DEPARTMENT OF HEALTH &~D HUMAN SERV:CES
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`FOOD AND DRUG ADMINIS,RATION
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`CENTER FOR DRUG ~VALUATION AND RESEARCH
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`1
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`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
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`ADVISORY COMMITTEE
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`Wednesday, June 6, 2001
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`8:15a.m.
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`Ho:iday Inn
`Bethesda, Maryland
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
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`FOOD AND DRUG ADMINIS,RATION
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`CENTER FOR DRUG ~VALUATION AND RESEARCH
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`1
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`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
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`ADVISORY COMMITTEE
`
`Wednesday, June 6, 2001
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`8:15a.m.
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`Ho:iday Inn
`Bethesda, Maryland
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 1 of 400
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`PART::LCIPANTS
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`Claudia H. Kawas, M.D., Cor.sultar.t and Actir..g
`Chairman
`Sandra Titus, Ph.D., Executive Secreta~-:y
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`MEMBERS:
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`Ella P. Lacey, ?h.J., Consumer Rep~esentative,
`LaRoy P. Penix, M.D.
`Richard D. Penn, M.D.
`Gerald Van Belle, Ph.D.
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`CONSTJLTII.NTS:
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`Gustavo C. Roman, M.D.
`Jerry S. Wolinsky M.D.
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`XYREM CONSU!,TA..'JTS:
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`VOTING:
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`Pippa Simpson, Ph.D.
`Carol Falkowski, Ph.D.
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`NON-VOTING:
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`Christine A. Sannerud, Ph.D.
`Jerry Frankenhcim, Ph.D.
`Jo-Ellen Dyer, Ph.D.
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`ON PONE-LINK - NON-VOTING:
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`Ronald Chervin, M.D.
`Christian Guilleminault, M.D.
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`FDA:
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`Robert Temple, M.D.
`Russell Kat=, M.D.
`Ranjit Mani, M.D.
`Jo~n Feeney, M.D.
`Deborah R. Leidcrman, M.D.
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` PAR1003
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`C 0 N T E N 7 S
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`Call to Order and Introductions
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`Conflict of Interest
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`FDA Overview, Russell Katz, M.D.
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`Orphan Medical Presentation:
`Introduction, David Reardan, Ph.D.
`Medical Need, Emmanuel Mignot, M.D.
`Efficacy, William Houghton, M.D.
`Polysomnographic Effects of Xyrem, Jed Black, M.D.
`Safety and Summary of Risk/Benefit Assessment,
`William Houghton, M.D.
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`FDA Response to the Presentation, Ranjit Mani, M.D.
`Committee Discussion and Deliberations
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`FDA Invited Speakers on Risk Management. Issues:
`Epidemiology of GHB Abuse Issues,
`Carol Falkowski
`Adverse Medical Effects with GHB,
`Jo Ellen Dyer
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`Sponsor Pn~sentation on Risk Managem~nt. and Abuse
`Liability, Bob Balster, Ph.D.
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`Risk Management, Patti Engel, R.N., BSN
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`Open Public Hearing:
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`Sharon Fitzgerald, Littleton, Colorado
`Richard T... Gelulla, MSW, National Sleep
`Foundation
`AbbeyS. Meyers, National Organizat:ion
`for Rare Disorders, Inc.
`Robert L. Clo'...ld, Narcolepsy Network
`Cindy Pek-3-rick
`Eric C. Strain, M.D., College on Problems of
`Drug Dependence
`Deborah Zvorsec, Ph.D., Her..nepin Cnur:ty
`Medical Center
`Trinka Porrata, LAPD
`Matt Speakman
`Charles F. Cichon, National As so:::\ i::lt.:!.or.. of Drug
`Diversion Investigators
`Debbie A~umba'...lgh, Michael's ~essage
`Foundation, Inc.
`Brian A. Hunter, Young Adults with ~arcolepsy
`Joe Spillane, Pbarm.D., ABAT
`r-1ali Einen
`Sand1: a Jon.:-:s
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`Continued Committee Discussion u.nd DeliDcrat.ions
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`P R 0 C R E D I N G S
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`Call to Order and Ir.t~·od'J.ctions
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`DR. KAWAS: Good morning, everyone, and
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`welcome to the Wednesday, June 6, 2001 meeting of
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`the Peripheral and Central Nervous Sy£;tem Advisory
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`Committee. My name is Claudia Kawus, and I think
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`we can begin with introductions, please, perhaps
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`over by Dr. Temple•s side.
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`DR. TEMPLE: Bob Temple,
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`I am the Office
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`Di~·ector.
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`DR. KATZ: Russ Katz, Division of
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`12 Neuropharmacological Drug P~·oducts, FDA.
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`DR. FEENEY:
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`John Feeney, neurology team
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`leader, FDA.
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`DR. MANI: Ranjit Mani, medical reviewer,
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`Neurophi:irm., FDA.
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`DR. LEI DERMAN: Deborah ~.eiderman,
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`18 Director, Controlled Substance Staff, FDA.
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`DR. SIMPSON: Pippa Simpson, University of
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`20 Arkansas Medical Sciences, biostatistician.
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`DR. FALKOWSKI: Carol Falkowski, drug
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`abuse researcher, Hazelden Foundation.
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`DR. ROMAN: Gustavo Romar:., Professor of
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`24 Neurology at the University of Texas, San Antonio.
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`DR. WOLINSKY:
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`Jerry Wolinsky, Professor
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`of Neurology, Unive~·sity of Lexas, nouston.
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`DR. TITUS' Sandy Titus, FDA, the
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`administ~ator of the Peripheral ar.d Central Nervous
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`System Committee.
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`DR. PENN:
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`Richa~d Penn, neurosurgeon at
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`the University of Chicago.
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`DR. LACEY: Ella Lacey, p~ofessor emerita,
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`Illinois University, Carbondale, Tllinois.
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`DR. VAN BELLE, Gerald Van Belle,
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`10 Department of Biostatistics, from the University of
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`11 Washington.
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`DR. PENIX: LaRoy Penix, Associate
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`Professor of Neurology at Moorehouf.;e School of
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`14 Medicine.
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`DR. SANNERUD: Christina Sannerud, Drug
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`and Chemical Evaluation Section, D-::-ug Enforcement
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`Administ~ation.
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`DR. DYER,
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`I am Jo Dyer, with the
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`19 University of California, San Francisco and the San
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`Francisco Poison Control System, Ca~ifornia.
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`DR. FRANKENHEIM:
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`Jerry Frankenheim,
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`pharmacologist, National Institute on Drug Abuse.
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`DR. Y.AWAS; Today we have met to discuss
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`the conside;.ation of Xyrem, proposed to reduce the
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`incidence of cataplexy and to imp:ove the symptom
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`of daytime sleepiness for persons with narcolepsy.
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`The main focus of the deliberutions will also be on
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`risk management issues.
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`If we could ask Dr. Titus to begin with
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`the conflict of interest statement?
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`Conflict of Interest Statement
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`DR. TITUS: Before I begin the conflict of
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`interest statement, I just wunt to announce that we
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`have two people on line with us, Dr. Chervin and
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`10 Dr. Guilleminault. They are both in a room
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`listening to us and will participate with us on the
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`The following announcement addresses the
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`issue of conflict of interest with regard to this
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`15 meeting and is made a part of the record to
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`preclude even the appearance of such at this
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`17 meeting.
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`The special government employees
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`participating in today's meeting have been screened
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`for interests in Orphan Medical's Xyrem and for
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`interests in the products and sponsors deemed by
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`the agency to be competing. Bused on the agency's
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`review of each participant's response to the
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`conflict of interest screening, it has been
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`determined that there is no potential for a
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` PAR1003
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`conflict of ir.terest with regayd to this meeting.
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`With respect to FDA 1 s invited guests,
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`there are reported affiliations which we believe
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`should be made public to allow the participants to
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`objectively evaluate their. comments.
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`Dr. Ronald Chervin would like to disc:ose
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`fo~- the record that he has a contract with Cephalon
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`to study Provigil, but not for use in narcolepsy.
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`He is the principal investigator, however, no funds
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`from Cephalon, present or past, have contributed to
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`his personal salary and none have been made
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`available for his non-research related use.
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`Further, in previous years Dr. Chervin was a
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`co··investigator with Cephalon in a narcolepsy
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`clinical trial.
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`Christian Guillemin.ault has been the
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`administrator of the Sleep Disorder Clinic in Palo
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`18 Alto, California, where the study of Xyrem was
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`performed by a team of researchers.
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`In the event that the discussions involve
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`any other products or firms not already on the
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`agenda for which an FDA participant has a financia:
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`inter.est, the partici.pants ar-e aware of the: need to
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`exclude themselves f~om such involvement and their
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`exclusion will be noted for the- ~ecord.
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`With respect to all other participants, we
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`ask in the interest of fairness thut tney add:ess
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`any current or previous involvement with any fi:!:"m
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`whose products they may wish to comment upon.
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`Thank you.
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`DR. KAWAS: Thank you very much, Dr.
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`Titus. We will begin with D~. Russell Katz, of the
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`FDA, who will give us the FDA overview of the
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`issues.
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`I want to point out to the committee
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`10 members that they have much of the materials that
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`they will be seeing during this meeting in front of
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`them.
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`FDA Overview
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`DR. KATZ: Thanks, Claudia. First, I
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`15 would like to welcome the committee back. You we~e
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`here just a few months ago so I appreciate your
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`coming back so soon.
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`We have a number of invited guests who arc
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`augmenting the committee today, and many of them
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`are experts in the evaluation of issues related to
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`d:-ug abuse, and I would just like to welcome them,
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`in particular Drs. Simpson, Sannerud and
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`Frankenheim.
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`We have two other experts who will
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`actually be speakers later this morning. Dr. Dyer
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`1 will speak on her e::-:pe1.·ience wi t!-1 GMB use and
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`2 misuse in cases she has seen, and Dr. Falkowski
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`3 will talk about the epidemiology of GHB abuse in
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`the United States.
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`Fir.ally, as Dr. Titus mentioned, we have
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`two acknowledged experts in sleep disorders who are
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`attending the annual sleep meetings in Chicago, but
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`who have agreed to sit in a hotel room for howeve~-
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`long this takes and participate by phone. So, Drs.
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`10 Guilleminault and Chervin, whereve~- you are, thank
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`you. Thanks for being here.
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`As you know and as you have heard, today
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`we will ask you to discuss NDA 21-196, which was
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`submitted by Orphan Medical for the use of Xyrem,
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`gamma hydroxybutyrate or better known as GHB, for
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`the treatment of cataplexy and excessive daytime
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`sleepiness in patients with narcolepsy.
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`7.2
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`GHB is a simple molecule and it is
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`ubiquitous in mammalian tissues, its function
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`though is not really well known.
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`Its relevant
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`regulatory history goes back to about 1990, and
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`prior to that date it was freely available in
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`':1ealth food stores. But in 1990 tf:.e agency began
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`to receive reports of widespyead recreational use
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`in a number of different types of folks, for a
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`number of different types of reasons, or GH3 and
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`began to get numerous reports of serious adverse
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`events associated with its misuse.
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`It was not entirely clear that all of
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`these events were necessarily related to GHB.
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`It.
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`was difficult to interpret some of these reports
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`because there were concomitant medications that
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`were unreported and it wasn't entirely clear
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`9 whether or how much GHB was in a particular
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`preparation that someone had taken. Those scrt.s of
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`issues made it difficult to completely inte1·prt~t.
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`the reports, but many of the reports were of events
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`that were known to be consistent with GHB's effect
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`as a potent CNS depressant, including things like
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`levels of consciousness. So, it was reasonable t.rJ
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`believe that GHB was at least in part respor.siblc
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`for some of these reports.
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`As a result of these reports, the agency
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`it.
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`illegal to use. However, illicit use cont.inu<:!d and
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`continues to this day, not only with GHB but with
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`two related d~ugs which are precursors, GBL und
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`1,4-butanediol, and there have been simila~ reports
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`of serious adverse events associated with the :lf;e
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`of these products.
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`So, against this backg~·ound of '...lse, the
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`investigation of GHB as a treatme~t for cataplexy
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`began. Based on the results of a single trial
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`performed by the sponsor and their commitment. to
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`perform additional trials, the sponsor was granted
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`a treatment IND in December of 1998. For those of
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`you unfamiliar with a treatment IND, it is
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`basically a mechanism to permit use of an
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`investigational drug outside the context of a
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`controlled trial for a serious disease for which
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`there aren't other available treatments.
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`It is
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`usually granted relatively late in the developme~t
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`of a drug so that by the time you grant it ycu have
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`some reasonable idea, based on controlled data,
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`that the drug is probably effective and reasonably
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`Just anothe~ relevant piece of histo~y. in
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`2000 Congress passed a law which placed GHB in
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`Schedule I and also placed it into Schedule III for
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`any approved uses that may be granted.
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`The NDA that we are discussing today was
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`submitted in September of 2000 by the company, und
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`it contains the results of four controlled t~ials
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`which the sponsor believes establish substantia~
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`evidence of effectiveness for cataplexy and
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`excessive daytime sleepiness in patier1ts wit~
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`narcolepsy.
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`It also contains, obviously, safety
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`experience.
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`T iust want to talk about the safety
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`experience for just. a little bit. As you know from
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`the briefing documents, much of the safety data in
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`the application was not generated by the company
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`but by an individual investigator under his own
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`individual invcstiqator IND. This is Dr. Scharf,
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`and he is an acknowledged expert in the use of GHB
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`and he has been treating patients under his IND for
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`about 16 years. His data comprise almost 30
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`percent of the patient safety database in the NDA.
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`constitutes about 70 percent of the total patient
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`exposure.
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`As part of a routine investigutior.. of tt:.e
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`NDA to look at. sou~-ce documents, the agency
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`investigators found that they were unable to locate
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`some critical source documents of Dr. Scharf 1 s IND,
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`and it was diffic:1lt to confirm the sponsor 1 S
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`submission of Dr. Scharf 1 S data. Ho~ever,
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`subsequent to that, Dr. Scharf has made extensive
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`efforts to p~·ovide the additional source documents
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`and ager.cy investigators have reinspected that
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`data.
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`I believe t:-te conclusion of that
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`investigation is that we find that the records, for
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`the most part, do support the spor.sor•s
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`descriptions of Dr. Scharf's data. And, we believe
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`we can make certain statements about that data at
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`this point.
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`We were particularly interested in the 80
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`or so patients that Dr. Scharf treated that did not
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`move on into the company's treatment IND. He
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`treated a totul of 143, or thereabouts, patients,
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`60 of whom went into the sponsor's treatment TND.
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`So, we had a good idea of what was happening to
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`those patients but there were about 80 that didn't
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`and who were basically discontinued from treatment
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`under Dr. Scharf's own IND.
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`So, except for a handful of patients, we
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`believe we know why those 80 patients discontinued
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`and their status.
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`I believe we can suy reasonably
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`comfortably say that nothing catastrophic that we
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`don't know about happened to those patients but,
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`unfortunately, we have relatively little
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`adverse events in that cohort of 80. Other than
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`patient diaries, we have essentially no
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`documentation about exactly whut dose those
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`patients took and for how long.
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`I huve gone into this at some depth
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`because the safety experience in the NDA is
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`relatively small as compared to a typical NDA, and
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`thut is by agreement. This is an orphan product.
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`Based on the sponsor's estimated prevalence of
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`cataplexy of about 25,000, it received orphan
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`designation and one wouldn't necessarily expect
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`somewhere in at least 10000 to 2000 patients in the
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`typical NDA, would be submitted in un orphan
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`application. So, we agreed with the sponsor that
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`about 500 patients treated for appropriate
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`durations, at appropriate doses would be
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`acceptable.
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`But, given the relatively small database
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`and some of these residual questions about a
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`reasonable proportion of it, that is to say Dr.
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`Scharf's data, that may take on some additional
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`21 meaning and we would like you to think about that
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`22
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`as the day goes on.
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`23
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`24
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`25
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`Ir. addition to the safety and the
`
`effectiveness data which is ~equi~ed ir. an NDA of
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`course, tr.c sponsor has proposed a detailed risk
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`IPR of U.S. Patent No. 7,668,730
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`management p~-ogram, ar..d that hu.s thre~?. goals: to
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`inform putients and physicians about. the risks of
`
`GHB; to minimize the risks to those patients; and
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`also to micimize the likelihood that. subjects for
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`whom the drug has not been prescribed will be
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`exposed to it. This latter point not only refers
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`to diversion and its use illicitly by folks who
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`shouldn 1 t be taking it, but also to the accidental
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`use of GHB in the home, perhaps by small children,
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`and you will hear how GHB is administered and what
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`form it is prepared in, and we thir.k that is a
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`pot.ential risk. So, we would lik~ you to think
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`about that as the day goes on too.
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`As far as the risk managP.ment program, you
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`15 will hear about it in great detail from the company
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`16
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`but, in bri."?.f, it consists of a coup:e of sort of
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`17 major components. One is that the product will be
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`18
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`made availahle through a central pharmacy and will
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`19
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`be shipped directly to the patient at home.
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`20
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`P~ysicians and patients will also receive detailed
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`21 materia:.::; about the risks and t::-.te appropriate use
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`22
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`of t~c drJg after the first prcscript.io~ is filled.
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`23 Actually, t.hey will receive tt:.os..-: materials
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`24
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`initially and all subsequent refi~·ls of
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`25
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`pre::;criptions will be contir.gent upon patients and
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
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`1
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`physicians documenting that they have read these
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`2 materials, und they understand the risks and how to
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`take the drug appropriately.
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`All patients and physicians will be
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`entered into a registry, and there will be close
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`surveillance instituted to ensure that untoward
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`events ar·e minimized, for example, to ensure that
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`patients don 1 t go from doctor to doctor trying to
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`get refills of prescriptions that are
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`10
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`inappropriate.
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`11
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`12
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`13
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`So, with these data and against the
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`background of misuse of GHB out in the population
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`at large, we bring you today's application and we
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`14 will ask you to formally vote on three questions.
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`15
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`One is whether or not you think that substantial
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`16
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`evidence of effectiveness has been submitted for
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`17
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`the indications that the sponsor has proposed, that
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`18
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`is to say, cataplexy and excessive daytime
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`sleepiness in patients with narcolepsy.
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`If you
`
`find that they haven't, we would be very interested
`
`to know whether or not you feel that substantial
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`evidence has been submitted fo~- either of those two
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`indications.
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`While you listen to the effectiveness
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`data, we would like you to pay particular attention
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` PAR1003
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`to the question of dose ar:.d for which dose you
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`thir.k evidence of effectiveness has been submitted.
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`If you find there is substantial evidence of
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`effectiveness for a particular indication, we ~eed
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`to ask you whether or not GHB can be considered
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`safe in use given appropriate labe1ing. Now, we
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`are not goi.ng to discuss necessarily the specifics
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`of proposed labeling but, nonetheless, we ask you
`
`to think of it in that context.
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`Again, in assessing the safety of the
`
`product, we ask you to conc~ntrate on at least the
`
`question of what dose you have found to be
`
`effective and whether or not there is sufficient
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`safety experience at that dose for the drug to be
`
`approved.
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`Finally, we want to tak~ a formal vote on
`
`the question of whether or not you think it is
`
`required or should be required that the drug be
`
`approved only with the risk management program of
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`some type, not necessarily the o~c specifically
`
`proposc·d by the company. Obviously, the company
`
`has proposed a risk management program but we need
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`to know whether or not you thir:.k it. is mandatory
`
`that it be approved with such a p!"ogram in place.·
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`If you do, we have a number of questions that we
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 17 of 400
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`would like you to discuss -- not necessarily take a
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`fo::-mal vote on but discuss with regard to a risk
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`management program and some of the provisions that.
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`the sponsor has proposed.
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`There are some asp-=:cts of the prog1·am that
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`they have proposed that we would like you to pay
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`particular attention to and discuss. For example,
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`there is some considerable sympathy in the agency
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`for including a provision in the risk management
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`10
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`program that would restrict t.he use of the drug to
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`patients with whatever indication you believe has
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`been supported, that is to say, to restrict as much
`
`as possible off-label presc::ibing. That is one
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`possibility.
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`There is also some enthusiasm internally
`
`for physicians and patients to document that they
`
`have reviewed the relevant mate;.ials before the
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`first prescription is filled. So, we would like
`
`you to think about that as w~ll as we talk about
`
`the risk management program.
`
`So, as you can see from the agenda, the
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`company is going to present thP. safety and
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`effectiveness data, after ·which Dr. Mani, from the
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`24 Division, will come up and p!.·esent briefly some of
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`25
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`our views about the data yo1J will have just heard.
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 18 of 400
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`Specifically, I believe we t1avc some different
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`views about the evidence submitted for establ ish.ir:.g
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`a claim for excessive daytime sleepiness in
`
`narcolepsy, and there may b0. ot.her additional
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`safety issues that we would li}:c to bring up at
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`that time, in particular the question of an event
`
`that has been called sleep walking.
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`I think with that as background, I will
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`turn it back to Dr. Kawas. Thank you.
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`10
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`DR. KAWAS: Thank you, Dr. Katz. Orphan
`
`11 Medical presentation is to follow. Dr. David
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`12
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`13
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`14
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`Reardan, Orphan Medical?
`
`Orphan Medical Presentation
`
`DR. REARD&~: Hi. Good morning. Good
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`15 morning, ladies and gentlemen, members of the
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`16
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`committee and FDA.
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`17
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`18
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`[Slide]
`
`My name is ~avid Reardan, and I represent
`
`19 Orphan Medical as heud of regulatory affairs.
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`20
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`21
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`22
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`23
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`24
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`25
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`Orphan Medical is a small, 60-person firm,
`
`dedicated to the developmer.t of orphan drugs. We
`
`have obtained marketing app~·oval for six orphan
`
`products from FDA since we werP. founded, in 1994.
`
`The fi!.·m became involved with Xyrem when
`
`approached by FDA thut same yeur, and Xyrem was
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 19 of 400
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`20
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`1
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`designated an orphan drug in 1994. Today we will
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`share with you the data that ha5 been collected
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`3 with respect to the efficacy and safety since our
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`4
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`.5
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`6
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`7
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`8
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`IND was submitted, in 1996 .
`
`[Slide]
`
`Dr. Mignot, direct at- of the Narcolepsy
`
`Institute at Stanford University, will present a
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`picture of a narcoleptic patient and the serious
`
`9 medical need such patients have for new therapeutic
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`10
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`treatments.
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`11
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`12
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`13
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`14
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`15
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`16
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`Dr. Houghton is the chief medical officer
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`and chief operating officer at Orphan Medical, and
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`he will present next on thP. efficacy that has been
`
`collected. Dr. Houghton was chair of anesthesia
`
`and critical care in Australia.
`
`Dr. Black, di rer..:::tor of the Stanford Sleep
`
`17 Clinic and an investigator for several trials, will
`
`18
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`share with you the EEG pharmacology of Xyrem. Dr.
`
`19 Houghton will then present the safety data and
`
`20
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`21
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`22
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`23
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`24
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`25
`
`finish up with a benefit/risk assessment.
`
`Following preser.tutions by two FDA invited
`
`speakers with respect to GEB abuse, Dr. Balster,
`
`director of the Institute for Drug and Alcohol
`
`Studies at the Medical Col~~ge of Virginia, will
`
`share with you his views o~ abuse liability.
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 20 of 400
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`21
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`1
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`Since there is public abuse of GHB and its
`
`analogs, the company has developed a risk
`
`3 management program for Xyrcm t~at will be p~esented
`
`4
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`5
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`6
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`8
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`9
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`10
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`11
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`12
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`by Patti Engel, our vice president of marketing and
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`sales.
`
`(Slide]
`
`In addition to those presenting today, the
`
`following experts are available in the audience to
`
`answer questions from the committee or FDA:
`
`D~-
`
`Emsellem, Dr. Hagaman and Dr. Ristanovic are all
`
`directors of their respective sleep institutes, and
`
`have been investigators in our clinical trials.
`
`13 Dr. Okerholm is a consultant. in the area of
`
`14
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`15
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`16
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`17
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`18
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`19
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`20
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`21
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`22
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`23
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`24
`
`pharmacokinetics and drug metabolism; Dr. Reno in
`
`the area of toxicology; and Dr. Richard Trout, who
`
`is a professor emeritus in statistics from Rutgers,
`
`is here if there are any statistical questions.
`
`(Slide]
`
`This is the chemical structure of sodium
`
`oxybate, more commonly known as gamma
`
`hydroxybutyrate, or GHB. Notice that it is a
`
`simple 4-carbon hydroxy fatty acid and, as such,
`
`quite easy to synthesize.
`
`In fact, kits have been
`
`illegally p::-omoted on the Internet for its
`
`25 manufacture.
`
`If an amino group were to replace
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` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 21 of 400
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`•i:
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`this alcohol functional group at position 4, you
`
`would have GABA, gamma aminobutyric acid, anothe!""
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`CNS active chemical. Oxybate is a natural compound
`
`in the human body.
`
`[Slide]
`
`Gamma hydroxybutyrate was first discovered
`
`in the 1960's by Dr. Labore, in France, and was
`
`investigated as an analog for GABA.
`
`It was found
`
`to have hypnotic properties and was first approved
`
`10
`
`in France, and later a few other countries of
`
`l l Europe, as an adjunct in anesthesia.
`
`It was used
`
`12
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`1.1
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`14
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`IS
`
`lf'i
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`17
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`18
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`19
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`20
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`21
`
`in labor and delivery for quite a few years. The
`
`injectable form is still available today in parts
`
`of Europe.
`
`In the 1970's initial work was begun in
`
`Canada to test its propert.ies in narcolepsy.
`
`Following initial promise for use in patients with
`
`narcolepsy two controlled trials were conducted by
`
`independent investigato~s. one in the U.S. and one
`
`in The Netherlands.
`
`In 1994, due to the promising
`
`investigator trials, FDA Off.ice of Orphan Products
`
`2~
`
`approached Orphan Medical to consider the cumpound
`
`2~'!.
`
`24
`
`2S
`
`fer development.
`
`Since there was no patent protection and
`
`the market was very small, no other firms were
`
` PAR1003
`IPR of U.S. Patent No. 7,668,730
` Page 22 of 400
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`1 willing to consider the development of GH3 foY
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`2
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`S
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`9
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`narcolepsy at the time. Orphan Medical agreed to
`
`sponsor this medicution. Our new drug application
`
`was submi tt.ed in October of 2000 and was designated
`
`by FDA for priority review.
`
`The clinical development has been fairly
`
`straightforward and all controlled trials ccnducted
`
`to date have shown sodium oxybate to be effective
`
`and safe for the treatment of narcolepsy. This
`
`10
`
`project has been mude more difficult becaus0 of the
`
`11
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`12
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`13
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`1·1
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`abuse situation.
`
`[Slide]
`
`Let me explain why Xyrem is not going to
`
`be a factor in the abuse of GHB and its prccur.sors.
`
`15 Orphan Medicul was aware abuse existed at the time
`
`16
`
`the company agreed to sponsor development of Xyre.m.
`
`17 At this same time, Internet was burgeoning. Due to
`
`18
`
`its ease of synthesis and ready availability ot
`
`19
`
`precursor chemicals. GHB was initially an P.asy
`
`20
`
`target for promoters of illegal drugs.
`
`But GHB is not the only problem. GRL and
`
`22
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`23
`
`24
`
`1, 4 -butanediol are p:::-ecursor chemicals that :::an be
`
`easily converted to GHB and arc, in fact, ccnverted
`
`to GHB in the human body. These precu~·so:.s are
`
`25 widely available as bulk chemicals and are being
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` PAR1003
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` Page 23 of 400
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`illegally used in the United States, and the abuse
`
`problem is growing.
`
`Federal legislation, enacted in 2000,
`
`helped to control the availability of GHB and GBL
`
`but not 1, 4 -b"...Itanediol and otter p:rccursor
`
`chemicals that can be used for the same purpose.
`
`In many states, even with GHB schedules, GBL and
`
`1,4-butanediol are not controlled.
`
`We believe that approval of Xyrcm for. use
`
`10
`
`by patients with narcolepsy will not add to the
`
`11
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`12
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`13
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`14
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`15
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`16
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`general abuse problem of GHB and its numerous
`
`precursors.
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`[Slide]
`
`The proposed indication for which we are
`
`asking FDA for marketing approval is to reduce the
`
`incidence of cataplexy and to improve the symptom
`
`17
`
`of daytime sleepiness in patients with narcolepsy.
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`18
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`19
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`20
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`21
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`22
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`23
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`24
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`25
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`[Slide]
`
`Narcolepsy fits the definition of orphan
`
`disease in the United States, with less than
`
`200,000 patients. There are estimated to be about
`
`135,000 patients, of which 55 percent a~e
`
`diagnosed, with about 24,000 seeking treutment for
`
`cataplexy.
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`[Slide]
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` PAR1003
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`B
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`9
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`I would now like to introduce you to Dr.
`
`Emmanuel Mignot., from Stanford. Dr. Mignot has
`
`been widely published in this area a~d is
`
`considered one of the premiere internfltionai
`
`expe~·ts on narcolepsy. He has not participated in
`
`any of our. clinical trials.
`
`Medical Need
`
`DR. MIGNOT:
`
`It is my privilege to talk to
`
`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 na~colepsy.
`
`13
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`14
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`[Slid"]
`
`I am going to try to summarize in a few
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`15 minutes really a lot o
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