`40WALIg
`nak
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHETIC, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`HFD-170, Room 9B-45, 5600 Fishers Lane, Rockville MD 20857
`
`Tel:(301)443-3741
`
`
`
`
`
`MEMORANDUM
`
`DATE:
`
`~
`
`November5, 1999
`
`TO:
`
`FROM:
`
`File, NDA 21-038
`
`.
`
`Bob A. Rappaport, M.D.
`Deputy Director, DACCADP
`Team Leader, Anesthetic Drug Group
`
`RE:
`
`Supervisory Review of NDA 21-038, Dexmedetomidine HC]
`
`
`
`BACKGROUND:
`
`NDA 21-038, Dexmedetomidine HCl, was submitted by Abbott Laboratories Inc. on
`December 18, 1998.
`Dexmedetomidine is a potent and highly selective a-2-
`adrenoreceptor agonist.
`The sponsor claims that
`their product producestitratable,
`predictable sedation in an ICU setting, from which patients are easily arousable and
`cooperative. The sponsor also claims that their product provides improved analgesia in
`the postoperative ICU setting.
`The a-2-adrenoreceptor agonist detomidine was
`developed for use as a sedative/analgesic in horses and cattle and was registered for
`marketing in Finland in 1983. Medetomidine, launched in 1987 in Scandinavia, was a
`more selective a-2-adrenoreceptor agonist used as a sedative/analgesic in cats and dogs.
`It was approved for veterinary use in the US in 1997. The sedative and analgesic activity
`of medtomidine are believed to reside predominantly in its dextroenantiomer
`dexmedetomidine. The enantiomer was first synthesized by Farmos Groupin Finland in
`1986. Numerous perioperative indications have been evaluated since that time. Farmos
`merged with Orion Corp.
`in 1990, and Orion licensed the injectable dosage form of
`dexmedetomidine for clinical use to Abbott Laboratories in 1994.
`
`oo
`
`trials of dexmedetomidine with various modes of
`Orion conducted 56 clinical
`administration including rapid intravenous infusion, continuous intravenous infusion,
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 1
`
`
`
`
`
`intramuscular injection, as well as transdermal and oral administration. Abbott initiated
`its own Clinical development program and completed 21 studies (13 Phase I and 8 Phase
`TIT) in the US, Canada and Europe. They also completed 2 studies in Japan: a Phase I
`safety and pharmacokinetic study of rapid infusion in 9 healthy males, and a Phase II
`safety and dose response study ofrapid infusion in 109 patients. The sponsor reported
`that the case report forms for these 2 studies were unavailable and they did not include
`the data in the ISS database.
`——
`
`The clinical studies of the effectiveness and safety of this new formulation have been
`reviewed [submitted August 29, 1999] by Charles Cortinovis, M.D. Dr. Patricia Hartwell
`contributed two addenda [submitted September 13, 1999 and October 27, 1999]
`reviewing safety data in the original application, a supplementary safety package, and the
`120-Day Safety Update. The application has also been reviewed by Jonathan Ma, Ph.D.
`(biostatistics), Suresh Doddapaneni, Ph.D. (clinical pharmacelogy and biopharmaceutics),
`' Harry Geyer, Ph.D. (pharmacology/toxicology), Michael Theodorakis, Ph.D. (chemistry),
`and BeLinda A. Hayes, Ph.D. (abuse liability).
`In this memo, I will briefly review the
`effectiveness and safety data summarized in the primary clinical review, as well as any
`relevant information found in the primary reviews from the other disciplines, and make
`appropriate recommendationsfor action on the NDA.
`
`-
`
`_
`
`EFFECTIVENESS:
`
`Evidence ofefficacy has been submitted in twoclinical studies W97-245 and W97-246.
`
`Study W97-245:
`
`~-
`
`This was a randomized, double blind, placebo-controlled, parallel group study conducted
`at 33 centers in Canada and Europe. The Study consisted of two parts. Part I] was an
`open-label evaluation of dexmedetomidinein up to 4 patients per site. This portion of the
`study was designed to allow the investigators to become familiar with the observed
`clinical effects of dexmedetomidine priorto starting the double-blind portion ofthe study.
`Patient data from Part I was notincluded in the efficacy analyses.
`—
`
`In Part II of the study, adult postoperative patients who required a minimum of6 hours of
`ventilation and sedation in the ICU setting were randomized to either dexmedetomidine
`or placebo for sedation. Within one hour of admission to the ICU,patients were
`
`>.
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 2a
`
`
`
`
`
`administered a loading dose 6.0 jg/kg/hour over a 10 minute period, followed by a
`maintenance infusion of 0.4 yg/kg/hour.
`The infusion rate could be adjusted by
`increments of 0.1 yg/kg/hour in order to maintain a Ramsay Sedation Score’ of 3 or
`higher. However,
`it was required that the rate be maintained between 0.2 and 0.7
`ug/kg/hour. Following extubation, the infusion rate was adjusted to achieve a Ramsay
`Sedation Score of 2 or above. Study drug infusion was continuedfor at least 6 hours after
`extubation and, at the discretion of the investigator, up-to a maximum of 24 hourstotal
`study drug infusion.
`
`Rescue medications were limited to midazolam for sedation and morphine for pain. After —
`extubation, paracetamol was administered when clinically indicated. When the
`investigators judged that there was need for an increase in sedative medication, they were
`to first adjust the maintenance dose of dexmedetomidine. ..Midazolam was-administered
`as bolus doses of 0.02 mg/kg. Using the Ramsay Sedation Score,
`the patient was
`assessed prior to and 10 minutes after every rate change in study drug or administration
`of midazolam.
`If the patient required 3 bolus doses of midazolam within any 2 hour
`period, after appropriate adjustments of the study drug infusion rate, further midazolam
`was administered as a continuous infusion at 0.01 to 0.02 mg/kg/hour.
`
`The need for analgesic administration was assessed either by direct communication with
`the patient regarding pain, or by the presence of abnormal autonomic signs such as
`sweating, tachycardia and hypertension. Morphine was administered for pain as 2-mg
`intravenous boluses.
`
`The protocol specified primary efficacy parameter was the total dose of midazolam in
`milligrams administered during the period that the patient was intubated. The efficacy
`analysis was based on the Intent to Treat [ITT] population and analysis on the Evaluable
`population was also performed. A second primary efficacy endpoint was analyzed based
`on a recommendation madebythe Division biostatistician, Dr. Permutt, at a development
`meeting with the sponsor. This endpoint was a comparison of the numbers of patients
`whofell into one of the following three categories of midazolam use:
`
`1. No dose
`(0 mg)
`2. Subthérapeutic dose
`(0-4 mg)
`3. Therapeutic dose
`(>4 mg)
`This outcome measure was not specified in any amendmentto the protocol. However,
`the.analysis was undertaken priorto breaking the study blind.
`-
`
`
`
`' 6 = asleep, no response
`5 = asleep, sluggish response to light glabellar tap or loud auditory stimulus
`4 = asleep but withbrisk response to light glabellar tap or loud auditory stimulus
`3 = patient responds to commands
`°
`2 = patient cooperative, oriented, and tranquil
`| = patient anxious, agitated, or restless
`:
`
`.
`Dexmedetomidine
`NDA 21-038
`
`~
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 3
`
`
`
`Secondary efficacy parameters listed in the protocol for this study included?:
`
`-1.
`
`2.
`
`3.
`
`Use of morphine for pain - as assessed by total dose used with
`dexmedetomidine as compared to placebo (mg/hr)
`Use of paracetamolfor pain after extubation — as assessed bytotal dose used
`with dexmedetomidine compared to placebo (mg/hr)
`Time to extubation — measured as time.of arrival
`extubation
`
`in ICU until
`
`time of
`
`However, the secondary efficacy parameters listed in the study report were:
`
`NAVELNS
`
`Total dose of midazolam during study drug administration
`Total dose ofmorphine during study drug administration
`Total dose of morphine by time period
`-
`‘Ramsay Sedation Score
`Ratio’ of Ramsay Sedation Score of “1” during study drug administration
`Timeto extubation and weaning duration
`Nurses’ and patients’ assessment
`
`These changes in secondary outcome measures were not specified in any amendmentto
`the protocol.
`
`Results:
`
`Eighty-six patients were enrolled and 85 treated in Part I of the study.
`
`In Part II of the study, 178 patients were randomized to dexmedetomidine and 175 to
`placebo. All patients were administered study drug and comprised the ITT population.
`Two dexmedetomidine treated and 6 placebo patients were excluded from the Evaluable
`patient set.
`
`Dr. Cortinovis’ Table 4
`patient disposition:
`—s <5
`-— “LS.
`
`[page 22 of his review}, reproduced below, summarizes the
`
`
`
`? This informationdiffers from that documented by Dr. Cortinovis in the medicalofficer’s review and by
`Dr. Main the Statistician’s review.
`It is based on documentation provided by Dr. Patricia Hartwell who
`examined the original documents at my request.
`
`> The ratio is the Proportion ofassessments that equal | divided by the total number ofassessments forthe
`
`patient.
`
`=-
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 4
`
`
`
`
`Table1.
`
`SSCSPlacebo|Deeredetomnicine
`
`
`
`
`"Non-Evaluablepatients———SSCS~C~CSCSCSCSCOSSC~C~C~C‘CSCS
`
`
`
`
`
`
`
`[ReasonsforNon-Evaluability(PatientNumbes)_—-|+iSSCS
`
`
`
`5
`
`
`
`
`
`7601
`* Patientscould have had more than one reason for non-evaluability
`Modified Sponsor's Table 8.1a Vol. 8/10-62-73
`
`Nine patients in the dexmedetomidine group and 10 in the placebo group were
`discontinued from the study prematurely. Each of these patients discontinued due to
`adverse events.
`
`Primary Efficacy Analyses:
`
`1.
`
`required statistically significantly less midazolam
`Dexmedetomidine patients
`compared to the placebo treated patients in both the ITT and Evaluable patient
`analyses. Dr. Cortinovis’ Table 8, page 25 of his review, summarizes these results
`and is reproduced below:
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`Dexmedetomidine
`NDA 21-038
`
`Petition for Inter Partes Review of US 8,455,527
`. Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 5i
`
`
`
`
`
`
`
`Table 2.
`
`Total Dose of Midazolam (mg) During Intubation
`Placebo
`Dexmedetomidine
`
`TreatmentEffect
`p-Value’
`(173d
`PY
`178
`
`
`[MeantSEM_——S~di*BOED=iaT——CSC~irSCS
`EvaluablePatieisY_—[169s |
`* p-value>from ANOVA
`
`
`
`
`
`SEM = Standard Error of Mean
`Modified Sponsor’s Table 8.2a Vol. 8/10-62-74
`
`2.
`
`Statistically significant. differences were observed between the treatment groups in
`both the ITT and Evaluable analyses, with the majorityof the dexmedetomidine
`treated patients requiring no midazolam comparedtothe majority of placebo
`patients who required greater than 4 mg of midazolam. Dr. Cortinovis’ Table 9,
`page 25 of his review, summarizes these results and is reproduced below:
`
`Table 3.
`
`Total Dose Categories of Midazolam During Intubation
`Placebo
`Dexmedetomidine
`
`Treatment
`Effect
`p-Value’
`
`
`
`
`
`Intent-to-Treat PatientsEE (178s—i(i‘zKOOL
`ragsa
`
`
`[>0mgtoamg——SSSSSCS~SC9)36RD)dS
`
`
`
`[SameSSSSOG)Sd
`
`
`
`[valuablePatients(X)SCSCdCSCSC~OTC
`
`OmeCSCSSHYOTITISSTCSCSCSC~* x
`
`
`
`
`
`[>0mgtodmeSSS32009)30020%—)dCs
`
`
`33(19%) Td
`94(56%)
`|
`
`* p-value from chi-square
`Modified Sponsor’s Table 8.2b Vol. 8/10-62-75
`
`Secondary Efficacy Analyses:
`
`Their were ne- differences in any of the analyses when performed on either the ITT or
`Evaluable patient data sets. The following table, based on Dr. Ma’s Table 3.3, page 6 of
`his review,summarizes the results for six of these analyses:
`
`z
`
`Dexmedetomidine
`NDA 21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 6
`
`
`
`
`
`Table 4.
`
`Total dose of midazolam during drug
`administration (mg/hour)
`
`Total dose of morphine during drug
`administration (mg/hour)
`
`Placebo
`N=175
`Mean + SEM*
`
`Dexmedetomidine
`N=178
`Mean + SEM
`
`p-value
`Treatment Effect
`
`1.19 (0.23)
`
`0.29 (0.07)
`
`0.0001
`
`0.83 (0.07)
`
`0.47 (0.06)
`
`<0.0001
`
`Total dose of morphine during0to 6.5
`hours (mg)
`oO
`8.5 (0.79) --
`4.9 (0:56)
`<0.0001
`
`<0.0001
`
`
`
`Total dose of morphine during 6.5 to
`end (mg/hour)
`Ramsay Sedation Score AUC during
`drug administration
`
`Ratio of Ramsay Sedation Score of 1
`during drug administration (%)
`
`*SEM = Standard Error of Mean
`
`0.42 (0.08)
`
`as
`0.24 (0.05)
`
`0.042
`
`3.3 (0.05)
`
`3.6 (0.05)
`
`<0.0001
`
`7 (0.8)
`
`3 (0.5)
`
`:
`
`As noted by Dr. Main his review, the Ramsay Sedation Score itself (AUC) was not a
`useful endpoint to consider as, for both groups, dosetitration and rescue medication were
`used to maintain the patients at a specified level of sedation indicated by the Ramsay
`Score. However, a smaller ratio of Ramsay score of 1, for any particular patient, might
`indicate less anxiety during the treatment period. Statistically significant center effects
`were noted for most secondary endpoints indicating that patients in different countries
`either required and/or were administered differing amounts of sedative and analgesic
`medications.
`
`The following additional: secondary endpoints were discussed by Dr. Cortinovis in his
`review:
`—— “1S,
`
`Time to extubation and weaning duration:
`- a
`
`Nostatistically significant differences were noted in time to readiness for extubation or
`actual extubation, when that time was measured either from ICU arrival orstart of study
`drug. Nostatistically significant differences were found between the treatment groupsfor
`median duration of weaning.
`
`Nurses’ and patients’ assessment
`
`Dexmedetomidine treated patients had a statistically significantly lower patient
`managementindex’ [defined on page 30 of Dr. Cortinovis’ review] score compared with
`Dexmedetomidine
`NDA 21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 7
`
`
`
`placebotreated patients. However,the actual numerical differences were notlikely to be
`clinically relevant, according to Dr. Cortinovis.
`
`Patient satisfaction survey
`
`The dexmedetomidine treated and placebo patients rated similarly their present
`experience with sedation compared to prior experiences, their comfort during the ICU
`sedation, their remembrance ofpain, discomfort from breathing tube, people and noise,
`and whetheror not they would have the same sedative treatment in the future. However, |
`61% of dexmedetomidine treated patients compared to 52% of placebo patients rated
`their overall experience as “better than expected.”
`
`.
`
`-
`
`Data Integrity:
`
`-
`
`The, Division of Scientific Investigations’ [DSI] Clinical Inspection Summary for this
`application notes that one of the two pivotal study sites inspected by DSI was found to
`have protocol violations which may compromise someofthe data arising outof that site.
`That site in Study W97-245 enrolled 5 out of 45 patients out of sequence; and one of
`those five subjects appeared to be a seven year old child who did not meetthe inclusion
`criterion for age. DSI has requested clarification of the discrepancies and recommends
`that, until the matters are clarified and foundto be satisfactory, we not use the data from
`those five subjects in support ofthe application.
`
`Dr. Thomas Permutt, biostatistics teamleader, has reviewed the data and the DSI
`recommendations and has concluded that removal of the data from those five patients
`would notaffect the outcomeofthe efficacy analyses.
`
`-
`
`Study W97-246:
`
`This was a randomized, double blind, placebo-controlled, parallel group study conducted
`at 3€
`centers in Canada and Europe. The Study consisted of two parts. Part I was an
`open-label evaluation of dexmedetomidinein up to 4 patients per site. This portion of the
`study was designed to allow the investigators to become familiar with the observed
`clinical effectSofdexmedetomidine priorto starting the double-blind portion of the study.
`Patient data from Part I was not included in the efficacy analyses.
`
`In Part II of the study, adult postoperative patients who required a minimum of6 hours of
`ventilation and sedation in the ICU setting were randomized to either dexmedetomidine
`or placebo for sedation. Within one hour of admission to the ICU, patients were
`administered a Joading dose 6.0 j1g/kg/hour over a 10 minute period, followed by a
`
`:-
`
`Dexmedetomidine
`NDA 21-038
`
`' Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 8rr
`
`
`
`_
`
`The infusion rate could be adjusted by
`maintenance infusion of 0.4 yg/kg/hour.
`increments of 0.1 jg/kg/hour in order to maintain a Ramsay Sedation Score‘ of 3 or
`higher. However,
`it was required that the rate be maintained between 0.2 and 0.7
`pg/kg/hour. Following extubation, the infusion rate was adjusted to achieve a Ramsay
`Sedation Score of 2 or above. Study drug infusion was continued for at least 6 hours after
`extubation and, at the discretion of the investigator, up to maximum of 24 hourstotal
`study drug infusion.-
`-
`
`Rescue medications were limited to propofol for sedation and morphine for pain. After
`extubation, paracetamol was administered when clinically indicated. When the ©
`investigators judged that there was need for an increase in sedative medication, they were
`to first adjust the maintenance dose of dexmedetomidine. Propofol was administered as
`bolus doses of 0.02 mg/kg. Using the Ramsay Sedation Score, the patient was assessed
`prior to and 10 minutes after every rate change in study drug or administration of
`propofol. Ifthe patient required 3 bolus doses of propofol within any 2 hour period,after
`appropriate adjustments ofthe study drug infusion rate, further propofol was administered
`as a continuous infusion at 0.5 to 4.0 mg/kg/hour.
`
`The need for analgesic administration was assessed either by direct communication with
`the patient regarding pain, or by the presence of abnormal autonomic signs such as
`sweating, tachycardia and hypertension. Morphine was administered for pain as 2-mg
`intravenousboluses.
`
`in
`The protocol specified primary efficacy parameter was the total dose of propofol
`milligrams administered during the period that the patient was intubated. The efficacy
`analysis was based on the Intent to Treat [ITT] population and analysis on the Evaluable
`population was also performed. A second primary efficacy endpoint was analyzed based
`on a recommendation made bythe Division biostatistician, Dr. Permutt, at a development
`meeting with the sponsor. This endpoint was a comparison of the numbersofpatients
`whofell into one of the following three categories of propofol use:
`
`(0 mg)
`1. No dose
`(0-50 mg)
`2. Subtherapeutic dose
`(>50 mg)
`3--<Therapeutic dose
`This outcome measure was not specified in any amendmentto the protocol. However,
`the analysis.was undertaken prior to breaking the study blind.
`
`~
`
`—
`
`“6 = asleep, no response
`5 = asleep, sluggish response to light glabellar tap or loud auditory stimulus
`4 = asleep but with brisk responseto light glabellar tap or loud auditory stimulus
`3 = patient responds to commands
`2 = patient cooperative, oriented, and tranquil
`| = patient anxious,agitated, or restless
`:
`
`.
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 9aDLL
`
`
`
`IO
`
`Secondary efficacy parameters listed in the protocol for this study included':
`
`-1. Use of morphine for pain -
`as assessed by
`dexmedetomidine as compared to placebo (mg/hr)
`2. Use of paracetamol for pain after extubation - as assessed by total dose used
`with dexmedetomidine compared to placebo (mg/hr)
`3. Time to ex_tubation - measured as time of arriY.al in ICU until time of extubation
`
`total dose used with
`
`However, the secondary efficacy parameters listed in the study report were:
`
`I. Total dose·of propofol during study d11,1g administration
`2. Total dose of morphine during study drug administration
`3. Total dose of morphine by time period
`...
`4. Ramsay Sedation Score
`5. Ritio6 of Ramsay Sedation Scpre of "l" during study drug administration
`6. Time to extubation and weaning duration
`7. Nurses' and patients' assessment
`
`These changes in secondary outcome measures were not specified in any amendment to
`the protocol.
`
`Results:
`
`Ninety-three patients were enrolled and 92 treated in Part I of the study.
`
`In Part II of the study, 203 patients were randomized to dexmedetomidine and 198 to
`placebo. All patients were administered study drug and comprised the ITT .population.
`Three dexmedetomidine treated and 7 placebo patients were excluded from the Evaluable
`patient set.
`
`Dr. Cortinovis' Table 18
`patient disposition:
`
`[page 44 of his review], reproduced below, summarizes the
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`~This information differs from that documented by Dr. Cortinovis in the medical officer's review and by
`Dr. Ma in the Statistician's review. It is based on documentation provided by Dr. Patricia Hartwell who
`examined the original documents at my request.
`6 The ratio is the pro_p_onion of assessments that equal I divided by the total number of assessments for the
`patient.
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 10
`
`
`
`Table5.
`
`11
`
`
`
`ia
`intent to Treat Patients (All Treated) rig
`
`
`
`TintenttoTreatPatients(All_——S—~STreated)
`
`
`7 BS
`7d
`
`
`evaluablePatientsSSCSISC—~dOCC
`
`
`
`
`ReasonsforNon-Evaluability(PatientNumbers)[||———S——*d
`
`
`"InsufficientIntubationSSCS.SSCSCSC*dA
`
`
`
`[“EnrolledwieeSSSSSSCSCSC—~SSSCS
`Modified Sponsor’s Table 8.1a Vol. 8/10-86-73
`
` CSCS
`
`Fourteen patients in the dexmedetomidine groupand 8 in the placebo group were
`discontinued from the study prematurely. Mostof these patients discontinued due to
`adverse events. —
`.
`
`Primary Efficacy Analyses:
`
`1. Dexmedetomidine patients_required statistically significantly less propofol
`compared to the placebotreated patients in both the ITT and Evaluable patient
`analyses. Dr. Cortinovis’ Table 22, page 47 of his review, summarizes these
`results and is reproduced, with modifications, below:
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`z-
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 11SSSS
`
`
`
`Table6.
`
`Total Dose of Propofol (mg) During Intubation
`Placebo
`Dexmedetomidine
`
`
`Treatment Effect
`p-Value’
`
`
`Intent to Treat Patients (N)___-|198_———~—S—S—~«dPT
`31335538
`72x175
`
`
`EvaluablePatients (N) aee
`
`
`
`Mean + SEM
`505+56.40
`73+17.76
`<0.0001
`* p-value from ANOVA
`SEM=Standard Error of Mean
`Modified Sponsor’s Table 8.2a Vol. 8/10-86-73
`
`2. Statistically significant differences were observed between the treatment groups
`in both the ITT and Evaluable analyses, with the majority of the
`oO
`dexmedetomidinetreated patients requiring no propofol compared to the
`majority of placebo patients who required greater than 50 mg of propofol. Dr.
`Cortinovis’ Table 24, page 48 of his review, summarizes these results andis
`reproduced, with modifications, below:
`
`-
`
`"
`
`Table 7.
`
`Total Dose Categories of Propofol During Intubation
`Placebo
`Dexmedetomidine
`
`
`
`
`Treatment
`Effect
`p-Value*
`
`[030001
`[ntent-io-Treat Patients (N)
`}198
`
`
`
`Pome~*~AR) [122(60%H) ———
`
`
`> Omg to 50mg
`30(15%)
`43(21%) po
`38(19%) PF
`121(61%)
`
`
`
`
`EvaluablePatients(N)_———S—S~dST«di200SSSC~C~—~—~SCOTTC*d~
`
`
`omeSCSI.ROTO-SdC*sS“C“‘“SCSC‘d
`[SomgwosomeSS30016%)JaI)dtSSC—*d
`
`
`1is(60%)|38g)<iSSSC—~*™
`* p-value from chi-square
`Modified Sponsor’s Table 8.2b Vol. 8/10-86-74
`
`
`
`Secondary Efficacy Analyses:
`
`Their were no differences in any of the analyses when performed on either the ITT or
`Evaluable patient-data sets. The following table, based on Dr. Ma’s Table 3.6, page 10 of
`his review, summarizes the results for six of these analyses:
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 12
`
`Dexmedetomidine
`NDA 21-038
`
`
`
`
`
`
`p-value
`Treatment Effect
`
`
`
`<0.0001
`
`
`Dexmecetomidine
`Placebo
`N = 198
`N = 203
`Mean + SEM*
`Mean + SEM
`
`
`39 (4.1)
`5.3 (1.2)
`
`
`Total dose of morphine during drug
`
`administration (mg/hour)
`0.89 (0.07)
`0.43 (0.05)
`<0.0001
`
`Total dose of morphine during 0 to 6.5
`
`
`8.5 (0.64)--
`4.1 (0.47)
`<0.0001
`hours (mg)
`
`
`
`Total dose of morphine during 6.5 to
`
`
`0.55 (0.07)
`0.16 (0.03)
`<0.0001
`end (mg/hour)
`
`
`
`
`
`
`Ramsay Sedation Score AUC during
`
`drug administration
`3.1 (0.04)
`3.4 (0.04)
`<0.0001
`
`
`Ratio of Ramsay Sedation Score of |
`
`
` during drug administration (%)
`7 (0.7)
`4 (0.5)
`0.0008
`
`*SEM = Standard Error of Mean
`
`Table 8.
`
`13
`
`Total dose of midazolam during drug
`administration (mg/hour)
`
`
`
`
`
`.
`
`As noted by Dr. Main his review, the Ramsay Sedation Score itself (AUC) was not a
`useful endpoint to consideras, for both groups, dose titration and rescue medication were
`used to maintain the patients at a specified level of sedation indicated by the Ramsay
`Score. However, a smaller ratio of Ramsay score of 1, for any particular patient, might
`indicate less anxiety during the treatment period. Statistically significant center effects
`were noted for most secondary endpoints indicating that patients in different countries
`either required and/or were administered differing amounts of sedative and analgesic
`medications.
`
`The following additional secondary endpoints were discussed by Dr. Cortinovis in his
`review:
`
`Time to extubation and weaning duration:
`
`Nostatistically significant differences were noted in time to readiness for extubation or
`actual extubation, when that time was measured either from ICU arrival or start of study
`drug. Nostatistically significant differences were found between the treatment groups for
`median duration of weaning.
`
`Nurses’ and patients’ assessment
`
`Dexmedetomidine treated patients hadastatistically significantly lower patient
`managementindex[defined on page 52 of Dr. Cortinovis’ review] score compared with
`2.
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 13
`
`
`
`14
`
`placebo treated patients. However, the actual numerical differences werenotlikely to be
`clinically relevant, according to Dr. Cortinovis.
`
`Patient satisfaction survey
`
`rated similarly their present
`The dexmedetomidine treated and placebo patients
`experience with sedation compared to prior experiences, their comfort during the ICU
`. sedation, their remembrance of pain, discomfort from breathing-tube, people and noise,
`and whetheror not they would have the samesedative treatment in the future. However,
`70% of dexmedetomidine treated patients compared to 60% of placebo patients rated
`their overall experienceas “better than expected.”
`
`Subgroup Analyses of Efficacy:
`
`oO
`
`Dr. Mahas reviewedthe sponsor’s subgroup analyses and reports a few exceptions to the
`overall findingsofsignificant efficacy of dexmedetomidine. These include:
`
`1. Of the 43 patients in both groups at the five German centers in Study 245,
`only 1 (5%) in the treated group required 0 mg of midazolam during the
`intubation period. Atthe other centers more than 50% ofthetreated patients
`required no midazolam.
`;
`2. For the 20 patients at the single Austrian center in Studies 245 and 246,
`similar amounts of midazolam and propofol were required by the placebo and
`dexmedetomidinetreated groups.
`3. When analyzed by type of surgery, similar amounts of midazolam were
`required by the 34 patients undergoing head and neck surgery in Study 245
`(p=0.96). Statistically significant differences were found for the two treatment
`groups
`for patients undergoing cardiac surgery,
`laparotomy and other
`surgeries in that study andall types of surgery in Study 246. However, the p-
`value for head and neck surgery for Study 246 was 0.052.
`
`~
`
`SAFETY: -= »-
`
`—————————~__—___——- ta from the ISS
`The originalNDA submission excluded the
`database. This fact was discovered by Dr. Cortinovis after the submission had beenfiled.
`In a teleconference in late May of 1999, the sponsor claimed that they had not included
`this data because it came from studies performedto assess different indications than the
`one that is the subject of this application. The sponsor was informed that it would be
`necessary for them to compile, analyze and submit this missing data. The sponsor
`informedus that it would take a minimum of two monthsto complete the assignment and
`an early August submission was agreed upon. The new data was submitted on August
`16, 1999. This submission was found to be incomplete, with missing case report forms
`
`“{CRF’s], CRF’s‘from the ~-
`: which had not been translated, and missing
`
`/7
`
`“ey
`
`Dexmedetomidine
`NDA21-038
`
`
`
`
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 14
`
`
`
`15
`
`form tabulations.
`case report
`the sponsor
`During a follow-up teleconference,
`acknowledged the missing data andstated that they had determined someofthe data to be
`not useful due to unavailability of CRF’s or the omission of data from CRF’s. They
`were told to immediately provide as much of the data as possible and written
`explanations for any data which would not be submitted. These final portions of the
`safety database have been submitted piecemeal since that time. In her first addendum to
`the medical review, Dr. Hartwell has evaluated this late data in full and carefully
`delineates
`the various parts, based on GCP suitability, availability of primary
`documentation, and overall importanceto the safety profile of dexmedetomidine.
`
`In an attempt to incorporate the recently submitted data into the exposure database, Dr.
`Hartwell created two tables [see pages 5 and 6 ofherfirst addendum] which summarize
`the number of studies and the number ofpatients included in the supplemental ISS,
`broken down by GCP suitability and by those with available CRF’s.
`She then
`incorporated the patients from the supplemental submissions into a table [page 6 of her
`first addendum]ofall exposed patients, updating Dr. Cortinovis’ Table 32 [page 57 of his
`review]. At this time, based on the information available from the sponsor,it appears that
`a total of 3338 subjects have been exposed to dexmedetomidine in clinical studies.
`However, the sponsor has categorized 11 Phase I studies (109 subjects) and 4 Phase II/II
`studies (146 subjects) as containing inadequate information; and this data was not
`included in the supplemental ISS. Thus, the overall ISS database includes 3083 subjects
`exposed to dexmedetomidine.
`
`Extent of exposure by dose is summarized in the table below, based on Dr. Cortinovis’
`Tables 7 and 22 [pages 24 and 47, respectively, of his review] and Dr. Hartwell’s Tables
`4 and 5 [page 7 of her first addendum]:
`-
`
`-
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`-
`
`.
`
`-
`
`|
`
`|
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 15
`SSSs
`
`Dexmedetomidine
`NDA21-038
`
`
`
`Table 9.
`
`Minimum
`Maximum
`
`N (
`
`
`
`
`
`178
`7.0 + 2.95
`
`16.6 + 5.0
`
`la
`
`coed i Te riaa 8 Cn at
`N/A
`N/A
`
`~ N/A
`
`N/A
`
`
`
`
`MeanTotalDurationTotal Duration
`0.13 + 0.05 hn +SD
`
`167
`
`
`
`
`
`Mean Total Dose
`
`
`1518
`267
`
`
`
`ug/kg) + SD
`4.29 + 3.09
`1.00 + 0.67
`
`Mean Total Duration
`
`
`
`N
`1475
`106
`
`
`(hr) + SD
`10.10 + 6.54
`0.05 + 0.03
`
`
`
`Minimum *
`0.02
`0.02
`Maximum
`
`Phase III Study 245:
`| as
`Mean Total Dose
`
`N
`
`
`(ug/kg) + SD
`
`
`Mean Total Duration
`|
`
`N
`
`
`
`(hr) +SD
`afolo
`
`
`Phase III Study 246:
`
`Mean Total Dose
`
`
`N
`
`
`(ug/kg) + SD
`Mean Total Duration
`
`
`
`N
`St is.
`
`
`
`(hr) + SD
`N.B. The total N forall patient/subject listings in this table does not equal the total N for the safety
`database. Thétotal N here falls between the total N for patients exposed and the total N for patients in the
`database (those with adequate and available data), based on availability of dose and duration information
`from the different studysites.
`
`
`
`;2 maeSeeseekfete2AEoneaSETS:Sereete>faeryresi
`
`14.7+ 4.51
`
`N/A
`
`N/A
`
`During her review of the safety data, Dr. Hartwell requested more specific information on
`exposure by dose and duration from the sponsor. Dose by duration exposure data forall
`treated patients in the Phase II/III continuous infusion studies is summarized in Dr.
`Hartwell’s Table! from page 2 of her second addendum:
`
`=
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1019 — Page 16
`
`
`
`17
`
`Table 10. Extent of Exposure — Frequency of Duration by Dose
`Phase IV/III Continuous Infusion Studies — All-Treated Patients
`
`(brs)
`
`=
`
`oesoes[eee[oie[>it[ere|Tovaae
`saeat
`PeSTrosts
`|8a
`p80aeSt8
`EFSROD
`pziaie|ot32oS8
`Piaofk0t09
`peSHooESESSeeS|te20|oSsae
`STES
`
`eeea
`|)22626|8a
`|2628fo
`|28-30|
`REeeee
`Total|sso|a7|osfom|owefeePees
`
`
`
`From Sponsor's Table of Duration by Dose, Suppiementto NDA, 10-27-99, Exhibit 4
`N.B. The total N correspondsto the total numberof