agency

  20   investigators found that they were unable to locate

  21   some critical source documents of Dr. Scharf's IND,

  22   and it was difficult to confirm the sponsor's

  23   submission of Dr. Scharf's data.  However,

  24   subsequent to that, Dr. Scharf has made extensive

  25   efforts to provide the additional source documents 
                                                                 13

   1   and agency investigators have reinspected that

   2   data.  I believe the conclusion of that

   3   investigation is that we find that the records, for

   4   the most part, do support the sponsor's

   5   descriptions of Dr. Scharf's data.  And, we believe

   6   we can make certain statements about that data at

   7   this point.

   8             We were particularly interested in the 80

   9   or so patients that Dr. Scharf treated that did not

  10   move on into the company's treatment IND.  He

  11   treated a total of 143, or thereabouts, patients,

  12   60 of whom went into the sponsor's treatment IND.

  13   So, we had a good idea of what was happening to

  14   those patients but there were about 80 that didn't

  15   and who were basically discontinued from treatment

  16   under Dr. Scharf's own IND.

  17             So, except for a handful of patients, we

  18   believe we know why those 80 patients discontinued

  19   and their status.  I believe we can say reasonably

  20   comfortably say that nothing catastrophic that we

  21   don't know about happened to those patients but,

  22   unfortunately, we have relatively little

  23   well-documented data regarding other less serious

  24   adverse events in that cohort of 80.  Other than

  25   patient diaries, we have essentially no 
                                                                 14

   1   documentation about exactly what dose those

   2   patients took and for how long.

   3             I have gone into this at some depth

   4   because the safety experience in the NDA is

   5   relatively small as compared to a typical NDA, and

   6   that is by agreement.  This is an orphan product.

   7   Based on the sponsor's estimated prevalence of

   8   cataplexy of about 25,000, it received orphan

   9   designation and one wouldn't necessarily expect

  10   that a safety database of a typical size, which is

  11   somewhere in at least 10000 to 2000 patients in the

  12   typical NDA, would be submitted in an orphan

  13   application.  So, we agreed with the sponsor that

  14   about 500 patients treated for appropriate

  15   durations, at appropriate doses would be

  16   acceptable.

  17             But, given the relatively small database

  18   and some of these residual questions about a

  19   reasonable proportion of it, that is to say Dr.

  20   Scharf's data, that may take on some additional

  21   meaning and we would like you to think about that

  22   as the day goes on.

  23             In addition to the safety and the

  24   effectiveness data which is required in an NDA of

  25   course, the sponsor has proposed a detailed risk 
                                                                 15

   1   management program, and that has three goals: to

   2   inform patients and physicians about the risks of

   3   GHB; to minimize the risks to those patients; and

   4   also to minimize the likelihood that subjects for

   5   whom the drug has not been prescribed will be

   6   exposed to it.  This latter point not only refers

   7   to diversion and its use illicitly by folks who

   8   shouldn't be taking it, but also to the accidental

   9   use of GHB in the home, perhaps by small children,

  10   and you will hear how GHB is administered and what

  11   form it is prepared in, and we think that is a

  12   potential risk.  So, we would like you to think

  13   about that as the day goes on too.

  14             As far as the risk management program, you

  15   will hear about it in great detail from the company

  16   but, in brief, it consists of a couple of sort of

  17   major components.  One is that the product will be

  18   made available through a central pharmacy and will

  19   be shipped directly to the patient at home.

  20   Physicians and patients will also receive detailed

  21   materials about the risks and the appropriate use

  22   of the drug after the first prescription is filled.

  23   Actually, they will receive those materials

  24   initially and all subsequent refills of

  25   prescriptions will be contingent upon patients and 
                                                                 16

   1   physicians documenting that they have read these

   2   materials, and they understand the risks and how to

   3   take the drug appropriately.

   4             All patients and physicians will be

   5   entered into a registry, and there will be close

   6   surveillance instituted to ensure that untoward

   7   events are minimized, for example, to ensure that

   8   patients don't go from doctor to doctor trying to

   9   get refills of prescriptions that are

  10   inappropriate.

  11             So, with these data and against the

  12   background of misuse of GHB out in the population

  13   at large, we bring you today's application and we

  14   will ask you to formally vote on three questions.

  15   One is whether or not you think that substantial

  16   evidence of effectiveness has been submitted for

  17   the indications that the sponsor has proposed, that

  18   is to say, cataplexy and excessive daytime

  19   sleepiness in patients with narcolepsy.  If you

  20   find that they haven't, we would be very interested

  21   to know whether or not you feel that substantial

  22   evidence has been submitted for either of those two

  23   indications.

  24             While you listen to the effectiveness

  25   data, we would like you to pay particular attention 
                                                                 17

   1   to the question of dose and for which dose you

   2   think evidence of effectiveness has been submitted.

   3   If you find there is substantial evidence of

   4   effectiveness for a particular indication, we need

   5   to ask you whether or not GHB can be considered

   6   safe in use given appropriate labeling.  Now, we

   7   are not going to discuss necessarily the specifics

   8   of proposed labeling but, nonetheless, we ask you

   9   to think of it in that context.

  10             Again, in assessing the safety of the

  11   product, we ask you to concentrate on at least the

  12   question of what dose you have found to be

  13   effective and whether or not there is sufficient

  14   safety experience at that dose for the drug to be

  15   approved.

  16             Finally, we want to take a formal vote on

  17   the question of whether or not you think it is

  18   required or should be required that the drug be

  19   approved only with the risk management program of

  20   some type, not necessarily the one specifically

  21   proposed by the company.  Obviously, the company

  22   has proposed a risk management program but we need

  23   to know whether or not you think it is mandatory

  24   that it be approved with such a program in place.

  25   If you do, we have a number of questions that we 
                                                                 18

   1   would like you to discuss -- not necessarily take a

   2   formal vote on but discuss with regard to a risk

   3   management program and some of the provisions that

   4   the sponsor has proposed.

   5             There are some aspects of the program that

   6   they have proposed that we would like you to pay

   7   particular attention to and discuss.  For example,

   8   there is some considerable sympathy in the agency

   9   for including a provision in the risk management

  10   program that would restrict the use of the drug to

  11   patients with whatever indication you believe has

  12   been supported, that is to say, to restrict as much

  13   as possible off-label prescribing.  That is one

  14   possibility.

  15             There is also some enthusiasm internally

  16   for physicians and patients to document that they

  17   have reviewed the relevant materials before the

  18   first prescription is filled.  So, we would like

  19   you to think about that as well as we talk about

  20   the risk management program.

  21             So, as you can see from the agenda, the

  22   company is going to present the safety and

  23   effectiveness data, after which Dr. Mani, from the

  24   Division, will come up and present briefly some of

  25   our views about the data you will have just heard.  
                                                                 19

   1   Specifically, I believe we have some different

   2   views about the evidence submitted for establishing

   3   a claim for excessive daytime sleepiness in

   4   narcolepsy, and there may be other additional

   5   safety issues that we would like to bring up at

   6   that time, in particular the question of an event

   7   that has been called sleep walking.

   8             I think with that as background, I will

   9   turn it back to Dr. Kawas.  Thank you.

  10             DR. KAWAS:  Thank you, Dr. Katz.  Orphan

  11   Medical presentation is to follow.  Dr. David

  12   Reardan, Orphan Medical?

  13                   Orphan Medical Presentation

  14             DR. REARDAN:  Hi.  Good morning.  Good

  15   morning, ladies and gentlemen, members of the

  16   committee and FDA.

  17             [Slide]

  18             My name is David Reardan, and I represent

  19   Orphan Medical as head of regulatory affairs.

  20   Orphan Medical is a small, 60-person firm,

  21   dedicated to the development of orphan drugs.  We

  22   have obtained marketing approval for six orphan

  23   products from FDA since we were founded, in 1994.

  24             The firm became involved with Xyrem when

  25   approached by FDA that same year, and Xyrem was 
                                                                 20

   1   designated an orphan drug in 1994.  Today we will

   2   share with you the data that has been collected

   3   with respect to the efficacy and safety since our

   4   IND was submitted, in 1996.

   5             [Slide]

   6             Dr. Mignot, director of the Narcolepsy

   7   Institute at Stanford University, will present a

   8   picture of a narcoleptic patient and the serious

   9   medical need such patients have for new therapeutic

  10   treatments.

  11             Dr. Houghton is the chief medical officer

  12   and chief operating officer at Orphan Medical, and

  13   he will present next on the efficacy that has been

  14   collected.  Dr. Houghton was chair of anesthesia

  15   and critical care in Australia.

  16             Dr. Black, director of the Stanford Sleep

  17   Clinic and an investigator for several trials, will

  18   share with you the EEG pharmacology of Xyrem.  Dr.

  19   Houghton will then present the safety data and

  20   finish up with a benefit/risk assessment.

  21             Following presentations by two FDA invited

  22   speakers with respect to GHB abuse, Dr. Balster,

  23   director of the Institute for Drug and Alcohol

  24   Studies at the Medical College of Virginia, will

  25   share with you his views on abuse liability. 
                                                                 21

   1             Since there is public abuse of GHB and its

   2   analogs, the company has developed a risk

   3   management program for Xyrem that will be presented

   4   by Patti Engel, our vice president of marketing and

   5   sales.

   6             [Slide]

   7             In addition to those presenting today, the

   8   following experts are available in the audience to

   9   answer questions from the committee or FDA:  Dr.

  10   Emsellem, Dr. Hagaman and Dr. Ristanovic are all

  11   directors of their respective sleep institutes, and

  12   have been investigators in our clinical trials.

  13   Dr. Okerholm is a consultant in the area of

  14   pharmacokinetics and drug metabolism; Dr. Reno in

  15   the area of toxicology; and Dr. Richard Trout, who

  16   is a professor emeritus in statistics from Rutgers,

  17   is here if there are any statistical questions.

  18             [Slide]

  19             This is the chemical structure of sodium

  20   oxybate, more commonly known as gamma

  21   hydroxybutyrate, or GHB.  Notice that it is a

  22   simple 4-carbon hydroxy fatty acid and, as such,

  23   quite easy to synthesize.  In fact, kits have been

  24   illegally promoted on the Internet for its

  25   manufacture.  If an amino group were to replace 
                                                                 22

   1   this alcohol functional group at position 4, you

   2   would have GABA, gamma aminobutyric acid, another

   3   CNS active chemical.  Oxybate is a natural compound

   4   in the human body.

   5             [Slide]

   6             Gamma hydroxybutyrate was first discovered

   7   in the 1960's by Dr. Labore, in France, and was

   8   investigated as an analog for GABA.  It was found

   9   to have hypnotic properties and was first approved

  10   in France, and later a few other countries of

  11   Europe, as an adjunct in anesthesia.  It was used

  12   in labor and delivery for quite a few years.  The

  13   injectable form is still available today in parts

  14   of Europe.

  15             In the 1970's initial work was begun in

  16   Canada to test its properties in narcolepsy.

  17   Following initial promise for use in patients with

  18   narcolepsy two controlled trials were conducted by

  19   independent investigators, one in the U.S. and one

  20   in The Netherlands.  In 1994, due to the promising

  21   investigator trials, FDA Office of Orphan Products

  22   approached Orphan Medical to consider the compound

  23   for development.

  24             Since there was no patent protection and

  25   the market was very small, no other firms were 
                                                                 23

   1   willing to consider the development of GHB for

   2   narcolepsy at the time.  Orphan Medical agreed to

   3   sponsor this medication.  Our new drug application

   4   was submitted in October of 2000 and was designated

   5   by FDA for priority review.

   6             The clinical development has been fairly

   7   straightforward and all controlled trials conducted

   8   to date have shown sodium oxybate to be effective

   9   and safe for the treatment of narcolepsy.  This

  10   project has been made more difficult because of the

  11   abuse situation.

  12             [Slide]

  13             Let me explain why Xyrem is not going to

  14   be a factor in the abuse of GHB and its precursors.

  15   Orphan Medical was aware abuse existed at the time

  16   the company agreed to sponsor development of Xyrem.

  17   At this same time, Internet was burgeoning.  Due to

  18   its ease of synthesis and ready availability of

  19   precursor chemicals, GHB was initially an easy

  20   target for promoters of illegal drugs.

  21             But GHB is not the only problem.  GBL and

  22   1,4-butanediol are precursor chemicals that can be

  23   easily converted to GHB and are, in fact, converted

  24   to GHB in the human body.  These precursors are

  25   widely available as bulk chemicals and are being 
                                                                 24

   1   illegally used in the United States, and the abuse

   2   problem is growing.

   3             Federal legislation, enacted in 2000,

   4   helped to control the availability of GHB and GBL

   5   but not 1,4-butanediol and other precursor

   6   chemicals that can be used for the same purpose.

   7   In many states, even with GHB schedules, GBL and

   8   1,4-butanediol are not controlled.

   9             We believe that approval of Xyrem for use

  10   by patients with narcolepsy will not add to the

  11   general abuse problem of GHB and its numerous

  12   precursors.

  13             [Slide]

  14             The proposed indication for which we are

  15   asking FDA for marketing approval is to reduce the

  16   incidence of cataplexy and to improve the symptom

  17   of daytime sleepiness in patients with narcolepsy.

  18             [Slide]

  19             Narcolepsy fits the definition of orphan

  20   disease in the United States, with less than

  21   200,000 patients.  There are estimated to be about

  22   135,000 patients, of which 55 percent are

  23   diagnosed, with about 24,000 seeking treatment for

  24   cataplexy.

  25             [Slide] 
                                                                 25

   1             I would now like to introduce you to Dr.

   2   Emmanuel Mignot, from Stanford.  Dr. Mignot has

   3   been widely published in this area and is

   4   considered one of the premiere international

   5   experts on narcolepsy.  He has not participated in

   6   any of our clinical trials.

   7                           Medical Need

   8             DR. MIGNOT:  It is my privilege to talk to

   9   you today about narcolepsy.  I have been working on

  10   narcolepsy for about 15 years, both at the level of

  11   basic research as well as clinical care.  I am a

  12   medical doctor and I see patients with narcolepsy.

  13             [Slide]

  14             I am going to try to summarize in a few

  15   minutes really a lot of data about narcolepsy and

  16   how it impacts people.

  17             [Slide]

  18             First, I would like to start briefly by

  19   reviewing the symptoms of narcolepsy.  Narcolepsy

  20   is usually associated with 5 different symptoms.

  21   The most disabling and the most problematic in

  22   patients with narcolepsy is sleepiness.  Patients

  23   with narcolepsy are sleepy all the time; tired;

  24   they have sleep attacks; they cannot stay awake for

  25   a long period of time, and it is usually why they 
                                                                 26

   1   come to see the doctor.  They just cannot live a

   2   normal life.  Especially in work conditions, as you

   3   probably know, it is very difficult -- you have to

   4   be awake all day long and it is a major problem in

   5   narcolepsy.

   6             Now, it is not enough to diagnose

   7   narcolepsy.  Narcolepsy is not just sleepiness and

   8   there are a lot of other medical conditions that

   9   are associated with sleepiness.  Patients with

  10   narcolepsy also have a series of symptoms that

  11   correspond to the fact that they go very quickly

  12   into rapid eye movement sleep.  As probably many of

  13   you know, rapid eye movement sleep is a stage of

  14   sleep that only occurs 1.5 or 2 hours after you

  15   fall asleep where you are actively dreaming but

  16   your body is completely paralyzed and you have

  17   these rapid eye movements.

  18             Patients with narcolepsy go into REM sleep

  19   extremely quickly, sometimes in a few minutes, and

  20   that leads to a series of symptoms where patients

  21   sometimes are half way through REM sleep, being

  22   still awake.  Consequently, they may experience odd

  23   symptoms that we call the dissociated REM sleep

  24   event, abnormal REM sleep event.  Those are

  25   cataplexy, hypnagogic hallucinations and sleep 
                                                                 27

   1   paralysis.

   2             An example is cataplexy.  When a patient

   3   gets emotionally excited, typically when they are

   4   happy, they meet a good friend, sometimes when they

   5   are angry but most often when they are joking, in a

   6   nice environment and happy about something, they

   7   may feel suddenly weak; they become paralyzed;

   8   sometimes they fall down to the ground, completely

   9   paralyzed and they cannot move.  In very rare cases

  10   they may even go into REM sleep.  We believe

  11   somehow being emotionally excited stimulates the

  12   paralysis of rapid eye movement sleep that every

  13   one of us experiences during sleep, except that in

  14   patients with narcolepsy it may occur in the middle

  15   of the day in response to emotion.

  16             Also, when they fall asleep they sometimes

  17   have hallucinations because they go so quickly into

  18   REM that sometimes they dream while they are still

  19   awake.  I remember a patient, for example, who

  20   every night would fall asleep and he would see

  21   someone coming and strangling him.  Or, they may

  22   hear people talking; or see people walking in the

  23   room.  It can be very frightening and it can be a

  24   very terrible experience for patients with

  25   narcolepsy. 
                                                                 28

   1             Another symptom of abnormal REM sleep that

   2   patients with narcolepsy have as well is called

   3   sleep paralysis.  When they wake up from a nap or

   4   when they fall asleep, sometimes they again go so

   5   quickly into REM and disassociated REM sleep events

   6   that sometimes they may be paralyzed from REM but

   7   still be awake.  Basically, they would wake up from

   8   sleep and they cannot move, not even their little

   9   finger.  It can be very scary.  It lasts a few

  10   minutes and then finally they can move.  Some

  11   patients with narcolepsy have multiple episodes of

  12   sleep paralysis when they nap during the day, and

  13   so forth, and that is another very bothersome

  14   symptom.

  15             Finally, patients with narcolepsy,

  16   contrary to what people way, don't sleep too much;

  17   their main problem is that they just cannot stay

  18   awake.  They fall asleep very quickly in many

  19   circumstances, but they are unable to stay asleep

  20   for a long period of time.  In fact, patients with

  21   narcolepsy don't sleep 20 hours a day.  What

  22   happens is that at night they don't sleep well.

  23   Often that is another symptom that is very

  24   bothesome.  They fall asleep very quickly at night

  25   but after one hour they cannot sleep again.  They 
                                                                 29

   1   are just awake and cannot sleep.

   2             Then, all these symptoms are quite severe

   3   and, of course, affect the lives of patients.  And,

   4   since GHB is recommended in cataplexy, which is

   5   muscle atonia triggered by emotion, I will just

   6   show you a quick video of a patient with cataplexy.

   7             This is a boy, a 9-year old.  Narcolepsy

   8   usually starts during adolescence and here the

   9   clinicians are trying to make him laugh to just try

  10   to elicit the symptom, and you see he is falling

  11   down and he is completely paralyzed and he is

  12   losing his muscle tone.  Some of these patients

  13   have that many time per day and it can be extremely

  14   socially disabling.  You can imagine being at a

  15   party or being with some friends and having this

  16   happen to you.  In this kid it was particularly

  17   severe.

  18             Most cases of narcolepsy start during

  19   adolescence but occasionally it starts as early as

  20   5 years of age.  It peaks around 15 years of age.

  21   It is often extremely problematic because I am sure

  22   you realize when you have this type of thing

  23   happening to you and sleepiness at school,

  24   especially when you are 15 years old, when you are

  25   an adolescent, it really wrecks your life apart, 
                                                                 30

   1   especially when it is not properly diagnosed.

   2             [Slide]

   3             There have been a number of studies, and I

   4   won't have time to review them, that have shown

   5   that the quality of life of patients with

   6   narcolepsy is extremely impaired, as much as

   7   depression, epilepsy or other reference conditions

   8   in almost all the scales that you look at.

   9   Clearly, it is a very socially disabling disorder.

  10             [Slide]

  11             It is also, of course, a disorder that

  12   impacts just your daily life.  For example, driving

  13   -- patients with narcolepsy have a very increased

  14   rate of accidents and sometimes many of them refuse

  15   to drive just because of falling asleep or having

  16   cataplexy while driving.

  17             [Slide]

  18             We have objective tests for diagnosing

  19   narcolepsy.  In fact, it is not just a

  20   psychological disorder.  You can actually use a

  21   test like the Multiple Sleep Latency Test, where

  22   you ask patients to come to the sleep lab.  You

  23   check that they sleep normally and the following

  24   day you ask them to nap every two hours and you

  25   measure how fast they fall asleep.  You see, 
                                                                 31

   1   normally people won't fall asleep or nap in the

   2   middle of the day, or they would fall asleep with a

   3   15-minute latency in the dark.  A patient with

   4   narcolepsy, as soon as you switch off the light,

   5   they are sleeping.  In a few minute latency, they

   6   are asleep.  So, we have objective ways to show

   7   that these people have a problem.

   8             [Slide]

   9             Also, in this nap you see that they go

  10   very quickly into REM sleep.  Normal people won't

  11   have REM sleep before one hour after falling

  12   asleep, but patients with narcolepsy will go

  13   straight into REM.  You can actually demonstrate --

  14   we call that sleep onset REM period -- that

  15   patients with narcolepsy have all this sleep

  16   abnormality and REM abnormality using sleep

  17   testing.

  18             [Slide]

  19             Current treatment for narcolepsy is

  20   completely symptomatic.  We don't treat the cause

  21   of the disease; we only treat the symptoms.

  22   Typically, the treatment now uses two drugs, two

  23   lines of drug.  A patient with cataplexy will be

  24   treated usually with two drugs.  One is a stimulant

  25   which would be a classical amphetamine-like 
                                                                 32

   1   stimulant or this more recent drug that was just

   2   approved that is called modafinil, Provigil, which

   3   works on sleepiness.  It will keep a patient awake

   4   but will never normalize him; it only improves him.

   5   And, they all have a lot of side effects.  You

   6   know, the stimulants can even produce psychosis in

   7   some rare cases but, of course, they raise blood

   8   pressure.  They produce psychological changes.

   9   They have a lot of other side effects.

  10             We all know now that they all increase

  11   dopamine in the brain.  We have done a series of

  12   studies which have shown that.  Even modafinil, the

  13   most recent drug -- we know now that it works by

  14   increasing dopamine in the brain.  And, they don't

  15   have anything different from each other so some of

  16   them are definitely safer than others.

  17             For the antidepressants, for the treatment

  18   of cataplexy -- this works well on sleepiness but

  19   it doesn't work on cataplexy or nightmares, or

  20   hallucination or sleep paralysis.  For this you use

  21   antidepressants.  Why?  Because antidepressants

  22   depress REM sleep and they also suppress cataplexy

  23   and all the other abnormal dreaming that patients

  24   with narcolepsy have.  The problem is they also

  25   have a lot of side effects.  Actually, the new 
                                                                 33

   1   SSRI, they don't work as well as the old

   2   tricyclines.  Often you even have to use the old

   3   tricycline antidepressants because norepinephrine

   4   uptake inhibition seems to be the mode of action of

   5   these drugs, more than serotonin.  They don't

   6   really work that well and, of course, they have a

   7   lot of side effects and a lot of different

   8   problems.

   9             [Slide]

  10             Finally, I want to stress again that we

  11   need new treatments for narcolepsy just because all

  12   the treatments we have now just don't make people

  13   normal.  They just help them to be better.  You can

  14   best illustrate that using the MSLT/MWT, which is a

  15   slightly different test where, instead of measuring

  16   how fast people fall asleep in the dark, you ask

  17   people to try to stay away in the dark and you see

  18   that normal people can stay awake.  They don't fall

  19   asleep in 20 minutes, whereas patients with

  20   narcolepsy fall asleep very dramatically after a

  21   few minutes in the dark.

  22             Even if you treat them with modafinil

  23   which is a very good treatment for narcolepsy,

  24   which was recently approved, you improve them but

  25   they never become normal.  Then, it is clear that 
                                                                 34

   1   what we have is not enough.  We just need better,

   2   and this would be the same for amphetamines.  Even

   3   high dose amphetamines don't normalize these

   4   patients.  That has been shown by multiple studies.

   5             [Slide]

   6             We have worked for more than 15 years

   7   trying to find the cause of narcolepsy, and

   8   recently we have isolated the gene for narcolepsy

   9   in a canine model where the disease is genetically

  10   determined, and we found that it was a receptor for

  11   a norpeptide that is called hypocretin.  We found

  12   that in humans with narcolepsy it is not like dogs

  13   with narcolepsy; it is not the receptor but a

  14   peptide called hypocretin which is expressed in

  15   about 10,000 cells in the brain, here in the

  16   hypothalamus, which is missing in patients with

  17   narcolepsy.

  18             This is brain tissue of a patient with

  19   narcolepsy.  You see here is the normal; everything

  20   is gone.  If you measure in the cerebrospinal

  21   fluid, this is a normal level in a normal person,

  22   or in patients with MS or other neurological

  23   symptoms, and you see in all patients with

  24   narcolepsy that this hypocretin molecule is gone.

  25   We know now that the cause of narcolepsy is not 
                                                                 35

   1   dopamine or norepinephrine, which is the current

   2   treatment for narcolepsy, which are stimulants and

   3   antidepressants acting through these

   4   neurotransmitters, and probably replacing this

   5   hypocretin would be an ideal treatment for

   6   narcolepsy.  But this finding was only made one

   7   year ago and it is going to take probably 10 years

   8   or many years before we actually have a treatment

   9   based on this new discovery.

  10             [Slide]

  11             To summarize the medical need, I think I

  12   have convinced you that narcolepsy is a serious and

  13   disabling condition that needs treatment, and these

  14   patients are in desperate need of better treatment.

  15   As you will see from the presentation afterwards,

  16   GHB is one of the effective treatments which helps

  17   a lot of people.  So, current treatments like

  18   amphetamines and antidepressants don't work well in

  19   terms of efficacy.  They have a lot of side

  20   effects.  They all work the same way but they don't

  21   act on the cause of the disease and, clearly, we

  22   know that GHB, even though it probably doesn't act

  23   on hypocretin, acts differently from other drugs.

  24   And, it is one more drug that would be available to

  25   help a lot of patients with narcolepsy. 
                                                                 36

   1             Finally, even though there have been

   2   numerous, very recent developments that are very

   3   exciting in the hypocretin area, unfortunately, you

   4   all know it takes a long time until drugs are

   5   available and it is going to take probably many

   6   years until this available.

   7             This is a very quick summary of what we

   8   know about narcolepsy to date.  Thank you.

   9             DR. REARDAN:  Thank you, Dr. Mignot.  Dr.

  10   Houghton will now present the data which has been

  11   assembled in support of the efficacy of Xyrem.  Dr.

  12   Houghton is a qualified anesthesiologist, with 18

  13   years of clinical experience in critical care

  14   medicine and numerous years experience in

  15   pharmaceutical drug development.  Bill?

  16                             Efficacy

  17             DR. HOUGHTON:  Good morning.

  18             [Slide]

  19             I am sorry to start with such a complex

  20   diagram but this just outlines the pattern of

  21   studies that we will be talking about this morning.

  22   On the left-hand side here are the 4 controlled

  23   studies on which the assessment of efficacy will be

  24   based, but what is unusual about this program is

  25   that patients, in an uncommon way, move to 
                                                                 37

   1   extension protocols.  So, as Dr. Katz pointed out,

   2   even though the total database may be small, the

   3   total duration of exposure of patients is quite

   4   promising.

   5             The first study that I will talk about is

   6   entitled OMC-GHB-3, and the patients, at the

   7   completion of this short-term treatment study did

   8   progress to a long-term, open label study and then

   9   had the opportunity to move into one of the

  10   treatment IND protocols, with some of them still

  11   participating in that study.

  12             A second contributor to that protocol was

  13   the patients who completed the first 6-month safety

  14   treatment IND protocol, and the significance of all

  15   of that is that it was from this protocol that the

  16   patients are represented in the long-term pivotal

  17   blinded efficacy study that supports the long-term

  18   efficacy of Xyrem.

  19             [Slide]

  20             The first and pivotal study is a

  21   randomized, double-blind, placebo-controlled,

  22   parallel group, multi-center trial comparing the

  23   effects of three doses, 3 g, 6 g and 9 g of orally

  24   administered Xyrem with placebo for the treatment

  25   of narcolepsy.  As I mentioned, this was a study 
                                                                 38

   1   conducted in 136 patients in 16 centers.

   2             [Slide]

   3             The primary efficacy parameter was the

   4   change in the number of total cataplexy attacks in

   5   the last two weeks of the treatment period compared

   6   to the two weeks of the baseline period.

   7             Secondary efficacy parameters that were

   8   considered included complete and partial cataplexy

   9   attacks; daytime sleepiness; inadvertent sleep

  10   attacks during the day; hypnagogic hallucinations;

  11   sleep paralysis; and a clinical global impression

  12   of change.

  13             [Slide]

  14             Patients naive to sodium oxybate therapy

  15   were chosen with a bona fide diagnosis of

  16   narcolepsy for at least 6 months.  They were

  17   required to have a record of a polysomnograph or

  18   Multiple Sleep Latency Test within the last 5 years

  19   to exclude other causes of daytime sleepiness, and

  20   particularly sleep apnea.

  21             They were required to have a history of

  22   daytime sleepiness and cataplexy for at least 6

  23   months, and recurrent daytime naps that occurred

  24   almost daily in the preceding 3 months.

  25             [Slide] 
                                                                 39

   1             The overall study design was divided into

   2   5 stages.  Firstly, there was a screening period in

   3   which the patients were required to qualify for

   4   entry criteria and then withdrawn from their

   5   existing anti-cataplectic medications over a 4-week

   6   period to avoid rebound phenomena which were

   7   considered a safety consideration.  At the end of

   8   this withdrawal period they entered a washout

   9   period, which was determined by at least 5 times

  10   the half-life of their preceding drug to remove any

  11   effects of those drugs.  However, if patients

  12   weren't on any cataplectic medications, they were

  13   still required to remain 5 days in that washout

  14   period to familiarize themselves with the use of

  15   diaries.

  16             They then proceeded to a baseline period

  17   of 2 to 3 weeks, using daily diary recording to

  18   establish the severity of their disease and to

  19   confirm that they had reached a stable stage in

  20   their disease.  They then entered a 4-week blinded,

  21   randomized treatment period, with a visit at 2

  22   weeks, a telephone call the day after commencing

  23   treatment, and then safety telephone calls 3 times

  24   a week during the treatment period, at the end of

  25   which they were abruptly withdrawn from drug and 
                                                                 40

   1   followed up 3 to 5 days later to assess any rebound

   2   phenomena and any adverse experiences that may have

   3   ensued.

   4             [Slide]

   5             As is shown here, the patient groups were

   6   very evenly balanced at baseline.  They represented

   7   a fairly severe group of narcoleptics, with an

   8   average incidence of cataplexy of around 34 per

   9   week at baseline.

  10             There was a dose-response relationship

  11   across the doses based on median change in the

  12   total number of cataplexy attacks that, when

  13   compared to placebo, approached significance at the

  14   9 g dose, with a p value of 0.0529, and achieved

  15   highly significant change at the 9 g dose.

  16             [Slide]

  17             This dose relationship is clearly shown in

  18   the plot of median change from baseline in the

  19   number of cataplexy attacks per week, and the

  20   spread of the data is demonstrated as the quartile

  21   lines around these median values.

  22             [Slide]

  23             A more clinically relevant presentation of

  24   the data is the percentage change in the number of

  25   cataplexy attacks from baseline.  This was 
                                                                 41

   1   calculated as the distribution of percentage change

   2   values for each individual patient and is again

   3   presented as the medians.  This representation

   4   clearly shows that the major change in cataplexy

   5   occurs in the first 2 weeks, but with ongoing

   6   change in the subsequent 2 weeks, as represented in

   7   2 of the dose groups.

   8             [Slide]

   9             Secondary efficacy variables included

  10   assessment of excessive daytime sleepiness using

  11   the validated Epworth Sleepiness Scale which rates

  12   the patient's feeling of daytime somnolence by

  13   scoring on a scale of 0-3 the probability of

  14   falling asleep in the circumstances of 8 common

  15   life scenarios.  This results in a potential

  16   maximum score of 24.

  17             [Slide]

  18             This slide demonstrates a clear

  19   dose-related reduction in the Epworth Sleepiness

  20   Scale, reaching a significant level of 0.0001 in

  21   the 9 g group compared to placebo.  This change was

  22   incremental beyond the effects of stable dosing of

  23   stimulants because stimulant medications were

  24   maintained constant throughout the study.  In all

  25   Xyrem-treated groups some patients improved beyond 
                                                                 42

   1   the defined narcolepsy range, with some patients in

   2   the 6 g and 9 g groups actually improving into the

   3   normal range as rated by the Epworth Sleepiness

   4   Scale.

   5             The second component of daytime

   6   sleepiness, the number of inadvertent naps during

   7   the day, was also significantly reduced compared to

   8   placebo in the 6 g group and 9 g dosing.

   9             [Slide]

  10             The severity of the disease at baseline

  11   was rated by the principal investigator according

  12   to the following validated scale.  Then, at the end

  13   of the treatment period a blinded global impression

  14   of change according to the rating shown here was

  15   made, rating from very much improved through no

  16   change to very much worse.

  17             [Slide]

  18             Assignment of these modal values indicated

  19   a primary distribution of the placebo patients

  20   mainly to no change or minimally improved, but

  21   there is an obvious predominance of assignment in

  22   the 9 g dose to very much improved and much

  23   improved.

  24             [Slide]

  25             Because of the complexity of presenting 
                                                                 43

   1   these assigned categories, a post hoc

   2   simplification was applied to group the patients

   3   that showed clear clinical improvement into a

   4   responder group, and all others were called

   5   non-responders.  This again displays the

   6   dose-response trend in the categorical data, with a

   7   clear statistical difference between the 9 g group

   8   and the placebo group.

   9             [Slide]

  10             Other secondary measures that achieved

  11   significant change included the number of

  12   awakenings at night, subjective sleep quality,

  13   morning alertness, the ability to concentrate.

  14   Hypnagogic hallucinations and sleep paralysis,

  15   which had a much lower incidence at baseline,

  16   showed a non-significant trend towards improvement.

  17             [Slide]

  18             The next study that I would like to

  19   present is the study that was suggested by the FDA

  20   to provide evidence of long-term efficacy of Xyrem

  21   based on the return of cataplexy following the

  22   cessation of long-term treatment with the active

  23   drug.

  24             [Slide]

  25             Patients entered this blinded, randomized 
                                                                 44

   1   study from the long-term open-label study I showed

   2   you initially having completed the GHB-2 protocol

   3   and proceeded into the GHB-3 protocol for periods

   4   up to 2 years, or from the initial treatment IND

   5   protocol.  This provided assessment of potential

   6   adverse consequences of the abrupt withdrawal of

   7   long-term therapeutic doses of Xyrem as well.

   8             Patients having taken the drug for 6

   9   months to 3.5 years were screened, and after

  10   blinded randomization entered a single blind

  11   baseline period in which daily diaries were used to

  12   record the severity of their cataplexy.  They then

  13   entered a double-blind phase of 2 weeks wherein

  14   they were randomized in a 50 percent ratio to

  15   either continued, unchanged dose of Xyrem in a

  16   blinded fashion or to placebo.  Randomization was

  17   performed in a centralized manner to ensure equal

  18   representation of dosing in the comparative groups.

  19             [Slide]

  20             The primary efficacy variable was the

  21   change in the number of cataplexy attacks in the

  22   double-blind period compared to baseline.  There

  23   was a median change of zero in the Xyrem group but,

  24   as seen, there was a marked increase in the

  25   incidence of cataplexy in those randomized to 
                                                                 45

   1   placebo.  This was highly significant.

   2             [Slide]

   3             When the median change from baseline by

   4   week was calculated, you can see that there was a

   5   step-wise increase in cataplexy which supported the

   6   long-term efficacy of the drug in a statistically

   7   significant manner, but they represent a gradual

   8   return of cataplexy rather than an acute rebound

   9   phenomenon.

  10             [Slide]

  11             I will now present very briefly some

  12   supportive data from 2 early controlled, crossover

  13   design studies that have been published, and for

  14   which Orphan Medical purchased the databases and

  15   included in the NDA submission.

  16             [Slide]

  17             The first was a study conducted by Dr.

  18   Lawrence Scrima, then of the University of

  19   Arkansas, in 20 patients, 10 males and 10 females,

  20   using a dose of 50 mg/kg, much lower than some of

  21   those in the previous studies and equivalent to

  22   about 3.5 g per day in a 70 kg man.

  23             Following the withdrawal of

  24   anticataplectic medications, he recorded a baseline

  25   period during which the patients were required to 
                                                                 46

   1   have a minimum of 10 cataplexy attacks, then were

   2   randomized into an initial treatment period of 29

   3   days, followed by a washout period of 6 days, and

   4   then crossed over to the alternate treatment, again

   5   followed by a washout of 6 days.  Stimulants were

   6   continued throughout this study and all patients

   7   were actually transferred to methylphenidate as

   8   their stimulant.

   9             [Slide]

  10             The primary efficacy measures are

  11   identified, with the average number of cataplexy

  12   attacks compared to baseline and objective

  13   sleepiness index as determined by the Multiple

  14   Sleep Latency Test.  This was to represent a

  15   measure of daytime sleepiness.

  16             Because of logistic issues in the study

  17   conduct and methodologic issues in design and

  18   definition, this is presented as supporting data

  19   only to represent cataplexy response at a lower

  20   dose.  As can be seen, this patient group again

  21   represented a reasonably severe narcoleptic

  22   population.  They had a baseline measure of 20

  23   cataplexy attacks per week.  There was an initial

  24   fairly significant placebo response, as was shown

  25   in the previous studies, but by week 3 and week 4 
                                                                 47

   1   statistically significant differentiation between

   2   placebo and active treatment was shown, and there

   3   was a statistically significant overall response in

   4   the study.  There was no significant change in the

   5   sleepiness index as the measure of daytime

   6   sleepiness, however, in this study.

   7             [Slide]

   8             The second study that I will present very

   9   briefly was conducted by Dr. Lammers, in The

  10   Netherlands.  It is, again, a randomized, blinded,

  11   crossover design study in 24 narcoleptics.  The

  12   other significant difference in this study was that

  13   concomitant medications for both cataplexy and

  14   excessive daytime sleepiness were continued

  15   throughout the study.

  16             Following a 1-week baseline to establish

  17   disease severity, the patients were randomized to a

  18   4-week treatment period at a dose of 60 mg/kg in

  19   divided nightly doses, followed by a washout period

  20   of about 3 weeks, and then a baseline period of 1

  21   week again preceding a second treatment period of 4

  22   weeks.

  23             [Slide]

  24             As is obvious here, the severity of

  25   cataplexy during the baseline period was much lower 
                                                                 48

   1   in this study, potentially the consequence of

   2   continued anticataplectic medication in some

   3   patients.  But, again, there is a significant

   4   response.  According to the statistical plan which

   5   was very scant that was represented in the

   6   published study, and agreed to by the FDA, there

   7   was an incorrect or unsatisfactory statistical

   8   management of this study.  The change in cataplexy

   9   was not statistically significant.   When the

  10   results of this study were submitted by Orphan,

  11   they were reanalyzed with an ANCOVA analysis as had

  12   been applied in the GHB-2 study, and this change

  13   was significant according to the ANCOVA analysis.

  14             [Slide]

  15             Other measures that showed significant

  16   improvement included hypnagogic hallucinations and

  17   daytime sleep attacks again.

  18             [Slide]

  19             Although not eligible for determination of

  20   efficacy since it is an open-label study, I would

  21   like to briefly mention three aspects of the

  22   follow-on study to the pivotal GHB-2 study.  And,

  23   117 patients chose to participate entering the

  24   study at the 6 g per day dose and then slowly

  25   titrating to clinical efficacy between the doses of 
                                                                 49

   1   3 g and 9 g.  This study, therefore, represents the

   2   proposed clinical use of the drug and, although

   3   primarily a safety study, represents some important

   4   dynamic information.

   5             [Slide]

   6             This slide shows the response in cataplexy

   7   over the 12-month period.  What is surprising is

   8   that the maximum nadir occurred at about 8 weeks,

   9   and then the sustained efficacy was maintained

  10   across the 12 months in all dose groups.

  11             [Slide]

  12             A similar pattern was seen in the Epworth

  13   Sleepiness Scale, which shows the same time frame

  14   with maximum response at about 8 weeks, and then

  15   maintained efficacy over the course of 12 months in

  16   this open-label study.  What is also interesting to

  17   note is that most of the patients in most dose

  18   groups were maintained beyond the defined

  19   narcolepsy range.

  20             [Slide]

  21             When the distribution of doses to which

  22   the patients were titrated is shown, it is seen

  23   that 6 g per day is the most common dose, followed

  24   by the 9 g dose group.

  25             [Slide] 
                                                                 50

   1             This represents the pattern of dosing seen

   2   in other open-label studies where doses were

   3   titrated to clinical response.  What is important

   4   to note is that there is not a change in dosing

   5   between the 6-month and the 12-month dosing groups,

   6   suggesting no tolerance development to maintain the

   7   dynamic effects shown.

   8             [Slide]

   9             This slide represents the cohort of

  10   patients that entered the SXB-21 protocol via the

  11   GHB-2 and then GHB-3 protocol.  Represented here is

  12   the incidence of cataplexy for each individual

  13   patient at the baseline in GHB-2.  They were then

  14   maintained in the study I have just shown you over

  15   the course of up to 2 years, and this is the

  16   incidence of cataplexy of each of the individual

  17   patients in the single-blinded baseline in the

  18   SXB-21 protocol.  When the paradigm of random

  19   assignment to placebo is shown, then there is

  20   certainly a demonstration of efficacy between those

  21   who were randomized to the placebo group in SXB-21

  22   versus those that maintained their Xyrem treatment,

  23   which certainly helps to support the efficacy

  24   statement in the GHB-3 protocol.

  25             [Slide] 
                                                                 51

   1             Finally and to summarize, we have

   2   presented data to show efficacy of sodium oxybate

   3   to reduce cataplexy in 4-week treatment periods in

   4   a dose-related manner that is highly statistically

   5   significant at the 9 g dose, and approaching

   6   statistical significance at the 6 g dose.

   7             We have presented supportive data

   8   demonstrating statistically significant efficacy of

   9   the lower doses, and demonstrated statistically

  10   significant efficacy in terms of daytime

  11   sleepiness, using the Epworth Sleepiness Scale,

  12   again at 9 g.  In a scale used in the Lammers study

  13   at 60 mg/kg daytime sleep attacks were

  14   statistically significantly reduced in all 3

  15   studies.  We supported the long-term efficacy of

  16   Xyrem with return of cataplexy when blindedly

  17   assigned to placebo in the SXB-21 protocol.

  18             [Slide]

  19             I would now like to very briefly summarize

  20   the pharmacokinetics studies that were conducted by

  21   Orphan Medical.

  22             [Slide]

  23             In total, we conducted 8 clinical

  24   pharmacokinetic studies, including 2 studies in

  25   narcoleptic patients and 6 in healthy human 
                                                                 52

   1   volunteers.  This slide lists the 8 pharmacokinetic

   2   studies by their primary objective.

   3             The studies included a single dose pilot

   4   study in 6 narcoleptics, and a second study in

   5   narcoleptic patients comparing acute and chronic

   6   dosing over an 8-week period.  Normal volunteer

   7   studies were conducted to examine the kinetics of

   8   Xyrem with respect to gender differences, dose

   9   proportionality and the effects of food.  Also, 3

  10   drug interaction studies were performed with

  11   Zolpiden, protriptyline and modafinil as

  12   representatives of the 3 classes of drugs used

  13   commonly to treat the symptoms of narcolepsy.

  14   Lastly, an in vitro study, using human hepatic

  15   microzymes, was conducted to assess the effects of

  16   oxybate.

  17             [Slide]

  18             I will only present the studies that have

  19   a significant message, and in very brief summary

  20   form.  This slide displays the results of the dose

  21   proportionality study that compared nightly dose of

  22   4.5 and 9 g given in 2 equally divided doses at

  23   bedtime and 4 hours later.  A randomized, 2-day

  24   crossover design was utilized, and doubling the

  25   dose from 4.5 to 9 g resulted in a nearly 4-fold 
                                                                 53

   1   increase in the area under the time concentration

   2   curve.  The peak plasma concentration and the time

   3   to peak concentration changed significantly with

   4   doubling the dose, the latter suggesting

   5   capacity-limited absorption.  C                                          
                                        max was higher after

   6   the second dose than with the first nightly dose,

   7   as has been seen in other studies with divided

   8   dosing.

   9             These findings indicate non-linear

  10   kinetics and capacity-limited elimination and

  11   absorption, as reported in previously published

  12   studies.

  13             [Slide]

  14             The results of the effect of food study

  15   are displayed graphically on this slide.  In this

  16   randomized, crossover study 34 healthy subjects

  17   were dosed with 4.5 g of Xyrem on 2 occasions 1

  18   week apart, either after an overnight 10.5 hour

  19   fast or immediately following a high fat

  20   standardized breakfast.  After the high fat meal

  21   the peak plasma concentration decreased by almost

  22   60 percent.  The median time to achieve peak levels

  23   increased from 45 minutes to around 2 hours, and

  24   the AUC decreased by 37 percent.  All of these

  25   differences were statistically significant.  The 
                                                                 54

   1   apparent half-life was not significantly altered.

   2   Thus, the presence of food significantly reduces

   3   systemic exposure to GHB, a finding not previously

   4   reported.

   5             In the 3 volunteer kinetic studies the

   6   urinary excretion of Xyrem was measured, and renal

   7   excretion was shown to be a minor pathway of

   8   elimination, accounting for less than 5 percent of

   9   the administered drug.

  10             [Slide]

  11             As an example of the drug interaction

  12   studies, on this slide we present the modafinil

  13   results.  The upper graph indicates that

  14   co-administration of 200 mg of modafinil had no

  15   impact on the kinetics of Xyrem.  The lower graph

  16   demonstrates that 4.5 g of Xyrem had no clinically

  17   significant effect on the kinetics of a standard

  18   dose of modafinil.

  19             Likewise, in the Zolpiden protriptyline

  20   interaction studies, no significant kinetic

  21   interactions were found.  In the separate in vitro

  22   study using human hepatic microzymes, sodium

  23   oxybate was found to have no effect on 6 cytochrome

  24   p450 enzymes either to inhibit or induce their

  25   activity. 
                                                                 55

   1             [Slide]

   2             So in summary, Xyrem oral solution is

   3   rapidlyh absorbed and eliminated with a half-life

   4   of about one hour.  The drug displays non-linear,

   5   dose-dependent kinetics, indicative of

   6   capacity-limited absorption and elimination.  Xyrem

   7   kinetics are similar in men and women and do not

   8   change with chronic administration at therapeutic

   9   doses.

  10             [Slide]

  11             Chronic dosing did not change the kinetics

  12   of Xyrem in a patient population, and a high fat

  13   meal appreciably delayed absorption and reduced

  14   total systemic exposure to the drug.  Three

  15   separate in vivo drug interaction studies, as well

  16   as the in vitro p450 enzyme study, would suggest

  17   the probability of significant drug-drug

  18   interaction with Xyrem is minimal.  Thank you very

  19   much.

  20             DR. REARDAN:  Thank you.  I would now like

  21   to introduce Dr. Jed Black, from Stanford

  22   University Sleep Center, and he will present on the

  23   polysomnographic effects of Xyrem and GHB.

  24                Polysomnographic Effects of Xyrem

  25             DR. BLACK:  Good morning, ladies and 
                                                                 56

   1   gentlemen.  I would like to summarize the body of

   2   data that has been collected over the past 25 years

   3   which characterizes the effects of gamma

   4   hydroxybutyrate or sodium oxybate on sleep

   5   parameters.  I will then speculate briefly on a

   6   possible mechanism whereby these effects on sleep

   7   result in a robust improvement in daytime

   8   narcolepsy symptoms seen with this agent.

   9             This has been a particular focus of my

  10   research in sleep over the past years.  That is,

  11   how does what happens in the brain at night affect

  12   various aspects on daytime function and alertness?

  13             It is unexpected that a medication that

  14   objectively markedly improves sleep quality also

  15   improves measures of daytime alertness as this

  16   finding has never been observed with traditional

  17   hypnotics or sleep aids.  To pursue an

  18   understanding of this possible interaction, 6

  19   investigations have been conducted in humans.

  20   These studies explored the effect of sodium oxybate

  21   on a variety of nocturnal sleep parameters, using

  22   electroencephalography during sleep and a

  23   laboratory test known as polysomnography.

  24             The first 3 studies found an increase in

  25   slow wave sleep.  Slow wave sleep, also known as 
                                                                 57

   1   stages 3 and 4 sleep, is the deepest portion of

   2   sleep and correlates positively with functions of

   3   daytime concentration, attention and alertness in

   4   normal subjects.  These studies also reveal a

   5   reduction in nocturnal awakenings with GHB.

   6             The more recent studies of Scrima, Lammers

   7   and Orphan Medical explored both measures of

   8   nocturnal sleep as measured by polysomnography, or

   9   PSG, and measures of daytime sleepiness with the

  10   Multiple Sleep Latency Test, or daytime alertness

  11   with the Maintenance of Wakefulness Test.

  12             [Slide]

  13             These 2 studies, the design of which has

  14   been reviewed by Dr. Houghton, again found

  15   significant reductions in slow wave sleep, that is

  16   to say stage 3-4 sleep or slow wave sleep, and

  17   reductions in nocturnal awakenings.  Additionally,

  18   the Scrima group reported a reduction in stage 1

  19   sleep, a very light stage of sleep, and the Lammers

  20   group noted significant reduction in the percentage

  21   of time patients spent awake during nocturnal

  22   polysomnography.

  23             [Slide]

  24             The most recent study, a multi-center

  25   trial performed at 4 sites with an enrollment of 25 
                                                                 58

   1   patients, was designed to further explore the

   2   effects of sodium oxybate on nocturnal sleep

   3   parameters and daytime measures of sleepiness and

   4   alertness.  In this open-label study patients were

   5   kept at a stable stimulant dose throughout the

   6   protocol.  Cataplexy medications were tapered,

   7   followed by a 2-week washout and baseline period.

   8   Sodium oxybate was initiated at 4.5 g in a divided

   9   nightly dose for 4 weeks, then increased to 6, then

  10   7.5, then 9 g for 2 weeks each.  Nocturnal

  11   polysomnography and the Maintenance of Wakefulness

  12   Test, or MWT, were obtained at the time points

  13   noted here.

  14             [Slide]

  15             This study revealed the expected increase

  16   in slow wave, or stages 3-4 sleep, and increase in

  17   delta power.  Delta power is the measure of the

  18   depth of sleep.  It incorporates the combination of

  19   the amplitude of the slow frequency waves and the

  20   prevalence of those waves through the night to

  21   produce a single number called delta power.  Delta

  22   power is another measure found in a variety of

  23   animal and human studies to correlate positively

  24   with sleep quality.  The calculation of this value

  25   requires sophisticated processing which was 
                                                                 59

   1   unavailable for the prior studies.  The increments

   2   in slow wave sleep and delta power were found to be

   3   dose related.  Dose-related improvements in daytime

   4   alertness and subjective sleepiness were also

   5   observed.

   6             [Slide]

   7             The dose-response increase in the number

   8   of minutes of slow wave sleep is illustrated in

   9   this slide, with an increase from 6 g up to the 9 g

  10   dose.  The total duration of slow wave sleep

  11   increased to over 5-fold that of baseline at the 9

  12   g dose.

  13             It is important to note that while these

  14   results are predicted to be dose related, time on

  15   medication cannot be factored out as a potential

  16   contributor to these increments.

  17             [Slide]

  18             Delta power, which characterizes slow wave

  19   activity throughout the entire sleep period, not

  20   just during stages 3 and 4, was also found to

  21   increase in a dose response fashion with a 50

  22   percent increase noted at the 9 g dose over

  23   baseline.

  24             [Slide]

  25             The Maintenance of Wakefulness Test, or 
                                                                 60

   1   MWT, is a daytime evaluation which places the

   2   patient in a dimly lit room in a semi-recumbent

   3   position, with nothing to do and with the

   4   instruction to remain awake.  The duration of

   5   sustained wakefulness was measured in this study

   6   over 40-minute intervals across 4 periods, spaced 2

   7   hours apart during the day.  Substantial

   8   dose-related increases in the ability to remain

   9   awake were observed at both the 4.5 g and 9 g

  10   doses.

  11             [Slide]

  12             As previously noted, the MWT was not

  13   performed at the 6 g nor 7.5 g doses in this

  14   protocol.  Similar marked reductions were found in

  15   the Epworth Sleepiness Scale scores.  In this

  16   measure the individual rates their own potential to

  17   fall asleep in a variety of more sedentary daytime

  18   activities.

  19             [Slide]

  20             A post hoc analysis of the possible

  21   correlations between sodium oxybate-related changes

  22   in nocturnal parameters with changes in daytime

  23   measures revealed the strongest correlation

  24   occurring with delta power and Epworth Sleepiness

  25   Scale scores.  This was a negative correlation, 
                                                                 61

   1   such that the greater the delta power, the lower

   2   the daytime sleepiness.  In addition, trends toward

   3   significant correlations between delta sleep and

   4   MWT scores, and between slow wave sleep and Epworth

   5   and MWT scores were observed.

   6             [Slide]

   7             In conclusion, studies of sodium oxybate's

   8   effects on sleep demonstrate increases in measures

   9   of restorative sleep, including dose-related

  10   increments in slow wave and delta sleep, coupled

  11   with and correlated with improvements in measures

  12   of daytime alertness and sleepiness.

  13             It is postulated that sodium oxybate works

  14   directly to enhance brain neurochemical activity

  15   critical to the restorative mechanisms of slow wave

  16   sleep and of slow wave activity during the total

  17   sleep period.  Such enhanced activity may be the

  18   cause of substantial improvement in both subjective

  19   and objective measures of sleepiness and alertness

  20   observed with sodium oxybate in narcolepsy.

  21             DR. REARDAN:  Thank you, Dr. Black.  Dr.

  22   Houghton will now present the safety summary

  23   overview of Xyrem and finish up with a benefit/risk

  24   assessment.

  25                  Safety Overview and Summary of 
                                                                 62

   1                     Risk/Benefit Assessment

   2             DR. HOUGHTON:  Thank you.

   3             [Slide]

   4             I am sorry to horrify you with this

   5   complex diagram again but it is just to outline the

   6   15 studies that will be referred to today as the

   7   updated safety database.  The Lammers study was

   8   excluded because adverse events were not recorded

   9   in the classical way and, as Dr. Katz explained,

  10   the Scharf study was separated and will be

  11   explained again later.

  12             [Slide]

  13             The safety profile was reported based on

  14   exposure of 479 narcoleptic patients and 125

  15   healthy volunteers from the pharmacokinetic

  16   studies.  This represents an exposure of greater

  17   than 6 months in 360 patients in total, and greater

  18   than 12 months in 296 patients, which represents a

  19   total patient-year exposure of 1328 years with the

  20   Scharf database included.

  21             [Slide]

  22             When exposures were restricted to the

  23   studies other than the Scharf database, 399

  24   narcoleptics and 125 subjects represent exposure in

  25   524 persons.  This represents exposure of greater 
                                                                 63

   1   than 6 months in 296 patients and greater than 12

   2   months in 223 patients, for a total exposure of 330

   3   patient-years.

   4             [Slide]

   5             In the open-label studies patients were

   6   titrated between the doses of 3-9 g in divided dose

   7   at night.  This slide represents the distribution

   8   of patients across this defined dose range and,

   9   again, identifies the 6 g dose as the most commonly

  10   used, followed again by the 9 g dose.  In fact,

  11   approximately 80 percent of patients were titrated

  12   within the 6-9 g range.

  13             [Slide]

  14             In the updated integrated safety database,

  15   composed of 402 patients, 399 of whom were treated

  16   with active drug and 3 patients received placebo

  17   only, it can be seen that 65 percent of patients

  18   completed therapy or were ongoing in the treatment

  19   IND study.  Thirty-five percent have discontinued

  20   treatment for the reasons noted here, with 13

  21   percent discontinuing due to adverse events; 2

  22   percent discontinuing because of lack of efficacy;

  23   and there were 2 deaths that occurred in the

  24   treatment IND studies, both due to suicide.

  25             [Slide] 
                                                                 64

   1             Across all of these studies, 82 percent of

   2   treated patients reported any adverse event, as did

   3   70 percent of patients exposed to placebo.  It is

   4   important to note that the placebo exposure

   5   represents 4 weeks as compared to active drug

   6   treatment over a much longer period of up to 4

   7   years.  Hence, severe adverse event

   8   discontinuations and serious adverse events are

   9   significantly greater in the active treatment

  10   groups.

  11             [Slide]

  12             When considered in terms of dose at onset,

  13   there seemed to be a slight preponderance of

  14   incidence in the 9 g group.

  15             [Slide]

  16             This slide represents the most frequent

  17   adverse events reported across the integrated

  18   database.  There was a consistent pattern of events

  19   across the study.  Nausea, dizziness, sleep

  20   walking, are represented here as a partial

  21   representation of the term sleep disorder, enuresis

  22   and confusion were most frequently considered dose

  23   related, while others represent intercurrent

  24   illness.

  25             [Slide] 
                                                                 65

   1             This profile is reinforced by

   2   consideration of the controlled trials in which

   3   there is represented a balanced exposure to placebo

   4   and active medication.  Again, dizziness, nausea,

   5   pain, sleep disorder, confusion, infection,

   6   vomiting and urinary incontinence separate.  A dose

   7   relationship was shown introduction eh GHB-2 trial

   8   for confusion, nausea, dizziness and urinary

   9   incontinence.

  10             [Slide]

  11             In the SXB-21 trial the most common

  12   adverse events that were reported are shown here.

  13   The incidence was very low in this study of

  14   patients on long-term treatment, but what is

  15   relevant is the data that looks at the possible

  16   presentation of a withdrawal syndrome with the

  17   abrupt cessation of long-term therapy.

  18             [Slide]

  19             This is in marked contrast to a severe

  20   syndrome that is being described in the abuser

  21   population who have significantly escalated both

  22   dose and frequency of dosing.  When we looked at

  23   symptoms that could relate to a withdrawal

  24   phenomenon, we saw only 2 patients with anxiety in

  25   a circumstance of escalating cataplexy, 1 patient 
                                                                 66

   1   with dizziness, 1 insomnia, 1 sleep disorder that

   2   actually in verbatim terms, was increased

   3   awakenings, and 1 patient with somnolence as their

   4   narcolepsy worsened.

   5             [Slide]

   6             I would like to now address the Scharf

   7   database.  This was conducted under an investigator

   8   IND commencing about 10 years before Orphan's

   9   involvement, without any of the rigors of external

  10   monitoring, and really represents over 16 years

  11   experience in the use of the drug rather than drug

  12   development clinical research with regulatory

  13   disciplines.

  14             Patients were scattered all over the

  15   country and, hence, the data is based primarily on

  16   diary recordings without medical review and

  17   interpretation, leading to a significant

  18   discontinuation rate for lack of compliance.  Dose

  19   accountability and titration were less clearly

  20   defined and less controlled.  Patients had less

  21   defined entry criteria and represent a broader

  22   profile of associated pathologies.  On this basis,

  23   the study data has been reported separately to the

  24   integrated database, as Dr. Katz had suggested.

  25             [Slide] 
                                                                 67

   1             We will address the Scharf open-label

   2   experience in terms of dosing exposure, patient

   3   disposition, adverse event incidence over 16 years,

   4   and then to try and establish some parity with the

   5   integrated database.  We have considered the

   6   adverse event experience reporting in just the

   7   first 6 months of the study.

   8             [Slide]

   9             Patient disposition in the Scharf database

  10   is represented in this slide.  At the time of

  11   database closure 63 patients transferred into the

  12   SXB-7 protocol.  The FDA expressed concern

  13   regarding the accountability of the 80 patients

  14   that did not continue.  We provided a narrative

  15   account for each individual patient, with updated

  16   status where possible, in the form of a major

  17   amendment.  In addition, FDA requested further

  18   clarification of adverse events initially deemed

  19   uaevaluable, which we have also provided.

  20             Of these 80 patients, 8 continued in the

  21   Scharf trial under his treatment IND.  The 71

  22   patients who withdrew had received oxybate for from

  23   5 days to 10 years, and the reasons for early

  24   withdrawal of the 71 patients were primarily

  25   classified into non-compliance, adverse event and 
                                                                 68

   1   cost.

   2             [Slide]

   3             The adverse event profile reflects the

   4   length of the study.  The relatively large numbers

   5   of viral infection, flu syndrome, pharyngitis, etc.

   6   shouldn't be worrisome considering the 16 years

   7   duration of the study.  However, of particular

   8   interest is the unusual incidence of sleepwalking

   9   and urinary incontinence and these will be

  10   discussed in some detail later.

  11             [Slide]

  12             The most frequent adverse events in the

  13   first 6 months of the Scharf trial are shown here.

  14   When compared to the integrated safety database,

  15   few adverse events separate in incidence.  Most

  16   notable are somnolence, infection, viral infection

  17   and malaise.  There were few new adverse events

  18   reported after the first 6 months.

  19             The FDA requested further information

  20   regarding the following adverse events of

  21   particular interest.  They were represented by

  22   incontinence and convulsions, confusion,

  23   neuropsychiatric events and sleepwalking.

  24             [Slide]

  25             I will address incontinence first.  In 
                                                                 69

   1   their review of the GHB-2 trial, submitted in

   2   October, 1998, the FDA requested an analysis of

   3   adverse event terms for incontinence in association

   4   with central nervous system adverse events

   5   suggestive of seizure.

   6             [Slide]

   7             We responded by initiating the following:

   8   a questionnaire to all investigators to review the

   9   history of abnormal nocturnal observations that

  10   could be suggestive of seizures; a detailed

  11   urologic history preceding oxybate therapy and any

  12   new neurologic symptoms.

  13             Examination of the databases for potential

  14   correlation between central nervous adverse events

  15   that could be related to seizures and incontinence,

  16   either urinary or fecal, was undertaken.  Review of

  17   both preclinical and clinical data in the

  18   literature was performed and an overnight EEG

  19   recording after a 9 g dose was conducted in 6

  20   patients who had reported incontinence during their

  21   oxybate therapy.  An expert opinion was provided by

  22   Dr. Nathan Chrone, a neurologist of Johns Hopkins

  23   University.

  24             [Slide]

  25             The issue as represented is shown here.  
                                                                 70

   1   Urinary incontinence was presented by 8 patients

   2   reporting 15 events in the GHB-2 study, by 13

   3   patients reporting 51 events over the 2-year period

   4   of GHB-3, and in the Scharf study by 33 patients

   5   reporting 140 events.

   6             When central nervous system events were

   7   analyzed for contemporaneous reporting, 2 patients

   8   in each of the GHB-2 and -3 trials recorded such

   9   events corresponding to episodes of incontinence,

  10   as did 7 patients in the Scharf database.

  11   Relatively few incontinence events were temporally

  12   associated with the CNS adverse events suggestive

  13   of seizure.  No potential seizure genesis was

  14   reported by bed partners in response to specific

  15   questions, and many of the partners reported

  16   relevant urinary symptoms such as frequent nocturia

  17   preceding the Xyrem treatment.

  18             [Slide]

  19             Single events of fecal incontinence

  20   occurred in 4 patients in 4 different trials.

  21   Association between these incontinence events and

  22   central nervous system adverse experiences were

  23   present only in 1 patient in the Scharf trial and 1

  24   in the pharmacokinetic SXB-11 trial.  In this

  25   patient the event of fecal incontinence was 
                                                                 71

   1   definitely associated with a seizure in a patient

   2   with a known pre-study history of seizures.  The

   3   subject in the SXB-11 effect of food study was a

   4   patient who, while significantly obtunded and with

   5   respiratory obstructive symptoms, had a brief

   6   episode of fecal incontinence.

   7             [Slide]

   8             In conclusion, there was limited support

   9   for a relationship between incontinence and

  10   seizures from the clinical trials, the prospective

  11   EEGs or from the literature.

  12             [Slide]

  13             The vast majority of events that could

  14   have been coded as convulsions were actually

  15   recorded under the COSTART dictionary as cataplexy

  16   events.  One patient in the integrated trial

  17   database did not represent this classification and

  18   he has been investigated by a neurologist for

  19   seizure genesis.  His fugue state and automatic

  20   behavior episodes have been deemed part of his

  21   narcolepsy syndrome.

  22             In the Scharf database two patients with

  23   definite seizures recorded history of preexisting

  24   disease, and two other patients recorded seizure

  25   events without definitive diagnosis but with 
                                                                 72

   1   complicated polypharmacy.

   2             [Slide]

   3             To now address confusion, in the

   4   integrated safety database 30 patients or 70

   5   percent reported 48 events recorded as confusion,

   6   leading to discontinuation from study in 3

   7   patients.  A possible dose relationship was

   8   suggested by a review of the entire database.  In

   9   the Scharf database, again 7 percent of patients

  10   reported 15 such events, with no discontinuations

  11   and no dose relationship pattern observed.

  12             [Slide]

  13             The coding of confusion embodied a wide

  14   range of verbatim terms, as shown here.  These do

  15   not represent confusion based on a standard medical

  16   status examination.  They do not differentiate

  17   between nighttime events from those of awakening or

  18   arousal parasomnias.  These events led to no dosage

  19   adjustment in 37 instances, but dose was reduced in

  20   4 events, led to temporary discontinuation

  21   following 4 events, and 3 patients discontinued

  22   permanently because of a side effect of confusion.

  23             [Slide]

  24             When the GHB-2 controlled trial was

  25   considered with respect to confusion, the highest 
                                                                 73

   1   incidence in the databases is represented in this

   2   4-week study by 10 patients.  The highest incidence

   3   was seen in the 9 g dose, and 6 of the 10 developed

   4   during the first week of treatment.  Seven of these

   5   10 events were in patients over the age of 50.  The

   6   difference in this study, of course, was the

   7   assigned doses rather than dose titration.  It is

   8   important to note that 1 event was reported in a

   9   placebo patient.

  10             [Slide]

  11             In conclusion, the term represents a

  12   symptom report rather than confusion defined in a

  13   medical sense by formal mental status examination,

  14   and all resolved usually without interruption of

  15   therapy or dose modification.  Confusion and other

  16   associated symptoms are not unexpected with

  17   sedating medications.  The blinded, controlled

  18   trial results suggest that a higher incidence may

  19   result without dose titration.

  20             [Slide]

  21             Neuropsychiatric events will now be

  22   reviewed.  The adverse event database was searched

  23   for terms that could represent neuropsychiatric

  24   symptoms, and this led to the classification shown

  25   in this slide.  Fifty-two patients reported 57 such 
                                                                 74

   1   events in the integrated safety database, of whom

   2   12 discontinued as a result of these events.  In

   3   the Scharf database 41 patients reported 84 such

   4   events, leading to 2 patient discontinuations.

   5             [Slide]

   6             Of these 57 events, 1 occurred while a

   7   patient was on placebo.  This slide lists the terms

   8   examined and some, such as stupor and coma, failed

   9   to represent neuropsychiatric events.  Many

  10   represented symptoms of narcolepsy such as

  11   hypnagogic hallucinations COSTART-coded to the term

  12   hallucinations.  The most frequent was clinical

  13   depression, and this represents a symptom rather

  14   than a diagnosis of major depressive disorder.

  15   Depressive symptoms are frequent accompaniments in

  16   narcolepsy, and this is well recorded in the

  17   literature.  Suicide was attempted in 4 patients

  18   with major preexisting psychiatric history, and

  19   resulted in death in 2 of these patients.  The

  20   other representations of psychotic disorders and

  21   the patient with manic depressive disorder also

  22   occurred in patients with preexisting major

  23   psychiatric disease.  As is shown, a similar

  24   profile of reported symptoms is found in the Scharf

  25   database. 
                                                                 75

   1             [Slide]

   2             In conclusion, most patients with major

   3   events had a preexisting psychiatric disorder.

   4   Many events do not qualify as neuropsychiatric

   5   disorders, as was represented by the terms pointed

   6   out.  Assignment of causality is very difficult

   7   because narcolepsy is associated with depression

   8   and even mechanistically there has been an

   9   association between psychosis and the central

  10   processes in narcolepsy.  As Dr. Mignot mentioned,

  11   stimulant medications are associated with central

  12   nervous system side effects that are represented by

  13   neuropsychiatric symptoms.  And, it is true to say

  14   that in many patients, particularly in the Scharf

  15   database, pre-study screenings were deficient.

  16             [Slide]

  17             To lastly address sleepwalking, in the

  18   integrated safety database 7 percent of patients

  19   reported such events, whereas in the Scharf

  20   database 32 percent of patients reported events

  21   that were listed as sleepwalking.  In the Scharf

  22   trial, however, these reports were primarily data

  23   listings in patient diaries in response to a

  24   specific leading question, listed as a line item in

  25   the diary. 
                                                                 76

   1             [Slide]

   2             The listing of this term did not receive

   3   the benefit of medical consideration of a

   4   differential diagnosis of somnambulism, and since

   5   most patients were not seen by the investigator no

   6   clarification was provided.  Post hoc consideration

   7   was rendered impossible given the lack of

   8   information regarding sleep stage, time of night,

   9   relationship to drug dosing, and could be

  10   representative of any of the differential diagnoses

  11   listed on this slide.

  12             [Slide]

  13             In the controlled trials only 3

  14   sleepwalking events were reported, 2 of which

  15   occurred on active treatment and 1 occurred in a

  16   patient during placebo treatment.

  17             [Slide]

  18             Hence, in conclusion, the incidence in the

  19   integrated safety database of 7 percent is not

  20   particularly dissimilar to the range reported in

  21   the literature for normal patients.  This was

  22   reported by Dr. Mahowald, of Minneapolis, as

  23   between 4-10 percent in a publication in 1998, and

  24   between 1-7 percent by Dr. Roger Broughton of

  25   Canada. 
                                                                 77

   1             Diary recording without medical

   2   classification represents a potential increased

   3   reporting in the Scharf trial.  The slight increase

   4   in incidence over the general population may

   5   certainly be representative of Xyrem effects with

   6   increase in slow wave sleep, but REM behavior

   7   disorder, common in narcolepsy, mayou be a separate

   8   consideration.

   9             [Slide]

  10             To summarize the safety profile of this

  11   drug, we based our assessment to date on 604

  12   patients, which represents 524 patients excluding

  13   the Scharf database.  Dosing was between 3-9 g per

  14   day in divided nightly dosing.  The common adverse

  15   events were certainly headache, unspecified pain,

  16   nausea, dizziness, and less common but important

  17   adverse events were vomiting, confusion,

  18   restlessness, agitation, sleepwalking and enuresis.

  19             [Slide]

  20             All events have been reversible.  There

  21   were no significant changes in lab values or vital

  22   signs identified across the studies.  There was no

  23   evidence of organ toxicity outside the

  24   pharmacologic effects in the central nervous

  25   system.  There was no diversion or consumption of 
                                                                 78

   1   clinical trial supplies by any family members

   2   during the trials, and there was certainly no

   3   evidence of Xyrem diversion in our database.

   4             [Slide]

   5             I would like to conclude with the

   6   statement that Xyrem was generally well tolerated.

   7             [Slide]

   8             To commence a risk/benefit assessment, I

   9   would like to remind you of the indication proposed

  10   by Orphan Medical for the use of Xyrem.  That is,

  11   to reduce the incidence of cataplexy and to improve

  12   the symptom of daytime sleepiness in patients with

  13   narcolepsy.

  14             [Slide]

  15             As has been pointed out, narcolepsy is an

  16   uncommon disease, with an incidence of around 0.05

  17   percent and, as such, has been qualified for orphan

  18   designation.  There are no therapies approved for

  19   the treatment of cataplexy.  Because of this, the

  20   FDA were very kind to apply a priority review to

  21   our submission and we are very appreciative of that

  22   recognition.  Current off-label therapies, so well

  23   described by Dr. Mignot, are unsatisfactory.

  24   Excessive daytime sleepiness has approved therapies

  25   but these do not address cataplexy.  There is 
                                                                 79

   1   clearly a medical need existing beyond the

   2   therapies available.

   3             [Slide]

   4             The benefits of Xyrem in the trials

   5   presented were based on patient diary recordings,

   6   investigator ratings of overall clinical

   7   improvement in overall disease severity, and

   8   objective measures of changes in sleep architecture

   9   and daytime response.

  10             [Slide]

  11             Clinical benefit in the short-term

  12   reduction in cataplexy was shown by the

  13   dose-related reduction in cataplexy in the GHB-2

  14   and Scrima studies and in the long-term efficacy in

  15   the SXB-21.  Subjective changes in the Epworth

  16   Sleepiness Scale have been well demonstrated, and

  17   reduction in daytime sleep attacks have accompanied

  18   this change.  Early objective Maintenance of

  19   Wakefulness Test data supported these changes in

  20   daytime sleepiness.  The global impression of the

  21   investigators for overall changes in disease

  22   severity also showed a significant dose

  23   relationship.

  24             [Slide]

  25             Xyrem was generally well tolerated when 
                                                                 80

   1   used in the proposed dose range, with the most

   2   common side effects reported including nausea,

   3   dizziness, headaches, pain and confusion.  Less

   4   common but important associated effects include

   5   enuresis and sleepwalking, with a possible dose

   6   relationship suggested.  Although there were 11

   7   deaths in the Scharf trial over 16 years and 2

   8   deaths by suicide in the integrated database, no

   9   deaths were associated with Xyrem.

  10             [Slide]

  11             In relation to the specific FDA inquiries,

  12   there is a possible relationship between Xyrem

  13   therapy and somnambulism but further definition is

  14   required.  There is a marked discrepancy between

  15   the reported incidence in the Scharf study of the

  16   32 percent, recorded solely by diary entry in

  17   response to a leading question, and the 7 percent

  18   in the integrated database, which is really in the

  19   range in public literature for the normal

  20   population.  In the controlled trials there were

  21   only 3 such reports in total, 2 recorded in active

  22   treatment and 1 during placebo treatment.

  23             [Slide]

  24             Confusion is also an adverse accompaniment

  25   of sedative hypnotic drugs and has been identified 
                                                                 81

   1   as an occasional side effect of Xyrem.  Dose

   2   titration may assist in limiting this side effect

   3   but it remains an important component of patient

   4   and physician education.

   5             [Slide]

   6             The incidence of enuresis with Xyrem

   7   treatment supports an association that may be dose

   8   related, but any association of these events with

   9   seizure activity is very weak.  In terms of Xyrem

  10   causing seizures at the therapeutic doses, there

  11   was no reliable support for such causality.  In

  12   this regard, the coding to the COSTART dictionary

  13   terms of cataplexy as convulsion was confusing.

  14   However, there were 2 patients recording seizures

  15   with preexisting causes.  Two further patients in

  16   the Scharf database reported seizures where

  17   confounding contributions rendered assignment very

  18   difficult.  One patient in the Orphan studies

  19   represented a complex history of symptoms

  20   characterized by fugue state and these symptoms

  21   have been attributed to his narcolepsy syndrome.

  22             [Slide]

  23             No significant measures were seen in

  24   laboratory measures, vital signs or ECG measures

  25   and these changes were comparable across the 
                                                                 82

   1   treatment groups.  There was no evidence of organ

   2   toxicity at therapeutic doses that were not part of

   3   the central nervous system pharmacology of the

   4   drug.

   5             [Slide]

   6             We did not identify any evidence of

   7   kinetic or dynamic tolerance in the narcoleptic

   8   populations studied and the absence of drug-drug

   9   interactions in the 3 classes of drugs commonly

  10   used in narcolepsy, along with the absence of

  11   either induction or inhibition of the oxybate p450

  12   enzyme system make it possible to predict that

  13   drug-drug interactions should be minimal.

  14             [Slide]

  15             Although a serious withdrawal syndrome has

  16   been described in the abuser population that

  17   relates to escalation in both dose and frequency of

  18   dosing, no evidence of withdrawal has been

  19   demonstrated in patients maintained on long-term

  20   therapeutic doses in narcolepsy.  Following abrupt

  21   discontinuation of long-term dosing in the blinded

  22   study, only 2 patients reported anxiety but in the

  23   presence of worsening cataplexy, with 1 patient

  24   reporting mild dizziness and 1 report of insomnia.

  25             [Slide] 
                                                                 83

   1             We have not attempted in any way to

   2   minimize the issue of abuse with GHB or its

   3   precursors.  We recognize that this is a serious

   4   problem, but stress the fact that this has been

   5   peripheral to the development program in

   6   narcolepsy.  We have detected no evidence of abuse,

   7   diversion or self-escalation of dosing in patients

   8   in clinical trials.  Great efforts have been

   9   applied to working with the appropriate expert

  10   bodies to plan a restricted distribution system to

  11   support in every way the unique bifurcated

  12   scheduling legislated by Congress and to plan

  13   physician and patient education to minimize the

  14   possibility of diversion.  This will be greatly

  15   facilitated by the documentation centrally of

  16   prescribing and patient use.  This will be

  17   described in detail to you later.

  18             [Slide]

  19             In conclusion, I would propose that we

  20   have established statistically and clinically

  21   significant evidence for the reduction in

  22   cataplexy, and for improvement in daytime

  23   sleepiness when used concomitantly with stimulant

  24   medications.

  25             Xyrem is generally well tolerated, with a 
                                                                 84

   1   safety profile well characterized in this orphan

   2   population by long-term exposure.  The medical

   3   benefits clearly outweigh the risks for a

   4   therapeutic agent that may be the first single

   5   agent to address the multiple symptoms of

   6   narcolepsy.  Thank you very much.

   7             DR. REARDAN:  I would just like to thank

   8   the committee and FDA for your attention.  I

   9   believe Dr. Mani has some comments, or we are now

  10   happy to take questions from the committee.

  11             DR. KAWAS:  The FDA will give us a

  12   response to the presentation, and then we will

  13   probably take a break before we have questions,

  14   unless the committee has anything burning they need

  15   to ask now.  Dr. Ranjit Mani will present for the

  16   FDA.

  17                 FDA Response to the Presentation

  18             DR. MANI:  What I propose to do in the

  19   next few minutes is address two issues where our

  20   views diverge somewhat from those of the sponsor.

  21             [Slide]

  22             The first is the effect of GHB on measures

  23   of daytime sleepiness in narcolepsy.

  24             [Slide]

  25             This overhead illustrates how many 
                                                                 85

   1   measures of daytime sleepiness there were in the

   2   GHB efficacy trials.  As you can see, GHB-2 had 3

   3   measures of daytime sleepiness; the Scrima study

   4   had 2, of which 1 was primary; and the Lammers

   5   study had 2.  I will draw your attention to the

   6   fact that, with the exception of the Scrima study,

   7   the remaining measures were all designated as being

   8   secondary.

   9             [Slide]

  10             Because what is considered statistically

  11   significant does depend or could depend on the

  12   number of comparisons made, I think it is also

  13   important to illustrate how many secondary efficacy

  14   measures there were in each trial.  In the GHB-2

  15   trial I was able to count a total of 10; in the

  16   Scrima study 17; and in the Lammers study 7.

  17             [Slide]

  18             This is based on data provided by Orphan.

  19   As you can see, in the GHB-2 trial the Epworth

  20   Sleepiness Scale measure did reveal a fairly

  21   clear-but efficacy for GHB but only at the 9 g

  22   dose.  The p value of 0.001 probably remains

  23   statistically significant even when adjustment is

  24   made for multiple comparisons.

  25             On the other hand, the frequency of 
                                                                 86

   1   daytime sleep attacks and duration of daytime sleep

   2   attacks should probably be considered negative

   3   evidence of efficacy if adjustment is made for

   4   multiple comparisons.

   5             [Slide]

   6             Again, in the Scrima study one primary

   7   efficacy measure was sleepiness index of the

   8   Multiple Sleep Latency Test.  Here, the results

   9   must be considered negative whether adjusted for

  10   multiple comparisons or not.

  11             [Slide]

  12             The other measure was the frequency of

  13   daytime sleep attacks, again negative whether

  14   adjusted for multiple comparisons or not.

  15             [Slide]

  16             In the Lammers study the severity of

  17   daytime sleepiness was 1 of 7 secondary efficacy

  18   measures which is probably negative when adjusted

  19   for multiple comparisons.  On the other hand, the

  20   frequency of daytime sleep attacks was positive,

  21   but using an ANCOVA which was not a protocol

  22   specified analysis.

  23             [Slide]

  24             So, here are the problems as we see them

  25   with the proposed claim for excessive daytime 
                                                                 87

   1   sleepiness.  Most measures were secondary.  The

   2   only measure that was primary was negative.  The

   3   majority of measures were negative after adjustment

   4   of the Type 1 error for multiple comparisons.  The

   5   effects were inconsistent across studies, and the

   6   clearly positive results on the GHB-2 trial on the

   7   Epworth Sleepiness Scale were not replicated.  As

   8   mentioned, the approval of modafinil for the

   9   treatment of excessive daytime sleepiness was based

  10   on replicated results in 2 efficacy studies.  And a

  11   minor point, the results on the GHB-2 study were,

  12   to some extent, confounded by concurrent stimulant

  13   use, raising the question, among other questions,

  14   of whether Xyrem is effective as monotherapy for

  15   the treatment of excessive daytime sleepiness.

  16             [Slide]

  17             The second issue that I want to address

  18   briefly is that of sleepwalking.  As you can see, I

  19   have put it in quotes.  As Bill Houghton has

  20   already emphasized, we do not know what these

  21   episodes represent.  They have not been clinically

  22   characterized.

  23             [Slide]

  24             The term sleepwalking does not correspond

  25   to the medical entity of somnambulism.  The term is 
                                                                 88

   1   based entirely on patient diary entries, and there

   2   has been no attempt to characterize the episodes

   3   further and define what clinical entity they

   4   correspond to.

   5             The incidence of these episodes, whatever

   6   they may represent, was approximately 32 percent.

   7   The majority of patients did list as having more

   8   than one episode.  A single patient had a total of

   9   346 episodes over a 5-year period.  As already

  10   said, an adequate clinical description is lacking,

  11   and the episodes cannot be said to be completely

  12   benign.

  13             There was one patient who is reported to

  14   have overdosed twice during two consecutive

  15   episodes of sleepwalking.  During one episode the

  16   patient became comatose and needed to be

  17   hospitalized, needed to be on a ventilator for some

  18   hours but completely recovered.  A second pat had

  19   multiple episodes of sleepwalking.  She was found

  20   by her husband to be smoking, apparently

  21   inadvertently.  During one such episode her clothes

  22   were set on fire.  The fire was put out.  She was

  23   taken off GHB and did not have any further such

  24   episodes.  A third patient is reported to have

  25   swallowed nail polish remover during an episode, 
                                                                 89

   1   without any serious consequences.

   2             I would also like to add one minor point

   3   in response to  Dr. Houghton's presentation.  That

   4   is, I believe that in the Scharf study there was

   5   one patient who was withdrawn from the study

   6   because he felt that he had benefitted from Xyrem

   7   and decided that these benefits could be extended

   8   to a circle of friends who also received part of

   9   his own supply, again apparently without serious

  10   consequences.  Thank you.  That is really all I

  11   have to say.

  12             DR. KAWAS:  Thank you, Dr. Mani.  Does the

  13   committee have any questions they would like to ask

  14   before the break?  If not, we will reconvene this

  15   meeting at 10:30 sharp.

  16             [Brief recess]

  17                       Committee Discussion

  18             DR. KAWAS:  Will you please have a seat so

  19   we can reconvene this session?  This meeting of the

  20   Peripheral and Central Nervous System Advisory

  21   Committee is now reconvened.  We appreciate the

  22   presentations from the sponsor and the FDA, and the

  23   floor is open for questions.  The first question is

  24   going to come from someone who has been patiently

  25   sitting on the phone.  Dr. Chervin, can you hear 
                                                                 90

   1   me?

   2             DR. CHERVIN:  Yes, thank you.

   3             DR. KAWAS:  Dr. Chervin, we can't year you

   4   yet, if you will give us a moment to do whatever it

   5   is we have to do?

   6             DR. CHERVIN:  Can you hear me now?

   7             DR. KAWAS:  Give it a shot.

   8             DR. CHERVIN:  I have a question perhaps

   9   for Dr. Houghton.  In regard to the safety

  10   experience with the 1328 patient years, were there

  11   any reports that alcohol was taken in the evening

  12   in combination with GHB?  If so, what was the

  13   outcome?

  14             DR. HOUGHTON:  It was certainly

  15   recommended as a contraindication in our protocols.

  16   The advice to the patient was that they not consume

  17   alcohol during the studies.  I can't vouch for the

  18   fact that it was entirely complied with, but we

  19   don't have protocol or database record of

  20   consumption of alcohol during the trials.  There

  21   certainly is record of patients having imbibed

  22   during the Scharf study and I am not in a position

  23   to clarify that.

  24             DR. GUILLEMINAULT:  This is Dr.

  25   Guilleminault.  I have also a question, and it is 
                                                                 91

   1   for Dr. Mani, about the sleepiness data.  Was there

   2   the slow wave sleep information looked at for

   3   sleepiness?  As you know, delta power greatly

   4   improves alertness and there are many studies,

   5   sleep deprivation studies and investigation into

   6   sleep disorders such as obstructive sleep apnea,

   7   where it is very clear that decrease in delta power

   8   and in slow wave sleep has a big impact on the

   9   alertness, and the more delta power you have and

  10   the more slow wave sleep you have, the better

  11   alertness the next day.

  12             So, one of my understandings is that this

  13   drug has an impact on slow wave sleep and delta

  14   power.  Was there any analysis of that in data

  15   looking at alertness?

  16             DR. MANI:  To the best of my knowledge, it

  17   was not listed as an efficacy measure in any of the

  18   controlled studies that I looked at.

  19             DR. GUILLEMINAULT:  Okay.  The second

  20   question is maybe a question about my ignorance.  I

  21   did not understand exactly the statistic about the

  22   ESS because in the investigation of the results of

  23   the ESS there was an investigation with negative

  24   studies.  All the results, when you look at

  25   everything there, was there a positive p value?  
                                                                 92

   1   Was there a statistical difference?  Because I

   2   don't understand the manipulation which was done.

   3   Maybe through poor knowledge, I have never seen

   4   this type of manipulation.

   5             DR. REARDAN:  Dr. Guilleminault, which

   6   study are you referring to when you ask about the

   7   Epworth Sleepiness score?

   8             DR. GUILLEMINAULT:  I think OMS-2.

   9             DR. REARDAN:  Is that for Dr. Mani, or do

  10   you want to pose that to the company?

  11             DR. GUILLEMINAULT:  No, I was asking that

  12   because Dr. Mani reported that he looked at that

  13   study and classified the results, and my

  14   understanding, and it may be a wrong understanding,

  15   is that he made a subdivision in looking at the

  16   results and I did not see completely the

  17   statistical rationale for that approach.

  18             DR. MANI:  Are you referring to the

  19   statistical adjustments for multiple comparisons?

  20   Is that what you mean?

  21             DR. GUILLEMINAULT:  No, the Epworth

  22   Sleepiness Scale study in GHB-2, secondary efficacy

  23   daytime sleepiness on your slide, and I did not

  24   understand exactly how that was analyzed, the type

  25   of analysis that was done or redone. 
                                                                 93

   1             DR. MANI:  Perhaps I should ask the Orphan

   2   statisticians to explain that in greater detail,

   3   but the analysis was an ANCOVA.

   4             DR. GUILLEMINAULT:  The microphone must be

   5   poorly placed because we cannot hear the response.

   6             DR. MANI:  Can you hear me now?

   7             DR. GUILLEMINAULT:  Yes.

   8             DR. MANI:  The analysis was an ANCOVA.  I

   9   mean, perhaps I should get the Orphan study

  10   statistician to explain the analysis to you in

  11   greater detail.

  12             DR. REARDAN:  I am just asking Dr. Richard

  13   Trout, the statistician, to comment on how the

  14   Epworth Sleepiness score was statistically

  15   analyzed.

  16             DR. TROUT:  Hi.  My name is Dick Trout.

  17   First of all, the analysis was just as you

  18   described, that is to say it was an analysis of

  19   covariance which was preplanned.  I think the

  20   concern that you expressed was the fact that it was

  21   listed as a secondary efficacy measure --

  22             DR. GUILLEMINAULT:  Right.

  23             DR. TROUT:  -- as compared to a primary,

  24   and there was a number of secondary efficacy

  25   measures, but even if one adjusted for the multiple 
                                                                 94

   1   testing which I think you were concerned about, the

   2   9 g separation from the placebo group would still

   3   be significant.  We already adjusted for the

   4   multiple testing with regard to the dosing issue,

   5   using Dunnett's test, but your concern was with

   6   regard to the fact that there were a number of

   7   secondary efficacy measures which would then

   8   diminish the effect.

   9             DR. GUILLEMINAULT:  Okay, thank you.

  10             DR. PENN:  I can see that the claim for

  11   helping daytime sleepiness is going to be one that

  12   we will want to look into very carefully, and I

  13   want to ask our FDA statistician a question about

  14   that in a general sort of way.  If you were a

  15   gambling person, which I assume a statistician

  16   would not be --

  17             [Laughter]

  18             -- from the data that you have looked at

  19   for 9 g, would you say that in a good controlled

  20   trial you would bet on it working to decrease

  21   daytime sleepiness?  It looks like the strongest

  22   data is at 9 g and that is what the company is

  23   suggesting.  I am going to ask you to bet on that,

  24   and then I am going to make a point.

  25             DR. MANI:  You addressed the question to a 
                                                                 95

   1   statistician; I am not a statistician.

   2             DR. PENN:  Oh, I am sorry.  Anybody else

   3   want to gamble with this?

   4             DR. REARDAN:  Coming up to the podium is

   5   Dr. Sharon Yan, who is the FDA statistician that

   6   has been working on the Xyrem program.

   7             DR. YAN:  Basically we rely on the results

   8   that were prespecified, and a lot of results that

   9   we looked at -- and you want me to bet -- after

  10   looking at those results, most people would bet

  11   that the data shown, for example, the 9 g it seems

  12   that it is highly positive; it is highly

  13   significant, but we rely on the analysis which is

  14   prespecified.  Without that, the data information

  15   -- it is hard to bet on anything.

  16             DR. PENN:  But I am asking you how you

  17   would bet on that if you had to make a bet now in

  18   Las Vegas, and the point I am trying to make is

  19   that it seems to me a reasonable bet that it does

  20   help daytime sleepiness but that they haven't

  21   presented two clean studies that show at 9 g that

  22   that is the case.  And, is there going to be some

  23   middle ground to this where that claim can be put

  24   in language that would be acceptable later on?  So,

  25   I wanted to see if you agree that that analysis 
                                                                 96

   1   then presenting of the problem is the correct one,

   2   that is, that there is very strong suggestive

   3   evidence, not as strong as we often want for a

   4   claim, that it helps daytime sleepiness.  When you

   5   sit back and you look at all the data, would you

   6   bet on that helping daytime sleepiness?

   7             DR. KAWAS:  Perhaps Dr. Katz could help

   8   with this response.

   9             DR. KATZ:  Yes, again, I will just sort of

  10   reiterate something that Dr. Yan has already said,

  11   which is that whether or not we personally believe

  12   something is true or what we would bet on is not

  13   really the standard.  The standard which we apply

  14   is what the law requires, which is substantial

  15   evidence of effectiveness, ordinarily defined,

  16   unless there is some compelling reason to do

  17   otherwise, as data from at least two adequate and

  18   well-controlled trials demonstrating effect.  We

  19   have adopted by tradition a usual sort of

  20   statistical rule by which we decide whether or not

  21   a study is "positive" for a particular indication.

  22   So, I think that is the standard.  Unless there is

  23   some, as I say, very compelling reason to apply

  24   some different standard, like what would I bet on

  25   or what my personal belief is, that is the standard 
                                                                 97

   1   we need to apply.  Again, unless there is a view

   2   that there is some compelling reason to apply some

   3   different standard, we would ask you as a committee

   4   whether you think that the evidence for that

   5   particular claim meets that standard.

   6             DR. PENN:  So, once again the question

   7   should go then to Orphan, whether or not they feel

   8   they have met that standard on two separate

   9   occasions using their 9 g amount, and I haven't

  10   gotten a clear-cut idea in my mind whether they are

  11   really claiming that or just showing us data that

  12   would be for a good bet.

  13             DR. YAN:  May I clarify one thing?  For

  14   the analysis for daytime sleepiness for GHB-2 the

  15   sponsor showed it was highly significant, with a p

  16   value of 0.001, and I analyzed the data with the

  17   original scale and, as I analyzed it, it shows that

  18   the normal assumption was validated and then the

  19   log transformation to then improve the data, and I

  20   used nonparametric analysis to analyze the p value,

  21   and it is not that small.  As I remember, the p

  22   value is 0.03 or something.

  23             DR. REARDAN:  I can comment on the trials.

  24   We have GHB-2, obviously, where the trial was very

  25   effective.  I don't think there is a dispute with 
                                                                 98

   1   FDA on that.  The question is do we meet the

   2   standard of two well-controlled trials for that

   3   indication.  The data in support of that comes from

   4   the Lammers study.  The sleepiness scale used there

   5   was something he developed, not a validated scale

   6   but it was statistically significant for daytime

   7   sleepiness, albeit in a very small, 24-patient

   8   crossover trial.

   9             So, we have a small supportive study.  We

  10   have the large controlled study, GHB-2.  That is

  11   the evidence basically.  Bill, do you want to

  12   comment?

  13             DR. HOUGHTON:  Yes.  We are not trying to

  14   make this something that it is not in any way, and

  15   if you apply the absolute, most rigorous standards

  16   of normal drug development to our database, we have

  17   a small database.  We did have the two components

  18   that were statistically significant.  This was

  19   supported by the reduction in daytime sleep attacks

  20   which are very clinically significant to the

  21   patient, and we had two components of statistical

  22   significance there.

  23             The other issue, and I know that this from

  24   a pure mathematical sense is problematic, is the

  25   evidence of long-term support in daytime sleepiness 
                                                                 99

   1   claim with the GHB-3 protocol, which showed the

   2   Epworth Sleepiness Scale and the daytime sleepiness

   3   reduced and maintained over the long period of

   4   time.  The fact then that the objective data in

   5   SXB-20 was so strongly supportive and the change in

   6   Maintenance of Wakefulness Test is an objective

   7   measure and was clearly positive was very

   8   important.

   9             The part that concerns me from a clinical

  10   point of view is if you look at the patient

  11   profiles as they enter the studies, they are on

  12   stable doses of stimulants and, yet, their ratings

  13   are very low.  The real issue is that daytime

  14   sleepiness with current medications isn't well

  15   addressed.  So, the question is not only have we

  16   shown absolute irrevocable evidence of long-term

  17   efficacy for daytime sleepiness with the existence

  18   of the present treatments for long-term

  19   effectiveness, what we didn't do is ask for a claim

  20   in daytime sleepiness.

  21             [Slide]

  22             Our proposed indication was to improve the

  23   symptom.  We didn't attempt to do studies that

  24   displaced the stimulant therapies.  What we are

  25   really looking at is a hand-in-glove approach that 
                                                                100

   1   actually makes patients better as an incremental

   2   change, and all therapies up to now have been very

   3   separate.  The symptoms of daytime sleepiness and

   4   those of the associated REM phenomena have been

   5   treated by entirely separate medications.  If there

   6   is a component of Xyrem that assists in daytime

   7   sleepiness as an incremental change, we think it is

   8   very clinically important and that is what we

   9   sought to present today.  I want to stress very

  10   clearly that we are not looking for the claim of

  11   daytime sleepiness; we are looking at an

  12   improvement in the symptom thereof.

  13             DR. KAWAS:  Dr. Houghton, can I ask you

  14   then, to my reading, that indication is actually

  15   two indications, I mean, cataplexy and sleepiness

  16   being a separate one. When I was reading the

  17   materials that you very carefully provided us,

  18   obviously for cataplexy the GHB-2 and the SXB-21

  19   study speak to that issue as pivotal trials.  I was

  20   going to ask you which were the two that speak to

  21   the issue of daytime sleepiness.  Now I understand

  22   them to be the GHB-2 and the Lammers small trial

  23   with the questionnaire that was developed there.

  24   In both of those cases, however, we are talking

  25   about subjective sleepiness from the Epworth scale 
                                                                101

   1   and the other question.  Since there are factors

   2   that can influence someone's subjective feelings of

   3   sleepiness, do you have any objective measures that

   4   support the indication of daytime sleepiness?

   5   Specifically, the one trial that I am aware of that

   6   had an MSLT and did daytime sleepiness as a primary

   7   outcome measure, in fact, appears to be not

   8   supportive of the indication.

   9             DR. HOUGHTON:  Yes, in the Scrima trial he

  10   used the MSLT measure and that was not

  11   statistically significant, as shown.  The objective

  12   data that we propose supports very strongly the

  13   effect of adequate dosing of GHB was the SXB-20

  14   trial that Dr. Black discussed.  That is not only a

  15   profound improvement in the MWT at the 9 g dose but

  16   a defined dose response across all doses.  That is

  17   very positive data.

  18             DR. KAWAS:  In ten patients, it appears.

  19             DR. HOUGHTON:  Twenty-one.

  20             DR. MANI:  May I also add that that was an

  21   open-label, non-randomized study?

  22             DR. HOUGHTON:  Sure, but using an

  23   objective measure.

  24             DR. RISTANOVIC:  I am I am Ruzica

  25   Ristanovic, medical director of Sleep Disorders 
                                                                102

   1   Center, in Evanston, Illinois.  I would like to

   2   comment on add-on Xyrem in the presence of other

   3   stimulants.  Other studies attempt to try to

   4   document the effectiveness of other stimulants in

   5   narcolepsy-related sleepiness documents, including

   6   the most rigorous trial of modafinil in

   7   double-blind, placebo-controlled studies.  They

   8   document that these drugs improve sleepiness but

   9   very seldom outside of the range of pathological

  10   sleepiness as measured by Multiple Sleep Latency

  11   Test and Maintenance Wakefulness Test.  So, the

  12   patients remain sleepy.  That is the message.

  13   Add-on treatments are approved for other

  14   indications in other neurological diseases, such as

  15   epilepsy.  So, I assume that this application for

  16   that particular indication is not for monotherapy

  17   but as an add-on to concurrent use of stimulants.

  18   I would like to bring this to your attention.  So,

  19   patients do remain sleepy on stimulants and they

  20   need additional treatments.

  21             DR. KAWAS:  Dr. Temple?

  22             DR. TEMPLE:  Dr. Houghton also seemed to

  23   be  distinguishing between monotherapy and add-on

  24   therapy.  That is not the problem.  The problem is

  25   whether there is adequate support for use as an 
                                                                103

   1   addition for whatever else the patient is on, and

   2   whether there are well-controlled studies that

   3   support that.  So, add-on would be perfectly fine.

   4   That is usually true in a lot of conditions, not

   5   just neurological ones, where you continue to give

   6   standard therapy and try to improve it.

   7             I just want to make one observation about

   8   the evidence.  We do expect to see replicated or

   9   reproduced findings.  Some of the issues here are

  10   whether the fact that the endpoints are secondary

  11   and need some correction means that there isn't

  12   adequate support.  A lot of these things are

  13   matters of judgment that the committee can weigh in

  14   on.  Not everything is, you know, a yes/no.  Some

  15   of the things are moderately subtle and that is why

  16   this is being brought to you for judgment.  There

  17   is one study that is obviously stronger than the

  18   rest but the others can be considered, and you sort

  19   of have to think about how many real endpoints

  20   there really are; how much of a correction is

  21   needed.  Those are difficult discussions but worth

  22   considering.

  23             DR. KAWAS:  Dr. Katz?

  24             DR. KATZ:  I agree, but I think we would

  25   still have to have the application meet the 
                                                                104

   1   standard of independent replication, in other words

   2   two trials.  You can decide that one of the other

   3   trials actually does meet the usual standard,

   4   again, taking into consideration the multiplicity

   5   and that sort of thing.  All I am saying is that I

   6   don't think we can say we have one study that looks

   7   good.  If you believe that GHB looks good and the

   8   others sort of contribute to a feeling that it

   9   probably is okay, I mean, we really need two

  10   independent sources that you believe demonstrate

  11   the effectiveness.

  12             The only other point I wanted to add is to

  13   something, Claudia, you said which has to do with

  14   Dr. Houghton's view that they are not going for a

  15   claim of daytime sleepiness; they just want, I

  16   guess, to have language in the labeling that says

  17   that it improves that symptom.  Most of the drugs

  18   we approve are for symptomatic claims, so there is

  19   no question that the inclusion of this language in

  20   the indication is a claim as we always understand

  21   that term.

  22             DR. KAWAS:  Dr. Guilleminault, followed by

  23   Dr. Wolinsky, please.

  24             DR. GUILLEMINAULT:  If you look at all the

  25   published data on modafinil, on amphetamine, on 
                                                                105

   1   methylphenidate, none of these drugs ever

   2   normalized all the objective tests on alertness and

   3   daytime sleepiness.  None of them, including the

   4   modafinil data which were approved by the FDA.  The

   5   MSLT and MWT for all these drugs are pitiful.  The

   6   only data which shows significance was the Epworth

   7   Sleepiness Scale, which is a subjective scale, in

   8   all these trials.  So, we cannot expect to have any

   9   positive result with subjective tests in any of

  10   these drugs.  We will always have to rely on

  11   subjective tests even if the subjective test is not

  12   great.  Everybody in the field agrees that the

  13   Epworth Sleepiness Scale is the most used scale

  14   despite the fact that it has a lot of downfall, and

  15   we have to remember that when we look at what has

  16   been approved and what is being used.

  17             DR. KAWAS:  Thank you, Dr. Guilleminault.

  18   I think that many people would agree with those

  19   comments, but my question to you would be not

  20   whether or not the Epworth Scale subjective

  21   measurements are good but do we have two

  22   randomized, controlled trials that show an

  23   improvement in subjective sleepiness.

  24             DR. GUILLEMINAULT:  That was my initial

  25   question because my understanding is, when the 
                                                                106

   1   statistician from the FDA responded, she said that

   2   when she did a nonparametric analysis she found out

   3   that she had a p value of 0.03.  So, my

   4   understanding is that she had a significant finding

   5   even when she did the reanalysis.  That was my

   6   understanding of her response.

   7             DR. KAWAS:  Would you like to comment, Dr.

   8   Yan?

   9             DR. YAN:  I am sorry, the previous number

  10   is not right.  I checked.  The number for the

  11   nonparametric analysis, the p value was 0.0109.

  12             DR. WOLINSKY:  I have a couple of

  13   questions first for some information before I ask

  14   the real question.  For the informational questions

  15   perhaps Dr. Mignot could help with.  So, the first

  16   question I have is if you could enlighten us or

  17   re-enlighten us about how many patients that have

  18   narcolepsy have had cataplexy as a component

  19   symptom.  What proportion?

  20             DR. MIGNOT:  In most case series it is

  21   about 70 percent.

  22             DR. WOLINSKY:  The second question is that

  23   at least for most of these studies which were done

  24   and presented to us since cataplexy was being

  25   measured, as is appropriate, the number of 
                                                                107

   1   cataplectic attacks was relatively high.  I think

   2   in these studies it was around 20 cataplectic

   3   attacks per week.  So, how many of the 70, 75

   4   percent of patients with narcolepsy who have

   5   cataplexy have cataplectic attacks at that level?

   6             DR. MIGNOT:  I would guess 20 percent.

   7             DR. WOLINSKY:  Thank you very much.

   8             DR. MIGNOT:  Yes, roughly.

   9             DR. WOLINSKY:  And then they would fall

  10   down below that level for the remainder of the 55

  11   percent of narcoleptics with cataplectic attacks.

  12             DR. MIGNOT:  If you analyze the spread of

  13   the number of cataplexy episodes per week, but you

  14   have to balance that also with the efficacy of

  15   current treatments.  A lot of people that currently

  16   have cataplexy that is relatively mild just don't

  17   want to take the antidepressants because they have

  18   so many side effects, especially sexual side

  19   effects, dry mouth, all these problems --

  20             DR. WOLINSKY:  This is not the question

  21   though.  So, now the question to Orphan which has

  22   really, truly become an orphan drug question, is

  23   since all of the studies that have been done have

  24   enriched for cataplexy, do we have any data that

  25   would suggest that if cataplexy is adequately 
                                                                108

   1   controlled or if there is no cataplexy so we don't

   2   have to worry about the control of cataplexy there

   3   would be any effect of the drug on daytime

   4   sleepiness in non-cataplectic narcoleptics?

   5             DR. REARDAN:  I think Jed Black wants to

   6   make a comment on that.

   7             DR. BLACK:  Just a comment on the

   8   prevalence of cataplexy in the 70-75 percent of

   9   folks with narcolepsy that had cataplexy, the

  10   frequency of events -- this is something that Dr.

  11   Mignot is not aware of, the cataplexy was

  12   subdivided into major events and minor events.

  13   About 20 percent or so would have the major events

  14   to that level, but when we look at the minor events

  15   a far greater percentage of that 70 percent, which

  16   may be up to 80, 90 percent of that 70 percent,

  17   will have that number of minor effects.  Those are

  18   not complete attacks where they fall down.  In

  19   fact, with most narcoleptic patients, they

  20   distinguish between the two and they will often

  21   only report to the physician the major events.  But

  22   in the diaries that Orphan had set up all the

  23   events are characterized.

  24             DR. WOLINSKY:  So, the second question --

  25             DR. BLACK:  We have no idea.  That is an 
                                                                109

   1   excellent question that I think needs to be

   2   determined, but in the studies that have been

   3   completed that question cannot be answered.

   4             DR. REARDAN:  Jed, the only study I can

   5   think of maybe is SXB-20 where cataplexy was not an

   6   entry criterion and I don't know what the cataplexy

   7   incidence in that trial was.  Bill is shaking his

   8   head -- we didn't record it and we didn't

   9   quantitate it.

  10             DR. BLACK:  We can't comment on that.

  11             DR. REARDAN:  It is true that in most of

  12   our studies patients were selected because at entry

  13   criteria they had to have a baseline cataplexy.

  14             DR. KAWAS:  Dr. Penix?

  15             DR. PENIX:  Before we address the two

  16   separate indications issue -- and I guess, Dr.

  17   Black, I could direct this question to you -- in

  18   the GHB-2 study you did look at all cataplexy

  19   events, I guess, and then total and partial

  20   cataplexy.  In the background material, in the

  21   separation of the two it appeared that there was no

  22   significant difference in any of the three doses of

  23   GHB on total or complete cataplexy but your effect

  24   was primarily in partial cataplexy.  Is that

  25   correct? 
                                                                110

   1             [No verbal response]

   2             So, my question in that regard is what is

   3   the clinical significance of partial cataplexy, and

   4   you mentioned that patients frequently do not want

   5   treatment for partial cataplexy.  So, is this a big

   6   problem?  I presume that the patients that would

   7   perceive a problem would be the ones with the

   8   complete cataplexy but there we see no significant

   9   difference.  So, is there a problem there with

  10   that?

  11             DR. BLACK:  I think this is a good point,

  12   and the difficulty comes in trying to separate the

  13   two because it is not sort of a box of partial and

  14   a box of complete; it is a gradation, you know,

  15   ranging from small partials to large partials and

  16   the completes.  So, I think this analysis is

  17   difficult to perform.  Clinically the degree of

  18   improvement with traditional anticataplectic

  19   medications that we use is similar.  So, the

  20   reduction in partial -- if that is all that is

  21   being seen here and I am not convinced that

  22   clinically that is the case -- while the

  23   statistical analysis didn't demonstrate a

  24   significant difference in the complete cataplexy

  25   attacks, clinically there is an improvement in all 
                                                                111

   1   the different categories, and it is very

   2   substantial in traditional anticataplectic

   3   medications as well as with GHB.

   4             DR. PENIX:  Could Dr. Mignot comment on

   5   the clinical significance of partial cataplexy?  Is

   6   it a big problem?

   7             DR. MIGNOT:  Yes, it is a big problem.  In

   8   fact, the problem is especially the social aspect

   9   of cataplexy, when you have to realize that you are

  10   just in the middle of a crowd and are meeting some

  11   friends, and you can never tell when it is going to

  12   happen.  It may happen in very odd circumstances.

  13   So, often even the doctors don't know what it is

  14   and they just look at it and they wonder why this

  15   person is kind of losing slight control and has to

  16   sit down.  There is also almost a social aspect

  17   with fear of cataplexy that can occur at any time,

  18   any moment and, yes, it is a very significant

  19   problem.

  20             Again, it is a balancing act because the

  21   drugs that we use are somewhat effective but they

  22   have all these side effects and you just have to

  23   choose between two evils.  I am pretty sure that,

  24   for example, GHB, based on my relatively limited

  25   experience, has less side effects than 
                                                                112

   1   anticataplectic classical tricyclic

   2   antidepressants, and that a lot of patients would

   3   prefer to take GHB even for partial cataplexy.

   4             DR. PENIX:  The case that you showed of

   5   the nine-year child I assume is complete cataplexy

   6   --

   7             DR. MIGNOT:  Yes.

   8             DR. PENIX:  -- but you are also saying

   9   that patients with partial cataplexy have a

  10   significant impairment of their life.

  11             DR. MIGNOT:  Absolutely.  But, as Dr.

  12   Black mentioned, it is not an "all or none."  I

  13   mean, most patients, the ones that are complete,

  14   have a lot of partial cataplexy.  You never know

  15   how bad it is going to be.  Most of them are small,

  16   little attacks, and sometimes they may even be

  17   perceived only by the patient.  Sometimes the face

  18   may melt; the head drops.  Sometimes they just have

  19   to sit down; sometimes they don't have to sit down.

  20   I showed a young kid because it is more dramatic,

  21   but you would see the same thing in some of the

  22   patients with partial cataplexy occasionally.

  23             DR. BLACK:  I am realizing that a

  24   definition may be useful here.  In general when we

  25   were describing patients who documented the partial 
                                                                113

   1   versus complete, we told them to think about

   2   complete as an episode where they fall to the

   3   ground with complete paralysis or where, if they

   4   weren't sitting, they would have fallen to the

   5   ground with complete paralysis.  Otherwise,

   6   anything else is partial -- so, slurred speech,

   7   head drops, dropping things are the partials, and

   8   those become very important for quality of life and

   9   daytime performance.  Driving, those kinds of

  10   things can become a very significant event for

  11   partials.

  12             DR. MIGNOT:  Yes, one thing I should also

  13   emphasize is that in a very large number of series

  14   that, for example, have analyzed several hundred

  15   patients with narcolepsy and cataplexy, as a mean

  16   the large majority of patients have several attacks

  17   per day, several attacks per week.  Between several

  18   attacks per day and several attacks per week, that

  19   is generally partial or complete attacks and it is

  20   not something that appears just once, you know,

  21   every ten years.  It is really something that

  22   occurs regularly and sometimes totally

  23   unexpectedly.

  24             DR. KAWAS:  Dr. Falkowski?

  25             DR. FALKOWSKI:  That leads me to a 
                                                                114

   1   question just for clarification.  For the purposes

   2   of these clinical trials, were the cataplectic

   3   events something that was just perceived by the

   4   patient and recorded in a diary, or were they

   5   verified by some third party?

   6             DR. REARDAN:  These were taken from

   7   patient diaries.  So, it is patient recorded

   8   episodes.

   9             DR. HAGAMAN:  I am Dr. Hagaman and I just

  10   wanted to address the partial versus the complete

  11   cataplectic events.  I think that you have to take

  12   it on an individual basis.  We have patients that

  13   come in that are teenagers that have tests in front

  14   of them and they have a partial cataplectic event

  15   and they drop their pencil; people that cut hair

  16   that have scissors in their hands and they drop

  17   their scissors.  So, even though they have not had

  18   a complete event, this has been a very debilitating

  19   event in their lives.  So, it is a continuum and I

  20   think you just have to really look at each person

  21   as an individual and what they are doing.

  22             DR. KAWAS:  Dr. Dyer?

  23             DR. DYER:  How variable in the same

  24   patients are the number of cataplectic attacks per

  25   week?  What is the variance in that? 
                                                                115

   1             DR. MIGNOT:  We have looked at that quite

   2   a bit.

   3   Actually, I did some diaries in a large number of

   4   patients with cataplexy.  It is really totally

   5   unpredictable and that is one of the most scary

   6   parts about cataplexy when you have narcolepsy.  Of

   7   course, if something emotional is going to happen,

   8   say a patient is going to go to a wedding, often

   9   they will kind of fear that event much more because

  10   they think it is very likely that they are going to

  11   have cataplexy in front of everyone and, indeed,

  12   they may actually have a lot more cataplexy because

  13   it is an emotional event.

  14             Still, I have followed, for example,

  15   patients and sometimes they may have like 80 for

  16   one week and then the following week they may have

  17   only three or four.  I mean, it can really vary

  18   quite a bit.  And, one of the main reasons is

  19   really that emotion is something that is very

  20   variable.  In fact, someone mentioned how easy it

  21   is to observe cataplexy.  It is very difficult to

  22   get it on tape because typically the patient come

  23   to your office; he really wants to show you what it

  24   is but, you know, he is tense and it just will not

  25   occur but as soon as he leaves the office and 
                                                                116

   1   something happens -- boom, he is going to collapse.

   2   So, it is very difficult to predict and it is quite

   3   variable.

   4             DR. ROMAN:   For Dr. Mignot also, you

   5   mentioned that cataplexy probably is the result of

   6   what you called dissociated REM.  However, if I

   7   recall correctly, the polysomnographic analysis has

   8   shown that Xyrem actually decreases the amount of

   9   REM sleep and increases delta sleep.  Would you

  10   like to speculate on what could be the mechanism of

  11   action to improve the cataleptic component?

  12             DR. MIGNOT:  That is a very, very

  13   difficult question.  One of the difficult

  14   questions, of course, is the mode of action of GHB.

  15   I have looked into it myself for quite a while

  16   because I was trained as a pharmacologist, and it

  17   is not clear.  There are two camps.  Some people

  18   think it acts on GHB receptors, specific receptors;

  19   others think that it acts through the GABA-B

  20   receptors.  We know that it has some strong effect

  21   on dopamine transmission.  If you inject GHB in

  22   animals the rate of activity of dopaminergic cells

  23   shuts down and dopamine can increase in the brain

  24   proportionally to the dose.  We have done quite a

  25   bit of studies that have shown that the 
                                                                117

   1   dopaminergic system is very important to regulate

   2   both wakefulness and also cataplexy and the

   3   regulation of emotion.  I believe it is by changing

   4   the balance of the dopaminergic system, that

   5   improves cataplexy the following day maybe by

   6   increasing dopamine in the brain during the night,

   7   but this is highly speculative and a lot more

   8   research needs to be done.

   9             The fact that it does not increase REM --

  10   first, it is quite variable because some studies

  11   have shown that it does increase REM and this

  12   contrasts dramatically with what all hypnotics do.

  13   If you take MVN or all the other

  14   benzodiazepine-like hypnotics, what they do is

  15   actually, rather, reduce slow wave sleep and reduce

  16   REM sleep.  Xyrem doesn't do that.  It actually

  17   promotes slow wave sleep and, if anything, would

  18   promote REM sleep or doesn't change it.  That is

  19   still, you know, much more in the right direction

  20   of promoting normal sleep, including REM sleep.

  21             The last comment I want to mention is that

  22   it is not sufficient -- if you know a lot about

  23   narcolepsy, it is not sufficient to just explain

  24   narcolepsy as a disorder of REM sleep.  Indeed,

  25   they have all this transition to REM sleep but they 
                                                                118

   1   also have impaired wakefulness per se.  For

   2   example, if you do MSLTs they don't always go into

   3   REM.  They will often just fall asleep into normal

   4   sleep.  So, it is not only REM sleep that is

   5   disregulated in narcolepsy, it is also wakefulness

   6   and by improving slow wave sleep you presumably

   7   also can improve the wake aspect of narcolepsy.  My

   8   answer may be a little complicated but I would be

   9   happy to discuss it in more detail.

  10             DR. KAWAS:  Dr. Van Belle?

  11             DR. BLACK:  Just another comment on that,

  12   the Broughton study showed an increase in REM at a

  13   lower dose.  The first dose of the SXB-20 that I

  14   participated in showed at 4.5 g the first night an

  15   increase in REM, which was then followed by a

  16   dose-related decrease in REM over time, which is

  17   very different from REM suppressant agents where

  18   there is a robust, or in fact the largest effect

  19   that can often be seen on the first night of

  20   administration.

  21             So, we don't know exactly why it is that

  22   over time the REM with higher doses is reduced, and

  23   why with the first dose, and with the lower doses,

  24   as has been demonstrated here with Roger

  25   Broughton's work, why the REM is increased.  There 
                                                                119

   1   has been established sort of a competitive reaction

   2   between slow wave sleep and REM sleep.  It appears

   3   that there may be factors that regulate slow wave

   4   sleep that also are important in regulating the

   5   appearance, or lack thereof, of REM sleep.  It may

   6   be that gama hydroxybutyrate is sort of normalizing

   7   slow wave activity which then results in a more

   8   normal control or regulation of the REM or

   9   REM-related events.

  10             DR. KAWAS:  Can I ask for my

  11   clarification, what dose the company is proposing?

  12             DR. REARDAN:  Bill, can you take that

  13   question?

  14             DR. HOUGHTON:  Yes, the dosage regimen

  15   that we are proposing is that patients be started

  16   at 4.5 g and then titrated between the range of 3-9

  17   g to clinical efficacy.  Although in the strictest

  18   mathematical sense the only statistical efficacy in

  19   the GHB-2 study was clearly defined at 9 g, that

  20   may well represent that the study was too short

  21   because in the open-label study that followed, as I

  22   showed, the maximum nadir occurred at 8 weeks, and

  23   when those patients were followed over the course

  24   of 12 months they maintained efficacy across the

  25   dose range.  Certainly, there is an advantage in 
                                                                120

   1   terms of the important side effects to dose

   2   titration.  In all of the treatment IND protocols

   3   and the safety studies the data was generated at

   4   between 3-9 g.  Now, 80 percent of the patients

   5   were maintained between 6 g and 9 g, but there was

   6   certainly facility for down-titration from the 4.5

   7   or maintenance there as well.

   8             DR. KAWAS:  Thank you.  Dr. Van Belle?

   9             DR. VAN BELLE:  It seems to me that there

  10   is reasonable agreement with respect to efficacy

  11   for cataplexy at least between the FDA and the

  12   sponsor.  So, I would like to get back to the

  13   secondary endpoints.  I would like to ask a

  14   question to the sponsor's statistician, Dr. Trout,

  15   as to whether he thinks that multiple comparisons

  16   is a problem.  Secondly, if multiple comparisons

  17   are a problem, how he would adjust.

  18             DR. REARDAN:  Do you want to put this in

  19   relation to a specific trial or all the trials in

  20   general?

  21             DR. VAN BELLE:  Well, I bring it up in

  22   connection with the analysis of Dr. Mani where he

  23   clearly comes to conclusions that differ from yours

  24   with respect to the efficacy of some of these

  25   secondary endpoints. 
                                                                121

   1             DR. TROUT:  You know, it is hard to answer

   2   that question.  I think the way I would answer that

   3   is as follows:  The GHB-2 analysis, the results

   4   that we found and also that were expressed earlier

   5   were very strong.  So, even with the fact that

   6   there is some multiplicity, we also have, remember,

   7   some other outcome measures which were related to

   8   this particular general area in terms of daytime

   9   sleep attacks.  So, there were at least two

  10   measures that suggested improvement with respect to

  11   that particular outcome.

  12             The other second study that has been

  13   discussed is the Lammers study, and that study is

  14   obviously much smaller.  It is obviously a weaker

  15   study, and there is some issue with regard to

  16   whether the appropriate method of analysis was

  17   there.  So, I think that is a harder one to

  18   address.

  19             Now, there are two kinds of multiplicity

  20   going on here, which you are well aware of.  One is

  21   the multiplicity with regard to the multiple dosing

  22   levels and that was accounted for in our analyses.

  23   The question that was brought up by Dr. Mani with

  24   regard to the multiplicity of secondary endpoints,

  25   and I am not a betting man but I think there is 
                                                                122

   1   certainly evidence to suggest that daytime

   2   sleepiness is being affected possibly.  But I don't

   3   go to Las Vegas nor Atlantic City.

   4             DR. KAWAS:  Actually, while we have Dr.

   5   Trout up, I would ask him with regard to excessive

   6   sleepiness on the Epworth Scale in the GHB-2 study,

   7   while there certainly was a difference in the two

   8   groups, there were also major baseline differences

   9   in sleepiness for the responders and the

  10   non-responders.  In fact, those that appeared to

  11   respond had a baseline that was better than the

  12   improvement in the other group.  There was a

  13   significant difference.  Are you concerned about

  14   these and how these might affect the results?

  15             DR. TROUT:  There is always concern about

  16   baseline differences, and that was attempted to be

  17   accounted for in two mechanisms, one, we looked at

  18   change from baseline and we also did a covariate

  19   adjustment to try to account for that.

  20             DR. KAWAS:  Dr. Katz?

  21             DR. KATZ:  I would like to ask Dr. Trout a

  22   question also.  Dr. Yan mentioned that we didn't

  23   believe that the data were normally distributed,

  24   and when you transformed the data it didn't really

  25   help very much.  I don't want to get bogged down in 
                                                                123

   1   a hyper-arcane discussion about normally

   2   distributed data, but when we did that we got a p

   3   value for that comparison -- I guess it was the

   4   Epworth, of about 0.01 --

   5             DR. MANI:  I am sorry, it wasn't the

   6   Epworth.  You are talking about the Lammers study

   7   where you are talking about the frequency --

   8             DR. KATZ:  I thought we were talking about

   9   GHB-2.

  10             DR. MANI:  Oh, sorry, fine.

  11             DR. KATZ:  So, if we are right, it takes

  12   the p value which was 0.0001 or something like that

  13   to 0.01, and then when you get to the multiple

  14   comparisons issue it makes it less weak. I agree if

  15   you take a p value of 0.001 or 0.0001, no matter

  16   what you do to it as far as a multiple comparison,

  17   it is still going to be significant.  But if it is

  18   0.01 it is a little different story.  So, I am just

  19   wondering, again without getting into excruciating

  20   details, what about this question of the data being

  21   normally distributed and not necessarily being

  22   improved very much by transforming it?  Is there

  23   common agreement about that or not?

  24             DR. TROUT:  My recollection, and it has

  25   been sometime since I have seen the results of the 
                                                                124

   1   analysis, is that it suggested that we didn't see a

   2   particular problem with the normal distribution as,

   3   for example, was the case with cataplexy which was

   4   clear.  I am not sure if Dr. Yan did a

   5   nonparametric covariance analysis or not.  I

   6   haven't seen those analyses.  And, I think the

   7   point was made earlier that that would be, I think,

   8   an appropriate thing to do in order to account for

   9   some potential baseline differences.  If she did,

  10   then whether it is a reflection of a decreased

  11   sensitivity of a nonparametric analysis or whether

  12   it is a normal distribution -- I can't answer that

  13   without seeing the data.  Maybe it was just a

  14   standard, nonparametric analysis which might help

  15   account for the difference.

  16             [Comment away from microphone; inaudible]

  17             DR. TROUT:  No, I know that but Dr. Yan

  18   did a nonparametric analysis because she was

  19   concerned about the normality, and did look at the

  20   log transformation and it didn't have any impact on

  21   that, which doesn't surprise me at all.

  22             DR. KAWAS:  I would like to ask the

  23   sponsor, I mean, there clearly was a dose

  24   relationship in terms of the adverse events.  Were

  25   any other factors looked at that may be related to 
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   1   the adverse event profile, things like age, even

   2   previous psychiatric history, other medications?

   3   Whether or not they drank alcohol?  Anything?

   4             DR. HOUGHTON:  No, we didn't go as far as

   5   an alcohol history.  Certainly for the major

   6   psychiatric, a preexisting history of major

   7   psychiatric disease emerged.  Major psychiatric

   8   disease was actually a protocol exclusionary

   9   criterion, but in those that, for instance

  10   attempted suicide, post-study it was discovered

  11   that they had a previous psychiatric history and in

  12   actual fact in one of the patients a previous

  13   suicide attempt had been made.  There was major

  14   depressive disease reported in those, but for those

  15   who developed psychosis there was definite recorded

  16   preexisting psychiatric history.

  17             In terms of age, we haven't done a

  18   breakdown of the database, and in most instances

  19   there was not a dose relationship.  There were just

  20   instances that were mentioned in the presentation.

  21   Confusion and sleepwalking suggested a dose

  22   relationship.  In the GHB-2 protocol which was

  23   obviously blinded, there was the association with

  24   nausea, vomiting, confusion and enuresis that was

  25   definite, but that didn't extend across the whole 
                                                                126

   1   study database.  So, the relationship with dose is

   2   not well defined.

   3             DR. KAWAS:  But how about relationship

   4   with anything else?  For example, were the patients

   5   who had confusion more likely to be the elder

   6   patients?  You might be able to tell I am in aging.

   7             DR. HOUGHTON:  I can identify well.  Do we

   8   have a breakdown of confusion by age?  A range

   9   would be still useful.

  10             [Slide]

  11             Here is a slide that shows that the

  12   distribution of age was between 25 and 73 years,

  13   with 67 percent over 50 years of age, but the range

  14   is still wide.  There is the distribution across

  15   doses.  Four events at 3 g, 10 at 4.5, 12 at 6 g, 8

  16   events at 7.5, and 13 events at 9 g.

  17             DR. KAWAS:  Thank you.  Do we have any

  18   other questions from the committee?  If not, we

  19   will move on.  Dr. Katz?

  20             DR. KATZ:  A quick question, if I heard

  21   you correctly, there were 14 events reported as

  22   convulsions, but when you went back and looked at

  23   that, 13 of them were actually cataplexy.  So,

  24   presumably cataplexy was a verbatim term.  How is

  25   it that cataplexy got coded as convulsions? 
                                                                127

   1             DR. REARDAN:  The COSTART dictionary puts

   2   cataplexy in as a convulsion.  It is a definition.

   3   Convulsion has ten different terminologies,

   4   verbatim events, and they all code up to

   5   convulsion.

   6             DR. WOLINSKY:  Along those lines, how come

   7   there were only that few number of convulsions when

   8   we were studying cataplexy in the trial?  I mean, I

   9   don't know that it is easy to explain this in both

  10   sides of one's mouth.

  11             DR. HOUGHTON:  No, and we are not trying

  12   to.  If there was a cataplexy event that occurred

  13   of a severity to be seen as unusual for that

  14   patient, and the patient volunteered it as an

  15   event, then it was recorded as an adverse event.

  16   Or, there may have been injury related to the

  17   cataplexy events.  We do have representation in the

  18   database.  I can recall absolutely a fractured

  19   ankle in the washout study.  So, there were

  20   traumatic events associated with a major cataplexy

  21   event that would have been of sufficient impression

  22   on the patient to report as a separate event.

  23             DR. WOLINSKY:  But then the event would

  24   not have been withdrawal from the primary measure

  25   of efficacy even though it was also registered as 
                                                                128

   1   an adverse event?

   2             DR. HOUGHTON:  I am sorry?

   3             DR. WOLINSKY:  Was it still counted as an

   4   event in the measure of efficacy if it was also

   5   shifted to be counted as an adverse event?

   6             DR. REARDAN:  Yes, the patient diaries

   7   recorded cataplexy.  If they record cataplexy as an

   8   event itself, that was part of the efficacy

   9   outcome.  It wasn't necessarily an adverse event.

  10   If they had an adverse event -- fall and break an

  11   ankle, cataplexy is coded as part of that adverse

  12   event.  It is the cause of the adverse event and so

  13   it shows up in the database.

  14             DR. KAWAS:  Dr. Simpson?

  15             DR. SIMPSON:  I have two questions.  One

  16   really was just a clarification of this business

  17   about the sleepiness.  I think we have all agreed

  18   that there has to be some adjustment for multiple

  19   comparisons on the sleepiness index, and the GHB-2

  20   study, even if you make an adjustment, there are

  21   certainly some of the indices about sleepiness

  22   which seem to be significant.  But coming back to

  23   the Lammers study, have we established whether or

  24   not, once we have made an adjustment, we have any

  25   significance there or not?  Because that is the 
                                                                129

   1   pivotal trial, isn't it, because we need two?

   2             DR. REARDAN:  Remember that the Lammers

   3   study was a very small trial, 24 patients.  Daytime

   4   sleepiness was a secondary endpoint in that study,

   5   and I forget the p value.  Maybe Dr. Yan or Dr.

   6   Katz could comment.  I don't think any formal study

   7   of multiple analysis was done, except maybe by Dr.

   8   Yan --

   9             DR. YAN:  No.

  10             DR. REARDAN:  -- and I think she needs to

  11   comment on that.

  12             DR. YAN:  For Lammers study there was no

  13   prespecified analysis, except the Wilcoxon assigned

  14   rank test.  It was across the study and we

  15   considered it not very appropriate, and for a

  16   secondary analysis none of the statistical analyses

  17   were specified.  The problem with this Lammers

  18   study is that if you use different statistical

  19   analyses which are considered appropriate, you get

  20   a very different result.  Some could be less than

  21   0.05 and some ranged to something like 0.2.  So,

  22   the results are not consistent and we don't have a

  23   reliable method to see which one we could consider.

  24             DR. REARDAN:  We don't disagree with that.

  25   I mean, the problem with Lammers is that it was a 
                                                                130

   1   one-sentence statement about how he was going to

   2   analyze it, and it was an inappropriate statistical

   3   analysis for a crossover study.  So, that creates

   4   issues about not having a prospective statistical

   5   plan appropriate for the study.  But even in that

   6   initial Wilcoxon analysis the daytime sleepiness

   7   was statistically significant.  It was not

   8   corrected for multiple analyses.

   9             DR. KAWAS:  Dr. Simpson?

  10             DR. SIMPSON:  I just have another question

  11   that I wondered if you could clarify.  In a lot of

  12   these studies you talk about an intent-to-treat

  13   analysis, but when I read it I wasn't clear whether

  14   or not that meant the patients that were randomized

  15   were actually included always in the analysis or

  16   not.

  17             DR. REARDAN:  Yes, the intent-to-treat

  18   would include every patient who received drug.  Is

  19   that correct?

  20             DR. TROUT:  Yes, every patient who

  21   received at least one dose.

  22             DR. SIMPSON:  So, how did you then deal

  23   with the patients who dropped out?

  24             DR. TROUT:  In the GHB-2 analysis we

  25   selected an endpoint.  So, in order for the patient 
                                                                131

   1   to be included in that analysis there had to be at

   2   least one post-baseline measure of cataplexy or

   3   sleepiness, or whichever outcome you want.  So, it

   4   was an endpoint analysis that was done in order to

   5   accommodate that.

   6             DR. KAWAS:  It looks like we are

   7   completely behind schedule and we will have a very

   8   late lunch, I will warn everyone.  The FDA's

   9   invited speakers on risk management issues is the

  10   next component of this discussion.  The first

  11   speaker is going to be Dr. Carol Falkowski, of the

  12   Hazelden Foundation, in Minnesota, who will be

  13   speaking on the epidemiology of GHB abuse issues.

  14          FDA Invited Speakers on Risk Management Issues

  15                 Epidemiology of GHB Abuse Issues

  16             DR. FALKOWSKI:  Hello.  Good morning,

  17   almost afternoon.

  18             [Slide]

  19             This is the title of my talk, GHB Abuse in

  20   the United States.  I am Director of Research

  21   Communications at the Hazelden Foundation.  I have

  22   been a member of the National Institute on Drug

  23   Abuse's Community Epidemiology Work Group since

  24   1986.  I am author of a book, called, "Dangerous

  25   Drugs: An Easy-to-Use Reference for Parents and 
                                                                132

   1   Professionals."  What is missing from this overhead

   2   is that I served on the Drug Abuse Advisory

   3   Committee for the FDA from 1995 through 1999.

   4             [Slide]

   5             In the very short time that I have, I am

   6   going to try and just hit the big points about what

   7   we know about the abuse of GHB in the United

   8   States, starting off with measuring drug abuse.

   9   There are a number of things that are thought to

  10   bear when we talk about measuring something as

  11   complex and multi-dimensional as drug abuse.  This

  12   includes population surveys.  It includes hospital

  13   emergency room episodes; medical examiner data;

  14   addiction treatment data; law enforcement data, as

  15   well as ethnographic studies that look at specific

  16   populations of users that are more anthropological

  17   and ethnographic in nature.

  18             [Slide]

  19             I also want to make the point that all

  20   data systems have limitations, and this is

  21   particularly true in the case of new drugs of

  22   abuse.  For example, if we are talking about GHB

  23   and trying to measure the number of patients who

  24   have presented to addiction treatment centers

  25   across the country with GHB as their primary drug 
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   1   of abuse, it is now the case that it is often

   2   grouped in a category of drugs called sedative

   3   hypnotics.  It is not its own line item.  So, in

   4   preparation for a meeting like this it is very hard

   5   to get an accurate count of the extent to which GHB

   6   itself is the presenting drug of abuse.

   7             Similarly, surveys that are conducted --

   8   we have not added GHB to the National Household

   9   Survey or the Monitoring the Future Survey,

  10   although to the Monitoring the Future Survey that

  11   looks at drug use among 8th, 10th and 12th graders

  12   ecstasy, another club drug, has been added.

  13             Also, in terms of law enforcement

  14   indicators, there is no field test for GHB so it is

  15   hard to also get that indication of it as well.

  16             In addition, new methods of abuse are hard

  17   to track.  I recall, in 1986, when we started at

  18   the national level wanting to track crack cocaine,

  19   we knew about how to track cocaine but, all of a

  20   sudden, we were looking at it by a different route

  21   of administration.  So, it was a challenge to all

  22   of us to start switching our data systems just to

  23   measure crack instead of cocaine, to make that

  24   distinction.

  25             Existing data systems are slow to respond, 
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   1   and there is a system-wide learning curve when a

   2   new drug of abuse appears on the scene.  That means

   3   it is a learning curve in terms of emergency room

   4   personnel, treatment providers, law enforcement, as

   5   well as prevention agencies, and that is why we

   6   rely on a lot of the scientific literature put out,

   7   particularly in emergency medicine, to inform the

   8   field about emerging drugs of abuse and how people

   9   present with those problems.

  10             [Slide]

  11             My background in this has been as part of

  12   the Community Epidemiology Work Group.  This is a

  13   group of drug abuse researchers from twenty cities

  14   in the country that has been convened by the

  15   National Institute on Drug Abuse since 1976.  This

  16   model of drug abuse epidemiology has also been

  17   adapted in different parts of the world.  There is

  18   a similar group in Europe, in Canada, Mexico and

  19   Asian cities.

  20             [Slide]

  21             The Community Epidemiology Work Group is

  22   an early warning epidemiological surveillance

  23   network that detects new drugs of abuse, patterns

  24   of use and populations at risk.

  25             [Slide] 
                                                                135

   1             It involves researchers looking at the

   2   same data from different geographic areas and in

   3   this case, as I mentioned, there are people like me

   4   in twenty cities in the country who write

   5   quantitative reports on drug abuse twice annually,

   6   and we are convened by the National Institute on

   7   Drug Abuse twice a year.

   8             [Slide]

   9             Having done this and written over twenty

  10   reports on drug abuse trends in my city and met

  11   with my colleagues, it has given me a sort of

  12   broad-based perspective on how emerging drugs are

  13   measured and how we get a handle on them.  But

  14   everyone looks at medical examiner data.  We look

  15   at the data from the Drug Abuse Warning Network,

  16   which is data from a representative sample of nine

  17   federal short-stay hospitals with 24-hour emergency

  18   rooms, and that is conducted in 21 cities, as well

  19   as some other areas of the country.

  20             We also look at treatment data, law

  21   enforcement data and price, purity, trafficking and

  22   the sale of drugs, as well as supplemental research

  23   data and information from multiple sources.

  24             [Slide]

  25             I want to start my introduction to GHB by 
                                                                136

   1   telling you about the abuse of a group of drugs

   2   that are called club drugs.  That is really the

   3   first time in a long time we have had a name like

   4   club drugs applied to drugs because they are used

   5   in a particular setting.  That is why they came to

   6   be called club drugs.  It is a mixed category of

   7   drugs.  It includes stimulant drugs as well as

   8   depressant drugs that are used in nightclub

   9   settings.  GHB is also known in these settings as

  10   liquid X, gamma, G, easy lay, Georgia Home Boy or

  11   great hormones at bedtime.  MDMA or 3,4 methylene

  12   dioxide methamphetamine is ecstasy, e or x.

  13   Ketamine is known as special K.  It is a veterinary

  14   anesthetic, a dissociative drug similar in effects

  15   to PCP.  Flunitrazepam, Rohypnol is a long-acting

  16   benzodiazepine, which was dubbed the original date

  17   rape drug which is a drug not approved for medical

  18   use in this country; methamphetamine and LSD.

  19             If there is one point to make about club

  20   drugs as a term, one thing that has emerged is the

  21   fact that clearly these drugs are not limited to

  22   club settings and I will be talking to that in a

  23   moment.  It is not just clubs where they are used.

  24             [Slide]

  25             To give you a little slice of the 
                                                                137

   1   progression of GHB and how it came on the CEWG

   2   radar screen, it was first mentioned in 1990

   3   through a poison information center from my

   4   colleague in Miami.  Then, from 1990 to 1994 it

   5   appeared in the Miami and the New York city

   6   reports.  In 1996 it appeared in 6 other cities,

   7   and by the year 2000 most cities in this 21-city

   8   work group were reporting GHB.  It reports 23

   9   deaths in the 20 CEWG cities, and I refer you to a

  10   handout that I prepared that sort of gives the

  11   chronology of how my colleagues describe the

  12   growing abuse of GHB in their cities.

  13             [Slide]

  14             Now, in terms of user typologies, they

  15   tend to be young adolescents through adulthood.

  16   There is really no age group but when we look at

  17   population surveys in this country of who are drug

  18   abusers, by and large the biggest bulk of drug

  19   abusers are people who are under the age of 35.

  20             The motive for use is multiple.  It

  21   includes not only intoxication, but also people

  22   seeking intoxication effects in the absence of

  23   alcohol.  I have had people describe it to me as it

  24   gives them the effects of alcohol without having to

  25   waste that time drinking alcohol.  This is by young 
                                                                138

   1   people who haven't developed the taste.

   2             It is also used by weight lifters and body

   3   builders for its alleged anabolic effects.  It is

   4   also marketed in nutritional supplements to promote

   5   better sex, better sleep and some people take it to

   6   counter the effects of other club drugs.  One of

   7   the characteristics of drug abuse in nightclubs

   8   that has come up over the past year is the fact

   9   that people seem to have the impression that if you

  10   take just a little bit of this and a little bit of

  11   that nothing can really hurt you in a club setting.

  12   So, you might take a little bit of ecstasy to get

  13   you going, with a little bit of cocaine to keep you

  14   there, and maybe a little bit of heroin to take the

  15   edge off.  This sort of mixing and matching is also

  16   part of the user typology.

  17             The settings it is used in are nightclubs,

  18   raves, parties, but also in homes, in health clubs,

  19   gyms and other settings.  The sources of it come

  20   from health food stores, mail order kits, the

  21   Internet or at these clubs where it is being used

  22   by the capful.  Sometimes at these clubs, because

  23   ecstasy dehydrates you, people have a lot of water

  24   bottles and it is not unusual to have a water

  25   bottle that may have GHB mixed in it, and for ten 
                                                                139

   1   bucks someone can get a swig of it.  This makes it

   2   very imprecise dosing, as you can imagine.

   3             [Slide]

   4             In terms of deaths, in terms of the

   5   consequences of use -- there is a huge bullet

   6   missing from this slide, which I will get to.  So,

   7   if everybody wants to find their slides and write a

   8   bullet in it, I would appreciate it.  Deaths --

   9   there have been 71 documented deaths, according to

  10   the Drug Enforcement Administration, through

  11   November of last year.  Again, the problem is that

  12   because it is a new drug of abuse people don't

  13   know.  You know, you have to know what you are

  14   looking for to be able to find something and this

  15   has clearly been the case in trying to document GHB

  16   deaths.  It is a huge issue and I hope we get

  17   enlightened on that this afternoon.

  18             Also, there have been adverse medical

  19   reactions, not only people who come into emergency

  20   rooms, but the countless people, which is quite

  21   hard to quantify, who have episodes but never get

  22   emergency room treatment for it.  But there have

  23   been medical reactions, adverse ones.

  24             Dependence -- there has been a reported

  25   increase in people presenting to addiction 
                                                                140

   1   treatment centers with GHB as their primary

   2   substance of abuse, and an increase in the reported

   3   addiction to GHB by those who may not make it to

   4   treatment programs.

   5             I work at the Hazelden Foundation.  We are

   6   based in Center City, Minnesota, with campuses in

   7   Chicago, New York City and West Palm Beach.  There

   8   were 5 patients in 1999 who had a history of GHB

   9   abuse, and that had grown to 39 in the year 2000

  10   and we are just one treatment center.

  11             Finally, the missing bullet on here is

  12   drug rape.  One thing we have seen in this country

  13   since the early 1990's is the use of drugs, this

  14   predatory use of drugs where you administer drugs

  15   to people without their knowledge for the purpose

  16   of disabling them to commit crime on them.  The

  17   first drug that came to this sort of notoriety was

  18   Rohypnol, but now we are in a situation where GHB

  19   is often used in drug-induced rape.  In fact,

  20   several years ago when President Clinton signed the

  21   federal date-rape law, the Samantha Reid and Hilary

  22   Farris Date Rape Act, that was in response to two

  23   cases of drug rape that were not related to

  24   Rohypnol but to GHB.  So, that bullet should be up

  25   there, drug rape. 
                                                                141

   1             Also, another bullet would include the

   2   trafficking, sale and manufacture, the law

   3   enforcement consequences.

   4             [Slide]

   5             Let's look at hospital emergency room

   6   episodes of GHB.  This looks at them from 1994

   7   through 1999.  You can see the increase in hospital

   8   emergency department mentions of GHB.  Mentions is

   9   sort of unusual term for people who aren't familiar

  10   with the Drug Abuse Warning Network, and it quite

  11   literally means, in a retrospective review of

  12   patient records, that they find a mention of GHB.

  13   Sometimes it is the sole drug that precipitated the

  14   medical emergency and sometimes it is used in

  15   combination with other drugs.  For every drug abuse

  16   episode in the Drug Abuse Warning Network there can

  17   be the mention of 4 drugs and alcohol, but when

  18   alcohol is used in combination with other drugs; it

  19   is not an alcohol tracking system.

  20             [Slide]

  21             So, this is what it looks like through

  22   1999.  This looks at it by half year increments.

  23   You can see this takes us into the year 2000 and we

  24   have the first half of the year 2000.

  25             I want to go back to just my opening 
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   1   remarks about club drug abuse.  I think in the

   2   general population when we think of club drugs, you

   3   know, what we hear about, what everybody is talking

   4   about, what seems to be in U.S. News and World

   5   Report, in Newsweek and Time Magazine is ecstasy.

   6             [Slide]

   7             This is from exactly one year ago.  This

   8   is Time Magazine from June 5, 2000.  It talks about

   9   ecstasy.  For many folks, club drugs -- you think

  10   ecstasy.

  11             [Slide]

  12             This was, I believe, from Time magazine as

  13   well.  You see the water bottle there.  If you

  14   didn't see Time magazine, you may have seen The New

  15   York Times Sunday magazine insert.  This is from

  16   January of this year, talking again about ecstasy.

  17   This is from January 2001.

  18             So, since it is in the same category of

  19   drug, I think it is relevant to look at how GHB

  20   emergency room episodes compare with those of

  21   ecstasy.

  22             [Slide]

  23             Ecstasy, or MDMA, is in the pink and GHB

  24   is in blue.  You can see in the first half of the

  25   year 2000 that GHB hospital emergency episodes have 
                                                                143

   1   surpassed those of ecstasy.

   2             [Slide]

   3             Efforts to control GHB -- a number of

   4   states have done things to try to control GHB abuse

   5   in their states.  This is sort of a listing of the

   6   scheduling of it in various different states.  It

   7   was added, as you know from the materials the

   8   committee received, to the Federal Control

   9   Substance Act.

  10             [Slide]

  11             Finally in conclusion, GHB is a

  12   significant, growing drug of abuse.  We have seen

  13   rapid growth in the adverse medical consequences

  14   related to GHB since 1999 and, in fact, hospital

  15   emergency mentions of GHB now surpass those of

  16   ecstasy or MDMA.  We have seen rapid growth in

  17   adverse medical reactions despite not only federal

  18   scheduling but the scheduling in numerous states.

  19   We have multiple user typologies.  This is not a

  20   substance that is sought after simply by people at

  21   parties and raves.  These products that contain GHB

  22   as well as its precursor drugs, GBL and 1,4-BD, are

  23   sought after by people who believe the claims on

  24   these nutritional supplements and take them for

  25   promoting muscle growth, for sleep; and take them 
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   1   for better sex, as well, and as I said, use it in

   2   sort of predatory way.  Dependence is clearly

   3   possible.

   4             So in closing, here we have a drug with an

   5   established widespread abuse record.  With GHB we

   6   needn't talk about abuse potential.  With GHB we

   7   have abuse reality.  We have a decade of GHB abuse

   8   in this country; a decade of deaths and hospital

   9   emergency room episodes and dependence.  We have

  10   escalating abuse of GHB in spite of recent efforts

  11   to control it and, yes, people acquire this drug

  12   and its precursors in many ways.  But make no

  13   mistake, the effects being sought are the GHB

  14   effects.  The chemical agent in the body that is

  15   producing these effects is GHB, and this

  16   undisputable fact is entirely relevant to our

  17   discussions today.

  18             I have to take issue with the statement

  19   from the sponsor that says Xyrem is not the

  20   problem.  If Xyrem equals GHB, then I believe it is

  21   a problem.  This drug, if approved, will exist

  22   outside the confines of this room.  Patients will

  23   use it outside the confines of clinical trials.  In

  24   America, in 2001 we have a serious, significant and

  25   growing problem with GHB abuse in this country, and 
                                                                145

   1   it just so happens that this coincides with Orphan

   2   Medical seeking approval for this drug.

   3             This drug already has avid followers, and

   4   there is no reason to assume that another source of

   5   GHB would not be sought after by these folks, and I

   6   think we need to bear that in mind throughout our

   7   discussions.  Thank you.

   8             DR. KAWAS:  Dr. Falkowski, can I ask you

   9   one question?  With regards to the emergency

  10   department data for GHB, I recognize the

  11   difficulties of all of this kind of data but, for

  12   example, MDMA is not infrequently the only drug and

  13   when they go to the emergency room that is clearly

  14   because of the MDMA.  Can you give us any kind of

  15   quantification or semi-quantification?  You

  16   mentioned that sometimes GHB is the only drug.

  17             DR. FALKOWSKI:  The question was how often

  18   is GHB used in combination, and let me find that.

  19             DR. KAWAS:  For the emergency room data.

  20             DR. FALKOWSKI:  Yes, that is what I am

  21   looking for.  I have it right here.  It is 70

  22   percent of the time.  Like many other drugs, GHB

  23   episodes involve drugs other than GHB as well.

  24             I would also like to add that I believe

  25   these hospital emergency room episodes 
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   1   underestimate GHB because drugs that are used in a

   2   predatory way, that are administered to people

   3   without their knowledge are not DAWN reportable.

   4   So, if someone comes to the emergency room and says

   5   I believe somebody gave me something and it is

   6   making me sick, that is not a DAWN reportable

   7   thing.  That is being addressed by the Substance

   8   Abuse and Mental Health Services Administration.

   9   But what that means is that people who are drugged

  10   with any sort of drug are not picked up by this

  11   particular reporting system.

  12             DR. KAWAS:  And, what are the most common

  13   drugs or classes of drugs that go along with GHB

  14   when people take them in combination?  What are the

  15   favorites?

  16             DR. FALKOWSKI:  It is probably ecstasy,

  17   MDMA, and to a lesser extent ketamine and also

  18   alcohol.

  19             DR. SANNERUD:  I have some data on the

  20   DAWN statistics too.  When drugs are used in

  21   combination, 50 percent alcohol, 11 percent

  22   stimulants, 8 percent marijuana, poly drugs,

  23   hallucinogens and sedatives and all these are at

  24   least at 3 and 2 percent each.

  25             DR. KAWAS:  Dr. Dyer, I believe you are 
                                                                147

   1   our next speaker.

   2             DR. KATZ:  Claudia, if I could just ask a

   3   question, and I don't know who best to direct it,

   4   but you said 70 percent of the time the reports are

   5   of GHB in association with something else.  So,

   6   presumably 30 percent of the time it is the sole

   7   drug.  I have a sort of methadologic question.  How

   8   reliable would you say that information is, just in

   9   general?  What is sort of the nature of the

  10   information that is recorded and from whom that

  11   allows us to conclude that, in fact, GHB is the

  12   only drug that was taken?  Who reports that, and

  13   how reliable are those reports, just as a general

  14   rule?  Number one.

  15             Number two, how many of the deaths and

  16   very serious adverse events were associated with

  17   GHB use alone?

  18             DR. FALKOWSKI:  I believe you could

  19   address the reliability of DAWN.  You are a DAWN

  20   reporter.  Again, regarding the deaths, you know,

  21   the Drug Abuse Warning Network also collects data

  22   from medical examiners, but the people in the

  23   20-city work group of mine rely more often on

  24   getting data directly from the medical examiners,

  25   first because it is more timely and also because it 
                                                                148

   1   casts a better net.  It captures situations that

   2   are not only due to drug-related toxicity but also

   3   ones where the use of drugs were considered by the

   4   medical examiner to be significant contributing

   5   factors to the death.  So, that is what I can say

   6   about deaths.

   7             Also, I have a table, if you are

   8   interested, that I could make available that shows

   9   exactly DAWN emergency room data for 1999 and what

  10   were the co-ingestants.

  11             DR. KAWAS:  Our next speaker is Dr. Jo

  12   Ellen Dyer, from the California Poison Control

  13   System at UCSF, speaking on adverse medical effects

  14   with GHB.

  15                 Adverse Medical Effects with GHB

  16             DR. DYER:  Thank you and good afternoon.

  17             [Slide]

  18             In 1990 I identified and made the first

  19   reports on GHB abuse from over-the-counter sales of

  20   GHB.  Over the next 11 years I have been following

  21   GHB.  I have an interest in it and I have been

  22   reporting on the progress, the adverse effects and

  23   the trends in use.

  24             [Slide]

  25             This is a description of the California 
                                                                149

   1   Poison Control System data of GHB reports to our

   2   center.  We logged these reports over 10 years.

   3   The first years are when the San Francisco center

   4   stood alone so it is a population base of 7 or 8

   5   million.  We became a system in '97 so we have 4

   6   years of data for the entire state.

   7             We are a medical toxicology consult

   8   service, so we are not a required or mandatory

   9   reporting center.  So, this reflects just the tip

  10   of the iceberg of use and abuse and adverse effects

  11   that are out there.

  12             [Slide]

  13             In our experience GHB produces a profound

  14   coma.  This has been known for over 40 years,

  15   starting out in surgical anesthetic studies where

  16   it was evaluated as an anesthetic and now through

  17   numerous occurrences of coma in users through this

  18   widespread public use, where accidental overdoses

  19   are occurring because of the narrow and variable

  20   therapeutic index for this drug.

  21             [Slide]

  22             Looking at 5 studies, anesthetic studies

  23   that cover over 700 patients -- there are many

  24   other studies; I just picked a small set of them --

  25   you see the effects of GHB in a controlled 
                                                                150

   1   situation.  GHB causes unconsciousness and a

   2   profound coma.  This is what is intended with an

   3   anesthetic.  The respiratory effects that are seen

   4   are Cheyne-stokes respiration.  There were

   5   aspirations.  There was a case of unexplained

   6   pulmonary edema.  In many of these cases the

   7   patients are intubated and the airway is attended

   8   to.  If their airway was left to chance in these

   9   situations, it would be compromised.  They lose

  10   their airway protective reflexes.  They have no

  11   gag.  So, with the high incidence of vomiting,

  12   about 30 percent in these studies, combined with

  13   the loss of gag, it is not difficult to see how

  14   aspiration is going to occur.

  15             There are cardiovascular effects, like

  16   bradycardia, and then there are isolated incidences

  17   where blood pressure rose up to 30-60 mmHg for

  18   unexplained reasons really.  There is myoclonus

  19   that we see.  There is an emergence delirium,

  20   confusion.  There are also secretions like

  21   salivation, vomiting, incontinence and diaphoresis.

  22             [Slide]

  23             If I look at 16 reports that cover 175

  24   cases of adverse events where GHB was in public

  25   use, you see these same physiologic responses to 
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   1   GHB.  You have profound coma.  They develop a mild

   2   respiratory acidosis; bradycardia; myoclonus;

   3   confusion; emergence delirium; and then the

   4   secretions.  This raises doubts for safety of use

   5   among a generalized public population.

   6             [Slide]

   7             If we look at a closer group where we did

   8   a study in our emergency department, and this is

   9   the San Francisco County emergency room that sees

  10   over 200 patients a day -- we looked at GHB

  11   overdoses that we had over 3 years.  This is just a

  12   retrospective descriptive study where we were

  13   trying to get a handle on what is going on.  We

  14   found that of those cases, about 33 percent had no

  15   co-ingestion.  This was documented by either

  16   toxicology or patient report.  Those patients came

  17   in, a quarter of them, with Glasgow Coma Score of

  18   3.  So, they were profoundly comatose and 33

  19   percent of them had coma scores between 4-8.  The

  20   coma lasted 15 minutes to 6 hours.

  21             Again, a third of the patients had these

  22   same symptoms, bradycardia, respiratory acidosis,

  23   hypothermia, vomiting.  We saw hypotension in about

  24   11 percent. Those cases were primarily cases where

  25   alcohol was co-ingested.  Then, on emergence these 
                                                                152

   1   patients are difficult to manage.  They can have an

   2   emergence delirium which includes combative,

   3   agitated behavior.

   4             [Slide]

   5             Because of that evidence and wanting to

   6   focus in closer and get some GHB levels to find out

   7   if that is truly what we were looking at, we did a

   8   prospective study over 6 months, looking at 15

   9   cases of GHB overdose, and 73 percent of those came

  10   in with a Glasgow Coma Score of 3.  Our intent was

  11   to document the presence of GHB, to detect the

  12   co-ingestants and what they were or if there were

  13   none, and then to verify that our ability to

  14   predict an overdose is truly GHB by the toxidrome

  15   that we are using, whether or not that was

  16   effective.

  17             So, all of these 15 cases did have GHB

  18   that was measurable.  They were young, ages 20-39;

  19   73 percent were male.  The study inclusion criteria

  20   were patients presenting with Glasgow Coma Scores

  21   less than 8 and 73 percent of these patients had a

  22   Glasgow Coma Score less than 3.

  23             In 5 of the cases there were no other

  24   drugs or alcohol detected.  The GCS was 3 in 80

  25   percent of those cases.  So, profound coma from 
                                                                153

   1   accidental overdose; no other obvious cause.

   2             [Slide]

   3             It is clear to us that there is really

   4   substantial evidence that GHB causes coma.  Coma is

   5   life-threatening, and these deaths are occurring

   6   from accident or injury and from respiratory

   7   compromise.  We are seeing that through aspiration;

   8   through apnea; through positional asphyxia -- these

   9   are profoundly comatose people, they can't even

  10   move to open their airway -- and through pulmonary

  11   edema.

  12             [Slide]

  13             So, I have reviewed 20 GHB related

  14   fatalities where I had autopsy reports.  I just

  15   sent letters to medical examiners asking for their

  16   reports.  In these cases, the ages ranged from 15

  17   to 46 years.  Three-quarters of them were male; 20

  18   percent of them had no concurrent ingestions.  If

  19   we look at those that had co-ingestants, the 80

  20   percent.  We will see that many of these substances

  21   are legal commonly ingested things.  Tylenol was

  22   one of them; caffeine; alcohol.  The levels of

  23   alcohol went up to 0.17 percent.  The legal limit

  24   for driving ranges from 0.08 to 0.1.  So, most of

  25   these cases were in the lower range, right around 
                                                                154

   1   the legal limit of driving, saying that they had

   2   maybe one or two drinks and none of these would

   3   reach an alcohol level that would cause coma.

   4             [Slide]

   5             The societal costs that were seen from GHB

   6   abuse, there are many driving under the influence

   7   arrests that have occurred with GHB.  There were a

   8   whole lot that were not recognized until GHB

   9   testing became available and now they are being

  10   recognized.  I don't go out really and collect this

  11   data but there are two vehicular manslaughter, I

  12   guess they would call it, cases where a person

  13   driving under the influence of GHB has hit and

  14   killed another individual.  One of those was in '96

  15   and one was in 2000.

  16             Another societal cost is the assaults

  17   where the victim is under the influence of GHB

  18   given to them or slipped to them by the assailant.

  19   It is common enough that they have a term for it.

  20   It is called being "scooped" by GHB.  The assailant

  21   then attacks the victim while they are unconscious

  22   or amnestic to the effects of the drug, making

  23   prosecution and even reporting of these very, very

  24   difficult.

  25             These are 4 cases.  There are others.  But 
                                                                155

   1   in these GHB was clearly documented as the cause.

   2   The first was a woman who was drugged and assaulted

   3   by her boss as they went out with a group of

   4   colleagues after work.  She had GHB in her urine.

   5   There were 10 victims of some DJs in Los Angeles

   6   that were slipping GHB into drinks and then

   7   assaulting them.  There was a 24-year old that was

   8   eventually prosecuted more for trafficking drugs

   9   after a woman had reported an assault to them and,

  10   in kind of the bargaining, he admitted, yes, he had

  11   drugged her twice with GHB and she has no memory of

  12   the first event at all.  Nothing.  The last is two

  13   15-year old females who were unconscious at a

  14   party.  One was hospitalized and one of these girls

  15   died.

  16             [Slide]

  17             We also see addiction as another burden

  18   from GHB abuse.  We are currently seeing one to two

  19   cases a month at our poison center, and this is

  20   eight cases that I collected.  The age range is

  21   young, 22-38, again three-quarters male.  The

  22   pattern just continues through all these of the

  23   demographics of who is using.  Of these, 63 percent

  24   started taking GHB for body building.  They had

  25   what they thought was kind of a legitimate use of 
                                                                156

   1   this dietary supplement.  In this group, 88 percent

   2   of them were employed or students.  These were

   3   functional members of society that have had trouble

   4   now because of this drug.  These are not people

   5   that really had drug-seeking behavior.  The onset

   6   of symptoms we see within 1-6 hours.  It progresses

   7   over a couple of days.  The duration is 5-15 days.

   8             Now, these are often unrecognized by

   9   healthcare professionals when they present for

  10   treatment.  GHB abuse addiction is not really very

  11   well known out there.  These are severe

  12   neuropsychiatric symptoms with autonomic

  13   instability that we see.  I have had physicians who

  14   have treated many, many cases of severe alcohol

  15   withdrawal that have called me up and said, my

  16   gosh, I am impressed; I am so impressed by this

  17   withdrawal symptom.  The patients become agitated,

  18   combative, delirious.  They are hallucinating.

  19   They require sedation, a milligram a minute of IV

  20   Ativan has been used over a few hours to gain

  21   control.  They require four-point leather

  22   restraints and intensive care.   One of the

  23   patients in this series died while being

  24   hospitalized for GHB withdrawal.

  25             [Slide] 
                                                                157

   1             Substantial and compelling evidence from

   2   case reports of accidental poisoning and from

   3   toxicology supported adverse events really shows us

   4   that these effects are due to GHB.  It is not some

   5   contaminant or something else that is causing

   6   these.  And, there is an insufficient or no safety

   7   margin between the effective level of the

   8   therapeutic dose of these drugs that these people

   9   are taking and the dose that causes these effects.

  10   As you can see from the sponsor's study, the

  11   adverse effects that they are reporting are very

  12   similar.  The confusion, the nausea, the vomiting

  13   are very similar to the things that we are seeing.

  14             One physician, Dr. Gallamberti from Italy,

  15   who is doing therapeutic use of GHB withdrawal

  16   states talks about a 15 percent problematic GHB use

  17   among his population.  This can be dose escalation.

  18   This can be GHB overdoses up to 10 times a year, or

  19   GHB dependence.

  20             [Slide]

  21             This slide just looks at the kinetics to

  22   illustrate that there is really a very narrow

  23   therapeutic index with this drug and there is a lot

  24   of variability.  The pharmacokinetics of GHB are

  25   capacity-limited absorption, capacity-limited 
                                                                158

   1   elimination.  The coefficient of variation of some

   2   of these parameters is 50 percent.  There is a lot

   3   of variation and we don't really know what the

   4   consequence in different populations and different

   5   people of these really variable kinetics is going

   6   to be, or why they are so variable.  You are used

   7   to using phenytoin.  It has capacity-limited

   8   elimination.  We know that when you are bumping the

   9   dose of a patient on phenytoin you have to be

  10   really careful because they can exponentially

  11   increase their level.  Well, the same thing happens

  12   with GHB and we don't know where that is yet.

  13   There is not enough experience.  And, with

  14   phenytoin the absorption is pretty good.  We know

  15   the bioavailability of IV phenytoin and oral

  16   phenytoin.  Here, I don't think it is so constant.

  17   It really changes with food and there is a

  18   capacity-limited absorption that is going to vary

  19   between patients.  So, this is a really difficult

  20   drug to control, particularly orally on an

  21   outpatient basis.

  22             [Slide]

  23             So, what is the current level of GHB abuse

  24   that is out there?  We really don't know.  If we

  25   wanted to project from one survey that was done, 
                                                                159

   1   Dr. Miotto, a UCLA physician that works addiction

   2   medicine did a 45-minute structured interview with

   3   42 GHB users.  Among that group, 69 percent had

   4   admitted that they had lost consciousness, had

   5   periods of consciousness laps from minutes to

   6   hours.  There was variability in the amnesia

   7   dependent upon how often people used.  Twenty-eight

   8   percent admitted having an overdose; 9 percent had

   9   been to the emergency department for an overdose.

  10             Now, there is an interesting misconception

  11   here where they don't consider the loss of

  12   consciousness to be an overdose, and people

  13   overdose and when they are in a profound coma are

  14   not taken to the emergency department.  So, there

  15   are really some problems there, and this gives us

  16   an example of the kind of under-reporting that is

  17   out there.

  18             If we try and extrapolate from the amount

  19   of drug that we are seeing marketed illicitly, this

  20   is just one arrest in Marin County, a small county

  21   north of San Francisco, where they had 207 L of

  22   butanediol.  The average street dose varies around

  23   2 g.  If you look at that, that is 103,500 doses in

  24   one capture at one house, and there are many, many

  25   of these.  There are lists of different amounts 
                                                                160

   1   that have been busted all over.

   2             Then there is the problem that Carol has

   3   already talked about, surveying and policing the

   4   issues of this type of new drug abuse.  There is no

   5   systematic method in place for data collection on

   6   this.

   7             There is rapid metabolism of the drug.  It

   8   clears from the blood in within about 6 hours; it

   9   clears from the urine within about 12 hours.  We

  10   can't test these people and find it.  When we are

  11   trying to get evidence in a drug assault case, it

  12   is gone.  It is really difficult to detect.  And,

  13   should we increase our level of detection to the

  14   very, very minute nanogram kind of range, then we

  15   are going to start running into the biological

  16   background so we aren't even going to be able to do

  17   that if we increase our ability to detect.  There

  18   are also very poor assays currently out there.

  19   None of the hospitals have an assay for this, and

  20   none of the law enforcement has a field kit for it.

  21   So, it has to be taken into a lab and specifically

  22   run through a complicated GC mass spec procedure to

  23   get a level out, which is expensive.

  24             The current documentation clearly grossly

  25   underestimates the amount of use that is out there. 
                                                                161

   1   And, it is very clear that there is a little, if

   2   any, safety margin with GHB use in the therapeutic

   3   doses that are proposed.  GHB is a very potent new

   4   drug of abuse.  It has been around 10 years.  We

   5   thought it was going to come and go as a fad, it

   6   hasn't and it is not going to.  The use is still

   7   increasing.

   8             There is a very high acute toxicity in

   9   accidental overdose -- coma, bradycardia,

  10   myoclonus, vomiting, aspiration -- we are seeing a

  11   lot of it, and it has very high abuse and addiction

  12   potential.  So, I think that we have to be very

  13   careful and it is very difficult to try and

  14   minimize these potential risks, the risks of having

  15   it get out into the drug abusing population but

  16   also among patients that we are going to be giving

  17   this drug to take at home.  At the poison center,

  18   every night at bedtime, 9 to 11 o'clock I am called

  19   by people that say, oh, I'm sorry, I accidentally

  20   took a double dose of my medication.  What should I

  21   do?  In this case, they are all going to go to the

  22   emergency room.  There is really not a margin of

  23   safety with this drug.  Thanks.

  24             DR. KAWAS:  Thank you, Dr. Dyer.  The next

  25   presentation is from the sponsor, presentation on 
                                                                162

   1   risk management and abuse liability, Dr. Bob

   2   Balster, from the Medical College of Virginia.

   3             DR. REARDAN:  Yes, I would like to now

   4   introduce Dr. Balster who will present his views

   5   with respect to abuse liability of Xyrem and GHB.

   6   Dr. Balster is a previous chair of the FDA Drug

   7   Abuse Advisory Committee and a widely published

   8   abuse pharmacologist from the Medical College of

   9   Virginia.  He is editor and chief of a leading

  10   addiction journal, Drug and Alcohol Dependence, and

  11   a past president of the College on Problems of Drug

  12   Abuse.

  13             Sponsor Presentation on Risk Management

  14                       and Abuse Liability

  15             DR. BALSTER:  Thank you very much, Dayton.

  16   Good morning or good afternoon, I guess it is now.

  17             [Slide]

  18             Well, as you have just heard, the

  19   development of Xyrem as a medication has taken

  20   place in a context of a national epidemic of the

  21   abuse of its constituent GHB, and also the abuse of

  22   a number of GHB-related drugs that I will tell you

  23   about.

  24             As Dr. Houghton told you, Orphan is very

  25   well aware of this problem and has consulted many 
                                                                163

   1   drug abuse experts to try to understand the problem

   2   better.  My own analysis of this situation is that

   3   Xyrem has certainly not contributed to the problem

   4   that exists today with the abuse of this class of

   5   compounds.  I guess where I may disagree a bit is

   6   that I am pretty convinced that Xyrem is not going

   7   to be a player in this over the long term.

   8             I think in order to understand and make an

   9   appropriate public health response to this

  10   situation, you need to know a little bit about what

  11   some of the causes are of this GHB abuse problem.

  12             [Slide]

  13             So, I hope to make two points in this

  14   presentation.  The first point is that I believe

  15   that the recent abuse of GHB-like substances

  16   probably reflects a ready availability more than

  17   their inherent pharmacological propensity for

  18   abuse.

  19             I think I will make this point by first

  20   off reviewing for you the incredible availability

  21   of these compounds, and then also review very

  22   quickly scientific studies that have been done on

  23   the abuse liability of GHB as it is compared to

  24   other drugs of abuse you might be familiar with.

  25   Secondly, I believe that Xyrem, if approved for 
                                                                164

   1   medical use, will not contribute to the public

   2   health problem of the abuse of these GHB-like

   3   substances in any significant way.

   4             [Slide]

   5             Before we continue, it is very important

   6   to know the cast of characters here.  I think next

   7   to the federal government, the next worst developer

   8   of abbreviations is a drug abuse research

   9   community, with MDMA, and PCP, and GHB, and BD --

  10   it must be hard to kind of keep track of the

  11   players but, of course, the drug we are talking

  12   about here is GHB, gamma hydroxybutyrate.  But

  13   there are a bunch of other drugs that are basically

  14   part of this national drug abuse problem.

  15             You have heard a little bit about them,

  16   but these precursors, gamma butyrolactone or GBL,

  17   1,4 butanediol or 1,4-BD are precursor compounds

  18   that, if obtained, can be easily and readily

  19   converted into GHB.  They also can be consumed

  20   directly because they are metabolized by the body

  21   into GHB.  So, they themselves are drugs of abuse

  22   like GHB.  Then there are others that are also

  23   available.

  24             Now, of all these chemicals only GHB is

  25   actually a scheduled drug.  It is Schedule I under 
                                                                165

   1   the Controlled Substances Act for the abusable

   2   versions, GHB; Schedule III for an approved medical

   3   product.  So, only GHB is scheduled.  Now, GBL is

   4   what is called listed so its availability is

   5   diminished.  These others are still freely

   6   available without any drug abuse controls.

   7             [Slide]

   8             You have heard a lot about GHB abuse but I

   9   am pretty convinced that what we are seeing here is

  10   something that has resulted from an amazing

  11   situation of the availability of these compounds.

  12   To remind you, GHB was available legally and

  13   legitimately through health food stores up through

  14   1990 when you could buy it anywhere, and the abuse

  15   problem with this drug began during that period of

  16   time.

  17             Then through that time and afterwards GHB

  18   could be obtained through the Internet.  There was

  19   an amazing number of sites set up to sell GHB.

  20   Then, as GHB became less easy to get because

  21   Internet sources dried up, the Internet sources

  22   were selling the precursors, etc., etc.  I will

  23   show you some data a little bit more, but these

  24   precursors are not going to disappear any time soon

  25   from public availability.  Now that the 
                                                                166

   1   availability of GHB has been restricted by the

   2   federal scheduling actions and actions by the FDA,

   3   people can now purchase the precursors and make

   4   their own GHB.  Essentially anyone can do that.  It

   5   is a very simple thing and the recipes are right

   6   there on the web.  As I said before, they

   7   themselves are widely abused. So, we have a class

   8   of chemicals here that are really basically part of

   9   what has been referred to as a GHB abuse problem,

  10   but it is really an abuse of a class of drugs, and

  11   you saw some evidence on that.

  12             [Slide]

  13             At this point I want to review the

  14   scientific literature on the laboratory studies of

  15   the abuse potential of GHB.  You may wonder why I

  16   would want to do that, I mean, why would I want to

  17   review literature on abuse potential when the

  18   reality of GHB abuse is clear to us from

  19   epidemiological data that Dr. Falkowski mentioned

  20   and clinical data.  The reason to do this is to try

  21   to understand what the basis for this is, and to

  22   know whether or not this wide abuse is due to some

  23   features of this incredible availability, or

  24   whether the drug has sort of the inherent

  25   pharmacological desirability that you would 
                                                                167

   1   associate with a really dangerous drug like cocaine

   2   or heroin where, no matter how many billions of

   3   dollar we throw at the problem, we are getting

   4   nowhere with it, or does GHB represent a drug which

   5   is less desirable or has less propensity for use.

   6             [Slide]

   7             Just to remind you, there is a

   8   well-established science of abuse liability

   9   evaluation, and it is used in evaluating new

  10   compounds that are under development.  It is useful

  11   in making decisions about drug abuse control, and

  12   data such as these are used widely by the FDA for

  13   making regulatory decisions.  All of these data are

  14   reviewed in your packages, but just to quickly tell

  15   you, first off, GHB is a unique drug.  It is not

  16   just another depressant drug like barbiturates or

  17   even benzodiazepines that have its own receptor and

  18   its own characteristics.

  19             In studies which are called drug

  20   discrimination studies, which allow you in a way to

  21   compare unknown drugs to known drugs of abuse,

  22   again, GHB lacks equivalence to these classical

  23   depressants like barbiturates or any other classes

  24   of drugs to which it has been directly compared.

  25             In self-administration studies -- these 
                                                                168

   1   are laboratory studies where you can actually

   2   measure what we call the reinforcing effects of the

   3   euphorigenic potential of these drugs -- actually

   4   in this particular class of studies GHB has very

   5   weak reinforcing effects.  It is difficult to

   6   obtain them in laboratory studies and there have

   7   been a number of those.  We did one of these

   8   ourselves in our laboratory and we essentially

   9   found no evidence of GHB self-administration under

  10   conditions where we reliably get

  11   self-administration of cocaine, heroin,

  12   barbiturates, etc., etc.

  13             The case of physical dependence is a

  14   little bit more complicated.  You heard from Dr.

  15   Dyer about the fact that abusers can develop

  16   dependence and show withdrawal signs, and there is

  17   no question about that.  These people are taking

  18   maybe 10 or more times the therapeutic dose.  We

  19   are talking about 70, 80, 100 grams a day, and they

  20   take them every 3 hours or so because they have to

  21   maintain the blood level.  Yes, in those cases you

  22   get dependence, but in patients receiving Xyrem,

  23   where they are getting it in lower doses and they

  24   are taking it only in the evening, as you have

  25   heard from the reports, there have not been 
                                                                169

   1   significant problems of dependence.  So, yes, it

   2   can occur in abusers but it isn't really an issue

   3   in patients.  Importantly, animal studies, for

   4   example, where you try to show the dependence of

   5   GHB and compare it, for example, to barbiturates,

   6   it is not easy to develop a model for GHB

   7   dependence in animal studies because it has less

   8   inherent dependence producing properties than these

   9   other drugs.

  10             [Slide]

  11             So, my conclusion when I reviewed the

  12   literature on the scientific studies of GHB, when I

  13   was asked to do that, I basically thought it looked

  14   a lot like what I would say is a Schedule IV drug.

  15   Schedule IV drugs, you remember, are

  16   benzodiazepines and chloral hydrate and drugs of

  17   this type, and that is sort where it fit.  It isn't

  18   like cocaine.  It isn't like heroin.  In fact, that

  19   analysis of looking at the data has been made by

  20   others with very much the same recommendation as

  21   mine, that is, it sort of fits pharmacologically

  22   with Schedule IV.

  23             For example, the WHO expert committee

  24   which met not too long ago to make a recommendation

  25   to the UN Commission, the WHO expert committee 
                                                                170

   1   recommended Schedule IV and, in fact, the UN

   2   Commission ultimately placed GHB in Schedule IV.

   3   Schedule IV, under the Psychotropic Convention is

   4   very analogous really to our Schedule IV that you

   5   are familiar with under the Controlled Substances

   6   Act.

   7             [Slide]

   8             We are not here to talk about GHB abuse

   9   which we know is a significant problem.  We are

  10   here to talk about Xyrem and what its role may be

  11   in the drug abuse problem in the United States.

  12   There are two issues we are really worried about

  13   here.  Number one, we are worried about the

  14   possibility that patients legitimately prescribed

  15   Xyrem will abuse it in some way, or misuse it or

  16   escalate and then, secondly, we are worried about

  17   whether or not it might be diverted into sort of

  18   illicit channels and become part of a problem in

  19   that way.

  20             [Slide]

  21             Turning first to the issue of patients,

  22   first off, I think most of you know, and it is

  23   important to always know this, that the development

  24   of abuse among patients receiving therapeutic doses

  25   of abuse drugs is a much smaller problem than some 
                                                                171

   1   people realize.  It is actually fairly unlikely to

   2   occur in a general sense.  Of course, in the trials

   3   with Xyrem there weren't problems of abuse; there

   4   wasn't evidence that people were escalating their

   5   dose or complaining and asking for more, and that

   6   sort of thing.

   7             It is important also to recognize that

   8   narcolepsy patients are patients that are receiving

   9   controlled substances all the time.  The stimulant

  10   class of drugs, all those drugs that Dr. Mignot

  11   spoke about are all scheduled compounds.  In fact,

  12   many of them are Schedule II where they can't even

  13   get them half the time because the production

  14   controls on Schedule II reduce their availability.

  15             Then the issue about their dependence, if

  16   you understand, for example, that with

  17   benzodiazepines, when you discontinue

  18   benzodiazepine administration you will often see a

  19   withdrawal syndrome, well, that is because

  20   benzodiazepines have this incredibly long duration

  21   of action with active metabolites that accumulate

  22   so that the body continually maintains levels of

  23   benzodiazepines.  So, when you quit using them

  24   there is a withdrawal syndrome.  With GHB, as you

  25   saw from Dr. Houghton's presentation, the duration 
                                                                172

   1   of action is just a couple of hours.  It would take

   2   many, many, many multiple daily uses, way more than

   3   the patients are going to get, to maintain the kind

   4   of levels of GHB that would be expected to produce

   5   dependence.  So, yes, in abuse cases where people

   6   are just going all day and all night but not with

   7   patients.

   8             [Slide]

   9             Turning now to illicit diversion of Xyrem,

  10   first off, that hasn't happened yet.  So, we are

  11   not aware of any diversion of any Xyrem through any

  12   of the products.  This is, of course, only in

  13   clinical development but I think it is important to

  14   know.  Most importantly, the company has been very

  15   much worried about this issue and has developed a

  16   distribution system that you are going to hear

  17   about, called the Success Program, which I

  18   personally believe is going to substantially

  19   prevent any opportunities for diversion.  Lastly,

  20   Xyrem, whether you approve it or not -- it is going

  21   to make very little difference in the overall

  22   availability of this whole class of chemicals in

  23   the national scene.

  24             [Slide]

  25             To illustrate that, this slide shows you 
                                                                173

   1   the product amounts anticipated, annual production

   2   amounts for this class of chemicals I mentioned to

   3   you.  So, if Xyrem is approved the anticipated

   4   first year production amounts of gamma

   5   hydroxybutyrate are about 82,000 kg.  GBL, gamma

   6   butyrolactone, the precursor that can be made into

   7   GHB easily and consumed itself, is 83 million kg, a

   8   thousand times more.  1,4-BD which is not a

   9   controlled substance and has no drug abuse control

  10   under it whatsoever right now, is widely available

  11   through all sources in large amounts, and is made

  12   in the neighborhood of 377 million kg.  For those

  13   of you who don't do the metric system, that is

  14   400,000 tons of 1,4-BD.  And, all of these drugs

  15   are basically substituting for one another.  So,

  16   whether you take Xyrem in or out of that graph, it

  17   is not going to make a difference.

  18             [Slide]

  19             In conclusion, I believe that the epidemic

  20   of abuse of GHB-like drugs has resulted really

  21   primarily from its extraordinary availability.  In

  22   fact, when GHB was controlled -- it is hard now to

  23   get GHB.  It is hard even for me to get GHB as a

  24   research scientist.  So, the problem has now

  25   switched to these precursors that are available. 
                                                                174

   1             Secondly, the scientific studies of GHB

   2   show that you are not talking here about cocaine or

   3   heroin.  It is a weak depressant of maybe the

   4   benzodiazepine, chloral hydrate type. Thirdly, I

   5   believe that Xyrem abuse is very unlikely among

   6   patients for the reasons I said.  Lastly, the

   7   contribution of Xyrem to the public health problem,

   8   which is the matter of concern, is essentially not

   9   significant.  So, you know, have your way with the

  10   drug in terms of efficacy and safety but I don't

  11   think you need to be worried that this drug is

  12   going to be a major factor in the drug abuse

  13   problem with this class of drugs.  Thank you.

  14             DR. KAWAS:  Yes, a quick question, Dr.

  15   Leiderman.

  16             DR. LEIDERMAN:  Yes, I would like to ask

  17   Dr. Balster two questions.  I would like you to

  18   comment on the species of animal that you are

  19   addressing when you talk about self-administration

  20   in drug discrimination studies.  Two, I would like

  21   you to comment on the data that those models show

  22   with other classes of drugs.

  23             DR. BALSTER:  All the studies are reviewed

  24   on that slide on abuse potential with laboratory

  25   animal studies, using fairly well developed 
                                                                175

   1   methodologies.  The self-administration studies

   2   that Dr. Leiderman referred to were studies that

   3   were done in monkeys in sort of a standardized

   4   method that is done through a program directed by

   5   the College on Drug Dependence.  Those are the

   6   models, and I can show you data if you give me the

   7   time to do it.  Maybe later, if the committee is

   8   interested, I can show you data.  But these are

   9   models in which basically it is extremely easy to

  10   get animals to actually literally self-inject most

  11   of the drugs of abuse -- cocaine, amphetamines,

  12   opiates of all types, barbiturates, depressants,

  13   benzodiazepines -- benzodiazepines are a little

  14   harder but in the model that was used that I showed

  15   the negative results from, benzodiazepines were the

  16   positive control.  So, basically the only area

  17   where that model has been not very successful and

  18   underestimates abuse potential is with

  19   hallucinogenic drugs and marijuana type drugs.

  20             DR. LEIDERMAN:  Yes, many of the Schedule

  21   I drugs.                      DR. REARDAN:  We just

  22   have about another ten minutes.  If we can prevail

  23   on the committee, we have one last speaker, and

  24   that will be Patti Engel, who is going to describe

  25   for you the risk management system that the company 
                                                                176

   1   has developed to help control diversion.  Patti?

   2                         Risk Management

   3             MS. ENGEL:  Good afternoon.  My name is

   4   Patti Engel, and I am here today to talk to you

   5   about the risk management program for Xyrem, which

   6   we call the Xyrem Success Program.

   7             [Slide]

   8             This program will ensure the responsible

   9   distribution of Xyrem, namely, to meet two goals.

  10   First, to ensure that patients who desperately need

  11   the medicine can get it.  Secondly, to keep this

  12   out of the hands of those people who might abuse

  13   it.

  14             [Slide]

  15             To develop this program we consulted

  16   broadly with a number of people interested in the

  17   issues not only germane to patients but also that

  18   of drug abuse.  As you can see, we spoke with drug

  19   diversion investigators, field law enforcement,

  20   forensics experts, toxicologists, pharmaceutical

  21   distribution experts, drug abuse trend experts.

  22             [Slide]

  23             Through those discussions we followed

  24   FDA's proposed risk management guideline, which is

  25   risk management through risk confrontation, in 
                                                                177

   1   essence egging the partners and the shareholders to

   2   not only identify the issues but also assess the

   3   risks, identify the options and select a strategy.

   4   The program that I am going to be sharing with you

   5   today is certainly a draft program that the company

   6   has designed after discussions with these numerous

   7   stakeholders.

   8             [Slide]

   9             This slide I show to you really to point

  10   out the standard route of distribution of a

  11   pharmaceutical product in our country today.  This

  12   includes not only commonly used medications like

  13   products for blood pressure control or products for

  14   arthritis, but also products under Schedule II,

  15   including such agents as amphetamines.  Typically,

  16   a product is manufactured and goes to a number of

  17   national, regional and local wholesalers,

  18   eventually getting to 63,000 retail drugstores

  19   around the country.  One can only imagine the

  20   number of loading docks, transport vehicles and

  21   hands that touch a pharmaceutical product in this

  22   traditional distribution system.

  23             [Slide]

  24             As we contemplated the distribution of

  25   Xyrem and how to do this responsibly to meet the 
                                                                178

   1   prior stated goals, we determined that a closed

   2   distribution system would best fit everyone's needs

   3   for this product.  The product is manufactured at

   4   one single manufacturing facility.  It is sent to

   5   one single national specialty pharmacy.  Eventually

   6   it goes by courier to patients with narcolepsy.

   7             [Slide]

   8             The benefits of this program are that not

   9   only is the product distributed from a central

  10   location, but all the controls and all the records

  11   are in one place.

  12             [Slide]

  13             So, how will this work?  Because a number

  14   of doctors prescribe medicines for narcolepsy, we

  15   will focus our promotional effects on those

  16   physicians.  They include such specialists as

  17   neurologists, pulmonologists, psychiatrists,

  18   internal medicine physicians and several primary

  19   specialties who practice sleep medicine.

  20             [Slide]

  21             Our small sales force will call on these

  22   physicians, communicating the clinical benefits of

  23   Xyrem in narcolepsy.  At those calls, the sales

  24   representatives will also review with each

  25   physician something that we call the physician 
                                                                179

   1   Success Program.  I will go into the details of

   2   this program in a more in depth fashion in just a

   3   moment.  But it is important to know that each

   4   physician will sign that they have reviewed this

   5   program with the sales representative and

   6   understand the program.  I should also note that at

   7   no time will we embark upon physician sampling.

   8             [Slide]

   9             I promised to come back to the components

  10   of the physician Success Program.  I know that many

  11   of you received copies of this but I would like to

  12   highlight some of the main points.  First, because

  13   we know individuals all learn differently -- some

  14   by hearing, some by reading, other methods -- we

  15   have made this a multi-faceted program which

  16   includes videos, brochures, pamphlets that describe

  17   four main areas.

  18             The first is to highlight to physicians

  19   that the distribution process for Xyrem is

  20   different, that their patients won't be able to get

  21   this at the corner drugstore.  The second important

  22   issue that this binder points out to physicians is

  23   the dosing and administration of Xyrem.  The next

  24   important issue is that of home storage and secure

  25   handling.  The fourth is an important module that 
                                                                180

   1   we call "doctor be wary" which is an educational

   2   module that educates doctors about the ways that

   3   drugs are commonly diverted in this country so they

   4   can be aware of patients who are attempting to

   5   illegitimately get a prescription from them for

   6   this product.  Each of the kits will also contain a

   7   number of unique prescribing forms for Xyrem which

   8   will be necessary in order for the prescription to

   9   be filled.  This is, in essence, a special

  10   prescription form.  As well, contact information

  11   will be provided should the doctor have any

  12   questions at all about the program.

  13             [Slide]

  14             Once the physician decides to prescribe

  15   Xyrem the physician faxes this special prescription

  16   to the specialty pharmacy.  Now, I am going to come

  17   back to how this prescription is verified.  So, I

  18   will ask you to hold on that point for just one

  19   moment.  But, based on that prescription and based

  20   on the patient's geographic location, the pharmacy

  21   assigns that patient to a dedicated pharmacy team.

  22   So, each time that the patient deals with the

  23   system they are talking with the same pharmacist

  24   and the same reimbursement specialist.

  25             [Slide] 
                                                                181

   1             I mentioned that as the prescription comes

   2   to the specialty pharmacy there will be a number of

   3   checks to determine if the physician is, in fact,

   4   eligible to prescribe Xyrem.  We will be utilizing

   5   DEA's NTIS or National Technical Information

   6   Services database to ensure that each physician has

   7   an active valid medical license, and also to ensure

   8   that that physician has current prescribing

   9   privileges which allow him or her to prescribe

  10   Schedule III medications in this country.  As a

  11   backup check, the specialty pharmacy will also be

  12   checking with the appropriate state medical board

  13   to determine that there are no pending actions on

  14   the behalf of the state for that given physician.

  15             [Slide]

  16             As a secondary step, the specialty

  17   pharmacy will also do a check on the patient in

  18   essence.  What they will do is when that

  19   prescription comes in they will call the

  20   prescribing physician's office to determine that,

  21   in fact, that patient is real and a prescription

  22   has, in fact, been written for that patient.

  23             [Slide]

  24             Once insurance reimbursement is obtained,

  25   the specialty pharmacy contacts the patient, first, 
                                                                182

   1   to determine the patient or the patient designee's

   2   location and availability for shipment, and also to

   3   describe to them the contents of the shipment.  I

   4   will come back to the details of this in just a

   5   moment, but it is important that you know that each

   6   patient, when they get their first prescription of

   7   Xyrem will receive a multi-faceted educational

   8   program called the Xyrem patient Success Program,

   9   and I will come back to the details of that in just

  10   a moment.

  11             In that same shipment they will also

  12   receive their Xyrem, and that will look something

  13   like this, with child resistant closure not only on

  14   the primary container but also on the dosing cups

  15   which are provided by the company.

  16             [Slide]

  17             The shipment that goes to the patient is

  18   sent by a special system that has a special, unique

  19   tracking system called the Rapid Trac System.  this

  20   system will allow detailed real-time tracking of

  21   that package which is delivered only by the

  22   authorized signature.  If the patient or their

  23   designee is not available for receipt of the

  24   package at the time agreed upon with the specialty

  25   pharmacy, the package will be returned to the 
                                                                183

   1   specialty pharmacy after one delivery reattempt.

   2   So, a package will not sit on a delivery truck or

   3   in a hub for weeks at a time or anything like that.

   4   If the package is lost the system will allow an

   5   investigation to begin regarding the shipment's

   6   whereabouts at that point of loss.

   7             [Slide]

   8             I spoke a moment ago about the patient

   9   Success Program.  Again, this is a multi-faceted

  10   program which includes video, brochures and

  11   pamphlets which deal with a number of important

  12   issues for patients.  First addressed, of course,

  13   is the distribution process since it is so

  14   important that the patients understand that the

  15   only way they will get Xyrem is through the special

  16   pharmacy and not at their corner drugstore.

  17             There is information about Xyrem's dosing

  18   and administration because we feel that that is an

  19   important message to be delivered in an

  20   understandable and a very consistent manner.

  21             There is information on home storage and

  22   secure handling, and we also are very clear with

  23   patients about the criminal and civil penalties

  24   that the public law assigns to any illicit use of

  25   Xyrem.  So, if I were, as a valid narcolepsy 
                                                                184

   1   patient, to take my Xyrem prescription and use it

   2   to conduct a rape or in an assault situation, or if

   3   I were to sell it to someone for illicit use I

   4   would be penalized, I would be subject to C-I

   5   penalties.  The patient Success Program also

   6   includes contact information for the specialty

   7   pharmacy should the patient have any questions at

   8   all, and also reimbursement information.

   9             [Slide]

  10             After the Rapid Trac System shows that the

  11   package has been received by the patient, the

  12   specialty pharmacist will call the patient within

  13   24 hours not only to confirm receipt of that

  14   package but also to again reiterate certain

  15   important points with the patient.  Those include

  16   the penalties for illicit use of Xyrem; Xyrem's

  17   dosing and administration; home storage and secure

  18   handling.  The pharmacist will also take the

  19   opportunity to discuss with the patient the

  20   child-resistant features on the primary container

  21   as well as the child-resistant features on the

  22   dosing cups that are provided.

  23             [Slide]

  24             The central data repository designed for

  25   Xyrem really allows for identification of a number 
                                                                185

   1   of unusual types of behavior, including any

   2   duplicate prescriptions, any attempts of

   3   over-prescribing, or any attempts at over-use by

   4   patients.  The benefit here is that that

   5   information is available prior to filling the

   6   prescription so appropriate pharmacist intervention

   7   can occur.

   8             [Slide]

   9             As you can see, the Xyrem Success Program

  10   is a comprehensive program which is designed to

  11   responsibly distribute this important medication in

  12   order that patients who need it have it available,

  13   and it is inaccessible for those who might abuse

  14   it.  Thank you.

  15             DR. REARDAN:  Dr. Kawas, that completes

  16   our presentation and we will turn this back over to

  17   you.

  18             DR. KAWAS:  Thank you very much.  I want

  19   to thank all of you for all of your nice

  20   presentations but, rest assured, you will have more

  21   questions in the afternoon.  We are running quite

  22   late so we are going to cut lunch a little short

  23   and we will plan on reconvening at 1:30, at which

  24   time the public hearing component of this meeting

  25   will happen. 
                                                                186

   1             [Whereupon, at 12:50 p.m., the proceedings

   2   were recessed for lunch, to resume at 1:30 p.m.] 
                                                                187

   1             A F T E R N O O N  P R O C E E D I N G S

   2             DR. KAWAS:  We will reconvene the meeting

   3   of the Peripheral and Central Nervous System

   4   Advisory Committee discussing Xyrem.  We are now in

   5   the open public hearing portion of this meeting,

   6   and we have quite a few people that we will be

   7   hearing from and additional people who want to add

   8   to the list.  I would like to ask all of the

   9   speakers to please do their best -- not their best,

  10   you must stay to five minutes.  You will have a

  11   one-minute warning sign with your timer.  If you go

  12   over, please don't take it personally but you might

  13   hear my voice ending your part for the meeting.

  14   This is in order to allow us to hear from everybody

  15   who wants to speak, as well as to get onto the

  16   deliberations of this committee.  The first speaker

  17   in the public forum is Sharon Fitzgerald of

  18   Littleton, Colorado.

  19                       Open Public Hearing

  20             MS. FITZGERALD:  Good afternoon.  I am

  21   Sharon Fitzgerald from Littleton, Colorado, and I

  22   am a narcoleptic.  I am a volunteer member for the

  23   Orphan Medical Patient Council and the Narcolepsy

  24   Network is paying for my travel and my hotel to

  25   allow me the privilege of speaking with you today.  
                                                                188

   1   Five minutes isn't long enough.  I have provided a

   2   longer version for you to read.  Please, please

   3   read it.  It explains my experiences with the five

   4   major symptoms of narcolepsy and how Xyrem gave

   5   back my American dream, the ability to pursue

   6   happiness without stumbling on the way when it gets

   7   tough, and without literally falling on my face

   8   when the goal of happiness is reached.

   9             I have had daytime sleepiness since 1969.

  10   It threatened my ability to be a good mother and

  11   protect my children, and it trapped me in a series

  12   of entry level jobs.  Not knowing it had a name, I

  13   tried to hide my problem from employers and I hid

  14   in restrooms for many years for 15-minute naps at

  15   unpredictable times lots of the time.

  16             My symptoms dramatically increased and

  17   worsened in 1977 when I was in law school.  I was

  18   raising school age kids on my own, being widowed at

  19   the age of 32.  In daytime, against my will, I took

  20   naps in my classes, going instantly from

  21   consciousness to dream state sleep, the switch

  22   being so quick that I actually wrote words from my

  23   dreams in my class notes about things like my

  24   mother and helicopters, and wondered where they

  25   came from when I read them.  These were usually 
                                                                189

   1   followed by a mark where I dropped my pen as I

   2   stopped writing, and that would startle me into

   3   wakefulness and I would stay awake for a while and

   4   take more notes.

   5             Going to sleep nearly every night, my mind

   6   created vivid illusions of my very worst fears,

   7   often a murderous rapist breaking into my house

   8   from behind wherever I was sitting or lying.  My

   9   knowledge of where I was, was accurate.  I could

  10   not scream.  I was paralyzed and I couldn't turn

  11   around to defend myself.  These are called, as you

  12   know, hypnagogic hallucinations.  I didn't know

  13   that at the time.

  14             At the same time, the symptoms of

  15   nighttime wakefulness became more severe.  I

  16   experienced long hours of anxiously lying awake,

  17   punctuated by times of intense dreaming so real and

  18   so vivid that in the daytime I couldn't remember

  19   whether events I remembered were real or dreamed.

  20   You may understand that I feared for my sanity, and

  21   this is when I sought medical help.

  22             I was my doctor's first experience with

  23   narcolepsy.  It took a very long time for him to

  24   find a diagnosis.  When he did, it was because of

  25   my mild cataplexy and he found the diagnosis an 
                                                                190

   1   announced that was the good news because the bad

   2   news was there was no treatment.  I self-medicated

   3   for years with Sudafed and coffee.

   4             With determination -- if you knew me you

   5   would know about it -- and special accommodations

   6   from the university I actually finally managed to

   7   graduate from law school, but I turned down the

   8   dream job that was offered, clerking for a district

   9   court judge, because I feared I would fall asleep

  10   in front of the courtroom.  He told me our first

  11   case would be about two nuns who had been brutally

  12   murdered and I feared I might experience cataplexy.

  13             By this time my cataplexy had increased to

  14   the point that all my facial muscles would relax

  15   and my speech would become momentarily slurred.  It

  16   passed so quickly that I couldn't hide it.  I was a

  17   sole practitioner.  I couldn't bill enough hours to

  18   earn a living.  I took Ritalin; I took

  19   antidepressants unsuccessfully.  I found a job with

  20   the State of Colorado.  It didn't require my legal

  21   expertise but I got lucky, I found out about the

  22   trials.  I had rebound cataplexy, like what they

  23   showed you in the pictures, and it was horrendous

  24   for several weeks, waiting to be on Xyrem and my

  25   secret was brought out at work.  But they didn't 
                                                                191

   1   fire me because I told them I was going on Xyrem.

   2             Its effects were immediate and dramatic.

   3   I have experienced no side effects.  I get good

   4   restful sleep.  I awaken refreshed.  I stay

   5   reliably awake at work with fewer stimulants and I

   6   don't fall down.  My supervisors noticed my

   7   increased wakefulness and rewarded it with

   8   committee chairmanships and memberships and, in

   9   1999, a promotion.  In 2000, January 1, I became an

  10   administrative law judge for the Division of

  11   Workers Compensation in the Colorado Department of

  12   Labor and Employment.  It is responsible; it is

  13   emotional.  I can do it.  My colleagues know I have

  14   narcolepsy and they know that with Xyrem it doesn't

  15   interfere with my job performance.  For years I was

  16   unable to safely carry my children or

  17   grandchildren.  I carried my newborn to his first

  18   examination and that is just the beginning of my

  19   story.

  20             DR. KAWAS:  Thank you, Ms. Fitzgerald.

  21   Next is Richard Gelula, the executive director of

  22   the National Sleep Foundation.

  23             MR. GELULA:  Thank you.  The National

  24   Sleep Foundation is an eleven-year old organization

  25   that was developed by the American Academy of Sleep 
                                                                192

   1   Medicine to educate the public about sleep and

   2   sleep disorders, and our leadership has always been

   3   drawn from the top tier of sleep experts, sleep

   4   scientists and sleep physicians.  We are

   5   independent.  We raise our money in a variety of

   6   ways including government grants, corporate grants,

   7   and many memberships, individual contributions that

   8   have played a major part, particularly from people

   9   and families affected by sleep disorders.  Our

  10   funding from Orphan Medical for the last two years

  11   has been a total of 160,000 out of a two-year total

  12   of about 5 million.  Our budget is about 2.5

  13   million a year.  And, their support has gone to

  14   broad activities -- sponsorship for National Sleep

  15   Awareness Week where they join in with other

  16   sponsors, and there is no name or brand specific

  17   recognition or benefit for them.  So, I wanted to

  18   point that out.

  19             The Foundation is qualified to address

  20   this and our interest is due to the fact that we

  21   have invested about a million dollars in narcolepsy

  22   research, including center grants for the genetic

  23   research done at Stanford.  We presently have one

  24   of our postgraduate fellowships at UCLA studying

  25   the neurophysiology of cataplexy.  We also have 
                                                                193

   1   established the National Narcolepsy Registry which

   2   has registered to serum DNA registry with about 700

   3   patients and family members registered.  That is

   4   managed at Montefiore Hospital in the Bronx, and it

   5   has been a resource for seven scientific

   6   investigations.

   7             To summarize the position of the National

   8   Sleep Foundation on sodium oxybate, the National

   9   Sleep Foundation calls upon this panel to fully

  10   consider the safety and efficacy of sodium oxybate

  11   for the treatment of narcolepsy and cataplexy, and

  12   to do so in a comprehensive context that fully

  13   recognizes the extreme psychological, emotional,

  14   economic, social and health toll that this

  15   affliction exacts from people who suffer from it.

  16             NSF does not presume to second-guess the

  17   evidence that has been submitted about the safety

  18   and efficacy of this drug, but it goes on record to

  19   say that such considerations should only pertain to

  20   affected patients and not other societal

  21   considerations.  It is safe and effective for

  22   people with narcolepsy, like the speaker before me.

  23   Sodium oxybate should be made readily available to

  24   them.  Any concern for illicit use should be

  25   addressed strongly through other channels, such as 
                                                                194

   1   law enforcement and professional licensing.  The

   2   fact that narcolepsy is an orphan disease, for

   3   which only one medication is currently indicated,

   4   would be weighed as a factor in favor of approval

   5   of sodium oxybate because it is likely that

   6   availability of an approved drug will foster faster

   7   diagnosis and more appropriate treatment, and will

   8   also -- and we think this is very important --

   9   stabilize patients who usually first experience the

  10   dreadful effects of narcolepsy and cataplexy during

  11   their developmental years, before the completion of

  12   their educations and initiations of a career.

  13             I would like to summarize a few key

  14   background points.  Narcolepsy and all of its

  15   primary characteristics, including cataplexy, are

  16   truly life-altering afflictions, a term that best

  17   connotes the life-diminishing and debilitating

  18   aspects of this disabling disease.  Untreated,

  19   narcolepsy not only causes vivid nightmares and

  20   undermines the safe and secure feeling that most

  21   people get when they go to sleep, but it makes

  22   daily existence, both objectively and subjectively,

  23   frightening and strange, even alienating to the

  24   self and others.  It makes the well-controlled

  25   process that routinely governs the existence for 
                                                                195

   1   almost all other humans, the alternating cycle of

   2   sleep and alertness, into something entirely

   3   different, an uncontrollable process where the

   4   maintenance of conscious attention becomes random

   5   and cannot be sustained or relied upon.  Both the

   6   phenomenon of overwhelming sleep attacks and the

   7   muscular weakness and collapse that occur with

   8   cataplectic attacks undermine the sense of

   9   predictability and confidence required to fully

  10   develop and function in our contemporary world.

  11             But a true understanding of narcolepsy

  12   goes beyond physiology.  The cumulative effects of

  13   the distinctive daytime and nighttime

  14   characteristics of this disease are truly

  15   traumatic.  They not only disrupt; they undermine

  16   and frighten and change the core experience of the

  17   individual, exacting a toll that ranges from

  18   difficulty coping and functioning to total

  19   disability.

  20             I think some key characteristics that

  21   should be taken into consideration are that

  22   narcolepsy is not well understood or accepted.

  23   People who suffer from this suffer alone.  They

  24   don't have generally the benefit of support groups,

  25   even though there is a fine support organization 
                                                                196

   1   out there, but the people are just spread out.

   2   There isn't enough concentration.  Most people with

   3   narcolepsy do not have a relative with the disease

   4   such that it is even strange to them.  People

   5   suffer a double blow because it is thought their

   6   sleepiness is volitional and a sign of laziness.

   7             Thus, I think it should come as no

   8   surprise that people with narcolepsy suffer from a

   9   high rate of depression.  It has been estimated

  10   from 30-70 percent in various studies.  The good

  11   news is that in one study health quality of life

  12   was improved through effective administration and

  13   medical treatment, and I think that would pertain

  14   as well to sodium oxybate.

  15             In sum, the National Sleep Foundation

  16   believes that narcolepsy exacts an unusual and

  17   cruel toll.  We really call upon this panel to

  18   continue to do the professional job that brought

  19   you here today and fully consider the personal,

  20   psychological, emotional and human aspects of this

  21   disease and the great need for an effective

  22   medication.  Thank you.

  23             DR. KAWAS:  Thank you, Mr. Gelula.  The

  24   next speaker is Ms. Abbey Meyers, who is president

  25   of the National Organization for Rare Disorders, 
                                                                197

   1   Inc.

   2             MS. MEYERS:  The National Organization for

   3   Rare Disorders, which is known as NORD, came

   4   together initially because voluntary agencies for

   5   many rare diseases worked together to pass the

   6   Orphan Drug Act.  So, we are the orphan drug folks

   7   who work to monitor the development of these drugs.

   8             I have several conflicts of interest with

   9   this drug because for 20 years I begged practically

  10   every company I ever met to pick up this drug and

  11   to adopt it.  It is a 20-year saga.  And, I wrote

  12   something for you that you will be able to read

  13   about the history of development of the drug.

  14             Also, about a year ago I bought some stock

  15   in this company.  If I wanted to make money I would

  16   have put it in Merck, but the idea with the drugs

  17   that they are developing is I feel I have to make

  18   my own personal investment in the survival of the

  19   company.

  20             For this drug FDA, rightfully, has asked

  21   for a risk management program, and there are

  22   several really good models to look at, most

  23   notably, I would like you to remember when you are

  24   discussing the risk management what happened with

  25   Clozaril because when Clozaril first got on the 
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   1   market with the drug for schizophrenia, they had a

   2   very stringent distribution program, and they were

   3   sued by 30 states, attorneys general, because the

   4   laws in those states said that you could not

   5   restrict the distribution.  In the settlement of

   6   that case, the federal court assigned us, NORD,

   7   with the task of distributing the drug to the

   8   people in this class action settlement.

   9             So, I am very sensitive to what happens.

  10   FDA approved Clozaril's distribution program but

  11   then the law said that they couldn't do it.  So,

  12   people really want the freedom to be able to get

  13   the drug when they want it, when their doctor

  14   prescribes it.

  15             The other program you should look at is

  16   thalidomide because it is an extraordinarily

  17   important drug, again very orphan.  Nobody wanted

  18   to go near it because of the liability problem.

  19   But they have a wonderful distribution program and

  20   I think it should be a good model for the field

  21   when there are drugs with specific dangers

  22   involved.

  23             I also want to give you several cautions.

  24   Don't make the distribution too restrictive.  For

  25   example, don't allow just certain specialists to 
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   1   prescribe it because people with narcolepsy have a

   2   great deal of travel problems.  Many of them don't

   3   have driver's licenses in many states.  They may

   4   hold on to their driver's license but actually if

   5   it was ever reported to the state that they had

   6   narcolepsy they would lose it.  It is just like

   7   epilepsy.  So, you have to be sensitive to that.

   8             There are many current problems with

   9   Ritalin and Dexedrine and the amphetamines that

  10   they are using because the government limits the

  11   amount of manufacture every year.  So, at the end

  12   of the year they run out of drug and there are

  13   times when they just aren't able to fill their

  14   prescriptions and they can't order it by mail order

  15   because it is a controlled substance.  So, these

  16   people have suffered so tremendously because of

  17   these distribution problems.  With those drugs,

  18   pharmacies don't stock a sufficient amount and they

  19   will only dispense one month at a time.

  20             Don't require a distribution program that

  21   is going to cause legal problems.  So, ask yourself

  22   that, whether the program that has been designed by

  23   Orphan Medical could be loosened up a bit.

  24             The other thing goes back to what you were

  25   talking about this morning, labeling.  You know, 
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   1   does this drug help with daytime sleepiness, etc.?

   2   I want to caution you that if you label this drug

   3   just for cataplexy with no effect on daytime

   4   sleepiness, there are a lot of insurance companies

   5   that are not going to reimburse for it.  So,

   6   labeling on a drug is extraordinarily important to

   7   patients because of the managed care insurance

   8   system.  So, try to be as liberal as you can on

   9   that, thinking about whether insurance companies

  10   are going to say no, except to just people with a

  11   particular type of narcolepsy.

  12             Also, recognize that it is a unique

  13   disorder that is just as crippling as epilepsy, and

  14   that these people are already paying a very heavy

  15   price because of the problems they have with their

  16   current drugs.

  17             Illegal use has to be handled, which I

  18   know that you are going to do, but you must pay

  19   attention to the valid use of this drug.  Thank

  20   you.

  21             DR. KAWAS:  Thank you, Ms. Meyers.  You

  22   are the first one who hasn't used all of your time

  23   and that is greatly appreciated.  The next one is

  24   Robert L. Cloud, from the Narcolepsy Network.

  25             MR. CLOUD:  Good afternoon, and I wish to 
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   1   thank the committee for the opportunity to address

   2   you on this issue.  My name is Bob Cloud, and I

   3   would like to briefly talk to you, first about my

   4   own long, personal use of Xyrem, and I will call it

   5   Xyrem not GHB or sodium oxybate and, secondly, my

   6   very serious concerns as director of Narcolepsy

   7   Network, which is a national non-profit, primarily

   8   patient organization.  In that capacity we have

   9   received funds, a minor amount of funds, perhaps

  10   ten percent of our revenues, from Orphan Medical

  11   over the last several years.

  12             First, my personal experience with Xyrem

  13   as a narcolepsy patient with cataplexy.  I am 57

  14   years old, married, have two adult children, and I

  15   am an attorney in private practice, primarily

  16   family, probate and criminal law which sometimes

  17   can be intense and have a few emotions attached to

  18   it.

  19             I believe I am the first American to have

  20   used Xyrem for narcolepsy, and I am probably the

  21   longest continuing user of Xyrem which now

  22   approaches 19 years every night without fail.  My

  23   narcolepsy/cataplexy symptoms began in the mid-30's

  24   and by age 39 included severe and recurring

  25   cataplexy together with excessive daytime 
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   1   sleepiness and sudden sleep attacks.  My cataplexy

   2   caused numerous daily episodes of complete body

   3   collapse, such that I couldn't leave my office or

   4   home without risk of harm to myself or others.

   5   Feeling any emotion, humor, anger or mere

   6   enthusiasm, would result in sudden immediate

   7   collapse.  I guess we are all ignorant of what

   8   diseases feel like that we don't have them, but my

   9   best description of the sudden collapse of

  10   cataplexy would be to imagine a puppet on strings

  11   and suddenly the strings, which are your muscle

  12   tone, are immediately let go and so you fall to the

  13   ground immediately, and your head comes down last

  14   and whips against whatever -- sidewalk or table

  15   corner or escalator or whatever might be there.  I

  16   have been rescued by police and emergency squads

  17   and life guards and well-meaning strangers and

  18   friends.

  19             Obviously no injury for me has been fatal

  20   because I am here, but unfortunately I do know

  21   others whose fall has occurred at the top of the

  22   stairs and they fell down backwards and killed

  23   themselves, and there are others that I don't know

  24   about.

  25             In 1982 my treating physician sent me to 
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   1   Sunnybrook Medical Center in Toronto, Canada to

   2   begin prescriptive use of Xyrem under the research

   3   being conducted by Dr. Mortimer Mamelak.  After

   4   three weeks I returned home and continued using

   5   Xyrem, always prescribed by my local physician

   6   under his own individual investigational new drug

   7   application.  My severe cataplexy symptoms

   8   disappeared almost overnight.  I was immediately

   9   able to return to my full-time law practice and I

  10   have continued to this day to use Xyrem under that

  11   individual application and subsequently in the

  12   clinical trials under the Orphan Medical

  13   application.  During these 19 years, I have never

  14   changed the dose.  I have never experienced

  15   tolerance.  I have never noted side effects.

  16   Simply stated, the drug is as safe and effective as

  17   it was on day one.  It is hard to imagine a

  18   pharmaceutical product having such a quick,

  19   complete, safe and enduring benefit.

  20             As director of Narcolepsy Network, I have

  21   said on a number of occasions that I think the

  22   greatest tragedy in the treatment of people with

  23   narcolepsy is that Xyrem or GHB has not been

  24   available so that other patients could benefit from

  25   it as I have.  Hopefully, this committee will 
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   1   remedy that.

   2             We are sensitive to the reports of

   3   injuries and deaths and other victimizations from

   4   the abuse of GHB and, as an organization, we work

   5   with law enforcement and community drug agencies to

   6   partake in their activities to limit that and

   7   correct that.  I think it is obvious that Orphan

   8   Medical is going above and beyond the call of duty

   9   to also contribute to restricting the unlawful use

  10   of GHB.

  11             In closing, I submit that our concern for

  12   patients with narcolepsy should receive your

  13   highest considerations so that people can

  14   rediscover their economic and particularly their

  15   family lives and avoid disability.  Thank you.

  16             DR. KAWAS:  Thank you, Mr. Cloud.  The

  17   next speaker is Cindy Pekarick from Pennsylvania.

  18             MS. PEKARICK:  Hi.  My name is Cindy

  19   Pekarick, and I am here today to tell you how GHB

  20   killed my daughter.  In October of 1998, my

  21   daughter Nicole, a college student and gym

  22   enthusiast met a new boyfriend who introduced her

  23   to a product called Renewtrient.  In November she

  24   researched the product over the Internet and

  25   received only positive information.  She could take 
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   1   it before bedtime and wake up in only four hours

   2   feeling refreshed, well-rested, and all her muscles

   3   would be completely recovered and ready for another

   4   workout.

   5             In December I found out she was taking

   6   this supplement.  I didn't believe the promises

   7   made by the advertisers.  Arguments ensued and she

   8   promised she wouldn't drink it anymore.  She was

   9   away at school from mid-January until April.

  10             In April she returned home.  She was

  11   behind in all her bills.  She was black and blue on

  12   her arms and legs.  She stopped attending classes,

  13   and she kept losing things.  In May I discovered

  14   she had essentially dropped out of school.

  15             In June I could see mild changes in her

  16   behavior.  She began taking power naps, as she

  17   called them.  She would sleep three hours in the

  18   middle of the day and get up at four o'clock and go

  19   to work.  She continued losing things and having

  20   difficulty paying her bills.  I searched her room

  21   and car but found no evidence of substance abuse.

  22             By July, my younger daughter, Noelle,

  23   informed me that Nicole was having problems.  She

  24   said, "mom, she isn't taking anything bad or

  25   illegal.  She takes a muscle supplement that 
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   1   doesn't agree with her.  Sometimes she has bad

   2   reactions and she doesn't even know it.  She

   3   embarrasses herself and me when she acts weird and

   4   then goes to sleep.  When she awakes she never

   5   remembers anything that she did.  She started

   6   taking it once in a while so she could go to sleep

   7   right away after work when she got home.  Then she

   8   started using it more often.  It disgusts me to see

   9   her out of control."

  10             It was at this time I discovered Nicole

  11   had been taking GHB since November.  I then began

  12   my own search over the Internet for more accurate

  13   information.  In August, Nicole was found having a

  14   seizure in a public bathroom.  She had urinated and

  15   defecated on herself while pulling at her clothes

  16   and hair and flailing her arms.  She was rushed to

  17   the hospital where we arrived to find her

  18   unconscious, intubated, with her arms, legs and

  19   waist strapped to the bed.  They claimed her

  20   seizure was violent.  She barely had a pulse when

  21   they found her.

  22             It was at this time I knew my daughter was

  23   addicted to whatever she was taking.  There is

  24   absolutely no other reason why a young, bright,

  25   healthy woman would take a supplement that was 
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   1   harmful.  I begged the doctors to transfer her to a

   2   treatment center for chemical dependency, but they

   3   said they wouldn't do it without the patient's

   4   permission.  She was clueless as to why she was

   5   hospitalized and she had no recall of anything that

   6   happened to her.  She was discharged.

   7             In September, Nicole, sweating profusely,

   8   with a red face and shaking hands while crying

   9   said, "mom, I have to talk to you.  I'm really

  10   scared.  I have a problem.  I can't stop drinking

  11   it."  I stood up, wrapped my arms around her and

  12   hugged her as hard as I could.  I told her that she

  13   was on her way to getting better, that

  14   acknowledging that "g" had a hold on her was a step

  15   in healing.

  16             On Monday morning, on her way to the

  17   treatment center, Nicole refused to go in.  She

  18   claimed that "g" wasn't addictive; that she did the

  19   research and she was just having reactions to it.

  20   She said she was now in control of her life and

  21   future.  She stayed in counseling and, by the end

  22   of September, Nicole had applied, transferred, and

  23   was accepted at the university.  She was excited.

  24   Things seemed okay on the surface but she was

  25   hiding tremors, hallucinations and insomnia.  She 
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   1   went days without sleeping but never told me.

   2             On October 3, 1999 at 2:00 p.m. she said

   3   she needed to take a nap before she went to work

   4   since she hadn't slept the night before.  She set

   5   the alarm for 4:00 p.m. but she never heard it.

   6   She was in her final sleep.  My firstborn child was

   7   found in bed, blue, at 6:00 p.m.  We found a bottle

   8   of GHB in the trunk of her car.  The autopsy

   9   revealed she had GHB and GBL in her system at the

  10   time of her death.  No other chemicals were found.

  11             Nicole was an honor student, captain of

  12   two varsity teams and graduated third in her class.

  13   For her undergraduate studies she majored in

  14   biology, with a plan to major in engineering for

  15   her master's degree.  Her ultimate goal was to

  16   become a biomedical engineer.  She wanted to be

  17   able to design body parts to help extend people's

  18   lives.  She understood that to function well, one

  19   had to be healthy.  She was a loving, sensitive,

  20   caring and intelligent woman.  Her only fault was

  21   that she was naive.  Thank you.

  22             DR. KAWAS:  Thank you, Mrs. Pekarick.  The

  23   next speaker is Eric Strain.  Doctor Strain is from

  24   the College on Problems of Drug Dependence.

  25             DR. STRAIN:  Thank you.  I would like to 
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   1   thank the FDA and the members of the Peripheral and

   2   Central Nervous System Drug Advisory Committee for

   3   providing me the opportunity to speak.  My name is

   4   Eric Strain.  I am a professor in the Department of

   5   Psychiatry at Johns Hopkins University School of

   6   Medicine.  I am a board-certified psychiatrist with

   7   qualifications in addiction psychiatry, and I am

   8   here today representing the College on Problems of

   9   Drug Dependence, CPDD.

  10             The College is the leading organization of

  11   drug abuse scientists in the United States.  I am

  12   also the former chairman of the FDA's Drug Abuse

  13   Advisory Committee.  I have sponsored my own travel

  14   to today's meeting, and I have no relationship with

  15   Orphan or other pharmaceutical companies that make

  16   narcolepsy products.

  17             There are two point that I would like to

  18   make during these brief comments.  The first is

  19   that the College on Problems of Drug Dependence

  20   would like to emphasize the importance of

  21   science-based assessments of new medications,

  22   especially as they relate to issues such as abuse

  23   liability evaluation and safety of abused products.

  24   The College wishes to stress the long history that

  25   has led to the establishment of reliable and valid 
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   1   methods for determining abuse potential.  This work

   2   includes both preclinical as well as clinical

   3   studies.  Several academic medical centers contain

   4   rich experience in this area of research.  Methods

   5   have been well tested, and outcomes from previous

   6   studies have helped inform and guide agencies such

   7   as the FDA in making determinations regarding abuse

   8   potential, therapeutic efficacy, and safety of new

   9   medications.

  10             CPDD has played a key role in such

  11   matters, as its members are the primary group that

  12   have conducted such studies.  The College wishes to

  13   strongly and forcefully advocate that decisions

  14   made by the FDA grow out of and be based upon

  15   well-conducted research, and whenever possible

  16   decisions should be derived from well-controlled

  17   studies and data driven.  In order to achieve such

  18   goals, advice on substance abuse related matters

  19   should be solicited from experts in the field.

  20             The second point I would like to make has

  21   to do with the Drug Abuse Advisory Committee.  As

  22   the former, and the last chairman of this advisory

  23   committee of the FDA, I believe it is important for

  24   me to comment upon its termination.  The Drug Abuse

  25   Advisory Committee has been dissolved by the FDA, 
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   1   and in the process the FDA has lost an important

   2   resource that can inform decisions regarding

   3   substance abuse.  To my knowledge, today's meeting

   4   is the first FDA advisory committee meeting since

   5   this termination where issues of drug abuse are an

   6   important element in your discussions.

   7             I am pleased to see that there are several

   8   drug abuse experts represented here today, however,

   9   I am concerned that the numbers do not allow the

  10   breadth of expertise that would have been found on

  11   the DAAC.  Such breadth is essential to fully

  12   consider all of the issues involved in advising the

  13   FDA on the abuse potential of new medications, the

  14   extent of the public health consequences of such

  15   abuse, additional data that the FDA should require

  16   companies provide, and recommendations regarding

  17   post-marketing surveillance.

  18             The College is particularly concerned that

  19   comparable experience and knowledge brought to the

  20   Drug Abuse Advisory Committee by experts in the

  21   drug abuse field is no longer readily available to

  22   the FDA.  In my experience as chairman of the

  23   committee, I was able to witness firsthand on

  24   repeated occasions the value of having a group of

  25   scientists and clinicians who could provide 
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   1   informed knowledge and experience to the FDA on

   2   matters such as those that appear to be on today's

   3   agenda.

   4             The loss of the DACC to the FDA is

   5   significant and substantial, and adequate

   6   representation of drug abuse issues on other

   7   advisory committees needs to be clearly

   8   demonstrated by the FDA.  I speak on behalf of the

   9   College in expressing the College's continued

  10   concern regarding the dissolving of this advisory

  11   committee.  Given the tragic consequences of drug

  12   abuse to our society, as exemplified by the

  13   previous speaker, its prevalence and the growing

  14   body of medications for the treatment of substance

  15   abuse disorders, it is particularly concerning that

  16   the FDA has decided to terminate this particular

  17   advisory committee.

  18             Again, I wish to thank the FDA and this

  19   advisory committee for allowing me to make these

  20   comments today.  The hope of the College is that

  21   these companies will spur tangible demonstration of

  22   FDA's commitment to having adequate outside input

  23   by experts in the drug abuse field in the advisory

  24   committee process either through the renewal of the

  25   Drug Abuse Advisory Committee or through adequate 
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   1   and substantial representation by drug abuse

   2   experts on other advisory committees where issues

   3   of drug abuse may be of substantial importance.

   4   Thank you.

   5             DR. KAWAS:  Thank you, Dr. Strain.  The

   6   next speaker is Deborah Zvorsec.  Dr. Zvorsec is

   7   from Hennepin County Medical Center in Minnesota.

   8             DR. ZVORSEC:  Thank you very much.  My

   9   research is in the area of gamma hydroxybutyrate

  10   abuse toxicity, addition and withdrawal.  Dr. Steve

  11   Smith and I, with others, published a case series

  12   in Morbidity and Mortality Weekly Report in

  13   February of '99 that described adverse events due

  14   to ingestion of dietary supplements containing GBL,

  15   GHB precursor.  I was the lead author of a case

  16   series of 1,4 butanediol toxicity that was

  17   published in The New England Journal of Medicine in

  18   January 2001.  These toxicity episodes included two

  19   deaths that occurred with no co-intoxicants and no

  20   evidence of aspiration or asphyxiation or

  21   adulterants.

  22             I will focus today on GHB addiction.  In

  23   the course of our work, Dr. Smith's and my name

  24   were listed on the project GHB help site.  We

  25   received calls from over 40 addicted patients from 
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   1   25 states, and have treated an additional 5 cases

   2   of inpatient withdrawal at HCMC in Minneapolis.

   3             The vast majority of these addicted people

   4   began using GHB to treat insomnia, anxiety,

   5   depression, chemical dependence or for

   6   body-building purposes, as recommended by

   7   marketers, websites and fringe pro-GHB physicians.

   8   Many, indeed, began with GHB, continued with GHB

   9   and never used any of the dietary supplement

  10   analogs.  Our patients began with small doses,

  11   often only at night, and discovered that it made

  12   them feel good; increased dosing frequency and, as

  13   tolerance developed, needed more GHB in order to

  14   feel good.  Within months, they were taking GHB

  15   every one to three hours around the clock to avoid

  16   withdrawal symptoms.  By the time they realized

  17   that they might be physically dependent, attempts

  18   to abstain resulted in severe anxiety, insomnia,

  19   panic attacks and hallucinations.

  20             Their addiction destroyed their lives.

  21   They lost their spouses.  They lost access to their

  22   children, their jobs.  They acquired tremendous

  23   debt to support their habit.  They became comatose

  24   while driving and crashed their cars, frequently on

  25   multiple occasions.  They called us in absolute 
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   1   desperation.  Their detox was frequently similar to

   2   the worst cases of delirium tremens, requiring

   3   large and often massive doses of sedatives, often

   4   with intubation.

   5             Almost all patients suffered weeks or

   6   months of profound depression and anxiety after

   7   detox, and some also experienced muscle twitching

   8   and tremors.  Of the over 40 patients we have

   9   worked with, only a scant handful have remained

  10   GHB-free, frequently despite CD treatment.  Many

  11   have detox'd numerous times but continue to

  12   relapse, sometimes within hours of discharge from

  13   treatment.  Unfortunately, many never lost faith in

  14   GHB and continued to be convinced that they could

  15   get back on it and use it responsibly.  They

  16   continue to argue its health benefits.

  17             One of our patients was a 50-year old

  18   businessman with his own business who began using

  19   GHB, not an analog, five years ago, initially for

  20   body-building purposes.  Within months he had

  21   increased his dosing to around the clock.  His life

  22   was entirely controlled by the need to have GHB

  23   with him at all times.  He tried numerous times to

  24   quit.  His wife was unaware of his addiction.  She

  25   described witnessing frequent frightening hypnotic 
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   1   states, punctuated with clonic movements.  She

   2   believed that his frequent states of apparent

   3   somnambulism were due to a sleep disorder but

   4   despaired when a sleep specialist could not cure

   5   him.  This woman is a very bright professional who

   6   was totally unaware of GHB, as is the case with

   7   many family members.  It was only on the morning of

   8   his admission that she learned the truth.  After

   9   six days of detox he was through the worse and

  10   appeared to be on the road to recovery.

  11   Psychiatrists treated him with sleeping meds and

  12   antidepressants, but within three days he was using

  13   GHB again to control anxiety attacks and

  14   depression.

  15             GHB is perhaps the most addictive drug

  16   ever abused.  Experienced drug users describe a

  17   euphoria that surpasses that of any other drug.

  18   Availability of off-label prescription presents

  19   profound personal and public health risks.  The

  20   fringe physicians who now promote GHB will be

  21   joined by thousands of mainstream physicians with

  22   the approval of the FDA.  The majority of

  23   physicians are ignorant of the diverse health risks

  24   of GHB, as are toxicologists and law enforcement

  25   officials.  Users will seek Xyrem from physicians 
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   1   who don't recognize sodium oxybate as GHB and are

   2   unfamiliar with the health risks.  Patients will

   3   obtain prescriptions for sleep disorders, also for

   4   insomnia, depression, anxiety, treatment of alcohol

   5   and drug dependence and other conditions for which

   6   it has been touted.

   7             We know that addicts often use GHB and its

   8   analogs interchangeably.  Their compound of choice

   9   is dependent on access, determined by cost,

  10   perceived quality, ease of procurement.  Clinical

  11   literature reports one user who spent $200 per day.

  12   That comes to $70,000 per year.  Our patients

  13   report ingestion of up to a bottle every one to two

  14   days, coming to $11,000 to $36,000 per year.  A

  15   Xyrem prescription will be a bargain for such

  16   users, who will then avoid the high prices, erratic

  17   availability and risks of supplement and solvent

  18   purchase.  We know that many people are afraid to

  19   buy or make their own GHB due to risks of

  20   contamination or errors of production.  Xyrem, a

  21   pharmaceutical product of controlled quality,

  22   available by legal prescription, and with very

  23   little risk if found in their possession, will be

  24   very attractive.  We know that users are watching

  25   for the release of Xyrem.  Recreational drug sites 
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   1   post links to narcolepsy sites and publications

   2   about Xyrem.  One hotyellow98.com, for example,

   3   instructs users "click here to find out when GHB

   4   will be released under the trade name of Xyrem."

   5             DR. KAWAS:  Your time is up, Dr. Zvorsec.

   6   Please finish.  Thank you very much, Dr. Zvorsec.

   7   Our nest speaker is Trinka Porrata of California.

   8             MS. PORRATA:  I wish I had time to tell

   9   you the stories of 200 dead people that I know of,

  10   hundreds of rape victims and thousands of GHB

  11   overdoses, and About Caleb Shortridge, to whom our

  12   website www.projectghb.org is dedicated, about

  13   Matthew Coda and Joshua Parks to whom our GHB

  14   addiction hotline is dedicated.  I wish I could

  15   tell you about Ben Croman, Mike Fox, Tyler Johnson

  16   and other young men from New Zealand to Sweden who

  17   either have or are right now considering suicide

  18   because of the withdrawal from this drug; about

  19   more than 300 people I personally know about who

  20   are horribly addicted to GHB, and who could each

  21   name at least one dozen people more just like them.

  22             I have lived and breathed GHB since June

  23   of 1996 when I was first assigned to handle it for

  24   the LAPD.  Four young men collapsed.  Two literally

  25   died and were brought back to life by the 
                                                                219

   1   paramedics.  One thing was clear, people were dying

   2   from GHB and it was being missed.  It has been a

   3   heartbreaking five years, mixed with the privilege

   4   of learning more and teaching others to recognize

   5   the rape, overdose and deaths and getting rape

   6   victims into treatment and addicts help.  It has

   7   been very lonely at times when the agencies who

   8   should care haven't.

   9             DEA has reviewed and documented 71 deaths

  10   related to GHB but, basically, stopped counting

  11   once the drug was controlled, for obvious reasons.

  12   No one at FDA has ever expressed interest in these

  13   cases.  My database now includes over 200

  14   GHB-related deaths.  In fact, Robert McCormick, of

  15   the FDA's Orphan Drug Unit, told me emphatically he

  16   did not care how many people had died nor were

  17   addicted to it because he intended to approve it

  18   anyway.  Something is wrong with this picture.

  19   This is the most horrid drug I have encountered in

  20   25 years as a police officer.

  21             Much new has come to light during the past

  22   two years, none of it good.  Around the world

  23   countries are just now awakening to their problems

  24   with GHB.  Schedule IV by WHO is simply an

  25   awakening to the problem.  As we speak, countries 
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   1   are restricting it.  France is backing away.

   2   England is struggling with it.  Sweden has an

   3   unrecognized addiction and suicide problem.  New

   4   Zealand tried it as a prescription drug and now

   5   realizes they screwed up royally.  NIDA is

   6   currently releasing $2 million in research on this

   7   drug.  This is not a time to be pushing it forward

   8   on an unsuspecting American citizenry.

   9             You are here today to approve GHB,

  10   disguised as sodium oxybate, for use with

  11   narcolepsy/cataplexy.  Orphan's investors have been

  12   assured that you will do so.  When the last meeting

  13   was cancelled the stock dropped 30 percent in

  14   frustration over it.  You have not seen my

  15   videotapes of the day-to-day struggle of GHB

  16   addicts showing that GHB clearly gives previously

  17   healthy people symptoms that can only be described

  18   as temporary narcolepsy/cataplexy, just like the

  19   nine-year old you saw in the tape.  Their heads

  20   ricochet off board room tables around this country.

  21   They break mirrors.  They are cut up.  They crash

  22   cars.  They die and kill others.  It is destroying

  23   them.  Their wives are terrified of their husbands

  24   and have no idea what is happening.  They are

  25   locked in psychiatric wards because doctors and 
                                                                221

   1   emergency rooms do not recognize GHB psychotic

   2   episodes.

   3             There are no answers for them.  So, how

   4   can you approve this drug for use?  My addicts

   5   suffer alone, much as narcoleptic/cataplectic

   6   patients do.  Many do not have insurance or their

   7   insurance will not pay for this drug that is not

   8   recognized as an addictive drug.

   9             I am deeply concerned about the off-label

  10   use policy, enabling any doctor ultimately to

  11   prescribe it for any condition as I have no faith

  12   that its use will be limited to

  13   narcolepsy/cataplexy.  Look at the chatter around

  14   Orphan about fibromylagia, a condition with vague

  15   symptoms for which a drug seeker could easily get a

  16   prescription.  I know the vast majority of doctors

  17   do not realize that sodium oxybate, Xyrem, is GHB.

  18   I see no significant talk on the legitimate

  19   narcolepsy websites about it, but the message

  20   boards where GHB addicts hand out are buzzing.  In

  21   fact, the key figures in illegal GHB Internet sales

  22   were posting on the website www.xyrem.com.

  23             There is very little drug diversion

  24   enforcement in the United States.  Only a handful

  25   of agencies devote any time to this.  It is a small 
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   1   portion of DEA effort.  States are not prepared.

   2   They are not able to handle it.  Therefore,

   3   Orphan's proposed voluntary -- key word, voluntary

   4   -- promises of distribution are frightening.

   5             More importantly, the issue goes beyond

   6   diversion of Orphan's product to use of Orphan as a

   7   shield for possession of GHB in general.  It would

   8   be unrecognized by law enforcement.  Once in

   9   possession of that prescription and a bottle of

  10   Xyrem, the addict will be home free.  There is no

  11   field test kit.  All investigations of GHB are

  12   difficult.  Encountering a prescription, real or

  13   counterfeit, and a bottle of Xyrem, real or

  14   counterfeit, the officer would have zero ability to

  15   identify it -- none; zero; nada.

  16             To those who claim real GHB is safe and

  17   only street stuff is dangerous, poppycock.  My

  18   addicts have used everything from European

  19   pharmaceutical grade to bad stuff.  The

  20   unprecedented split scheduling of GHB was unwise

  21   and unenforceable.  We were forced to accept it.

  22   It was political, not science.  The people in the

  23   clinical trials have reason to obey; people in the

  24   streets do not.

  25             If I were to convey to you but one 
                                                                223

   1   thought, it would be that not enough information is

   2   known about GHB to approve it for any purpose at

   3   this time, and certainly not appropriate for

   4   off-label use.  Any approval at this point will

   5   trigger an absolute further epidemic of general

   6   abuse because you will create an aura that it is

   7   safe.  I ask you please table this issue until the

   8   NIDA research comes in.  Please do not make this

   9   mistake.

  10             DR. KAWAS:  Thank you, Ms. Porrata.  Our

  11   next speaker is Matt Speakman from West Virginia.

  12   While Mr. Speakman is coming up, I just want to

  13   remind everybody I am not trying to be mean; I am

  14   not trying to be difficult, but we are trying to

  15   keep the public hearing section of this meeting

  16   down to under two hours and that will only happen

  17   if everyone sticks to their five minutes.  We would

  18   like to let the committee get a chance to have some

  19   more discussions for everyone.  So, we greatly

  20   appreciate honoring the time constraints.  Mr.

  21   Speakman?

  22             MR. SPEAKMAN:  Thanks.  I just wanted to

  23   say thanks.  This is kind of a unique experience

  24   addressing doctors.  It is really cool.

  25             My name is Matt Speakman and I have 
                                                                224

   1   narcolepsy.  I will describe very briefly my

   2   experience.  I have cataplexy also.  My first

   3   experience was in chemistry class my junior year in

   4   high school.  The professor pulled out the liquid

   5   nitrogen experiment and was freezing flowers and

   6   flicking them, making them shatter.  I got very

   7   excited and he called us to the front of the room

   8   and, on my way up to the front of the room, I felt

   9   my legs start to buckle.  This was the first time

  10   anything like this had happened.  I had had trouble

  11   laughing a little bit because cataplexy sometimes

  12   has onset with laughter and emotion, but it wasn't

  13   very serious.

  14             I eventually just realized that I was

  15   going to fall.  So, I went back to my desk and

  16   collapsed on the desk with my face down in my arms,

  17   kind of draped over the thing.  It was humiliating.

  18   I couldn't move.  I was awake and aware and I could

  19   still hear the class kind of looking around and

  20   what-not.

  21             This started to happen more regularly and

  22   I started to fall asleep during class.  My grades

  23   started slipping.  I had to stop swimming.  I was

  24   on the swim team.  Falling asleep in the pool is

  25   kind of dangerous.  So, I quit doing that.  Most of 
                                                                225

   1   my teachers suspected drug use and I don't blame

   2   them.

   3             But I managed to get into the University

   4   of Kentucky and I went there for a year.  I was

   5   unable to meet friends and my grades weren't very

   6   good because I spent most of my time in my dorm

   7   room.  I didn't make it to class very often; very

   8   hard to wake up.  It is very hard to keep

   9   consistent notes when you are falling asleep all

  10   the time.

  11             My parents weren't happy so they found,

  12   you know, I needed some other treatment.  So, I

  13   went to a doctor in Cincinnati who was part of the

  14   study for what is now Xyrem.  That was four years

  15   ago, and I am taking it nightly unless I pull an

  16   all-night study session or something like that.  I

  17   don't have any withdrawal symptoms when I don't

  18   take it.  I don't have any side effects when I do

  19   take it.  I sleep well.  I have no cataplexy.  I am

  20   here speaking to you right now and I certainly

  21   wouldn't be doing this without this treatment.  I

  22   used to take stimulants and antidepressants to

  23   control the cataplexy, none of which worked; they

  24   just had nasty side effects.  It wasn't very good.

  25             Two weeks ago I graduated from West 
                                                                226

   1   Virginia University with honors.  I am looking for

   2   a job --

   3             [Laughter]

   4             -- and I am thinking about going to grad

   5   school.  That is definitely on the bill, but I am

   6   going to need some money first.  So, first things

   7   first.  Right?

   8             I understand all the concerns about the

   9   illicit use and that definitely needs to be

  10   addressed, but this drug is working for

  11   narcoleptics and, you know, I have a girlfriend and

  12   I have a life, and I live normally.  A couple of

  13   years ago I got a job as a full-time camp counselor

  14   in Maine; drove there myself; had no problems.  I

  15   read the review they gave me after the summer was

  16   up and it said, this guy has the energy of a small

  17   power plant, which was nice to hear after suffering

  18   from narcolepsy for a couple of years.  So, I am

  19   happy.  I am working on success, and I just wanted

  20   to thank you for giving me the time to speak with

  21   you and I hope you can work all this thing out, but

  22   my main point was that the drug is working for

  23   narcoleptics and I want to thank the Narcolepsy

  24   Network for paying for my travel arrangements and

  25   my hotel.  I am not in any way tied to Orphan 
                                                                227

   1   Medical.  I don't care who makes it.  I just want

   2   to let you guys know it is working.  Thank you.

   3             DR. KAWAS:  Thank you, Mr. Speakman.  The

   4   next speaker is Charles Cichon, president of the

   5   National Association of Drug Diversion

   6   Investigators.

   7             MR. CICHON:  Good afternoon and thank you.

   8   My name is Charlie Cichon.

   9             DR. KAWAS:  My apologies.

  10             MR. CICHON:  No apology.  The nuns never

  11   got it in grade school; nobody has ever got it

  12   right.  I go everywhere from Ceechon to Chicken.

  13             [Laughter]

  14             I have a 16-year background in law

  15   enforcement, but for the last 12 years I have

  16   worked in the health regulatory field with the

  17   Maryland Board of Physician Quality Assurance, the

  18   state medical board licensing and regulatory agency

  19   for Maryland.  But I am here today as the president

  20   of the National Association of Drug Diversion

  21   Investigators.

  22             Established in 1987, the National

  23   Association of Drug Diversion Investigators, NADDI,

  24   was formed in Maryland, in Annapolis by a sergeant

  25   in the Ann Arundel County police department.  Our 
                                                                228

   1   organization is a unique organization whose members

   2   are responsible for investigating, prosecuting and

   3   preventing pharmaceutical drug diversion.

   4             NADDI has proven to be a valuable asset to

   5   law enforcement, the pharmaceutical industry and

   6   health regulatory professionals.  NADDI principal

   7   activities comprise cooperative education and

   8   training in the specifics of pharmaceutical drug

   9   diversion, investigation and prosecution; the

  10   sharing of investigated information and

  11   communication with a wide variety of interested

  12   parties with regard to the nature, scope and impact

  13   of pharmaceutical drug diversion; and the

  14   development of stronger effective measures to

  15   combat the problem of pharmaceutical drug

  16   diversion.

  17             NADDI supports the safety and efficacy of

  18   the new drug application, NDA 21-196, Xyrem,

  19   proposed to reduce the incidence of cataplexy and

  20   to improve the symptoms of daytime sleepiness for

  21   persons with narcolepsy.

  22             NADDI is aware that in many reported cases

  23   the use of GHB has changed from homemade GHB to

  24   ingesting of industrial chemicals that convert to

  25   GHB in the body.  (My car got towed away yesterday; 
                                                                229

   1   I lost my other glasses.  I noticed that when I was

   2   sitting in the back and I couldn't read my paper.

   3   So, I apologize.)

   4             We are also aware that there are no known

   5   cases which involved Xyrem.  Rather than consider

   6   the above issues as tangential, Orphan Medical has

   7   gotten involved, helping to educate and uncover

   8   solutions in conjunction with stakeholders such as

   9   NADDI.  In fact, since November of 2000, an Orphan

  10   representative appeared at our national conference

  11   in Columbus, Ohio, and for the last several months

  12   has been involved in several states in

  13   multi-regional training with over 600 NADDI

  14   members.

  15             Input has been sought regarding

  16   distribution systems that will minimize and

  17   identify potential diversion situations, allowing

  18   diversion investigators to more easily perform

  19   their jobs.  It is the job of the pharmaceutical

  20   diversion professionals to investigate potential

  21   diversion, however, Orphan is willing to cooperate

  22   with the appropriate local, state and federal

  23   agencies.  Thank you.

  24             DR. KAWAS:  Thank you.  The next one is

  25   Debbie Alumbaugh from Florida. 
                                                                230

   1             MS. ALUMBAUGH:  Good afternoon.  My name

   2   is Debbie Alumbaugh, from Florida, and I am the

   3   surviving mother of Michael Tiedemann.  He was 15

   4   years old when he died.  That was just over two

   5   years ago.  The cause of Michael's death was

   6   aspiration vomitus and GHB toxicity.

   7             Michael was a sophomore at a high school

   8   in Florida.  He was a black belt in karate, and he

   9   was also an instructor.  He had won several

  10   academic awards for reading, spelling, mathematics

  11   and music.

  12             On October 1, 1998, Michael came home from

  13   school and asked if he could go to the show with

  14   his friends.  It was unusual for a school night but

  15   we decided to let him go.  We required Michael to

  16   bring home a progress report every week from school

  17   and he had brought one home and he was making A's

  18   and B's in all of his subjects.  Before they left,

  19   one of Michael's best friends came into our home

  20   and they shot into Michael's bedroom.  This boy was

  21   only in there for five minutes and when he left

  22   Michael was passing out within ten minutes of this

  23   young man leaving our home.

  24             We found out 18 months after Michael died

  25   that when they left our home they drove three 
                                                                231

   1   blocks and started to play a game of basketball on

   2   the way to the show.  Michael had the ball and was

   3   going for a lay-up, and when he came down he was

   4   unconscious.  He lay there several minutes.  His

   5   friends, not knowing what to do or recognizing the

   6   red flags, giggled and laughed.  They scooped my

   7   son up and took him on to the movies.  We

   8   understand Michael never saw the first five minutes

   9   of the movie.  He passed out again.

  10             When they brought our son home, my husband

  11   looked at him and he asked him, Michael, are you on

  12   something?  Did you take something, son?  He said,

  13   no, dad, nothing.  Brad decided not to lecture

  14   Michael this late at night; he would talk to him

  15   tomorrow.  Brad never got that chance.  Michael

  16   died that night, alone in his bed.

  17             The next morning, when Brad went to wake

  18   Michael for school he could hear Michael's alarm

  19   blaring.  Michael had full intentions of getting

  20   up.  When he opened our son's door he knew he was

  21   dead.  The first thought that ran through his mind

  22   was to run, run out of the house and not look back.

  23   My son was on his bed, his eyes wide open, his

  24   mouth hanging open, his tongue swollen so much that

  25   my husband couldn't shut his mouth.  He had dry 
                                                                232

   1   vomit running down his chin into a puddle on his

   2   collarbone.  His hands were in a clawed position

   3   where he had tried to roll himself over but

   4   couldn't.  GHB takes away the gag reflexes and it

   5   paralyzes you.

   6             We didn't know why Michael had died.  None

   7   of his friends would speak up.  It took 12 weeks

   8   for us to find out that Michael had ingested GHB

   9   that evening.  It was the first and only time that

  10   this had happened.

  11             In the last three years, in Florida alone,

  12   we have lost 207 young lives to these drugs.  From

  13   1999 to 2000 our numbers have more than doubled in

  14   Florida alone.

  15             After several months after Michael died,

  16   he came to his father in a dream and said, dad it

  17   is wrong to destroy the body the way I have done.

  18   I need you and mom to go out and tell my friends

  19   and my generation of people my story, our tragedy.

  20   This put a burden on our hearts and we seemed to

  21   stop healing until one day Michael's father

  22   gathered up enough courage and strength and he made

  23   the first phone call.

  24             We now go to schools all over and share

  25   our story with students about GHB, and the tragedy 
                                                                233

   1   of our family.  Friday, June 1 our son would have

   2   been 18 and he would have graduated on that day.

   3   When we went to his grave one Friday, his

   4   graduating class had left white roses and the

   5   mascot for the graduation cap.  We missed prom; we

   6   missed graduation because of this drug.  Our voices

   7   have to be heard.  Please investigate this drug.

   8   It is not safe.  It is killing our children and it

   9   is not the pushers that are dying; it is our good

  10   kids that we are losing.  Thank you.

  11             DR. KAWAS:  Thank you, Ms. Alumbaugh.  The

  12   next speaker is Brian Hunter, of the Young Adults

  13   with Narcolepsy.

  14             MR. HUNTER:  Good afternoon.  My name is

  15   Brian Hunter.  I am the founder of Young Adults

  16   with Narcolepsy or YAWN.  I am also a medical

  17   student at the University of Minnesota and a person

  18   with narcolepsy and cataplexy.

  19             I would like to preface my comments today

  20   by disclosing that Orphan Medical has provided my

  21   organization with a minor grant and it provided a

  22   general grant to the Narcolepsy Network who has

  23   paid for my travel and accommodations to attend

  24   this meeting.

  25             YAWN is the first youth-focused online 
                                                                234

   1   narcolepsy support and advocacy organization.  We

   2   work at the grass roots level to advance public

   3   awareness of narcolepsy on behalf of young adults

   4   and others whose lives are affected by this often

   5   debilitating sleep disorder.

   6             As founder of YAWN, I believe I am in a

   7   unique position to comment on the issue currently

   8   under consideration by this committee.  I do not,

   9   and have not used Xyrem for treatment of my

  10   cataplexy but as the representative of many young

  11   adults in need of an effective treatment for their

  12   narcolepsy, I am compelled to present my views on

  13   the risk management issues pertaining to the safety

  14   and efficacy of Xyrem.

  15             Narcolepsy is most commonly diagnosed by

  16   the middle of the third decade of life, often 5-15

  17   years after the onset of symptoms, the most

  18   dramatic of which is cataplexy.  Excessive daytime

  19   sleepiness, combined with the impact of sudden

  20   attacks of cataplexy that may last from a few

  21   seconds to hours can be profoundly damaging to the

  22   interpersonal, educational and professional

  23   development of these young adults at an extremely

  24   critical point in their development.  Although I am

  25   fortunate only to experience rare and mild attacks 
                                                                235

   1   of cataplexy, I know others who are completely

   2   incapacitated by cataplexy and have not, or would

   3   not been able to achieve their personal

   4   professional goals without a medication like Xyrem.

   5             I submit that the risk for experiencing

   6   the negative impact of untreated cataplexy on the

   7   potential of so many young adults with narcolepsy

   8   is a serious issue that must be included in any

   9   discussion of risk management of Xyrem.

  10             Xyrem offers a singularly important

  11   therapy for the 65-70 percent of young adults with

  12   narcolepsy who suffer with cataplexy.  We must

  13   recognize the consequences of failing to approve

  14   Xyrem to treat the 1/1000 people suffering with

  15   narcolepsy.  For example, after forming YAWN, I was

  16   contacted by the parents of a 16-year old boy,

  17   living in a small town not three hours away from

  18   the nearest city.  This young man was bright.  He

  19   did well in school, and was active in his community

  20   until his 12th birthday when he began experiencing

  21   severe episodes of cataplexy that lasted for hours.

  22             When I first spoke to him on the phone he

  23   told me that his condition was so severe that he

  24   was forced to spend five days a week in a nursing

  25   home, and he is still there.  What are the costs of 
                                                                236

   1   providing nursing home care in a public institution

   2   for a 16-year old boy for the next 60 to 70 years?

   3   By not adequately controlling his cataplexy, what

   4   are his chances for becoming a contributing member

   5   of our society?  Unfortunately, this man's story is

   6   all too common.  Unless something is done about the

   7   current environment of limited access to inadequate

   8   pharmaceutical therapies, the future of young

   9   adults suffering with cataplexy will remain bleak.

  10             This, however, does not have to be the

  11   case.  In fact, a brighter future has been achieved

  12   by the lucky few who have participated in Xyrem

  13   clinical trials.  They have become success stories.

  14   To these young adults with narcolepsy Xyrem has

  15   meant the difference between a life within an

  16   institution and having the opportunity to achieve

  17   their goals, free from the physical constraints of

  18   their disease.  Xyrem has enabled many young

  19   adults, my friends, to earn their Ph.D.'s or become

  20   lawyers, doctors or to simply be good parents.

  21             These are people who took Xyrem and

  22   couldn't have succeeded otherwise.  Yet, there

  23   continue to remain thousands of other talented and

  24   capable young adults who have not yet had a chance

  25   to fulfill their dreams.  They are the reason I 
                                                                237

   1   formed YAWN and why I am here testifying before you

   2   today.  We can no longer afford to neglect the

   3   potential of so many young adults by failing to

   4   provide them with the only medication known to be

   5   safe and effective.  It is our responsibility to

   6   protect their right to pursue a happy and

   7   productive life by having access to medications

   8   like Xyrem that will effectively treat their

   9   disease.

  10             Thank you for allowing me to present these

  11   remarks to you today.  I urge you to approve the

  12   NDA for Xyrem.  There really are lives at stake.

  13             DR. KAWAS:  Thank you, Mr. Hunter.  The

  14   next one is Joe Spillane.

  15             DR. SPILLANE:  I would like to also say

  16   thank you for an opportunity to speak to the FDA

  17   and to this committee on this important issue.

  18             I work at Broward General Medical Center

  19   which is a community hospital in south Florida.  My

  20   experience with GHB is as a pharmacist and in

  21   clinical toxicology.  I also teach as an associate

  22   professor at the College of Pharmacy at NOVA

  23   Southeastern University.

  24             Our experience in the emergency department

  25   is very similar to what Dr. Dyer mentioned.  We 
                                                                238

   1   have a lot of GHB overdoses.  We had 48 overdoses

   2   associated with GHB in 1999.  That number increased

   3   by 60 percent to 77 in 2000.  We have more GHB

   4   overdoses than ecstasy.  We have more GHB overdoses

   5   than oxicondon.  I think it is important that I

   6   just underscore the immensity of the problem

   7   associated with GHB abuse.  Most of our overdoses

   8   come in with people who have altered mental status

   9   and, basically, they just need a short period of

  10   supportive care, airway management.  Most wake up.

  11   Many of them -- and I think this is important to

  12   point out, many of them mention that somebody had

  13   given them GHB, put it into their drinks, and so

  14   forth.  As such, the media an many people have

  15   advised don't accept a drink from anybody but the

  16   bartender.  We had a bartender up in our ICU about

  17   a month ago, and when he did recover I spoke with

  18   him and he said, yes, I chronically use GHB.  A lot

  19   of my friends in the beverage industry also do.

  20   And, I think we can understand what the potential

  21   problems could be with that.

  22             We have also treated five withdrawal cases

  23   and, again, the numbers might not be that big but

  24   this is just one hospital and, since it is a

  25   difficult thing to identify, we are probably 
                                                                239

   1   missing cases and I am sure there are cases missed

   2   throughout the country.

   3             There have been nine deaths where, in the

   4   estimation of the medical examiner in Broward

   5   County, a county of 1.6 million people -- nine

   6   deaths were caused by GHB and I think it is

   7   important to point out that at least one of those

   8   deaths was with GHB alone, with no co-intoxicants

   9   and no alcohol level.

  10             I guess my major concerns are with the

  11   scheduling and some of the off-label prescribing

  12   issues, and the voluntary nature of this

  13   distribution system.  I kind of just want to

  14   summarize briefly by saying I think there are four

  15   questions that are major concerns of mine and I

  16   hope this committee addresses those concerns.

  17             The first one is, is it really wise to

  18   rely upon an essentially voluntary, supposedly

  19   closed-loop distribution system, designed by the

  20   manufacturer, to prevent diversion of an

  21   increasingly popular, highly lethal, addictive and

  22   abused substance?

  23             My second question is, is it prudent to

  24   require very little governmental regulatory

  25   oversight of such a system when the strict 
                                                                240

   1   adherence to that system may not be in the best

   2   financial interest of the entity responsible for

   3   that strict adherence?

   4             My third question is, is it responsible to

   5   rely solely on those with a vested interest in

   6   demonstrating little or no diversion to verify that

   7   little or no diversion is occurring?  It is my

   8   understanding that that is essentially what we may

   9   be doing here.  I think there was an example of how

  10   this could be problematic just in today's

  11   proceedings.  I certainly was under the impression

  12   by several people who spoke today that there was no

  13   diversion in the clinical trials.  I think Dr.

  14   Mani, from the FDA, said that, indeed, there were

  15   some cases of diversion.  So, I just think that is

  16   a potential concern.

  17             My fourth question is does it demonstrate

  18   judicious foresight to establish a precedent for

  19   sort of circumventing existing scheduling and

  20   distribution processes, and couldn't such a

  21   precedent be used in the future to the financial

  22   benefit of pharmaceutical manufacturers and to the

  23   detriment of drug diversion prevention?

  24             I would like to commend Orphan for their

  25   work and bringing a medication that they feel is 
                                                                241

   1   effective to those who could benefit from it.  I

   2   think a mandatory, not voluntary, system of

   3   distribution, with adequate governmental regulatory

   4   controls and any restrictions on off-label

   5   prescribing would advance another one of their

   6   stated goals, which is reducing abuse and

   7   diversion.  Thank you very much for having me.

   8             DR. KAWAS:  Thank you, Mr. Spillane.  The

   9   next one is Ms. Mali Einen.

  10             MS. EINEN:  Hello, and thank you for the

  11   opportunity to speak before you today.  I could

  12   tell you my story of my scars and bumps and bruises

  13   from my many falls from cataplexy, or I could tell

  14   you about my disappointment from having had to give

  15   up my career that I was dedicated to and loved, not

  16   to mention the loss of income and security.

  17   Instead, the part of my story I share with you

  18   today is the loss of the normal, everyday things

  19   that most parents take for granted.

  20             My name is Mali Einen.  I am a single

  21   mother from California with narcolepsy and what is

  22   considered severe cataplexy -- and a lot of

  23   nervousness.  As a person with narcolepsy, I was

  24   fortunate to be diagnosed fairly quickly after the

  25   onset of my symptoms.  I was diagnosed at the age 
                                                                242

   1   of 22 after first noticeable systems of narcolepsy,

   2   appearing at about age 22.

   3             In the early years my cataplexy was

   4   triggered mostly by strong emotions -- a truly

   5   funny joke or my young daughter saying something

   6   adorable.  As the years progressed, my cataplexy

   7   worsened, requiring less and less of an emotional

   8   trigger to cause a complete collapse -- unable to

   9   move or talk for seconds, sometimes even minutes at

  10   a time despite my daily medications.

  11             As my daughter grew and my cataplexy

  12   worsened, I was unable to attend her performances,

  13   school programs or sports activities without

  14   several full collapses.  My young, then seven or

  15   eight year old daughter would complain, why do you

  16   bother to come?  You spend most of your time passed

  17   out.  That is what she called cataplexy.  I

  18   wondered would she ever understand that it was my

  19   joy for her success and my love for her that

  20   prevented me from participating in these

  21   milestones.

  22             Several years later my daughter's simply

  23   relaying a story to me, excitedly, about her latest

  24   crush or her experiences with her friends would

  25   cause me to crumble, much like the film that Dr. 
                                                                243

   1   Mignot showed earlier today.  It dawned on me that

   2   I had not only given up my experiencing anything

   3   that might involve positive emotion, it had become

   4   difficult for me to even participate as a spectator

   5   in my daughter's life.

   6             During the years, I had been able to

   7   maintain success in my developing career as a money

   8   manager.  My workaholic, nose to the grindstone

   9   withdraw kept me away from the usual office fun and

  10   water cooler moments, while allowing me to avoid

  11   embarrassing cataplexy.  But this too had begun to

  12   erode.  Although the various medications allowed me

  13   to keep my cataplexy partially in check, it seemed

  14   that my nighttime sleep became more and more

  15   disrupted, sleepy during the day, yet never able to

  16   sleep more than an hour or two at a time at night.

  17             By 1996, my spotty nights of a few hours

  18   of sleep, my sneaking naps during the work day, and

  19   collapsing in exhaustion any time I sat still had

  20   affected my ability to continue to perform my job

  21   adequately.  Long ago my daughter had given up on

  22   my being able to read her a story or to help her

  23   with her homework.  My life had become dragging

  24   myself to and from work, attending to the basic

  25   needs of my daughter, while constantly working to 
                                                                244

   1   keep my emotions in check.  There was little room

   2   for fun and interaction. Sole provider for my

   3   daughter and myself, I finally voluntarily left my

   4   job.

   5             By this time I had become a complete slave

   6   to my next dose of medication to either control my

   7   cataplexy or to help keep me awake.  The

   8   medications didn't make me feel well; they made me

   9   feel horrible, yet, I was their slave.  I had never

  10   taken a back seat to finding better or best

  11   treatment options.  I tried no less than five to

  12   seven different antidepressants over the years with

  13   varying degrees of success, but each with such a

  14   cost.

  15             Within a year after I had left work, I

  16   became aware of a new medical study through

  17   Stanford, an experimental treatment for narcolepsy

  18   and cataplexy.  I started Xyrem.  My life changed!

  19   After a horrific washout period when, unmedicated,

  20   I was faced with my inability to care for myself,

  21   let alone my daughter, with mere thought causing

  22   collapse after collapse, I found that Xyrem

  23   controlled most of my cataplexy and I was thrilled

  24   how the better quality nighttime sleep allowed me

  25   to feel normal, almost good upon waking. 
                                                                245

   1             Although not required by the medical

   2   study, I began to voluntarily decrease my daily

   3   doses of amphetamines.  The better, less disrupted

   4   nighttime sleep allowed me not to be a slave to my

   5   next dose of stimulants in order to make it through

   6   the next several hours.  I now go many days without

   7   stimulants at all, and other days take 5 mg or less

   8   of Dexedrine.

   9             I not only began to be able to listen to

  10   my daughter's glee-filled stories of her day, I

  11   started to volunteer at her school.  I could joke

  12   with the kids; I could even watch Kelsey smash a

  13   winning serve across the volley ball court.  I must

  14   admit, occasionally a funny story or my evening

  15   interaction with my daughter still causes my facial

  16   muscles to slacken with a bob of the head, but my

  17   daughter now uses these opportunities to give me a

  18   hard time, knowing that I will recover in a second

  19   or two and we will have fun and enjoy our life

  20   together.

  21             I asked my now 17-year old, upon

  22   contemplating being here today, would you say my

  23   taking Xyrem has made a difference in your life?  I

  24   had expected the usual teenage disinterested reply.

  25   Instead, Kelsey responded, as tears welled in her 
                                                                246

   1   eyes, as much as I hate it sometimes, you are

   2   really a part of my life now; you know everything

   3   that's going on with me.

   4             It is for this that I am truly grateful to

   5   Orphan Medical and Xyrem -- and I think I forgot to

   6   say my conflicts of interest.

   7             DR. KAWAS:  That is the only reason we are

   8   going to let you go more over time.

   9             MS. EINEN:  I am a shareholder of Orphan

  10   Medical and a number of other stocks of products

  11   that I believe in.  Narcolepsy Network has

  12   generously paid for my air fare and accommodations,

  13   but they have not compensated me for my time, nor

  14   am I paid for the time away from my brand-new job

  15   back in the career which I had to leave five years

  16   ago.

  17             DR. KAWAS:  Thank you, Ms. Einen.  Next is

  18   Ms. Sandra Jones from California.

  19             MS. JONES:  Good afternoon, ladies and

  20   gentlemen.  My name is Sandra Jones, and I am from

  21   Los Angeles, California.  My travel expenses are

  22   being reimbursed by the Narcolepsy Network.  I am

  23   50 years old.  It was only 19 years ago that my

  24   mother truly became a mother to me, my brother and

  25   sister.  Nineteen years ago my mother began taking 
                                                                247

   1   what we now call Xyrem.  Within a week after she

   2   started taking this medicine we noticed the

   3   incredible change in her.  She could cook dinner

   4   without collapsing to the floor.  She could sit

   5   down and eat dinner with us without falling asleep.

   6   She could make a sound that we hadn't heard in a

   7   very, very long time -- laughter, and more laughter

   8   without falling to the floor.

   9             She became a totally new person to our

  10   family.  That was not the case nearly thirty years

  11   ago.  She quit her career as a nurse for fear of

  12   how the disease might affect her care of her

  13   patients.  She became sort of a recluse in her home

  14   and we grew used to seeing her sleeping throughout

  15   the day and staying up all night.  She was afraid

  16   she would fall and bring embarrassment to herself

  17   and especially to her family.  People just did not

  18   understand her disease.  She once collapsed at a

  19   party and people dismissed her as being a drunk.

  20   My mother didn't drink.  It was what the narcolepsy

  21   had done to her.

  22             This is an evil, evil disease and unless

  23   you have witnessed it firsthand you cannot

  24   understand the horrible ways it affects a person's

  25   live.  Imagine having a newborn child, my sister, 
                                                                248

   1   and not being able to hold her for fear of dropping

   2   her.  Imagine not being able to go to the grocery

   3   store for fear of falling in the aisle.  Imagine

   4   not being able to read stories to her children

   5   because she would fall asleep, not us.  Imagine not

   6   being able to drive a car for fear of collapsing

   7   behind the wheel.  This was my mother.

   8             But Xyrem changed all that.  It was a

   9   difference between night and day and mother quickly

  10   rediscovered the joys that she had missed for

  11   decades -- playing games with us, going dancing,

  12   going to the movies, celebrating family birthdays

  13   and holidays.  The day-to-day tasks that you and I

  14   take for granted, she could finally do as a normal

  15   person.  This was the mother that we had never

  16   known until Xyrem gave us her life back and her

  17   family back.  I have seen the difference.  I have

  18   lived the difference.  Please make this valuable

  19   medication available to people who have narcolepsy.

  20   They and their children will see the change in

  21   their lives.  Thank you.

  22             DR. KAWAS:  Thank you, Ms. Jones.  That

  23   concludes the section of open public hearing, and I

  24   want to thank everybody who expressed their views,

  25   information and helped the committee keep sight of 
                                                                249

   1   all the issues here.

   2             We will now reopen the questions from the

   3   committee to the invited speakers, sponsor and the

   4   FDA.  In particular, I would like to focus on the

   5   presentations that we had right before lunch

   6   involving the epidemiology, adverse medical events

   7   and the sponsor presentations on risk management

   8   and abuse liability.  So, who wants to start the

   9   questions from the committee with regard to some of

  10   those presentations?

  11         Continued Committee Discussion and Deliberations

  12             DR. SIMPSON:  I put up my hand under false

  13   pretenses because I had just one question really --

  14             DR. KAWAS:  We don't like false pretenses

  15   around here!

  16             DR. SIMPSON:  It was really relating to

  17   the efficacy.  I mean, a lot of the presentations

  18   we have just heard give the impression that the

  19   cataplexy was, if not completely controlled, almost

  20   completely.  Yet, when we look at the data we see

  21   that the median number of events at the end of some

  22   of the studies is about eight or so on drug.  So,

  23   do we have any data about how many people actually

  24   had no cataplectic events?

  25             DR. REARDAN:  I think that this question 
                                                                250

   1   was discussed to some extent this morning.  It

   2   dealt with complete cataplexy --

   3             DR. SIMPSON:  No, no, I am saying do we

   4   have data on the people who were, quote, cured?

   5   Were there any?

   6             DR. REARDAN:  We have a slide on that, I

   7   understand.

   8             [Slide]

   9             DR. HOUGHTON:  This is an example of the

  10   long-term data, and one of the problems with the

  11   controlled GHB-2 trial is that it may be too short.

  12   The reason that the time was restricted is because

  13   of the imposition of patients on placebo for longer

  14   periods of time.  But that represents a picture of

  15   the long-term response in terms of percentage

  16   change.  So, we have a control across all doses,

  17   demonstrated here for a 12-month period, around the

  18   90 percent or better mark.  Now, that doesn't mean

  19   to say people don't have any cataplexy, but it is

  20   certainly very significantly reduced.

  21             DR. KAWAS:  Dr. Katz?

  22             DR. KATZ:  Yes, we have seen this slide a

  23   number of times.  I just want to remind the

  24   committee that this is open, uncontrolled,

  25   non-randomized data, not the sort of data that we 
                                                                251

   1   would ordinarily rely on to draw any sort of

   2   conclusion about effectiveness of any sort.

   3             DR. KAWAS:  Maybe the sponsor could show

   4   us some of this data from one of the randomized

   5   trials?

   6             DR. HOUGHTON:  We could show you the

   7   change in the GHB-2 study again, which is the

   8   four-week study.

   9             [Slide]

  10             The data is median change from baseline.

  11   We had a median incidence of 23.5 in the 9 g group,

  12   a change from baseline of 16.1.  If we present that

  13   again as percentage change -- because, once again,

  14   it is complicated by the spread in the data.

  15             DR. SIMPSON:  I guess my question is if

  16   the median at the endpoint is 8.7, it means 50

  17   percent of the people were above it and 50 percent

  18   were below.  Now, how many were below, say, 1 or 2?

  19             DR. HOUGHTON:  Well, it depends on what

  20   their starting level was, and the conditions of

  21   entry were 3 cataplexy or more attacks per week.

  22   We did have patients with very high incidence.  So,

  23   in terms of absolute numbers, that is a very

  24   difficult response.  I am not trying to be evasive.

  25             DR. WOLINSKY:  The other piece of that 
                                                                252

   1   data though that you presented and might be worth

   2   looking at quickly is the randomized stop component

   3   of the trial.

   4             DR. HOUGHTON:  Sorry?

   5             DR. WOLINSKY:  When patients were

   6   randomized to be taken off --

   7             DR. KAWAS:  The 21 study.

   8             DR. REARDAN:  Right.  The question is on

   9   a-patient-by-patient basis, how many patients went

  10   from X amount of cataplexy to zero cataplexy.  Is

  11   that what you are trying to get at?

  12             DR. SIMPSON:  Zero or close to zero.

  13             DR. REARDAN:  That is in the data listings

  14   for the trial.  We didn't bring individual breakout

  15   of the data.  We brought summary information for

  16   the committee.  I don't know if Dr. Mani has a

  17   recollection or Dr. Katz.

  18             DR. KATZ:  You don't have a distribution

  19   of how many events patients had?  In other words,

  20   you know, X percent had two or fewer events; Y

  21   percent had between two and five events.

  22             DR. HOUGHTON:  No, we didn't break it down

  23   like that.  I think the slide that you were

  24   referring to was the one that I showed with

  25   individual patient plots, and I can show you that 
                                                                253

   1   quickly.

   2             [Slide]

   3             That is just an example of absolute

   4   numbers.  These were individual patients plotted.

   5   That was their incidence at the baseline, and that

   6   was some two years after this was conducted.  That

   7   is the sort of response they got when their active

   8   treatment was withdrawn.  That is the group in

   9   active treatment.  So, in terms of just absolute

  10   numbers, that is just a snapshot.  That is not a

  11   statistical presentation.  It happens to be every

  12   patient that came from that original trial through

  13   into this trial, and I show it as individual plots.

  14   It is the best impression of individual patient

  15   data I can give you to answer your question.

  16             DR. BLACK:  Just a comment on that.  In

  17   this section we do have placebo-controlled data and

  18   we have the number of cataplexy attacks on placebo

  19   versus active medications after patients have been

  20   on treatment for a long period.  Dr. Katz' comment

  21   is very good.  The data that has been generated

  22   over the open label, though it does suggest there

  23   is a time course till optimal effect of at least

  24   two months, is open label.  But this is

  25   placebo-controlled data, suggesting that the 
                                                                254

   1   average there of cataplexy attacks per day -- I

   2   don't know if you have the numbers of that, Dr.

   3   Houghton, but it is very low during the time of

   4   treatment unless they are taken off and then on the

   5   placebo-controlled portion.

   6             DR. KAWAS:  I have a question for the

   7   company as well as probably Dr. Dyer.  I want to

   8   hear both sides of why we heard such very different

   9   descriptions of the potential for withdrawal

  10   syndromes with this disorder.  I recognize fully

  11   that the company has studied individuals with

  12   narcolepsy and it is possible that alone could

  13   comprise the difference, but we do have a very nice

  14   withdrawal study in study 21, which is not

  15   typically the case, and the findings that were

  16   collected from that are in fairly sharp contrast to

  17   the stories that we have heard from Dr. Dyer with

  18   regard to withdrawal syndromes, and I wondered if

  19   both sides could tell me what the difference was.

  20   Is it dose?  What is the difference here?

  21             DR. REARDAN;  I will ask Dr. Balster, but

  22   I believe it is dose and frequency.  Bob, do you

  23   want to comment?

  24             DR. DYER:  I doubt that we disagree.

  25   Clearly, in my set of patients and what we use 
                                                                255

   1   nearly as a diagnostic parameter and which patients

   2   we should admit, even though their early symptoms

   3   are mild, is the frequency with which they are

   4   using it.  So, the kinetics of the drug show us a

   5   duration of activity around three or four hours.

   6   When these patients increase their frequency so

   7   that their body constantly is exposed to GHB, those

   8   are the ones that we feel become severely

   9   physically dependent and then go through this

  10   withdrawal syndrome that can have an onset within

  11   hours of discontinuing the drug.

  12             DR. KAWAS:  So, in your opinion it is

  13   frequency of dosing, not even the number of grams

  14   per day.

  15             DR. DYER:  As far as I can tell, it is

  16   frequency because if I take the sponsor's

  17   information, and for years I have spoken to the

  18   investigators that are doing this and they have

  19   said they have had no trouble.  Their patients have

  20   a 12-hour drug holiday daily, which is two to maybe

  21   three times what they are calling a half-life for

  22   this drug. So, the drug is completely eliminated

  23   from the body for a time period, and the patients

  24   have that become severely addicted, all of them --

  25   I mean, that is kind of diagnostic for the severe 
                                                                256

   1   withdrawal, somebody who is taking it every three

   2   hours around the clock.

   3             DR. BALSTER:  Yes, I agree completely with

   4   that, and maybe the analogy that would help you

   5   understand it would be the analogy, for example,

   6   with alcohol where really alcohol can produce a

   7   very significant physical dependence but you can

   8   drink it every evening with your meal and you won't

   9   become dependent because between that evening use

  10   and the next day it has cleared the body.  So,

  11   whatever physiological adjustments are necessary

  12   have corrected themselves.  So, we are in complete

  13   agreement.

  14             DR. KAWAS:  Thank you.  Dr. Katz?

  15             DR. KATZ:  Just as an extension of that,

  16   there was also the implication or the explicit

  17   statement that in some of those people who took it

  18   very frequently and ultimately, presumably, became

  19   addicted, they were compelled to take it more

  20   frequently.  In other words, there was a tolerance

  21   that developed and they had to increase their

  22   frequency to get the same sort of pharmacologic

  23   effect.

  24             So, I will just ask the same question that

  25   Dr. Kawas asked about withdrawal.  We have heard 
                                                                257

   1   from the company that patients who have taken the

   2   drug for years and years and years don't develop

   3   tolerance; they don't have to increase their dose;

   4   they don't increase the frequency of

   5   self-administration.  But, we are hearing that on

   6   the outside there are people in whom this

   7   phenomenon apparently does occur.  So, I will ask

   8   the same question.  Why the disparity?

   9             DR. DYER:  Again, there haven't been

  10   really good studies or anything scientific.  It is

  11   kind of my thoughts or opinions but, again, it is

  12   accommodation because you are taking it around the

  13   clock.  So you are accommodating.  Also, in the

  14   patients that are taking it -- well, I don't know,

  15   they are not really patients -- in the people who

  16   are abusing it there is a lot of the feeling that

  17   if a little is good, a lot is better.  They are

  18   taking it initially, these body builders, for this

  19   growth hormone burst.  So, they really feel like

  20   they are doing the right thing.  So, there is

  21   nothing to have them diminish their dose or hold

  22   their dose as it is.  Then, once they start taking

  23   it more frequently, the duration of the drug as it

  24   wears off in three or four hours, we think, gives

  25   them kind of a dopamine surge for which then they 
                                                                258

   1   are going to feel a little depleted and want to

   2   take that next dose.  Then there is also physical

   3   craving for that kind of high.  They are awake and

   4   feeling that kind of high as opposed to the

   5   patients that are taking it immediately upon going

   6   to bed and then sleeping through this euphoric --

   7   whatever the kids are trying to get that are

   8   abusing it -- if you can roll that into an answer.

   9             DR. BALSTER:  That is exactly the way I

  10   would see it too.  Just to add one further thing to

  11   that, the way to look at tolerance, you have to

  12   understand that it occurs through different effects

  13   at different rates and in different ways.  So, the

  14   therapeutic effect is one effect.  The intoxicating

  15   effect is a different effect.  And, commonly in

  16   abuse situations where persons are trying to

  17   maintain an intoxication, they have to escalate

  18   dose and frequency in order to do that, whereas the

  19   data obtained in these clinical trials, of course,

  20   is on the therapeutic effect.

  21             DR. DYER:  One other comment, in the

  22   alcohol abuse trials they did escalate their dose

  23   in more of a craving kind of manner.  That was

  24   about 15 percent.

  25             DR. KAWAS:  Dr. Roman? 
                                                                259

   1             DR. ENGEL:  I would like to add something,

   2   if I may, to this point that is based on the risk

   3   management system proposed by the sponsor.  As you

   4   saw, the data collected by the specialty pharmacy

   5   will include dose by patient.  And, because of

   6   that, the specialty pharmacy will be able to

   7   predict when is the appropriate timing for a given

   8   patient to have their prescription refilled.  So,

   9   for example, there are patients attempting to

  10   refill too soon, so to speak, that will be

  11   identified and it will be an opportunity for the

  12   pharmacist to interact with the physician very

  13   quickly, before a patient might get into a

  14   situation like which Dr. Dyer is describing with an

  15   overuse syndrome.

  16             DR. ROMAN:  A question perhaps again for

  17   Dr. Balster.  Is the pharmacology of GBL and 1,4-BD

  18   similar in animal experience to GHB?  Number two,

  19   if there is a difference, did I understand

  20   correctly that GBL and 1,4-BD are not currently

  21   drugs of abuse?

  22             DR. BALSTER:  Well, the first question,

  23   pharmacological comparisons of GBL, GHB and 1,4-BD,

  24   these haven't been very extensively done.  So,

  25   hopefully some of those NIDA grants that someone 
                                                                260

   1   was talking about will really take that question

   2   on.  But let me say that in a number of those

   3   studies that were done to describe the pharmacology

   4   of GHB, in some of these studies actually GBL was

   5   administered to the animal with the view that it

   6   was a prodrug for GHB.  I forgot who said it but

   7   someone said that so far as we know, all of the

   8   effects of GBL and 1,4-BD are really as a

   9   consequence of their conversion to GHB.  I believe

  10   that would be the current state of knowledge about

  11   that although it is imperfect.

  12             Now, the question about control, in a

  13   sense, yes, all of these drugs are potential drugs

  14   of abuse because they can be taken and basically

  15   are active in the case of precursors with

  16   metabolites.  So, yes, all of these are potentially

  17   drugs of abuse.  Only one of them is a controlled

  18   substance and one of them, by congressional action

  19   of last year, became what is called a listed drug,

  20   and I could explain that to you or, actually, Dr.

  21   Sannerud would know better than I what exactly that

  22   means.  But it essentially means that there is

  23   limited distribution.

  24             DR. ROMAN:  So, with GBL and 1,4-BD there

  25   is no control. 
                                                                261

   1             DR. BALSTER:  Well, as I say, for 1,4-BD,

   2   to my knowledge, there is no control.  I need to

   3   step back a little bit from that because we could

   4   get into too long of a discussion about what

   5   constitutes an analog under the specific language

   6   of the legislation.  So, it is possible for

   7   prosecuting attorneys to claim that one or another

   8   of these drugs are analogs of a controlled

   9   substance.  The Controlled Substances Act, in a

  10   sense, regulates analogs.  Now, 1,4-butanediol is

  11   questionably an analog, but that would be something

  12   that would be worked out in court.  So, I am not

  13   trying to tell you that someone could absolutely,

  14   with impunity, sell 1,4-BD to children and say that

  15   it wasn't a drug of abuse because I am sure that

  16   there would be authorities and prosecutors who

  17   would try to do something about that.  But in terms

  18   of the actual language of regulation, only GHB is a

  19   controlled substance.

  20             DR. SANNERUD:  GHB is a Schedule I

  21   controlled substance.  Butanediol and GBL are

  22   considered controlled substance analogs under

  23   federal law, which means they can be prosecuted, as

  24   GHB, with penalties and other things would apply if

  25   someone is caught trafficking, distributing or 
                                                                262

   1   clandestinely manufacturing or selling these

   2   compounds as well.  GBL is listed as a List I

   3   chemical, which means that there is record-keeping

   4   and registration required.  There are no retail

   5   sales of butanediol, and there is a graph in here

   6   with the product.  These are used in industrial

   7   uses.  So, this comparison is really a little bit

   8   misleading.  I don't know the numbers but GHB is

   9   not even marketed yet, so this number on production

  10   is only for clinical trials I assume.

  11             As far as the GHB and Xyrem they are both

  12   GHB.  There is no forensic analysis that is going

  13   to differentiate between the two.  So, when samples

  14   are submitted to labs there is no way to tell if it

  15   is the product or if it is something that is made

  16   at home.  So, for someone to say that there has

  17   never been any diversion of the product, there is

  18   no way to tell that because there is no way to

  19   differentiate between the two under forensic

  20   laboratory conditions.

  21             Another question I wanted to address is

  22   the quota issue.  Ms. Meyers brought up quotas for

  23   Schedule II compounds, the stimulants.  DEA sets

  24   the quota, as it will with GHB as well.  It has

  25   never been the case that drug has run out at the 
                                                                263

   1   end of the year because the quotas are set too low.

   2   If there is a problem with the drug manufacture the

   3   quotas can always be increased throughout the year,

   4   and they are done so on a regular basis.  So, there

   5   has never been the case where a drug has run out.

   6             DR. KAWAS:  Dr. Mani?

   7             DR. MANI:  I would just like to touch upon

   8   the issue of drug diversion during the clinical

   9   trials once again briefly.  Many speakers have

  10   asserted that there has been no evidence that Xyrem

  11   or GHB used in the clinical trials included in the

  12   database was diverted.  That may very well be true,

  13   barring the one exception that I cited earlier, and

  14   I have no firm evidence to the contrary.  However,

  15   I have gone through the NDA, reviewed the whole

  16   NDA, and I would be a little more hesitant in

  17   making that assertion, and I will tell you why, and

  18   that has to do with the way the drug was dispensed

  19   in the Scharf study which, as you know, occupied

  20   about 30 percent of the database in terms of

  21   patient numbers and about 70 percent of the

  22   database when you are talking about patient years

  23   of exposure.

  24             What happened here was that patients saw

  25   Dr. Scharf in Cincinnati, at least for an initial 
                                                                264

   1   visit, and had an appropriate diagnosis made and

   2   were then enrolled in the trial and then went back

   3   to whatever part of the country they came from.

   4   Prescriptions for medication were filled based on

   5   their returning completed diaries.  In some

   6   instances it appears, at least from my looking at

   7   the case report forms, that prescriptions were

   8   sometimes filled in advance or the diaries being

   9   returned, obviously to prevent the patient from

  10   running out of the drug.  But the important thing

  11   is that patients were not required to return unused

  12   supplies of medication prior to getting a fresh

  13   prescription, or to provide any formal accounting

  14   of how much medication they used or did not use.

  15   In the absence of any active surveillance of that

  16   kind, as I said, I would be quite hesitant in

  17   making the assertion that no medication was

  18   diverted.

  19             DR. REARDAN:  I need to make a qualifying

  20   statement here.  We do not disagree with Dr. Mani.

  21   However, under the company's clinical IND, our

  22   patients under IND didn't begin entering trials

  23   until 1996.  Patients were required to document

  24   their dose; to return their bottles.  The bottles

  25   were all qualified by volume in terms of what was 
                                                                265

   1   returned.  The incident that Dr. Mani refers to, I

   2   believe, occurred in 1986, when GHB was available

   3   as a nutritional supplement and Dr. Scharf's trial,

   4   again, was clinical practice.  There were a lot of

   5   issues on GCP compliance in that trial.  We do not

   6   take responsibility for accountability of drug

   7   under Dr. Scharf's trial.  So, I will just qualify

   8   that.  Okay?

   9             DR. MANI:  I agree.

  10             DR. FALKOWSKI:  I have a question and it

  11   has to do with the fact that we are talking about a

  12   method of taking this drug where you take half the

  13   amount at bedtime and then you wake up several

  14   hours later, but don't really wake up, and take the

  15   rest of it.  And, I am just wondering what would

  16   happen if you were confused.  It also involves

  17   mixing it ahead of time to the right strength.  I

  18   am asking this both to Dr. Dyer and the sponsor,

  19   what would happen if someone took 9 mg at once?

  20   You know, if someone got confused and took it all

  21   at once, what would be the expected outcome?

  22             DR. REARDAN:  I had a number of questions

  23   about this at the break from a couple of members of

  24   the committee -- how do they make it up, and so on.

  25   It might be worthwhile to ask Patti Engel to go 
                                                                266

   1   through that.  The other point about narcoleptic

   2   patients waking up, maybe Dr. Black, you could

   3   comment on how they wake up and take their second

   4   dose.

   5             DR. FALKOWSKI:  Right, but my bottom line

   6   question is what would happen to a person who

   7   inadvertently took all of their dose at once, and I

   8   really insist on an answer to that.  Thank you.

   9             DR. BLACK:  That question has been

  10   answered by patients who have taken inadvertently

  11   larger doses.  As far as the waking up at night,

  12   the patients that are here could probably respond

  13   to that, but the overwhelming majority are awake

  14   actually before the four hours later on their own

  15   and they are fully awake.  The medication is

  16   premixed so there is no mixing that needs to occur

  17   at that point.  There are folks who have taken

  18   extra doses and there is more sedation that occurs

  19   with the extra duration and the period of sleep is

  20   longer with the higher dose.

  21             DR. FALKOWSKI:  Is the answer then

  22   increased sedation?  Is that the answer to my

  23   direct question?

  24             DR. BLACK:  Yes, if the dose is increased

  25   there is increasing sedation and a longer sleep 
                                                                267

   1   period.

   2             DR. FALKOWSKI:  Okay.  Dr. Dyer, could you

   3   respond to that?

   4             DR. DYER:  It is my opinion that the dose

   5   would be around 100 mg/k and at that point you are

   6   going to have coma and some of the other side

   7   effects that we see in our club goers are very

   8   likely to be what you would see.  So, vomiting and

   9   aspiration is a possibility.  You know, the ability

  10   to hear and react to fire alarms, children,

  11   whatever, that is all going to be blunted.

  12             DR. FALKOWSKI:  Is it a possibility then

  13   that some of these people who may have double dosed

  14   would be in a coma but who would know, you know?

  15   Is that a possibility, sponsor?  I mean, who is to

  16   know?

  17             DR. BLACK:  I think that the question is a

  18   good one, and what I might call deep sleep someone

  19   else might call a coma.  But when we look at the

  20   brain wave activity of the folks with the higher

  21   doses, they have nothing in the EEG that would be

  22   consistent with straightforward coma.

  23             DR. FALKOWSKI:  But you didn't take EEGs

  24   on these people when they were sleeping in

  25   situations like this. 
                                                                268

   1             DR. BLACK:  Well, we have done EEGs on the

   2   folks when they have been sleeping at the 9 g dose

   3   but not on double the 9 g dose.

   4             DR. FALKOWSKI:  Okay.

   5             DR. KAWAS:  Dr. Katz, please.

   6             DR. KATZ:  Yes, a couple of things.  Maybe

   7   the best way to get at this if it is possible is to

   8   ask the company to show us any data that they have

   9   about what happened to patients who took, let's

  10   say, a single 9 g dose.  I don't know how many

  11   patients did that, but if there is data on that it

  12   would be nice to see.

  13             So, I don't know, maybe you could look for

  14   that while I get to the second part which is,

  15   again, just another variant about the question we

  16   were talking about before, this perceived disparity

  17   between patients and non-patients who take the drug

  18   recreationally.  We have heard again, not just in

  19   terms of withdrawal and addiction and tolerance but

  20   just in terms of serious adverse events, a number

  21   of the serious adverse events that we have heard

  22   about in the emergency room situation seem to have

  23   occurred at doses, presumably -- I don't know how

  24   reliable the dose information is in that setting, I

  25   am not sure, but presumably at doses that patients 
                                                                269

   1   routinely get and which they tolerate extremely

   2   well.  So, I will ask the same disparity question

   3   again there.

   4             DR. MIGNOT:  I think you have to realize

   5   also that you are talking about narcoleptic

   6   patients who also experience daytime episodes of

   7   overwhelming sleepiness that sometimes lead to

   8   confusion, and there are a lot of horror stories

   9   about narcoleptic patients, independently of GHB,

  10   at any moment of their life where they can

  11   sometimes be in a risky situation just because they

  12   have what we call automatic behavior, this

  13   overwhelming sleep attack where they really don't

  14   know what they are doing, where they may be driving

  15   or doing something dangerous.  I think that is also

  16   important to keep in mind.  The danger of taking

  17   two doses at a time, if it is relatively well

  18   dispensed, for narcolepsy patients I think needs to

  19   be put in perspective for their other symptoms.

  20             DR. REARDAN:  I am only aware of one case

  21   in our database.  It was a patient who

  22   inadvertently took 18 g and I think, Dr. Mani, you

  23   are well aware of that.  He did fall on his head.

  24   So, it is confusing as to whether it was a result

  25   of his 18 g dose -- you know, that was the best 
                                                                270

   1   estimate we had -- or in the fall he hit his head,

   2   but he did end up being taken to the emergency

   3   department and did need supportive care.  Oh, Bill

   4   is saying that was a normal dose.  I am sorry, let

   5   me get him to clarify.

   6             DR. HOUGHTON:  Yes, I am sorry.  That is

   7   one of the cases that we know very little about.

   8   It was a patient who was in the kitchen.  There was

   9   a loud bang.  His wife heard the noise and came in,

  10   and her husband was on the floor.  So, we got no

  11   dose relationship to that event.  We know nothing

  12   as to whether it is related to Xyrem.

  13             The 18 g overdose was the patient who was

  14   supposedly sleepwalking, in the Scharf database,

  15   who supposedly then took 18 g on top of his normal

  16   dose and was taken to hospital and ended up on a

  17   ventilator.

  18             Really, the best prevention we have of 9 g

  19   being taken together is the fact that the dose has

  20   to be made up into separate doses.  The

  21   instructions to the patient are very clear.  They

  22   make two doses up together, dilute it in the water;

  23   drink one when they get into bed and the other, in

  24   a sealed cup, put away.  Now, if they took the

  25   second dose in ten minutes or two hours, we have 
                                                                271

   1   not done that study and it is very dangerous to

   2   extrapolate that sort of dosing.  On one hand, I

   3   can quote the patient who took 180 g and was taken

   4   to hospital unconscious and walked out of hospital

   5   four hours later to be admitted to the psychiatric

   6   unit.

   7             I certainly don't want to propose that as

   8   the normal pharmacodynamic response.  We have not

   9   done a study that has escalated beyond the 4.5 g

  10   dose twice a night, and I think it is very

  11   dangerous to extrapolate.  It is also very

  12   dangerous to extrapolate the anesthesia data or

  13   some of the data that Dr. Dyer talked about this

  14   morning.  Doses were given up to 100 mg/kg

  15   intravenously.  If we believe the bioequivalence

  16   data, the absolute bioavailability data, that is

  17   equivalent to at least 300 mg/kg as an anesthetic

  18   dose, and that would be the best dose relationship

  19   we could give to dose escalation.  Again, without

  20   true data I am not prepared to extrapolate from

  21   that.

  22             DR. KAWAS:  Dr. Mani, do you still want

  23   the floor?

  24             DR. MANI:  Yes, very briefly, just as

  25   further evidence of how much individual variability 
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   1   there is in response to this drug.  There is a

   2   subject who Dr. Houghton had referred to in his

   3   presentation this morning, a healthy subject

   4   participating in a pharmacokinetic trial, a healthy

   5   young subject who received a single dose of 4.5 g

   6   and afterwards became obtunded, developed

   7   obstructed respiration perhaps because of his jaw

   8   falling back, became incontinent or urine and

   9   stool, and took a number of hours to recover but

  10   did not need any special supportive care.  So, even

  11   a 4.5 g dose may not be entirely safe for

  12   everybody.

  13             DR. HOUGHTON:  That story is somewhat true

  14   but not quite accurate.  The patient was easily

  15   arousable, walked to the bathroom after the event

  16   of passed urine, after resting back in bed had a

  17   normal sleep and, two hours later was awake and ate

  18   a normal lunch.  So, again, I can't account for the

  19   degree of obtundation but that still represented

  20   the maximum single dose in our database.  It was a

  21   single dose of 4.5 g after a 10-hour fast.

  22             DR. MANI:  Although those details about

  23   the patient being able to get up and go to the

  24   bathroom and eat her lunch, and so on, wasn't in

  25   the narrative that we have available. 
                                                                273

   1             DR. HOUGHTON:  We were collecting urine

   2   samples every two hours and I can assure you the

   3   patient was walked to the bathroom.  She certainly

   4   vomited at the time.

   5             DR. KAWAS:  Dr. Leiderman?

   6             DR. LEIDERMAN:  Very briefly because Dr.

   7   Mani raised one of the points that I wanted to, but

   8   the other question I had for the sponsor and the

   9   sleep neurophysiologists here, do you think that in

  10   some of the differential response that we are

  11   seeing in the narcolepsy patients as compared to

  12   the subjects who become dependent, addicted, have

  13   overdose problems that there may be a role not only

  14   of the basic neurophysiology of the narcoleptic

  15   brain but, of course these patients tended to be

  16   co-medicated with stimulants, and what role do you

  17   think that might be playing in the narcolepsy

  18   population?

  19             DR. REARDAN:  Is the concern that

  20   stimulants would still be present on board when

  21   they take their nightly dose of Xyrem?  Is that

  22   what you are after, or what?

  23             DR. LEIDERMAN:  Well, I am asking for your

  24   thoughts on, shall we say, the differential effects

  25   of GHB on the two populations, and one of the sort 
                                                                274

   1   of clear differences, taking sort of the first cut,

   2   is that narcolepsy patients are co-medicated with

   3   stimulants generally, whereas the abusing drug

   4   population, if anything, is self co-medicating with

   5   other CNS depressants or using GHB at high doses

   6   alone.

   7             DR. BLACK:  I think there are a number of

   8   questions that surface.  We have patients in

   9   protocols where they are wanting to remain on the

  10   protocols or wanting to be drug compliant.  There

  11   are reasons that they wouldn't abuse in addition or

  12   outside of the fact of co-pharmacy with stimulants

  13   and so forth.  So, it is hard to compare those two

  14   groups clearly.

  15             I think the best we can do is speculate.

  16   We have a number of patients that were not

  17   co-treated with stimulants as well, that were on

  18   just Xyrem, and they didn't self-escalate the dose

  19   or abuse the agent either.  I think the only way to

  20   do it would be to give high dose frequently to the

  21   narcolepsy patient population and see if they are

  22   similarly addictable, and then it would be also

  23   interesting to find out what percentage of the

  24   normal population is addictable as well.

  25   Obviously, those studies couldn't be done.  But I 
                                                                275

   1   think we can't compare the two and it is real hard

   2   to try to extrapolate the information we have to do

   3   a comparison.

   4             DR. KAWAS:  Dr. Dyer, followed by Dr. Van

   5   Belle, followed by Ella Lacey, followed by the

   6   questions that the FDA has asked us to consider.

   7   In between, we will get a quick demonstration of

   8   the mixing.

   9             DR. HOUGHTON:  Could I just add one point

  10   of clarification to Dr. Leiderman's question?

  11   There were patients in all of the studies that were

  12   not on stimulants.  In the GHB-2 study I think it

  13   was about 15 percent when we did a recent look at

  14   the database for Dr. Mani.  So, there was at least

  15   a proportion of patients represented in the

  16   database that weren't on stimulants as concomitant

  17   medication.

  18             DR. DYER:  There was one study, I believe

  19   it was done in rats where amphetamines and then a

  20   second with caffeine, where those were shown to

  21   kind of be antidotal to GHB poisoning, where it

  22   prevents the rats' loss of riding reflex.  So,

  23   there may be some of that issue if they are taking

  24   it concurrently.  One of the other things about the

  25   disparity, where I don't see the disparity as being 
                                                                276

   1   so much is that the narcoleptics are taking their

   2   dose at night.  We know pretty commonly from the

   3   surgical studies from what we see coming into the

   4   emergency room and from the adverse effects of the

   5   study, that GHB causes vomiting and incontinence.

   6   So, we are seeing that in both populations of

   7   patients.

   8             DR. CHERVIN:  Is anybody there?

   9             DR. KAWAS:  Yes, is that one of our phone

  10   consultants, Dr. Chervin or Dr. Guilleminault?

  11             DR. CHERVIN:  Sorry, it seems like we were

  12   completely cut off.

  13             DR. KAWAS:  Can you hear us now?

  14             DR. CHERVIN:  Just barely.  If there is

  15   any way you can make this signal more than barely

  16   audible, it would be helpful?

  17             DR. KAWAS:  We can barely hear you but it

  18   sounds like we are going to have to get the AV

  19   people on it, if you give us a moment.

  20             DR. CHERVIN:  I do have questions if I

  21   have time to ask them.

  22             DR. KAWAS:  I know that you are on a

  23   timetable, so we will put you in the middle of the

  24   six-person pileup, if we could let the speaker that

  25   is going now finish though. 
                                                                277

   1             DR. DYER:  So, there was another study

   2   where they took the patients and the patients that

   3   they gave the dose to and then forced or tried to

   4   maintain themselves awake, those were the patients

   5   that became confused.

   6             The other thing is that in our emergency

   7   department study where we were trying to verify our

   8   ability to predict GHB by toxidrome, we looked at

   9   patients that came in with a GCS score less than 8

  10   that were spontaneously breathing.  So, unlike most

  11   CNS depressants that cause profound coma, generally

  12   the breathing is still spontaneous and maintained.

  13   You see mild respiratory acidosis but it is not

  14   very common that these patients need to be

  15   intubated.  So, it is not contrary to be thinking

  16   that a patient might be comatose and survive the

  17   night.

  18             DR. KAWAS:  Dr. Van Belle, while we are

  19   still working on the audio, do you want to go ahead

  20   and ask your question?

  21             DR. VAN BELLE:  I just have a brief

  22   question with respect to age eligibility.  Will

  23   this medication be available to people under 18

  24   years old?

  25             DR. REARDAN:  The company has not 
                                                                278

   1   specifically developed data for pediatrics, and I

   2   think this would have to be something we work out

   3   with the agency but, typically, a medication

   4   approved for adults is not denied children.  FDA

   5   and Congress have tried to put incentives in to get

   6   sponsors to develop pediatric information.  In

   7   addition, narcolepsy is not generally a pediatric

   8   disease.  I don't know if either Dr. Mignot or Dr.

   9   Black want to comment further.  Dr. Katz?

  10             DR. KATZ:  Well, generally speaking,

  11   unless there is a good reason not to, we would

  12   limit the age that would be at least included in

  13   the indications or in labeling or dosage

  14   administration to the age of the lower limit of the

  15   age studied in the trials.  I don't know exactly

  16   what the youngest patient was in these trials.

  17             DR. REARDAN:  Bill Houghton is saying 12.

  18             DR. KATZ:  Okay, 12.  Again, if there was

  19   one patient who was 12 and everybody else was 18

  20   and above, we would say adults or 18 and above,

  21   that kind of thing.  It is true that there is no

  22   prohibition, obviously, from a physician writing a

  23   prescription for a drug for a child if it is only

  24   explicitly approved for an adult.  It happens

  25   obviously all the time.  But one of the questions 
                                                                279

   1   when we get to it with regard to risk management

   2   and that sort of thing is if there were no children

   3   studied, or children studied below a certain age,

   4   do you think attempts should be made to restrict it

   5   in this case?  So, you know, it is open for

   6   discussion.

   7             DR. MIGNOT:  To answer the question, onset

   8   of the disease is roughly between 15 and 25.  That

   9   is really when the bulk of the patients are coming

  10   in, especially for cataplexy, and I think it is

  11   very important to treat them early.  As there is

  12   more and more knowledge about narcolepsy being an

  13   important disease and being recognized early -- I

  14   think you have heard a lot of testimony about how

  15   important it is to treat them early so that they

  16   can go through normal schooling.  I think it will

  17   be very important to not be too restrictive towards

  18   the lower age.

  19             DR. KAWAS:  Dr. Lacey?

  20             DR. LACEY:  Two questions, one regarding

  21   the packaging.  With the packaging being in a

  22   bottle and it is child-resistant dosing, and all,

  23   but hearing about adolescents and their involvement

  24   with GHB, I wondered if you considered other

  25   packaging.  In deciding on this packaging, did you 
                                                                280

   1   consider individual dosage packaging at all, and

   2   what happened with that?

   3             DR. REARDAN:  We considered individual

   4   dosing packaging for sure.  We thought that was a

   5   greater potential for diversion as it is easy to

   6   take those individual doses.  I think maybe you

   7   would get some reassurance if Patti Engel can go

   8   through how we instruct the patients to dose and

   9   what the controls are for that.  Patti?

  10             MS. ENGEL:  Thank you.  To the point of

  11   individual dosing, we did speak quite extensively

  12   about that with law enforcement.

  13             DR. LACEY:  Yes, I am pretty convinced

  14   about the patient.  I am more concerned about

  15   others in the household who are exposed to a

  16   bottle.

  17             MS. ENGEL:  Right.  I will address that as

  18   well.  On the individual dosing, law enforcement

  19   was concerned about small containers that could be

  20   stuck in a pocket or purse, or slipped in someone's

  21   drink more easily.  One of the things I shared with

  22   you earlier is that the bottle itself comes with a

  23   child-resistant closure.  What is difficult to see

  24   from this distance, but it is something called a

  25   press-in bottle adaptor.  When the patient gets 
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   1   this, there is a little well, if you will, in

   2   there.  Even if a child can get this lid off, you

   3   can't drink it down.  What has to happen is there

   4   is a metered syringe provided.  It gets stuck in

   5   here and the patient removes a metered dose.  Okay?

   6   They then have two child-resistant dosing cups and

   7   these aren't fancy.  We took them because they are

   8   CPIS tested for child resistance, of course, and

   9   they put it in, preparing both doses by their

  10   bedside.

  11             Now, the dose itself is metered.  This

  12   Xyrem, to be frank, is not good tasting stuff.  It

  13   is sodium oxybate.  It is very salty.  Many people

  14   will dilute it.  How much they dilute it really is

  15   to their taste.  We did not want to cherry flavor

  16   it or anything like that that may make it more

  17   attractive to children.  Okay?  Does that answer

  18   your question?

  19             DR. LACEY:  It really wasn't the small

  20   children that I was concerned about as I was about

  21   the older, the adolescents in the household who can

  22   open it the same as I could.  So, I guess your

  23   answer was that law enforcement was concerned about

  24   the small dosages just being put in a pocket.

  25             MS. ENGEL:  That is right.  Remember, 
                                                                282

   1   illicit use of Xyrem also falls under C-I

   2   penalties, like heroin or LSD.  So, we will never

   3   be able to find a package that a 19- or a 21-year

   4   old will not be able to get into.  What we do,

   5   however, is to educate the Xyrem patient on a

   6   number of occasions of the penalties should that

   7   occur.  So, there is an element of patient

   8   responsibility with this.

   9             DR. LACEY:  Thank you.  The second

  10   question I have is about the suicide attempts that

  11   were presented by Dr. Houghton this morning.  That

  12   was in that list of adverse events I believe, and

  13   it has continued to bother me that we talk about it

  14   as a suicide attempt as though nothing else

  15   happened and I am just curious, I guess, in those

  16   attempts were some of the other adverse events also

  17   experienced by those persons who were suicide

  18   attempters?

  19             DR. REARDAN:  As you heard from Dr.

  20   Mignot, depression is very common in narcoleptics,

  21   but I will ask Bill to comment on that.

  22             DR. HOUGHTON:  In all the patients who

  23   attempted suicide there was preexisting disease.

  24   In terms of response to the dose taken, only one of

  25   the suicide attempts involved Xyrem, and that was 
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   1   the patient who took a very large dose, about 300

   2   ml of the drug which is equivalent to at least 150

   3   g, and he became comatose, incontinent of feces and

   4   urine, continued to breathe spontaneously, was

   5   found by his wife in the bathroom, transported to

   6   the emergency medical care, did not require

   7   intubation or ventilation, and walked out of

   8   hospital four hours later to be admitted to the

   9   psychiatric unit.  I certainly don't propose that

  10   as the norm.  There will be certainly unconscious

  11   patients at much lower doses.  So, please don't

  12   think I am proposing that as the pharmacodynamic

  13   profile of the drug.  But you asked me what the

  14   side effects of the suicide event were and that is

  15   the only data that I can give you.

  16             The second suicide event that was not

  17   fatal did not involve Xyrem.  One of the fatal

  18   attempts did not involve Xyrem at all.  The last

  19   suicide attack in the bipolar disorder patient was

  20   a real pharmacologic cocktail involving

  21   benzodiazepines, opiates, a number of drugs and

  22   some Xyrem.

  23             DR. LACEY:  But for those individuals who

  24   did have the suicide attempts, they did not have

  25   other -- not with the attempt directly but other 
                                                                284

   1   adverse events also in their report?

   2             DR. HOUGHTON:  No.  One of those was a

   3   lady who had a group of people to her home.  She

   4   asked them all to leave early, and when attempted

   5   to be contacted the next morning didn't respond,

   6   and when her attentions were sought she was found

   7   dead in the home.

   8             The second attempt was a young lady who

   9   took an overdose of buspirone and told her father

  10   immediately.  Her behavior was normal to that

  11   point.  So, that is an example.

  12             DR. KAWAS:  Dr. Chervin or Dr.

  13   Guilleminault, can you hear us now?  You guys are

  14   next in the line up.

  15             DR. CHERVIN:  Thank you.  I have two

  16   questions.  Please tell me if it has been covered

  17   and I just was not able to hear it, but I read in

  18   some of the material that was distributed prior to

  19   the meeting about comparisons of the therapeutic

  20   index or the therapeutic window for GHB to that of

  21   other drugs that are currently approved and used.

  22   I was wondering if perhaps Dr. Dyer or Dr.

  23   Falkowski or Dr. Balster could address that

  24   comparison.

  25             DR. DYER:  Is that the comparison of LD-50 
                                                                285

   1   in rats?

   2             DR. CHERVIN:  I guess it was rats, and it

   3   was LD-50 and effective dose, and they looked at

   4   the ratio.

   5             DR. DYER:  The problem I have with some of

   6   the rat data, lethal dose data, is the deaths we

   7   see are often secondary to coma.  It takes high

   8   doses to cause pure respiratory depression.  We

   9   have some patients that idiosyncratically have a

  10   pulmonary edema, but most of the deaths are

  11   secondary to unprotected coma and loss of airway.

  12   So, I don't know that that would extrapolate or

  13   come from rat data at all.  I don't think you would

  14   see that.

  15             DR. CHERVIN:  Is there any other way to

  16   get at the issue of is Xyrem going to be more

  17   dangerous than other drugs that are used carefully

  18   when indicated?

  19             DR. REARDAN:  Dr. Chervin, I have some

  20   data on LD-50 that will help.  Oral GHB has an

  21   LD-50 on the order of 9000 mg/kg in rats, and about

  22   3500 mg/kg in mice.  The IV LD-50 is about a third

  23   of that for GBL and for butanediol it is on the

  24   order of 2000 mg/kg.  If you look at the effective

  25   dose, we are in the range, I believe, of about 
                                                                286

   1   50-120 mg/kg recommended for the narcoleptic

   2   patients.  Now, that is just on an LD-50 basis.  I

   3   don't know if Dr. Mani wants to comment on the

   4   therapeutic range, or Dr. Katz.

   5             DR. KATZ:  I don't think we really know.

   6   I am not sure if the animal data is relevant at

   7   all.  And, I don't think we have data that, in a

   8   systematic, adequate way, explores the full dose

   9   response both with efficacy or tolerability.  As

  10   you have said, you have done a trial where the

  11   maximum dose, fixed dose, was 9 g per night and,

  12   you know, we either decide that that was a

  13   tolerable dose or it wasn't.  And, you have the

  14   dose response for the effectiveness, and that is

  15   all you have.  As you acknowledge, you haven't

  16   explored higher doses so I don't think we really

  17   know, and I don't know how you would really get at

  18   the question of how the therapeutic window, if

  19   there is one, compares to other drugs that are in

  20   common use.  Some drugs that are used, there is a

  21   belief that they have a very narrow therapeutic

  22   windows, and some are wide.  I don't think you can

  23   say more than that.

  24             DR. REARDAN:  I don't disagree.

  25             DR. GUILLEMINAULT:  I have a question.  
                                                                287

   1   Narcoleptic patients have hypnagogic

   2   hallucinations.  They may even shoot -- if a gun is

   3   available they may hurt their bed partner because

   4   they are keeping their hallucination.  How much

   5   does Xyrem decrease hypnagogic hallucinations,

   6   which is a very significant side effect which may

   7   kill neighbors and may kill even bed partners?

   8             DR. REARDAN:  If I understand the

   9   question, Dr. Guilleminault, it is how much did

  10   Xyrem reduce hypnagogic hallucinations in our

  11   trials, and I guess my first response is the

  12   incidence was very low and we did not see a

  13   statistical significance in GHB-2.  I don't know if

  14   Dr. Houghton wants to comment further on hypnagogic

  15   hallucinations.

  16             Just while they are finding the data, it

  17   is fair to say that the incidence of hypnagogic

  18   hallucinations recorded in the four-week trial was

  19   very low.  There was a trend towards improvement

  20   that certainly didn't reach statistical

  21   significance.  There was a better representation in

  22   the long-term open-label study and we could show

  23   that but I am loathe to do so because I certainly

  24   don't want to claim it as efficacy.  I think we

  25   will be able to find the GHB-2 data. 
                                                                288

   1             [Slide]

   2             DR. HOUGHTON:  In the Lammers study there

   3   was a reduction from 0.87 hypnagogic hallucinations

   4   per night over the 4-week treatment period to 0.28

   5   incidence per night, with a p value of 0.008.  That

   6   is one set of figures.

   7             DR. MIGNOT:  Just to sort of expand on

   8   what you said, if only about 40-60 percent of

   9   patients we narcolepsy/cataplexy have hypnagogic

  10   hallucinations as their symptoms or sleep

  11   paralysis, then obviously that must reduce the

  12   power for the trial because they have only about

  13   half of the patients they included who even had

  14   that symptom.

  15             [Slide]

  16             DR. REARDAN:  This is a slide from GHB-3.

  17   I guess that is open label, I don't know if we want

  18   to go into that.  What it shows is median change

  19   from baseline to visit number and out through 12

  20   months.  You see a median change in hypnagogic

  21   hallucinations, a reduction of 0.35 per day.  Is

  22   that right?

  23             DR. KAWAS:  Dr. Penis and then Dr.

  24   Falkowski and then this committee will be looking

  25   at the questions that the FDA has asked us to vote 
                                                                289

   1   on.

   2             DR. PENIX:  I think we have to anticipate

   3   several different possibilities in the treatment of

   4   patients with any drug, and I am somewhat concerned

   5   about the fact that the effective dose of Xyrem

   6   appears to be the maximum dose available, number

   7   one.  Secondly, in regards to the possible

   8   protective effects of stimulants on the side effect

   9   of sedation, and whether we should consider Xyrem

  10   as a monotherapy drug or as an adjunctive

  11   treatment, and the question I would like to ask --

  12   I think Dr. Houghton may have presented this data

  13   of talked about it, of the 15 percent of patients

  14   who did not receive stimulants while on Xyrem

  15   whether there was a difference in the maximum dose

  16   escalation in those patients compared to the ones

  17   who were on stimulants.  I am not sure if we can

  18   answer the question, but if there is data on that,

  19   if there is a difference.

  20             DR. HOUGHTON:  No, we don't have data

  21   separate for those on stimulants and those not on

  22   stimulants.  There was only about 15 percent in

  23   that controlled trial that were not on stimulants.

  24   So, we hadn't plotted that at all.  Remember that

  25   stimulants are taken in the morning and usually the 
                                                                290

   1   last dose at lunch because narcoleptics are really

   2   trying to sleep at night and stimulants really

   3   complicate that, and the half-life of the gama

   4   hydroxybutyrate is about an hour.

   5             So, even after their second dose their

   6   plasma levels on awakening in the morning are

   7   extraordinarily low.  So, a contribution of

   8   stimulants to change that is quite unlikely.  We

   9   certainly didn't see an abnormal sleep response in

  10   the normal volunteers in any of the pharmacokinetic

  11   studies, except the one patient who became

  12   obtunded, and she was awake four hours later and

  13   ate lunch, and then went home that day.  So, the

  14   only real suggestion of data I could give you in

  15   the absence or stimulants is the single dose

  16   response or the repeat dose response in the

  17   pharmacokinetic studies, and that certainly didn't

  18   appear to be different at all.

  19             DR. BLACK:  I would just comment on the

  20   notion of a potential protective effect with

  21   stimulants.  With the traditional stimulants, they

  22   are relatively short acting and there is a

  23   phenomenon called rebound hypersomnia as the

  24   medication wears off -- well demonstrated in

  25   animals and humans -- where the individual becomes 
                                                                291

   1   more sleep than they would have been had they not

   2   taken a medication; often a problem for those with

   3   narcolepsy who are using those medications.

   4             Rather than those stimulants keeping

   5   people more awake and less affected by the Xyrem

   6   dose, there is the potential for even greater

   7   sleepiness with that rebound hypersomnia.  That has

   8   not been well explored, but I think it would be

   9   erroneous to assume that there is any protective

  10   effect from the traditional stimulants.  From the

  11   longer acting stimulant, modafinil, sleep studies

  12   have been done to suggest that there is no impact

  13   one way or the other on sleep in terms of depth of

  14   sleep and so forth.

  15             DR. KAWAS:  Dr. Falkowski?

  16             DR. FALKOWSKI:  I have to take issue --

  17   well, I already did with the statement that Xyrem

  18   will not contribute to the public health problem of

  19   abuse of GHB-like substances because I think it

  20   will and I want to take just a few minutes to

  21   elaborate on why that might be something I couldn't

  22   cover in the confines of my 15 minutes as well as

  23   covering those other points.

  24             I had occasion last week, in Philadelphia,

  25   to present at a conference on drug abuse addiction 
                                                                292

   1   professionals from around the country, and since I

   2   speak about drugs of abuse, when I got to  GHB I

   3   said, so, tell me about GHB in your community.

   4   Having heard from 15 people from 15 distinct parts

   5   of the country on this, a common theme emerged and

   6   that had to do with the fact that people who were

   7   abusing it couldn't quite get the dosing right

   8   because they kept passing out.  Passing out became

   9   sort of a way of life.  I think in Dr. Dyer's data

  10   we even saw that as well.

  11             This is a drug that causes people to lose

  12   consciousness and in some cases respiratory arrest.

  13   Well, I think this is particularly relevant because

  14   if dosing is the problem I believe that this will

  15   only make more attractive a predictable dose as a

  16   known entity in a prescription product. "Gee, I can

  17   get around all these dosing problems by getting the

  18   prescription."

  19             I am also concerned that none of the

  20   sponsor's packaging that I looked at even mentions

  21   the word gamma hydroxybutyrate, or did I miss that?

  22   I looked for it; I didn't see that.  That concerns

  23   me because, as we have seen with oxicodon, we know,

  24   for example -- and I think it is a good case, we

  25   know that narcotic addicts will seek out 
                                                                293

   1   prescription narcotics for predictable dosing and

   2   for predictable purity.  And, we have seen an

   3   increase once long-acting oxicodon was developed --

   4   we have seen an expansion in its prescribing not

   5   just for chronic pain but for the treatment of even

   6   acute pain.  That plays out to the tune of 300,000

   7   oxicodon prescriptions in 1998 and over 5 million

   8   oxicodon prescriptions in the year 2000.

   9             What people have to do, what drug seekers

  10   have to do to acquire it is go to a doctor and

  11   feign pain.  This happens with unsuspecting doctors

  12   and it is happening in all parts of the country.

  13             Now, diversion of drugs does not occur by

  14   people storming with machine guns the one central

  15   manufacturing.  It occurs at the patient-doctor

  16   level.  And, I am very concerned about the

  17   possibility of folks who are having trouble.

  18   Again, this is a diverse population; it is not just

  19   kids using drugs.  This is weight-lifters, these

  20   are people seeking effects, going to a doctor and

  21   saying, gee, you can get around all that; just go

  22   to a doctor and tell him you are sleepy.  Just go

  23   to a doctor and tell him you collapsed.  This is

  24   really seriously my concern about this, and I don't

  25   think that these two issues are separate.  This 
                                                                294

   1   drug has a huge following.

   2             DR. KAWAS:  I would now like to focus on

   3   the questions that the FDA has asked us to vote on.

   4   Do you feel very strongly that your comments are

   5   necessary before that?

   6             DR. RISTANOVIC:  I am going to make a

   7   comment extremely brief.  The comment is very brief

   8   because in today's time we know how to diagnose

   9   narcolepsy.  So, there is no way, even if someone

  10   is trying to malinger, to be given a diagnosis

  11   without appropriate testing in the sleep lab.  That

  12   is a prerequisite.

  13             DR. KAWAS:  Thank you.

  14             DR. RISTANOVIC:  That is all.

  15             DR. KAWAS:  The FDA has given us three

  16   questions that they want this panel to vote on, and

  17   a whole page and a half of other items that they

  18   would like this committee to discuss.

  19             So, I would first like to ask them if it

  20   is acceptable to facilitate the discussion, can I

  21   make the decision to split the first question into

  22   two?

  23             DR. KATZ:  Absolutely.

  24             DR. KAWAS:  Thank you.  It might be the

  25   only thing that gets done quickly today.  The first 
                                                                295

   1   question is going to be has the sponsor

   2   demonstrated efficacy of Xyrem for the proposed

   3   indication to treat cataplexy?  I am opening the

   4   floor for discussion on that.  Yes, Dr. Katz?

   5             DR. KATZ:  Again, I think it is very

   6   important for us to hear a discussion about dose

   7   and which dose.  I mean, I mentioned that earlier

   8   in my comments this morning, but if you could

   9   address that it would be very helpful.

  10             DR. KAWAS:  Absolutely.  In fact, maybe I

  11   would like to facilitate this part because I think

  12   this is the easiest thing that is going to happen

  13   in the next hour.  To my mind, there have been two

  14   pivotal studies that have suggested efficacy for

  15   this drug in relationship to cataplexy at the 9 g

  16   level.  Maybe by making that not overly provocative

  17   comment we can stimulate discussion.  Does anyone

  18   want to comment on the dose or the effect on

  19   cataplexy before we vote?

  20             DR. FALKOWSKI:  Is that the recommended

  21   dose?  It is not.  That is why I am sincerely

  22   confused because the study seemed to show efficacy

  23   at 9 g, yet, the recommended dose is something

  24   other than that and that needs explanation.  I

  25   don't understand that. 
                                                                296

   1             DR. KAWAS:  Any other comments?  Richard?

   2             DR. PENN:  I was going to make it a motion

   3   so we would save some steps.  I think it is very

   4   clear that what you said is a good summary of the

   5   case that, in fact, they haven't set the dose at 9.

   6   They have suggested a different dose regimen and

   7   that has to be looked into very carefully.  But the

   8   one thing I think we all we agree on is your

   9   statement.  I would, therefore, put it as a motion,

  10   since we are supposed to do a motion so that that

  11   has been shown.

  12             DR. KAWAS:  Would you like to make a

  13   comment, Gerald, before we pick the motion that is

  14   about to be on the floor?

  15             DR. VAN BELLE:  Sure.  Well, I think it is

  16   the issue of dose response that I am struggling

  17   with in this case in terms of the pharmacokinetic

  18   model.  If you assume that there is a

  19   pharmacokinetic model that is dose related, I would

  20   say if evidence has been shown for an effect at 9

  21   there is probably an effect at 8.5 as well.  Well,

  22   where do you draw the line at that time, and I

  23   don't quite know where to do that.  I think there

  24   is ambiguous evidence for an effect at 6 and one

  25   study showed that.  So, if you want the technical 
                                                                297

   1   answer, I think there is only evidence for clinical

   2   effectiveness at 9 but that ignores, to my mind,

   3   the pharmacokinetic aspects of the data so I am

   4   struggling with this.

   5             DR. KAWAS:  Could we restate Dr. Penn's

   6   motion that this committee vote on whether or not

   7   there has been efficacy demonstrated of this drug

   8   for the treatment of cataplexy and, specifically at

   9   the dosage of 9?

  10             DR. SIMPSON:  This may be my ignorance,

  11   but when something is labeled, for example, that it

  12   is efficacious at a dose of 9, does that mean that

  13   a doctor would necessarily prescribe it at 9?  He

  14   could prescribe it quite a lot higher, couldn't he?

  15             DR. PENN:  That is going to get us into

  16   the next thing, which is how this is going to be

  17   monitored.  Because it sounds like we want to put

  18   an absolute dose limit and we don't want to allow

  19   variability in the population.  By the technical

  20   way we are going to allow this out, if they are

  21   going to be watching how much a patient can take,

  22   then is a doctor going to be allowed the latitude a

  23   patient more, and you are asking can they be given

  24   less?  I think the answer is usually the doctor

  25   makes that decision.  Everybody understands that is 
                                                                298

   1   the mean does that you have to use but that doesn't

   2   mean your patient will respond to it.  So, there is

   3   the latitude unless we put into force this

   4   voluntary program.

   5             DR. KAWAS:  I would like to focus this

   6   committee back on the questions or we will never --

   7   well, we will have everyone on a plane without a

   8   quorum in order to vote on these issues.

   9             The first question really isn't so much

  10   about safety and what a doctor will do, the FDA has

  11   just asked us have they demonstrated efficacy for

  12   this drug in either of the two indications.

  13             DR. FALKOWSKI:  I believe they have

  14   demonstrated efficacy for reducing cataplexy in

  15   cataplectic narcoleptics on stimulant drugs.  I

  16   think that is what their studies have shown us

  17   today.

  18             DR. KAWAS:  Okay.  We will be taking a

  19   vote and everyone's vote is going to count.  Are

  20   there any other comments people want to make before

  21   we put Dr. Penn's motion on the floor?

  22             DR. SIMPSON:  I really agree that they

  23   haven't necessarily demonstrated efficacy in

  24   treating cataplexy but really in reducing

  25   cataplexy. 
                                                                299

   1             DR. KAWAS:  Do you want to put your motion

   2   on the floor again?

   3             DR. PENN:  The company has shown efficacy

   4   at 9 g per day using a 4.5 divided dose for

   5   treating cataplexy in narcoleptic patients.

   6             DR. KAWAS:  These votes are going to have

   7   to be recorded individually I think.  So, can we

   8   start with everyone who agrees that the sponsor has

   9   demonstrated efficacy of Xyrem for the proposed

  10   indication to treat cataplexy?  Please raise your

  11   hands now.

  12             I just want to remind everybody that the

  13   voting members of the committee actually are sort

  14   of in the central part of the table, beginning with

  15   Dr. Simpson and then going around to Dr. Penix.

  16   All who agree the company has demonstrated efficacy

  17   for cataplexy, raise your hand.

  18             [Show of hands]

  19             How about if we go around and identify,

  20   and start with Dr. Penix for the record?

  21             DR. PENIX:  I agree.

  22             DR. KAWAS:  Just your name.

  23             DR. PENIX:  Dr. Penix.

  24             DR. VAN BELLE:  Van Belle.

  25             DR. PENN:  Penn. 
                                                                300

   1             DR. KAWAS:  Kawas.

   2             DR. WOLINSKY:  Wolinsky.

   3             DR. ROMAN:  Roman.

   4             DR. KAWAS:  All the people who do not feel

   5   the company has shown efficacy for the treatment of

   6   cataplexy, please raise your hand and start

   7   identifying.

   8             [Show of hands]

   9             DR. SIMPSON:  Simpson.

  10             DR. FALKOWSKI:  Falkowski.

  11             DR. LACEY:  Lacey.

  12             DR. KAWAS:  I think that was everyone, so

  13   no abstentions in that case.

  14             Moving on to the next hard one, has the

  15   sponsor demonstrated --

  16             DR. KATZ:  Dr. Simpson and Falkowski, I

  17   believe in your comments you said you thought there

  18   was an effect demonstrated, or something, but the

  19   vote went the other way.  I just want to

  20   understand.

  21             DR. FALKOWSKI:  Right, I believe that they

  22   have demonstrated that there is some evidence of

  23   efficacy for reducing cataplexy in cataplectic

  24   narcoleptics on stimulant drugs.  These studies

  25   have been conducted on people who were already on 
                                                                301

   1   stimulant drugs.  We don't know about the

   2   cataplectic narcoleptics who weren't.  So, I wanted

   3   to reflect what we actually looked at, the

   4   scientific evidence.

   5             DR. KATZ:  And, would that be the basis

   6   for your no vote as well?

   7             DR. SIMPSON:  Well, mine is really that

   8   they reduced cataplectic events.  I guess my

   9   understanding of treating it is that they couldn't

  10   sort of cure it.

  11             DR. PENN:  May I just clarify?  I didn't

  12   mean cure.  My motion was not cure, nor did I say

  13   monotherapy.

  14             DR. KATZ:  Right.  From the point of view

  15   of an effect, you know, that sort of language only

  16   being applied to a cure, the vast majority of

  17   things we treat and give claims for in indications

  18   are for symptomatic, non-curative treatment.  So,

  19   it is perfectly acceptable for us -- and I think it

  20   was implied in Dr. Penn's motion that to vote yes

  21   you wouldn't necessarily have to conclude that the

  22   drug cures it or wipes these attacks out, but just

  23   that there is a decrease in these attacks compared

  24   to the control.

  25             DR. FALKOWSKI:  And you can call it 
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   1   monotherapy but what the subjects were in these

   2   studies were subjects with the condition that were

   3   already under medication for this condition.  So,

   4   to take that leap to say, well, therefore, if you

   5   have people with this condition who are not on

   6   stimulant drugs, does that follow?  I don't believe

   7   it does.

   8             DR. KATZ:  We will take that under

   9   advisement.

  10             DR. KAWAS:  The next question, has the

  11   sponsor demonstrated efficacy of Xyrem for the

  12   proposed indication to reduce excessive daytime

  13   sleepiness in patients with narcolepsy?  The floor

  14   is open for discussion on this point.

  15             At the risk of putting myself back in the

  16   same place as last time, I would summarize what we

  17   have seen today with regards to excessive daytime

  18   sleepiness that there was one study, in a

  19   double-blind fashion, that showed subjective

  20   changes in sleepiness with the Epworth Scale, and

  21   that would be the GHB-2 study.  The other study

  22   which is being held up as a pivotal study with

  23   regards to daytime sleepiness was the Lammers

  24   study, which is a small study.  Otherwise, I feel

  25   that the evidence with regards to daytime 
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   1   sleepiness was very weak at best, in particular,

   2   the only study that proactively made daytime

   3   sleepiness the primary outcome measure as well as

   4   using objective measures with the MSLT was, in

   5   fact, negative.  All the other studies were open

   6   label.  So, here I have a little more --

   7   considerably more difficulty actually seeing that

   8   the sponsor has demonstrated efficacy for daytime

   9   sleepiness.  So, what are the committee's thoughts

  10   on this?  What are the committee's comments on

  11   this?  Jerry?

  12             DR. WOLINSKY:  As I tried to point out

  13   before, I think this is such an enriched patient

  14   population for purposes of the endpoints that were

  15   studied, it is hard to know that one could

  16   generalize daytime sleepiness effects in a full

  17   population of narcoleptics.  So, I agree that the

  18   data is weak and it is also in a very enriched

  19   population.

  20             DR. KAWAS:  I am not sure I understand.

  21   For clarification, enriched with what?  You mean

  22   enriched for cataplexy?

  23             DR. WOLINSKY:  Enriched for cataplexy

  24   which is not present in all narcoleptics and is not

  25   always present at this frequency.  So, I don't 
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   1   think that we would know.  I would not know as a

   2   clinical that if I had a narcoleptic with sleep

   3   attacks or daytime sleepiness but no cataplectic

   4   attacks whether I could expect the drug to work or

   5   not, and I saw no data to tell me that I could.

   6             DR. KAWAS:  Any other comments?  Any other

   7   thoughts before we call the vote on this question?

   8             DR. PENN:  I move that the company has not

   9   provided information to prove that daytime

  10   sleepiness is affected by Xyrem, and I would make a

  11   comment on my motion, that if the company sees this

  12   as an important thing they can do a post-approval

  13   study on that specific item and that would be

  14   appropriate.  I was leaning at the beginning of

  15   this to think that there was too much need for full

  16   proof on an orphan drug that this might be the case

  17   and I was going to give them the benefit of the

  18   doubt, but considering the potential for abuse in

  19   patients who will say they are just sleepy and the

  20   regulatory problems with that, I think we had

  21   better be quite strict on this.

  22             DR. KAWAS:  Can you make that motion

  23   without the addendum?

  24             DR. PENN:  No, no, the addendum is just my

  25   comment. 
                                                                305

   1             DR. KAWAS:  Good.  Give me the short

   2   motion.

   3             DR. PENN:  They didn't prove their point.

   4             DR. KAWAS:  The language is has the

   5   sponsor demonstrated efficacy of Xyrem for the

   6   proposed indication to treat excessive daytime

   7   sleepiness in patients with narcolepsy?  So, a vote

   8   of yes the way I just worded it would suggest that

   9   the company has shown efficacy, similar to the last

  10   vote.  A vote of no would suggest that the company

  11   has not shown efficacy for that particular

  12   indication.  So, all in favor of yes, the company

  13   has shown efficacy for the indication of daytime

  14   sleepiness, please raise your hand.

  15             [No show of hands]

  16             All if favor of no?

  17             [Show of hands]

  18             Let the record show that it was unanimous.

  19   It might be the only time today.

  20             DR. TITUS:  And enter nine names please

  21   into the record.

  22             [Drs. Penix, Van Belle, Penn, Kawas,

  23   Wolinsky, Roman, Falkowski, Simpson and Lacey voted

  24   against the motion]

  25             DR. KAWAS:  Now, the second question that 
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   1   the FDA has asked us to vote on is has the sponsor

   2   established the safety of Xyrem when used for the

   3   proposed indication for which substantial evidence

   4   of effectiveness has been submitted?

   5             Now, given our previous vote, we are

   6   talking about substantial evidence for the

   7   effectiveness to treat cataplexy, and I want to go

   8   ahead and put in here that I think most of the

   9   committee members have been of the opinion that the

  10   substantial evidence is almost exclusively in the 9

  11   g dose range.  So, I think we are talking about has

  12   the sponsor established safety of Xyrem when used

  13   for cataplexy at a dose of 9 g per day, for the

  14   most part.  The floor is open for discussion on

  15   this question.

  16             DR. SIMPSON:  Could one of the physicians

  17   put the adverse events that one can see in the 9 g

  18   in perspective?

  19             DR. KAWAS:  Let me let Dr. Katz and Dr.

  20   Mani answer the question.  Dr. Katz?

  21             DR. KATZ:  Yes, this is why the dose which

  22   you think is effective is important.  It might be

  23   useful, before you decide whether or not the safety

  24   has been established at 9 g, to have a look at what

  25   the total exposure at the 9 g dose is and whether 
                                                                307

   1   or not you think that is acceptable, as a first

   2   step, independent of whether or not it seemed to

   3   have been tolerated, with enough people at 9 g with

   4   sufficient duration.  So, I don't know if the firm

   5   could put up a slide.  I think Ranjit has an

   6   overhead.

   7             DR. KAWAS:  Slide 67 from the company,

   8   updated ISS database, summary patient exposure by

   9   dose.  By my calculations we are talking about 60

  10   years, person years of exposure on the 9 g dose

  11   from the integrated data set.

  12             DR. MANI:  I am sorry, I don't believe it

  13   is patient years, is it?  It is the number of

  14   patients.

  15             DR. KAWAS:  Well, I calculated it because

  16   there were 13 patients who had been on it for 2

  17   years or more and 34 patients who had been on it 12

  18   months or more.  So, it was just 2 times 13 plus

  19   34.  That is the way I cam to the 60 person year

  20   estimate.  I actually didn't give them any credit

  21   for the 6-month exposure.

  22             Actually, I have a question to ask of the

  23   company, do each years subsume the others?  So, the

  24   13 individuals who were in the 2-year category, are

  25   they also included in the 62 who are in the 6-month 
                                                                308

   1   category and the 34?

   2             DR. REARDAN:  Yes, I believe that is

   3   correct, Dr. Kawas, the 13 patients would be

   4   included in the 34, and the 34 would be included in

   5   the 62.

   6             DR. KAWAS:  So, the math is more

   7   complicated than I made it out to be, actually.  It

   8   still comes to about 47 patient years of exposure

   9   by my calculation.  I believe that the standard

  10   generally if it is considered acceptable is

  11   considerably higher than that.  Perhaps Dr. Katz

  12   would like to comment on that, particularly in the

  13   case of an orphan drug with a relatively small

  14   patient population.

  15             DR. KATZ:  Yes, the typical minimum

  16   requirements for an application for a standard drug

  17   that is not an orphan -- we will start there

  18   because we have such standards written, is at least

  19   1500 patients total or subjects total, with at

  20   least 300-600 for 6 months for a chronic disease

  21   and at least 100 for a year.  That is the standard

  22   ICH minimum data package for safety.

  23             As you point out, this is an orphan

  24   condition.  I guess the company estimates the

  25   prevalence of narcolepsy patients with cataplexy is 
                                                                309

   1   about 25,000 or 24,000, something like that.  And,

   2   we had agreed prior to the submission of the NDA

   3   with the company that, because it is an orphan with

   4   a fairly small prevalence, that they wouldn't

   5   really have to have the full data set that a

   6   typical NDA would have, and we agreed that a total

   7   of about 500 would be in the ball park.  It is

   8   understood that at least some significant

   9   percentage of those patients should be at a

  10   therapeutic dose because the safety accrued at the

  11   dose that is less than therapeutic isn't

  12   particularly contributory.

  13             So, while I don't believe -- the company

  14   can correct me if I am wrong, but I don't believe

  15   we set in stone what would the minimum numbers be

  16   that would be sufficient for either 6 months or a

  17   year or total active therapeutic dose.  I don't

  18   believe we signed a contract about that, but I

  19   think the implication is that a big chunk of the

  20   data ought to be at therapeutic dose.  So, I can't

  21   give you an absolute answer but I will throw it

  22   back to you and ask would you think that the

  23   exposure at the therapeutic dose that you have seen

  24   is sufficient to characterize the safety profile

  25   reasonably and that we could write labeling that 
                                                                310

   1   would adequately inform prescribers about what the

   2   panoply of risks is at 9 g?

   3             DR. ROMAN:  Could that be solved with a

   4   post-release very strict follow-up on these

   5   patients, Dr. Katz?

   6             DR. KATZ:  We really have to be assured

   7   that the drug is safe in use at the time of

   8   marketing.  We cannot rely on post-marketing data

   9   to say, well, we will find out if it is safe in

  10   use.  We have to make a decision about whether it

  11   is safe in use as described in labeling, whatever

  12   that is going to look like, at the time of

  13   approval.  There may be additional information we

  14   would like to have in Phase IV but the fundamental

  15   finding of whether or not it is safe in use must be

  16   made prior to approval.

  17             DR. ROMAN:  A second point that I would

  18   like to make is that probably you can say that up

  19   to 9 g per day, not that there is sort of the

  20   middle of the road -- probably it would be

  21   recommended to start with a lower amount and

  22   increase according to tolerance and effects, but it

  23   is up to 9 g per day.  That is sort of the upper

  24   limit.  It happens to be the most effective one and

  25   sort of therapeutic dose but probably you would 
                                                                311

   1   like to start with the lowest possible amount.

   2             DR. KAWAS:  I think the company shares

   3   your interest, but my take on this is we don't want

   4   to put out there that a drug is efficacious at one

   5   dose and safe at another.  I mean, I think it is

   6   incumbent on us to feel confident that both of

   7   those characteristics go with whatever dose we

   8   think is appropriate.

   9             In response to your question, Dr. Simpson,

  10   and I don't know if I understood it correctly but

  11   you said what is the clinical significance, is that

  12   from the perspective of a clinical?

  13             DR. SIMPSON:  Well, that is part of it.

  14   Just speaking as a statistician though, the safety

  15   evidence isn't there with those kind of numbers,

  16   obviously.  I mean, I think everybody knows that.

  17             DR. KAWAS:  I think that is really more

  18   the question that is on hand here --

  19             DR. SIMPSON:  Yes.

  20             DR. KAWAS:  -- because from the

  21   perspective of a clinical, this drug actually --

  22   you know, if you didn't tell me what the drug was

  23   and just showed me ten safety profiles that have

  24   gone by this committee in the last decade, or

  25   whatever, I suspect this would look like one of the 
                                                                312

   1   best ones.  Nobody died from it.  No major

   2   laboratory abnormalities were detected.  But it is

   3   very, very, very few subjects that we are talking

   4   about, and I think that is considerable concern to

   5   us.

   6             DR. SIMPSON:  There actually was one

   7   suicide which could be attributed to this.

   8             DR. KAWAS:  It still puts it in probably

   9   the best of the ten.  Dr. Katz?

  10             DR. KATZ:  Dr. Racusin, on our safety

  11   team, just reminded me of sort of a simple rule

  12   that we use to decide what sort of size of a risk

  13   you can cap with a given exposure, it is called the

  14   rule of thirds, but basically with a cohort of 60

  15   patient years you could be comfortable with ruling

  16   out a risk of no greater than 1/20, which is

  17   --what? -- 5 percent.  So, in other words, there

  18   could be a rate of 5 percent of something bad with

  19   a cohort of 60 that you would not have even seen in

  20   that cohort.  So, just to sort of give you an idea

  21   of what sorts of potential risks are there that we

  22   might not have seen yet with this cohort size.

  23             DR. VAN BELLE:  Just a small correction,

  24   Dr. Katz.  I believe that it should be 3/60, which

  25   is 15 percent rather than 20 percent. 
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   1             DR. KAWAS:  Do we have any other comments

   2   before we give a shot at trying to vote on the

   3   safety?

   4             DR. WOLINSKY:  I very much share your

   5   concern about approving the drug at one effective

   6   dose and then saying the safety is really at a

   7   lower dose than what is effective.  On the other

   8   hand, I do think that we have some reasonable data

   9   on the efficacy side that says that the dose ranged

  10   somewhere between 6-9 g is effective for a

  11   substantial proportion of patients, which we then

  12   give us not roughly 50 years of patient exposure

  13   but closer to 200 years of patient exposure.

  14             DR. KAWAS:  I agree with that comment, Dr.

  15   Wolinsky, but I really would want to point out that

  16   almost all of the SEs appear at the 9, not at the 6

  17   range.  So, you know, you are stacking the deck a

  18   little.

  19             DR. WOLINSKY:  I thought actually, as I

  20   saw the listing of the adverse reactions, they

  21   clustered in two modal distributions.  One was at

  22   the high range and one was, surprisingly, below 6.

  23             DR. KAWAS:  Actually, maybe we will take a

  24   look at that.  Could Xyrem put up slide number 70

  25   for us, updated ISS database does distribution of 
                                                                314

   1   adverse events?

   2             [Slide]

   3             I think that is what you are talking

   4   about.  It is not a perfect dose response.  I mean,

   5   something pops up in the middle, the 6 range

   6   actually in terms of SAEs at 12 percent for the 6 g

   7   dose.

   8             DR. WOLINSKY:  And if I heard correctly,

   9   and I don't know how they were distributed, at

  10   least some of those serious adverse events were

  11   cataplectic episodes.

  12             DR. KAWAS:  But even then, I mean, I would

  13   point out that we are talking about a 3-fold

  14   increase in discontinuations due to AEs in the 9

  15   versus the 6.  I mean, it is a 3-fold difference.

  16             DR. WOLINSKY:  I take your point.

  17             DR. PENN:  On the other hand, once again,

  18   that looks like a pretty safe drug to me when you

  19   are only talking about 15 percent of people

  20   dropping out for AEs, and the real-life situation

  21   is that these patients are going to be titrated up

  22   to the 9 and, as we saw from that graph of the

  23   unacceptable information from the standpoint of the

  24   study results, in experience over a number of years

  25   you can run patients certainly at lower doses than 
                                                                315

   1   9.  So, I think that should be influencing our

   2   opinion of the safety data.

   3             DR. KAWAS:  Thanks.  Dr. Katz?

   4             DR. KATZ:  Yes, I think the critical

   5   question here is not whether those numbers at 9 g

   6   are acceptable or not, although that is an

   7   important question, but to me the question is --

   8   and you have certainly been talking about that, do

   9   you have enough experience to be comfortable at the

  10   dose you think is effective.  I think, I mean my

  11   sense of what people are saying -- you didn't vote

  12   on it yet, but my sense is that you felt that at 9

  13   g there just isn't really that much data.  I don't

  14   want to preempt your vote, but it sounds like the

  15   general consensus was there wasn't enough data

  16   there -- forget about what the data actually

  17   showed, but there just wasn't enough to be able to

  18   be comfortable that we have adequately

  19   characterized the safety at 9, which is what we

  20   have to do.  The only vote you took on

  21   effectiveness was effectiveness at 9 g.  So, if you

  22   think it is useful to reopen a discussion about

  23   whether or not you think there is effectiveness at

  24   6 g, and if you do, then you have considerably more

  25   exposure to think about.  So, that is your call.  I 
                                                                316

   1   mean, Dr. Wolinsky suggested that he thought there

   2   might be some evidence of effectiveness at 6.  I

   3   don't know how the others feel, and I leave it up

   4   to you as to whether or not you want to reopen that

   5   question because if you do think there is

   6   effectiveness at a lower dose, it increases your N

   7   from the point of view of safety.  So, I just throw

   8   that out.

   9             DR. KAWAS:  I actually think that is

  10   probably worth our doing.  With regards to

  11   effectiveness at 6 g, what are the thoughts of the

  12   committee?  I will start by saying that I suspect

  13   that there is effectiveness for at least many

  14   patients at 6 g, partly for all the reasons that

  15   other members of the committee have said, but also

  16   because there appears to be a fairly prominent

  17   dose-response curve not only in terms of AEs but

  18   also in terms of efficacy.  And, what isn't

  19   factored into a total dose is the levels of

  20   particular patients, the weights of particular

  21   patients or whatever, but the data shows me that at

  22   least a subset of patients appear to be responding

  23   at least in some of the trials to 6 g.  Dr. Katz?

  24             DR. KATZ:  Study 21, the withdrawal study.

  25             DR. HOUGHTON:  That is the slide that I 
                                                                317

   1   would really like to show if I could.

   2             DR. KATZ:  The dose there was 50 mg/kg, is

   3   that correct?  What was the distribution of doses

   4   in that study?

   5             [Slide]

   6             DR. HOUGHTON:  This is shown here.  There

   7   was an equal distribution of patients at the 6, 7.5

   8   and 9 g and if you look at that paradigm of acute

   9   withdrawal, the response to placebo randomization

  10   is obviously very robust at 6 and 7.5 g, as it is

  11   at the 9 g.  The problem with the GHB-2 study is

  12   that it is only a 4-week study and the slope of the

  13   line hadn't plateau'd at the end of 4 weeks.  When

  14   we did apply that to open label, even though it was

  15   open label we still saw the maximum nadir at 8

  16   weeks.  So, if you then take a group of patients

  17   who have been on active treatment for a very long

  18   time and are then randomized to placebo, if you

  19   believe that is a support for long-term efficacy

  20   then efficacy is supported at 6 g and 7.5 g.

  21             DR. KAWAS:  Would members of the committee

  22   like to comment on this data or any other data

  23   showing efficacy or non-efficacy at 6 g?  Yes?

  24             DR. SIMPSON:  I do think that this trial,

  25   in fact, is very impressive.  I just want to remind 
                                                                318

   1   everybody of the caveat of this, that the people

   2   that you were looking at long-term exclude all

   3   those people who have dropped out for adverse

   4   events.

   5             DR. KAWAS:  I think that is a very good

   6   point.  I mean, this was a study done in responders

   7   rather than just random narcoleptics.  Individuals

   8   in this group represented probably are individuals

   9   who felt they were getting benefit or saw benefit.

  10             DR. SIMPSON:  And provided the drug is

  11   safe, then in fact this might be a fair rule to

  12   look at to say, yes, the drug is effective.

  13             DR. MANI:  I would just like to point out

  14   that these comparisons are not of randomized

  15   groups.

  16             DR. KATZ:  They are not randomized to

  17   dose.

  18             DR. MANI:  They are not randomized to

  19   dose.

  20             DR. KATZ:  It is obviously a randomized

  21   study.  So, they are not randomized to dose in the

  22   sense of typical dose response.  These are doses

  23   that presumably they had been responding to in open

  24   experience, and there is not as balanced across the

  25   doses, that is true.  And, the numbers are quite 
                                                                319

   1   small on each dose.  On the other hand, you have

   2   already decided that in toto it is a study that

   3   demonstrates effectiveness.

   4             DR. KAWAS:  I mean, I think even though we

   5   all recognize these are responders, the fact that a

   6   group of individuals on 6 g who, when withdrawn,

   7   showed this effect at least told me that there was

   8   a subgroup that did respond, as I said before, to

   9   6.  The question is how big is that subgroup, and

  10   when we are talking about indications and efficacy

  11   do we feel that on the whole 6 is a dose to which

  12   people respond based on all the evidence that we

  13   have seen so far?

  14             DR. FALKOWSKI:  And I would also like to

  15   say I am a little uncomfortable with the idea of

  16   saying that we have so many patient hours for most

  17   drugs but, because this is orphan status, we have

  18   it but we don't have -- Dr. Katz' remarks -- but we

  19   don't have any numbers.  Well, that, to me, puts

  20   the sponsor in a difficult situation about, you

  21   know, what is adequate in trying to develop a new

  22   drug and it makes it very difficult for us here to

  23   try to reach a conclusion.  Enlighten me, here.

  24             DR. GUILLEMINAULT:  Can we make a comment,

  25   as a sleep expert, on the issue? 
                                                                320

   1             DR. KAWAS:  I am sorry, who is speaking?

   2             DR. GUILLEMINAULT:  Yes, can we make a

   3   comment on that issue as sleep experts?

   4             DR. KAWAS:  Please.  Yes, you are on the

   5   air.

   6             DR. GUILLEMINAULT:  Okay.  The comment

   7   that I want to make is that currently there is no

   8   drug for cataplexy which is at a fixed dosage.

   9   None.  Because there is a certain amount of

  10   variability from patient to patient, and a patient,

  11   for example, can respond at 20 mg of fluoxetine or

  12   60 mg of fluoxetine.  In general terms, it is

  13   unrealistic to believe that there will be a single

  14   dose which will control all cataplectic attacks for

  15   all narcoleptic patients.  So, you have dose

  16   ranges, and I think that that is what these studies

  17   are showing.  Looking at the data that you have,

  18   efficacy for some patients is at 6 or for some

  19   patients at 9.  And, that is the clinical

  20   experience, 20 years of clinical experience.  That

  21   is the best that you are going to get.  So, your

  22   efficacy for some is 6 and for some is 9.  All

  23   drugs used for cataplexy are like that.  All

  24   patients respond following that scheme.

  25             DR. KAWAS:  Thank you.  Dr. Katz, would 
                                                                321

   1   you like to comment on Dr. Falkowski's concerns

   2   about the orphan status?

   3             DR. KATZ:  The only written rules that I

   4   am aware of which talk about numbers that are

   5   adequate, or are potentially adequate, for an NDR,

   6   or for a typical NDR, there are no numbers written

   7   down anywhere as policy or guidance.

   8             So, as I say, had agreed that a total of

   9   500 was appropriate -- we, the company and the

  10   division.

  11             DR. FALKOWSKI:  So they came up short.

  12             DR. KATZ:  Well, that is the question we

  13   are asking.  There was, on our part, that at least

  14   a big chunk of that would be at a therapeutic dose.

  15   So that is why we are asking you whether or not you

  16   think it is adequately chararacterized.

  17             I just want to make one other comment with

  18   regard to the 6-gram effectiveness and to ask the

  19   company just -- should make this explicit, although

  20   I think Dr. Trout said it a couple of times.

  21             In Study 2, the p-value for the 6-gram

  22   versus placebo contrast was 0.0529, or 0.053, I

  23   believe.  That was including a correction for

  24   multiple comparisons given the three doses.

  25             So you have one study which, basically, 
                                                                322

   1   has a p-value of 0.05 at the 6-gram dose; right?

   2   And then you have what you have seen.  So I just

   3   remind the committee of that.

   4             DR. FALKOWSKI:  And that was the four-week

   5   study, the GHB-2 study; right?  Okay.DR. KATZ:  i

   6

   7             DR. KAWAS:  Any final comments before we

   8   take a vote on the sponsor establishing the safety

   9   of Xyrem when used for the proposed -- well,

  10   actually --

  11             DR. SIMPSON:  Would it be appropriate to

  12   do a revote on the efficacy?

  13             DR. KAWAS:  Not revote, but we can do

  14   another vote on whether or not the panel thinks

  15   that there was efficacy demonstrated at --

  16             DR. SIMPSON:  A dose between 6 and 9.

  17             DR. KAWAS:  Well, I think we will have to

  18   say either a dose of 6 or a dose of 7.5 or

  19   something like that.

  20             DR. KATZ:  Well, if you conclude it is

  21   effective at 6 and you have already concluded it is

  22   effective at 9, it would be sort of odd if it

  23   wasn't effective at 7.5.  So, if you just want to

  24   vote it at 6, we will take it from there.

  25             DR. KAWAS:  Okay.  We are voting on 6.  
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   1   Has the sponsor demonstrated efficacy of Xyrem for

   2   the proposed indication to treat cataplexy at the

   3   dose of 6 grams per day?  All in favor?  All who

   4   agree that the efficacy has been demonstrated,

   5   raise your hand.

   6             [Show of hands.]

   7             DR. KAWAS:  Let's start and identify

   8   yourself as we are going around.

   9             DR. SIMPSON:  Simpson.

  10             DR. ROMAN:  Roman.

  11             DR. WOLINSKY:  Wolinsky.

  12             DR. LACEY:  Lacey.

  13             DR. KAWAS:  All who do not feel that the

  14   company has demonstrated efficacy at 6 to treat

  15   cataplexy, raise your hand.  Start identifying at

  16   that end.

  17             DR. PENIX:  Penix.

  18             DR. VAN BELLE:  Van Belle.

  19             DR. PENN:  Penn.

  20             DR. KAWAS:  And I am the lone abstention,

  21   I think.

  22             DR. FALKOWSKI:  Over here.

  23             DR. KAWAS:  Oh; and Falkowski.  So we have

  24   a split committee for you on 6.  If I vote, I break

  25   it.  Actually, I am fairly convinced that there is 
                                                                324

   1   efficacy at 6.  So Kawas.

   2             Now, safety.  We are now talking safety

   3   between 6 to 9.  We are now talking about a lot

   4   more patient hours, patient years.  The floor is

   5   open for discussion for safety between 6 and 9

   6   grams a day.

   7             DR. PENN:  Can the company give us the

   8   number of patient years exposure 6, 7, 9, total

   9   because we can't do it from your data that we have

  10   seen here.  How close to the magic 500 are you?

  11   Patient years; excuse me.

  12             DR. KATZ:  Not patient years.  250

  13   patients greater than six months, if I added that

  14   up correctly.  That is without Dr. Scharf.  This is

  15   now with, so the numbers are bigger.  Without Dr.

  16   Scharf, I calculate about 250 patients for at least

  17   six months.  Is that about right?

  18             DR. VAN BELLE:  I got 399.

  19             DR. KATZ:  Greater than six months?

  20             DR. VAN BELLE:  Yes.

  21             DR. KATZ:  At 6 and above?  We can just

  22   split the difference.

  23             DR. VAN BELLE:  How many Ph.D.s does it

  24   take to add nine numbers?

  25             DR. KATZ:  I am not a Ph.D.  I can't be 
                                                                325

   1   expected to.  Can you put the slide back without

   2   Dr. Scharf?

   3             DR. KAWAS:  I come to about 150 patient

   4   years of exposure just looking at the individuals

   5   who were on at 12 months or more.

   6             DR. REARDON:  This is the data without Dr.

   7   Scharf included from the ISS.

   8             DR. KAWAS:  I think it is important that

   9   we know exactly what we are looking at so thank you

  10   for pointing that out to us.  On the other hand, I

  11   will say that it is to -- my personal impression

  12   was that Dr. Scharf's data, although it was the

  13   most extensive and the longest term, was collected

  14   the least systematically.  Given some of the other

  15   issues that were brought up about it, it is

  16   probably to your advantage to stick with this

  17   dataset in terms of AEs.

  18             Okay; then the vote is about to be called

  19   for.  If the sponsor has established the safety of

  20   Xyrem when used for the proposed indication at the

  21   dose of 6 to 9 grams per day.  All who think yes,

  22   raise your hands.

  23             [Show of hands.]

  24             DR. KAWAS:  Wait a minute.  Something very

  25   funny just happened here.  It seemed like more 
                                                                326

   1   people were willing to say it was safe at 9 than

   2   are willing to say it is safe at 6 to 9?  Let me

   3   try again.  Who thinks it is safe, raise your hands

   4   now.

   5             [Show of hands.]

   6             DR. KAWAS:  Identify yourself from that

   7   end.

   8             DR. ROMAN:  Roman.

   9             DR. WOLINSKY:  Wolinsky.

  10             DR. PENN:  Penn.

  11             DR. KAWAS:  Kawas in there.  Anyone else?

  12   Who does not think it is safe, raise your hands,

  13   that safety has been demonstrated, established

  14   safety at the dose from 6 to 9 raise your hand now?

  15             [Show of hands.]

  16             DR. KAWAS:  Has not been demonstrated to

  17   your satisfaction.  Falkowski, Simpson, Lacey,

  18   Penix?  Anyone else?

  19             DR. VAN BELLE:  Van Belle abstains.

  20             DR. KAWAS:  And one abstention.  We are

  21   really helping a lot.

  22             DR. KATZ:  I didn't count.  Was that a

  23   split?

  24             DR. KAWAS:  Right down the middle.  Really

  25   helping. 
                                                                327

   1             The third question that the FDA has asked

   2   us to consider is the adoption of a risk management

   3   plan necessary for the safe use of Xyrem.  I would

   4   like to focus us on that question.  First, in a

   5   yes/no way rather than the details of whether or

   6   not, of what belongs in a management program if we

   7   think yes, or what doesn't belong if we think yes.

   8             DR. FALKOWSKI:  I thought part of our

   9   discussion was going to be different elements of

  10   that.

  11             DR. KAWAS:  That is the next part.  First,

  12   let's decide do we need a risk-management program,

  13   yes or no.  And then, if we do, what should be the

  14   elements.  Jerry?

  15             DR. WOLINSKY:  I think there are really

  16   two issues here.  I wish there weren't, but there

  17   are two.  One is the risk-management program and

  18   whether it is critical for the patient population

  19   in which the drug seems to be indicated.  I

  20   actually don't think that is important.

  21             Then the question is is there a risk-management

  22   program that is necessary for the

  23   concerns about the societal risk at large.  There,

  24   I think the answer is absolutely yes.  Because of

  25   that conflict, we may be in an unusual position if 
                                                                328

   1   we favor this drug, favoring, potentially, making a

   2   precedent step in which we put unusual controls on

   3   physicians and patients, more so than we have had

   4   in the past.

   5             I am not sure there is anything wrong with

   6   that, but I am not sure that this is a large enough

   7   forum in which this question should be addressed.

   8             DR. KATZ:  There certainly are precedents

   9   for risk-management programs being necessary for

  10   the safe marketing of the drug.  I don't know that

  11   there are many, but there are certainly -- and I

  12   think you heard about some.  So there is this

  13   precedence for a risk-management program.

  14             Now, the details--I don't know

  15   specifically which details you are thinking about--may make

  16   this more of a precedent.  But, certainly,

  17   risk-management programs of this type or similar

  18   type have been used and have been approved.

  19             DR. WOLINSKY:  I don't disagree with that,

  20   but I think we are talking about whether or not

  21   there is an inherent problem with the drug in terms

  22   of the efficacy, safety level that we are seeing.

  23   Most of the risk-management programs that I am

  24   aware of that have been put in place have been put

  25   in place for the protection of the patient not the 
                                                                329

   1   protection of society.

   2             DR. KATZ:  Again, you have made a

   3   distinction which we have not yet explicitly made.

   4   It is a fair distinction.  I am not sure everyone

   5   agrees that there would be no need for a risk-management

   6   program if it was just--if you weren't

   7   worried about the societal questions.  But it is a

   8   fair point for sure.

   9             DR. PENIX:  Also, isn't it the difference

  10   in the fact that this is a controlled substance and

  11   the other drugs are not that the safety measures

  12   that are put in place for the protection of the

  13   patients are usually not controlled substances.  So

  14   that may be a difference in this particular case.

  15             DR. WOLINSKY:  This is controlled, but I

  16   am not sure that the controlled substances have

  17   this much potential control on them is what we are

  18   suggesting here.

  19             DR. FALKOWSKI:  I have a question which is

  20   has the FDA ever been in a position where they have

  21   a drug coming before them that has already been

  22   scheduled?  This seems to be unique.

  23             DR. LEIDERMAN:  Could I just answer a

  24   couple of these questions?

  25             DR. KAWAS:  Please, Dr. Leiderman. 
                                                                330

   1             DR. LEIDERMAN:  Let me refer you to a

   2   table.  It is actually the last page in your blue

   3   FDA briefing package book.  It actually lists

   4   several examples of risk-management plans for

   5   different drugs that come from different classes

   6   and for different therapeutic indications that are

   7   all in place for various safety reasons within the

   8   FDA, and they range from other controlled

   9   substances, potent opiates in the case of Actiq and

  10   fentanyl, to mifeprex and thalidomide. The risks

  11   and the intended protected individuals may be

  12   different in each case.  Obviously, in thalidomide,

  13   the risk isn't to the patient but to the accidental

  14   fetus.  Similarly, much of the consideration in

  15   Actiq, which is a potent opiate, was concern for

  16   other individuals within the household and, again,

  17   not for an opiate-tolerant severely debilitated

  18   pain patient.

  19             So, to answer Dr. Penix' question, in

  20   fact, or Dr. Falkowski's, some of these have been

  21   already scheduled drugs.  I think what is unusual

  22   but not absolutely unique is to start out with a

  23   drug that is basically in Schedule I and then to be

  24   bringing it into the therapeutic arena but, again,

  25   it is not entirely unprecedented either. 
                                                                331

   1             DR. KAWAS:  Thank you.  I can't help but

   2   point out that it is probably unprecedented, but

   3   this drug has gone from over the counter, a

   4   completely unregulated food supplement that could

   5   be bought by anybody ten years ago to Schedule I,

   6   which seems to me even more unusual.

   7             So we are back to the question about the

   8   adaption of a risk-management plan necessary for

   9   the safe use of Xyrem.  I think the comments that

  10   have been made, that Dr. Wolinsky made, was it may

  11   not be necessary for the safe use but it is

  12   necessary for other reasons.

  13             Can we amend what we vote on, whether or

  14   not it is necessary, period, for whatever reasons

  15   and vote on it in that regard?

  16             DR. KATZ:  Yes; I would prefer you did,

  17   actually.

  18             DR. KAWAS:  Okay.  The real question is is

  19   a  risk-management program necessary.  I have a

  20   feeling we are ready to vote on that.  So I will

  21   call the question.  All in favor say aye.

  22             [Chorus of ayes.]

  23             DR. KAWAS:  No?

  24             DR. PENN:  No.

  25             DR. KAWAS:  Let the record show that Dr. 
                                                                332

   1   Penn voted no.  Any abstentions?

   2             [No response.]

   3             DR. KAWAS:  Dr. Penn, do you want to give

   4   your comments, since you were the descending

   5   opinion.

   6             DR. PENN:  I think this is a very

   7   complicated issue and I don't think we can resolve,

   8   at the end of a committee meeting, the

   9   responsibilities toward the general population of

  10   controlling the drug and the FDA controlling it for

  11   a group of patients.

  12             I see that the whole issue is being

  13   distorted in the same way that drugs for treating

  14   pain have been a problem and that is if we limit

  15   the drug with all these regulations, that the

  16   patient population, which is quite small, will not

  17   be served.

  18             That certainly has been true with narcotic

  19   drugs over the years, that many, many physicians

  20   have underprescribed narcotics for a long period of

  21   time.  I think we will see the same here except

  22   there won't be the same push to get it accepted by

  23   cancer patients.  The narcolepsy group is much too

  24   small.

  25             So it is going to be a very hard balance.  
                                                                333

   1   I also worry about the idea of "voluntary" ways of

   2   doing this.  They are not voluntary on the company.

   3   The company wants to get the drug out and they

   4   realize that they can't do it unless there are

   5   societal controls on the drug and they are willing

   6   to do it.

   7             But I don't like the precedent of the drug

   8   company deciding for a physician whether, for

   9   example, somebody 17-years old will get the

  10   medication or whether somebody, because of

  11   different metabolism of the drug, might not be used

  12   on a slightly higher dose than 9.

  13             Those are things that we have

  14   traditionally let the treating physician do and we

  15   have also not let the company choose who are the

  16   treating physicians.  So I think this is something

  17   that needs a large amount of debate and that is why

  18   I was being obstinate and voting no on this without

  19   qualification.

  20             DR. KAWAS:  Thank you.  Rusty?

  21             DR. KATZ:  Just as far as the dose and the

  22   limitations, that is something that can be

  23   discussed in the context of what type of risk-management

  24   program you think needs to be in place.

  25   You could have a risk-management program that 
                                                                334

   1   doesn't say you cannot ever give a dose greater

   2   than 9 grams.

   3             In a typical drug, when we have labeling,

   4   we have information that the drug is effective or

   5   safe only up to dose X, we don't usually say, "You

   6   can't possibly give any more."  We just say, "Here

   7   is the data.  There is no data above dose X."

   8             So it isn't part and parcel of any risk-management

   9   program that you would automatically

  10   limit the dose.  I supposed you could, but it is

  11   not presupposed that that must be the case.

  12             DR. PENN:  But you might limit age.  The

  13   other thing is who is going to make these

  14   decisions.  We were given this in the context of a

  15   very particular type of risk management.  I think

  16   the devil is in the details in these types of

  17   situations and to vote yes or no is very difficult

  18   without knowing exactly what details we are talking

  19   about.  They make major substantive differences.

  20             DR. KAWAS:  Let's go on.

  21             DR. KATZ:  That is why I wouldn't ask you

  22   to vote on the details.

  23             DR. KAWAS:  That is what I was going to

  24   say.  Let's go on to the details.  I want to remind

  25   the committee, particularly because of the lateness 
                                                                335

   1   of the hour, if there is a detail that is not

   2   important to you, please don't fill up too many of

   3   the airwaves with it so we can get to the ones that

   4   are important to you.

   5             So the first one is should there be a

   6   requirement for additional safeguards; i.e.,

   7   keeping drugs in a locked storage space in the

   8   patient's home.  Just for a straw vote to begin

   9   with.  How many people think that there should be

  10   the requirement for a locked cabinet in the

  11   patient's home?  Anyone who thinks yes?  Straw

  12   vote.  Anyone who thinks no?  Straw vote.

  13             I think we have got a clear preponderance

  14   here.  I think I will at least express my thinking

  15   is that we don't require patients to keep Demerol

  16   or Valium or Halcion or anything else in a closed

  17   cabinet, many of the drugs that are potentially at

  18   least as abusable as this.

  19             Having said that, I think that almost all

  20   drugs belong in a locked cabinet.  That is the real

  21   issue here and I am not sure to what extent

  22   requiring it would make one difference or another.

  23             So, should there be a requirement for

  24   additional safeguards?  Can I say, in general, that

  25   the committee felt that that was not essential, necessary. 
                                                                336

   1             Should there be additional warnings on the

   2   labeling of the dose cups and/or bottle?  Any

   3   comments?

   4             DR. WOLINSKY:  I heard something that I

   5   thought was very insightful from one of the people

   6   who talked to us in the public session and that it

   7   would be useful if there was some distinguishing

   8   feature about the bottles that could not easily be

   9   counterfeited and this was be in everyone's best

  10   interest.

  11             DR. KAWAS:  Thanks.  I assume that would

  12   be something that the company would do to the

  13   bottle rather than something the patient--

  14             DR. WOLINSKY:  I assume so.

  15             DR. DYER:  Are the dose cups to be labeled

  16   because those are not?  So additional would be

  17   additional to that or additional to what is

  18   required by law, because they should definitely be

  19   labeled.

  20             DR. KATZ:  If I can just interject.  I

  21   don't think there is anything required by law.

  22   This is what the patient keeps at home.  Right now,

  23   I think they are just as you see them.  There is

  24   nothing on them.  There is no labeling of any sort;

  25   is that right?  They are just blank? 
                                                                337

   1             DR. KAWAS:  Would the company like to

   2   comment?  Is any additional labeling planned for

   3   the dose cups?  Or maybe it is about to be planned

   4   for the dose cups?

   5             MS. ENGEL:  Actually, no.  As you know,

   6   the poison-control system nationwide is going to a

   7   central 800 number as well as having a logo that is

   8   "Mr. Yuck" like but better tested for kids.  That

   9   we expect to be ready in October.  At that point,

  10   the central pharmacy will put into each of the

  11   packages three stickers, one for the bottle and one

  12   for each dose computer that will include that "Mr.

  13   Yuck" type symbol plus the central 800 number for

  14   the entire poison-control system nationwide.

  15             DR. DYER:  My concern is that if the

  16   bottle ever leaves the little dose caps--if you go

  17   away for a night, I am going to take my two doses

  18   with me.  If they are separated from that bottle,

  19   no one is ever going to know what it is.

  20             MS. ENGEL:  As I said, there are three of

  21   those labels that will go, so one for each--no; it

  22   does not.

  23             DR. DYER:  It needs to say what it is.  If

  24   you go stay at a friend's for the night and you

  25   have narcolepsy and you take those two bottles with 
                                                                338

   1   you, child-resistant caps are designed to keep

   2   children out for one to two minutes.  That is it.

   3   Somebody will get into that and, if they do, there

   4   is no way to know what it is.

   5             When they call that number to the poison

   6   center, they say, "I have a bottle with a "Mr.

   7   Yuck" sticker on it."  It needs to say Xyrem and

   8   now many milligrams.

   9             DR. KAWAS:  I would like to call the

  10   question.  Should there be additional warnings on

  11   the labeling of the dose cups and the bottle of

  12   GHB?  Do I need to separate those two out or can I

  13   put the dose cups together with the bottle.

  14             Let's start with should there be labelings

  15   on the bottles.  All in favor raise their hands?

  16             [Show of hands.]

  17             DR. KAWAS:  Is that almost unanimous?  No?

  18   Labels on the dose cups saying that it is Xyrem or

  19   GHB or something.  That is unanimous, please note

  20   on the record.

  21             How about should there be additional

  22   warnings on the dose cups and/or bottle of GHB?  I

  23   am not sure, maybe I should ask, what is the

  24   definition of additional?  What is supposed to be

  25   on there already?  Dr. Katz? 
                                                                339

   1             DR. KATZ:  I think we are probably mostly

   2   thinking of the cups.  There was supposed to be

   3   nothing on cups.  So anything you put on is

   4   additional.  I don't know about the bottle.  I

   5   don't know if we were thinking specifically about

   6   the bottle.  I assume that has all the usual

   7   required statements, whatever they are.

   8             DR. KAWAS:  Are you satisfied by our vote

   9   that there needs to be labeling on the dose cups?

  10   I think, though, I am starting to feel from the

  11   committee that there is some expression of wanting

  12   certain kinds of warnings added?  No?

  13             DR. DYER:  If I could just add in, by law,

  14   you have to have "Keep out of reach of children,"

  15   "Don't take with depressant drugs," "Avoid

  16   hazardous machinery."  So those kinds of standard

  17   things would be on there and I don't know that

  18   anything else would be required.

  19             DR. KAWAS:  Dr. Lacey?

  20             DR. LACEY:  If this is a scheduled

  21   substance with implications for--legal

  22   implications, why wouldn't we put that type of

  23   warning in as few words as possible there.  Maybe

  24   it would deter someone.

  25             DR. DYER:  There is already a requirement 
                                                                340

   1   for "Federal law prohibits dispensing of this drug

   2   to other than who it is prescribed."  There is

   3   already a label like that required on

   4   prescriptions.

   5             DR. PENIX:  It could also attract certain

   6   people as well, I think.

   7             DR. KAWAS:  Yes; these warning labels have

   8   a mixed response.  Can we move on to special

   9   concern or advice regarding limitations on the

  10   quantity supplied at any one time.  Perhaps the

  11   sponsor can correct me but my recall is that it is

  12   going to be dispensed at one month and then--a

  13   maximum of one-month supply at a time?  Is that

  14   correct?

  15             DR. REARDON:  We had proposed to the

  16   agency initially to start at one month with each

  17   patient.  As the patients and pharmacists get

  18   experience, that might be extended to three months

  19   or could be kept to one month.

  20             I think the FDA is asking should there be

  21   a regulatory or legal description on the length of

  22   period that a Schedule III drug should be

  23   prescribed.

  24             DR. KAWAS:  Rusty?

  25             DR. KATZ:  I am not sure we meant that 
                                                                341

   1   question to be generic with regard to any Schedule

   2   III.  We want to know whether or not, in this

   3   particular risk-management program, there ought to

   4   be a provision that says you only get one month at

   5   a time, or you only get three months at a time.  We

   6   just wanted to know what you felt about that.

   7             DR. KAWAS:  The floor is open for

   8   discussion.  First, do people think there should be

   9   any restrictions on the amount, period, and then we

  10   can discuss the timing.  So straw vote.  All people

  11   who think that we should be talking restriction of

  12   some sort or another raise their hand.  And people

  13   who don't think we need to be talking restriction

  14   on length of time, raise your hands.

  15             We have got a roughly split straw vote

  16   with the probable preponderance on the no time

  17   limit.  Does that help enough?

  18             DR. KATZ:  Sure.  If that is what you

  19   think, it is helpful.  I can't guarantee we will

  20   agree.

  21             DR. KAWAS:  Having worked in sleep

  22   laboratories as well as doing other physician

  23   things where certain drugs--I mean, my personal

  24   rule has been that drugs that have the kind of

  25   potential for trouble, of which there are many, 
                                                                342

   1   many, many of them already in our armamentarium, I

   2   never give out more than one month's supply with

   3   three refills.

   4             DR. FALKOWSKI:  That is why I think that,

   5   particularly with this, we need to be cognizant of

   6   that and that there should be a limitation on that.

   7   That is all I wanted to say.  And I also don't know

   8   where it comes in, or where this discussion

   9   happens, but I really believe that a drug, if you

  10   look at the third page from the back of the

  11   materials the FDA provided about just the

  12   scheduling criteria for drugs, that this drug,

  13   although it is efficacious for people with

  14   cataplexy, with narcolepsy or else on stimulant

  15   drugs, that it clearly--

  16             DR. KAWAS:  Your point it getting lost.

  17             DR. FALKOWSKI:  It should be in Schedule

  18   II.  I believe it should have the dispensing

  19   restrictions that are more consistent with a

  20   Schedule II drug and I don't believe that would put

  21   undue burden on the patients because most of them

  22   are already on Schedule II drugs because they are

  23   on methamphetamines or other drugs.

  24             Somehow, I wanted to say that today.

  25   Thank you. 
                                                                343

   1             DR. KAWAS:  Do you feel satisfied with

   2   what you have heard on that question, Rusty?

   3             DR. ROMAN:  Claudia, one more point is how

   4   are the patients going to be selected.  I think

   5   would should at least mention that the patient

   6   should have a clear diagnosis of narcolepsy with

   7   polysomnogram and MSLT

   8             DR. KAWAS:  You are jumping to Question 6,

   9   but why don't we go ahead and do that since I agree

  10   that is an important point and I am worried we

  11   won't get to it.

  12             So what are your thoughts?

  13             DR. ROMAN:  That patients should have a

  14   recent polysomnogram followed by MSLT in order to

  15   confirm the diagnosis of narcolepsy.

  16             DR. PENN:  Who is going to decide whether

  17   it really is narcolepsy or not?  The government?

  18   The company?  The person who reads the test?  The

  19   doctor that is taking care of the patient?  That is

  20   why I mean the details are very important.  You can

  21   say that it sounds good that we should have a

  22   diagnosis, but these are important points.

  23             DR. KATZ:  Can I just clarify what we

  24   meant?

  25             DR. KAWAS:  Thank you. 
                                                                344

   1             DR. KATZ:  We meant the treating

   2   physician, in other words, would make the

   3   diagnosis.  We certainly, obviously, are not going

   4   to get involved in the diagnosis of a patient from

   5   where we sit.  The company didn't anticipate that

   6   they would either if I can speak for them.

   7             No; we just meant do you think that the

   8   patients have to have a bona fide diagnosis, does

   9   the physician who is writing the prescription have

  10   to assert, in writing, before the prescription will

  11   be filled that, yes, this patient has narcolepsy.

  12             Then you can throw this apart and say do

  13   they have to assert that the patient has cataplexy

  14   and that is what you have decided the effectiveness

  15   data supports.  So that is a subtlety or nuance of

  16   the question you can get to.  But specifically with

  17   regard to who is going to make the diagnosis, if

  18   you meant that question seriously, we meant the

  19   prescribing physician.

  20             DR. KAWAS:  Response to that?  Dr. Roman,

  21   do you want to give your opinion and then Dr.

  22   Wolinsky has a question or comments.

  23             DR. ROMAN:  I think that there are

  24   diagnostic criteria that are sort of fairly well

  25   accepted, at least here in the USA.  The question 
                                                                345

   1   of should it be a certified polysomographer or

   2   should it be one of the certified centers in the

   3   nation, we will start getting into the problem of

   4   what happened with the patient who lives in the in

   5   the middle of nowhere and has no way to get to the

   6   next sleep center at 500 miles.

   7             DR. KAWAS:  Excuse me, but that is not

   8   what Dr. Katz asked you.  He wants to know do you

   9   think the physician needs to certify, however they

  10   come to this decision, that the person has

  11   narcolepsy, that they need to certify up front,

  12   this person definitely has narcolepsy.

  13             DR. ROMAN:  One of the speakers mentioned

  14   that it is relatively simple to get a sleep attack

  15   and narcoleptic episodes that are real enough to

  16   fool the best unsuspecting doctor.  So, since we

  17   have objective ways of making a diagnosis of

  18   narcolepsy, I think we need to use that for the

  19   protection of the public at large.

  20             DR. KAWAS:  Thanks.  Jerry?

  21             DR. WOLINSKY:  I think this actually

  22   frames what is my concern from before about

  23   protecting, or treating patients and protecting

  24   society.  Now I want to get back more to protecting

  25   people who are treated.  That really gets to an 
                                                                346

   1   issue that we run away from in this country and

   2   that is, if we want to be able to push the envelope

   3   to be able to provide drugs that may be helpful for

   4   patients with true orphan diseases, we probably

   5   also have to say that we are willing to make sure

   6   that those people have what they say they have and

   7   that the drugs are being used in the context of the

   8   set of patients in whom they were originally

   9   tested.

  10             It is one thing to talk about hemorrhoid

  11   cream but it is another thing to talk about a drug

  12   with a narrow therapeutic window and a diagnosis

  13   which can be made with accuracy by experts most of

  14   the time and could be misapplied by others a lot of

  15   the time.

  16             This becomes a critical issue so that if

  17   someone is not willing to monitor this, all that we

  18   do, in looking at the hard science of what is

  19   presented to us, flies out the window as soon as

  20   the drug gets approval.

  21             DR. HAGAMAN:  Can I make one quick

  22   comment?  I think, as a physician treating these

  23   patients, if they have had a PSG and MSLT in the

  24   past, there is really no need to bring them back in

  25   for another one.  At that point, you have to trust 
                                                                347

   1   the physician's judgment that yes, they do have a

   2   diagnosis of narcolepsy, they have had the PSG MSLT

   3   done.

   4             DR. WOLINSKY:  I don't think the panel was

   5   questioning that at all.

   6             DR. MIGNOT:  Especially because, in such

   7   cases, you will have to stop medications which is

   8   another problem.

   9             DR. KAWAS:  I don't think that was being

  10   suggested.  So let's move on if we could, please.

  11             DR. SIMPSON:  I don't know if this fits

  12   under it, but the way the question is worded,

  13   should there be restricted prescribing for the

  14   product.  I just want to put in a plea for

  15   prescribing for children.  As far as I can see,

  16   there have been no pharmacokinetic studies in

  17   children and children's pharmacodynamic and

  18   pharmacokinetic profile can be very different from

  19   adults.

  20             So, given its complex pharmacokinetic

  21   profile, as it is, I would be very concerned if it

  22   was prescribed in children based, as is usual, on a

  23   way to a BMI.

  24             DR. KAWAS:  I am not sure that we have

  25   answered your question.  Actually, I still have a 
                                                                348

   1   question that I want the committee to focus on

   2   unless Dr. Katz feels otherwise.  Is it important

   3   that we decide whether or not it needs to be

   4   restricted to people with cataplexy as a component

   5   of their illness?

   6             DR. KATZ:  I am not sure whether or not

   7   you think you have made some sort of recommendation

   8   about whether or not it needs to be restricted to

   9   patients with narcolepsy globally yet.  Do you

  10   think you have, because I didn't hear it if you--

  11             DR. KAWAS:  No; I don't think we have.

  12   You are talking now about certifying that the

  13   person has narcolepsy, at least on some signature

  14   level.

  15             DR. KATZ:  We did not put in how we you

  16   would know that the patient has narcolepsy.  We

  17   anticipated that the physician would make the

  18   diagnosis appropriately.   We didn't ask--I don't

  19   think we did anyway--about whether or not there

  20   should be specific diagnostic criteria that they

  21   have checked off or they have had a recent, or ever

  22   had a polysomnogram.

  23             We anticipate, for purposes of this

  24   question, that the diagnosis would be up to the

  25   physician to make appropriately without any 
                                                                349

   1   additional specific requirements, but I suppose you

   2   could say patients must have a history of

   3   polysomnography and other tests, a multiple sleep

   4   latency test or an MPT before they can be

   5   prescribed this.

   6             You could decide that you think that that

   7   is appropriate.  We left it open intentionally.

   8             DR. KAWAS:  I think the committee needs to

   9   discuss that particular point.  I want to make the

  10   comment, though, before we get too far, I would

  11   tend to leave it open and I recognize all of the

  12   things of modern medicine that all of the people in

  13   this committee are familiar with because we sit at

  14   major medical centers.

  15             But there are people with narcolepsy and

  16   cataplexy at places that do not have access to

  17   sleep-disorder centers and polysomnography.  I

  18   think that needs to be kept in mind or discussed on

  19   some level as we are cogitating about this.

  20             DR. ROMAN:  The problem is that you need

  21   to go through the differential diagnosis of

  22   excessive daytime sleepiness and the differential

  23   diagnosis of cataplexy.  In most cases, that is

  24   going to require at least a polysomnogram, a sleep

  25   test, to rule out obstructive sleep apnea, 
                                                                350

   1   restlessness, and what have you.

   2             So, in most patients, at least those who

   3   present for the first time to get this medication,

   4   I don't see how you can avoid doing these tests.

   5             DR. BLACK:  I hate to interrupt, but a

   6   point that I think is worth bringing up is that the

   7   condition indication here is cataplexy.  Cataplexy

   8   is a clinical diagnosis not confirmed by any

   9   testing or MSLT.  If you are going to limit it to

  10   cataplexy, I think it is important to recognize

  11   that you can't make any verification on the

  12   diagnosis with MSLT as far as the cataplexy goes.

  13             DR. KAWAS:  Since we have you up there,

  14   what percentage of people have isolated cataplexy

  15   without narcolepsy and sleep attacks?

  16             DR. BLACK:  It is incredibly rare.

  17             DR. KAWAS:  Thanks.

  18             DR. BLACK:  Incredibly so.  But, on the

  19   other hand, the incidence of cataplexy and

  20   sleepiness without an  MSLT that confirms it is a

  21   modest subset.  In other words, if you have

  22   cataplexy, you won't necessarily have two sleep-onset REM

  23   periods on your MSLT, so we need to keep

  24   that in mind so that we don't potentially limit

  25   folks with true sleepiness and cataplexy and 
                                                                351

   1   narcolepsy that don't show the MSLT findings.

   2             It is not 100 percent specific or

   3   sensitive.

   4             DR. KAWAS:  We have some people over on

   5   this side who wanted to--

   6             DR. LEIDERMAN:  I just wanted to be clear

   7   about the question that I think we were asking.

   8   What was discussed internally within the agency was

   9   the concern about off-label use.  We all know that

  10   drugs are used often more frequently for other than

  11   their labeled indications.  The question we wanted

  12   to pose for this specific drug, does the committee

  13   recommend restricting its prescription to the

  14   labeled indication.

  15             DR. KAWAS:  So, actually, I think maybe,

  16   put in that context, we could call the question and

  17   try a vote here.  In the opinion of this committee,

  18   are we recommending that this drug needs to be

  19   restricted in some fashion to on-label use?  All in

  20   favor?

  21             [Show of hands.]

  22             DR. KAWAS:  Almost unanimously.  Negative?

  23             [One hand raised.]

  24             DR. KAWAS:  One negative vote from Dr.

  25   Penn. 
                                                                352

   1             DR. VAN BELLE:  I am going to abstain

   2   because I was out of the room.

   3             DR. KAWAS:  Dr. Van Belle is abstaining.

   4   Everyone else voted yes; am I correct?  So, did we

   5   give you a better answer this time?

   6             DR. KATZ:  Yes.  All your answers are

   7   good.

   8             DR. PENN:  Isn't this the first time

   9   anybody has ever suggested that the FDA should be

  10   restricting off-label use of drugs?

  11             DR. KATZ:  I doubt.  I don't know.

  12             DR. PENN:  Isn't it stated in the FDA, all

  13   of your regs, that you do not regulate medicine and

  14   off-label use is up to the physician?

  15             DR. KATZ:  I don't know if it says we

  16   don't regulate medicine but, certainly, I think we

  17   have the authority to do, I think, plenty of things

  18   that some people might consider practice of

  19   medicine.  So I don't think, as far as I know,

  20   there is any--as far as I know, there is no legal

  21   bar to this if that is the question you are asking.

  22   I think we have done it in the past.

  23             DR. KAWAS:  I think that I want to make

  24   the comment that even if it was the first time that

  25   the FDA was doing this, it certainly is not new to 
                                                                353

   1   medicine.  Now, insurance companies routinely make

   2   us do this.

   3             DR. FALKOWSKI:  I have one question, I

   4   guess, or one concern, and I just want

   5   clarification.  Did I not read this correctly?  I

   6   tried to read it all, but nowhere does it says

   7   gammahydroxybuterate.  Is this correct, sponsors,

   8   that there is not the word gammahydroxybuterate in

   9   any of these doctor or patient things.

  10             In terms of issues here, I think it is

  11   very important that the doctor information says

  12   what this is.

  13             MS. ENGEL:  As we worked with our

  14   colleagues in law enforcement, they urged us not to

  15   put gammahydroxybuterate as the generic name of the

  16   materials, et cetera, because they felt, for

  17   example, if you are a patient, and you have

  18   something in your home that says

  19   gammahydroxybuterate, that might actually be an

  20   attractant to a babysitter or someone else.

  21             So the attempt, based on the advice of law

  22   enforcement, was to separate that out.

  23             DR. FALKOWSKI:  I am not talking about

  24   patient materials--to the doctors.  Will the

  25   doctors get to know?  They don't have their 
                                                                354

   1   materials sitting around their home.

   2             DR. KAWAS:  Excuse me.  Dr. Katz, is this

   3   a question you would like the committee to discuss?

   4             DR. KATZ:  I think it is an interesting

   5   question.  I think we can work it out.  The point

   6   is well taken and, as the company says, they have

   7   gotten conflicting advice for good reasons as well.

   8   I think we can work it out.

   9             DR. KAWAS:  Great.  Thanks.

  10             DR. LEIDERMAN:  I just wanted to respond

  11   to Dr. Penn's comment about restrictions on

  12   prescribing.  Actually, there is some very recent

  13   precedence in the non-CNS drug arena.  The drug,

  14   mifepristone, in fact, was approved under very

  15   restricted distribution.  It requires signed

  16   documents by both physician and patient to be

  17   returned to the distributor before--and only a

  18   restricted group of physicians who certify to a

  19   certain ability to handle the complications are, in

  20   fact, allowed to prescribe the drug.

  21             So that is a precedent in the non-CNS

  22   arena.

  23             DR. KAWAS:  I am told that somebody on one

  24   of our phone lines would like to make a comment?

  25   Can you hear us? 
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   1             DR. CHERWIN:  Yes; I had wanted to make a

   2   comment several comments ago, just to briefly

   3   reiterate.  I agree with Dr. Black said which may

   4   be important that not all patients with cataplexy

   5   have positive sleep studies.  So, in addition to,

   6   perhaps, in some cases, sleep studies not being

   7   available, this is another concern.

   8             DR. KAWAS:  Thank you.

   9             DR. CHERWIN:  Another thing is that

  10   cataplexy is not always a crystal-clear diagnosis.

  11   Not too many people have talked about that, but

  12   there can be cataplexy in the eye of one physician

  13   that does not exist in the eyes of another

  14   physician.  That is a potential problem.

  15             Finally, the International Classification

  16   of Sleep Disorders, which is to the sleep field

  17   similar to what the DSM is to psychiatrists, does

  18   not specifically require a sleep study diagnose

  19   narcolepsy.

  20             I thought those three things might be

  21   salient to the discussion especially--since we sort

  22   of jumped to the appropriate prescribing section,

  23   maybe we can run through the questions there and

  24   see how many of them we can quickly comment on for

  25   Dr. Katz and the agency. 
                                                                356

   1             Should physicians document that they read

   2   the material sent to them before the pharmacy fills

   3   the initial prescription?  If we took a straw vote

   4   right now, how many people would say yes?  How many

   5   people would say no?  Since we have got a split

   6   here, of the people who are on the yes side right

   7   now, would some of you like to comment on what kind

   8   of documentation you want?

   9             I mean, are we talking a signature saying,

  10   "I have read the materials that were sent to me,"

  11   or are we talking about something more than that?.

  12   Jerry?

  13             DR. WOLINSKY:  Again, it sort of depends

  14   what we require or what might be expected for a

  15   diagnosis rather than what would be required.  I

  16   think if a sleep specialist is comfortable with the

  17   diagnosis in that patient, and refers the patient

  18   back to treatment to that physician who is back in

  19   North Dakota that you keep mentioning that can't

  20   possibly have all of the diagnostic tests around,

  21   then I think it is important that that physician in

  22   North Dakota knows what they have signed on to.

  23             If it is the sleep specialist who has got

  24   150 patients on treatment because they are very

  25   expert at this, if they have signed the document 
                                                                357

   1   once, that is probably enough for me.

   2             But I think these are details that I am

   3   not sure that we need to work out today.  There are

   4   plenty of things that can be worked out by Russ and

   5   his people.

   6             DR. KAWAS:  Russ and his people gave us

   7   this question.

   8             DR. KATZ:  And we didn't anticipate,

   9   necessarily, a vote.  But right now, as I

  10   understand the program, the initial prescription is

  11   filled and then the physician and the patient have

  12   to send back a card that says, "Yes; I read this

  13   stuff."  It was just some sentiment internally for

  14   all of that documentation that, "Yes; I have read

  15   it.  Yes; I understand it," that is to happen even

  16   before the first prescription was filled.

  17             We are going to get into major problems if

  18   we try and apply a different standard to different

  19   types of treating physicians, the expert versus the

  20   non-expert.  Actually, this was one of the issues

  21   that I actually did want.  A lot of them are not

  22   necessarily that critical but this was one of the

  23   few that I really wanted some discussion on.  There

  24   are a lot of other details I think we can take care

  25   of. 
                                                                358

   1             DR. WOLINSKY:  But I guess I was saying

   2   that, that even the expert would sign it.  He just

   3   wouldn't have to sign it every time he gives out a

   4   new dose.

   5             DR. KATZ:  No, no, no, no.  We don't

   6   anticipate that.

   7             DR. KAWAS:  Once.

   8             DR. KATZ:  I just meant the first time you

   9   give a dose to a particular patient, you would sign

  10   a card before the initial prescription was filled

  11   for that patient.  That is what I think we

  12   anticipate.

  13             DR. FALKOWSKI:  On a patient by patient?

  14             DR. KAWAS:  I want to make the comment

  15   that I am comfortable with the notion of physicians

  16   having to sign for this potentially, but I am not

  17   comfortable with what was suggested as a mechanism

  18   to have it happen by the sponsor and that is

  19   sending a drug representative to the physician's

  20   office.  I really feel very strongly that is not

  21   the way this should be done.

  22             Dr. Penix?

  23             DR. PENIX:  This is a question for Dr.

  24   Katz.  What is the purpose of the physician signing

  25   such a document? 
                                                                359

   1             DR. KATZ:  It is just to acknowledge that

   2   they have read the material and that they are

   3   familiar with its safe use and that they have

   4   spoken to the patient about its safe use.

   5   Actually, that is a separate question, but it is

   6   all combined--that they know how the drug should be

   7   used, what its risks are, what the penalties are

   8   for inappropriate use.

   9             DR. KAWAS:  Doesn't it also sort of

  10   acknowledge that this is a somewhat unusual drug in

  11   some sense because every drug has all these risks

  12   in prescribing and we don't ask any physician to

  13   sign for all those drugs.

  14             I sense on the committee a growing concern

  15   that the more drugs we have to sign for, the more

  16   uncomfortable they are becoming.  But I think,

  17   really, it points out to the physician who is

  18   signing it that there is something different here.

  19             DR. PENIX:  I think, also, in that sense,

  20   it is important for the physician-information

  21   packet that they are aware that this drug is GHB

  22   and so, therefore, they may understand why it is

  23   required for them to sign this information.

  24             I think that is really the bottom line.

  25   So I think it would be useful for a treating 
                                                                360

   1   physician to know what type of drug this is.

   2             DR. FALKOWSKI:  I would say yes only if it

   3   says it is GHB.

   4             DR. DYER:  Wouldn't CII make that implicit

   5   to know that this is a drug that has illegal

   6   implications and would be dangerous?

   7             DR. KATZ:  It is Schedule III.

   8             DR. DYER:  I am saying it belongs in

   9   Schedule II.

  10             DR. KATZ:  I think that question has been

  11   dealt with definitively.  It has been legislated as

  12   Schedule III by Congress.

  13             DR. FALKOWSKI:  Right.  That was

  14   legislated at another time.

  15             DR. PENIX:  Not to belabor this, but I

  16   agree with that drug company's position not to let

  17   the patient information--or not include GHB in the

  18   patient information.  But I think the treating

  19   physician should be aware of that.

  20             DR. KAWAS:  I think that is a very

  21   important point because physicians do have a

  22   knowledge base of GHB even if it is from the

  23   newspaper or whatever to insure that they

  24   understand what it is.

  25             DR. ROMAN:  It also has the legal 
                                                                361

   1   implications of a physician somewhere who has been

   2   prescribing this at a higher rate than expected for

   3   that population.  He may find his licensing--and a

   4   problem if they find that he is prescribing more of

   5   these, let's say more than a couple of patients in

   6   a year, or whatever it is that delimits.

   7             So we need to look into that because there

   8   is potentially a risk for medical licensing.

   9             DR. KAWAS:  Can we see if we have shifted

  10   the straw vote from about a 50:50 split to

  11   something that is more consensuslike for the

  12   agency?  On the question, should physicians

  13   document that they read the material sent to them

  14   before the pharmacy fills the initial prescription,

  15   presumably, some of those materials would

  16   incorporate the fact that what this drug really is

  17   is GHB whether or not it is on the bottle.

  18             All in favor?

  19             [Show of hands.]

  20             DR. KAWAS:  Nos?

  21             [Show of hands.]

  22             DR. KAWAS:  And no abstentions.  So let

  23   the record show that nos were Dr. Richard Penn and

  24   Dr. Gerald Van Belle.  The remainder of the

  25   committee voted yes.  No abstentions. 
                                                                362

   1             Should physicians be required to

   2   demonstrate safe use and appropriate dosage

   3   preparation to patients before the first

   4   prescription and be required to document that it

   5   has been accomplished?  Do we want to try a straw

   6   vote and see if we can keep on going?

   7             I think I will make the comment that

   8   patient education is too important and sorely

   9   underdone in this medical world that that is true

  10   for everything.  I think, personally, that it would

  11   be the hope that, with all drugs, that the

  12   healthcare team will insure these demonstrations.

  13   I am going to suggest that we do not need to

  14   require any specific demonstration or any specific

  15   certification of this process.

  16             I see some heads going in different

  17   directions.  Let me get a straw sense on this one.

  18   Should physicians be required to demonstrate safe

  19   use and dosage?  How many people are going to say

  20   yes?  Straw vote.

  21             DR. FALKOWSKI:  Is the intent here that it

  22   just be demonstrated regardless of who does it,

  23   whether it is a nurse or a physician?  What is your

  24   intent?

  25             DR. KATZ:  The intent was that--I don't 
                                                                363

   1   think we necessarily meant the physician but

   2   someone responsible in the physician's employ.  It

   3   shows them how to draw it up and how much your dose

   4   is.

   5             DR. FALKOWSKI:  Should somebody

   6   demonstrate how you administer this drug before the

   7   patient takes it.  So I think that is a good

   8   question.  Can we take a vote on that?

   9             DR. KAWAS:  You mean someone in the

  10   physician's office should be required to

  11   demonstrate it and, in some way, ascertain it.  The

  12   question is called on that.  Who votes yes?

  13             DR. VAN BELLE:  Before we vote, there is a

  14   further addition to that statement here, and it

  15   says, "And be required to document that it has been

  16   accomplished."  Are you intending to have that

  17   included as well?

  18             DR. KAWAS:  I think everything that

  19   happens in a physician's office needs to be

  20   documented.  So, yes.  That is why we are writing

  21   twenty-seven page H&Ps right now.

  22             So we have got one vote yes?  Is that all?

  23   Dr. Falkowski.  No votes?

  24             [Show of hands.]

  25             DR. KAWAS:  Abstentions. 
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   1             [One hand raised.]

   2             DR. KAWAS:  We have got one abstention

   3   with Dr. Simpson and the remainder of the committee

   4   voted no.

   5             DR. WOLINSKY:  Having voted no on that in

   6   terms of the office personnel and the physician, it

   7   seems to me that it would be advantageous to the

   8   company to have first doses shown in the home when

   9   medication arrives.  This is actually the effective

  10   education.

  11             What goes on in the physician's office, my

  12   bias is, may not be as effective as with home nurse

  13   agents.

  14             DR. KAWAS:  I think we are not going to

  15   repeat the restricted prescribing for the drug

  16   question.  We have gone over that adequately, I

  17   hope.

  18             But the next one, does the risk-management

  19   program assure appropriate prescribing or

  20   sufficiently reduce the risks of misuse or

  21   overdose.  I am not quite sure where to start with

  22   this one.  Actually, Dr. Katz, which components of

  23   the risk-management program are you asking us to

  24   comment on?

  25             DR. KATZ:  That is a fair question.  This 
                                                                365

   1   is sort of a global question, I think.  To the

   2   extent that you have seen the details of the

   3   proposal, is there anything that leaps out at you

   4   as being absolutely inappropriate, or is there

   5   something that is not there that is a glaring

   6   omission that you all believe absolutely should be

   7   there?

   8             I think that is sort of the sense of the

   9   question.

  10             DR. PENN:  Yes.  I don't think the

  11   potential problems of the drug are explained to the

  12   patient adequately.  That is, the narcoleptic

  13   patient won't necessarily know that this is an

  14   abused drug or if they take it in the wrong way

  15   that they can get into a lot of trouble and that

  16   the real education has to be to the patient in some

  17   manner.

  18             I usually think that is the responsibility

  19   of the physician to do that, but I don't see that--I mean,

  20   we are protecting the patient from knowing

  21   what the name of the drug is.  We are protecting

  22   them from knowing what the real side effects might

  23   be.

  24             It doesn't say that if you take double the

  25   dose, it may have more than double the effect and 
                                                                366

   1   that you may go into coma and become incontinent

   2   and have seizure--well, probably not seizure but

   3   stop breathing or something unpleasant like that.

   4             I think the emphasis should be on the

   5   patient understanding the medication and how to use

   6   it.  The  narcoleptic community suffers enough and

   7   has pretty good ways of letting each other know

   8   about the disease.  Maybe you should use their

   9   ability to instruct patients on the proper way to

  10   do it and combine it in some way.

  11             But that is where I think the glaring

  12   error is.  This is a drug with very little leeway

  13   for dosing and people have to understand they

  14   shouldn't use it during the day, for example,

  15   because they won't have this period of time off.

  16             So I think there is a huge amount to be

  17   done.  I just don't like to see it done in this

  18   mandatory fashion because I don't think it will

  19   work.  You will get a lot of signed papers, but you

  20   won't get the education you need done.

  21             DR. KATZ:  But I just want to clarify.  I

  22   understand your reservations about the entire

  23   process but,  given that there is a document that

  24   goes to the patient that ostensibly tells them what

  25   they need to know about using the drug safely, you 
                                                                367

   1   believe that that document that is currently

   2   written really needs to be beefed up as far as

   3   communicating to the patient what the risks are and

   4   how to use it?

   5             DR. PENN:  Yes; I think that the patient

   6   has to know what it is, that it is an abused

   7   substance that potentially can be abused.  It would

   8   be like our not telling patients who use oxicodon

   9   not to chop it in two and take it.  That gets them

  10   into trouble and they ought to know about that.

  11             So there is a lot of education that has to

  12   be done with this medication.

  13             DR. FALKOWSKI:  I think I already

  14   addressed this question by saying I think the word

  15   gammahydroxybuterate should appear for patients and

  16   particularly for the physicians, the prescribing

  17   physicians.  What is the secret?  The way to have a

  18   drug come into the market when it is already a

  19   substance of abuse is not to pretend it doesn't

  20   exist and not even call it what it is.

  21             I don't think that is an informed approach

  22   for physicians to know what it is.

  23             DR. LACEY:  Just as one presenter, and I

  24   don't remember who, today gave us the common names,

  25   the club names and everything.  I think the patient 
                                                                368

   1   actually should be provided with as much of that

   2   information as possible.  To not want to put it on

   3   the printed book or something because it is exposed

   4   to someone else is one thing.  But the patient

   5   should be provided as much information as possible

   6   to know what they are dealing with.

   7             DR. KAWAS:  Any other comments before we

   8   move on to the next question?  Jerry?

   9             DR. VAN BELLE:  Let me just make a

  10   comment.  I agree with that and, also, from the

  11   practical point of view, we have already heard this

  12   afternoon that the narcolepsy website network is

  13   just far flung.  If this is going to be approved by

  14   the FDA, the word will be out in the next fifteen

  15   minutes.

  16             So to play coy and not put it on one set

  17   of labels is just not going to work.

  18             DR. ROMAN:  I completely agree.  The USA

  19   Today had the title, "Company wants date-rape drug

  20   approved for a sleep-disorder treatment."  If that

  21   is in the newspapers--

  22             DR. FALKOWSKI:  This question is--it is my

  23   understanding, and I asked for clarification for

  24   this prior to the beginning of this meeting today--that we

  25   are voting here on specific questions.  Is 
                                                                369

   1   the determination of approval made upon FDA's

   2   consideration of what we talked about today?

   3             DR. KATZ:  Well, sure.

   4             DR. FALKOWSKI:  Is it made today?

   5             DR. KATZ:  Is the decision about what to

   6   do with the application made today?  Absolutely

   7   not, no.  Your opinions are all advisory.  We take

   8   them very seriously and then we go back and we

   9   discuss it internally and we come to a decision, by

  10   the PDUFA due date.

  11             DR. KAWAS:  Going to the next question,

  12   can I ask, Dr. Katz--tell us what do you mean by

  13   certification and certification of physicians for

  14   prescribing?

  15             DR. KATZ:  There was some sense,

  16   internally, on the part of some people that

  17   physicians should--first of all, that it might be

  18   restricted to use only by sleep experts or

  19   physicians would have to somehow take a test to

  20   show that they know about narcolepsy, that sort of

  21   thing, that they are appropriate prescribers in

  22   some sense.

  23             DR. KAWAS:  So we are not talking about

  24   the same thing that we were talking about

  25   previously, documenting that they have read 
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   1   whatever materials with the first prescription that

   2   they write?

   3             DR. KATZ:  It is something more than that.

   4             DR. KAWAS:  Okay.  Let's take a straw vote

   5   on that.  I think we can get past that one

   6   potentially fast, then.  We are talking about more

   7   than just documenting that you have seen materials.

   8   Should certification of physicians, or some other

   9   restrictions, for prescribing Xyrem be required?

  10   Straw vote.  How many people think yes?  How many

  11   people think no?  How many people are abstaining?

  12             Let the record show that Dr. Wolinsky

  13   abstained.  I am not sure, but I need to know why.

  14             DR. WOLINSKY:  Well, I am internally

  15   conflicted on this.  When I say conflicted, I don't

  16   mean that I have some stockholdings anywhere but

  17   that I am--

  18             DR. KAWAS:  Anyone knows when they use

  19   that word they have time on the floor.

  20             DR. WOLINSKY:  I haven't come to a final

  21   decision in my own mind, but I would lean towards,

  22   I guess, certification of physicians when the

  23   circumstances are special.  That doesn't actually

  24   keep patients from assessing care.  It may mean

  25   that they have to be diagnosed in an appropriate 
                                                                371

   1   situation and then can be cared for by a physician

   2   who is willing to educate themselves about how to

   3   best use the drug.

   4             I know that most of my colleagues won't

   5   like this but I think that this is where we have to

   6   go if medicine is to maintain credibility with an

   7   increasingly complex medical world that we live in.

   8             DR. KAWAS:  Now to go backwards to No. 5,

   9   which the questions deal with safe use by the

  10   patient.  Should the patient sign an informed

  11   consent form before receiving the initial shipment

  12   of the drug?  Straw vote.  How many people think

  13   yes?  How many people think no?

  14             I won't ask Dr. Penn.

  15             DR. PENN:  I am worried about the medical-legal

  16   implications of informed consent in this

  17   situation.  What does informed consent mean?  Who

  18   signs it?  All the things we get to in the

  19   controlled trials and that we deal with daily in

  20   the university setting.

  21             It seems to me that, unless we work out

  22   the details, I can't feel comfortable voting for

  23   it.

  24             DR. KAWAS:  Actually, I abstained on the

  25   straw vote.  My concern, and maybe my question is, 
                                                                372

   1   informed consent about what?  Presumably, we are

   2   talking about some version of the education that we

   3   have said they need to have.  So is this just an

   4   acknowledgment of that education?  What is it we

   5   want to make sure that they are informed about and

   6   get a signature to verify that?

   7             DR. KATZ:  Usually, informed consent is--it mostly

   8   emphasizes the potential risks.  There

   9   are drugs, of course, that have informed consent as

  10   part of their approval.  So that was the question.

  11   Given the potential risks of this particular

  12   treatment, do people think that patients need to

  13   sign an informed consent.

  14             It is unusual, but there certainly are

  15   precedents for it.

  16             DR. PENIX:  I think informed consent does

  17   imply a certain medical-legal situation but,

  18   perhaps, a contract like they use in many pain-management

  19   centers so that the patients acknowledge

  20   the problems with the dispensing of the drug and

  21   that type of thing.  So maybe a contract would be a

  22   better idea than an informed consent.

  23             DR. KATZ:  Again, we put it on the list

  24   because it was raised internally at several

  25   discussions that we had.  It doesn't mean that we 
                                                                373

   1   necessarily, as a group, endorse it or most of us

   2   think it is a good idea.  It was an option.  We

   3   wanted to see what you thought about it.

   4             DR. WOLINSKY:  Call that question again.

   5             DR. KAWAS:  Does that mean you want to

   6   change your vote?

   7             DR. WOLINSKY:  I would like to withdraw my

   8   yes because this is much more complicated than

   9   immediately meets the eye and goes beyond what we

  10   really need, given all the other things that are

  11   already in this package.

  12             DR. KAWAS:  Okay.  Do we need any more

  13   discussion before we call the question the second

  14   time?  Any other comments people want to make?

  15   Should patients sign an informed-consent form

  16   before receiving the initial shipment of the drug.

  17   All who think yes, raise their hand.

  18             [Show of hands.]

  19             DR. KAWAS:  Let's go around the table and

  20   identify the yes votes.

  21             DR. SIMPSON:  Simpson.

  22             DR. FALKOWSKI:  Falkowski.

  23             DR. ROMAN:  Roman.

  24             DR. LACEY:  Lacey.

  25             DR. VAN BELLE:  Van Belle. 
                                                                374

   1             DR. KAWAS:  All who think no.

   2             DR. WOLINSKY:  Wolinsky.

   3             DR. KAWAS:  Kawas.

   4             DR. PENN:  Penn.

   5             DR. PENIX:  Penix.

   6             DR. KAWAS:  Okay; we are set there.

   7             Furthermore, should the patients be

   8   required to return a registry form before receiving

   9   the first shipment?  Now, I assume that a registry

  10   form that we are talking about is kept by the

  11   sponsor?

  12             DR. KATZ:  Again, this analogous to what

  13   we talked about with the physician.  The idea here

  14   was right now, the plan calls for such a form to be

  15   submitted after the first prescription is filled,

  16   that they have read the materials, they have

  17   received them and they have read them.

  18             The question here was just whether or not

  19   you think that all has to happen before they even

  20   get the first dose.

  21             DR. KAWAS:  To my mind, that simplifies it

  22   considerably, then.  Straw vote.  How many people

  23   think yes, it should be done before not after or

  24   with the first dose.

  25             DR. SIMPSON:  Is this in addition to the 
                                                                375

   1   consent form?

   2             DR. KAWAS:  This is different than the

   3   consent form; yes.

   4             DR. SIMPSON:  So, would it be in addition?

   5   I mean, if they did the consent form, would they

   6   need to fill out another form and send it in?

   7             DR. KAWAS:  I am not sure I am the right

   8   person to answer that because I don't know whether

   9   or not there is going to be a consent form.  But

  10   maybe Dr. Katz could--

  11             DR. KATZ:  We asked it separately.  They

  12   are two different things, although they are very

  13   closely related, I suppose.  If you sign a informed

  14   consent that says, "I know what the risks are.

  15   "The card--what do we call it--a registry card.

  16   That presumably could be something that says, "I

  17   have read the material.  I assert that I know how

  18   to draw the appropriate dose up.  I know how to mix

  19   it.  I know that I have to mix both doses first."

  20             They have a sense of how it is supposed to

  21   be taken.  So you would imagine it would have

  22   different information, could have different

  23   information, than an informed-consent form.

  24             DR. KAWAS:  So the registry, actually,

  25   has--it is not just a name, address, serial number 
                                                                376

   1   of a person who is getting the drug.  That is not

   2   what we are talking about in the registry form?  We

   3   are talking about--

   4             DR. KATZ:  I think the idea here was, as I

   5   said before, whether or not, analogous to the

   6   question with regard to the physicians, that they

   7   have read the materials, what I intended, anyway,

   8   for this question was the exactly analogous

   9   situation for the patient.

  10             Should the patient have to send the form

  11   back.  It would be a registry form, I suppose, in

  12   terms of who they are, but the pharmacist already

  13   knows who they are so they get into the registry

  14   that way, I suppose.

  15             But whether or not they have read the

  16   material and they understand what the risks are and

  17   they understand how to take the appropriate dose,

  18   just before the first dose.

  19             DR. KAWAS:  Okay.  Now I think we can

  20   better take a straw vote.

  21             DR. SIMPSON:  I just wanted to say I

  22   thought the consent form was that.

  23             DR. KAWAS:  But, having rephrased it for

  24   us, I think essentially what we are saying is now

  25   we have said that we want the physicians to certify 
                                                                377

   1   that they have read, know and understand some of

   2   the issues, the question is, should we ask the

   3   patients to do the same thing.

   4             All who think yes, raise your hand.

   5             [Show of hands.]

   6             DR. KAWAS:  And nos?

   7             [Show of hands.]

   8             DR. KAWAS:  I think we have got a bunch of

   9   abstentions, mostly.  Would you like to comment no

  10   your thinking?

  11             DR. PENIX:  I think it is just pretty

  12   complicated.  I am not sure what a registry is

  13   going to do, what the drug company is going to do,

  14   with the information, who should keep the

  15   information.  There are a lot of different issues,

  16   so I guess, in the late hour, I am going to

  17   abstain.

  18             DR. LACEY:  I would think these two things

  19   could be combined into one some way or the other.

  20   If they can't, it is just getting to be too

  21   complicated in terms of all the forms and whatever,

  22   so they are losing interest in it.

  23             DR. KAWAS:  Are you talking about the

  24   patient or the committee?  No; I think that

  25   something really important was just said here, 
                                                                378

   1   actually.  I think that if we put too many layers

   2   that nobody is going to pay attention to any single

   3   layer here.  The whole idea is to do exactly the

   4   opposite, to have both the patients and the

   5   physicians taking this seriously.

   6             Anybody can write in a patient's chart, "I

   7   have demonstrated how to do a safe dosage through

   8   the patient," and signed their initials.  That only

   9   takes a few seconds.  Getting them to spend the

  10   time to do it in the office is quite a different

  11   thing.

  12             Obviously, what is more important is what

  13   is actually done and not what is certified.  But

  14   let me see if I am getting the flavor from this

  15   committee that, in general, they think there should

  16   be one certification, registration, informed-consent process

  17   or whatever for both physician and

  18   for patient.  Is that the gist of what we have been

  19   saying?

  20             All who agree with that statement, straw

  21   vote, yes.  All who think no.

  22             DR. PENN:  I abstain.

  23             DR. KAWAS:  Oh, gosh.  And Dr. Penn

  24   abstains and we are not going to even bother

  25   finding out why. 
                                                                379

   1             Dr. Katz?

   2             DR. KATZ:  Given the late hour and the

   3   list that still remains, I don't think we really

   4   need much in the way of discussion or even a vote,

   5   or a straw vote, on any of the other remaining

   6   issues.

   7             I would ask, though, the committee members

   8   to just sort of quickly glance at it, or not, as

   9   you wish.  But, again, if there is anything that

  10   strikes you as being a glaring omission in the

  11   program as proposed and as amended by your previous

  12   votes, just sing out.  But I don't think we need

  13   any detailed discussion of the rest.  I think we

  14   can sort of work it out.

  15             DR. KAWAS:  I would like to make the

  16   comment that, at least on the postmarket

  17   surveillance, I think there should be required

  18   postmarketing reporting, surveillance, monitoring.

  19             DR. PENIX:  In addition to the usual

  20   adverse effects, of course.

  21             DR. KAWAS:  Are there any other comments

  22   or thoughts from the committee particularly on the

  23   items we didn't specifically discuss like central

  24   pharmacy, postmarketing surveillance or other

  25   recommendations on protecting-- 
                                                                380

   1             DR. SIMPSON:  I guess there was just one

   2   issue brought up about who would police the

   3   policemen.

   4             DR. KAWAS:  You want to more specific in

   5   which policemen we are talking about?

   6             DR. SIMPSON:  The issue was whether the

   7   drug companies should be policing the correct usage

   8   of the drug and then, if that were the case, who

   9   would be policing that the drug company were doing

  10   it right.  And, if the physicians are supposed to

  11   be making sure that the patients are doing it

  12   right, and so on.  That is what I mean.  There is

  13   layer on layer here.

  14             DR. KAWAS:  Let's start with the first

  15   layer about if there is a surveillance or whatever

  16   from the company.

  17             DR. KATZ:  Again, in some sense, we are

  18   always in a position to oversee what the companies

  19   do in terms of meeting their appropriate reporting

  20   requirements and this sort of thing.

  21             I think there is an understanding that

  22   what comes out of this registry and the experience

  23   will be reported to us.  It will have to be

  24   reported to us.  We will be working in close

  25   cooperation with the company to make sure that this 
                                                                381

   1   happens.

   2             We won't be down at the first line making

   3   sure that the pharmacist is calling the patients

   4   within 24 hours.  But, like many other things,

   5   there is an understanding that the company is

   6   responsible for making sure any given system of

   7   surveillance is working appropriately and we have

   8   interactions with them periodically.

   9             So that is as far as we have gotten.

  10             DR. LEIDERMAN:  There are also precedents,

  11   at least for independent monitoring committees.

  12   And that has certainly been in approval agreements

  13   in the past.  So that is the kind of thing that I

  14   think we need to work out.

  15             DR. KAWAS:  Unless there are any more

  16   burning comments or thoughts or theories, I would

  17   really like to thank the company, the agency, the

  18   members of the panel and all the invited speakers

  19   as well as the speakers from the public forum for

  20   this interesting and challenging day

  21             This meeting is now adjourned.

  22             [Whereupon, at 6:00 p.m., the meeting was

  23   adjourned.]

  24                              - - - 