CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`SUMMARY REVIEW
`
`
`
`Page 1 of 27
`
` Insys Exhibit 2005
`CFAD v. Insys
`IPR2015-01800
`
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`Page 2 of 27
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`

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`
`OSE/DRISK
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Sharon Hertz, M.D.
`CDTL
`Luke Yip, M.D.
`Clinical Review
`Yan Zhou, Ph.D.; Dionne Price, Ph.D.
`Biostatistics Review
`Elizabeth Bolan, Ph.D.; Dan Mellon, Ph.D.
`Pharmacology Toxicology Review
`Julia Pinto, Ph.D.; Prasad Peri, Ph.D.
`ONDQA-CMC/Quality Review
`OPS/NDMS-Microbiology Review Bryan Riley, Ph.D.
`CDRH/ODE/DAGID/GHDB
`LCDR Alan Stevens, Jacqueline Ryan, M.D.
`Clinical Pharmacology Review
`Wei Qiu, Ph.D.; Yun Xu, Ph.D.
`OSI
`John Lee, M.D.; Susan Thompson, M.D.
`Project Management
`Kathleen Davies; Sara Stradley, M.S.
`OSE/DMEPA
`Anne Tobenkin, Pharm.D.; Lubna Merchant, Pharm.D.;
`Kellie Taylor, Pharm.D., MPH; Carol Holquist, R.Ph.
`Doris Auth, Pharm.D.; Megan Moncur, MS; Gita
`Toyserkani, Pharm.D., M.B.A.; Claudia Karwoski,
`Pharm.D.
`Sharon Mills, BSN, RN; Barbara Fuller, RN, MSN;
`LaShawn Griffiths, MSHS-PH, BSN;
`L. Shenee’ Toombs, Pharm.D.
`Chad Reissig, Ph.D.; Silvia Calderon, Ph.D.
`
`OMP/OMPI/DMPP
`
`OMP/OPDP/DDTCP
`Controlled Substances Staff
`
`OND=Office of New Drugs
`OMP: Office of Medical Policy
`OMPI=Office of Medical Policy Initiative
`OPDP= Office of Prescription Drug Promotion
`DMPP = Division of Medical Policy Programs
`DDTCP: Division of Direct-to-Consumer Promotion
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention
`DRISK= Division of Riak ManagementOSI=Office of Scientific Investigations
`CDTL=Cross Discipline Team Leader
`ONDQA=Office of New Drug Quality Assessment
`OPS/NDMS=Office of Pharmaceutical Sciences/New Drug Microbiology Staff
`CDRH/ODE/DAGID/GHDB=Center for Devices and Radiological Health/Office of Device Evaluation/Division of
`Anesthesiology, General Hospital, Infection Control, and Dental Devices/General Hospital Devices Branch
`
`
`
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`2
`
`Reference ID: 3066841
`
`Page 3 of 27
`
`

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`
`
`1. Introduction
`
`Insys Therapeutics, Inc. submitted this 505(b)(2) application for their sublingual,
`transmucosal, immediate-release formulation of fentanyl, packaged in a single-dose
`spray device. The referenced drug product application is Actiq, NDA 20-747. A
`single efficacy study was required for this NDA as this is our standard requirement for
`505(b)(2) applications for reformulated opioid drug products for which there are no
`changes to the route of administration or patient population. In addition, several
`pharmacokinetic studies and two open-label safety studies were submitted in support of
`this application. Of note, the reviews for this application often refer to the product as
`fentanyl sublingual spray or FSS.
`
`2. Background
`
`The following summary of the history and development of the transmucosal,
`immediate-release fentanyl (TIRF) product class has been reproduced from page 2 of
`Dr. Hertz’s review:
`
`
`This application represents the sixth NDA for a transmucosal immediate-release fentanyl
`(TIRF) product indicated for the management of breakthrough pain in patients with
`cancer, 18 years of age and older, who are already receiving and who are tolerant to
`regular opioid therapy for their underlying persistent cancer pain. Actiq was the first oral
`transmucosal fentanyl product approved and is a lozenge on a stick that is moved
`between the gum and the buccal mucosa. Actiq was approved under Subpart H, in large
`part because of the risk for accidental pediatric exposure due the similarity in appearance
`to a lollipop. A RiskMAP was created to attempt to manage the risks associated with this
`product. In addition to providing some methods to try and minimize the risk for
`accidental pediatric exposure, other goals described in the RiskMAP included preventing
`use in opioid non-tolerant patients and other unsafe off-label use. Fentora (NDA 21-947)
`was the second oral transmucosal fentanyl formulation approved and is a tablet that is
`placed between the buccal mucosa and gum where it dissolves with an element of
`effervescence. Fentora was approved with a RiskMAP comparable to Actiq.
`
`Onsolis (NDA 22-266), Abstral (NDA 22-510) and Lazanda (NDA 22-569) followed
`Actiq and Fentora. Onsolis is formulated as a bioerodible membrane that adheres to the
`buccal mucosa. Abstral is a sublingual tablet formulation. Lazanda is formulated as a
`nasal spray. These three products were approved with risk evaluation and mitigation
`strategies (REMS). The reason for the switch to a REMS is described below.
`
`The indication for this group of products, the management of breakthrough cancer pain in
`adult patients who are already receiving, and who are tolerant to, opioid therapy for their
`underlying persistent cancer pain is narrow for two reasons. First, the population
`identified has a specific need for a treatment to address cancer-associated breakthrough
`pain, which is characterized by a quick onset, often high severity, and relatively short
`duration. These formulations of fentanyl are designed to have a relatively rapid rise to
`Cmax and a relative short duration of effect. Fentanyl is a very potent opioid that can
`cause respiratory depression in microgram quantities. For this reason, the indication also
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`3
`
`Reference ID: 3066841
`
`Page 4 of 27
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`Page 8 of 27
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`

`
`from
`recommendation
`approval. The
`preclude
`that would
`NDA
`Pharmacology/Toxicology is that NDA 202788 be approved with no post-
`marketing requirements.
`
`I concur with the review team that there are no outstanding nonclinical pharmacology
`or toxicology concerns that would preclude approval of this application.
`
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The following summary of the clinical pharmacology data and review has been
`reproduced from pages 6 through 9 of Dr. Hertz’s review:
`
`
`The applicant submitted four clinical pharmacology studies in support of this application.
`Three studies were in healthy subjects: a pilot, single ascending dose PK study, a single-
`dose
`relative bioavailability study
`(BA), and a single-dose, crossover, dose
`proportionality study that included an evaluation of the effects of temperature and pH.
`One study enrolled cancer patients to evaluate the effects of oral mucositis on PK.
`
`As summarized by Dr. Qiu, fentanyl is highly lipophilic. The plasma protein binding is
`80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and
`lipoproteins contribute to some extent. Fentanyl is metabolized in the liver and in the
`intestinal mucosa to norfentanyl by cytochrome P450 3A4. Norfentanyl was not found to
`be pharmacologically active in animal studies. Fentanyl is primarily (more than 90%)
`eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.
`Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is
`excreted unchanged in feces. The metabolites are mainly excreted in the urine.
`
`As described by Dr. Qiu, the mean absolute bioavailability of Fentanyl Sublingual Spray
`400 mcg in comparison to fentanyl citrate intravenous injection 100 mcg was 72.1% for
`AUClast and 75.6% for AUCinf, normalized for dose. One 400 mcg spray of FSS
`resulted in 34% and 36% greater Cmax and AUCinf values, respectively, compared to an
`Actiq dose of 400 mcg, under fasting conditions.
`
`The average Tmax ranged between 1.25 hours for the 100 mcg and 200 mcg doses to
`0.67 hours for the 600 mcg dose. The mean half life was 5.25 hours for the 100 mcg
`dose, 8.45 hours for the 200 mcg dose, and up to 11.99 hours for the 800 mcg dose.
`While the half-life seems long for a drug intended to treat a breakthrough pain, the shape
`of the PK profile demonstrates a large early peak with a long tail as shown in the figure 1
`(p. 8) from Dr. Qiu’s review. The shape of the PK profile is compatible with the intended
`use of the product.
`
`
`
`
`
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`8
`
`Reference ID: 3066841
`
`Page 9 of 27
`
`

`
`
`
`
`
`Figure 1 Mean Fentanyl Concentration-Time Profiles after Administration of Single Doses of Fentanyl
`Sublingual Spray 100 mcg (Treatment A), 200 mcg (Treatment B), 400 mcg (Treatment C), 600 mcg
`(Treatment D), and 800 mcg (Treatment E) from Study INS-06-004
`
`
`
`
`The systemic exposure of fentanyl increased in an approximately dose proportional
`manner over the 100 mcg to 800 mcg range, under fasting conditions based, on Cmax and
`AUC, except for the lower bound of the 90% confidence interval which was slightly low
`for the Cmax of the 600 mcg dose relative to the 800 mcg dose and for the 100 mcg and
`200 mcg doses for AUC.
`
`There was no clinically important effect from pre-treating the oral cavity with hot or cold
`water. There were small decreases in fentanyl exposure after pretreatment with a low pH
`beverage and small increases following a high pH beverage, but these were small enough
`to be of no clinical importance.
`
`There were important findings in cancer patients with oral mucositis. In patients with
`Grade 1 mucositis, mean fentanyl Cmax and AUClast values were 73% and 52% greater,
`respectively, than with patients without mucositis following the administration of a 100
`mcg fentanyl sublingual spray.
`
`Two patients with Grade 2 mucositis were studied. Fentanyl Cmax values were 7-fold
`and 4-fold greater than the mean Cmax values obtained in patients without mucositis for
`the two patients. However, the highest Cmax in the Grade 2 mucositis patient was only
`3-fold greater than the highest Cmax in the group without mucositis. The corresponding
`fentanyl AUClast values were 17-fold and 3-fold higher than the average values in
`patients without mucositis. Figure 2 from Dr. Qiu’s review (p. 10) shows the individual
`PK profiles of patients without mucositis on the right and with mucositis on the left. In
`the figure on the left, the PK profile with the notably high fentanyl concentrations was
`from one of the patients with Grade 2 mucositis.
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`9
`
`Reference ID: 3066841
`
`Page 10 of 27
`
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`Page 11 of 27
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`I concur with the review team that there are no outstanding concerns regarding the
`clinical pharmacokinetic and biopharmaceutics data that would preclude approval of
`this application.
`
`6. Clinical Microbiology
`
`No clinical microbiology data were necessary for this application.
`
`7. Clinical/Statistical-Efficacy
`
`The following summary of the efficacy data and reviews has been reproduced from
`pages 9 through 14 of Dr. Hertz’s review:
`
`
`With five approved products in the TIRF class, there has been a fair amount of
`experience with understanding the efficacy of these products. Fentanyl, a mu opioid
`agonist, is a known analgesic, available as intravenous, transmucosal and transdermal
`formulations. The current application relies on the Agency’s prior findings of efficacy
`for Actiq, the listed drug referenced in the application, and one adequate and well
`controlled clinical trial. As FSS delivers fentanyl with a PK profile similar to Actiq, but
`not bioequivalent, the clinical trial was required to confirm that this new formulation
`provides efficacy in the intended population.
`
`Drs. Yip and Zhou have reviewed Study INS-05-001 in detail. This was a multicenter,
`placebo-controlled, 10-period crossover study in opioid-tolerant cancer patients with
`breakthrough pain. Key inclusion criteria included adult patients with a diagnosis of
`cancer and persistent cancer pain or its treatment of moderate or less intensity, taking at
`least 25 mcg of transdermal fentanyl per hour or 60 mg of oral morphine per day, 30 mg
`of oxycodone per day, 8 mg of oral hydromorphone or equivalent per day, around-the-
`clock, for at least one week, and, on average, one to four episodes of BTCP over the
`previous week at least partially controlled by supplemental medication of at least 5 mg
`immediate-release morphine or an equivalent short-acting opioid (e.g., oxycodone,
`hydrocodone, or acetaminophen with codeine.) Key exclusion criteria included the
`presence of painful erythema, edema or ulcers under the tongue, brain metastases, or
`clinically relevant abnormalities in vital signs, liver enzymes or serum creatinine.
`Concomitant use of CYP 3A4 inducers or inhibitors was prohibited.
`
`Patients not using Actiq or Fentora prior to the study were titrated onto FSS according to
`the following algorithm:
`
`
`(cid:131)
`
`(cid:131) Start with the 100 mcg dose of FSS. Treat one episode of breakthrough pain.
`(cid:131)
`If this dose was effective and tolerated, the next episode of was treated with the
`same dose of FSS.
`If pain relief was inadequate after 30 minutes then the patient was to re-dose
`with one additional FSS dose.
`If the pain continued for 30 minutes following the re-dose, patients were
`instructed to take their usual analgesic medication as rescue medication.
`If a patient consistently required an additional 100 mcg of FSS at two
`subsequent breakthrough pain episodes, the patient proceeded to the next higher
`FSS dose strength, 200 mcg.
`
`(cid:131)
`
`(cid:131)
`
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`11
`
`Reference ID: 3066841
`
`Page 12 of 27
`
`

`
`This continued until a successful dose was identified or a maximum dose of 1600 mcg
`(two 800 mcg sprays) failed to work and the patient then exited the study. Patients
`previously using Actiq or Fentora were allowed to begin on doses of FSS greater than
`100 mcg based on their prior TIRF doses and then continued with titration according to
`the algorithm.
`
`Patients were titrated to a successful dose, defined as a dose of FSS that consistently
`treated two consecutive breakthrough pain episodes and that was tolerated, and were
`supplied with a 10-dose drug pack containing 10 separate unit doses, marked 1 to 10.
`Patients were instructed to self-administer each dose, starting at unit dose 1 and working
`through to unit dose 10, in order, for each of 10 individual episodes of target
`breakthrough cancer pain. Patients were instructed to wait at least four hours between
`treated breakthrough pain episodes, and to treat no more than two breakthrough pain
`episodes with study drug in a given day.
`
`One hundred and sixty-one patients were screened and 131 were enrolled in the study.
`One patient never received study drug. Of the 130 patients that entered titration, 32
`(25%) withdrew prior to entering the double-blind crossover phase of the study. Dr. Yip
`explored the reasons for discontinuation during titration and the most common reasons
`were adverse events and inability to titrate to a successful dose.
`
` total of 45 patients were identified as having protocol violations. One patient (Subject
`110003) was discontinued from the study during the titration period for a protocol
`violation. The patient was found to have lied about having cancer and, in fact, did not
`have cancer. The patient was not included in the double-blind period. Two patients
`(Subject 110-007 and 110-006) were noted as not meeting the inclusion criterion of
`“experience persistent pain related to the cancer or its treatment of moderate or lesser
`intensity in the 24 hours prior to assessment by a verbal rating scale at the Screening
`Visit” and waivers were not granted for their participation. The Applicant was asked
`why the patients were enrolled and included in the study and queried the investigator.
`The response was that both patients had persistent cancer pain that was rated as severe at
`screening, but generally had pain of moderate intensity and so were enrolled. Based on
`this explanation, including these patients appears acceptable. The remaining violations
`were reviewed and were not sufficient to warrant discontinuation from the study.
`
`Of the 98 patients who entered the double-blind period, three patients discontinued early,
`and 79 completed all 10 doses of blinded study drug. Patient disposition is presented in
`the following table from Dr. Zhou’s review.
`
`
` A
`
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`12
`
`Reference ID: 3066841
`
`Page 13 of 27
`
`

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`Table 1 Patient Disposition
`
`Source: Table 2 (p. 8) from Dr. Zhou’s review
`
`
`
`The demographic characteristics of the study population are presented in the following
`table from Dr. Zhou’s review. As a crossover design, there were no concerns about
`imbalance across treatment groups. The study patients were mostly white and less than
`65 years of age.
`
`Table 2
`
`Source: Table 3 (p. 8) from Dr. Zhou’s review
`
`
`
`The final dose after titration ranged from 100 mcg to 1600 mcg. The distribution of final
`titrated dose is presented in the following table.
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`13
`
`Reference ID: 3066841
`
`Page 14 of 27
`
`

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`
`Table 3 Final titrated dose.
`SUBSYS Dose
`
`100 mcg
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`1200 mcg
`1600 mcg
`
`Total No. (%)
`n=96
`4 (4%)
`7 (7%)
`14 (15%)
`15(16%)
`23 (24%)
`20 (21%)
`13 (14%)
`
`The primary efficacy analysis was the summed pain intensity difference over 30 minutes
`(SPID30), based on the mean of the SPID30 across each episode for each treatment, i.e.
`the seven active-treated episodes were averaged and the three placebo-treated episodes
`were averaged. As noted by Dr. Zhou, her analysis differed from the applicants in that
`she included all 96 patients in the ITT population, regardless of the number of episodes
`treated and whether they were compliant with treatment order. Using the full ITT
`population, excluding data subsequent to the use of rescue mediation, and using last
`observation carried forward to impute missing values, Dr. Zhou was able to replicate the
`applicant’s primary analysis and demonstrate that FSS was statistically superior in
`reducing pain intensity using the SPID30. The following table shows Dr. Zhou’s results
`from the primary efficacy analysis.
`
`Table 4
`
`Source: Table 5 (p. 10) from Dr. Zhou’s review
`
`Dr. Zhou conducted subgroup analyses for gender and age. She found no statistically
`significant interaction between gender and treatment, although there was an interaction
`between age and treatment, with a smaller effect size for older patients. Statistically
`significant differences in favor of FSS for the SPID30 analysis remained for both groups,
`patients under the age of 65 and patients 65 years of age and older. These results are
`shown in the following table.
`
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`Reference ID: 3066841
`
`
`
`14
`
`Page 15 of 27
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`

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`Table 5
`
`Source: Table 6 (p. 11) from Dr. Zhou’s review
`
`
`
`
`There were too few non-white patients (13%) for a meaningful subgroup analysis based
`on race.
`
`The secondary efficacy analyses included total pain relief at 30 minutes (TOTPAR30)
`and Patient Global Evaluation of Study Medication at 30 minutes. These analyses found
`statistically significant difference between active and placebo treatments in favor of the
`active drug. Additional analyses of SPID and TOTPAR at 5, 10, 15, 45 and 60 minutes
`were conducted by the applicant on an evaluable population of 92 patients. The applicant
`claimed these were statistically significantly different between treatments and favored
`active drug, however, these evaluations were not corrected for multiplicity and were not
`repeated with the full ITT population as they are not included in labeling.
`
`In addition, the use of rescue medication was examined by the applicant. Among the
`evaluable population, rescue medication was used by patients during 28% of episodes
`treated by placebo compared to 10% of episodes treated by active drug.
`
`Overall, Study INS-05-001 was successful in demonstrating the efficacy of FSS in
`reducing breakthrough pain in opioid-tolerant cancer patients.
`
`
`Of importance, Dr. Zhou's analysis of the primary endpoint also differed from the
`applicant's analysis in that it appropriately accounted for the correlation arising from
`the multiple measurements of each patient.
`
` I
`
` concur with the review team that the study has demonstrated that Subsys is effective
`for the proposed indicated use.
`
`
`
`8. Safety
`
`The following summary of the exposure data has been reproduced from pages 14
`through 15 of Dr. Hertz’s review:
`
`
`The applicant describes 490 subjects exposed to FSS and making up the safety database,
`however 107 patients from two PK studies were pretreated with naltrexone and so, would
`not have been able to contribute safety data other than local reactions. Study INS-09-011
`was a single dose study of FSS in cancer patients evaluating the effects of mucositis
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`15
`
`Reference ID: 3066841
`
`Page 16 of 27
`
`

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`Table 6
`
`
`
`Reference ID: 3066841
`
`enrolling 18 subjects. The primary safety database is based on studies INS-05-001
`(Study 001), the efficacy study, and INS-06-007 (Study 007), an open-label safety study
`lasting up to 90 days that rolled patients over from Study 001 and enrolled novel patients.
`There were 359 subjects who took a least one dose of FSS from these two studies that
`contributed to the safety database. The 359 patients represent 130 patients who
`underwent titration and 98 who entered the double-blind period of Study 001, 90 who
`rolled over from Study 001 to Study 007, and 179 novel patients who enrolled in Study
`007.
`
`The extent of exposure from Studies 001 and 007 is presented in the following table from
`the applicant:
`
`
`
`This database is sufficient in size to evaluate the safety of the FSS formulation, in
`conjunction with what is already known about the safety of fentanyl. Among these
`patients, nearly half were treated for at least three months or longer. The most common
`reason for discontinuing FSS throughout the studies was adverse event. As a cancer
`patient population on around-the-clock opioids, opioid-related adverse events are
`expected. The addition of FSS could be expected to exacerbate opioid-related adverse
`events. The population would also be expected to have adverse events related to their
`underlying cancers.
`
`
`The following summary of the data regarding deaths has been reproduced from pages
`15 through 18 of Dr. Hertz’s review:
`
`
`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`
`16
`
`Page 17 of 27
`
`

`
`
`
`
`
`Reference ID: 3066841
`
`There were 92 deaths during the clinical studies. The ISS reports 85 deaths, although the
`total based on the two studies, Study 005 and Study 007, adds up to 92. The applicant
`explained the different numbers based on the reporting periods. For the ISS, events
`during the study or within 30 days were reported. For the individual studies, all events,
`even those later than 30 days from the end of the study were reported, and seven of the
`deaths occurred later than 30 days after the last administration of study medication. One
`death was attributed as treatment-related according to the applicant. The dose of FSS and
`the number of patients who died and had SAEs and early withdrawal due to an AE is
`provided in the following table from the ISS. There were proportionately more deaths
`among patients taking the highest dose of FSS, but this may reflect worse underlying
`disease.
`
`Dr. Yip reviewed the narratives for patients who died during the clinical trials. During
`Study 001, there were three deaths. One patient with metastatic lung cancer started
`titration on FSS and was admitted to the hospital with evidence of advancing metastatic
`disease of the spine, one week after starting study drug. He died three weeks later
`without further exposure to study drug. The second patient had pancreatic cancer and
`died at least two weeks after his single exposure to study drug. The third patient had
`cervical cancer. She titrated to the 1600 mcg dose of study drug and entered the double-
`blind period. She was admitted to hospice care and died two weeks later and the last date
`of study drug dosing was not reported. The first two cases were clearly unrelated to
`study drug. Given that the third patient tolerated the drug during titration and entered the
`double-blind period, it is unlikely that her death during hospice care was related to study
`drug.
`
`Of the remaining 89 deaths during Study 007, Dr. Yip summarized his review as follows:
`
`
`The CRFs, data listings, and narratives were reviewed for each death. There
`were 77 patients who died of cancer progression and 12 who died of other
`reasons: sepsis (2), pulmonary embolism (2), cardiopulmonary arrest, cardiac
`failure, cardiac arrhythmia, aspiration pneumonia, intracranial hemorrhage,
`stroke, renal failure, and respiratory distress (aspiration). Of the 12 patients who
`died of other reasons, eight appeared to have died as a result of underlying
`malignancy, progression of disease, complications of the underlying disease,
`treatments, concomitant medications, or other events surrounding the AEs (i.e.,
`sepsis (2), pulmonary embolism (2), heart failure, intracranial hemorrhage,
`stroke, and rena