CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202788Orig1s000
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`
`SUMMARY REVIEW
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`Page 1 of 27
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`CFAD v. Insys
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`Subject
`NDA #
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`A licant Name
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`Date of Submission
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`PDUFA Goal Date
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`Proprietary Name /
`S -
`Established
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`Dosage Forms / Strength
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`Name
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`Proposed Indication
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`Reference ID: 3066841
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`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
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`DIVISION 01-‘ ANESTHESIA , ANALGESIA, AND ADDICTION PRODUCTS
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`Summary Review for Regulatory Action
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`Jan .
`4,2012
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`Bob A. Rappaport, M.D.
`Director
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`Division of Anesthesia, Analgesia, a11d Addiction
`Products
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`Division Director Summary Review
`202788
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`Ins s Theraeutics, Inc.
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`March 14, 2011
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`4, 2012
`Janua
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`Subsys
`Fentan lSublin lSra
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`Single-dose sublingual spray
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`100 me, 200mc, 400 me, 600 me, 800 Inc
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`Management of breakthrough pain in patients with
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`cancer, 18 years of age and older, who are already
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`receiving and who are tolerant to regular opioid therapy
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`for their underlyingpersistent cancerpain
`A o n roval
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`Page 2 of 27
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`OSE/DRISK
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`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.
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`OMP/OMPI/DMPP
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`OMP/OPDP/DDTCP
`Controlled Substances Staff
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`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
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`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
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`2
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`Reference ID: 3066841
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`Page 3 of 27
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`1. Introduction
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`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.
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`2. Background
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`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:
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`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.
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`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.
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`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
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`Page 4 of 27
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`reflects the need for patients to be opioid-tolerant, a physiological state in which patients
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`are more tolerant to the CNS depression and respiratory depression associated with
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`opioids.
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`it became clear that
`Based on the postmarketing history of the approved products,
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`prescribers have found the T[RFs to be useful in patients without cancer pain, both in the
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`setting of chronic pain with episodes of breakthrough pain and other painful conditions.
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`In the Actiq RiskMAP quarterly reports, the use of Actiq in noncancer pain has exceeded
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`its use in cancer pain, although it is used primarily in opioid-tolerant patients with
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`chronic noncancer pain.
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`Postmarketing trends have also shown an increasing number of nonopioid—tolerant
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`patients being prescribed TIRFS and reports of deaths in opioid noutolerant patients. The
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`TlRFs are not bioequivalent with one another, and in spite of warnings in the labeling,
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`have been inappropriately substituted in the pharmacy and by prescribers. As a result. the
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`Agency determined the risks associated with these products would be better addressed
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`through a REMS than the original risk management programs. Abstral, Onsolis and
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`Lazanda were approved with REMS. To reduce the burden to the healthcare community,
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`a TIRF class REMS has been developed. All five of the previously approved products
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`are being rolled into this class REMS including Actiq and Fentora which have yet to
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`stand up their own individual REMS. Subsys will be a part of this class REMS as well.
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`3. CMC
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`The following summary of the CMC, microbiology and device data and reviews has
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`been reproduced from pages 3 through 6 of Dr. Hertz’s review:
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`The following is lrom Dr. Pinto’s review:
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`The drug substance. fentanyl base, is a narcotic analgesic and a Schedule II
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`controlled substance
`that binds
`to opioid receptors. The Chemistry.
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`Manufacturing, and Control (CMC) information for Ftanyl base is provided in
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`‘hm’ The API is made by
`°"" at
`DMF
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`M W facility which is recommend as adequate by OC (report attached
`their
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`in the appendix). The API will be stored and shipped
`‘W’
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`and has a retest period 01
`mm The
`D
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`DMF has been reviewed and found to be adequate (P. Maturu, Rev #4 June 2009
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`and J. Pinto, Rev #5, Oct 2011).
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`The drug product is formulated as a sublingual, single-dose spray in concentrations of
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`1 mg/ml, 2 mg/ml, 4 mg/ml, 6 mg/ml and 3 mg/ml, with a total 511 per vial of W"
`The dose is
`M“) The formulation
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`consists of the active substance. in dehydrated alcohol. propylene glycol, water. xylitol
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`and menthol. The ptunp consists of an actuator. insert. spray pin, needle. stopper. glass
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`vial and via] holder.
`W’
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`Three packaging configurations are planned containing 6, 14, or 28 devices in a carton.
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`Each carton includes a disposal system to accommodate both used and unused devices.
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`NDA 202788
`
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`Subsys
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`
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`
`Division Director’s Review and Summary Basis for Approval
`
`
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`January 4, 2012
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`Reference ID: 3066841
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`Page 5 of 27
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`"ml and a
`The disposal system consists of a plastic container
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`sealable pouch. The
`lmmcontairier is used for the collection and disposal of fentanyl
`solution from unused FSS units; the pouch is designed for the disposal of used/discharged
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`FSS units. The DP is made by DPT at their Lakewood. NJ facility which was inspected
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`has be recommended as adequate.
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`9”" bottle. holding 28 units of the
`Dr. Pinto reviewed extraction studies of the
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`maximum strength drug product. The studies were "intended to evaluate the amount of
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`recoverable fentanyl. The results show that there is some recovery of fentanyl with
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`extraction using acetone. alcohols (dehydrated. isopropanol), ethyl acetate and 6N HCl.
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`The most fentanyl recovered was
`5’ m using dehydrated ethanol which is equivalent
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`to about 1.3%. Heat. shaking, and pH adjustments. did not result in any additional
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`fentanyl being extracted. This is dismissed fiuther in Section 11.
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`The used FSS spray devices are intended to be placed in an unlabeled scalable pouch that
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`is disposed in the trash. Unused devices are to be disposed of in the pouch after the
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`contents are sprayed into a
`M” disposal system. The system consists of a 100
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`cc plastic (HDPE) bottle
`M "l’
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`Each individual FSS unit will be enclosed in a child-resistant blister package. As
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`reviewed by Dr. Reissig of the Controlled Substances Staff, in a test of 50 children
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`(n=50), aged 42-51 months, the FSS package was found to be 98% child resistant.
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`The recommended storage temperature is 25° C (77° F) with exclusions permitted from
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`15° to 30°C (59°-86°F) and an expiry of 36 months is supported.
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`Dr. Pinto conchided that there were suflicient CMC data to assure the identity. strength,
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`purity, and quality of the drug product. provided in the NDA submission. The drug
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`substance manufacture and product attributes were referenced to DMF Mmwhich was
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`reviewed as Adequate (P. Maturu, June 2009 and J. Pinto. Rev #5. Oct 2011). The Office
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`of Compliance has issued an “Acceptable” overall recommendation for all facilities
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`involved in production of the product.
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`There were two outstanding deficiencies in the drug product stability protocol and
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`stability specifications identified by Dr. Pinto in her initial review. The applicant has
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`responded to information requests as noted below:
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`1. There are insufficient data to support the lack of testing for both weight loss
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`and ethanol content for batches made at the
`Mm (commercialization).
`(EH4)
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`the sponsor:
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`Therefore the following IR comments have been sent to
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`IR (4): There is insufficient commercial scale product history, to suppo11 the
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`lack of testing for both weight loss and ethanol assay during stability. Maintain
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`both the ethanol assay test and the weight loss test during routine stability
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`testing. Further propose a release and stability specification for weight loss.
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`NDA 202788
`
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`Subsys
`
`
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`
`
`Division Director’s Review and Summary Basis for Approval
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`January 4, 2012
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`Reference ID: 3066841
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`Page 6 of 27
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`Response: The applicant agreed to continue to test both weight loss and ethanol assay
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`during stability and provided updated specifications and a stability study protocol. Dr.
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`Pinto found this response to be adequate.
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`IR(5): There is insuflicient commercial scale product history. to support the
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`M“) proposed for stability testing. The first three production scale
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`be included in the stability study.
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`Response: The applicant has committed to testing the first three production scale batches
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`and a yearly production batch of the 4mg/ml intermediate strength in the stability study.
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`The annual stability batches will include the lmg/ml, 4mg/ml and 8mg/ml batches. Dr.
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`Pinto found this response to be adequate.
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`1R(6):
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`MM)
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`Update the release and stability specifications to include testing for pH with data
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`driven acceptance criterion.
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`Response: The applicant has added the pH testing parameter to the release and stability
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`specifications. A pH range was not proposed as a specification. but will be added once
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`suflicient data is collected on the full scale batches. Dr. Pinto found this response to be
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`adequate.
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`In addition. she also notes the following deficiencies:
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`in
`IR (3): The specification proposed for Spray Actuation Content is not
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`accordance with the FDA guidance for Nasal Sprays. Tighten the proposed
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`specification to be in agreement with the FDA guidance (e.g., individual sprays
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`to within d:l5 percent of the target weight and their mean weight to within i:l0
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`percent of the target weight).
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`Response: The applicant has requested to retain the currently proposed specification until
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`data from the full scale batches become available. At that time. they commit to providing
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`an update on the specification in the annual report. The current specification is M”
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`mm and the
`Dr. Pinto found this response adequate
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`sponsor does not have sufficient data, this parameter can be evaluated once there is
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`sufficient data.
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`mm must
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`The microbiology review by Dr. Riley notes that this product
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`meet microbial
`limits acceptance criteria at release. The initial acceptance criteria
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`submitted by the applicant were
`M” the acceptance criteria for a liquid oral
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`product suggested by USP. but the administered dose is small enough that the mm’
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`acceptance criteria are not of concern and are acceptable. Similarly, while aqueous drug
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`products should have controls in place to ensure the absence of Burkholderia cepacia,
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`since this product is
`“’m” there is no concern for B. cepacia.
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`A consultative review was conducted by LCDR Alan Stevens of CDRH. LCDR Stevens
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`reviewed the device constituent for this Combination Product and provided an assessment
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`of the Failure Modes and Eflects Analysis. He found the following deficiencies:
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`NDA 202788
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`Subsys
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`Division Director’s Review and Summary Basis for Approval
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`January 4, 2012
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`Reference ID: 3066841
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`Page 7 of 27
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`1. You have provided a design failure modes and effects analysis. For each
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`component,
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`you have identified potential failure modes and associated causes. You claim to
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`have
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`idtified design controls for each failure mode and. based on the analysis.
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`conclude that no further mitigations are required. However, no design controls
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`are identified. Instead, the dFMEA has identified manufacturing controls. Please
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`modify the dFMEA to identify design controls and provide evidence that
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`implemtation of the design controls are effective.
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`Dr. Ryan reviewed the response from the applicant and found the dFMEA submitted was
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`comprehensive and that all of the risk priority numbers fell within an acceptable range.
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`The most common failures resulted in under dosing or no doses. The failures have a
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`severity rating of three or less which Dr. Ryan notes is acceptable. She concludes the
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`device issue is adequately resolved.
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`I concur with the review team that there are no outstanding product quality concerns
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`that would preclude approval of this application.
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`4. Nonclinical PharmacologyIToxico|ogy
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`The following summary of the nonclinical pharmacology and toxicology data and
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`review has been reproduced from page 6 of Dr. Hertz’s review:
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`The following is from Dr. Bolan’s review.
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`The pharmacology and toxicology of fentanyl have been well characterized. No
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`nonclinical toxicology studies were deemed necessary to characterize the safety
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`of fentanyl for this product unless abnormalities arose during monitoring of
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`pulmonary frmction in the clinical studies. No abnormalities in pulmonary
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`function were noted in the clinical studies therefore, no nonclinical studies with
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`fentanyl were conducted.
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`The excipients used in the FSS formulation are all found at higher levels in
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`drugs previously approved by FDA and do not pose any toxicologic concerns.
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`Extractable and leachable assessments were conducted with the
`M“)
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`FSS container closure system. Drug Master File mm for the
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`M") is referenced by the Applicant. The
`M“) are
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`used in over 150 approved drugs. many with similar aqueous formulations to
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`FSS. The Agency’s previous finding of safety for the M” material will be
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`relied on in order to support its safety.
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`The impurities/degradants in the drug substance and drug product are controlled
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`at acceptable levels. A structural alert for mutagenicity was identified in the
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`drug product degradant
`Mm The Applicant conducted an
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`Ames Assay which showed a negative result for mutagenicity, therefore mm
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`can be regulated as a typical non-genotoxic impurity according to ICH
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`Q3B(R2). The drug product specification set for “ml in this NDA is acceptable.
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`There are no unique nonclinical issues associated with this product compared to
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`the referenced fentanyl product. There are no outstanding concerns with this
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`NDA 202788
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`Subsys
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`Division Director’s Review and Summary Basis for Approval
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`January 4, 2012
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`Reference ID: 3066841
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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.
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`I concur with the review team that there are no outstanding nonclinical pharmacology
`or toxicology concerns that would preclude approval of this application.
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`5. Clinical Pharmacology/Biopharmaceutics
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`The following summary of the clinical pharmacology data and review has been
`reproduced from pages 6 through 9 of Dr. Hertz’s review:
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`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.
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`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.
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`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.
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`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.
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`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
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`8
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`Reference ID: 3066841
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`Page 9 of 27
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`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
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`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.
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`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.
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`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.
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`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.
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`NDA 202788
`Subsys
`Division Director’s Review and Summary Basis for Approval
`January 4, 2012
`
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`9
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`Reference ID: 3066841
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`Page 10 of 27
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`Figure 2. Fentanyl plasma concentration-time profiles in subjects without mucositis (left panel)
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`and subjects with mucositis Grade 1 or 2 (right panel) from Study INS-09-011
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`-up---n-can-nu-—
`M-ynuu--tuunnnnn
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`KBQBCSEGBSESCESC
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`O0.
`II
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`F9-I— O-OOII
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`O-O-<0
`*0-O n 0-9-01:
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`u r¢4Ii
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`g...
`coo.
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`O C O G
`O O E
`O C i O O O |fl
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`Dr. Qiu recommended avoiding the use of fentanyl sublingual spray in patients with
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`Grade 2 and worse mucositis and dose reduction should be done for the patients with
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`Grade 1 mucositis.
`I agree with Dr. Qiu that there is no clinically impomnt effect of
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`temperature or pH. Based on the information submitted with the original NDA, I also
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`concurred that FSS should not be used by patients with Grade 2 mucositis or higher and
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`that there should be a contraindication for this population. As the starting dose of FSS is
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`100 mcg, the lowest dose, there is no way to reduce the starting dose for patients with
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`Grade 1 mucositis. However, as patients using FSS are meant to be opioid-tolerant.
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`increased monitoring for respiratory and central nervous system depression when
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`initiating dosing is sufficient to ensure patient safety.
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`4!!) (4)
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`the applicant sought additional information about
`the patient with the 17-fold increase in AUC. According to additional information
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`obtained after the investigator contacted the patient’s family member, the patient brought
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`Actiq to the study site and surreptitiously used the Actiq during the study. An
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`amendment to the NDA was submitted December 20. 2011 documenting this. It is hard
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`to understand exactly how a subject could use an Actiq dose without detection during a
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`clinical pharmacology study, but the sustained fentanyl level over 12 hours does seem
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`more compatible with additional dosing of a fentanyl product as an explanation. The
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`mean oral bioavailability of FSS is approximately 70%. If mucositis resulted in a 100%
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`exposure to the fentanyl. it would not result in a 17-fold increase in AUC. However, the
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`fentanyl level was 0 at baseline and without more information. it is not possible to know
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`whether the Cmax was influenced by the use of Actiq or not, and the Cmax was
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`approximately 3-fold higher than the highest Cmax in the non-mucositis patients in the
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`study. Given that the intended population is opioid—tolerant, and gven that the patient
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`with Grade 2 mucositis in question tolerated the high levels of fentanyl without
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`respiratory depression,
`it seems reasonable not to contraindicate the use of FSS in
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`patients with Grade 2 mucositis.
`In place of the recommendation will be a
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`recommendation to avoid use of FSS in patients with Grade 2 mucositis or higher unless
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`the benefit is expected to outweigh the possible risk of respiratory depression.
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`NDA 202788
`
`
`Subsys
`
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`
`Division Director’s Review and Summary Basis for Approval
`
`
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`January 4. 2012
`
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`
`SEKISIIEIIECSGSGEGBSB
`
`
`Reference ID: 3066841
`
`
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`Page 11 of 27
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`

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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