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`Case 1:15-cv-OO697-RGA roument 39-6 Filed 01/29/16 Page 1 oLZAPageID#:—337——
`
`l0
`
`Secondary efficacy parameters listed in the protocol for this study included’:
`
`assessed by total dose used with
`--1. Use of morphine for pain — as
`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 embation - measured as time of arrival in ICU until time of embed on
`
`However. the secondary efficacy parameters listed in the study report were:
`
`1. Total dose'of propofol during study drug administration
`2. Total dose of morphine during study drug adminisu'ation
`3. Total dose of morphine by time period
`M.
`4. Ramsay Sedation Score
`‘ -
`5. Ratio“ of Ramsey Sedation Score of “ l ” during study drug administration
`6. Time to extuban‘on 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 emailed 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 demedetomidine 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
`
`-2
`
`APPEARSTHISWAY
`0NDRIGINAL
`
`v
`
`_
`
`' ‘
`
`-
`
`_
`
`l
`l
`
`I
`l
`
`..
`
`" This information differs from that documented by Dr. Cortinovis in the medical officer's review and by
`Dr. Ma in the Statisrician's review.
`It is based on documentation provided by Dr. Patricia Hartwell who
`examined the original documents at my requesr.
`° The ratio is the propgrtion of assessments that equal 1 divided by the total number of assessments for the
`patient.
`-'
`a
`—
`
`Dexmedetomidine
`NDA 2 HI] 8
`
`
`
`HOSPIRA_00000260
`
`

`

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`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 2 of 24 PagelD#s 338
`
`Table 5.
`
`intent to Treat Parienu (All Treated)
`Non-Evalunble patients
`Evakuable Patients
`
`
`
`Modified Sponsor’s Table 8.1a Vol. B/iO-BGJS
`
`I Fourteen patients in the demedetomidine grouprand 8 in the placebo group were
`discontinued from the study prematurely' Most of these pefients discontinued due to
`adverse events._
`‘ -
`
`Pfimary EficacyAnafyses:
`
`l. Dexmedelomidine patients_required statistically significantly less propofol
`compared to the placebo treated patients in both the HT and Evaluable patient
`analyses. Dr. Cartinovis‘ Table 22. page 47 of his review, smnmarizes these
`reshlts and is reproduced. with modifications, below:
`
`APPEARS THIS WAY
`
`0H ORIGINAL
`
`3' '
`
`Dexmedetomidine
`NDA 21-038
`
`
`
`HOSPIRA_00000261
`
`

`

`Case 1:15-cv-00697-RGA Document 39-6 Filed 01/29/16 Page 3 of 24 PageID #: 339
`Case 1:15-QV-00697-RQA_ Documeanaefi—Ejled 01/29/16 Page 3 Of 24 PageID #: 339
`
`Table 6.
`
`Total Base of Propol’ol (mg) During lntuhation
`
`Treatment Effect
`
`
`-
`Its——
`
`
`
`
`-
`
`Evaluabletmenum)
`Meanxsam
`" p-value from ANOVA
`SEM = Standard Error of Mean
`Modified Sponsor's Table 8.23 Vol. sue-earn
`
`I_EE——
`sows-40
`
`
`
`
`2. Statistically significant differences were observed between the treatment groups
`in both the IN“ and Evaluable analyses. with the majority of the
`'
`dexmedetomidine treated patients requiring no propofol compared to the
`majority of placebo patients who required greater than 50 mg of prepofol. Dr.
`Cortinovis‘ Table 24, page 48 of his review, summarizes these results and is
`reprodueed, with modifications, below:
`
`Total Dose Categories of Propofol During lntubation
`Table 7.
` Treatment
`Placebo
`Demedetomidine
`
`
`Effect
`
`
`
`
`
`
`
`
`
`
`p-Value"
`Ia-
`Isa——
`mum} 42am: _
`121(61%) 38mm) —
`
`Iii—Eli!—
`
`_—
`
`
`
`am——
`" p-value from chi-square
`Modified Sponsor‘s Table 3.2]: Vol. ll! til-8644
`
`_H
`
`
`
`
`
`Secondary Efiicacy A nalyser:
`:2: at.
`
`Their were no dificrences in any of the analyses when performed on either the ITT or
`Evaluable patientfiata 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:
`
`qr
`
`'—
`
`Dexrnedetor'nidirte
`NDA 214038
`
`
`
`HOSPIRA_00000262
`
`

`

`*
`
`i
`
`
`
`g
`
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`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 4 of 24 PagelD #: 340
`
`IS
`
`Table 8.
`
`Placebo
`N a I98
`Mean 2!: SEM‘
`
`Dexmedetornidine
`N e 203
`Mean 1 SEM
`
`p-value
`Treatment Effect
`
`Total dose of midazoiarn during drug
`administration (mgfhcur)
`
`39 (4.1}
`
`5.3 (1.2)
`
`0.0003
`
`Total dose of morphine during drug
`administration (mg/hour)
`
`Total dese of morphine during 0 to 6.5
`hours (mg)
`‘
`
`Total dose of morphine during 6.5 to
`end (armour)
`
`Ramsay Sedation Score AUC during
`drug administration
`
`0.39 (0.07)
`
`0.43 (0.05)
`
`8.5 (0.64»
`
`4.1 {0.47)
`
`0.55 (0.0?)
`
`0.16 {0.03}
`
`<0.0001
`
`3.! (0.04)
`
`3.40104)
`
`(0.0001
`
`Ratio of Ramsay Sedation Score of I
`during drug administration We)
`
`7 (0.7)
`
`4 (0.5)
`
`'SEM = Standard Error of Mean
`
`As noted by Dr. Ma in his review, the Ramsay Sedation Score itself (AUG) 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. Statistically significant center effects
`were noted for most secondary endpoints indicating that patients in different coumries
`either required andfor were administered differing amounts of sedative and analgesic
`medications.
`
`The following additional secondary endpoints were discussed by Dr. Cortinovis in his
`review:
`
`mu
`_.
`Time to exrubatign 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.
`
`Nurse-3‘ and patients' asscssment
`
`statistically significantly lower patient
`Dexmedetomidine treated patients had a
`management indéi‘ [defined on page 52 of Dr.:ConinoVis' review] Score compared with
`:— -
`Demedetomidine
`NDA 21-038
`
`
`
`HOSPIRA_00000263
`
`

`

`Case 1:15-cv-00697-RGA Document 39-6 Filed 01/29/16 Page 5 of 24 PageID #: 341
`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 5 of 24 PagelD #: 341
`
`I4
`
`placebo treated patients. However, the actual numerical difi'erenees were not likely 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 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:T
`
`finbgroup Analyses of Efficacy:
`
`i: _
`
`Dr. Me has reviewed the sponsor's subgrOUp analyses and reports a few exceptions to the
`overall findings of significant efficacy of dexnicdetotrudine. These include:
`
`1.. 0f 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
`dexrnedetomidine treated groups.
`3. When analyzed by type of surgery, similar amounts of midazolaru 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-
`valuc for head and neck surgery for Study 246 was 0.052.
`
`'-
`
`SAFEIX: 4:
`
`-"'--———_...---..._..-—-—- tta from the 138
`The original‘NDfA- submissionexcluded the
`database. This fact was disoovered 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 easess 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 Augusr submission was agreed upon. The new data was submitted on August
`16, 1999. This submission was [bond to be incomplete, with missing case report forms
`[CRF’s]. CRF‘sfrorn the .'-..———---.
`1 which had not been translated, and missing
`
`I?
`
`Deemedetornidinc
`no». 21.033
`
`
`
`
`i
`
`I
`
`I
`
`
`
`HOSPIRA_00000264
`
`

`

`Case 1:15-cv-00697-RGA Document 39-6 Filed 01/29/16 Page 6 of 24 PageID #: 342
`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 6 of 24 PagelD #: 342
`
`—
`
`—
`
`
`
`15
`
`the sponsor
`follow-up teleconference,
`During a
`form tabulations.
`case report
`acknowledged the missing data and stated that they had determined some of the data to be
`not usefirl due to unavailability of CRP‘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 submittedpiecemeal since that time.
`In her first addendum to
`the medical review, Dr. HartWell has evaluated this late data in full and oarefitlly
`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 inetlrporate 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 patienm. 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 IL’III
`studies (146 subjects) as containing inadequate information; and this data was not
`included in the supplemental 158. Thus. the overall [38 database includes 3083 subjects
`exposed to dexrnedetomidine.
`-
`
`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]:
`
`“
`
`v
`
`_
`
`APPEARS THIS WAY
`0" ORIGINAL
`
`Dexmcdetomidine
`NDA 2l-‘038
`
`
`
`HOSPIRA_00000265
`
`

`

`Case 1:15-cv-00697-RGA Document 39-6 Filed 01/29/16 Page 7 of 24 PageID #: 343
`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 7 of 24 PagelD #: 343
`
`'.
`
`Phase 5 udies:
`Mean Total Dose
`N
`
`_
`‘
`
`.
`
`"
`
`l
`m
`
`H
`
`"
`
`I
`
`l
`
`'
`
`'
`
`3.52 t 3.97
`
`0.90 a: 0.63
`
`174
`7.65 i 3.26
`0.72
`
`-.
`
`.
`
`'-
`
`.,
`
`'- ' ‘4'.
`_
`
`1513
`4.29 x 1.09
`
`.
`.
`
`,. -
`
`__
`
`_.
`
`_
`
`“
`
`.
`
`257
`1.00 1 0.6?
`
`10.10 1‘: 6.54
`
`0.05 i 0.03
`
`
`
`"
`
`.
`
`"
`.
`
`"
`
`.
`
`0.02
`
`. ..
`
`;
`
`2
`
`66
`,9. z (175
`
`- —
`
`I
`
`._
`
`(mtg): so
`Mean Total Duration
`" N
`'
`(hr) x SD
`Minimum
`Maximum
`
`‘
`
`PhaseHStudies:
`Mean Total ose
`N
`tug/kg) :t SD
`__....__.____n
`Mean Total Duratio
`N
`
`(hr) 3: SD
`Minimum ‘
`
`Phase [I] Study 245:
`Mean Total Dose
`
`g“
`
`N
`(uglkg) 1 SD
`Mean Total Duration
`N
`{hr} 3 so
`
`Phase [11 Study 246:
`Mean Total Dose
`
`(items) 1 SD
`Mean T tel Duration
`N
`a-'.:. w.
`
`x
`
`a '
`
`-
`
`fl "
`
`I
`
`h H '
`
`'
`
`u
`
`i
`
`n H
`
`a
`
`178
`7.0 :l: 2.95
`
`.
`
`.
`
`.
`
`. _
`
`14.? i 4.5]
`
`MM
`
`Nl'A
`
`NB. The total N [got all patientlsuhject listings in this table does not equal the total N for the safety
`database. Th'é 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 duration information
`from the different study sites.
`
`During her review of the safer),r data. Dr, Hartwell requested more. specific informati on on
`exposure by dosc and duration from the sponsor. Dose by duration exposure data for all
`treated patients in the Phase IUIII continuous infiasion studies is summarized in Dr.
`HattweH's Table-l from page 2 of her second addendum:
`
`--—
`
`3
`
`Demedetomidine
`NDA 21-038
`
`
`
`HOSPIRA_00000266
`
`

`

`Case 1:15-cv-00697-RGA Document 39-6 Filed 01/29/16 Page 8 of 24 PageID #: 344
`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 8 of 24 PagelD #: 344
`
`I?
`
`Table 10. Extent of Exposure‘ Frequency of Duration by Dose
`Phase IUIII Continuous Infusion Studies — All-Treated Patients
`
`
`
`From Sponsor's Table of Duration by Dose. Supplemcnnn NBA. Ion-99, Exhibil 4
`NB. The total N corresponds to the total number of 93mm: with available tot-J Wan dm u in my Tflsl: 9. above. Homer.
`flier: was I discrepancy in the total N between the sponsor's ISS Supplemcnl (submitted August 16. 1999}. Appendix C. Table
`ll .2. p. 6% incl Supplemental Infunnuion submitted on Oelobei' 27, 1999 (p. T}. This discreme of 2 patients lupus to he a
`sample and! In addition.
`
`063:: by duration exposure data for all treated patients in the Phase I continuous infusion
`studies is summarized in Dr. Hartwell‘s Table 1 from page i of her second addendum:
`
`Table 11. Extent of Exposure - Frequency of Duration by Dose
`Phase 1 Continuous Infusion Studies — All-Treated Patients
`
`..
`
`
`
`nm
`
`
`
`N “nun-“un-
`“Hum-unm-
`““““““-“
`
`
`“mm-"nun"
`“mun-i-n
`
`
`mun-"nun"
`
`“unnu-J-“n
`
`
`“unnmmnu
`
`
`“umu-m—i-m
`“nun-Innu-
`
`
`““—“"““._-
`
`
`“nun—Il—
`
`
`Frorn Sponsor's Table offlumion by Dose. Supplement Io NDA. Iii-1739. Exhibit l
`NB. The Intel N map-ends to Us: lam numbet ul'pnljenls with available total duration data as in my Table 9. above.
`
`m—
`
`Deaths:
`
`‘—
`
`Amongst the 3083 dexmedetomidine treated patients. there were 12 deaths in the Abbott
`sponsored clinical studies and 1 death in w-— :ported to the
`Demedetornidine
`NBA 21-038
`
`'-
`
`
`
`
`
`HOSPIRA_00000267
`
`

`

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`Case 1:15-cv-OO697-RGA Document 39-6 Filed 01/29/16 Page 9 of 24 PagelD #: 345
`
`_
`
`'
`
`13
`
`original NDA [total deaths equals 16 with the additional deaths reported during the
`review period; see below].
`In all Of the studies combinedjherir were 8 deaths in the
`placebo groups (N = l495) and none in the comparator groups (N = 407) reported to the
`ori ginal NDA.
`
`Dr. Cortinovis has summarized the 12 Abbott deaths in his review and Dr. Hartwell has
`
`n in her addendumr-While there were no deaths that
`;
`summarized '
`could clearly be attributed directly to dexmedetornidine, a few of the cases raise concerns
`regarding intraoperative or postoperative cardiovascular events which may have,
`ultimately. contributed to the patients' deaths.
`
`'
`
`
`
`Patient 1115, Study'95-DDZ. was an elderly male who underwent a low
`anterior colon resection. The patient experienced intermittent hypotension
`and the dexrnedetomidine infusion was discontinuedafier only two hours.
`The‘patient experienced a cardiac arrest two days later. An autopsy did
`document severe atherosclerotic cardiac disease. Dr. Cortinovis assessed
`
`this case as unrelated to study drug. However. if the episodic hypotension
`was exacerbated by the dexmedetomidine infusion,
`it
`is possible that
`significant damage was done to the myocardium, allowing an already
`diseased organ system to deteriorate and fail over the next We days.
`
`Patient 0622, Study 95—004, was a 59 year old male who underwent
`coronary artery bypass
`surgery and developed acute renal
`failure
`postoperatively. Dr. Cortinovis determined this case to be unrelated to
`study drug. The exact postoperative course leading to death is not clear,
`but the renal failure could certainly have been directly or indirectly related
`to dexmedetomidine. a drug with an established adverse event profile that
`includes hypotension. HOWever. it is important to note that the patient‘s
`preoperative
`medical
`_ problems
`included
`hypertension,
`hypercholesterolemia, paroxysmal atrial
`fibrillation. and chronic renal
`insufficiency-
`
`Patient [0202. Study W97-246, was a 74 year old male who undcment
`coronary" artery
`bypass
`surgery
`and
`deVeloped
`hypotension
`postopemtively, soon after the dexmedetomidine infitsion was started.
`Episodes of hypotension continued and the study drug Was discontinued 9
`hours—after initiation. The patient then developed renal insufficiency, but
`was reportedly stable over the next 3 days. He then suffered an acute
`myocardial infarction and died. Dr. Cortinovis assessed the relationship of
`study drug to this patient's death to be "doubtful."
`Again,
`the
`postoperative hypotension may have been a complication of. or have been
`complicated by, the dexmedetornidine infusion. Over time, this may have
`resulted in a deterioration in cardiac function and contributed to the
`
`patient‘s terminal events.
`
`':
`
`'
`
`Dexrncdetnmidine
`NDA 2 l 4138
`
`
`
`HOSPIRA_00000268
`
`

`

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`
`19
`
`Patient 109, Study 9?-249, was 47 year old who underwent coronary
`bypass surgery. Approximately 14 hours following initiation of the
`dexrnedetomidine infusion,
`the patient developed circulatory collapse.
`hypotension and an acute myocardial
`infarction.
`The infusion was
`discontinued and the patient returned to the operating room for repair of an
`incomplete coronary revascularization. The patient-died of mutiorgan
`failure following that procedure. Dr. Cortinovis determined that
`the
`proximate cause of death is not clear, but “...is of the opinion that the
`cause of death was the direct result of the surgical repair." [page 63 of his
`review]
`As with the
`above cases.
`this patient's postoperative '
`cardiovascular collapse may haVe bean directly or indirectly related to the
`dexmedetomidine infilsion.
`
`Patient 21], Study 3005006, was a ‘73 year old male who underwent
`coronary
`artery
`bypass
`surgery
`and
`received
`infusions
`of
`dexniedetomidine both
`intraoperatively and
`postoperatively.
`His
`postoperative course was complicated by hyperglycemia, acidosis,
`hemodynantic
`instability,
`and decreased urine output.
`Following
`extubation he became agitated and confused,
`requiring sedation and
`supplemental oxygen to maintain his saturation. Three days after surgery
`the patient’s intravenous line became disconnected and he died of massive
`blood loss. The investigators concludedrhat the death was not due to
`study drug.
`Dr. Hartwell states that “...i.t‘ dexrnedetomidine was a
`contributor or initiator of the patient’s confusional state and if the patient’s
`ongoing confusion and agitation was
`the cause of an inadvertent
`intravenous disconnection] the "satay agent rr'tt'fst be secondarily implicated
`in this patient’s death. From the data provided,
`it is not possible to
`completely discount dexmedetornidine
`as
`a
`factor
`in
`the
`initial
`agitationfconfitsion episode.“ [page 9 of‘her addendum] As Dr. Hartwell
`notes, the patient’s change in mental status may have been due to multiple
`factors.
`Certainly,
`the documented hemodynarnic
`instability and
`decreased urine output may both have been the result 'of dexmedetomidine
`induced hypotension and hypoperfusion. and have resulted in hypoxic-
`ischemicxencephalopathy.
`
`At Dr. I-lnr'ttyell’it:request.l the sponsor provided information on two additional deaths
`reported with minimal information in the lZO-Day Safety Update from ongoing. blinded
`Phase 11 studies.
`'
`
`Patient 104. Study W98-263, was a 79 year old female with multiple
`medical
`problems was
`treated with
`a
`continuous
`infusion of
`dexrnedetomidine in the ICU following myocardial infarction and cardiac
`arrest and resuscitation. During treatment she experienced recurrent
`hypotension and bradycardia. All treatments were discontinued after l8
`hours and_t_he patient died of multiorgan failure. Dr. Hanwell’s conclusion
`
`E
`
`Dexmedetoniidine
`NBA 21-038
`
`'
`
`-
`
`
`
`
`
`HOSPIRA_00000269
`
`

`

`
`
`_
`4
`
`-
`
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`
`20
`
`that the sponsor cannot rule out that study drug contributed to the patient‘s
`demise is appropriate.
`
`Patient 101. Study W98-264, was a 58 year old male with multiple
`medical problems treated with a continuous infusion of demedetomidine
`in the ICU. The patient experienced two episodes of transient hypotension
`which respOnded readily to reduction in the-dexrnedetomidine infusion
`rate. The patient received dettmcdetomidine for a total of 50 hours, at
`which time all supportive care was withdrawn.
`The patient died of
`'multiorgan failure soon after. Once again, Dr. Hartwell‘s conclusion that
`the sponsor” cannot rule out that study-drug contributed to the parient‘s
`demise is appropriate.
`
`_
`
`--
`
`Dr. Hartwdl next compared data on deaths submitted' to the sponsur’s IND for
`dexmedetbistidine, ;%—f—flmud Report dated 3-24—99] and that submitted to the
`original NBA and the Safety Update. Nine deaths not reported to the NDA or Safety
`Update were documented in the Annual Report. One death occurred in a patient exposed
`to dexmedetontidine, 3
`in placebo treated patients, and five in patients without
`documentation of treatment group. Clarification of this data was requested of the Sponsor
`in- September I999 and received on October I, 1999.
`In that conununieation, the sponsor
`explains that serious adverse events [SAE's]. presumably incorporating deaths, occurring
`greater than 24 hours after discontinuation of treatment were included in a special
`company database, but not necessarily in the NDA database.
`
`Clarification of the discrepancies was requested of the sponsor. On pages 6 and 7 of her
`second addendum, Dr. Hartwell summarizes the infomation received from the sponsor.
`Only 1 of the patients in this group of deaths was exposed to dexmedetomidine.
`
`-
`
`I1601, Study 97-246, was a 73 year old male who underwent
`Patient
`pneumonectorny for lung cancer. He received a continuous infusion of
`dexmedetomidine for 7 hours at constantly decreasing doses. His course
`was complicated by severe hypotension requiring treatment with
`dopamine,
`followed by cardiac arrest
`from which the patients was
`resus'fitzittrd. He died five days later. The investigator attributed the death
`to “poor cardiac function —- myocardial hypersensitivity to dopamine", and
`determined it to be "unrelated" to study drug. As per Dr. Hartwall‘s
`discussion, it remains possible that dcxmedetomidine exposure contributed
`to the patient's death.
`_
`
`Digegptiguafions:
`
`Dr. Corrine vis has summarized the narratives of all 4! patients who discontinued due to
`adverse events in his review. No clearcut trends or conclusions may be drawn from those
`surrunaries.
`
`Demedetomidlne
`NBA 21-033
`
`W
`
`HOSPIRA_00000270
`
`

`

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`'
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`‘_
`
`2 l
`
`My review of the sponsor‘s Table 2.1.5.11, “Summary of Discontinuation Due to
`Adverse Events; All Treated Patients in PhaSe 11le Continuous Infusion Studies”. pages
`166-163, Volume 1.302. revealed no events resulting in patient discontinuation that
`occurred with a frequency greater than I%.
`In particular. circulatory failure, hypotension,
`cardiac arrhythmias. myocardial infarction and hypoxia each occurred in less than I% {of
`both dexmedetornidine treated and placebo patients. My review of the sponsor’s Table
`2.2.5.11, “Summary of Discontinuation Due to Adverse Events; All Treated Patients in
`Phase llflll Continuous Infusion lCU Sedation Studies“, pages 275-27?, Volume 1.303.
`revealed similar findings.
`
`In the lZO-Day Safety Update, the sponsor reported on I treated subject who discontinued
`due to an adverse event. That subject suffered a seizure after receiving study drug and
`discussed below under Serious Adverse Events.
`'
`
`It is worth noting here that there are discrepancies in the numbers of patients listed as
`disoontinuations in the sponsor's initial 188 documents and the follow-up documents.
`There are also discrepancies internally Within the original 155. Howevur, With all
`available data regarding this patient subset having been reviewed by either Dr.
`Cortinovis. Dr. Hartwell, or myself, there is no evidence that the adverse event profile
`was unusual or unexpected. Thus. it is unlikely that a hill accounting of discontinued
`patients would provide new information that would significantly affect our decision
`regarding approvability.
`
`Serious Adverse
`
`e
`
`5:
`
`Dr. Cortinovis‘ review of SAE's consisted of copies of modified sponsor‘s tables which
`summarized the incidence of all SAE's in all clinical trials. Thereforce. I requested that
`Dr. Hartwell undertake a more thorough analysis of this data.
`
`‘-
`
`trials
`in her first addendum. Dr.- Harnvell. reports- that 5 subjects in the Phase I
`experienced SAE‘s. The events that Dr. Hartwell concludes are possibly related to study
`drug exposure are sinus arrest (2), bradycardia, hypotension, convulsions. and allergic
`reaction after transdetmal application.
`
`In the Phase ll/‘lll trials, Dr. Hartwell reports that 9% of patients in the Abbott Sponsored
`continuous‘infusion studies and 11% of patients in the non-Abbott sponsored continuous
`infusion studies eitpericnced SAE's. The overall incidence was similar to the randomized
`placebo population for these studies (9% and 10%,
`respectively}.
`In the Abbott
`continuous
`infusion studies.
`the only SAE‘s occurring more frequently in the
`dexmedetomidine treated patients compared to the placebo treated patients were:
`hypotension (4% vs. 2%), hypertension (2% vs. 1%), and bradycardia (2% vs. 0%). All
`other SAE's occurred in less than 1% of dexmedetomidine treated patients. Similar data
`is unavailable for the non-Abbott studies.
`
`Dexmedetomidlne
`NDA 21-03:!
`
`W
`
`HOSPIRA_00000271
`
`

`

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`22
`
`As summarized in Dr. Hartwell’s Table 3, page 4 of her second addendum, the incidences
`of the treatment emergent SAE’s myocardial infarction and cardiac arrest were less than
`1% in both the dexmedetornidine treated and placebo treated patients.
`in her Table 4 on
`page 4 of the addendum, Dr. Hartwell summarizes the treatment entergent respiratory
`adverse events in the Phase IUIII continuous infilsion studies. The incidences of all
`
`eventsweresimilarbetweenthedexmedetomidineandtheplacobotreatedpatients.
`
`In her first addendum, Dr. Hartwell summarizes the SAE‘S reported to the lZO-Day
`Safety Update. Most of these events appeared to be unrelated to study drug exposure.
`Three patients {two of whom have already been discussed in the section of Deaths}
`experienced hemodyinarnic instability which mi ght have been directly or indirectly related
`to dexmedetomidine exposure. One subject in a Phase I study experienced a_ single
`seizure after receiving an infilsion of 1.25 rig/m1, dexrnedetomidine for approximately
`18.5 hours. Although he had no history of seizure disorder." he did have a history of head
`trauma. Neitertheless, the dexmedetomidine may have directly or indirectly contributed
`to this event. Dr. Hartwell concludes that the overall incidence of SAE'S in the l20-Day
`Safety Update is consistent with what has been reported in the original and in the
`supplementary NDA submissions.
`
`-
`
`..
`
`!
`
`l|
`
`l I
`
`Once again. as with the reporting of Deaths, the sponsor explained that SAE‘s reportedly
`occurring greater than 24 hours after discontinuation of treatment were included in a
`special company database, but not necessarily in the NBA database. Consequently, as
`Dr. Hartwell notes on page 5 of the second addendum:
`"...inaccuracies in both the
`identification of serious adverse events and the total number of events reported for each
`study are a possibility."
`'
`
`Other Adverse Events:
`
`“
`
`Dr. Cortinovis' Table 42, page 99 of his review [reproduced below]. surrunarizes the
`incidence and dose association of the most common adverse events seen in the PhaSe I
`
`continuous infusion studies. Dry mouth and somnolence were extremely common—in
`some target concentration groups (up to 73% and 85%, respectively)' with some non-dose
`relatedness possibly explained by incomplete reporting.
`Pi... It.
`
`5 —
`
`Dexmedetoniidine
`NBA 21-038
`
`
`
`HOSPIRA_00000272
`
`

`

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`Table I2. Most Common' Treatment Emergent Advane Events By TI rget Dexmedelomidine Plasma
`
`23
`
`Concentration: AllDexmedetonlldineTreatedSubjeels Pl:useIContinuousInfusionStudies
` Target Dexmwelnmidine Plasma Concerto-anon (oz/ml.) —
`Increasing
`Dex Cone
`1.25
`0.5
`our:
`0.:
`0.1-0.2
`
`04:22)
`(NI-l2)
`(use!)
`{14-34)
`ran-:9)
`mazs)
`
`1 0(4 5%)
`12( i 00%)
`39(64%}
`270995)
`39(66%}
`2496?.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“5%;
`0
`2 [9%]
`l( 5%)
`5 (23%)
`0
`' 20%)
`“8%)
`fins)
`40 8%)
`
`
`9(75%}
`10(8396]
`“33%)
`
`|
`
`1
`
`_
`
`‘
`
`
`
`
`
`
`Adverse Evenlh
`Subjects with :1 least
`one "mount-emergent
`adverse event
`
`Mouth dry
`Somnolenee
`_Headach_e
`Hypotension
`' Nausea
`Hypoxia
`Dizziness
`Bradyeardia
`Muscle centurion:
`
`
`
`12(20'56}
`8( 13%)
`I 108%}
`9( I 5%)
`20%)
`H2926)
`“2%)
`315%)
`' '
`
`
`
`
`
`9(26'fd
`205993)
`5( I 5%)
`I “47%)
`2(693)
`0
`10%}
`O
`
`l6(2?%)
`I IX l 7%)
`15 (25%)
`9:: I 5%)
`905%}
`10%)
`3 (5%} »
`“1%)
`
`
`
`
`
`
`
`500%)
`I T(63%)
`2(8%])
`“(515%)
`“4%)
`D
`3 (I256)
`HHS)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2(9'23)
`0
`0
`I (5%)
`0
`“5%)
`
`
`
`"8%)
`0
`"8%)
`4 {33%}
`
`
`
`-
`"
`
`use.)
`O
`[(5%)
`16%)
`
`
`
`5 {3%}
`5(8an
`40%)
`[(2%]
`s [3%)
`20%}
`310%}
`GENE}
`0'
`3 {5%)
`3 {5%}
`O
`CI
`um.)
`0
`a
`2 {3%)
`|(2%}
`"2%)
`
`
`
`
`
`“3%)
`0
`0
`2(6%)
`"3%)
`10%)
`[(3%)
`0
`3 (9%]
`
`«12%)
`NM}
`I696}
`a
`-.
`{J
`2(6‘5’5}
`0
`
`3 [5%)
`80-196}
`40%]
`3 (5%}
`A {5%)
`40%)
`40%)
`0
`5 (8%]
`3 (5%)
`O
`56%}
`D
`40%)
`2 (3%)
`2 (3%)
`“7%)
`“2%)
`O
`
`"4%)
`"4%)
`mm;
`
`involuntary
`Pallor
`Apnea
`Stupor
`Hypakimia
`Pain
`Phal'yngilis
`Paresfllesia
`Xemphlhal'rnie
`Fatigue
`Hallucination
`Vomiting
`Agilation
`Promo:
`Rhinitis
`Back pain
`Vision abnormal
`Abdominal pain
`Conjunctivitis
`Sponsor‘s Table 43. 188 Vol. 13110-239435
`a: Experienced MET/3 ol'ail deumedetomidine—mzed subjects in Lhe Phase I studies
`b: Subjects may have been eonnteo in more than one column iflhey received Munch! in more than one treatment
`period. but a subjeel was counted only once in a given eoiumn.
`Dex = Dexmedetomidine Cones - eoneenu'ations
`
`['22. K5 .
`
`The most common adverse events occurring in the Phase IMH continuous infilsion
`studios arc-summed in Dr. Cortinovis' Table 43 [page 100 of his review], reproduced
`below:
`
`5
`
`'-
`
`Dexmedeton'iidine
`NBA 21-033
`
`
`
`HOSPIRA_00000273
`
`

`

`(IN-92) r- atienls with at least
`
`.
`
`‘
`
`.
`
`'
`
`'
`
`'
`
`290395)
`5(693)
`24(279’0
`819%)
`40%}
`J (3%)
`1912214.}
`1 (1%)
`mm
`2(2%}
`5 (5%)
`
`91:3 193‘} ' '
`39: I 3%)
`“(13%)
`2 I093} .
`12(49'.)
`“(5%)
`90%)
`17(695}
`mm)
`90%)
`NW.)
`«3%)
`9(399}
`40%)
`90%;
`
`659%)
`45(20%}
`280216}
`121596)
`“(6%)
`states}
`«4%)
`“16%)
`“11(594.)
`«2%)
`70%)
`5(2an
`60%}
`63%)
`3 (1%)
`
`'
`
`36(21%}
`28( I6%)
`“(8%)
`istsni
`«2%)
`1mm)
`40%)
`can.)
`60%)
`5 (3%}
`«2%)
`«2%;
`613%)
`I I{6%}
`«2%)
`
`i
`
`-
`
`-
`
`25 (27%)
`1:: 13%}
`5 {5%)
`_ IOU 1%)
`5 [5%)
`ctr/.3
`«my
`.t {1%)
`313%}
`3 (3%)
`1 (tea)
`3 {mi
`zine)
`60%}
`«4%)
`
`'
`
`“502%;
`Hypotensinn
`"(10%)
`Hypertension
`51 (12%)
`Nansen
`28(693)
`Bfidycerdie
`25 {5%}
`Tachycardia
`2mm)
`‘ Fever
`“(3%)
`Hypoxia
`limit}
`Anemia
`140%)
`Vomiting
`l3 (3%)
`Hemorrhage NOS
`100%)
`Pain
`'
`‘
`:3 (3%)
`Rigor:
`Hams)
`Atrial fibrillation
`3 (41%}
`Mouth dry
`9mm
`Agitation
`Sponsor's Table 4a 158 Vol. B