CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-196
`
`MEDICAL REVIEW
`
`

`

`Review and Evaluation of Clinical Data 1
`
`NDA (Serial Number)
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`
`Correspondence Date:
`Date Received I Agency:
`Date Review Completed
`Reviewer:
`
`21196
`Orphan Medical Inc.
`Xyrem®
`Narcolepsy
`Amendment To NDA
`
`5l16l02
`5/17/02
`6/13/02
`Ranjit B. Mani, M.D.
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ....................................................................................... 1
`
`1. BACKGROUND ............................................................................................ 5
`
`2. APPROVABLE LETTER OF APRIL 9,2002 5
`
`Assessment of Xyrem’s Potential to Induce Respiratory Depression ....................................................... 6
`
`Adequacy of the Safety Database ................................................................................................................ 6
`
`Promotional Materials ................................................................................................................................. 7
`
`Postmarketing Issues.................................................................................................................................... 8
`
`3.
`
`LIST OF ALL CLINICAL STUDIES IN THIS APPLICATION ........................ 8
`
`3.1
`
`3.2
`
`Efficacy And Safety Trials ............................................................................................................ 8
`
`Pharmacokinetic Trials
`
`........................................................................................................ 9
`
`4. CONTENTS OF SUBMISSION ..................................................................... 9
`
`5.
`
`SCOPE OF REVIEW ................................................................................... 10
`
`6. COVER LETTER ......................................................................................... 10
`
`7. ORGANIZATION OF REVIEW OF OMC-SXB-ZO RESPIRATORY DATA
`
`CONTAINED IN CURRENT SUBMISSION ....................................................... 14
`
`8. RESPIRATORY DATA IN STUDY OMC-SXB-20 AS CONTAINED IN
`
`EARLIER REVIEW COMPLETED 3/4/02 .......................................................... 14
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 2 of 128
`6/13/02
`
`8.1
`
`8.2
`
`8.3
`
`8.4
`
`8.5
`
`8.6
`
`8.7
`
`8.8
`
`Background ................................................................................................................................. 14
`
`Outline Of Protocol For OMC-SXB-ZO Study........................................................................... 15
`
`Instruments For Measuring Respiratory Event Data ............................................................... 19
`
`Respiratory EffectMeasures..........19
`
`Methods Of Analyzing Respiratory Data ....21
`
`Results ............................................................................................................................................ 21
`
`Sponsor’s Conclusions ............38
`-.
`
`Reviewer’s Comments .................................................................................................................39
`
`9. ADDENDUM TO REVIEW OF RESPIRATORY DATA IN STUDY OMC-
`
`SXB-20 AS CONTAINED IN EARLIER REVIEW/ADDENDUM COMPLETED
`
`3/29/02
`
`.......
`
`.......
`
`............
`
`.......
`
`.......
`
`.....
`
`40
`
`9.1
`
`9.2
`
`9.3
`
`9.4
`
`Background ..................................................................................................................................40
`
`Description Of Patients With Pre-Existing Moderate To Severe Sleep Apnea ...................... 41
`
`Description Of A Single Patient With Mild Sleep Apnea At Baseline ......................................47
`
`Reviewer’s Comments ..................................................................................................................48
`
`10. RESPONSE IN CURRENT SUBMISSION REGARDING RESPIRATORY
`
`DATA IN OMC-SXB-20.. .......
`
`......
`
`......
`
`......
`
`.....
`
`50
`
`10.1
`
`10.2
`
`10.3
`
`10.4
`
`Variability In Sleep-Disordered Breathing ............................................................................ 50
`
`Variability In Respiratory Event Parameters In OMC-SXB-ZO.......................................... 59
`
`Sponsor’s Conclusions ............................................................................................................ 85
`
`Reviewer’s Comments.............................................................................................................. 86
`
`11. RISK MANAGEMENT PROGRAM ELEMENTS .......
`
`.....
`
`...... .. ...... . ....... 87
`
`1 1.1
`
`1 1.2
`
`11.3
`
`11.4
`
`Risk Management Program Proper ...................................................................................... 88
`
`Xyrem® Physician Success Program Elements ..................................................................... 89
`
`Xyrem® Patient Success Program Elements ....................................................................... 89
`
`Post-Marketing Program Elements ....................................................................................... 91
`
`12. PROPOSED LABELING................ ........
`
`.....
`
`..... . ....... . ......
`
`............... 91
`
`

`

`Ranjit B. Mani. MD, HFD-120 Medical Review
`NBA 21196 , Xyrem. Orphan Mediaal Inc.
`
`Page 3 of 128
`6/13/02
`
`12.1
`
`12.2
`
`12.3
`
`12.4
`
`12.5
`
`12.6
`
`12.7
`
`Black Box Warning .................................................................................................................. 92
`
`Clinical Pharmacology ...........................................................................................................95
`
`Clinical Trials ...................................................................................................................... 97
`
`Contraindications ...................98
`
`Warnings ...........................................................................................................................99
`
`Precautions ............................................................................................................................. 103
`
`Adverse Reactions.........104
`
`12.8
`
`Drug Abuse And Dependence ............................................................................................ 104
`
`13. PROPOSED PATIENT MEDICATION GUIDE.............. ......
`
`106
`
`What is the most important information I should know about Xyrem® / What should I
`I 13.1
`avoid while taking Xyrem ......................................................................................................................... 106
`
`13.2
`
`How should I store Xyrem® .................................................................................................. 107
`
`13.3 .
`
`Directions for using Xyrem® .............................................................................................. 107
`
`14. PROPOSED ADVERTISEMENT .....
`
`......................
`
`.....
`
`.....
`
`..... 107
`
`15. DRUG STABILITY AND EXPIRATION DATING ......
`
`16. FOLLOW-UP OF PATIENTS AT STUDY SITE #8
`
`.......
`
`107
`
`107
`
`16.1
`
`Background ............................................................................................................................ 107
`
`Extent To Which Site # 8 (Martha Hagaman, MD) Participated In Orphan-Conducted
`16.2
`Clinical Studies Included In NDA ........................................................................................................... 108
`
`16.3
`
`16.4
`
`Additional Information Requested From Sponsor .............................................................. 108
`
`Reviewer’s Comments........................................................................................................ 112
`
`17. AUDIT OF STUDY SITE #5
`
`.............
`
`.........
`
`112
`
`18. ADDITIONAL INFORMATION ABOUT A PATIENT AT SITE #41112
`
`18.1
`
`18.2
`
`18.3
`
`Background ............................................................................................................................ 112
`
`Extent To Which Site #41 Enrolled Patients In Orphan-Sponsored Studies .................... 113
`
`Teleconference With Dr Mamelak: May 30, 2002 ............................................................... 113
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medial Review
`NDA 21196 , Xyrem, Orphan Medical lnc.
`
`Page 4 of 128
`6/13/02
`
`18.4
`
`Conclusions ............................................................................................................................ 114
`
`19. EXPOSURE DATA
`
`...... .. .......
`
`.........
`
`.....
`
`114
`
`19.1
`
`19.2
`
`19.3
`
`19.4
`
`19.5
`
`Overall Schematics For Clinical Trials In Narcoleptic Patients Included In NDA .......... 115
`
`Tables ...................................................................................................................................... 116
`
`Sponsor’s Overall View Of Adequacy Of Exposure........................................................... 117
`
`Additional Request For Information From Sponsor......................................................... 118
`
`Reviewer’s Comments..........................................................................................................119
`
`20. ADVISORY COMMITTEE MEETING............ .....
`
`......
`
`.......
`
`120
`
`20.1
`
`20.2
`
`203
`
`Key Items Voted On .............................................................................................................. 120
`
`Additional Recommendations ........................................................................................... 121
`
`Additional Comments .......................................................................................................... 122
`
`21. RISK-BENEFIT EQUATION AND OVERALL CONCLUSIONS
`
`........... 122
`
`22. RECOMMENDATIONS............................. .......
`
`...... .. ......
`
`..... .. ........
`
`127
`
`

`

`Ranjit B. Mani, MD, HFD—12O Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 5 of 128
`6/13/02
`
`1. Background
`
`This submission, an Amendment to the sponsor’s New Drug Application (NDA)
`for Xyrem®, is a response to a second Approvable action letter dated 4/9/02.
`
`An earlier and initial Approvable action was taken in a letter dated 7/2/01. That
`Approvable action was based on the original NDA for Xyrem®, which was
`submitted on 9/30/00, and a Major Amendment that was submitted on 3/23/01;
`the original NDA was granted priority review status. The application was also
`discussed at a meeting of the Peripheral And Central Nervous System Drugs
`Advisory Committee which was held on 6/6/01. Please see the following Agency-
`created documents, related to those 2 applications for full details
`. The efficacy and safety reviews of the original NDA
`. The clinical review of the Major Amendment
`. The transcript of the Advisory Committee meeting
`. The text of the Approvable letter
`
`The sponsor responded to the initial Approvable letter with a submission dated
`10/5/01; this submission led to the Approvable action letter of 4/9/02. Please see
`my reviews of that submission, and the text of the Approvable letter of 4/9/02 for
`full details
`
`The indication currently being pursued by the sponsor is as follows:
`
`“Xyrem® (sodium oxybate) oral solution is indicated for the treatment of cataplexy in patients with
`narcolepsy"
`
`Xyrem® has been developed by Orphan Medical, Inc. for the treatment of
`narcolepsy under IND # F" and Treatment lND # r” . Data obtained from
`individual sponsor-investigator lNDs #s: M“ (M. Scharf) and'M“-M' (L. Scrima)
`have also been used in support of this application.
`
`‘
`
`In this review the words/phrases/acronyms “y-hydroxybutyrate,”
`"gammahydroxybutyrate," "GHB." “sodium oxybate,” and “Xyrem®" have been
`used interchangeably.
`
`Prior to reviewing the contents of the submission, it will be helpful to outline the
`text of the main Approvable letter of 4/9/02 and list in tables all clinical studies
`that have been included in this NBA.
`
`2. Approvable Letter 0f April 9, 2002
`
`The Approvable letter was accompanied by
`c Labeling
`. A medication guide
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical lnc.
`
`Page 6 of 128
`6/13/02
`
`0 A summary of the risk management program
`
`Only the text of the Approvable letter proper is below:
`
`Your October 5, 2001, amendment constituted a complete response to our July 2, 2001, approvable letter.
`
`We also acknowledge receipt of your submission dated April 3, 2002, containing the results of the
`completed rat carcinogenicity study.
`
`We also refer to the April 2, 2002, meeting between you and FDA.
`
`We have reviewed this application under the restricted distribution regulations contained in
`21 CFR 314.520 of Subpart H.
`
`We have completed the review of this application, as amended, and it is approvable. The remaining issues
`that you will need to address before this application may be approved are outlined below.
`
`
`
`Assessment ofXyrem ’5 Potential to Induce Respiratory Depression
`
`in our July 2, 2001 Approvable Letter we asked you to perform a formal assessment of the respiratory
`effects of Xyrem prior to marketing. Such assessments are routinely required in the evaluation of sedative-
`hypnotic dmg products. Subsequently, we agreed to review the results of SXB-20, an uncontrolled
`polysomnographic study previously performed to evaluate the effect of Xyrem on different sleep stages.
`You believed the results of the respiratory monitoring in SXB-20 provided enough reassurance to allow
`approval while formal, controlled studies could be performed post-approval.
`
`We have reviewed the results of SXB-20 and are concerned that Xyrem may produce clinically important
`deleterious effects on respiratory function during sleep, especially in patients with sleep apnea. While there
`was marked variability in the data collected, 2 of the 4 patients with moderate-severe sleep apnea had
`marked elevations over baseline in the RBI (respiratory distress index) while on treatment. Absent a control
`group, it is impossible to distinguish between variability and a dnrg effect as the cause of these elevations.
`As discussed in our meeting of April 2, 2002, we believe that these changes may represent a clinically
`significant worsening of respiratory function at night related to treatment with Xyrem in at least one, and
`perhaps in both, patients. We acknowledge that you believe that none of the patients experienced a
`clinically relevant decline in respiratory function. We agreed that you may submit a comprehensive
`response to our stated concerns in lieu of a definitive assessment of Xyrem's effect on respiratory function
`in response to this letter. While it is possible that we may find your arguments convincing (if we do, you
`would still need to perform an adequately designed trial to definitively address this question in Phase 4), it is
`also possible that we will remain concerned that Xyrem may cause an important deterioration of nighttime
`respiratory function.
`If this is the outcome, you will be required to perform an adequate study addressing
`this issue prior to approval.
`
`Adequacy of the Safety Database
`
`As you know, the size of the safety database in your application is, and remains, with the Safety Update,
`small by the usual standard. The number of patients who reached the highest daily dose, ngs/day, did not
`change appreciably with the Safety Update and is only 141, 74 of whom were treated for at least 6 months.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NBA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 7 of 128
`6/13/02
`
`
`
`
`
`
`Given this small experience, we are particulany concerned about the results of a recent site audit, which
`have raised questions about the acceptability of the data generated at this site. As a result of this audit, we
`
`now believe that one or more additional site audits will be needed prior to approval. The next site audit is
`planned within a month.
`
`Once the above issues are adequately addressed, we are prepared to approve Xyrem for the treatment of
`cataplexy in narcolepsy under Subpart H as requested in your March 12, 2002 letter. Upon initial marketing
`under Subpart H, the distribution of Xyrem will be regulated as described in 21 CFR 314.520. Attached to
`this letter are proposed labeling and an outline of a proposed risk management program that is acceptable
`to us. The primary component of the risk management program is a central pharmacy.
`
`
`
`
`
`
`
`Also attached to this letter are marked up versions of the documents you plan to send to doctors and
`patients as part of your Physician and Patient Success Programs, including draft product labeling and a
`
`draft Medication Guide for distribution with Xyrem. All of these documents, and the Specific details of the
`
`risk management program, are subject to change pending your response to this Approvable Letter, and
`therefore should be considered provisional at this time.
`
`
`
`
`
`
`D l
`
`\mw&wmflflmawmfi;mm’mm.
`
`Wmefivezmfiw
`
`I
`
`

`

`Page 8 of 128
`Ranjit B. Mani. MD, HFD—120 Medical Review
`
`NBA 21196 . Xyrem, Orphan Medical Inc. 6/13/02
`
`3. List of All Clinical Studies In This Application
`
`l have listed these studies in 2 categories
`0 Efficacy and safety studies
`0 Pharmacokinetic studies
`
`3.1 Efficacy And Safety Trials
`All oatients enrolled in these trials had narcoles .
`Study #
`Number of
`
`Duration
`
`Status
`
`-_-_—
`
`
`
`
`
`. lacebo—oontrolled, . arallel-arm
`
`extensvon stud
`O-n-labelunoontrolled stud
`
`_OMC-SXB-a
`
`Lammers
`
`OMC-SXB-21
`
`Randomized, double-blind,
`placebo-controlled, cross-over
`stud
`Randomized. double-blind,
`placebo-controlled, cross-over
`stud
`On-label uncontrolled stud
`Randomized, double-blind,
`placebo-controlled, parallel-arm,
`RANDOMIZED WITHDRAWAL
`study after long-ten'n open label
`treatment
`
`escalation stud
`
`a - roval
`
`185 atients
`
`20 patients
`
`-
`25 patients
`
`143 oatients
`55 patients
`
`'
`
`Complete
`
`Complete
`
`Complete
`
`
`
`
`
`‘GHB and placebo were each used for 4 weeks
`"Period of randomized withdrawal
`0
`The number of patientslisted for ongoing studies are those enrolled as of 6/30/01.
`o
`OMC-GHB-Z and OMC-SXB—21, as well as the Scrima and Lammers studies, were primarily intended to assess the
`efficacy of Xyrem® in treating cataplexy.
`
`
`
`gray—v ., d‘-»~~,: —.- -
`
`.
`
`

`

`Page 9 of 128
`Ranjit e. Mani, MD, HFD—120 Medial Review
`
`NBA 21196 , Xyrem, Orphan Medical lnc. 6/13/02
`wwflwwemw—w--»~».y.e..,....t._e.v.,,.. “my,“NW,» _
`
`‘ ‘N/‘F’flfl.
`
`.
`
`OMCi-éyBJ-ZO was intended to assess the effects of 4 different doses of Xyrem® on sleep architecture
`
`Further comments about some of the above studies are below
`Study #
`Comments
`
`OMC-GHB-B
`
`OMOSXBJ
`
`Extension to OMGGHB-Z.
`Treatmentvnai've -atients excet for a stn-le oatient -reviousl
`Extension to
`OMC-GHB-3 (53 patients )
`OMC-SXB-6 (121 patients)
`Scharf Studv (66 patients)M
`
`OMC—SXB~20 (20 patients)
`vauwpwm
`
`in OMC-GHB-Z and OMC-GHB—3
`
`
` —_
`
`The numbers in parentheses in this cell refer to the number of patients entering OMC-SXB-‘I from each study
`
`3.2 Pharmacokinetic Trials
`
`125 health subsets and 19 narcoleotic oatients unarticiated in these trials
`
`—_
`'The 6 narcoleptic patients participating in this study also enrolled in the Scharf study
`”The 13 narcoleptic patients participating in this study also enrolled in OMC-SXB-G
`
`4. Contents Of Submission
`
`The submission is in electronic format. The cover letter is also available in paper.
`
`The contents of the submission include the following separate sections
`. Cover letter
`
`"Clarification" of respiratory data in OMC—SXB-20
`0
`0 Response to labeling contained in Approvable letter of 4/9/02 (redlined/annotated
`and clean PDF versions; Word versions)
`. Response to the following Risk Management Program elements contained in the
`Approvable letter of 4/9/02 (redlined/annotated and clean PDF versions; Word
`versions)
`0
`Risk Management Program proper
`0 Medication Guide
`
`0 Xyrem® Success Program (Physician and Patient)
`0
`Post-Marketing Evaluation Form
`. Chemistry, Manufacturing, and Controls data: Stability Update supporting 36 month
`expiration dating.
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medial Review
`NBA 21196 , Xyrem, Orphan Medical inc.
`
`Respiratory
`
`Page 1 1 of 128
`6/13/02
`
`A key issue identified in your approvable letter of April 9, 2002
`was in relation to possible effect of Xyrem on respiratory
`function. Citing data from trial SXB-ZO, we have shown the
`following:
`
`0 The discussion in the attached report confirms variability
`in sleep disordered-breathing that is characteristic of the
`disease, as supported by the literature. Since there was
`no association between numerical changes in Respiratory
`Disturbance Index and oxygen desaturation in any patient in
`this study,
`these changes do not represent a safety
`concern.
`
`0 Although study OMC—SXB-ZO was not designed as a randomized,
`blinded, controlled study, it does present objective
`measures of respiratory events, sleep architecture and
`oxygen saturation data. Each patient provides their own
`control as represented by baseline measures. Confirmation
`of non-oxybate effect is available from initial P56
`recordings (prior to CessatiOn of anti-cataplectic
`medications).
`Interpretation of intra-patient variability
`is limited by lack of randomization in this study, but is
`strongly supported in the literature.
`
`0 There is no dose-related effect demonstrated in the
`
`incidence of sleep-disordered breathing events that could
`support a pharmacologic response attributable to sodium
`oxybate in the dose range studied from 4.5-Sg/night. There
`is disassociation between the numerical representations of
`Respiratory Disturbance Index and the effects on oxygen
`saturation in this study,
`indicating such events are brief
`in duration and have not led to prolonged decreases in
`ventilation with consequent hypoxia. Since the primary
`measure of respiratory function is gas exchange,
`the
`
`APPEARS THlS WAY
`0N GRiGlNAL
`
`

`

`Page 12 of 128
`Ranjit B. Mani. MD, HFD—120 Medial Review
`
`NDA 21196 , Xyrem, Orphan Medical Inc. 6/13/02
`
`absence of desaturation does not represent a decline in
`respiratory function.
`
`Postvhpproval Safety Monitoring study
`
`With regards to the Post-Marketing Safety Evaluation Program, we
`would like to highlight two key points with respect to the
`enclosed materials:
`
`1.
`
`2.
`
`It is our understanding from the language you placed in the
`letter to doctors that safety information on 1000 patients
`followed for six months on Xyrem therapy will fulfill our
`obligation for this program. Can you please confirm your
`agreement?
`
`It is important to ensure that the post-approval safety
`assessment provides optimal opportunity for accurate
`interpretation. We agree with the changes proposed by FDA,
`but have added some information fields to enhance our joint
`ability to analyze the data captured and prevent bias. We
`request FDA concurrence with Our proposed changes.
`
`Lab-ling
`
`there are three
`Relative to the proposed package insert,
`important issues that we wish to emphasize with this transmittal
`letter,
`listed below. We respectfully ask FDA to pay particular
`attention to these concerns in your review of the enclosed
`materials.
`
`3.
`
`P-valuee. We can find no evidence in any RDA correspondence
`between FDA and Orphan Medical that the p-values currently
`listed in the FDA proposed label for Trial 1
`(our clinical
`trial OMC-GHB-Z) are correct, nor can we find a source from
`whence they originated.
`In our submissions and both the
`advisory briefing booklets received from FDA, all p-values
`provided by Orphan Medical and FDA are in agreement. Yet
`in both the insert provided to the company in July 2001,
`and the most recent in April 2002, FDA has quoted p-values
`that differ (documents attached).
`
`We request adoption of the p—values agreed upon at the FDA
`advisory meeting for Xyrem to be placed into the package
`insert for Trial 1.
`The proposed values we have revised in
`the attached package insert are in agreement with the
`statistics we provided with our NBA, FDA’s own statistics
`provided publicly at the advisory committee meeting, and
`the statistics now in the published peer-reviewed
`literature (article attached).
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 13 of 128
`6/13/02
`
`4.
`
`FDA removed all proposed language with
`Phnrnaoodynnnics.
`respect to the pharmacology of oxybate. We agree with FDA
`in that the mechanism of action of xyrem is unknown at this
`time. However, We have included language that we believe
`communicates factual and useful information under the
`
`heading “Pharmacodynamics”. Presentation of information in
`this manner is consistent with other recently approved CNS
`drugs including Geodon® (ziprasidone HCl), Adderall® (mixed
`salts of amphetamines), and Ambien® (zolpidem tartrate)
`(professional inserts attached). We strongly support some
`description of known pharmacology and would seek discourse
`with FDA should you disagree.
`
`Black Box Harning. Although we agree with the most of the
`statements proposed by FDA within the black box,
`the
`Company is Concerned that a lengthy black box may not be
`read in its entirety by physicians. Physicians may be more
`likely to read and retain the most pertinent points if they
`appear first in a summary paragraph.
`In this submission,
`we propose a black box with language very similar that
`proposed by FDA. However,
`the sentences in the black box
`were reorganized so that the most important information
`appears in the first paragraph of the black box, with more
`detailed information following in subsequent paragraphs.
`In addition,
`some connecting language was omitted in order
`make the language more concise and decrease the length of
`the black box.
`
`As proposed in a recent E—mail. we have issues with two
`statements made within the black box.
`The first is the
`statement regarding plasma levels of BBB in recreational
`users and the second is the statement regarding the
`protective effects of stimulants. While we concur with all
`other statements made within the black box, we respectfully
`request that these two sentences be omitted and have
`proposed such with this submission.
`Expiration Dating:
`
`6.
`
`Please find enclosed evidence supporting a proposed expiry
`period for Xyrem of 36 months.
`Included in this submission
`are stability report summaries as well as statistical
`projections consistent with the FDA SAS validated protocol
`for predicting shelf life.
`
`As we can sell only product with six months or greater to
`expiry,
`the previously requested -‘-month expiration date
`would necessitate destruction of approximately two—thirds
`
`of our inventory.. We would greatly appreciate your
`advising the company of FDA’s intended decision with
`respect to expiration dating at the earliest opportunity.
`The reason We request this is to facilitate our production
`planning operations and DEA Schedule I quota requirements
`for bulk drug substance which has a long lead time
`(estimated at 9-12 months).
`
`

`

`page 14 of 123
`Ranjit B. Mani, MD, HFD—120 Medical Review
`W________6fl3m
`
`7. Organization Of Review Of OMC-SXB-ZO Respiratory Data
`Contained In Current Submission
`
`In addition to specifically reviewing the interpretation of respiratory data
`contained in the current submission, I believe it will be helpful to first provide
`summaries of such data from this study as contained in 2 previous reviews
`completed by me
`. My main review of the sponsor’s Response to the Approvable letter of 7/2/01,
`which was submitted on 10/5/01. This review was completed on 3/4/02
`. An addendum to my main review of the Response to the Approvable letter of
`7/2/01. This review was completed on 3/29/02
`
`I will then review the OMC-SXB-20 respiratory data clarification contained in the
`current submission.
`
`8. Respiratory Data In Study OMC-SXB-20 As Contained In
`Earlier Review Completed 3/4/02
`
`The summary contained in this section addressed material submitted in the
`earlier Response to Approvable Letter dated 10/5/01.
`
`8.1 Background
`
`This was an open-label study that was intended to evaluate the effects of 4
`doses of Xyrem® on sleep architecture.
`
`The final study report for OMC-SXB-ZO was submitted on 12/16/00, i.e., after the
`original NDA submission (but within the same review cycle), and was reviewed
`by me along with that submission. The effects of Xyrem® on sleep architecture
`as derived from this study are described in my Efficacy Review of the original
`NDA. Safety data from this study are described in my Safety Review of the
`original NDA.
`
`Arterial oxygen saturation data from all-night recordings, and data on the
`frequency and severity of specific respiratory-event-related measures were
`collected as part of the polysomnogram recordings in this study but were not
`included in the final study report submitted on 12/16/01.
`
`In the Approvable letter that was issued on 7/2/01 it was noted that although
`GHB was a central nervous system depressant and therefore capable of
`producing respiratory depression, no formal assessment of its effects on
`respiration had been performed. It was recommended that a study be performed
`to assess the effects of GHB on respiration. The following was stated in the
`Approvable letter:
`
`“The study should examine the effects of the recommended dosing regimen (2 doses nightly, including the
`highest recommended dose-9 gms divided), with both doses given in the fasted state. The study should
`include patients who are and who are not receiving concomitant stimulant treatment, a positive control, and
`
`

`

`Ranjit B. Mani, MD. HFD—120 Medial Review
`NBA 21196 , Xyrem, Orphan Medial lnc.
`
`Page 1 5 of 128
`6/13/02
`
`patients with concomitant illnesses that might increase their risk of respiratory depression (e.g., patients with
`COPD, sleep apnea, etc.).'
`
`At a meeting with the sponsor held on 7/16/01 the Division agreed that the
`planned study described in the Approvable letter could be done as part of a post-
`marketing commitment provided that an analysis of respiratory data from OMC—
`SXB-20 that was to be submitted as part of the then-upcoming
`Amendment/Response To Approvable Letter (that was eventually submitted on
`10/5/01) addressed our concerns about a potential respiratory depressant effect
`of Xyrem®.
`'
`
`The analysis of respiratory data from OMC-SXB—ZO presented below is post-hoc
`and was not planned as part of the original protocol. The original protocol and the
`plan for analyzing respiratory data are summarized below
`
`8.2 Outline Of Protocol For OMC-SXB-ZO Study
`
`8.2.1 Objectives
`
`8.2.1.1 Primary
`The primary objective of this study was to characterize the polysomnographic
`sleep architecture in narcoleptic patients at four GHB doses: 4.5 g, 6.0 g, 7.5 g
`and 9.0 g daily
`
`8.2.1.2 Secondary
`
`The secondary objectives of the study were to
`0 Assess the effect of Xyrem® on sleep as measured by the Epworth
`Sleepiness Scale
`0 Assess the effects of Xyrem® on common symptoms of narcolepsy as
`measured by the Narcolepsy Symptoms Assessment
`0 Assess EEG measures of wakefulness under soporific conditions using the
`Maintenance of Wakefulness Test
`
`. Assess the safety of Xyrem®
`
`8.2.2 Design/Summary of Investigational Plan
`
`This was an open-label uncontrolled study divided into 2 phases. Stimulant
`medication was maintained at a constant level during the trial. The overall design
`is summarized in the following diagram
`
`APPEARS rags E’s’A‘!
`0N GENERAL
`
`

`

`Ranjit B. Mani, MD, HFD—120 Medical Review
`NDA 21196 , Xyrem, Orphan Medical Inc.
`
`Page 16 of 128
`6/13/02
`
`
`
`8.2.2.1 Phase I
`
`This phase lasted 4 weeks
`0
`In the initial 2 weeks of this phase patients were withdrawn from tricyclic
`antidepressants, selective serotonin re-uptake inhibitors and hypnotics
`in the last 2 weeks of this phase patients remained free of tricyclics
`
`.
`
`An overnight polysomnogram was performed at the beginning and end of this
`phase. The Epworth Sleepiness Scale questionnaire was administered at about
`the time of each polysomnogram
`
`8.2.2.2 Phase II
`
`This phase began with the patient receiving 4.5 g of GHB nightly for the initial 4
`weeks. At the end of this period the dose was increased to 6.0 g nightly, and then
`further to 7.5 g nightly and 9 g nightly, at 2 week intervals. Each total nightly dose
`of GHB was administered in 2 equal divided doses 2.5 to 4 hours apart.
`
`Overnight polysomnograms were performed on the night of the first dose of
`Xyrem® and on the last night of each dose. The Epworth Sleepiness Scale was
`administered at the end of each dosing period
`
`8.2.2.3 Duration
`
`10 weeks
`
`>
`
`8.2.3 Sample Size
`
`20-30 planned
`
`8.2.4 Key Inclusion Criteria
`
`Informed consent
`
`Age 2 18 years
`American Sleep Disorders Association criteria for narcolepsy
`Use of stable doses of tricyclic antidepressants or selective serotonin re-
`uptake inhibitors for narcolepsy for at least 3 weeks. If taking stimulants must
`have been on a stable dose for at least 3 weeks
`
`

`

`Page 1 7 of 128
`Ranjit B. Mani, MD, HFD.120 Medical Review
`
`NBA 21196 , Xyrem, Orphan Medical lnc. 6/13/02
`
`lf female must be
`