CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`SUMMARY REVIEW
`
`
`
`
`
`

`

`D FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTI-IESIA , ANALGESIA, AND ADDICTION PRODUCTS
`
`
`Summary Review for Regulatory Action
`
`4, 2012
`_ Janu
`Bob A. Rappaport, MD.
`Director
`
`Division of Anesthesia, Analgesia, and Addiction
`Products
`
`Subject
`Division Director Summary Review
`NBA #
`202788
`
`
`
`Date of Submission
`PDUFA Goal Date
`
`March 14, 2011
`Jan .
`4, 2012
`
`Proprietary Name /
`Established S Name
`
`Subsys
`Fentan lSublin lSra
`
`Dosage Forms I Strength
`
`Proposed Indication
`
`Single-dose sublingual spray
`100 mec, 200 me, 400 mc, 600 Inc
`
`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 lmderlyingpersistent cancer pain
`A - roval
`
`Reference ID: 3066841
`
`

`

`
`
`
`
`
`
`
`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.
`
`OSE/DRISK
`
`
`
`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
`
`

`

`
`
`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
`
`

`

`reflects the need for patients to be opioid-tolerant, a physiological state in which patients
`are more tolerant to the CNS depression and respiratory depression associated with
`opioids.
`
`it became clear that
`Based on the postmarketing history of the approved products,
`prescribers have found the TIRFs to be useful in patients without cancer pain, both in the
`setting of chronic pain with episodes of breakthrough pain and other painful conditions.
`In the Actiq RiskMAP quarterly reports, the use of Actiq in noncancer pain has exceeded
`its use in cancer pain, although it is used primarily in opioid-tolerant patients with
`chronic noncancer pain.
`
`Postmarketing trends have also shown an increasing number of nonopioid-tolerant
`patients being prescribed TIRFs and reports of deaths in opioid nontolerant patients. The
`TIsz are not bioequivalent with one another, and in spite of warnings in the labeling,
`have been inappropriately substituted in the pharmacy and by prescribers. As a result, the
`Agency determined the risks associated with these products would be better addressed
`through a REMS than the original risk management programs. Absu'al, Onsolis and
`Lazanda were approved with REMS. To reduce the burden to the healthcare community,
`a TIRF class REMS has been developed. All five of the previously approved products
`are being rolled into this class REMS including Actiq and Fentora which have yet to
`stand up their own individual REMS. Subsys will be a part of this class REMS as well.
`
`3. CMC
`
`The following summary of the CMC, microbiology and device data and reviews has
`been reproduced from pages 3 through 6 of Dr. Hertz’s review:
`
`The following is from Dr. Pinto’s review:
`
`The (hug substance, fentanyl base, is a narcotic analgesic and a Schedule II
`controlled substance
`that binds
`to opioid receptors. The Chemistry,
`Manufacturing, and Control (CMC) information for Fentanyl base is provided in
`DMF
`m“) The API is made by
`M“) at
`theii
`(W4) facility which is recommend as adequate by CC (report attached
`in the appendix). The API will be stored and shipped
`W"
`and has a retest period 01
`(b) (4) The
`DMF has been reviewed and found to be adequate (P. Maturu, Rev #4 June 2009
`and J. Pinto, Rev #5, Oct 2011).
`
`The drug product is formulated as a sublingual, single-dose spray in concentrations of
`1 mg/ml, 2 mg/ml, 4 mg/ml, 6 mg/ml and 8 mg/ml, with a total fill per vial of W"
`The dose is
`m“) The formulation
`consists of the active substance, in dehydrated alcohol, propylene glycol, water, xylitol
`and menthol. The pump consists of an actuator. insert. spray pin, needle, stopper. glass
`vial and vial holder.
`1") (4)
`
`Three packaging configurations are planned containing 6, 14, or 28 devices in a carton.
`Each carton includes a disposal system to accommodate both used and unused devices.
`
`NDA 202788
`
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`Reference ID: 3066841
`
`

`

`“(4) and a
`The disposal system consists of a plastic container
`scalable pouch. The
`(D) (4) container is used for the collection and disposal of fentanyl
`solution from unused FSS units; the pouch is designed for the disposal of used/discharged
`FSS units. The DP is made by DPT at their Lakewood, NJ facility which was inspected
`has been recommended as adequate.
`
`”(4) bottle, holding 28 units of the
`Dr. Pinto reviewed extraction studies of the
`maximum strength drug product. The studies were intended to evaluate the amount of
`recoverable fentanyl. The results show that there is some recovery of fentanyl with
`extraction using acetone, alcohols (dehydrated, isopropanol), ethyl acetate and 6N HCl.
`The most fentanyl recovered was
`M (4) using dehydrated ethanol which is equivalent
`to about 1.3%. Heat, shaking, and pH adjustments, did not result in any additional
`fentanyl being extracted. This is discussed further in Section 11.
`
`The used FSS spray devices are intended to be placed in an unlabeled scalable pouch that
`is disposed in the trash. Unused devices are to be disposed of in the pouch after the
`contents are sprayed into a
`(b) (4’ disposal system. The system consists of a 100
`cc plastic (HDPE) bottle
`0N4”
`
`Each individual FSS unit will be enclosed in a child-resistant blister package. As
`reviewed by Dr. Reissig of the Controlled Substances Staff, in a test of 50 children
`(n=50), aged 42-51 months, the FSS package was found to be 98% child resistant.
`
`The recommended storage temperature is 25° C (77° F) with excursions permitted from
`15° to 30°C (59°-86°F) and an expiry of 36 months is supported.
`
`Dr. Pinto concluded that there were sufficient CMC data to assure the identity, strength.
`purity. and quality of the drug product, provided in the NDA submission. The drug
`substance manufacture and product attributes were referenced to DMF (b) mwhich was
`reviewed as Adequate (P. Maturu, June 2009 and J. Pinto, Rev #5, Oct 201 1). The Office
`of Compliance has issued an “Acceptable” overall recommendation for all facilities
`involved in production of the product.
`
`There were two outstanding deficiencies in the drug product stability protocol and
`stability specifications identified by Dr. Pinto in her initial review. The applicant has
`responded to information requests as noted below:
`
`1. There are insufficient data to support the lack of testing for both weight loss
`and ethanol content for batches made at the
`(m4) (commercialization).
`00(4)
`
`the sponsor:
`
`Therefore the following IR comments have been sent to
`
`IR (4): There is insufficient commercial scale product history, to support the
`lack of testing for both weight loss and ethanol assay during stability. Maintain
`both the ethanol assay test and the weight loss test during routine stability
`testing. Further propose a release and stability specification for weight loss.
`
`NDA 202788
`
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`Reference ID: 3066841
`
`

`

`Response: The applicant agreed to continue to test both weight loss and ethanol assay
`during stability and provided updated specifications and a stability study protocol. Dr.
`Pinto found this response to be adequate.
`
`IR(5): There is insufficient commercial scale product history, to support the
`”(4’ proposed for stability testing. The first three production scale
`batches and a yearly production batch of the 4mg/ml intermediate strength is to
`be included in the stability study.
`
`Response: The applicant has committed to testing the first three production scale batches
`and a yearly production batch of the 4mg/ml intermediate strength in the stability study.
`The annual stability batches will include the lmg/ml, 4mg/ml and 8mg/ml batches. Dr.
`Pinto found this response to be adequate.
`
`IR(6)Z
`
`(D) (4)
`
`Update the release and stability specifications to include testing for pH with data
`driven acceptance criterion.
`
`Response: The applicant has added the pH testing parameter to the release and stability
`specifications. A pH range was not proposed as a specification, but will be added once
`suflicient data is collected on the full scale batches. Dr. Pinto found this response to be
`adequate.
`
`In addition, she also notes the following deficiencies:
`
`IR (3): The specification proposed for Spray Actuation Content is not in
`accordance with the FDA guidance for Nasal Sprays. Tighten the proposed
`specification to be in agreement with the FDA guidance (e.g., individual sprays
`to within $15 percent of the target weight and their mean weight to within 110
`percent of the target weight).
`
`Response: The applicant has requested to retain the currently proposed specification until
`data from the full scale batches become available. At that time, they commit to providing
`an update on the specification in the annual report. The current specification is
`“(4)
`
`“M" and the
`Dr. Pinto found this response adequate
`sponsor does not have sufficient data, this parameter can be evaluated once there is
`sufficient data.
`
`M“) must
`The microbiology review by Dr. Riley notes that this product
`meet microbial limits acceptance criteria at release. The initial acceptance criteria
`submitted by the applicant were
`M“) the acceptance criteria for a liquid oral
`product suggested by USP, but the administered dose is small enough that the
`00(4)
`acceptance criteria are not of concern and are acceptable. Similarly. while aqueous drug
`products should have controls in place to ensure the absence of Burkholderia cepacia.
`since this product is
`M (4)) there is no concern for B. cepacia.
`
`A consultative review was conducted by LCDR Alan Stevens of CDRH. LCDR Stevens
`reviewed the device constituent for this Combination Product and provided an assessment
`of the Failure Modes and Effects Analysis. He formd the following deficiencies:
`
`NDA 202788
`
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`Reference ID: 3066841
`
`

`

`1. You have provided a design failure modes and effects analysis. For each
`component,
`you have identified potential failure modes and associated causes. You claim to
`have
`
`identified design controls for each failure mode and, based on the analysis,
`conclude that no further mitigations are required. However, no design controls
`are identified. Instead. the dFMEA has identified manufacturing controls. Please
`modify the dFMEA to identify design controls and provide evidence that
`implementation of the design controls are effective.
`
`Dr. Ryan reviewed the response from the applicant and found the dFMEA submitted was
`comprehensive and that all of the risk priority numbers fell within an acceptable range.
`The most common failures resulted in under dosing or no doses. The failures have a
`severity rating of three or less which Dr. Ryan notes is acceptable. She concludes the
`device issue is adequately resolved.
`
`I concur with the review team that there are no outstanding product quality concerns
`that would preclude approval of this application.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The following summary of the nonclinical pharmacology and toxicology data and
`review has been reproduced from page 6 of Dr. Hertz’s review:
`
`The following is from Dr. Bolan‘s review.
`The pharmacology and toxicology of fentanyl have been well characterized. No
`nonclinical toxicology studies were deemed necessary to characterize the safety
`of fentanyl for this product unless abnormalities arose during monitoring of
`pulmonary function in the clinical studies. No abnormalities in pulmonary
`function were noted in the clinical studies therefore, no nonclinical studies with
`fentanyl were conducted.
`
`The excipients used in the FSS formulation are all found at higher levels in
`drugs previously approved by FDA and do not pose any toxicologic concerns.
`Extractable and leachable assessments were conducted with the
`M“)
`FSS container closure system. Drug Master File th4) for the
`M“) is referenced by the Applicant. The
`(b) (4) are
`used in over 150 approved drugs. many with similar aqueous formulations to
`FSS. The Agency’s previous finding of safety for the M“) material will be
`relied on in order to support its safety.
`
`The impurities/degradants in the drug substance and drug product are controlled
`at acceptable levels. A structural alert for mutagenicity was identified in the
`drug product degradant
`M0) The Applicant conducted an
`Ames Assay which showed a negative result for mutagenicity, therefore (DNA)
`can be regulated as a typical non—genotoxic impurity according to ICH
`Q3B(R2). The drug product specification set for M“) in this NDA is acceptable.
`
`There are no unique nonclinical issues associated with this product compared to
`the referenced fentanyl product. There are no outstanding concerns with this
`NDA 202788
`
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`Reference ID: 3066841
`
`

`

`
`
`
`
`
`
`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
`
`

`

`
`
`
`
`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
`
`

`

`Figure 2. Fentanyl plasma concentration-time profiles in subjects without mucositis (left panel)
`and subjects with mucositis Grade 1 or 2 (right panel) from Study INS—09-011
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`
`Dr. Qiu recommended avoiding the use of fentanyl sublingual spray in patients with
`Grade 2 and worse mucositis and dose reduction should be done for the patients with
`Grade 1 mucositis.
`I agree with Dr. Qiu that there is no clinically important effect of
`temperature or pH. Based on the information submitted with the original NDA, I also
`concurred that FSS should not be used by patients with Grade 2 mucositis or higher and
`that there should be a contraindication for this population. As the starting dose of FSS is
`100 mcg, the lowest dose, there is no way to reduce the starting dose for patients with
`Grade 1 mucositis. However, as patients using FSS are meant to be opioid—tolerant,
`increased monitoring for respiratory and central nervous system depression when
`initiating dosing is suflicient to ensure patient safety.
`
`0’) (4)
`
`the applicant sought additional information about
`the patient with the 17-fold increase in AUC. According to additional information
`obtained after the investigator contacted the patient’s family member, the patient brought
`Actiq to the study site and surreptitiously used the Actiq during the study. An
`amendment to the NDA was submitted December 20, 2011 documenting this. It is hard
`to understand exactly how a subject could use an Actiq dose without detection during a
`clinical pharmacology study, but the sustained fentanyl level over 12 hours does seem
`more compatible with additional dosing of a fentanyl product as an explanation. The
`mean oral bioavailability of FSS is approximately 70%. If mucositis resulted in a 100%
`exposure to the fentanyl, it would not result in a 17-fold increase in AUC. However, the
`fentanyl level was 0 at baseline and without more information, it is not possible to know
`whether the Cmax was influenced by the use of Actiq or not, and the Cmax was
`approximately 3-fold higher than the highest Cmax in the non-mucositis patients in the
`study. Given that the intended population is opioid-tolerant, and given that the patient
`with Grade 2 mucositis in question tolerated the high levels of fentanyl without
`respiratory depression, it seems reasonable not to contraindicate the use of FSS in
`patients with Grade 2 mucositis.
`In place of the recommendation will be a
`recommendation to avoid use of FSS in patients with Grade 2 mucositis or higher unless
`the benefit is expected to outweigh the possible risk of respiratory depression.
`
`NDA 202788
`
`10
`
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
`Reference ID: 3066841
`
`

`

`
`
`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
`
`

`

`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
`
`

`

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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