_L__ page(s) have been
`removed because it
`
`contains trade secret
`
`and/or confidential
`
`information that is not
`
`disclosable.
`
`

`

`Ranjit a. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N-BZ), Xyrem® , Orphan Medical Inc.
`
`.
`
`Page 19 of 21
`3/29/02
`
`\____________\\
`
`Extent To Which Site # 8 (Martha Hagaman, MD) Participated In Orphan-
`Conducted Clinical Studies Included In NDA
`
`A total of 46 unique patients have been enrolled at this site in clinical trials
`included under this NDA. A number of patients have participated in more than 1
`study
`
`The number of patients enrolled in each study, at Site #8 and in the entire study
`is listed in the following table
`
`
`
`Number Enrolled In Entire Study
`Number Enrolled At Site #8
`Study #
`136
`18
`OMC-GHB—Z
`118
`16
`OMC-GHB-3
`185
`15
`OMC-SXB-G
`236
`20
`OMC-SXB—7 (Cohort 1")
`32
`1
`OMC»SXB-7 (Cohort 2")
`
`OMC-SXB-Zt 55 7
`
`'Cohort #1 is composed of all patients enrolled in the OMC-SXB-7 study through 9/30/00, the cut—off date for the initial
`(120-Day) safety update included in this NDA.
`" Cohort #2 is composed of all patients enrolled in the OMC-SXB-7 study from 9/30/00 through the cut-off date for the
`current safety update (6/30/01) included in this NDA
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N—BZ), Xyrem® , Orphan Medical inc.
`
`Page 20 of 21
`3/29/02
`
`Re-Analysis Of Efficacy Data Excluding Site #8
`
`Dr Sharon Yan has repeated the primary efficacy analysis for the 2 key efficacy
`studies, OMC-GHB-2 and OMC-SXB-21, excluding data from Site #8. The results
`may be summarized as follows
`
`OMC-GHB-2
`
`The overall p-value for the overall GHB (all groups) vs placebo comparison was
`0.0023, with GHB being superior to placebo. For the comparison of individual
`dose groups vs placebo, a statistically significant difference was seen only
`between the 9 g dose and placebo.
`
`OMC-SXB-21
`
`The p-vaiue for the GHB—placebo comparison was 3 0.0001 with GHB being
`superior
`‘
`
`Note that at the time the Hagaman site was inspected, it was possible for those
`conducting the inspection to confirm the accuracy of the efficacy data for the
`OMC-GHB-2 and OMC-SXB-21 studies using patient diaries for that site as
`source documents
`
`Comments
`
`. A total of 38 unique patients with narcolepsy were enrolled in Orphan-
`sponsored clinical trials at the Hagaman study site (site #8). Note that the
`entire safety database for this NDA (excluding the Scharf open-label trial)
`consists of only 466 patients with narcolepsy.
`o All except 2 of the patients at this site participated in longer-term safety
`studies.
`
`. The initial results of the inspection of the Hagaman site, based on the FDA
`Form 483 and direct feedback from those who conducted the inspection
`raises a very serious concern about the reliability of the safety data obtained
`from this site. Key items contributing to this concern were as follows
`
`. An inability to match data noted in Case Report Forms with those noted in source
`documents in many instances
`- The impression that data in the Case Report Forms and source documents may
`not have adequately captured the full range of more troublesome adverse events
`seen in patients at this study site. Contributing to this impression were the
`general lack of clinic/progress notes, and phone logs and the indication that
`studies were inadequately supervised by Dr Hagaman (she was residing in
`——
`for many months while the study site was located in Nashville)
`
`‘
`
`. More importantly, the results of the inspection have raised equally serious
`concerns about Orphan’s oversight of its clinical trials. Inspections of one or
`more additional centers, particularly large centers, also contributing to the
`safety database appear to be warranted.
`0 Dr Hagaman has submitted a detailed response to the Form 483 which is
`currently being reviewed; however, it will not be possible for our concerns
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (N-BZ). Xyrem® , Orphan Medical lnc.
`
`Page 21 of 21
`3/29/02
`
`regarding this site to be adequately resolved during the course of the current
`review cycle.
`There is no concern at present that efficacy data obtained from the Hagaman
`site for studies OMC-GHB-2 and OMC-SXB-21 have been compromised in
`any way
`
`Recommendations
`
`In my earlier review of this Amendment, completed on 3/4/02, i had
`recommended that Xyrem® “be approved for the treatment of cataplexy,
`provided, and only if, key elements of a risk management plan are imposed
`as a condition for approval; these key elements are prohibition of the off-label
`use of Xyrem®, and the imposition of Subpart H of the Accelerated Approval
`Regulations."
`Since that time
`
`.
`
`Fresh concerns have emerged about the respiratory depressant effects of
`Xyrem®, especially in patients with obstructive sleep apnea, a condition that is
`reported to co-exist frequently with narcolepsy
`. The reliability of the long-term safety data from a study site, and, more
`importantly, of the sponsor’s overall oversight of its clinical trial program have
`been seriously called into question
`Under these changed circumstances I would recommend that an Approvable
`letter be-issued again for this application, instead of an Approval letter as
`originally recommended.
`As the next steps in addressing the above concerns I would recommend the
`following
`.
`inspection by the Agency of one or more additional study sites involved in the
`treatment lND study OMC-SXB-7; the site chosen should have recruited a fairly
`high proportion of patients participating in the trial. The purpose of such an
`inspection would be to determine if deficiencies of safety data are more
`widespread than hitherto supposed.
`. Completion by the sponsor of a controlled study of the effects of Xyrem® on
`respiration in patients with compromised pulmonary function, including those with
`obstructive sleep apnea.
`
`Ranjit B. Mani, MD.
`Medical Reviewer
`
`J. Feeney, M.D.
`
`rbm 3/29/02
`CC:
`
`HFD420
`
`NDA 21196 (N82)
`
`

`

`———-—---..--—-.-.--.-----------—---------—-n-n-uanunnu.n-u-ut-nnap-on.-.-----------------.---—----—-----------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`-.-..-n-—-----—-—-.---u---------—------——--------n..----—.---—--.---——----------------------------------------------
`
`Ranjit Mani
`4/3/02 02:07:05 PM
`MEDICAL OFFICER
`
`John Feeney
`4/3/02 02:24:26 PM
`MEDICAL OFFICER
`
`see my cover memo for my thoughts on this application
`
`.wi.¢
`
`

`

`Review and Evaluation of Clinical Data
`
`NDA (Serial Number)
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`
`Correspondence Date:
`Date Received IAgency:
`Date Review Completed
`Reviewer:
`
`21196 (N-BZ)
`Orphan Medical Inc.
`Xyrem®
`Narcolepsy
`Amendment To NDA
`
`10/5/01
`1019/01
`3/4/02
`Ranjit B. Mani, MD.
`
`1. Background ................................................................................................... 4
`2.
`List of All Clinical Studies In This Application ................................................ 5
`2.1 Efficacy And Safety Trials .......................................................................... 5
`2.2 Pharmacokinetic Trials .............................................................................. 6
`
`3. Contents Of Submission ................................................................................ 6
`
`4. Cover Letter .................................................................................................. 6 ~
`
`4.1 Risk Management And Other Clinical Issues ............................................. 7
`4.2 Labeling Issues ........................................................................................ 10
`43 Chemistry and Manufacturing issues ....................................................... 10
`4.4 Postmarketing Issues .............................................................................. 10
`Safety Update ............................................................................................. 11
`5.1 Studies Included In Safety Update ........................................................... 11
`5.2 Study OMC-SXB—7 ................................................................................... 11
`5.3 Protocol 1.“
`........................................................................... 31
`
`5.
`
`5.4 Protocol
`
`”WWW“
`
`........................................................................... 42
`
`5.5 Reviewer’s Comments About Safety Update ........................................... 5O
`Status Of Patients Enrolled In Scharf Study Who Had Not Entered
`6.
`Treatment IND Study OMC—SXB-7 As Of 5/31/99 .............................................. 50
`6.1 Background ............................................................................................. 50
`6.2 Sponsor’s Methods .................................................................................. 51
`6.3 Overview .................................................................................................. 51
`
`6.4 Summary Of Individual Patient Disposition And Time Of Most Recent
`Contact ........................................................................................................... 52
`
`6.5 Narratives For Selected Patients ............................................................. 53
`
`6.6 Reviewer’s Comments ............................................................................. 54
`
`7. Analysis Of Sleepwalking ............................................................................ 54
`7.1 Background ............................................................................................. 54
`7.2 Literature Review Of ”Sleepwalking” And Related Disorders ................... 55
`7.3 Methods Of Analysis ................................................................................ 56
`7.4 Integrated Clinical Trials .......................................................................... 56
`7.5 Scharf Trial .............................................................................................. 62
`
`7.6 Sponsor’s Conclusions ............................................................................ 67
`7.7 Reviewer’s COmments ............................................................................. 68
`
`8. Respiratory Data In Study OMC-SXB-20 .................................................... 68
`8.1 Background ............................................................................................. 68
`
`

`

`Ranjit B. Mani, MD. HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical lnc.
`
`Page 2 of 127
`3/4/02
`
`8.2 Outline Of Protocol For OMC-SXB-20 Study ........................................... 69
`8.3 instruments For Measuring Respiratory Event Data ................................ 73
`8.4 Respiratory Effect Measures ................................................................... 73
`8.5 Methods Of Analyzing Respiratory Data .................................................. 75
`8.6 Results ..................................................................................................... 75
`
`8.7 Sponsor's Conclusions ............................................................................ 92
`8.8 Reviewer's Comments ............................................................................. 93
`
`9.
`
`Stimulant Use In Clinical Trials Of Xyrem® ................................................. 94
`9.1 Background ............................................................................................. 94
`9.2 Methods ................................................................................................... 94
`
`9.3 incidence Of Stimulant Use ..................................................................... 94
`
`9.4 Duration Of Exposure To Stimulants ....................................................... 95
`9.5 Additional Comment By Sponsor ............................................................. 96
`10. Risk Management Plan ............................................................................... 96
`10.1 Summary Of Risk Management Program As Currently Proposed By
`Sponsor .......................................................................................................... 96
`The drug product kit will consist of .................................................................. 99
`10.2Proposed Physician Success Program .................................................. 100 '
`10.3Proposed Patient Success Program ...................................................... 103
`10.40ffice Of Post-Marketing Drug Risk Assessment Comments On Risk
`Management Program .................................................................................. 104
`10.5Reviewer’s Comments ........................................................................... 105
`
`11.
`
`Interaction Of GHB With Human Hepatic Microsomal CYP450 lsoenzymes
`106
`
`12. Chemistry, Manufacturing And Controls .................................................... 107
`13. Proposed Labeling .................................................................................... 107
`14. Proposed Patient Medication Guide .......................................................... 107
`14.1 Contents ................................................................................................ 107
`
`14.2 Comments ............................................................................................. 111
`
`15. Proposed Advertisement ........................................................................... 111
`15.1 Text Of Advertisement ........................................................................... 111
`
`15.2Reviewer’s Comments ........................................................................... 112
`
`16. Updated Exposure Data ............................................................................ 112
`16.1 Overall Schematics For Clinical Trials in Narcoleptic Patients Included In
`NDA .............................................................................................................. 112
`
`16.2Tables .................................................................................................... 113
`
`16.3Sponsor’s Overall View Of Adequacy Of Exposure ...............................‘1 14
`16.4Additional Request For Information From Sponsor ................................ 115
`16.5Reviewer’s Comments ........................................................................... 116
`
`17. Comments ................................................................................................. 117
`
`17.1 Safety Update ........................................................................................ 117
`17.281atus Of Patients Enrolled In Scharf Study Who Had Not Entered
`Treatment IND Study OMC—SXB-7 As Of 5/31/99 ........................................ 117
`17.38leepwalking .......................................................................................... 117
`17.4 Respiratory Data In Study OMC—SXB-2O ............................................... 118
`17.58timulant Use In Clinical Trials Of Xyrem® ........................................... 118
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 3 of 127
`3/4/02
`
`17.68ummary Of Risk Management Program .............................................. 119
`17.7lnteraction Of GHB With Human Hepatic Microsomal CYP450 lsoenzymes
`120
`
`17.8Chemistry, Manufacturing And Controls ................................................ 120
`17.9Proposed Patient Medication Guide ...................................................... 120
`17.10 Proposed Advertisement .................................................................... 120
`17.11 Proposed Labeling ............................................................................. 120
`17.12 Updated Exposure Data ..................................................................... 120
`18. Advisory Committee Meeting .................................................................... 121
`18.1 Key Items Voted On ............................................................................... 121
`18.2Additional Recommendations ................................................................ 122
`
`18.3Additional Comments ............................................................................. 122
`
`19. Risk-Benefit Equation And Overall Conclusions ........................................ 123
`20. Recommendations .................................................................................... 127
`
`:3 WAY
`we vaéiuii‘lAL
`
`A; $253 THIS WAY
`Oil ORIGINAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`Ranjit B. Mani. MD, HFD-‘lZO Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 4 of 127
`3/4/02
`
`1. Background
`
`This submission, an Amendment to the sponsor’s NDA, is a response to an
`Approvable letter dated 7/2/01.
`
`The Approvable action was based on the original NDA for Xyrem®, which was
`submitted on 9/30/00, and a Major Amendment submitted on 3/23/01; the original
`NDA was granted priority review status. The application was also discussed at a
`meeting of the Peripheral And Central Nervous System Drugs Advisory
`Committee which was held on 6/6/01. Please see the following Agency-created
`documents for full details
`
`. The efficacy and safety reviews of the original NDA
`The clinical review of the Major Amendment
`The transcript of the Advisory Committee meeting
`The text of the Approvable letter
`
`Subsequent to the issuance of the Approvable letter, 2 further meetings were
`held with the sponsor
`. A meeting on 7/16/01 to discuss the sponsor’s action plan in response to the
`Approvable letter; and the structure of the current Amendment
`. A meeting on 10/1/01 to discuss the items in the Approvable letter (pertaining
`to the risk management plan and labeling) that the sponsor disagrees with.
`Please see the minutes of these meetings and pertinent reviews for full details.
`
`In addition to the above meetings a communication from the sponsor on 7/25/01
`outlined the proposed contents of the Amendment including the Safety Update.
`The Division agreed with the sponsor’s proposal.
`
`The indication currently being pursued by the sponsor is as follows:
`
`“Xyrem® (sodium oxybate) oral solution is indicated for the treatment of cataplexy in patients with
`narcolepsy"
`
`Xyrem® has been developed by Orphan Medical, lnc. for the treatment of
`narcolepsy under IND # w‘ and Treatment IND # ’w-w Data obtained from
`individual sponsor-investigator INDs #s W (M. Scharf) and
`(L. Scrima)
`have also been used in support of this application.
`
`in this review the words/phrases “y-hydroxybutyrate (GHB)”, “sodium oxybate”,
`and “Xyrem®” have been used interchangeably.
`
`Prior to reviewing the contents of the submission, it will be helpful to list in tables
`all clinical studies that have been included in this NDA, including those described
`for the first time in the current submission.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 (N82), Xyrem, Orphan Medical |nc.
`
`Page 5 of 127
`3/4/02
`
`2. List of All Clinical Studies In This Application
`
`/«-\
`
`l have listed these studies in 2 categories
`. Efficacy and safety studies
`. Pharmacokinetic studies
`
`2.1 Efficacy And Safety Trials
`
`All oatients enrolled in these trials had narcoles .
`Study #
`Design
`Number of
`Patients
`
`
`
`
`
`Duration
`
`
`
`
`Status
`
`
`
`
`
`Up to 24 months
`
`185 natients
`268 patients
`
`20 patients
`
`6 months
`_
`24 months or until
`a uroval
`4 weeks‘
`
`Complete
`
`3
`55 patients
`
`17 ears
`.-
`2 weeks“
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`OMC—GHB—B
`
`OMC—SXB 6
`OMC-SXB-7
`
`Scrima
`
`'
`
`OMC-SXB-21
`
`placebo-controlled, parallel-arm
`Open-label, uncontrolled,
`extension stud
`O-en-label uncontrolled stud
`Open-label uncontrolled study
`
`Randomized, double-blind,
`placebo-controlled, cross-over
`stud
`
`placebo-controlled, cross-over
`stud
`Ocen-label uncontrolled stud
`Randomized, double—blind,
`
`placebo-controlled, parallel-arm.
`RANDOMIZED WITHDRAWAL
`study after long-term open label
`treatment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'GHB and placebo were each used for 4 weeks
`“Period of randomized withdrawal
`The number of patients listed for ongoing studies are those enrolled as of 6/30/01.
`OMC-GHB-Z and OMCvSXB-21, as well as the Scrima and Lammers studies, were primarily intended to assess the
`efficacy of Xyrem® in treating cataplexy.
`. -
`' is primarily intended to assess the efficacy of Xyrem® in treating the excessive daytime sleepiness of
`narcolepsy
`OMC-SXB-ZO was intended to assess the effects of 4 different doses of Xyrem® on sleep architecture
`
`Further comments about some of the above studies are below
`Study #
`Comments
`
`OMC-GHB-3
`OMC-SXB-G
`OMC—SXB—7
`
`Extension to OMCvGHB-Z.
`Treatment-naive uatients (exceot for a sin-le atient creviousl
`Extension to
`OMC-GHB~3 (53 patients )
`OMC-SXB-6 (121 patients)
`Scharf Studv (66 patients)
`
`OMC-SXB-ZO (20 patients)
`
`The numbers in parentheses in this cell refer to the number of patients entering OMC-SXB-7 from each study
`
`in OMC-GHB-2 and OMC-GHB-3
`
`Meek‘we;_.,fl A.uuee-.e.s.,.,...mm,, _«wcm\..~a.w,m.esm:~_______—____—-_—__J
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196 (N-BZ), Xyrem, Orphan Medical lnc.
`
`2.2 Pharmacokinetic Trials
`
`Page 6 of 127
`3/4/02
`
`125 health sub'ects and 19 narcoleptic satients anarticiated in these trials
`
`
`
`—_
`
`
`
`
`
`
`
`
`
`-
`
`-
`
`
`
`
`
`’The 6 narcoleptic patients participating in this study also enrolled in the Scharf study
`"The 13 narcoleptic patients participating in this study also enrolled in OMC-SXB-6
`
`3. Contents Of Submission
`
`'-
`
`The submission is in electronic format and has been provided on a CD-ROM.
`The cover letter is also available in paper.
`
`The contents of the submission include the following separate sections
`. Cover letter
`
`Proposed labeling
`Risk management program
`Proposed advertisement
`Report of an in-vitro study evaluating the inhibitory potential of GHB towards
`human hepatic microsomal cytochrome P450 isozymes
`
`r'x
`
`0
`
`Information about the status of 11 patients who were enrolled in the Scharf
`study and had not entered the treatment IND study #OMC-SXB-7 as of
`5/31/99
`
`Analysis of sleepwalking
`
`Report on the respiratory effects of Xyrem® in Study #OMC-SXB-ZO
`
`Data about stimulant use in clinical trials of Xyrem®
`
`Safety update
`
`References supporting labeling annotations
`
`Pertinent FDA correspondence
`
`Each of the above items, except the last two, are reviewed below, although not in
`the same order
`
`4. Cover Letter
`
`The cover letter
`
`0 Outlines the contents of the submission
`
`. Requests that the submission be assigned a 2-month user fee goal
`0 Addresses individual items in the Approvable letter
`
`The following summarizes the sponsor’s view ofhow individual items in the
`Approvable letter have been addressed in this submission. The items in the
`approvable letter are themselves highlighted in bold and/or italic headings, in the
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 7 of 127
`3/4/02
`
`same order as in the cover letter accompanying this submission, with the
`sponsor’s response under each heading.
`
`4.1 Risk Management And Other Clinical Issues
`
`4.1.1 Prescribers must state, in writing, that a patient has narcolepsy with
`cataplexy before drug will be released to the patient
`
`The company’s view is that this requirement “impinges on the practice of medicine” and
`“goes against 30 years of FDA policy and numerous Congressional debates that FDA’s
`jurisdiction does not extend to the practice of medicine.”
`
`o
`
`The sponsor has proposed an alternative plan outlined below. This issue was discussed
`at the meeting between the sponsor and the Division that was held on 10/1/01, and the
`sponsor understands that this issue will undergo further review inside the Agency and
`additional discussion with Orphan Medical before any final determination is made. The
`alternative plan proposed by the sponsor is as follows:
`.
`Prescribers must certify in writing with each prescription that they have read the
`product labeling and physician education materials for Xyrem®
`Prescribers must certify that they understand that Xyrem® is only approved for the
`treatment of cataplexy with narcolepsy
`Prescribers must certify that they have educated the patient with respect to dosage
`preparation and administration
`Prescribers must state the diagnosis of each patient
`.
`. A sample of the proposed prescription sheet has been enclosed in this submission
`together with the Physician Success Program, as have the types of information that
`will be collected as part of the Patient Registry.
`
`.
`
`4.1.2 Prescribers must state in writing that they have read the educational
`materials provided to them before educational materials will be sent to the patient
`
`The prescribing and enrollment forms that are proposed as part of the Physician
`Success Program includes certification by the physician of having read the educational
`materials
`
`4.1.3 Patients must state, in writing, that they have read the educational materials
`provided to them before their first prescription is filled.
`
`The sponsor states the following
`. Based on agreement reached at the sponsor—Division meeting on 10/1/01 the
`prescription could be filled based on the patient confirming to the pharmacist on the
`phone that he/she had read the education materials
`. The sponsor will ensure that the patient receives the Patient Success Program
`education materials prior to receiving the first prescription; these materials will be
`provided either by the physician or the pharmacy in advance of the first shipment of
`Xyrem®.
`
`4.1.4 A single prescription must be limited to a maximum of 3 months supply of
`drug, and the maximum dose prescribed must be no more than 9 gms/day, given
`in 2 equally divided doses. Prescriptions for a dose greater than 9 gms/day, or for
`more than 3 months supply, must not be filled by the pharmacist.
`
`The sponsor’s response is as follows:
`
`

`

`Ranjit B. Mani, MD. HFD—120 Medical Review
`NBA 21196 (N—BZ), Xyrem, Orphan Medical Inc.
`
`Page 8 of 127
`3/4/02
`
`0 The sponsor agrees to limit the quantity of drug supplied to a patient at any single
`time to 3 months and anticipates that most insurance companies will limit such a
`supply to one month
`0 The sponsor proposes that after completion of the post-marketing surveillance
`program and after review of this program by the Agency, individuals could receive
`upto a 6-month supply (which is permitted under Schedule III)
`11 patients in the current treatment IND are using Xyrem® doses in excess of 9
`g/day (upto 12 g/day). These doses have been reached by titration and have been
`well-tolerated. The sponsor therefore believes that it is not appropriate for a
`prescription in excess of 9 g/day to be refused by a pharmacist solely on the basis
`that the 9 g/day dose is being exceeded. A clear statement has however been made
`in the labeling and educational materials that safety and efficacy has not been
`established beyond a dose of 9 g/day
`
`0
`
`4.1.5 Patients must be seen and evaluated by the prescriber with the issuance of
`each new prescription (every 3 months), at which time a detailed account of the
`patient’s experience on treatment must be provided. Prescribers must submit
`reports of all serious adverse reactions to you every 3 months initially, with the
`longer term reporting requirements to be further negotiated with the Agency. The
`patient registry that is an intrinsic part of this program must also be used to
`actively monitor for evidence of abuse, misuse, and diversion. You will need to
`incorporate these elements into your Risk Management Program documents.
`
`.
`
`The sponsor has responded as follows
`a The physician will complete the safety data collection form at each visit as part of a
`post-marketing commitment. A description of this requirement and a form to collect
`the required safety data are included in the Physician Success Program. The
`sponsor states: “it was agreed that this is a temporary requirement which when
`completed would no longer be required.”
`in addition the sponsor proposes the following
`o
`The physician be required to evaluate the patient every 3 months until the post-marketing
`surveillance database is reviewed by the Agency
`The safety data form be completed twice for each patient (at 3 and 6 months) at the time
`of prescription renewal for the first 1000 patients entered into the registry
`o The registry will include information on dosage and refills will be available for review
`by regulatory agencies charged with policing abuse, misuse and diversion (i.e., the
`DEA and state boards of pharmacy). Orphan Medical guarantees the creation and
`maintenance of the registry (which is incorporated into the contract with the central
`pharmacy). However the sponsor has no legal right of access to patient pharmacy
`records to actively monitor for diversion, abuse and misuse
`
`.
`
`4.1.6 The educational materials you have prepared must note prominently that
`Xyrem® is gamma hydroxybutyrate, or GHB, and that this is the same compound
`that is used illicit/y.
`
`This is clearly stated in the educational materials that are part of the Physician and
`Patient Success Programs, and in the labeling and patient medication guide.
`
`4.1.7 The individual dosing cups must be labeled with the dose and name of the
`drug.
`
`On each occasion when the drug is dispensed the pharmacist will place stick-on labels
`on the dosing cups and medication bottle. These labels will contain patient specific
`instructions about dosing. The patient will receive the Xyrem® kit in a box; the kit will
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical inc.
`
`Page 9 of 127
`3/4/02
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`include the bottle with labeling, place-in-bottle-adaptor (PIBA Well) inserted by the
`pharmacist, oral syringe and 2 dosing cups with labels that include the dose and name
`of drug
`
`
`
`4.1.8 A safety update for the ongoing studies, OMC-SXB-7 and i
`should be provided (the latter study is intended to assess the efficacy of Xyrem®
`in treating excessive daytime sleepiness). Even though the data for Study: v“
`may still be blinded, safety data may still be submitted. We would be happy to
`discuss with you appropriate ways in which this might be accomplished.
`
`The safety update is included in this submission and is consistent with what the sponsor
`proposed in the communication of 7/25/01. The safety update includes data from Studies
`OMC-SXB-7,W
`
`4.1.9 The status of the 11 patients who were enrolled in the Scharf study and had
`not entered the treatment IND study #OMC-SXB-7 as of 5/31/99, needs to be
`described to the extent possible.
`
`The response to this request is included in this submission.
`
`4.1.10 An analysis should be provided of all patients in the entire safety database
`listed as having “sleepwalking” as an adverse event. Such an analysis should
`include detailed clinical descriptions of the episodes, whenever they can be
`obtained from source documents, and the following additional elements:
`demographics, relationship to dose, frequency, seriousness, reason for
`discontinuation, further evaluations (e. g., 5565 and polysomnograms) and
`outcome.
`
`The requested analysis is included in the submission.
`
`4.1.11 As a CNS depressant, sodium oxybate is capable of producing respiratory
`depression. However, your application contains no formal assessment of this
`potential. Such assessments are routinely required in the evaluation of sedative-
`hypnotic drug products. For this reason, you should perform such a study. The
`study should examine the effects of the recommended dosing regimen (2 doses
`nightly, including the highest recommended dose-9 gms divided), with both doses
`given in the fasted state. The study should include patients who are and who are
`not receiving concomitant stimulant treatment, a positive control, and patients
`with concomitant illnesses that might increase their risk of respiratory depression
`(e. g., patients with COPD, sleep apnea, etc). In addition, plasma level data should
`be obtained at appropriate times. We would be happy to discuss the design of
`such a study with you. We believe there is sufficient suggestion of occasional
`respiratory depression in the clinical studies to ask that these data be collected
`prior to marketing.
`
`The sponsor states the following (both of which were agreed to by the Division earlier)
`. A report is included in this submission for Study OMC-SXB-20 that describes the
`effects of escalating doses of Xyrem® on oxygen saturation and the frequency and
`severity of events representing sleep-disordered breathing
`. A study in pulmonary-compromised patients is planned post-approval; a draft
`protocol for such a study will be submitted shortly
`
`.-‘.
`
`.n
`
`.-_,,...._,7..
`
`‘.
`
`‘_
`
`.
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 (N-BZ), Xyrem, Orphan Medical Inc.
`
`Page 10 of 127
`3/4/02
`
`4.1.12 While there do not appear to be any important effects of sodium