`DfVISION OF ANESTHETIC, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`HFD-170, Room 98-45, 5600 Fishers Lane, Rockville MD 20857
`-
`- . ·--
`
`Tel:(301)443-3741
`
`DATE:
`
`TO:
`
`FROM:
`
`MEMORANDUM
`-··
`
`November 5, 1999
`
`File, NOA 21-038
`
`Bob A. Rappaport, M.D.
`Deputy Director, DACCADP
`Team Leader, Anesthetic Drug Group
`
`RE:
`
`Supervisory Review of NOA 21-038, Dexmedetomidine HCl
`
`BACKGROUND:
`
`NOA 21-038, Dexmedetomidine .HCl, was su,bmitted .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 produces titratable,
`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 a-2-adrenoreceptor agonist detomidine was
`the postoper_a~iye ICU setting.
`developed for use as a sedative/analgesic in horses and cattle and was register'!d 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 analge~ic activity
`of medtomidine are believed
`to
`reside predominantly
`in
`its dextroenantiomer
`dexmedetomidine. The enantiomer was first synthesized by Farmos Group in 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.
`
`I __ _
`
`I
`
`Orion conducted 56 clinical trials of dexinedetomidine with vanous modes of
`administration including rapid intravenous infusion, continuous intravenous infusion,
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 1
`
`
`
`2
`
`intramuscular injection, as well as transdennal and oral administration. Abbott initiated
`its own clinical development program and completed 21 studies (13 Phase I and 8 Phase
`11/111) 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 of rapid infusion in 109 patients. The sponsor reported
`that the case report fonns for these 2 studies were unavailable and they did not include
`the data in the ISS d~tabase.
`
`The clinical studies of the effectiveness and safety of this new fonnulation have been
`reviewed [submitted August 29, 1999] by Charles Cortinovis, M.D. Dr. Patricia Hartwell
`contributed two addenda [submitted Septemb_er 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 reyiewed by Jonathan ·Ma, Ph.D.
`(biostatistics), Suresh Doddapaneni, Ph.D. (clinical pharmacGlogy 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 infonnation found in the primary reviews from the other disciplines, and make
`appropriate recommendations for action on the NDA.
`
`EFFECTIVENESS:
`
`Evidence of efficacy has been submitted in two clinical 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 dexmedetomidine in 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 prior to starting the double-blind portion of the study.
`Patient data from Part I was not included in the efficacy analyses.
`·
`
`, .... ~-·-i--..
`
`In Part II of the study, adult postoperative patients who required a minimum of 6 hours of
`ventilation and sedation in the ICU setting were randomized to either dexrnedetomidine
`or placebo f'~} sedation. Within one hour of admission to the "ICU, patients were
`
`DexmedetOlllidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 2
`
`
`
`3
`
`ad.ministered a loading dose 6.0 µg/kg/hour over a 10 minute period, followed by a
`maintenance infusion of 0.4 µg/kg/hour. The infusion rate could be adjusted by
`increments of 0.1 µg/kg/hour in order to maintain a Ramsay Sedation Score 1 of 3 or
`higher. However, it was required that the rate be maintained between 0.2 and 0.7
`µg/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 a maximum of 24 hours total
`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· ad.ministered
`as bolus doses of 0.02 mg/kg. Using the Ramsay Sedation Score, the patient was
`assessed prior to and I 0 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 ad.ministration 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 ad.ministered for pain as 2-mg
`intravenous boluses.
`
`The protocol specified primary efficacy parameter was the total dose of midazolam in
`milligrams ad.ministered 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 by the Division biostatistician, Dr. Permutt, at a development
`meeting with the sponsor. This endpoint was a comparison of the numbers of patients
`who fell into one of the following three categories of midazolam use:
`
`1. No dose
`2. Sumnerapeutic dose
`3. Therap~utic dose
`
`(0 mg)
`(0-4 mg)
`(>4 mg)
`
`This outcome measure was not specified in any ~endment to 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 response to light glabellar tap or loud auditory stimulus
`3 = patient responds to commands
`2 = patient cooperative, oriented, and tranquil
`1 = patient anxious,· agitated, or restless
`
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 3
`
`
`
`4
`
`Secondary efficacy parameters listed in the protocol for this study included2:
`
`as assessed by total dose used with
`·- 1. Use of morphine for pain -
`dexrnedetomidine as compared to placebo {mg/hr)
`2. Use of paracetamol for pain after extubation - as assessed by total dose used
`with dexrnedetomidine compared to placebo {mg/hr)
`Time t~ extubation - measured as time._of arrival in ICU until time of
`extubation
`
`3.
`
`However, the secondary efficacy parameters listed in the study report were:
`
`1. Total dose ofmidazolam during study drug administration
`2. Total dose of morphine during study drug admi~stration
`3. Total dose of morphine by time period
`4. -Ramsay Sedation Score
`_
`5. Ratio3 of Ramsay Sedation Score 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:
`
`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 dexrnedetomidine and 175 to
`placebo. All patients were administered study drug and comprised the ITT population.
`Two dexrnedetomidine treated and 6 placebo patients were excluded from the Evaluable
`patient set.
`
`Dr. Cortinovis' Table 4
`patient disposition:
`
`[page 22 of his review], reproduced below, summarizes the
`
`-. ··-
`
`: This infonnation 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.
`3 The ratio is the pro_p_?rtion of assessments that equal 1 divided by the total number of assessments for the
`patient.
`
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 4
`
`
`
`Table 1.
`
`Intent to Treat Patients (All Treated)
`Non-Evaluable patients
`Evaluable Patients
`Reasons for Non-Evaluability (Patient Numbers)"
`Insufficient Study drug therapy
`Insufficient Intubatioll'
`Received disallowed medication
`
`IOOl,4104
`I ()Q l,-11705
`1303,6004,
`7601 ..
`• patients_ could have had more than one reason for non-evaluab1hty
`Modified Sponsor's T_able 8.la Vol. 8/10-62-73
`
`5
`
`Placebo
`175
`6
`169
`
`Dexmedetomidine
`178
`2
`176
`
`1806
`1806
`6106
`
`Nine patients in the dexmedetomidine group and 10 in the placebo group were
`discontinu~g from the study prematurely. Each of these patfonts discontinued due to
`adverse events.
`
`Primary Efficacy Analyses:
`
`1. Dexmedetomidine patients required statistically significantly less midazolam
`compared to the placebo treated patients in both the IIT 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
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 5
`
`
`
`· Table 2.
`
`Total Dose of Midazolam (mg) During Intubation
`Placebo
`Dexmedetomidine
`
`Intent to Treat Patients (N)
`Mean±SEM
`Evaluable Patients (N)
`Mean± SEM
`• p-value from ANOV A
`SEM = Standard Error of Mean
`Modified Sponsor's Table 8.2a Vol. 8/10-62-74
`
`175
`18.61±4.02
`169
`18.46±4.14
`
`178
`4.83±1.43
`176
`4.56±1.42
`
`6
`
`Treatment Effect
`
`p-Value .
`
`0.0011
`
`0.0014
`
`2.
`
`Statistically significant differences were observed between the treatment groups in
`both the IIT and Evaluable analyses, with the majority of the dexmedetomidine
`treated patients requiring no midazolam compared to· iii~ majority of placebo
`patients who required greater than 4 mg ofmidazolam. 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
`
`Intent-to-Treat Patients (N)
`Omg
`>Omg to 4 mg
`>4 mg
`:::valuable Patients (N)
`Omg
`>O mg to 4 mg
`>4mg
`* p-value from chi-square
`Modified Sponsor's Table 8.2b Vol. 8/10-62-75
`
`175
`43(25%)
`34(19%)
`98(56%)
`169
`43(25%)
`32(19%)
`94(56%)
`
`178
`108(61%)
`36(20%)
`34(19%)
`176
`107(61%)
`36(20%)
`33(19%)
`
`·-
`
`Treatment
`Effect
`
`p-Value .
`
`<0.001
`
`<0.001
`
`.
`
`Secondary Efficacy Analyses:
`
`Their were no:.differences in any of the analyses when performed on either the IIT or
`Evaluable patient data sets. The following table, based on Dr. Ma's Table 3.3, page 6 of
`his review, summiu"izes the results for six of these analyses:
`. ....
`- -..
`
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 6
`
`
`
`7
`
`Table 4.
`
`Total dose of midazolam during drug
`administration (mg/hour)
`
`Total dose of morphine during drug
`administration (mg/hour)
`
`Placebo
`N CZ 175
`Mean ±SEM*
`
`Dexmedctomidine
`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 during o to 6.5
`. hours (mg)
`-
`
`8.5 (0.79) --
`
`Total dose of morphine during 6.5 to
`end (mg/hour)
`
`0.42 (0.08)
`
`4.9 (0;56)
`...
`o·.24 (0.05)
`
`<0.0001
`
`0.042
`
`Ramsay Sedation Score AUC during
`drug administration
`
`Ratio of Ramsay Sedation Score of 1
`during drug administration (%)
`
`*SEM =Standard Error of Mean
`
`3.3 (0.05)
`
`3.6 (0.05)
`
`<0.0001
`
`7 (0.8)
`
`3 (0.5)
`
`<0.0001
`
`As noted by Dr. Ma in his review, the Ramsay Sedation Score itself (AUC) was not a
`useful endpoint to consider as, 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 l, for any particular patient, might
`indicate less anxiety during the treatment period. s·tatistically 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:
`
`.--~·:.i.· ..
`
`Time to extubation and weaning duration:
`
`No statistically· significant differences were noted in time to readiness for ex!Ubation or
`actual extubation, when that time was measured either from ICU arrival or start of study
`drug. No statistically significant differences were found between the treatment groups for
`median duration of weaning.
`
`Nurses' and patients' assessment
`
`lower patient
`treated patients had a statistically significantly
`Dexrnedetomidine
`management index· [defined on page 30 of Dr .. Cortinovis' review] score compared with
`Dexmedetorttidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 7
`
`
`
`8
`
`placebo treated 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 experienees, their comfort during the ICU
`sedation, their remembrance of pain, discomfort from breathing ·tube, people and noise,
`and whether or not they would have the same sedative treatment in the future. However, .
`6-1 % of dexmedetomidine treated patients compared to 52% of placebo patients rated
`their overall expetie.iice 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 some of the data arising out of 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 meet the inclusion
`criterion for age. DSI has· requested clarification of the discrepancies and recommends
`that, until the matters are clarified and found to be satisfactory, we not use the data from
`those five subjects in support of the 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 not affect the outcome of the efficacy analyses.
`
`Study W97-246:
`
`This was a randomized, double blind, placebo-controlled, parallel group study conducted
`at 3c centers in Canada and Europe. The Study consisted of two parts. Part I was an
`open-label evaluation of dexmedetomidine in up to 4 patients per site. This portion of the
`study was designed to allow the investigators to become familiar with the observed
`clinical effec&-of·dexmedetomidine prior to 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 patient~ who required a minimum of 6 hours of
`ventilation and sedation in the ICU setting were randomized to either dexmeoetomidine
`or placebo for sedation. Within one hour of admission to the ICU, patients were
`administered a loading dose 6.0 µg/kg/hour over a 10 minute period, followed by a
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 8
`
`
`
`9
`
`maintenance infusion of 0.4 µg/kg/hour. The infusion rate could be adjusted by
`increments of 0.1 µg/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
`µg/kg/hour. Foil owing 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 hours total
`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 in~rease 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 ~~ore, the patient was assessed
`prior to and I 0 minutes after every rate change in study. drug or administration of
`propofol. lf"the patient required 3 bolus doses of propofol within any 2 hour period, after
`appropriate adjustments of the 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
`intravenous boluses.
`
`The protocol specified primary efficacy parameter was the total dose of propofol in
`milligrams administered during the period that the patient was intubated. The efficacy
`analysis was based on the Intent to Treat [IIT] population and analysis on the Evaluable
`population was also performed. A second primary efficacy endpoint was anacyzed based
`on a recommendation made by the Division biostatistician, Dr.· Permutt, at a development
`meeting with the sponsor. This endpoint was a comparison of the numbers of patients
`who fell into one of the following three categories of propofol use:
`
`I. No dose
`2. Subtherapeutic dose
`3 .'-.::l"herapeutic dose
`
`(0 mg)
`(0-50 mg)
`(>50 mg)
`
`This outcome me~ure was not specified in any amendment to the protocol. However,
`the analysis-~as undertaken prior to breaking the study blind.
`
`' 6 = asleep, no response
`5 = ~leep, sluggish response to light glabellar tap or loud auditory stimulus
`4 = asleep but wilh brisk response to light glabellar tap or loud auditory stimulus
`3 = patient responds to commands
`2 = patient cooperative, oriented, and tranquil
`1 = patient anxious;agitated. or restless
`
`Dexmedetomidine
`NDA21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 9
`
`
`
`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 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 10
`
`
`
`11
`
`Table 5.
`
`Intent to Treat Patients (All Treated)
`Non-Evaluable patients
`Evaluable Patients
`Reasons for Non-Evaluability (Patient Numbers)
`Insufficient Intubation
`Received disallowed medication
`Enrolled twice
`Modified Sponsor's Table 8.la Vol. 8110-86-73
`
`Placebo
`I98
`7
`191
`
`1
`s- .. -
`I
`
`Dexmedetomidine
`203
`3
`200
`
`NIA
`3
`NIA
`
`Fourteen patients in the dexmedetomidine group and 8 in the placebo group were
`discontinued from the study prematurely. Most of these p~~j,ents discontinued due to
`adverse events.-
`
`P~imary Efficacy Analyses:
`
`1. Dexmedetomidine patients_required statistically significantly less propofol
`compared to the placebo treated patients in both the ITI 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
`
`...... ~--..i- ...
`
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 11
`
`
`
`Table 6.
`
`Total Dose of Propofol (mg) During Intubation
`Placebo
`Dexmedetomidine
`
`Intent to Treat Patients (N)
`Mean± SEM
`Evaluable Patients (N)
`Mean± SEM
`• p-value from ANOV A
`SEM = Standard Error of Mean
`Modified Sponsor's Table 8.2a Vol. 8/10-86-73
`
`198
`513±55.58
`191
`505±56.40
`
`203
`72±17.51
`200
`73±17.76
`-
`
`12
`
`Treatment Effect
`
`p-Value .
`
`<0.0001
`
`<0.0001
`
`2. Statistically significant differences were observed between the treatment groups
`in both the IIT and Evaluable analyses, with the !Jlajority of the
`dexmedetomidine treated patients requiring no propofol compared to the
`majority of placebo patients who required greater than 50 mg ofpropofol. Dr.
`Cortinovis' Table 24, page 48 of his review, summarizes these results and is
`reproduced, with modifications, below:
`
`Table 7.
`
`Total Dose Categories of Propofol During Intubation
`Placebo
`Dexmedetomidine
`
`Intent-to-Treat Patients (N)
`Omg
`> Omg to 50 mg
`> ~Omg
`Evaluable Patients (N)
`Omg
`>O mg to SO mg
`> 50 mg
`• p-value from chi-square
`Modified Sponsor's Table 8.2b Vol. 8/10-86-74
`
`198
`47(24%)
`30(15%)
`121(61%)
`191
`46(24%)
`30(16%)
`115(60%)
`
`203
`122(60%)
`43(21%)
`38(19%)
`200
`120(60%)
`42(21%)
`38(19%)
`
`--
`
`Treatment
`Effect
`p-Value•
`<0.001
`
`<0.001
`.
`
`Secondary Efficacy Analyses:
`
`Their were no differences in any of the analyses when performed on either the ITT or
`Evaluable patieni:data sets. The following table, based on Dr. Ma's Table 3.6, page 10 of
`his review, sUmmarizes the results for six of thes~ analyses:
`
`Dexmedetomidine
`NOA 21~38
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 12
`
`
`
`13
`
`Table 8.
`
`Total dose of midazolam during drug
`administration (mg/hour)
`
`Total dose of morphine during drug
`administration (mg/hour)
`..
`Total dose of morphirle during 0 to 6.5
`hours (mg)
`
`Total dose of morphine during 6.5 to
`end (mg/hour)
`- -
`Ramsay Sedation Score AUC during
`drug administration
`
`Ratio of Ramsay Sedation Score of I
`during drug administration(%)
`
`*SEM =Standard Error of Mean
`
`Placebo
`N = 198
`Mean ±SEM*
`
`Dexmedetomidine
`N =203
`Mean± SEM
`
`p-value
`Treatment Effect
`
`39 (4.1)
`
`5.3 (1.2)
`
`-
`
`·-
`
`<0.0001
`
`0.89 (0.07)
`
`0.43 (0.05)
`
`<0.0001
`
`8.5 (0.64) -
`
`0.55 (0.07)
`
`4.1 (0.47)
`...
`0.1.6 (0.03)
`
`<0.0001
`
`<0.0001
`
`3.1 (0.04)
`
`3.4 (0.04)
`
`<0.0001
`
`7 (0.7)
`
`4 (0.5)
`
`0.0008
`
`As noted by Dr. Ma in his review, the Ramsay Sedation Score itself (AUC) was not a
`useful endpoint to consider as, 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 o.f 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 colintries
`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:
`,. ..
`-
`No statistically 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. No statistically significant differences were found between the treatment groups for
`median duration of weaning.
`
`Nurses· and patients' assessment
`
`lower patient
`Dexmedetomidine treated patients had a statistically significantly
`management index· [defined on page 52 of Dr., Cortinovis' review] score compared with
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 13
`
`
`
`14
`
`placebo treated patients. However, the actual numerical differences were not likely 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 of pain, discomfort from breathing- tube, people and noise,
`and whether or not they would have the same sedative treatment in the future. However,
`70% of dexmedetomidine treated patients compared to 60% of placebo patients rated ·
`their overall experience as "better than expected.:'
`
`Subgroup Analyses of Efficacy:
`
`...
`
`Dr. ·Ma has reviewed the sponsor's subgroup analyses and reports a few exceptions to the
`overall findings of significant efficacy of dexmedetomidine. These include:
`
`I. Of the 43 patients in both groups at the five German centers in Study 245,
`only I (5%) in the treated group required 0 mg of midazolam during the
`intubation period. At the other centers more than 50% of the treated 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
`dexmedetomidine treated 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 and all types of surgery in Study 246. However, the p(cid:173)
`value for head and neck surgery for Study 246 was 0.052.
`
`SAFETY: ,--:.::. ·-.>.
`
`The original ND.A submission excluded the - - - - - ita from the ISS
`database. This fact was discovered by Dr. Cortinovis after the submission had been filed.
`In a teleconference in late May of 1999, the sponsor claimed that they had not included
`this data because it came from studies performed to 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
`informed us that it would take a minimum of two months to complete the assignment and
`an early August submission was agreed upon. The new data was submitted on August
`17 16, 1999. This submission was found to be incomplete, with missing case report forms
`[CRF's], CRF's Jrom the : - -
`-: which had not been translated, and missing
`
`Dexmedetomidine
`NOA 21-038
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 14
`
`
`
`15
`
`the sponsor
`teleconference,
`tabulations. During a follow-up
`case report fonn
`acknowledged the missing data and stated that they had detennined some of the 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 importance to 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 of her first addendum] which summarize
`the number of studies and the number of patients 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] of all exposed patients, updating Dr. Cortinovis' Table 32 [page 57 of his
`review]. At this time, based on the infonnation 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 111111
`studies (146 subjects) as containing inadequate infonnation; 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
`
`_ .. =
`
`.
`
`_ .......
`
`Dexmedetomidine
`NOA 21.;0JS
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1019 – Page 15
`
`
`
`Table 9.
`
`Continuous
`Infusion
`
`Rapid
`Infusion
`
`IM
`Administration
`
`16
`
`Phase I Studies:
`Mean Total Dose
`N
`(µg/kg) ±SD
`Mean Total Duration
`N
`(hr)± SD
`Minimum
`Maximum
`Phase II Studies:
`Mean Total Dose
`N
`(µg/kg) ±SD
`Mean Total Duration
`N
`(hr)± SD
`Minimum·
`Maximum
`Phase III Study 245:
`Mean Total Dose
`N
`(µg/kg) ±SD
`Mean Total Duration
`N
`(hr)± SD
`Phase III Study 246:
`Mean Total Dose
`N
`(µg/kg) ±SD
`Mean Total Duration
`·-.:.::. ·,».
`N
`(hr)± SD
`N.B. The total N for all patient/subject listings in this table does not c:qual the total N for the safety
`database. The total 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 duratiol! information
`from the different study sites.
`
`36
`3.86 ± 3.33
`
`10
`0.02 ± 0.00
`0.02
`0.02
`
`~62
`1.91 ± 0.75
`
`NIA
`
`NIA
`
`NIA
`
`NIA
`
`NIA
`
`174
`3.52 ± 3.97
`
`174
`7.65 ± 8.26
`0.72
`24.02
`
`1518
`4.29 ± 3.09
`
`1475
`10.10±6.54
`0.02
`39.58
`
`178
`7.0 ± 2.95
`
`16.6 ± 5.0
`
`203
`7.1±2.81
`
`1