Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196. Xyrem, Orphan Medical, Inc.
`
`.- co tuned an Dan at but
`Ago at
`
`"12:“- w-
`
`
`
`7/22/1937
`
`7/30/1939
`
`Page 16 of 93
`6/14/01
`
`tones to:
`
`M“
`
`Adverse men:
`
`'22 overdose.
`”emu“ ““3“ by
`
`
`
`
`
`
`ig’r. Mm"
`1:21'/?ossib)e arug-
`
`Iz‘duced Lu '
`
`1 ~ crease in short ~L£rm
`
`
`iemry {3:514:57 Lem
`.
`
`amM-s i a ':
`
`
`19h ANA
`itcr/i’cssihle Drug~
`srduced 1.2.“
`
`
`
`
`
`
`
`osnxnle pulmn; ry
`.cxicx’ty
`personalzzation.
`-nocicnal lability.
`lyperlcnia, and paw
`hes:
`
`
`
`
`
`
`
`
`3/25,’1965
`
`elm/1991
`
`Adverse Event
`
`6/21/1588
`
`5/3/2589
`
`Adverse Event
`
`6/3/1357
`
`7/15,’l§E7
`
`Adverse Event
`
`
`
`
`1/15/1991
`,
`10/2411?“
`11/6/1994
`
`4/22/1999
`,
`4/30,1§=5
`5/30/1595
`
`I zen-nan:
`“’9’“ “a"
`Adverse Event
`‘weiling ct ankles anc‘
`Mvezee Event
`
`adverse Evenl
`
`
`
` _
`
`11/16/1987
`7/2¢/1sss
`
`7112/1952
`12/31/1992
`
`Adverse ‘svcn:
`Adverse Event
`
`'fif'fzzd d‘u‘m‘k’
`
`Note that in the original NDA 12 patients were listed as having discontinued
`treatment on account of non-fatal adverse events. Patient #01-243 was listed in
`the original NDA as having discontinued treatment on account of weight loss; he
`is not listed in the above table but is listed in the table in Section 7.4.1 since he
`
`died 4 months after study drug discontinuation reportedly from a myocardial'
`infarction. Patients 01006 and 01-270 were not in the original table.
`
`7.5 Review Of Individual Narratives And Case Report Forms
`l have reviewed the narratives and individual Case Report Forms for all 80
`Scharf study patients who did not enter the treatment IND. l have also reviewed
`the Case Report Forms for the 63 patients in the Scharf study who subsequently
`entered the treatment lND.
`.
`
`The information contained in the narratives and Case Report Forms is discussed
`under the following headings.
`
`7.5.1 Source Of Case Report Forms
`
`
`~-—~
`The Case Report Forms for the Scharf study were created by.
`_
`a contract organization hired by the sponsor W for that purpose as well
`as for data management, statistical analysis and report writing. The Case Re'pOrt
`Forms were created from the available source documents generated over the
`preceding 15 years over which the study had been conducted.
`
`7.5.2 Structure Of Case Report Forms
`
`The Case Report Forms were composed of the following separate entry items
`. Demographics
`. Date of diagnosis of narcolepsy
`. Date of pre-treatment polysomnogram
`a Mean latency on Multiple Sleep Latency Test
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`Date of commencement of GHB
`
`Page 17 of 93
`6/14/01
`
`Daily dose of GHB at commencement
`Previous narcolepsy medications
`Concomitant medications at study entry
`Medical history
`Physical examination
`Dosing record
`Results of hematology, clinical chemistry, urinalysis and electrocardiogram testing
`done during study
`Adverse events
`
`Medications used to treat serious adverse events
`
`Disposition data: assessment date. whether patient was still enrolled in study, if
`discontinueda date of last dose, and reason for discontinuation
`
`7.5.3 Deficiencies In Structure Of Case Report Forms And Additional Related
`Concerns
`
`After reviewing all Case Report Forms for the Scharf study the following items
`were identified that rendered the review of the data contained in the forms
`
`problematical
`The sheets on which entries are made and even entries on individual sheets
`
`(i.e., listings of adverse events) are not arranged in chronological order
`making review difficult. Neither are the sheets grouped by category.
`A clear distinction is not always made between the screening history and
`physical examination, e.g., symptoms are sometimes entered instead of .
`abnormalities of physical examination
`There are no entries for any follow-up visits to either the study center in
`Cincinnati or to any physicians located where patients were living.
`There are no entries in the Case Report Forms that would indicate that the
`study site regularly contacted participating patients over the telephone to
`ascertain their status (i.e., status of narcolepsy, adverse events, and
`concomitant medications). Such determinations appear to have been based
`largely, if not almost entirely, on patient diaries
`Dosing records appear to have been reconstructed based on patient diaries
`and not on the study center’s records of what patients were instructed to take
`Adverse event entries appear to be based at least partly on patient diaries. It
`is therefore unclear to what extent adverse events that might have been
`captured by more active regular surveillance by the study center may have
`been capture
`For patients who were irregular or lacking in accuracy in making diary entries
`or returning their diaries, records of dosing and adverse events could be
`unreliable
`'
`It is unclear how the last date of dosing was determined for patients who
`discontinued from the study; it appears to have been based on diary entries in
`a substantial number. in other instances where the last date of dosing was
`unknown, patients may have taken study drug for several months after the
`last diary—based entries were made in the Case Report Form.
`The Case Report Forms do not actually document the clinical status of
`patients at the time of study drug discontinuation. Indirect inferences
`
`_
`
`

`

`Ranjit e. Mani. MD, HFD—120 Medical Review
`NBA 21196, Xyrem. Orphan Medical, Inc.
`
`Page 18 of 93
`6/14/01
`
`regarding their clinical status can be made from the last dosing change,
`adverse event, electrocardiogram and laboratory data in the Case Report
`Forms if these were sufficiently close temporally to when GHB was stopped.
`Such data can provide some reassurance that these patients were not
`gravely ill at the time of discontinuation; if they were in fact very seriously it is
`unlikely for them to have been able to complete their diaries. Admittedly in a
`number of patients who discontinued from the Scharf study, posttreatment
`confirmation of health status is available from attempts at follow—up
`0 For patients who did not enter the treatment lND but did continue in the
`Scharf study, no follow—up information (i.e., adverse events, laboratory and
`electrocardiogram data) is available after 1998-early 1999 which is when the
`Case Report Forms were created. The sponsor states that since these
`patients continued in the Schan‘ study no active recent attempts at follow-up
`were needed.
`
`. Many source documents (mainly in the “progress notes” category)
`supplied with the Case Report Forms are undated and unsigned.
`o The sponsor's narratives have in some instances, not included serious
`adverse events listed in the supplied Case Report Forms. The sponsor
`appears to have chosen only events that were considered by the investigator
`to be GHB-related for further description.
`‘
`For example, Patient # 01—012 (initials-—- 1 had an episode of “disorientation, stupor, and
`weakness" that necessitated hospitalization. This incident is not described in the sponsors
`narrative
`
`7.5.4 Deaths And Adverse Event Discontinuations
`
`7.5.4.1 Deaths
`
`None of the deaths listed above were causally attributable to GHB
`
`7.5.4.2 Adverse Event Discontinuations
`
`Narratives have been prepared by me for all individual adverse event
`discontinuations except Patient 01-271 (Initials \l and are contained elsewhere
`in this review, in the main Safety Review or both.
`
`in the case of Patient 01-271, a source document indicates that the patient‘s
`swelling resolved within a month of discontinuing GHB.
`
`7. 5.5 Patients Discontinued From Scharf Study For Non-Compliance
`
`7.5. 5.1 Background
`
`l have discussed these patients separately since the material that the investigator
`received from them (e.g., diary entries, laboratory and electrocardiogram data) is
`especially likely to have been deficient.
`w
`
`As indicated earlier, for the majority of patients in this category, material supplied
`with the Amendment did not contain information obtained actively by the
`investigator about their health status at the time of discontinuation. As I do not
`have direct access to the content of their diaries (except in the few instances
`where excerpts have been provided) and can make only indirect inferences from
`
`._._,.__, -_._‘.WW,‘—a_———~—_~— ..._. -- ~,——-————— —
`
`~
`
`.
`
`M... ~~ -
`
`—‘
`
`~—-—
`
`

`

`Page 19 of 93
`Ranjit 13. Mani, MD, HFD—120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical. Inc.
`6/14/01
`
`adverse event listings, dosing records, and laboratory/electrocardiogram data I
`have chosen to rely on whatever additional information has been provided about
`their status at the time of discontinuation for firm confirmation of their status at
`the time that treatment with GHB was terminated: such information is available in
`
`source documents (when provided), narratives and to a slight degree in the Case
`Report Forms themselves
`
`7.5.5.2 Summary Of Patients Who Were Discontinued From The Schan‘ Study
`For Non-Compliance
`
`24 patients were discontinued from the Scharf study on account of non-
`compliance: in 22 patients non-compliance involved not submitting study diaries
`sufficiently regularly, and in the remaining 2 patients, failure to follow dosing
`instructions. The details of these patients are in the next table
`
`Recorded Date
`01’ Last CHB
`Dose“
`
`Date Of Start 01'
`Last Adverse
`Event Recorded In
`
`Date 01’ Last
`Laboratory Test
`
`Date 01' Last
`Electrocardiogram
`
`Follow-Up After
`Discontinuation
`
`Case Report Form
`uncertain
`
`Patient it
`Initials
`
`Date Of Completion
`of Disposition
`Sheet’ In Case
`Report Form
`
`2/3/98
`
`2/28/98
`
`2/28/89
`
`2/7/89
`
`11/23/88
`
`11/23/88
`
`5/31/97‘ “
`
`4/19/91
`
`7/1/97
`
`7/1/97
`
`2/13/89
`
`5/1/97
`
`Unsuccessful attempt
`(in Match 2001)
`
`Last phone contact with patient
`on 8/ 19/97: patient had
`recently seen a liver specialist
`but outcome of assessment was
`
`1 01-201
`
`, 01-202
`
`2’19’98
`
`5/8/84
`
`4/17/84
`
`4/17/84
`
`4/21/84
`
`01 ~207
`,—
`
`01-209
`——_.
`01-210
`'———
`01212
`
`01-213
`u——_
`.tl't
`
`01-215
`a—s
`
`2/4/98
`
`2/6’98
`
`5/16/86
`
`2’27/98
`
`1/29/98
`
`5/3/85
`
`11/16/85
`
`12/23/85
`
`4/23/85
`
`8/13/85
`
`12/25/85
`
`10/22/84
`
`10/30/84
`
`7/23/85
`
`5/28/85
`
`7/25/85
`
`5/28/85
`
`3/13/85
`
`11/17/85
`
`12/24/85
`
`10/30/88
`
`10’29/88
`
`1/20/88
`
`1 1/1 1/85
`
`9/18/88
`
`Adverse events including
`
`
`peripheral edema resolved after
`
`
`study drug was withdrawn
`
`
`(contacted in March 2001)
`
`A source document (progress
`
`
`note) dated 1/18/91 indicated
`that after leaving the Scharf
`
`
`study the patient received GHB
`
`
`from another physician for
`“sometime”
`
`
`
`Patient clarified history of
`
`
`
`sui‘ide anempts prior to
`entering Scharf study
`
`
`(contacted1n March 2001)
`
`Telephone contact with patient
`
`
`inNovember 1988 indicated
`
`
`that patient had not received
`
`letta of discontinuation
` Adverse events including
`
`dininess and other symptoms
`had resolved
`
`

`

`Ranjit a. Mani, MD, Hmtzo Medical Review
`NBA 21196. Xyrem, Orphan Medical, Inc,
`Date Of
`Date 01' Last
`Date Of Completion
`Recorded Date
`Date 01' Start 01’
`Electrocardiogram Last
`of Disposition
`01 Last GHB
`Last Adverse
`Change
`Sheet‘ In Case
`Dose“
`Event Recorded In
`In GHB
`Report Form
`Case Report Form
`_—_—__ (contacted 1:: March 2001)
`1/28/98
`2/9/87
`2/16/87
`2/22/87
`2/9/37
`2/5/85
`
`Dose
`
`Page 20 of 93
`6/14/01
`Follow-Up After
`Discontinuation
`
`Date 01' Last
`Laboratory Test
`
`(
`
`_
`
`Patient it
`Initials
`
`01~216
`
`01-217
`O D O O O O 0
`
`01-222
`.’
`a t a a o t o o
`
`019223
`
`1/4/88
`
`No record
`
`1/12/87
`
`1/12/87
`
`6/18/86
`
`No adverse events
`Unknown but
`
`
`
`patient was
`recorded
`
`
`formally
`withdrawn from
`
`study on 7/5/88
`
`in a phone
`
`conversation
`4/22/87
`7/14/86
`
`10/13/86
`
`10/22/86
`
`01-240
`
`2/3/98
`
`2/11/98
`
`2/17/98
`
`01-746
`
`1 ,
`
`2118/98
`
`2/24/98
`
`2/25/98
`
`7/ 1 9/86
`
`7/ 1 5/86
`
`9/4/85
`
`5/6/85
`
`7/9/86
`
`No attempt
`
`4/21/88
`
`2/3/88
`
`>
`
`1/24/87
`
`12/1 1/86
`
`5/27/88
`
`5/29/87
`
`No record
`
`4/18/88
`
`No attempt but see footnote
`o a a o a. a c
`
`6/24/86
`
`10/5/86
`
`-.
`
`Study site received letter from
`
`
`patient dated 3/31/87
`
`No subsequent attempt at
`
`follow-u -
`
`No attempts at follow-up
`
`No
`record
`
`7/l6/86
`
`10/10/86
`
`Not attempted
`
`01-248
`—
`01-251
`_.__.
`01.256
`1
`T‘u v. or:
`1
`
`A
`
`2/27/98
`
`”7’“
`
`2/2698
`
`11/21/86
`
`“0’“
`
`1/31/85
`
`3.0.3.0...
`
`3/27/91
`
`No record of
`laboratorv tests
`7/29/87
`
`”9’“
`
`10/7/90
`
`4/11/86
`
`”9’”
`
`10/7/90
`
`11/21/86
`
`”‘3’”
`
`3/21/91
`
`2/26/98
`
`5/31/91
`
`3/4/91
`
`4/22/91
`
`12/29/89
`
`3/6/91
`
`4/8/98
`
`3/4/98
`
`7/31/97
`
`1/16/97
`
`12/30/97
`
`) 1/3/97
`
`1 1/30/96
`
`4/30/97
`
`5””
`
`1/25/97
`
`01-263
`—.
`
`
`
`Study coordinator spoke with
`
`
`
`patient on 11/27/91: he was
`still taking GHB at that time
`
`Study coordinator spoke with
`patient on 1/3/92 to request
`logs. Unclear whether he was
`still taking medication at that
`time.
`
`
`
`
`Additional follow-up not
`
`
`attem-ted
`
`
`Letter from patient dated on
`
`
`12/19/91 stating that GHB was
`of-benefit but that he
`discontinued that medication
`
`
`because of its bad taste
`
`
`
`3/19/99
`
`Unknown
`.‘....“....
`
`
`
`10/23/98
`
`777/98
`
`7/298
`
`/2/98
`
`
`
`
`Study coordinator spoke to
`patient on 2/11/99 to ask for
`
`
`study logs and to inform her
`that no further medications
`would be shipped out unless
`
`10' wire received
`‘The date entered in the disposition sheet is designated as an “assessment date.’ However, there is no evidence that the
`'assessment' consisted of an evaluation of the patient’s status. Data entered on this sheet consisted of the following
`owhether the patient was still enrolled in study
`—
`oil discontinued: date 01 last dose, and reason for discontinuation
`“The basis on which this date was determined is unclear. In addition there are inconsistencies between the source
`document and Case Report Form regarding the timing of the last dose
`’
`
`2 W .
`
`77.. . _ .. .- _ _-.-22- .. J. .2 --____.__, .-- ,‘ W__,_, ..V.....,_ .
`
`- —
`
`

`

`Page 21 of 93
`Ranjit e. Mani, MD, HFD~120 Medical Review
`
`NBA 21196, Xyrem, Orphan Medical, Inc. 6/14/01W
`"'The last recorded adverse event was during her initial period of treatment with GHB (see narrative in Section 7.5.10.1).
`However during her second period of treatment she was reported to have abnormal liver function tests but these were not
`recorded as an adverse event.
`"“A source document (letter to the patient dated 4/16/86) indicates that the last logs were received from this patient
`4/16/85
`”'"A source document (progress note) indicated that the last study logs from this patient were received in September of
`1985. Also note that for this patient the last recorded GHB dose change is one day AFTER the date 01 the last recorded
`dose of GHB
`""“A source document (progress note) indicates that the last set of study logs were received from the patient on
`February 22, 1987
`""‘“A source document (progress note) indicates that the last set of study logs were received from the patient on
`February 21, 1986
`"'"“‘A letter from the patient dated 5/25/88 indicates that she submitted study logs from the period 712/87 to 4/21/88
`""""'A source document (progress note) indicates that the last set of study logs were received from the patient on July
`1987
`“""“"See narrative in Section 7.5.10.5
`'"""“"Last recorded diary entry was on 3/31/97
`"""""“Last recorded diary entry was on 10/31/98
`
`Note that
`
`. Except where otherwise indicated based source documents and narratives (that
`cover both the study and follow-up periods), for none of the patients in the above
`table was any information provided that indicated each patient’s health status, based
`on a telephone conversation or face—to-face assessment, at any time during the
`study or at study termination. Only indirect evidence of each patient’s health
`status is available from the adverse event records, dosing records, laboratory
`tests and electrocardiograms; under the circumstances the best that can ~ue
`assumed about their status is that if they were able to have these tests done
`and submitted and to submit daily logs for closing and adverse events, they
`were clearly alive and probably not gravely ill.
`. Based on the latter assumption, and also based on follow~up contacts when
`available, most patients in the above table are unlikely to have been dead or
`seriously ill at the time of study discontinuation, assuming that the date of
`study drug discontinuation is derived from patient diaries(the method used to
`obtain the last date of treatment with GHB is not clearly stated). The
`exceptions are Patients 01~240- —- ) and 01-268 """'.. in whom the dates of
`study drug discontinuation are unknown and on whom no follow-up
`information is available
`
`._..._) had an unresolved adverse event (a paranoid mental
`0 Patient 01-256 (
`state) at the time of discontinuation, the outcome of which is unclear.
`. Patient 01-063 (—r ‘) had an unresolved abnormality of liver functions
`
`7. 5. 6 Discontinuations On Account Of Protocol Deviations
`
`..
`These included 2 patients
`0
`Patient 01-276 (Initials «who failed to meet inclusion criteria: this patient did not have narcolepsy,
`had a diagnosis of iibromyalgia and myofascial pain syndrome and received GHB for a total of only 3
`months without any adverse events other than the flu syndrome. 3 weeks after stopping study
`-.'
`medication he wrote to the investigator stating that he continued to have pain and a sleep disturbance.
`Patient 01-211 (Initials v. who was a screening failure and did not receive study drug: this patient
`failed to meet criteria for narcolepsy
`
`.
`
`These patients do not need to be further accounted for.
`
`.. __. ~__, _.‘_......... -‘—...'——— ~—___‘ __ -ee’. _-........_ ~_‘. -
`-‘—~—>-~---
`.
`;
`‘ VV‘HVVJ—V-I-wfi,._ -eiw~;_.~-
`._..—~=...
`Y «HF.
`..
`
`

`

`Page 22 of 93
`Ranjit B. Mani, MD, HFD—120 Medical Review
`
`NDA 21196. Xyrem, Orphan Medical, Inc.
`6/14/01
`
`7.5.7 Discontinuations On Account Of Medication Cost, Medication Cost, Lack
`Of Efficacy, And Transfer To Another Study
`
`l have reviewed all the narratives, Case Report Forms and source documents for
`the 23 patients who discontinued from the Scharf study for the reasons cited in
`the above heading. In the absence of a specific statement of their health status at
`the time of discontinuation, I believe it is possible to indirectly infer that none of
`these patients had an overt grave illness that was not disclosed in these
`documents. i believe it is possible to make such an inference for the following
`reasons
`
`0 They were well enough to initiate study discontinuation on their own for the reasons
`cited. if they had additionally discontinued treatment on account of being seriously ill
`(other than with narcolepsy) it is likely that they would have disclosed the same to
`the investigator
`. The patient who transferred to another study did so because that individual had
`fibromyalgia and not narcolepsy; it seems unlikely that the investigator would have
`made the transfer if the patient had a serious treatment-emergent illness.
`0 Recent follow-up information is available for at least 2 of these patients
`
`7.5.8 Patients Continuing In Scharf Study
`
`7.5.8.1 Description
`
`8 patients continued in the Scharf trial, i.e., they did not enter OMC-SXB-7 or
`discontinue from the Scharf trial itself
`
`
`
`Date Of Last
`Laboratory Test
`
`Date Of Last
`Date Of Last
`Electrocardiogram Change In GHB
`Dose
`
`These patients are summarized in the following table. The data in the table are
`derived from the Case Resort Forms
`Patient tit/initials
`Date Of Completion of Date Of Start 01 Last
`
`
`Disposition Sheet' In
`Adverse Event
`Case Re-ort Form
`10/11/99
`
`
`1/23/99
`
`01~054i
`5/2/98
`
`
`01-065 V
`9/30/99
`999/99
`
`
`
`01-262. "
`3/26/98
`
`
`6/30/99
`
`01-269, 1
`6/1/99
`
`
`‘The date entered in the disposition sheet is designated as an “assessment date.” However. there is no evidence that the
`'assessment' consisted of an evaluation of the patient‘s status. Data entered on this sheet consisted of the following
`owhether the patient was still enrolled in study
`oif discontinued: date of last dose. and reason for discontinuation
`
`919/99
`
`5/9/96
`1/28/99
`
`Note that
`
`o
`
`For none of these patients were source documents provided that indicated each
`patient’s health status, based on a telephone conversation or face-to-face
`assessment, at any time during the study. Only indirect evidence of each patient’s
`health status is available from the adverse event records, laboratory tests and
`electrocardiograms.
`0 Neither was an attempt made by the sponsor to actively determine the current health
`status of these patients; the sponsor's reason not for doing so was that these .
`patients continued to be in the Scharf study as of 5/31/99.
`
`
`
`
`
`
`
`
`
`
`
`

`

`Ranjit B. Mani. MD, Hszo Medical Review
`NBA 21196, Xyrem. Orphan Medicat, Inc.
`
`7. 5. 8.2 Comments
`
`Page 23 of 93
`6/14/01
`
`. There is no direct or indirect information available about the health status of
`
`these patients beyond January 1999
`. The sponsor should be asked to make an active attempt to determine the
`current status of these patients
`
`7.5.9 Patients Subjected To Recent Attempts At Follow-Up
`
`7.5.9.1 Criteria For Recent Follow—Up
`
`The narratives for all 80 patients who participated in the Scharf study, who did
`not enter the treatment IND. and who were not continuing in the Scharf study
`were reviewed to see if additional follow-up information would be helpful.
`
`Where necessary present day follow-up was sought in some patients to obtain
`further information such as the reason for withdrawal, the patient’s medical
`history prior to enrollment, and whether adverse events continued after drug
`withdrawal. Such follow-up information was requested for 19 patients and
`collected by site personnel for 10 patients.
`
`Follow-up information was not felt to be needed for patients whose source
`documents indicated that their adverse events were unrelated to study-
`drug, and the documentation of their reason for discontinuation was
`devoid of latent adverse event or severe disease
`
`7.5.9.2 Summary Of Patients For Whom Recent Follow~Up Was Attempted
`According to the patient narratives in this Amendment follow-up was attemp‘ed in
`March 2001 on the natients listed in the followino table
`Patient #llnitials
`
`
`
`01-013]
`
`
`
`01-019/
`
`
`01-063/
`
`
`
`
`
`
`slee c in I
`
`burned down
`
`Non-compliance: failure to return
`diary logs and have laboratory tests
`done
`
`fre-uenc
`
`frontal lobe c st
`
`Non-compliance: failure to return
`logs and questionnaires
`
`Non-compliance: Failure to return
`diary logs
`
`Patient request on account of
`sleepwalking with a lighted cigarette
`
`5/31/97
`
`12/31/83
`
`5/14/84
`
`8/26/84
`
`Io us
`— adverse effects of GHB
`
`01-005/ _
`
`01-200/
`01-201/,
`
`
`
`01—203/
`
`01-206/
`
`
`
`01-215/
`
`01-238)
`
`littfti/(i‘ftfti
`
`
`
`
`
`
`
`
`
`
`
`
`
`Results Of Recent Follow-Up
`March 2001
`
`
`
`
`
`well
`
`Unsuccessful
`
`Adverse events including peripheral
`edema resolved after study drug
`was withdrawn
`Patient clarified history of suicide
`attempts prior to entering Scharf
`stud
`
`'
`'
`Being treated with
`dextroamphetamine. Cataplexy not
`-roblematical
`Adverse events including dizziness
`and other 5
`utoms had resoived
`
`
`
`
`
`
`
`
`
`7/15/87
`
`Adverse event: Depersonalization,
`emotional labilit and others
`
`Unsuccessful
`.
`
`
`
`-—p—‘.~_._._. --‘_r_\.. V.
`
`

`

`Page 24 of 93
`Ranjit a, Mani, MD, HFD-120 Medical Review
`6/14/01
`NBA 21196, Xyrem, Orphan Medical, Inc.
`
`Patient #Ilnitiats
`Date of Discontinuation Reason For Discontinuation
`Results Of Recent Follow-Up
`March 2001
`Adverse event: Weiht loss
`
`
`
`
`
`
`9/30/95
`
`
`
`
`
`01.21——
`
`7. 5. 9.3 Comments
`
`0 Based on patient narratives, follow-up was attempted on only 15 patients, out
`of the 19 designated for the purpose by the sponsor
`o Follow-up was successful in confirming the status of 8/15 patients on whom it
`was recorded as having been attempted
`a Follow-up was unsuccessful in 7/15 patients on whom it was attempted
`a No follow-up information is therefore available for 11/19 patients designated
`by the sponsor as appropriate for follow-up
`. A full list of the 19 patients designated by the sponsor for follow-up is not
`available
`
`7.5.10 Unresolved Adverse Events Of Concern
`
`7.5.10.1 Patient # 01-063 (Initials .-—.
`
`This 2&year-old woman with a previous history of narcolepsy and depression was treated with GHB during
`2 distinct periods. During the first period lasting 3 years adverse events experienced included sleep walking,
`enuresis and nausea. At the end of that period she was taken off the study drug after becoming pregnant
`but was asked to continue to maintain her sleep logs.
`'
`
`6 years later, at the patient's own request, she was resumed on GHB (this was apparently done based on
`telephone contacts alone). A few months later the investigator discontinued her participation in the study as
`she had failed to return her diaries or respond to the investigators request to have liver function tests done.
`
`
`
`
`
`Some relevant dates are as follows
`StartOflnitial PeriodOfGHB Treatment
`End Of lnitial Period Of GHB Treatment
`GHB treatment stopped on account of pr -.. nan
`Resumption Of GHB Treatment
`Last Dose Of GHB
`Unclear how this date was determined
`
`
`
`5/31/97
`
`‘
`
`
`
`
`
`
`
`
`9/29/97
`
`Last written request for logs
`(This request stated that if logs were not received by 10/3/97 3
`further shipment of GHB would not be authorized
`Last recorded phone contact with patient’
`Last safEl
`labolal
`tests
`Last electrocardi - ram
`L351 recorded adverse event
`Last Chane in GHB dose
`
`‘The patient indicated that she had not as yet had the requested laboratory tests done (the patient was requested to repeat tests
`done on 7/1/97 on account of liver function abnormalities). She also indicated that she had seen a liver specialist who was not
`concerned about her abnormalities of liver function attributing them to her being overweight
`-
`
`
`
`
`
`
`
`
`
`
`
`
`Her liver function tests on 7/1/97 were as follows
`AST: 26 U/L
`ALT: 28 U/L
`Alkaline phosphatase: 158 U/L
`GGT: 136 U/L
`
`Attempts to contact the patient in March 2001 were unsuccessful.
`
`Reviewer’s Comment: The minor liver function abnormalities are not of serious concern.
`
`~
`
`-
`
`,
`
`__.
`
`..._v_...,_. -——. N. ..~v—va,_‘v_~ ~—-.————~ _. ._‘
`
`-
`
`.
`
`,
`
`_
`
`,
`
`.
`
`.
`
`._ t .
`
`-
`
`.
`
`

`

`r“ 1l
`
`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 21196. Xyrem, Orphan Medical, inc.
`
`7.5.10.2 01-238 (Initials -——,
`
`Page 25 of 93
`6/14/01
`
`About 6 months after this 47‘year old man began taking GHB he was first reported to have impaired short-
`term memory. Over the next 1.5 years further such reports occurred leading to the dose of drug being
`reduced from 9 g/day, the most commonly used dose, to 3.75 g/day and to the drug’s discontinuation a
`short while later after a total of about 2 years of treatment. Concomitant medications included
`methylphenidate and methamphetamine. No information is provided about his clinical course after study
`drug discontinuation.
`
`7.5.10.3 01-254 (Initials . -,-
`
`This 61 year old woman had-been diagnosed with narcolepsy at age 34. Her medical history was also
`remarkable for 'Hashimoto goiter’, and episodes of sleep apnea. Previous medications for narcolepsy
`included dextroamphetamine, methylphenidate, and imipramine. Concomitant medications included natural
`thyroid 2 g/day and calcium supplementation. 11 months after beginning GHB in a dose of 3.8 g/day she
`was hospitalized with shortness of breath, fever and cyanosis. Chest x-ray revealed evidence of an
`interstitial pneumonia and she was treated with oxygen. GHB was discontinued at that time: her last dose
`was 4.5 glday. These symptoms appear to have resolved based on a letter from the patient to the study
`center written 5 months after the event. but no further details are available; earlier in the study she was
`reported to have ankle swelling.
`Reviewer’s Comment: This narrative is included here in spite of the apparent resolution of the
`patient’s symptoms; the adverse event was a serious one and warranted study drug
`discontinuation, very few clinical details are available and recent follow-up was attempted but was
`unsuccessful.
`
`7. 5. 10.4 01 -259 (Initials —--
`
`This 41-year old woman was diagnosed to have narcolepsy 4 years prior to study entry. Her medical history
`was otherwise unremarkable. Concomitant medications included methylphenidate and estrogen. GHB was
`begun in a dose of 5.3 glday. 3 days later the patient reported that she felt like a zombie, and had stiffness
`in her legs and chest together with excessive crying. Her dose of GHB was reduced to 3 g/day that day, to
`1.5 g/day the next day, was omitted once a further day later, and was then resumed at 1.5 g/day. A further 8
`days later the dose was reduced to 0.8 glday. As her symptoms had not resolved 3 month later the drug
`was stopped. No additional information is available despite recent efforts by the sponsor to contact the
`patient; it is unclear therefore if her symptoms eventually resolved.
`
`7. 5. 10. 5 Patient # 01-256 (Initials . "i‘
`
`This 16 year old boy had a previous history of narcolepsy and of blurred vision following an injury to the left
`eye, but no preceding psychiatric illness was recorded. He took GHB while participating in the Scharftrial at
`a dose ranging from 2.3 g to 4.5 g. Concomitant medications included pemoline and clomipramine, as well
`as possibly imipramine.
`'
`
`At an unspecified point in the study he was recorded as 'acting very paranoid.“ He carried a bat with him
`while at home, and felt someone was watching him. The time of onset of this adverse event. the dose of
`GHB that he was taking at that time, and whether this adverse event resolved or not is unclear .
`
`He also reported nausea and a tendency to eat excessively at night and gained weight.
`
`He was withdrawn from the study 2 years entry, on account of non—compliance (failure to return his sleep
`logs)
`
`7.5.10.6 Patient # 01-273 (Initials ~—
`This 59 year old woman with narcolepsy began GHB on 11/6/94 and remained on the drug until 9/36/95
`when she discontinued treatment at her own initiative on account of weight loss. Her last dose of GHB was
`. 2.3 glday.
`
`

`

`Ranjil e, Mani, MD, HFD-120 Medical Review
`NDA 21196, Xyrem, Orphan Medical, Inc.
`
`Page 26 of 93
`6/14/01
`
`While in the study she had tumors of the neck and parotid gland removed surgically; further details of these
`tumors are unavailable.
`
`Attempts to contact the patient by phone on 3/22/96, 6/6/96 and in March 2001 were unsuccessful
`
`7.6 Reviewer’s Comments
`
`. The extent to which patients participating in this study were systematically
`monitored for adverse events, either during telephone contacts or at formal
`visits, remains very uncertain and is certainly not documented in the Case
`Report Forms or in any source documents that have been provided in this
`submission.
`
`0 Conclusions made above by me that a number of patients who discontinued
`from the Scharf study were not seriously ill close to the time of their
`discontinuation are based on indirect inferences. Such conclusions are
`
`therefore based on less-than-optimal data
`. The following 16 patients who participated in the Scharf Study and did not
`continue in the treatment IND, must be considered inadequately accounted
`for
`Continued ln
`Scharf Stud
`01-004/ __
`01-027],_,
`01-054)
`01065:“
`01228. I
`01-252. __
`01-269
`
`01-283 v
`
`Discontinuations For
`Adverse Events
`01-238/ __
`01-254i _.
`01-259 —-
`01-273 v
`
`Discontinuations For
`Non-Com-Iiance
`01-240. _.
`01-268. a
`01-256i —
`01-063; V
`
`. Recent attempts to follow—up 5 of the patients in the above table have already
`been made. Attempts at determining current health status need to be made
`for the followino additional 11 oatients
`-._
`
`Continued ln
`Discontinuations For
`
`Scharf Stud
`01-2401-
`
`01-2681 ._..
`01-256. 9
`
` NomCom-liance
`
`
`3
`
`8. Narrative For Patient 01-064 Participating ln Scharf Study,
`A more detailed description of this patient who was recorded as having seizures
`has been supplied by the sponsor. Both a narrative and Case Report Form have
`
`been supplied, as has a consultation letter from
`MD, a neurologist
`
`in
`Dr —- consultation letter was written on 4/26/89 very
`soon after the patient was instructed to discontinue GHB (see below).
`
`8.1 Narrative
`
`This patient (initials r" was 13 years old at the time of study entry. 2 years prior to entering the study
`she had sustained a fall, was stated to have sustained a concussion and was found on CT scan to have a
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196, Xyrem, Orphan Medical. Inc.
`
`Page 27 of 93
`6/14/01
`
`left frontal cyst; a burr hole procedure was apparently done at the time she had her head injury. After her fall
`she began experiencing excessive daytime sleepiness and, later, cataplexy. The narrative states that
`“polysomnogram testing confirmed the diagnosis of narcolepsy.’
`
`Concomitant medications at study entry included slow‘release methylphenidate (dose unspecified) and
`protriptyline 10 mg t.i.d. Her medical history was also remarkable for a scoliosis.
`
`She is believed to have participated in the Scharf study for about 2 years, although the date of her last dose
`is uncertain. Her dose of GHB during the trial ranged from 3 g/day