Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 . Xyrem, Orphan Medical Inc.
`
`Page 88 of 128
`6/13/02
`
`In reviewing each of these documents, I have edited them. Each of the edited
`documents is separate from this review.
`
`Key changes to each of these documents are addressed below
`
`1 1. 1 Risk Management Program Proper
`
`Key changes to the program have been to the following components and are
`acceptable to the reviewer.
`
`The names of the manufacturer and distributor have been deleted based on
`
`advice that the sponsor has received from law enforcement bodies. The
`central pharmacy distributing the drug has been referred to as such, rather
`thanas_,_ ,
`"
`e
`
`The Risk Management Program summary that accompanied the Approvable
`Letter of 4/9/02 specifically stated that “all patient assignment of benefit forms
`and registry information would need to be signed and sent back to the central
`pharmacy before the first prescription is filled." The sponsor has altered this
`section to
`
`. Delete “assignment of benefits" forms from this statement. The sponsorjustifies
`this deletion on the basis that these forms are a legal contract between the
`pharmacy and patient which will be mailed out as a separate step for insurance
`billing purposes, if needed, and that it is not necessary for the form to be returned
`in order for a prescription to be filled unless the central pharmacy deems it
`necessary
`0 State that registry information will need only to be verified (and not signed and
`sent back to the pharmacy) before the first prescription is filled. The Xyrem®
`Patient Success Program materials do not contain any registry information.
`
`Under the “Drug Product Kit" heading the sponsor has deleted the following
`statement from the summary
`
`
`
`

`

`Ranjit B. Mani, MD. HFD—120 Medial Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`,
`
`Page 89 of 128
`6/13/02
`
`11.2 Xyrem® Physician Success Program Elements
`
`Only key changes are addressed below
`
`11.2.1 Letter To Physician
`
`Changes to this letter made by the sponsor are minor and acceptable. I have not
`made any changes to the document submitted by the sponsor.
`
`1 1.2.2 Physician Booklet (“Doctor Book’)
`
`The physician declaration that accompanied the Approvable Letter of 4/9/02 read
`as follows
`
`.
`‘
`.
`q
`Physician Dedarafion — Please initial each box
`C] I have read the materials in the Xyrem Physician Success Program
`
`.
`
`understand that there is not evidence that doses greater than 9 gmlday are safe.
`
`E] I verify that the patient has been educated with respect to Xyrem preparation, dosing and scheduling
`
`[j I understand that Xyrem is approved for the treatment of catmlexy in patients with narcolepsy
`
`D I understand that Xyrem has not been shown to be effective or safe for any other indication.
`
`I aiso
`
`In this submission the sponsor has edited the declaration to read as follows:
`rm - W
`m.
`
`
`
`These and other, more minor, changes to the label are acceptable. I have not
`made any changes to the document submitted by the sponsor.
`
`1 1.3 Xyrem® Patient Success Program Elements
`
`11.3.1 Letter To Patient
`
`The sponsor has made only very minor changes to this document. I have not
`made any changes to the document submitted by the sponsor.
`
`1 1.3.2 Patient Booklet (“Patient Book’)
`
`Key changes to this document as made by the sponsor are summarized below
`
`0 Under the heading “How soon might I see a change in my symptoms” the text
`that accompanied the Approvable Letter of 4/9/02 contained the following
`statement: “You can expect to see some improvement within the first weeks.”
`
`

`

`Page 90 of 128
`Ranjit B. Mani, MD, Hszo Medial Review
`
`NDA 21196 , Xyrem, Orphan Medical Inc. 6/13/02
`
`The sponsor has edited this statement to read as follows:
`
`You can expect to see some improvement within the first
`
`weeks of Xyrem’ therapy, however
`*
`W.
`
`l have further edited this statement so as to use language that might be
`understood by a lay person (see edited document for full details).
`
`0 Under the heading ‘What should I avoid while taking Xyrem®” the text that
`accompanied the Approvable Letter of 4/9/02 contained the following
`statement
`
`What should I avoid while taklng Xyrem?
`
`11.3.3 Patient Video
`
`The sponsor has submitted the script of a video that that is intended to instruct
`patients regarding the following
`0
`Preparation and use of Xyrem®
`o
`Precautions needed to ensure the in-home safety of Xyrem®
`0 Laws governing, and precautions to be taken against, the misuse of Xyrem®
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 , Xyrem, Orphan Mediwl lnc.
`
`Page 91 of 128
`6/13/02
`
`I have read the script of the video and found it acceptable.
`
`11.4 Post-Marketing Program Elements
`
`This program consists of the post-marketing safety evaluation form and
`accompanying documents.
`
`11.4.1 Instmctions
`
`0 Changes made by the sponsor to the document that accompanied the
`Approvable letter of 4/9/02 are minor and do not warrant further comment
`I have not made any changes to the document submitted by the sponsor.
`
`.
`
`11.4.2 Letter
`
`0 Changes made to the document that accompanied the Approvable letter of
`4/9/02 are acceptable and do not warrant further comment
`l have not made any changes to the document submitted by the sponsor.
`
`0
`
`11.4.3 Outline
`
`The sponsor has not made any changes to the form that accompanied the
`Approvable letter of 4/9/02
`
`11.4.4 Form
`
`o Changes made to the document that accompanied the Approvable letter of
`4/9/02 are acceptable and do not warrant further comment
`l have not made any changes to the document submitted by the sponsor.
`
`0
`
`11.4.5 Additional Item
`
`In the cover letter, the sponsor has asked the following question
`
`”It is our understanding from the language you placed in the letter to doctors that that safety
`information on 1000 patients followed for 6 months on Xyrem® therapy will fulfill our obligations for
`this program. Can you please confirm our agreement?"
`
`The answer to this question is, I believe, that the sponsor’s understanding is
`correct.
`
`12. Proposed Labeling
`
`This has been submitted in 3 separate formats: Microsoft Word, PDF (annotated)
`and PDF (“clean”)
`
`The key changes made to the label, that accompanied the Approvable action
`letter of 4/9/02, were to the following sections of the label. More minor changes
`are acceptable and are not reviewed below. I have edited the label submitted by
`the sponsor in a separate document.
`
`

`

` 15 page(s) of
`revised draft labeling
`has been redacted
`
`frOm this portion of
`the review.
`
`

`

`Ranjit B. Mani, MD, Hszo Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 107 of 128
`6/13/02
`
`.. ,»ahammer“;mrfimwaflk ,
`
`14. Proposed Advertisement
`
`This to be submitted separately to the Division of Drug Marketing, Advertising
`and Communications within about 2 weeks after the current submission.
`
`15. Drug Stability And Expiration Dating
`This section of the submission has been addressed by the Chemistry reviewer,
`Dr Thomas Oliver. He, and his Division, have recommended the following: "The
`requested tentative expiry of 36 months is acceptable.”
`
`16. Follow-Up 0f Patients At Study Site #8
`
`16. 1 Background
`
`Dr Martha Hagaman is/has been a principal investigator for the following
`Orphan-sponsored clinical trials of Xyrem®: OMC-GHB-Z, OMC—SXB-21,
`
`1 OMC-GHB-3, OMC-SXB-6 and OMC-SXB-7. Only the OMC-
`SXB-7 and MMMWV“; studies are currently ongoing as part of Treatment
`IND # «M. and IND # w/“respectively.
`. The St Thomas Hospital Institutional Review Board in Nashville, TN, had, in a
`letter dated 1/21/02, terminated the OMC-SXB-7 study at that hospital; Dr
`Hagaman was the Principal Investigator conducting the study at that site
`under the jurisdiction of that Institutional Review Board. The letter to Dr
`
`

`

`Ranjit B. Mani. MD, HFD~120 Medical Review
`NDA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 108 of 128
`6/13/02
`
`Hagaman cited a number of deficiencies in the conduct of the study as the
`reason for the Institutional Review Board’s action. Please refer to the text of
`
`that letter which was submitted to this Division under IND was“ (submission
`#056; correspondence date 1/24/02), and to the addendum (completed
`3/29/02) to my review of the eartier Response To Approvable Letter (dated
`10/5/01) for further details
`a An inspection of the Hagaman study site was performed by Patricia Smith,
`investigator, of the New Orleans District Office, and Ni Khin, MD, of the
`Division of Scientific investigations, accompanied by John Feeney, MD, of
`this Division. The inspection was performed from March 11-14, 2002. Data
`from four studies were reviewed at the time of the inspection; these studies
`were OMC-GHB-2, OMC-GHB-3, OMC-SXB-7, and OMC-SXB-21.
`
`An FDA Form 483 was issued to Dr Hagaman at the end of the visit. The
`deficiencies listed in the form were in the following areas: record-keeping,
`Institutional Review Board reporting, informed consent, and oversight.
`Several of the deficiencies noted were considered serious enough to raise
`questions about the reliability of the data from that site.
`
`16.2 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. Note that ‘~.»;«---~»-- an ongoing study of the
`efficacy of Xyrem® for excessive daytime sleepiness in narcolepsy, is not
`included in the table (only limited safety data for this study have been included in
`the application).
`
`Study #
`OMC-GHB-Z
`OMC—GHB-3
`OMC-SXB—S
`OMC—SXB—7 (Cohort 1’)
`OMC-SXB-7 (Cohort 2“)
`OMC—SXB-21
`
`Number Enrolled At Site #8
`1 8
`1 6
`1 5
`20
`1
`7
`
`Number Enrolled In Entire Study
`136
`1 1 8
`185
`236
`32
`55
`
`‘Cohort #1 is composed of all patients enrolled in the OMC-SXBJ 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
`
`16.3 Additional Information Requested From Sponsor
`
`The additional information request pertained largely to patients who discontinued
`from this study at Site #8 for reasons other than adverse events. The purpose of
`seeking this information was to confirm that these patients had not experienced
`any adverse events of concern, while participating in clinical trials of Xyrem®
`that were thus far unrecognized.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 109 of 128
`6/13/02
`
`Each request and the sponsor's response is summarized below
`
`16.3.1 Request #1
`
`16.3.1.1 Request (4/30/02)
`
`Patient #0810 discontinued from the OMC—SXB-7 study at Site #8. Please provide a detailed
`explanation as to why this patient discontinued from the study.
`
`16.3.1.2 Response (5/8/02)
`
`In summary, the submission indicates the following:
`hTis patient gDCHz participated in the following trials
`
`
`ClinicalTn_________a_______________lStart Date
`OMC-GHB-2 (Placebo arm)
`4/4/97
`OMC-GHB-3
`6/5/97
`OMC~SXB-7
`4/29/99
`
`.,
`
`. The patient received GHB for 2 years and 9 months with doses that ranged
`from 4.5 to 9 g/day
`. The patient discontinued from the OMC-SXB-7 trial on 2/12/02 (at Visit 12,
`Month 33). The summary reason for discontinuation was “patient request.” In
`the current submission, the sponsor indicates that the patient discontinued
`treatment at the time of transfer of OMC—SXB-7 study patients from Site #8 in
`Nashville to Atlanta (Site #8 was closed by the Institutional Review Board that
`had jurisdiction over that site).
`0 During a phone conversation between the investigator and patient on 5/4/02,
`the patient indicated that she did discontinued from the study as she did not
`want to travel to Atlanta and felt that her narcolepsy was under control.
`. The sponsor indicated that there was no evidence that the patient
`discontinued on account of an adverse event.
`
`16.3.2 Request #2
`
`16.3.2.1 Request (5/6/02)
`
`A number of patients participating in clinical trials at this site discontinued for reasons other than
`adverse events; for these patients the reasons cited include “withdrawal of consent," “patient
`request," etc. A table listing these patients is below
`
`Study #
`OMC-GHB-a
`OMC-GHB-3
`OMC-GHB~3
`OMC-GHB-3
`OMC—SXB—6
`OMOSXB-G
`OMC-SXB-6
`OMC—SXB-7
`
`Patient #
`0803
`081 1
`0815
`0820
`0836
`0837
`0838
`0845
`
`Reason For Discontinuation
`Withdrew consent
`Other
`Withdrew consent
`Other
`Patient request
`Patient request
`Patient non-compliance
`Protocol deviation
`
`For each of these patients, please provide as full a description as possible of the reason for
`discontinuation. Please also ascertain the current health status of these patients.
`
`16.3.2.2 Response {5/28/02}
`
`l have summarized the sponsor‘s response in the following table
`
`

`

`Page 1 10 of 128
`Ranjit B. Mani, MD, Hszo Medial Review
`
`NBA 21196 , Xyrem, Orphan Medical Inc.
`6/13/02
`
`Full reason for discontinuation’
`
`Present-day follow-up
`
`
`
`Study #
`
`Patient #
`llnitials
`
`
`
`0MC—GHB-3
`
`0803
`
`OMC-GHB-3
`
`
`
`
`
`“She (patient) does not feel like it’s doing any good and
`she hates wakin: u- to take the medication"
`Patient felt "the trial was too much trouble to take it and
`wake up to take it again.”
`
`OMC—GHB-3
`
`0815
`~—
`
`Study coordinator noted that “patient dropped dmg off and
`stated that she did want to continue in the study"
`
`OMC-GHB-3
`
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Unsuccessful
`
`Unsuwessful (previous phone number
`disconnected
`5/14/02: Being treated by a primary
`care physician and taking
`meth - henidate for narcoles
`Unsuccessful (phone number
`changed: new phone number
`un ublished
`
`Unsuccesle despite numerous
`Progress note states the following: “not sleeping well,
`0820
`,_.——~
`attempts
`grouchy, major mtaplexy 2 -3 times a day." The Case
`
`
`Report Form records that the investigator felt that
`
`
`discontinuing study medication was “in the patient's best
`
`
`interest.” Investigator recollected that “study medication
`
`
`
`
`did not seem to hel
`oatient discontinued.”
`
`Source documents and Case Report Form indicated that
`OMC~SXB~6
`0836
`the reason for discontinuation was headaches. However,
`—-~
`
`investigator, in a telephone conversation on 5/23/02,
`indicated that
`.
`Discontinuation was NOT because of headache since
`that symptom diminished
`
`Patient had requested to discontinue because of the
`com-lexi
`of maintainin the visit schedule
`Case Report Form recorded that “patient states that she
`
`
`has been healed at church on 1/8/00. She has had no
`
`wtaplexy since this time and has stopped taking
`
`medication and would like to come in for a termination
`visit."
`
`
`
`
`
`
`
`
`
`
`0837
`
`
`
`
`
`
`
`5/11/02: Patient reported that her
`wtaplexy symptoms remained much
`improved for 1 ’/2 months after
`discontinuing GHB. At present the
`patient is receian Dexedrine 60 mg
`PO OD. and Prozac 20 mg PO 0D.
`
`to control her 5
`toms of narcole-s
`
`
`
`
`Unsuccessful: phone number
`Patient stopped taking medication and missed 3
`
`disconnected
`subsequent study visits. Source documents state that
`
`
`
`patient terminated participation in the study “due to shift
`
`work and schedule chan-es.”
`
`
`5/11/02: Patient continues to be
`
`Patient ended participation in the trial on account of
`
`
`enrolled in the OMC-SXB-7 trial and is
`
`
`pregnancy (considered a protocol violation). She then re
`
`“doing well" at 6 g/day
`entered the trial with approval of the medical monitor,
`
`
`
`a- oarentl after her oorenan
`had ended
`
`
`
`’based on source document and/or Case Report Form
`
`OMC—SXB-6
`
`OMC—SXB-7
`
`0838
`
`l
`
`0845
`. /"‘
`
`16.3.3 Request #3
`
`1 6. 3. 3. 1 Request (5/1 6/02)
`
`This request for information concerns Patient #0824.
`
`This patient discontinued from both Studies OMC-GHB-Z and OMC-GHB-3 on account of difficulty
`breathing.
`
`. Could you supply us with a clinical description of the episodes of difficulty breathing, and how
`they were evaluated?
`
`0
`
`Please ascertain this patient’s current status. If an adequate description of the episodes of
`difficulty breathing is not available from source documents, perhaps the patient could now be
`asked to supply as much information about them, as possible, from memory.
`
`16.3.3.2 Response (5/28/02)
`
`The sponsor’s response consists of a summary and a full narrative
`
`16.3.3.2.1 Summary
`
`

`

`Ranjit B. Mani, MD, HFD~120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical lnc.
`
`Page 1 1 1 of 128
`6113/02
`
`The sponsor states the following
`o The response was based on source documents obtained from the investigator
`o The episodes of difficulty breathing were described by the patient as a
`“smothering feeling."
`. The events began 15-20 minutes after dosing and lasted 3-4 minutes during
`which period the patient was unable to move
`0 The source documents also include an opinion from a pulmonologist (David
`Hagaman, MD) who felt that the events represented sleep paralysis
`. Recent attempts (through 5/23/02) by the investigator to contact the patient
`have been unsuccessful
`
`16.3.3.2.2 Full Narrative
`
`This patient (initials: --—-\ was a 30 year old woman weighing 108 lbs. In addition to narcolepsy
`she had a past history of (unspecified) cardiac surgery (8/96) and hysterectomy (5/95).
`
`She entered the OMC—GHB-Z trial on 11/24/97, completing the withdrawal and washout phases on
`11/24/97 and 12/2/97, respectively. She began double-blind treatment (later confirmed to be GHB
`in a dose of 9 g nightly) on 12/19/97.
`
`On the evening of 12/21l97, the third evening of closing in the OMC-GHB-2 trial, she experienced a
`“smothering feeling" lasting 4 minutes. Study medication was discontinued on 12/21/97. Two days
`later, on 12/23/97, the patient experienced a second episode of a “smothering feeling“ at 2.45 AM
`lasting 5 minutes, without having taken any study medication since 12/21/97. These events were
`recorded by the investigator as being severe; the patient was reported to have recovered fully from
`the event
`
`She entered the OMC-GHB-3 open-label trial on 12/30/97 and while participating in that trial
`received the following doses of GHB
`Date
`Dose of GHB
`12/30/97 through 1/3/98
`3 g each evening
`1/4/98
`None
`1/5/98 through 1/10/98
`3 g each evening
`1/11/98 through 1/16/98
`1.5 g each evening
`After 1/16/98
`None (study medication completely discontinued)
`
`The patient was recorded as reporting experiencing a “smothering feeling” from 1/12/98 through
`1/16/98; the investigator recorded this event as being moderate in intensity, continuous, and
`associated with full recovering.
`
`All the events that were described by the patient as a “smothering feeling” were recorded by the
`investigator in the Case Report Form as “difficulty breathing." One of these events was described
`by the investigator in a source document as follows: “patient reports awakening approximately 15
`minutes after dosing on 1/16/98 with a feeling that she could not breathe, patient reports it lasted 3-
`4 minutes, states she could move during this episode, patient stopped drug at that time.”
`
`A pulmonologist MM“ saw the patient on 1/12/98 and stated the following: “last
`night had episode of sleep paralysis 15-20 minutes after dose, she had fallen asleep then waking,
`inability to move arms and legs, didn't feel that she could breathe , lasted 2-3 minutes then she fell
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical inc.
`
`Page 1 12 of 128
`6/13/02
`
`f\
`
`asleep, contacted Dr M-(medical monitor) will decrease dose to 1.5 g each night. This is sleep
`paralysis in my opinion.”
`
`16.4 Reviewer’s Comments
`
`. Despite the limited extent to which present-day follow-up was possible for a
`number of the patients for whom additional information was sought, it appears
`unlikely that any of the patients described in this section experienced adverse
`events of major concern (that we had previously been unaware of) while
`participating in clinical trials of Xyrem®
`It appears likely that the “difficulty breathing” experienced by Patient #0824
`was a symptom of sleep paralysis.
`
`o
`
`17. Audit of Study Site #5
`
`As a result of the serious deficiencies noted during the Agency inspection of
`Study Site #8, and in order to determine if there were more widespread faults in
`the conduct of the Orphan-sponsored long-term safety studies (especially Study
`OMC-SXB-7), it was decided to perform an inspection of Site #5 (Martin Scharf,
`PhD) since the latter enrolled the largest number of patients of any site
`participating in Study OMC-SXB-7.
`
`The inspection of Study Site #5 was conducted over several days, beginning
`4/22/02. The preliminary results of that inspection indicate that there were NO
`serious deficiencies at that site.
`
`18. Additional Information About A Patient At Site #41
`
`18.1 Background
`
`Dr Mortimer Mamelak is the Principal Investigator at Site #41, which is located in
`Toronto, Ontario, Canada.
`
`
`
`(a randomized, double-
`DC, a male patient enrolledIn Studies
`blind, placebo-controlled study intended to assess the effectiveness of Xyrem®
`
`for excessive daytime sleepiness accompanying narcolepsy) and
`(an open-label, uncontrolled extension study at Dr Mamelak’s study site. The
`patient had recently spoken with a representative of the Division of Scientific
`Investigations. In that conversation, the patient indicated that while participating
`in W he had recorded an increase in his own blood pressure; an
`elevation in blood pressure had also reportedly been recorded during a
`polysomnogram done at Dr Mamelak’s study site while he participated in the
`
`study. The patient also indicated that he had been discontinued
`from that study after being told that he did not have narcolepsy; this report was
`somewhat disconcerting to us, since a confirmed diagnosis of narcolepsy with
`cataplexy was a key requirement for enrollment in both studies.
`
`WWW
`Note that this patient participatedIn Studies 2.
`from October 2001 to March 2002. No safety data for this patient have been
`formally submitted to us by the sponsor: the cut-off date for all safety data
`
`
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 , Xyrem, Orphan Medical lnc.
`
`Page 1 13 of 128
`6113/02
`
`submitted under this NDA so far is 6/30/01; and this event does not appear to
`qualify as a special safety report that is to be submitted under the lND.
`
`18.2 Extent To Which Site #41 Enrolled Patients In Orphan-Sponsored
`Studies
`
`The table below is based on data submitted through the cutoff date of 6/30/01
`
`Number Enrolled At Site #41 Number Enrolled In Entire Study
`Study #
`0
`136
`OMC—GHB-2
`0
`1 18
`OMC-GHB-3
`0
`185
`OMC-SXB-6
`0
`236
`OMO-SXB-7 (Cohort 1‘)
`10
`32
`OMC-SXB-7 (Cohort 2“)
`n
`OMC~SXB-?1
`fir,
`mummM
`OMC—SXB-ZO
`1 1
`25
`
`
`‘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 OMGSXB-‘I study from 9/30/00 through the cut-off date for the
`
`current safety update (BBB/013 included in this NDA
`Trials OMC-SXB—7 and
`are ongoing, open-label studies, that are being undertaken as part of Treatment
`mm. \r___.-
`WW1?) a randomized, double-blind, placebo-controlled, parallel-arm study being conducted to determine
`the efficacy of Xyrem® for excessive daytime sleepiness in narcolepsy
`
`18.3 Teleconference With Dr Mamelak: May 30, 2002
`
`Our Division spoke with Dr Mamelak to obtain his description of the events that
`occurred with this patient. The teleconference was arranged with the consent of
`the sponsor, and was chaired by Dr R. Katz.
`
`Prior to the teleconference, Dr Mamelak had sent us documents that consisted of
`
`o A letter that he wrote to the Orphan Medical study monitor describing what
`happened
`0 The patient’s polysomnogram report.
`
`
`
`The key points that Dr Mamelak conveyed to us were as follows
`. This patient participated in both
`-~~v ~~--~~~~-~w~~ewwrww
`
`Dr Mamelak
`0 When the patient was screened for enrollment in
`had reviewed his previous sleep studies, including a polysomnogram and
`Multiple Sleep Latency Test; these were quite consistent with narcolepsy, as
`was the patient’s clinical history
`0 The patient reported no improvement while participating in
`could have been receiving either Xyrem® or placebo during that trial
`
`0 While participating in ,
`‘ he reported that his blood pressure,
`recorded 15 minutes after taking GHB, had risen from normal, prior to taking
`the drug, to 150/90. Dr Mamelak had recorded blood pressures of 140/92 and
`
`136/86, at entry into ewrem
`‘ respectively
`
`. During
`‘ he had reported that he was not sleeping well and that
`his cataplexy was not coming under control, both of which were unusual in Dr
`Mamelak's experience with patients administered GHB; these symptoms
`were reported despite a staged increase in his dose of GHB to 4.5 g twice
`
`
`
`but
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medial Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 1 14 of 128
`6/13/02
`
`each night. The patient attributed the lack of improvement in his cataplexy to
`not sleeping well.
`a Dr Mamelak then decided to perform a polysomnogram after the patient was
`taken off GHB
`
`. About month after the patient was believed to have discontinued taking GHB
`a polysomnogram was performed on this patient (the results of which had
`been made available to us earlier by Dr Mamelak). Several hours prior to the
`study, and prior to GHB being administered, elevations in blood pressure
`were noted by Dr Mamelak. During the polysomnogram, which was
`performed after he had received a dose of GHB similar to what he had taken
`earlier during the study, episodic elevations of blood pressure were again
`noted: however, the patient slept well, and did not have sleep apnea during
`the recording.
`'
`. Dr Mamelak informed the patient after the polysomnogram was performed
`(but before the study was scored) that, in view of his unusual symptoms
`(difficulty sleeping and lack of improvement in cataplexy, while taking GHB),
`his condition would need reassessment after the polysomnogram results were
`reviewed.
`
`0 Many subsequent attempts by Dr Mamelak to contact the patient were
`unsuccessful; he left multiple messages on the patient’s voice mail, and when
`the patient did not return (Dr Mamelak’s) phone calls, was concerned enough
`to contact the police in the patient’s hometown of .W The
`police checked on the patient and confirmed that he was well. However, the
`patient has not contacted Dr Mamelak and his supply of Xyrem® has not
`been returned (although Dr Mamelak understands that the patient may be
`making arrangements with Orphan Medical to return the latter)
`0 Dr Mamelak believes that this patient has both narcolepsy-cataplexy and
`hypertension. He has already recommended that the patient contacts his
`general practitioner to obtain treatment for his hypertension. Dr Mamelak
`would have liked for the patient to remain in the study; however, his failure to
`reply to phone messages led to his being withdrawn. He does feel that the
`patient could benefit from having his narcolepsy-cataplexy reassessed and
`treated.
`
`18.4 Conclusions
`
`0 Our Division believes that, in all likelihood, the patient misinterpreted what he
`was told about his condition by Dr Mamelak.
`o No further actidn is called for on the part of this Division in this specific
`instance.
`
`. We informed Orphan Medical, Inc. of our conversation with Dr Mamelak, and
`the conclusions that we reached after speaking to him.
`
`19. Exposure Data
`
`At the request of this reviewer the sponsor submitted on 2/18/02 updated
`exposure tables for Xyrem®. These were reviewed along with the previous
`Response To Approvable Letter (see my review completed on 3/4/02)
`
`

`

`Page 1 15 of 128
`Ranjit a. Mani, MD, HFD-120 Medias! Review
`
`NBA 21196 , Xyrem. Orphan Medical inc. 6/13/02
`
`19.1 Overall Schematics For Clinical Trials In Narcoleptic Patients Included
`In NBA
`
`The submission contained 2 schematics
`
`19.1.1 Schematic For Clinical Tn'als Sponsored By Orphan Medical Plus Scharf
`Trial
`
`
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`
`

`

`Page 1 16 of 128
`.
`Ranjit a. Mani, MD, HFD—120 Medial Review
`
`NBA 21196 , Xyrem, Orphan Medical Inc. 6/13/02
`
`19.1.2 Schematic For Clinical Trials Sponsored By Orphan Medical Alone
`
`hunted-unn—
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`
`19.2 Tables
`
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`
`19.2.1 Sponsor’s Methods For Creating Tables
`
`Tables were created for 2 different groups of patients
`0 The updated Integrated Clinical Trials database which included the following
`studies through the cut-off date of 6/30/01: OMC-GHB-Z, OMC-GHB-3, OMC-
`
`SXB-6, OMC-SXB—‘l, Scrima,
`.
`". and OMC-SXB-ZO
`o All patients subsumed by the above bullet plus the Scharf study
`
`The sponsor used the following methods for creating these tables
`0 Each patient dose was classified into one of 5 “standard” dose groups as in
`the followin- table
`"Standard" Dose Group Category
`. da
`
`0 da
`
`
`
`
`
`
`0 Each patient’s exposure to these 5 standard doses was calculated for both
`groups of patients and the number of patients at each dose level for each
`duration of exposure recorded in the tables. Assignment of patients to a
`dosing category was made based on continuous exposure time in that dosing
`category
`. For the "overall duration of exposure” category each patient's time of
`exposure was calculated regardless of dose.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medial Review
`NDA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 1 17 of 128
`6/13/02
`
`0 Patients who received placebo only were not included in the tables
`Duration of exposure was calculated based on a 28-day month
`0 Since each patient could be represented in more than one dose category for
`the specified duration of exposure the overall exposure numbers do not
`represent arithmetical summations of the numbers in individual dose
`categories
`
`19.2.2 Tables
`
`The sponsor has presented tables for different durations of exposure
`
`19.2.2.1 Duration of Exposure 2 6 Months
`
`The sponsor’s table is presented below
`
`
`
`mm
`
`
`
`
`mun—u
`
`man——
`
`
`
`19. 2. 2.2 Duration of Exposure 2 12 Months
`
`The sponsor’s table is presented below
`
`
`—oam um ow um sun—am
`_-—n—_-
`
`
`——“-m—
`
`19.2.2.3 Duration of Exposure 2 24 Months
`
`
`
`
`The sponsor’s table is presented below
`
`
`
`
`W—
`
`———__—
`
`19.2. 2.4 Sponsor’s Comments About Above Tables
`
`The sponsor has drawn attention to the following:
`. The most commonly used dose of GHB across the 3 durations of exposure
`was 6 g/day regardless of whether data from the long-term Scharf trial were
`included or excluded
`
`. The vast majority of patients used doses ranging from 4.5 to 9 g/day, across
`durations of exposure. The sponsor has proposed a starting dose of 4.5 g/day
`with a range of 3 to 9 g/day after titration (reviewer's note: this does not match
`with the dose range proposed by the sponsor in the proposed labeling)
`
`19.3 Sponsor’s Overall View Of Adequacy Of Exposure
`
`. The sponsor has provided comparisons of the adequacy of exposure to
`Xyrem® with and without the Scharf study database. The following table
`
`summarizes the data resented b the sonsor
`
`
`Stud Pool
`lnte_rated Clinical Trials Plus Scharf
`Inte-rated Clinical Trials Onl
`
`—— Health Sub‘ecs'
`Health Sub'ects'
`n2-_——I_
`e osurezeMonms ——__
`
`e ~sure212Monms—_—_
`Exusurezmmnms—___
`
`PatientoYears Of
`1585
`Not calculated
`622
`Not wlculated
`Ex 0 a sure
`
`
`
`
`
`
`
`
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`‘Healthy subjects were exposed to single doses only
`
`Page 1 18 of 128
`6/13/02
`
`. The entire database contains sufficient patient exposure sufficient to meet the
`ICH guidelines at 6 months (> 300 patients) and 1 year (> 100 patients) even
`if the Scharf study data are excluded.
`
`19.4 Additional Request For Information From Sponsor
`
`On 2/22/01, an additional request for information regarding exposure data was
`transmitted to the sponsor. The request and the sponsor’s response are
`summarized below
`
`19.4. 1 Request For Information
`
`What is the total number of” narcoleptic patients exposed to a 6-9 g/day dose
`range, _a_n_d to a 9 g/day dose, of Xyrem® for angduratlon in the following
`groupings? (These data should be updated through 6/30/01, consistent with your
`submissio