Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 . Xyrem, Orphan Medical Inc.
`
`Page 43 of 128
`6/13/02
`
`Figure 10. Duration 0: Oxygen Datamation w. Visit. by Patient -
`with .8303 < 90‘:
`first m1: of Right
`
`“tonnage of l-Soux Period
`
`
`
`figure 11. Duration of Oxygen fluctuation w. Val-it, by Patina! - Peanut-go a! l-Kmu- Period
`I10: 810, < OOI:
`Second 811! 0! Night
`
`
`
`Va-it
`
`The lowest SaOz recorded in this patient at each visit is summarized in the
`followin table which I have created from the data listings
`Lowesto nen saturation %
`
`
`
`

`

`Ranjit B. Mani. MD, HFD—120 Mediwl Review
`NBA 21196 . Xyrem, Orphan Medical Inc.
`
`9.2.2 Patient #17302
`
`Page 44 of 128
`6/13/02
`
`Clinical information is not available for this patient. Based on the RBI at Visit 2a,
`the baseline visit, the patient does appear to have had moderate pre-existing
`sleep apnea.
`
`RDl data for this patients are in the following table taken from the original data
`
`
`listins
`Res-irato Disturbance Index
`
`
`
`
`mI
`
`.
`
`
`
`
`-_II‘_
`
`
`___
`
`I-
`
`
`
`
`In a subsequent submission the sponsor has provided a comprehensive table of
`the patient’s respiratory event and oxygen saturation data, which I have copied
`below. Data for Visit 2b which were not included in the original data listings are
`highlighted in yellow.
`
`01mm”!
`
`VIII”
`I
`
`I
`
`I
`
`I
`
`M2.
`
`nun-uh ,
`Fl
`III
`I
`.
`
`um:
`_.
`
`Ml
`w, _.
`
`V|II5
`
`WI
`
`.
`
`N ,
`
`.
`
`.,. »
`
`CK!
`
`_ .
`
`"
`
`
`
`
`2n_Rosprmy_W_h¢hx
`
`.
`
`,
`'
`
`2M_Wl+ypapnea_lnlu_lR£M)
`Igwmnpneumug'
`-§
`2n_wrypma_m_1mem
`1n_met_O;_Snmon_r%UNt-§EN:
`M_Lm_og_snlm_m;_(NREua
`».
`,
`_
`g
`_
`”A, I ‘1
`..
`in_Lwest_OLSmn‘m_t%UREM,r
`
`I M
`. _Lox~!§l___
`. anon_t 34.
`'3
`“ n.
`'rniheutumwrruwoz-nxmmiwmmwmdmmrmmummmmmmygmmwnanaummnngmrmmwmm
`mmmmeummqmnmmmWMmmmad
`
`Note that the Respiratory Disturbance Index (for both halves of the night) was
`highest for this patient at Visit 3 (after 4 weeks of treatment at 4.5 g/day)
`
`9.2.3 Patient #17304
`
`This patient who discontinued Xyrem® during this trial on account of an adverse event was a 67 year old
`woman with a known history of narcolepsy (for 25 years), tonsillectomy, breast cancer in remission (treated
`with lumpectomy and radiation) and obstructive sleep apnea-hypopnea syndrome (confirmed by
`polysomnogram done over 1 '/2 years prior to her enrollment) . Concomitant medications included
`venlafaxine and modafinil.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medial Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 45 of 128
`6/13/02
`
`At screening this patient had a reportedly false-positive urine test for benzodiazepines. After entering the
`OMC-SXB-20 trial she failed to attend Visit 3 (on trial date 29) and indicated a desire to discontinue
`medication. However she then changed her mind and attended Visit 3 on Day 36. On Day 51, a day after
`beginning Xyrem® in a dose of 7.5 g/day she reported being “really sensitive” and her husband noted
`worsening snoring, and frequent and more severe episodes of apnea. By that time she had been treated
`with the following doses of Xyrem®: 4.5 g/day for 35 days and 6.0 g/day for 14 days. Xyrem® was
`discontinued on Day 51 on account of a perceived worsening in her obstructive sleep apnea—hypopnea
`syndrome. The adverse event was reported to have resolved by Day 52.
`
`Her last study visit was Visit 4.
`
`Several objective parameters — AHI (NREM), OMAs and RD! - all measured during the second half of the
`night showed no worsening at Wsits 3 and 4 as compared with Visits 1 and 2a. However the following were
`seen only at Visits 3 and 4
`0
`Increased AHl (REM and NREM), central apneas, hypopneas, and ROI during the first half of the night
`0
`increased AHI (REM) and central apnea during the second half of the night
`
`Changes in ROI over the course of the study are summarized in the following table which I have
`created from the data listings
`
`Visit
`
`I-
`
`Res . irato Disturbance index
`First half of ni- ht
`Second hatf of m ht
`87 09
`.
`36.02
`Not available
`100 87
`-
`
`27.39
`Not available
`
`47.77
`
`I‘-
`l- 57.92
`
`Oxygen saturation data are further summarized below. Lowest 8302 data are summarized in the
`followin. table
`
`Visit
`Lowesto nen saturation %
`
`
`-— Second half of niht
`E—
`
`
`
`01 available
`
`__
`
`
`
`
`
`Plots by visit for another oxygen saturation parameter, the percentage of the 4-hour period with an
`8302 < 90% are below, copied from a submission provided by the sponsor
`
`APPEARS HHS WAY
`0N GRiGlr‘iAL
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NBA 21196 . Xyrem, Orphan Medical Inc.
`
`Page 46 of 128
`6/13/02
`
`fox: Patinnt 01730! — Peron-Jug. of l—Houx
`21911:. 19. Dmtion of Oxygen “saturation vs. Visit,
`Period with 830, < 90%:
`lirst Half of night
`
`
`
`,fl ;
`
`.wvmysa’ev
`
`WyInZMe-aaeeaflvwé‘ t
`1mm
`
`*5
`
`.33:
`
`n Ia ”V
`
`
`
`
`
`figure 20. Dnzntion of Oxyqan Dosatutation vs. Visit, for Patient 017304 - Percentage of l-Houx:
`Period with 530, < 90%:
`Second Half a! Night
`
`
`
`3(er
`
`4,
`
`fivflfifflfiwmflmfl”mfi?hfl¢mgpffi;if;“11"”
`
`kin—RI:— .(,—1;»...u.
`
`. u ‘
`
`e a
`
`,
`
`..\-V.~,..=~r.v..._. ‘.
`
`.0. m , e.
`
`___, ”v,
`
`... H.-.» “N“,
`
`“7':
`.
`144*
`w~m€z§wfii<>l§fi¢g°
`
`. xmrmw“emit-1mm-
`my,» ;
`:. Mata?“
`W ,
`MK
`
`
`
`9.2.4 Patient #41306
`
`A clinical description is not available for this patient
`
`Changes in this patient’s RDl over the course of the study are summarized in the
`followin table
`
`
`
`Visit
`Resirato Disturbance Index
`W Second half of mm!
`19.43
`
`ii0!
`109
`
`
`l‘
`
`

`

`Ranjit B. Mani. MD. HFD—120 Medical Review
`NDA 21196 , Xyrem. Orphan Medial inc.
`
`
`
` Res . irato Disturbance index
`
`l-—_
`min——
`
`
`
`
`Page 47 of 128
`6/13/02
`
`The lowest SaOz recorded in this patient at each visit is summarized in the
`followin table which i have created from the data listings
`ViSIt
`Lowesto cen saturation %
`
`First half of nI-ht
`Second half of nioht
`
`
`
`
`
`
`
`I-__
`-—_
`___
`E-EE—E—
`__
`___
`E-—_
`
`
`
`9.2.5 Patient #42303
`
`A clinical description is not available for this patient
`
`Changes in this patient’s RDI over the course of the study are summarized in the
`following table
`
`
`
`The lowest SaOz recorded in this patient at each visit is summarized in the
`followin table which i have created from the data listings
`'
`'
`Lowesto oen saturation %
`
`First half of ni- ht
`Second half of niht
`_
`
`
`
`
`
`
`
`[_
`E-
`E—
`[=1—
`
`9.3 Description Of A Single Patient With Mild Sleep Apnea At Baseline
`
`9.3. 1 Patient #02630
`
`Patient #02630 completed the study but the data were not included in the 10/5/01
`submission as they were unreadable for the following reason: the nocturnal
`polysomnogram data for this patient were not convertible by the Stanford
`laboratory (the central reading facility for this study) as Site #26 used an optical
`disk recording system instead of a CD-R based system. The data for this patient
`were instead submitted on 3/12/02, in response to a specific query from the
`Division seeking to fully account for all patients participating in the study.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical lnc.
`
`Page 48 of 128
`6/13/02
`
`The investigator for Site #26 was contacted and asked to score both the
`respiratory event and oxygen saturation data for this patient. The scoring of the
`overnight polysomnogram data was then carried out by the a single technician
`consistent with that site’s clinical practice.
`
`9.3.1.1 Narrative
`
`This 58 year old man had a medical history significant for narcolepsy, obesity, “mild apnea,” plastic
`surgery for ptosis and on the ears, 3 submucous resection for a deviated septum and smoking.
`Concomitant medication included sertraline (withdrawn during the study as per protocol), a nicotine
`patch, nabumetone, methylprednisolone and cyclobenzapn’ne. While on treatment with GHB he
`experienced brief, intermittent anxiety, dizziness, nausea, and vomiting.
`
`9. 3. 1. 2 Table
`
`The following table provides respiratory event and oxygen saturation data for patient #026300.
`Note that he had a total AHI/RDl of 6.5 at Visit 1 which is consistent with mild sleep apnea.
`m1
`M h
`Visit 2b
`“.0! 4
`W5
`Vbllfi
`WW......WM mm. am»
`1 mmdmmumdwnm
` ..r
`2 " Halt Number 0! Hymns ondApmn
`1 WWWpom-a Index (NREM)
`2 " Hal! AmaNypopnn Index (NREM)
`1 Half WHypoma Index (REM)
`2 Half ApneaJHypopnea index (REM)
`1 Hthpnoan-flpopnol man (Total) -
`2 Hail manlypopnu lnou (Total)
`Obsmvc Apnea (NREM)
`Muted Apnoas (NREM)
`Central Apnus (NREM)
`W's (NREM)
`Gosh-cum Apnea: (REM)
`mm: Apnea: (REM)
`Comma Apnea (REM)
`Hypopnon (REM)
`W'Hyporma Nu (REM)
`W'Hypopnu thou (NREM)
`
`€144.
`
`
`
`|||||\||l
`
`“MM"
`
`WIWOO [[1de (Total)
`Lowest 0; Sim (is) (NREM) ”
`Lmst O; Saturation (6‘) (REM)
`
`l 5
`77 a wwwfimfi
`
`..
`
`. WWW/M
`"
`
`"loud02Saturationm)Mmmmammmm(§)mmmmMMImmm Thisisuiouflurfisi‘mjl
`mmiomunwmmmwwwmhmqswmr%)vmmmmmmm.mmuhmmdawmoq
`eventunot
`.
`
`9.3.1.3 Sponsor’s interpretation of results
`
`“In general, these data convey intra-patient variation across doses without a first
`night effect. This is consistent with the results demonstrated for the main OMC-
`SXB-20 respiratory events data obtained through centralized scoring."
`
`9.4 Reviewer’s Comments
`
`0 As noted earlier it is difficult to draw any firm conclusions from this study as a
`whole regarding the effect of sodium oxybate on respiratory parameters; the
`reasons for such a view are as follows
`
`0 The study was open—label and uncontrolled
`o The number of patients enrolled was small
`0 There was considerable inter-patient variability in changes from baseline in all
`parameters with standard deviations consistently exceeding means
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 , Xyrem, Orphan Medial Inc.
`
`Page 49 of 128
`6/13/02
`
`However when individual data listings for patients are reviewed concerns
`have been raised about the effects of Xyrem® on respiratory parameters in
`patients with pre—existing sleep apnea. Particularly noteworthy are 2 patients
`0
`Patient 17301 who had the following abnormalities:
`. An elevated RDl at baseline, falling in the ‘moderate to severe sleep apnea’ range
`increasing up to ~ 100 an extremely abnormal value, at Visit 3, after 4 weeks of
`treatment at 4.5 g/day
`. A steady increase over the course of the study (i.e., with increasing dose) in the
`period of time spent at an SaOz < 90%; by the end of the study almost 70% of a 4
`hour period had been spent at an oxygen saturation in that range.
`Patient 17304 who had the following abnormalities
`0 An elevated RDI at baseline falling in the severe sleep apnea range increasing
`further to ~ 100 at Visit 3 , after 4 weeks of treatment at 4.5 g/day
`o A perception by her husband that the severity of her snoring as well as apneic
`episodes had increased over the course of the trial leading her to discontinue at Visit
`4
`
`.
`
`Admittedly,
`.
`No evidence of a dose response in the severity of sleep apnea were seen in either of these patients
`.
`Changes in oxygen saturation parameters in these patients did not correlate with changes in RDl
`.
`It cannot be proven that the changes in respiratory parameters in these 2 patients were due to
`Xyrem® as opposed to spontaneous variability in the severity of sleep apnea
`The study cannot therefore be considered to provide reassurance that
`Xyrem®, clearly a central nervous system depressant drug, does not have a
`respiratory depressant effect, especially in patients with pre-existing
`obstructive sleep apnea. In this regard, it is noteworthy that narcolepsy and
`obstructive sleep apnea are reported to co—exist frequently.
`In order to provide reassurance that Xyrem® does not have a respiratory
`depressant effect, a formal controlled trial evaluating the effects of Xyrem® on
`respiratory parameters and oxygen saturation in patients with already
`compromised pulmonary function, and especially in those with obstructive
`sleep apnea, appears warranted. An alternative approach, contraindicating
`use of the drug in patients with obstructive sleep apnea, appears less
`desirable without the availability of “hard" data to support restricting the use of
`the drug in what must be a significant proportion of those with narcolepsy.
`This concern is especially justified given that at least 2 subjects reviewed
`earlier in the NDA, one a healthy subject and the other a patient with
`narcolepsy, appear to have developed depressed respiration when given
`doses of Xyrem® within the recommended range. In addition, at least one
`further subject participating in earlier clinical trials of Xyrem® was reported to
`have developed breathing difficulty on 2 separate occasions, once at a dose
`of 9 g/day and later at a dose of 3 g/day, and needed to discontinue Xyrem®
`on each occasion; although a narrative supplied by the sponsor suggests that
`the cause of the patient’s difficulty breathing may have been sleep paralysis
`that has not been substantiated (see additional details about this subject in
`Section 16.3.3.2 which tends to substantiate the assertion that the patient had
`sleep paralysis).
`
`

`

`Ranjit B. Mani, MD. HFD—120 Medical Review
`NDA 21196 . Xyrem. Orphan Medical Inc.
`
`Page 50 of 128
`6/13/02
`
`10. Response In Current Submission Regarding Respiratory
`Data In OMC-SXB-ZO
`
`The sponsor’s response is under 2 separate headings
`o Variability in sleep-disordered breathing
`. Variability in respiratory event parameters in OMC-SXB-20
`
`10.1 Variability In Sleep-Disordered Breathing
`
`The sponsor cites a number of publications that indicate that the ROI varies
`considerably even in the absence of a drug effect. l have reviewed these
`publications in regard to their relevance to the current application, and have
`summarized them below.
`
`10.1.1 Bliwise DL, Benkert RE, lngham RH. Factors associated with nightly variability in sleep-
`disordered breathing in the elderly. Chest 1991; 100(4): 973-976.
`
`The 71 subjects enrolled in this cohort study had a mean age of 74.6 years and were free
`from psychoactive medications and alcohol on both nights that they participated in the
`study, based on zero blood levels. On each night the subjects underwent
`polysomnographic monitoring. 13/ 71 subjects were determined to have high variability
`in sleep disordered breathing based on an absolute hypopnea—apnea index difference of
`2 10 events/hour between the 2 nights. The remaining 58 subjects were determined to
`have low variability. The following were noteworthy about the results of the study
`0
`In the high variability group the mean (i standard deviation) two-night absolute
`difference in apnea—hypopnea index was 19.4 i 12.2 events per hour. In the low
`variability group the mean (: standard deviation) two-night absolute difference in
`apnea-hypopnea index was 2.5 i 2.2 events per hour. The difference was considered
`statistically significant (p < 0.001)
`0 The higher variability group had a higher 2-night mean apnea hypopnea index (34.7
`i 19.3) than the lower variability group (7.4 i 9.1). The difference was considered
`statistically significant (p < 0.001)
`
`The frequency distribution for the absolute difference in AHI across the 2 laboratory
`nights is in the following figure which I have copied from the submission.
`
`APPEARS T511311!“
`05%! fiiiifiiiifl
`
`

`

`Ranjit B. Mani, MD, HFD~120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 51 of 128
`6/13/02
`
`
`
`79-5767» a 0 <9
`6
`7s};
`,
`e.....6b’6}‘9.:63'g’flgjh6)£335?.....
`
`‘
`, Am ABSOLUTE DIFFERENCE , _ ff];
`
`Since gross body position was constant for each subject in the higher variability group on both
`nights, the sponsor concluded that the variability in sleep disordered breathing in this might be
`related to upper airway anatomical factors that were inconstant from night to night.
`
`10.1.2 Wittig RM, Romaker A, Zorick FJ, Roehrs TA, Conway WA, Roth T. Night-to—night
`consistency of apneas during sleep. Am Rev Resp Dis 1984; 129(2):244-246.
`
`A case series of 22 patients was selected from a larger group of 50 adult male patients
`based on the following criteria
`0 At least polysomnographic studies performed within 90 days of each other (each
`recording lasted 8 hours)
`0 Not weight changes of > 10 lbs between the 2 studies
`0 No changes in medication in the interval between the 2 studies
`0 No treatments, surgical or otherwise, in the interval between the 2 studies
`
`These 22 patients were divided into 2 groups
`0
`Infrequent apnea (11 patients) with less than 100 apneic episodes during the first
`polysomnogram
`o Frequent apnea (11 patients) with greater than 100 apneic episodes during the first
`polysomnogram
`
`The consistency in the number of apneas between the 2 nights was examined.
`
`The key results of the study were as follows
`0 The frequent apnea group showed a consistent number of apneas on the 2 nights (I =
`0.92; p < 0.01). This group had a mean (i standard deviation) number of apneas on
`Nights 1 and 2 of 349.6 at 156.3 and 349.6 i 1668, respectively. This correlation is also
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medial Inc.
`
`Page 52 of 128
`6/13/02
`
`displayed graphically in the following figure which I have copied from the
`submission
`
`789
`
`-
`
`686
`
`598
`400
`
`NHIQHZ N O D
`
`9
`as? '3
`
`I:
`
`788
`
`a
`
`l
`‘
`‘196 288—389‘480 588 630
`
`N1 EHT 1
`
`o The infrequent apnea group showed a highly variable number of apneas between
`the 2 nights (r = 0.35; p > 0.10). This group had a mean (i standard deviation)
`number of apneas on Nights 1 and 2 of 40.4 i 28.4 and 33.2 i 29.8, respectively. This
`lack of correlation is also displayed graphically in the following figure which I have
`copied from the submission
`
`‘1 i:f},_1aa a;
`
`'muiz'iff;
`
`mm “
`
`0 Similar correlations were seen in the apnea index (apneas per hours of sleep)
`0 The frequent apnea group had mean (i standard deviation) apnea indices of 54.1
`i 20.6 and 56.0 :t 26.8 on Nights 1 and 2, respectively
`0 The infrequent apnea group had mean (i standard deviation) apnea indices of
`6.5 i 4.6 and 5.2 i 4.6, on Nights 1 and 2, respectively
`0 Apnea duration and type were consistent between the 2 groups
`
`

`

`Ranjit B. Mani. MD, Hszo Medical Review
`NBA 21196 . Xyrem, Orphan Medical Inc.
`
`Page 53 of 128
`6/13/02
`
`10.1.3 Mosko SS, Dickel MJ, Ashurst J. Night-to—night variability in sleep apnea and sleep-related
`periodic leg movements in the elderly. Sleep 1988; 11(4):340-348.
`
`In this prospective study, 46 community-dwelling subjects (30 women and 16 men) with a mean
`age of 68.7 years underwent 3 consecutive nights of polysorrmography; only 6 of these subjects
`were taldng medications for sleep which they were asked to continue.
`
`Key study results, pertinent to the current submission, were as follows
`0 A prominent f1rst»night effect was seen in the pattern of sleep as evidenced by greater total
`sleep time, shorter sleep latency, less waking afier sleep onset, better sleep efficiency, more
`REM sleep, shorter REM latency, and a greater number of REM periods on Nights 2 and 3,
`as compared with Night 1.
`o The fiequency histogram for RDI on each night is shown in the following figure which I have
`copied from the submission. Pairwise comparisons of the nightly distributions failed to show
`significant night-to-night differences. Note that in the figure below the number of subjects is
`displayed on the y-axis
`In!‘1
`
`i’
`
`InT'l“‘l"l‘r1"l'WW1'I'r‘r'i
`
`(a
`
`C)
`
`(5
`
`5<lO
`
`l0<15
`
`l5< 20 20( 2f: 25< 30
`
`>35
`
`R31
`
`0 Means and standard deviations for RDI for each night are in the following table, which I have
`copied from the submission. No statistically significant trends across nights were seen
`not
`tits)
`
`Night 1
`
`my» 2
`
`Niflit 3
`
`All night:
`
`4.7 : 1.2
`(0-354)
`4.3 : 7.4
`“Ll-‘03}
`5.3 : 8.}
`(0-503)
`4.8 = 7.6
`(0.2-0.0)
`
`0
`
`0
`
`Several individual subjects had “substantial” night-to-night variations in RDI large enough to
`influence diagnosis or treatment plan. Although the publication does not provide data for
`each subject or state how many subjects had “substantia ” night»to-night variations in RDI,
`the text states that a subject had an RDI of < 5 on one night and 25.3 on another night.
`If subjects were grouped into 2 categories based on a cut-off score of 5 RDI episodes per
`night, 20/46 (43%) subjects were classified differently on Nights 2 and 3 as compared with
`Night 1. The cut—offRDI score of 5 is stated to be used to group patients according to severity
`of sleep apnea.
`
`1"“
`
`

`

`Ranjit B. Mani, MD, HFDo120 Medial Review
`NDA 21196 . Xyrem, Orphan Medical Inc.
`
`Page 54 of 128
`6/13/02
`
`The authors of the article have concluded that “caution should be taken drawing conclusions from
`single-night studies, especially in individuals with relatively mild forms of sleep apnea where
`nightly variations could easily place them above or below an arbitrary cut-off score.”
`
`10.1.4 Bittencourt L, Suchecki D, Tufik S, et al. The variability of the apnoea-hypopnoea index. J
`Sleep Res 2001 ; 10(3):245-251.
`
`In this prospective study 20 patients with obstructive sleep apnea-hypopnea syndrome of both
`sexes and selected based on an age range of 30 —60 years underwent polysomnography on 4
`consecutive nights.
`
`Key results of the study, pertinent to the current application, were as follows:
`0 Mean apnea-hypopnea index (AHI) values were not significantly altered during the four
`nights of recording (p = 0.67). The intra—class correlation coefficient on the 4 nights was 0.92
`i 0.01 (SEM) with a 95% confidence interval ranging from 0.90 to 0.95. The following
`figure, copied fiom the submission, shows mean (3: SEM) for each of the nights for all 20
`patients enrolled in the study
`
`I : l
`
`noa
`
`liilillliiiliiliiiii:
`
`
`
`
`
`AHI(eventsIt")
`
`-|JNM
`
`pagan
`
`Night:
`
`Nights Nighu
`
`o Bland and Altman plots (see below) were used to analyze individual variability
`between the AHI values on the first versus each of the subsequent nights, and
`between the first night and the most deviating values. These indicated substantial
`variability unrelated to the initial value. The plots are below copied from the
`submission.
`
`APPEARS THIS WAY
`0N ORiGltiAl.
`
`

`

`Ranjit B. Mani, MD. HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medial Inc.
`
`Page 55 of 128
`6/13/02
`
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`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem. Orphan Medial Inc.
`
`Page 56 of 128
`6/13/02
`
`\
`
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`10.1.5 Mendelson WB. Use of the sleep laboratory in suspected sleep apnea syndrome: is one
`night enough? Cleveland Clinic Journal of Medicine 1994b; 61(4):299-303
`This prospective study was on 50 patients with a mean age of 50.2 years who presented to a sleep
`center and were clinically suspected of having obstructive sleep apnea; patients taking long-acting
`hypnotics or “major” analgesics were excluded from the study. They underwent 2 consecutive
`nights of polysomnography.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem. Orphan Medical Inc.
`
`Page 57 of 128
`6/13/02
`
`Patients who had an A}H 2 5 on at least of the nights, and in whom obstructive disordered
`breathing events (apneic and hypopneic) constituted > 50% of disordered breathing time were
`included in the analysis.
`
`Gross body position was not systematically recorded between nights
`
`Key results of the study that are pertinent to the current submission are below
`0
`Sleep and respiratory variables that showed a nominally statistically significant difference
`between the 2 nights based on group means are in the following table which I have copied
`from the submission. Note that the AHI, total number of disordered breathing events and
`minimum arterial oxygen saturation did not change significantly between nights (the author
`did not state precisely what these values were). The AHI was highly correlated between
`nights (r = 0.86; p < 0.0001) for the 49 patients who had an AHI of 5 or more on one of the 2
`nights.
`SLEEP AND RESPiRATORY VARIABLES
`THAT SlGNIFlCANTLY DlFFERED BETWEEN THE TWO NIGHTS {N=50)
`
`W _
`Total steep time. ninutes
`Sup latency. minutes
`Rapid-eyammment (REM) latency, minutes
`Sleep efficiency, 96
`Stage 1, minutes
`Stage 2. minutes
`Obstructive apnea time in REM steep, 96
`Baseline oxygen saturation in not-1115M sleep, 16
`Subjective sleep latency~ minutes
`Subjective total sleep, minutes
`
`W’
`
`By paired nest
`
`o
`
`o
`o
`
`The next table indicates the number of patients who had AHIs 2 5 and 2 10 on the first and
`second nights
`AHI
`Night 1
`Number of patients
`46
`
`Night 2
`Number of patients
`49
`
`2 5
`
`2 10
`
`42
`
`46
`
`57% of patients had a difference in AHI of at least 10 or more between Night 1 and Night 2
`In the current submission, the sponsor has drawn attention to the following table which
`summarizes mean (-J: SE) in sleep and respiratory measures in 46 patients who had an AHI of
`5 or more on the first night . The parameters that the sponsor wants to draw particular
`attention to are highlighted in red borders. The sponsor states that there was significant
`oxygen desaturation based on absolute minimum means of 78.9% and 68.9% during NREM
`and REM sleep, respectively.
`
`Wf
`
`irst night
`(mean 1 SEM)
`3556 2 11.1
`16.8 t 5,7
`1325 2 10.6
`69.1 t 4.5
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`712 2 4.8
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`

`

`Page 58 of 128
`Ranjit B. Mani. MD. HFD~120 Medical Review
`
`NDA 21196 , Xyrem, Orphan Medical Inc.
`6/13/02
`
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`10.1.6 Punjabi NM, Bandeen-Roche K, Marx JJ, Neubauer DN, Smith PL, Schwartz AR. The
`association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep.
`Sleep 2002; 25(3):307-314.
`
`This was a retrospective study carried out on a series of 2736 patients consisting all those
`who underwent an overnight polysomnogram in a specific sleep laboratory between
`January 1996 and September 1999. Based on specific criteria, the polysomnograms of
`1821 patients (who also underwent Multiple Sleep Latency Tests) was selected from this
`group for further analysis.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 . Xyrem, Orphan Medical Inc,
`
`Page 59 of 128
`6/13/02
`
`The only result of the study that appears pertinent to the current submission, and to
`which the sponsor has drawn attention, is the wide-range of sleep disordered breathing
`seen. This variability is seen in the scatter plot for the AHI (NREM) and AHI (REM) in
`the figure below which I have copied from the submission. The red line inserted by the
`sponsor into the figure is to demonstrate the potential for the RDI to be greatly in excess
`of the highest levels seen in the OMC-SXB-ZO study without an attributable relationship
`to a drug.
`
`
`
`FIGURE 5: Scatterplot ofNREAfiAHI and REM-AHI (dashed lines represent cut-
`poims for NkEMeAHJ quartiles). Punjabi 2002.
`
`There is no data available in the paper regarding clinical symptoms, medication
`use, or oxygen saturation, in this sample, and especially in those with a
`REM/ NREM AHI greater than 100. The authors concluded that sleep-disordered
`breathing during NREM sleep but not REM sleep, is associated with an
`increased risk of daytime sleepiness as daytime sleepiness as measured by the
`Multiple Sleep Latency Test.
`
`10.2 Variability In Respiratory Event Parameters In OMC-SXB-ZO
`
`The sponsor has first provided the study schematic and has highlighted the
`following aspects of the study and analysis
`
`

`

`Page 60 of 128
`Ranjit a. Mani, MD, HFD—120 Medical Review
`
`NBA 21196 , Xyrem. Orphan Medial Inc. 6/13/02
`
`.
`
`lntrasubject variability in measures of sleep-disordered breathing in this study
`were interpreted in the context of the following
`o The spontaneous variability in these measures as described in the medical
`literature
`
`- The presence or absence of a dose-response relationship in regard to these
`measures
`
`0 Although the study was deficient in that it was not randomized and controlled
`0 All study measures were objective and used the standard recording methods of a
`sleep laboratory.
`The Xyrem® dosing regime was controlled and accurate
`Each patient had 2 sets of measures recorded under conditions where he/she
`was not taking Xyrem®: Visit 1 (while still receiving anti-cataplectic medications
`other than Xyrem®) and Visit 2a (baseline, after washout of anti-cataplectic
`medications). Changes in measures of sleep-disordered breathing while taking
`Xyrem® could be compared against these baseline measurements
`
`For convenience I have again copiedgthe study schematic below
`
`if: OMC'SXB‘ZO. Virgina" {1.337 g 175::
`fl} Mt
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`The rest of the sponsor’s response is under the following headings (the headings
`have been modified somewhat by me)
`
`10.2.1 Criteria Applied To Diagnose Sleep-Disordered Breathing Events
`
`The sponsor states that while the well-documented variability in sleep-disordered
`breathing events is not well understood, this variability may be contributed to by
`sleep position, upper airway morphological features, sleep stage composition,
`and pulmonary status
`
`The classification of sleep—disordered breathing events in this study was based
`on the following publication.
`
`American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in
`adults: Recommendations for syndrome definition and measurement techniques in
`clinical research. Sleep 1999; 22(5):667-689.
`
`

`

`Ranjit s. Mani, MD, HFD-120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`,
`
`Page 61 of 128
`6/13/02
`
`These criteria, according to the sponsor, are more rigorous than those used in
`clinical practice, and are as follows
`
`A reduction in breathing occurring during sleep is defined as an apnea only if
`airflow
`
`1. Ceases for at least 10 seconds AND
`
`2.
`
`Is associated with an oxygen desaturation of 2 3% or is associated with
`arousal
`
`A reduction in breathing occurring during sleep was defined as a hypopnea only
`if Criterion 1 or 2 plus Criterion 3 is satisfied).
`1. A clear decrease (>50%) from baseline in a Valid measure of breathing during
`sleep (baseline is defined as the measured amplitude of stable breathing over
`the 2 minutes preceding the onset of the event if breathing is stable, or in the
`amplitude of the 3 largest breaths)
`ls associated with either an oxygen desaturation of 2 3% or arousal
`2.
`3. The event lasted 2 10 seconds
`
`The sponsor further states that, for both the above definitions, an oxygen
`desaturation 2 4% has now replaced the _>. 3% figure. By the more liberal current
`cr