CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`NDA 202788
`
`SubsysTM (Fentanyl)
`
`Sublingual Spray
`
`Insys Therapuetics, Inc
`
`Julia C. Pinto, Ph.D.
`
`Office of New Drug Quality Assessment, Division III
`
`Division of Anesthesia, Analgesia and Addiction Products
`
`Reference ID: 3064639
`
`

`

`
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 2
`
`Chemistry Review Data Sheet ........................................................................................................3
`
`The Executive Summary ................................................................................................................. 7
`
`I. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ............................................................
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable........................................................................................
`
`II. Summary of Chemistry Assessments......................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................... 8
`
`B. Description of How the Drug Product is Intended to be Used ............................................ 8
`
`C. Basis for Approvability or Not-Approval Recommendation .............................................. 8
`
`III. Administrative........................................................................................................................... 8
`
`A. Reviewer’s Signature .......................................................................................................... 8
`
`B. Endorsement Block ............................................................................................................. 8
`
`C. CC Block ............................................................................................................................. 8
`
`Chemistry Assessment .................................................................................................................... 9
`
`I. Review Of Cormnon Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data .........9
`
`S DRUG SUBSTANCE [Subsys (Fentanyl) Sublingual Spray, Insys] .................... 9
`
`P DRUG PRODUCT [Subsys (Fentanyl) Sublingual Spray, Insys] ...................... 14
`A APPENDICES .............................................................................. 57
`
`R REGIONAL INFORMATION ............................................................ 58
`
`II.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`A. Labeling & Package Insert ............................................................................................... 58
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion...................................... 62
`
`111.
`
`List Of Deficiencies/Comments Communicated .............................................................. 62
`
`Reference ID: 3064639
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Sheet
`
`1. NDA 202788
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: Dec 28, 2011
`
`4. REVIEWER:
`
`Julia C. Pinto, Ph.D.
`
`5. PREVIOUS DOCUIVIENTS:
`
`Previous Documents
`
`Original
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`
`Amendement
`Amendement
`
`6. SUBMISSIONS BEING REVIEWED:
`
`Submission! s! Reviewed
`Original
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`
`Amendement
`Amendement
`Amendement
`Amendment
`
`7. NAME AND ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Insys Therapuetics, Inc
`10220 South 51St Street
`Suite 2
`
`Phoenix, AZ 85044
`
`Document Date
`
`March 4, 2011
`April 5, 2011
`April 15, 2011
`April 29, 2011
`May 18, 2011
`May 20, 2011
`May 27, 2011
`June 3, 2011
`June 29, 2011
`
`July 7, 2011
`July 11, 2011
`
`Document Date
`March 4, 2011
`April 5, 2011
`April 15, 2011
`April 29, 2011
`May 18, 2011
`May 20, 2011
`May 27, 2011
`June 3, 2011
`
`June 29, 2011
`July 7, 2011
`July 11, 2011
`Dec. 21, 2011
`
`Reference ID: 3064639
`
`Page 3 of 19
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. Product Drug Code and Name:
`a) Proprietary Name: None
`b) Non-Proprietary Name (USAN): Fentanyl
`c) Code name/#(ONDQA only):
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: Type 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: FD&C ACT 505(b)(2)
`
`10. PHARMACOLOGICAL CATEGORY:
`
`Treatment of break through pain in patients with malignancies who are already receiving and
`who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.
`
`11. DOSAGE FORM: Sublingual Spray
`
`12. STRENGTH/POTENCY: 100, 200, 400, 600 and 800mcg in W" of solution
`
`13. ROUTE OF ADMINSITRATION: Sublingual
`
`14. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM:
`SPOTS product — Form Completed
`
` x
`
`Not a SPOTS product
`
`16. CHEMICAL NAlVIE, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`INN Name: Fentanyl
`USAN name: Fentanyl [p
`IUPAC name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] propanamide
`
`Molecular formula: C22H23N20
`
`Relative molecular weight 336.47 (base):
`
`CH3 CH2 CONCN—CHZ CH2<©
`
`Reference ID: 3064639
`
`Page 4 of 19
`
`

`

`‘ .A.R
`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`‘ -«fln
`
`t m ‘
`
`l7. RELATED/SUPPORTED DOCUMENTS:
`
`A. DMFs:
`
`£58Eaéaéga
`
`8
`
`O
`223.§
`
`IIIIIIIIIEIIIIEIH‘EH Illlllltll
`
`‘ Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 —Reviewedprevim151yandnorevision sincelastreview
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain Imder "Comments")
`
`2Adequate, Inadequate, orN/A (There is «rough data in the application, therefore the DMF did not need to
`be reviewed)
`
`Reference ID: 3064639
`
`Page 5 of 19
`
`

`

`
`
`Chemistry Review Data Sheet
`
`B. Other Documents:
`
`mm
`
`APPLICATION
`
`mm
`
`
`
`m 7241]
`
`Fentanyl Sublingual Spray
`
`18. Status
`
`ONDQA:
`CONSULTS/ CMC
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`Ma 2011
`
`B anRile ,PhD.
`
`satisfacto
`
`PhamvTox
`
`E- Bola“, Ph-D-
`
`_———
`_———
`Methods Validation ———
`WWW ——
`Categorical exclusion March 4, 2011
`
`J. Pinto
`
`Reference ID: 3064639
`
`Page 6 of 19
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202788
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`Sufficient CMC information, to assure the identity, strength, purity, and quality of the drug
`product, is provided in this NDA submission. The drug substance manufacture and product
`attributes are referenced to DMF (m4) and has been reviewed as Adequate (P. Maturu, Rev #4
`June 2009 and J. Pinto, Rev #5, Oct 2011). The Office of Compliance has issued an
`“Acceptable” overall recommendation for all facilities involved in production of the product. All
`DMFs are adequate. All outstanding deficiencies in the drug product stability protocol and
`stability specifications have been adequately addressed. From a quality perspective, this NDA is
`recommended for approval
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable-
`No Post Approval commitments are required.
`
`II. Summary of Chemistry Assessment
`
`A. Description of Drug Substance and Drug Product:
`
`The drug 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 (hm) (held by
`(bmr The API is made by
`M“) at their
`(m4) facility, mmwhich is recommend as adequate by CC (report
`attached in the appendix). The API will be stored and shipped
`mm
`and has a retest period of
`mar 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 fentanyl formulated in a sublingual, single dose, spray in concentrations of
`lmg/ml, 2mg/ml, 4mg/ml, 6mg/ml and 8mg/ml. The total fill per vial is
`“M". The solution
`components consist of the active substance, in dehydrated alcohol, propylene glycol, water,
`xylitol and menthol. The solution is intended for sublingual administration for mucosal
`absorption. The spray is a single-dose vial, stored in a carton that contains a disposal bottle
`(m4) and disposal bags, for the used vials,
`m“) bottles containing unused
`doses. The DP is made by M") at their
`“(4) facility which as been recommended as
`adequate by CC (CC report attached in the appendix. The clinical batches were made on a iii
`-
`4
`-
`scale. The proposed commercral scale 13
`(m )
`
`.
`.
`The manufacturing process rs
`
`4
`(m )
`
`Reference ID: 3064639
`
`Page 7 of 19
`
`

`

`
`
`Executive Summary Section
`
`The pump consists of an actuator, insert, spray pin, needle, stopper, glass vial and vial holder and
`assembled by
`(m4)
`(m4)
`. The
`ram) bottle to be used for disposal of any
`
`filled spray device is co-packaged with a
`unused vials.
`
`M“) bottle, holding 28 units of the maximum strength drug
`Extraction studies of the
`product were conducted 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“) pg using
`dehydrated ethanol which is equivalent to about 1.3%. Heat, shaking, and pH adjustments, did
`not afford any additional fentanyl to be extracted.
`
`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.
`
`B. Description of How the drug is intended to be used:
`
`SubsysTM (name under review by DMEPA) is an opioid analgesic indicated only for the
`management of breakthrough cancer pain in patients who are already receiving and who are
`tolerant to regular opioid therapy. Each dose is administered as a single spray under the tongue.
`Each spray delivers
`mm of solution containing either 100 mcg, 200 mcg, 400 mcg, 600 mcg
`or 800 meg of fentanyl base. There is no recoverable residual in the vial, afier dose delivery. Off
`the
`(m4) fill volume,
`(m4) is delivered and the remaining (m4) is retained by the pump
`assembly parts. Since this is a controlled substance, the applicant provides a
`mu) bottle
`into which excess drug is to be sprayed and disposed of in the trash.
`
`C. Basis for Approvability Recommendation
`
`Sufficient CMC information, to assure the identity, strength, purity, and quality of the drug
`product, is provided in this NDA submission.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemistry Reviewer: Julia Pinto, Ph.D.
`Pharmaceutical Assessment Leader: Danae Christodoulou, Ph.D.
`
`Project Manager: Kathleen Davies
`Branch Chief: Prasad Peri, Ph.D.
`
`11 Page(s) has been Withheld in Full as B4 (CCIITS) immediately following this
`
`Reference ID: 3064639
`
`Page 8 of 19
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JULIA C PINTO
`12/28/2011
`
`PRASAD PERI
`12/28/2011
`I concur
`
`Reference ID: 3064639
`
`

`

`
`
`NDA 202788
`
`SubsysTM (Fentanyl)
`
`Sublingual Spray
`
`Insys Therapuetics, Inc
`
`Julia C. Pinto, Ph.D.
`
`Office of New Drug Quality Assessment, Division III
`
`Division of Anesthesia, Analgesia and Addiction Products
`
`Reference ID: 3047930
`
`

`

`
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 2
`
`Chemistry Review Data Sheet ........................................................................................................3
`
`The Executive Summary ................................................................................................................. 7
`
`I. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ............................................................
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable........................................................................................
`
`II. Summary of Chemistry Assessments......................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................... 8
`
`B. Description of How the Drug Product is Intended to be Used ............................................ 8
`
`C. Basis for Approvability or Not-Approval Recommendation .............................................. 8
`
`III. Administrative........................................................................................................................... 8
`
`A. Reviewer’s Signature .......................................................................................................... 8
`
`B. Endorsement Block ............................................................................................................. 8
`
`C. CC Block ............................................................................................................................. 8
`
`Chemistry Assessment .................................................................................................................... 9
`
`I. Review Of Cormnon Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data .........9
`
`S DRUG SUBSTANCE [Subsys (Fentanyl) Sublingual Spray, Insys] .................... 9
`
`P DRUG PRODUCT [Subsys (Fentanyl) Sublingual Spray, Insys] ...................... 14
`A APPENDICES .............................................................................. 57
`
`R REGIONAL INFORMATION ............................................................ 58
`
`II.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`A. Labeling & Package Insert ............................................................................................... 58
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion...................................... 62
`
`111.
`
`List Of Deficiencies/Comments Communicated .............................................................. 62
`
`Reference ID: 3047930
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Sheet
`
`1. NDA 202788
`
`2. REVIEW #: l
`
`3. REVIEW DATE: Nov 16, 2011
`
`4. REVIEWER:
`
`Julia C. Pinto, Ph.D.
`
`5. PREVIOUS DOCUIVIENTS:
`
`Previous Documents
`
`Original
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`
`Amendement
`Amendement
`
`6. SUBMISSIONS BEING REVIEWED:
`
`Submission! s! Reviewed
`Original
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`Amendement
`
`Amendement
`Amendement
`Amendement
`
`7. NANIE AND ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Insys Therapuetics, Inc
`10220 South 51St Street
`Suite 2
`
`Phoenix, AZ 85044
`
`Document Date
`
`March 4, 2011
`April 5, 2011
`April 15, 2011
`April 29, 2011
`May 18, 2011
`May 20, 2011
`May 27, 2011
`June 3, 2011
`June 29, 2011
`
`July 7, 2011
`July 11, 2011
`
`Document Date
`March 4, 2011
`April 5, 2011
`April 15, 2011
`April 29, 2011
`May 18, 2011
`May 20, 2011
`May 27, 2011
`June 3, 2011
`
`June 29, 2011
`July 7, 2011
`July 11, 2011
`
`Reference ID: 3047930
`
`Page 3 of 64
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. Product Drug Code and Name:
`a) Proprietary Name: None
`b) Non-Proprietary Name (USAN): Fentanyl
`c) Code name/#(ONDQA only):
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: Type 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: FD&C ACT 505(b)(2)
`
`10. PHARMACOLOGICAL CATEGORY:
`
`Treatment of break through pain in patients with malignancies who are already receiving and
`who are tolerant to around—the-clock opioid therapy for their underlying persistent cancer pain.
`
`11. DOSAGE FORM: Sublingual Spray
`
`12. STRENGTH/POTENCY: 100, 200, 400, 600 and 800mcg in
`
`"”“’ of solution
`
`13. ROUTE OF ADMINSITRATION: Sublingual
`
`l4. Rx/OTC DISPENSED:
`
`NI Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM:
`SPOTS product — Form Completed
`
`
`x
`Not a SPOTS product
`
`16. CHEMICAL NAB/IE, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`INN Name: Fentanyl
`USAN name: Fentanyl [p
`IUPAC name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] propanamide
`
`Molecular formula: C22H23N20
`Relative molecular weight 336.47 (base):
`
`CH3 CH2 CONCN—CHZ CH2<©
`
`Reference ID: 3047930
`
`Page 4 of 64
`
`

`

`‘ .A-n
`
`‘ -«fln
`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`l7. RELATED/SUPPORTED DOCUMENTS:
`
`A. DMFs:
`
`5%
`3?8N"§'—
`
`§§ IIIIEIEEEH Illlllli*I
`
`lAction codes for DMF Table:
`l—DMFReviewed.
`
`Other codes indicate why the DMFwasnot reviewed, as follows:
`2—Type1DNIF
`3—Reviewedprevimlslyandnorevisionsincelastreview
`4 — Suflicient infonnation in application
`5—Authoritytorefelmcenotgranted
`6—DMFnotavailable
`
`7—01her(explainlmder"Conmmts")
`
`2Adequate,Inadequate,orN/A('Ihereisaloughdaiainflleapplication,thereforetheDlVIFdidnotneedto
`bereviewed)
`
`B. Other Documents:
`
`Reference ID: 3047930
`
`Page 5 of 64
`
`

`

`
`
`Chemistry Review Data Sheet
`
`mm
`
`APPLICATION
`
`mm
`
`“ 72411
`
`Fentanyl Sublingual Spray
`
`RELATED
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`Ma 2011
`
`B anRile ,Ph.D.
`
`
`
`Phamflox
`
`E.Bolan,ph.n.
`
`-_———
`————
`Methods Validation ———
`13mm ——
`EA
`Categorical exclusion March 4, 2011
`satisfacto
`
`J. Pinto
`
`Reference ID: 3047930
`
`Page 6 of 64
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202788
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`Sufficient CMC information, to assure the identity, strength, purity, and quality of the drug
`product, is provided in this NDA submission. The drug substance manufacture and product
`attributes are referenced to DIVIF
`(m4) and has been reviewed as Adequate (P. Maturu, Rev #4
`June 2009 and J. Pinto, Rev #5, Oct 2011). The Office of Compliance has issued an
`“Acceptable” overall recommendation for all facilities involved in production of the product. All
`DMFs are adequate. There are outstanding deficiencies in the drug product stability protocol and
`stability specifications. From a quality perspective, this NDA is recommended as approvable
`pending adequate resolution to these deficiencies (Detailed discussion in Section P.9).
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable—
`No Post Approval commitments are required.
`
`II. Summary of Chemistry Assessment
`
`A. Description of Drug Substance and Drug Product:
`
`The drug 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 (m4) (held by
`mm The API is made by
`M“) at their
`(hm) facility which is recommend as adequate by CC (report
`attached in the appendix). The API will be stored and shipped
`(m4)
`and has a retest period of
`mar 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 fentanyl formulated in a sublingual, single dose, spray in concentrations of
`1mg/ml, 2mg/ml, 4mg/ml, 6mg/ml and 8mg/ml. The total fill per vial is
`M“) The solution
`components consist of the active substance, in dehydrated alcohol, propylene glycol, water,
`xylitol and menthol. The solution is intended for sublingual administration for mucosa]
`absorption. The spray is a single-dose vial, stored in a carton that contains a disposal bottle
`M“) and disposal bags, for the used vials, and
`mm bottles containing unused
`doses. The DP is made by (m4) at their
`m“) facility which as been recommended as
`adequate by CC (OC report attached in the appendix. The clinical batches were made on a a;
`4
`.
`.
`(m ) scale. The proposed commercral scale is mm
`
`Reference ID: 3047930
`
`Page 7 of 64
`
`

`

`
`
`.
`.
`The manufactunng process 18
`
`4
`M”
`
`Executive Summary Section
`
`The pump consists of an actuator, insert, spray pin, needle, stopper, glass Vial and vial holder and
`assembled by
`mm).
`mm
`. The
`(mo bottle to be used for disposal of any
`
`filled spray device is co-packaged with a
`unused Vials.
`
`(m4) bottle, holding 28 units of the maximum strength drug
`Extraction studies of the
`product were conducted 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
`(I’m) using
`dehydrated ethanol which is equivalent to about 1.3%. Heat, shaking, and pH adjustments, did
`not afford any additional fentanyl to be extracted.
`
`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.
`
`B. Description of How the drug is intended to be used:
`
`SubsysTM (name under review by DMEPA) is an opioid analgesic indicated only for the
`management of breakthrough cancer pain in patients who are already receiving and who are
`tolerant to regular opioid therapy. Each dose is administered as a single spray under the tongue.
`Each spray delivers
`mm of solution containing either 100 mcg, 200 mcg, 400 mcg, 600 mcg
`or 800 mcg of fentanyl base. There is no recoverable residual in the vial, afier dose delivery. Off
`the
`(m4) fill volume,
`(”ml is delivered and the remaining (m4)
`is retained by the pump
`assembly parts.
`
`C. Basis for Approvability Recommendation
`
`Sufficient CMC information, to assure the identity, strength, purity, and quality of the drug
`product, is provided in this NDA submission. The drug substance manufacture and product
`attributes are referenced to DMF mm and has been reviewed as Adequate (P. Maturu, June
`2009 and J. Pinto, Rev #5, Oct 2011). The Office of Compliance has issued an “Acceptable”
`overall recommendation for all facilities involved in production of the product. All DMFs are
`adequate. There are two outstanding deficiencies in the drug product stability protocol and
`stability specifications. This NDA is recommended as approvable pending adequate resolution
`to these deficiencies (Detailed discussion in Section R9).
`
`Reference ID: 3047930
`
`Page 8 of 64
`
`

`

`
`
`Executive Summary Section
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemistry Reviewer: Julia Pinto, Ph.D.
`Pharmaceutical Assessment Leader: Danae Christodoulou, Ph.D.
`
`Project Manager: Kathleen Davies
`Branch Chief: Prasad Peri, Ph.D.
`
`55 Page(s) has been Withheld in Full as B4 (CCIITS) immediately following this page
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`Reference ID: 3047930
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`Page 9 of 64
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`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
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`/s/
`----------------------------------------------------
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`JULIA C PINTO
`11/21/2011
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`PRASAD PERI
`11/21/2011
`I concur
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`Reference ID: 3047930
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`