CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`208745Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`

`

`Memorandum
`
`DEPARTMENT OF HEALTH AND HUMAN
`SERVICES PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`From:
`
`January 11, 2017
`Hitesh Shroff, Ph.D.
`
`Application Technical Lead, Branch V
`Division of New Drug Products II
`
`Office of New Drug Products
`
`Through:
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch V
`
`Division of New Drug Products II
`Office of New Drug Products
`
`To:
`
`CMC Review #1 of NDA 208745
`
`Subject: final Recommendation for NDA 208745
`
`At the time when the CMC Review #1 was completed on October 6, 2016, it had
`noted the following pending issues:
`
`0 The label/labeling issues were not resolved.
`0 Final “Acceptable” recommendation from the Oflice of Process and Facilities
`was not issued.
`
`Because of these deficiencies, the NDA was not recommended for approval from the OPQ
`perspective.
`
`On October 11, 2016, the applicant submitted revised labeling. The CMC sections of the
`labeling were reviewed and found acceptable (Attachment -1).
`
`On December 5, 2016, the Oflice of Process and Facilities issued the overall “Approval”
`recommendation for the facilities involved in this NDA (Attachment — 2).
`
`W T
`
`his NDA is now recommnded for Approval from the OPQ perspective.
`
`Application Technical Lead’s Assessment and Signature
`
`~05'00'
`
`The NDA is recommended for Approval fiom quality perspective.
`Digitally signed by Hitesh N.
`HlteSh N m:3;FUSW
`..
`O ou=lIlS.ou=FDA.ou '
`”immmmmjk
`S
`Sh rofl: 'S 00348333.cn=meshN.Sh .--
`bam201701.121423240
`
`I-Iitesh Shrofl; PILD.
`Application Technical Lead, Branch V
`Division ofNew Drug Products 11
`January 11, 2017
`
`

`

`Attachment 1:
`
`Attachment 1:
`
`Labeling:
`Labeling:
`
`Klemorandnm
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMISTRATION
`CENTER. FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`
`October 13, 2016
`
`ani:
`
`_
`Rioo-Jhong Rhee, PhD.
`Moofiiong
`Chief, Branch v
`Division of New Drug Products II Rhee -S
`Office of New drug Products
`
`.. ”Mans
`a...»
`"Self-"Mme”; t
`B:§L”$fi£¥;‘$°"m
`
`To:
`
`Labeling Review #1 of NBA 208745
`
`Subject:
`
`Final Recommendation
`
`The Labeling review #1 has noted the following two pending issues:
`
`1. Manufacturer information [e.g.. name and location of business (street address. city. state
`and zip code)] is required in labeling and should‘oe located alter section 17. Patient
`counseling information
`2. “Do not remove the desiccant packet from the bottle" should be added in section
`16, How SuppliedJStorage and Handling.
`
`And because ofthese deficiencies. in the Labeling Review #1. this NDA was not
`recommended for approval from the labeling perspective.
`
`On October 11. 2016. the applicant amended the labeling and the above issues are
`satisfactorily resolved (see the Attachment).
`
`Recommendation:
`
`This NDA is now recommended for approwl from the labeling perspective.
`
`

`

`Attachment:
`16 HOW SIMSIORAGE AND HANDLING
`
`TRUIANGuflzsmpdnpdmmmmmdnaeblflapxkoflomndfldmwaml
`whiz mm.MpbWWWMIWMWWwan-
`“trauma-usual mmmmmmMamuapwu
`Wing“mfikboflwbfiplflnldmwmwumdded“rh3mgm
`hofianbullspflmlas:
`
`——
`
`m» mmmmmmmflmw
`
`Sue“momh1pmme.20to25°€(68b77°fi;mpmmdto 15w30’C(59»86°I-)1:«USP
`ConnolcdRoomTw].
`Emahaifi. mmm‘ rammmmcamumm. -
`Do not divide orW.
`PAID"! COl'NSEUNG INFORMATION
`
`MiseupummmaumAwmp-mmmmammde)
`
`Advisehfian;
`
`mg
`
`0 ummmczmcmmmpmmimmmmb-rmu
`PM. (I'm!
`
`WM‘
`
`- AccidmlhgesfimofTRlflANCEinchfltmMytchfldrnbsshéymoflgmymhh
`semiannualmam mantle stpsmeRUIANCEmdyudanofru-hof
`chfltkamdtod‘upoaeofunsedTRUlAfiCI-Zbacmcnmlll, mehum IISZIJ.
`..
`.
`anal;
`!.
`l
`
`E!
`
`0 TonkeflUlANCEmedflywflhawmlfoodlmeqgcadAd-Mmm].
`- Kabukmksdfipfiewhelflmhnmbunfiewm. Donahkemcbaunlhe
`min!
`0
`To mflmTRUIANCEuhhuwhok
`- Radium
`' mmLmuMcmhummmmuymm
`Ippksauceamlh
`ammmxfilmawmhhamw
`hawk-“Gait.
`- Tokeq'l'RUIANCEinld'yphce Pmmfiunmisun 1%!qu TRIHANCEhdlaigndhome.
`Dommvemtnmhbonlc Downtdividea
`Ranownddiscardpolymcoilm
`opal'ng MWMW'ISUHWWW (16)].
`
`TRITIANCEWB a Indie-arid Synergy Phrase-ink he.
`
`

`

`”huh- I W”.
`
`mm run
`1.1212017
`
`arm
`MM
`
`m c
`
`m
`
`Attachment 2:
`
`Facilities:
`
`mum.mm
`
`NBA-WW4.
`
`Em..."
`
`T‘s
`
`munch-w-
`mdmxnmaanan
`
`mun-mm.“
`
`Dflh- m- m“
`m mu
`
`wru-
`
`
`
`cup-.- in- u-pn n-
`may nun
`mM mum
`m n—y
`Imu
`3mm“ In,“
`
`an: may» nays-
`
`Imus
`up" My
`Imus
`m r.’
`WM 1mm
`m I'll!
`lmm
`up: no:
`10mm
`W VIM
`MM!
`nus
`A.”M ”I.“
`out:
`mm
`M MSG“
`cu.-
`mama
`MI
`an”
`
` aaaaaiaaaaa:
`
`
`
`

`

`Hitesh
`Shroff
`
`Digitally signed by Hitesh Shroff
`Date: 1/12/2017 02:33:27PM
`GUID: 502d1ab500002afd219fd67e3b9c99c8
`
`APPEARS THIS WAY ON
`ORIGINAL
`
`

`

`QUALITY ASSESSMENT
`
`FACILITIES
`
`Product Background:
`
`«9(4) drug
`The application provides for plecanatide immediate release-tablets (3 mg
`product, indicatedfor the treatment of adults with chronic idioipathic constipation. There is
`
`currently no marketed drug product using plecanatide drug substance; as such, this proposed
`
`drug product contains an NME.
`
`NDA/ANDA: NDA 208745
`
`Drug Product Name / Strength: Plecanatide Immediate-Release Tablets, 3 mg
`
`(m4)
`
`Route of Administration: Oral
`
`Applicant Name: Synergy Pharmaceuticals, Inc.
`
`Review Summary:
`
`There appear to be no significant or outstanding risks to the manufacturing process or
`final product based on the individual and composite evaluation of the listed facilities’
`inspectional history, relevant experience, and capabilities. The facilities are determined
`
`acceptable to support approval of NBA 208745.
`
`List Submissions being reviewed (table):
`
`0000 — Original
`
`0003 through 0007 — Quality Response to Information Request
`
`0011 — Quality Response to Information Request
`
`0018 — Quality Response to Information Request
`
`0030 through 31 — Quality Response to Information Request
`
`0037 through 40 — Quality Response to Information Request
`
`0044 — Quality Response to Information Request
`
`0048 — Quality Response to Information Request
`
`0051 — Quality Response to Information Request
`
`Highlight Key Outstanding Issues from Last Cycle: N/A
`
`6 Page(s) have been Withheld in Full as b4 (CCI/TS)
`immediately following this page
`
`

`

`Juandria
`Williams
`
`Vidya
`Pai
`
`Digitally signed by Juandria Williams
`Date: 11/22/2016 02 37:12PM
`GUID: 513b65ab0005b7cb48614cd3d341d717
`
`Digitally signed by Vidya Pai
`Date: 11/22/2016 02 51:29PM
`GUID: 53b581d20000464509a65e37ec9ad4a2
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Recommendation: As of this review, this 505 (b)(l) NDA is Not Ready for Approval
`in its present form per 21 CFR 314.125(b)(6) and 21 CFR 314.125(b)(13)
`
`NDA 208745
`
`Review 1
`
`Drug Name/Dosage
`
`Plecanatide tablets
`
`
`Administration
`
`Rx/OTC Dis ensed
`
`US aent, If a nlicable
`
`S erg Pharmaceuticals Inc. New York NY
`
`SUBMISSION(S)
`
`m
`
`DATENT
`REVIEWED
`m 1/29/2016 _§I°—
`2/26/2016
`0PF10NDP
`
`DISCIPLINE(S) AFFECTED
`
`3/25/2016
`
`DB, OPF
`
`3/30/2016
`DB,ONDP
`4/07/2016 —_
`——_m_
`
`m—
`
`—_m_
`———m_
`
`mm
`
`—
`—_m_
`
`

`

`QUALITY ASSESSNIENT
`
`Quali Review Team
`
`BRANCH/DIVISION
`
`DISCIPLINE
`—
`Drug Substance
`
`Matin Haber
`
`CDEIUOPQ/ONDP/
`DNDAPI/NDBII
`
`CDER/OPQ/ONDP/
`DNDPII/NDPBV
`
`Raanan Bloom
`
`Drug Product
`
`Zhengfang Ge
`
`Process
`
`Microbiolo 3
`Facili
`
`Bo Jiang
`Bo Jian .
`
`DER/OPQ/OPF/ DPAI/PABI
`DEWOP 0 /OPF/ DPAI/PABI
`
`Juandria Williams
`
`DER/OP O /OPF/DIA/IABIII
`
`Bio uharmaceutics
`
`Kal u ana Paudel
`
`CDER/OP 0 /ONDP/ DB/BBII
`
`Regulatory Business
`Process Manager
`
`Maureen Dewey
`
`CDER/OND/ODEIII/ DGIEP
`
`Application Technical Lead
`
`Hitesh Shroff
`
`Laborato OTR
`—n-
`ORA Lead
`
`N/A
`
`Paul Perdue Jr.
`
`Environmental Analysis
`
`CDEIUOPQ/ONDP/
`DNDPII/NDPBV
`
`N/A
`
`ORA/OO/OMPTO/
`
`DMPTPO/MDTP
`
`CDER/OPQ/ONDP
`
`

`

`QUALITY ASSESSNIENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`Item
`Referenced
`
`Date Review Comments
`Com » leted
`
`N/A
`
`--
`
`N/A
`
`N/A
`
`
`Pharmacolo 3 /Tox1colo 3
`
`N/A: There is enough data in the application. therefore. the DMD did not need to be reviewed
`
`B. Other Documents: IND, RLD, or sister a
`
`Iications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`74883
`
`Synergy Pharmaceuticals
`Inc. currently has an active
`IND for the investigational
`use of plecanatide for the
`treatment of chronic
`
`idio athic consti ation.
`
`2. CONSULTS: None
`
`Blostatlstlcs
`
`

`

`QUALITY ASSESSNIENT
`
`Executive Summary
`
`I.
`
`Recommendations and Conclusion on Approvability
`
`The applicant has provided sufficient CMC information to assure the identity,
`strength, purity, and quality of the drug product.
`
`The Office of Process and Facilities (OPF) has not made a final overall
`“Approval” recommendation for the facilities involved in this application as of
`this review.
`
`The claim for the Categorical Exclusion for the Environmental Assessment is
`granted.
`
`The label/labeling issues have not been completely resolved as of this review.
`
`Therefore, from the OPQ perspective this NDA is not deemed ready for
`approval at this time in its present form per 21 CFR 314.125(b)(6) and 21 CFR
`314.125Cb)(13), lmtil the above issues are satisfactorily resolved. (see Attachment
`H)
`
`II.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`(5)“)
`
`(b) (0
`
`only
`and
`Plecanatide tablets are proposed in
`3 mg strength tablets will be marketed. Plecanatide tablets are white to off-white,
`plain, round and debossed with “SP” on one side and “3” on the other side. Thirty
`tablets of Plecanatide are supplied in a bottle or in a child-resistant blister pack.
`
`Proposed Indication(s) including
`Intended Patient Population
`
`Plecanatide tablets are indicated in adults for
`treatment of chronic idiopathic constipation
`CIC
`
`Administration
`
`orall once dail
`
`1“
`
`

`

`"""'"
`Imam.)
`
`QUALITY ASSESSMENT
`
`""""‘
`--~----
`
`Quality Assessment Overview
`
`Drug Substance:
`The active pharmaceutical ingredient (API), plecanatide, in the dru
`c clic
`
`tide containin 16 amino acids and 2 disulfide bonds.
`
`oduct is a
`
`
` The detailed API manufacturing process is provided and it is well
`controlled. Plecanatide is fiilly characterized by mass spectroscopy, amino acid
`sequence analysis, proton and carbon MR spectroscopy, X—ray powder
`diffraction and optical rotation analysis.
`
`Plecanatide is an analogue of endogenous human peptide, uroguanylin, with
`replacement of Asp3 in human peptide with Glu3. The synthetic peptide is white to
`off-white powder and is soluble in water and slightly more soluble at acidic pH. It
`is a chiral compound wifl1 optical rotation of -154.5°:|:20.5°.
`
`The molecular formula of plecanatide is C65H104N13025$4 and the molecular weight
`is 1682 Daltons. The amino acid sequence ofplecanatide is shown below:
`
`I— ——|
`
`H-Asn'-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7- alB-gA5n9-Val'o-Alal l-Cys'2-'I‘hr'3-Gly'4-Cys'5-Leu'6-OH
`5—5
`
`The quality of the API is controlled b a s
`assa , uri
`, 9
`ified '
`urities
`
`ification includin identification,
`
`
`
`
`residual solvents, optical rotation and particle sizes, which
`
`are deemed adequate per Drug Substance reviewer, Dr. Martin Haber (see his
`drug substance review).
`
`The bulk API is acka ed into
`
`Drug Product:
`Plecanatide tablets, 3 mg, are supplied in an aluminum foil blister pack of 30
`tabelets or in a white, opaque, high-density polyethylene bottle with a screw-top
`polyethylene child-resistant cap with an induction seal and a polyester coil. In
`
`

`

`QUALITY ASSESSNIENT
`
`addition to the 3 mg of API, each tablet also contains USP grade inactive
`ingredients, microcrystalline cellulose and magnesium stearate.
`
`The drug product manufacturing process involves
`and packaging in blister or
`
`om)
`
`bottles.
`
`The drug product is controlled by a specification including identity, assay,
`impurities,
`om) content uniformity, dissolution, and microbes, and they
`are deemed adequate per drug product reviewer, Dr. Zhengfang Ge (see her drug
`product review).
`
`The Division of Pharmaceutical Analysis, FDA performed validation of two drug
`product analytical procedures. The method validation report dated 05 July, 2016
`stated that both methods were were evaluated and deemed acceptable for quality
`control and regulatory purposes (see Attachment IID.
`
`Based on the submitted stability data, 24-month expiration dating period is
`granted when stored at room temperature in the proposed blister packs and
`bottles. The applicant agreed that the expiration dating period is to be calculated
`from the manufacturing date of the drug product including the bulk hold-time.
`
`The applicant provided a claim for a categorical exclusion from an enviromnental
`assessment (EA) in accordance with 21 CFR Part 25.3 1(b). The required
`statement of no extraordinary circumstances was included.The claim was
`reviewed and found to be acceptable.
`
`B. Special Product Quality Labeling Recommendations (NDA only)
`None
`
`Final Risk Assessment (see Attachment I)
`
`75 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`

`

`maxim-(luau
`
`QUALITY ASSESSMENT
`
`nmuwrmnm
`
`LABELING
`
`NBA 208 745
`
`R
`
`Regional Information
`
`1.14 Labeling
`
`Labeling & Package Insert
`
`1. Package Insert
`
`(3) “Highlights” Section
`
`TRADENAME (pleeanafide) tablets, for oral use
`
`DOSAGE FORMS AND STRENGTHS—
`
`Tablets: 3 mg (Error! Reference source not found.)
`
`_ Information Provided in NBA
`25931111113139.131999.»___________________________________________________________
`Proprietary name and established name
`TRADENAME (plccanatide) tablets
`Tradename has not been designated.
`
`Inadequate
`
`
`
`
`_
`
`Dosage form. route of administration
`tabletS. for oral use
`
`_Adequate
`Controlled drug substance symbol (if
`N/A
`
`applicable)
`[Dosage Forms and Strengths (201.57(a)(8))
`Tablets: 3 mg
`
`_Adequate
`_
`N/A
`
`Whether the drugproduct is scored
`
`(b) “Full Prescribing Information” Section
`
`
`# 3: Dosage Forms and Strengths
`
`TRADENAME Tablets:
`
`0
`
`3 mg: white to off-white, plain, round tablet debossed with “SP” on one side
`and “3” for 3 mg on the other side.
`
`

`

`Mahatma-nun
`
`QUALITY ASSESSMENT
`
`\ maxim-luau».
`
`_ Information Provided in NBA
`
`‘ uate
`
`Ad '
`
`« uate
`
`Ad '
`
`« uate
`
`Active moiety expression of strength with
`e a
`'valence statement if a nlicable
`
`N/A
`
`A description of the identifying characteristics white to off-white, plain, round tablet debossed
`of the dosage forms, including Shape, colon
`with “SP” on one side and “3” for 3 mg on the
`coating, scoring. and imprinting, when
`other side
`Ad ‘
`applicable.
`
`#1 1: Description
`
`0”“ is a
`TRADENAME (plecanatide)
`guanylate cyclase-C agonist. Plecanatide is a 16 amino acid peptide with the following chemical
`
`name: L-Leucine, L-asparaginyl-L-u—aspartyl-L-a-glutamyl-L-cysteinyl-L-u—glutamyl-L—leucyl-
`
`L-cysteinyl-L-valyl—L-asparaginyl—L-valyl—L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-,
`
`cyclic (4—’12),(7—>15)-bis(disulfide)
`
`The molecular
`
`formula of plecanatide is C55H104N1302684 and the molecular weight
`
`is
`
`1682 Daltons. The amino acid sequence for plecanatide is shown below:
`
`l—S—S
`H—Asnl-Aspz—Glu3-Cys"’-Glu5-Leu6-Cys7-Vals-Asn9-Valw-Alal l-Cys12-Thrl3—Glyl4-Cys15-Leul6-0H
`|_—S_S—l
`
`The solid lines linking cysteines illustrate disulfide bridges.
`
`Plecanatide is an amorphous. white to off-white powder. It is soluble in water. TRADENAME
`tablets are
`cm as a 3 mg tablet for oral administration. The inactive ingredients are
`
`microcrystalline cellulose and magnesium stearate.
`
`

`

`mun—[mum
`
`QUALITY ASSESSMENT
`
`\ kmnhslmnm
`
`_ Information Provided in NBA
`Preprietary name and established name
`TRADENAME (plecanatide) should be revised
`to Tradename (plecanatide) tablets
`
`Inadequate
`tablet for oral administration
`Ade u uate
`
`Dosage form and route of administration
`
`Active moiety expression of strength with
`e a
`'valence statement if a nlicable
`
`N/A
`
`Inactive ingredient information (quantitative, if The inactive ingredients are microcrystalline
`injectables 21CFR201-100(b)(5)(iii)). listed by cellulose and magnesium stearate
`
`USP/NF names (if any) in alphabetical order Adequate
`
` (USP <1091>)
`
`
`
`Statement of being sterile (if applicable)
`Phannacological/ therapeutic class
`
`N/A
`guanylate cyclase-C agonist
`Ade u uate
`
`Chemical name, structural formula, molecular
`weight
`
`Provided.
`Ade u uate
`
`Ifradioactive, statement of important nuclear
`characteristics.
`
`N/A
`
`Other important chemical or physical properties Plecanatide is an amorphous, white to off-white
`($11611 as PKa 0r PH)
`powder. It is soluble in water
`Ade : uate
`
`HOW SUPPLIED section
`
`TRADENAME tablets are packaged in an aluminum foil unit dose blister pack of 30 in a child-resistant
`pack or in a white, opaque, high-density polyethylene round bottle with a screw-top polypropylene child-
`resistant cap and heat-activated induction seal. Each bottle container-closure system also contains a
`desiccant and a polyester coil.
`
`TRADENAME
`
`3 mg tablets are white to off-white, plain and round, debossed with “SP” on one side and “3” for 3 mg on
`the other side and supplied as:
`
`
`
`XXXXX-XXX—XX
`Bottle of 30
`
`
`XXXXX—XXX-XX
`
`Aluminum foil unit dose blister
`
`pack of 30 in a child-resistant
`pack
`
`Store at room temperature. 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see
`USP Controlled Room Temperature].
`
`

`

`-.A-n m ‘-‘-n
`
`m
`
`u—I-I-M—n-
`
`‘
`
`Strength ofdosage foam
`
`Available units (e.g., bottles of 100 tablets)
`
`Ade . uate
`
`Bottle of 30 counts and blister pack of 30
`Ade . uate
`
`Not . Innate
`
`Idmfification of dosage forms, e.g., shape,
`,
`'
`'
`'
`'
`'
`
`Provided
`Adequate
`
`Special handling (e.g., protect from light)
`
`“Do not remove the desiccant packet hour the
`bottle” should be added
`Not .
`.
`‘7 . unte
`
`Storage conditions
`
`Mamrfictmerldistributor name (21 CFR
`201.1 I
`5
`
`Provikd
`Ade . uate
`
`Not provided
`
`Information Request
`
`0 Manufacturer information [e.g., name and location of business (street address, city, state
`and zip code)] is required in labeling and should be located afier section 17 patient
`comseling information
`
`0
`
`“Do not remove the desiccant packet from the bottle” should be added in section 16 How
`Supplied
`
`Immediate Container Label
`
`3 tug/30 ct. Bottle Label
`
`
`
`3 tug/7 ct. sample label
`
`

`

`3MG 300T CALENDAR BLISTER
`
`QUALITY ASSESSMENT
`
`
`Reviewer’s Final Assessment: Adequate
`
`The bottle label contains proprietary name (space for Trade Name), emblished name (plecanatide),
`strength, net quantity, administration route (tablets), lot number, expiration, Rx only, storage, NDC
`
`number, bar code and manufacturer. The Information on the bottle label ls adequate
`
`The label on the blister contains trade name, expiration, lot number and bar code. The applicant needs
`to Include Trade Name (establlshed name) tablets X rn-Rx only and manufacturer on the
`bllster
`
`Information Request:
`
`

`

` QUALITY ASSESSMENT
`
`0
`
`Include “TradeName (establishedmme) tablets 3 m-”, “Rxonly” andname of
`manufactureronflleblistercard
`
`Amendment Submitted 7-Sep-2016
`
`The appieant revised the blister label as shown below. The revised label is adequate
`
`
`
`Carton Labeling
`
`

`

`'Dafln
`mil
`
`QUALITY ASSESSMENT
`
`
`
`Reviewer's Assessment: Adequate
`
`The bottle carton label contains Trade Name (plecanatide) tablets 3m-, net quantity, lot
`number, expiration, Rx only, storage, NDC number, bar code and manufacturer, “Keep out of reach of
`children". The special instruction for the storage includes ”protect from moisture. Do not remove the
`
`desiccant from inside the bottle. The carton also includes ”each tablet contains 3 mg plecanatide”. The
`
`lnfonnaflon an the bottle carton label ls adequate
`
`The carton label on the blister package includes Trade Name (plecanatide) tabletsB m-, net
`quantity, lot number, expiration, Rx only, storage, NDC number, bar code and manufacturer. The
`applicant should be asked to include ”Keep out of reach of children"
`
`Information Request:
`0
`Include “Keep out ofreach of children” on the carton ofthe blister package
`
`Amendment Submitted 7-Sep-2016
`
`The applicant revised the blister label as shown below. The revised label is adequate
`
`
`
`

`

`mmmrwum
`
`QUALITY ASSESSMENT
`
`nmrxwrmnm
`
`List of Deficiencies:
`
`0 Manufacturer information [e.g.. name and location of business (street address, city. state and zip
`code)] is required in labeling and should be located after section 17 patient counseling
`information
`
`0
`
`“Do not remove the desiccant packet from the bottle” should be added in section 16 How
`Supplied
`
`Primary Labeling Reviewer Name and Date:
`
`Zhengfang Ge. Ph.D.
`Branch V. DNDP lI/ONDP
`
`The labeling and labels are satisfactory from CMC perspective, except for the deficiencies noted
`
`above, and therefore, this application is not deemed ready for approval until the final labeling
`
`get resolved above deficiencies.
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`I concur with Dr. Ge’s assessment on the labeling and labels, and agree with that this
`
`application is not ready for approval till those two deficiencies are resolved.
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch V
`DNDP II/ONDP
`
`

`

`Moo Jhong
`Rhee
`
`Zhengfang
`Ge
`
`Digitally signed by Moo Jhong Rhee
`Date: 9/30/2016 12:24:50PM
`GUID: 502d0913000029f9798ca689a802fa55
`
`Digitally signed by Zhengfang Ge
`Date: 9/30/2016 12:07:39PM
`GUID: 508da7210002a030e76df4f60ccd142a
`
`34 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`APPEARS THIS WAY ON
`ORIGINAL
`
`

`

`QUALITY ASSESSM ENT
`
`BIOPHARMACEUTICS
`
`Product Background:
`
`NDA/ANDA: NDA 208745/N000 (A new molecular entity; NME)
`
`Drug Product Name / Strength: Plecanatide tablets/ 3 mg (one strength only)
`
`Route of Administration: Oral
`
`Applicant Name: Synergy Pharmaceuticals Inc
`
`Review Summary:
`
`The proposed drug product, Plecanatide immediate-release 3 mg tablet, is indicated for the
`
`treatment of chronic idiopathic constipation (CIC) in adults. The Applicant seeks approval of
`
`this NDA/N000 for an NIVIE via the 505(b)(1) regulatory pathway.
`
`Composition of proposed drug product:
`
`0:) (4)
`
`(5)“)
`
`0:) (4)
`
`were
`the to-be-marketed formulation of plecanatide tablets (3 mg
`proposed as shown in Table 1 below. @(4) the proposed 3
`(no) to-be-marketed
`tablet formulation had been tested clinically in the Phase 3 trials.
`
`Table 1: Composition of plecanatide Tablets, 3 mg
`
`(b) (4)
`
`
`
`
`
`Tablet Dosage Strength(m4)
`
`
`
`
`
`
`I The drug substance is corrected for assay (wt’wt%).
`(m4)
`
`Note: Plecanatide formulation is designed for locally acting in the GI lumen.
`
`one
`
`strength
`
`(no)
`
`The Applicant
`
`(hm developed 3
`
`(m4) mg tablet
`om)
`
`

`

`Z Mimi @122
`
`

`

`QUALITY ASSESSMENT
`
`Permeability:
`N/A
`
`Dissolution:
`
`Please see below.
`
`Dissolution Method and Acceptance Criteria
`
`including the
`report
`The Applicant has provided the dissolution method development
`justification for the proposed dissolution parameters, discriminating ability of the dissolution
`method, dissolution method validation, and dissolution data of the plecanatide tablets in this
`submission which were presented and reviewed in the respective sections below.
`
`A dissolution method (TR-00284) was developed, and proposed dissolution conditions are
`shown below.
`
`Table 4: Proposed dissolution method for plecanatide tablets
`
`Parameter
`
`USP Apparatus 2 (Paddles)
`35 mM Phosphate buffer pH 6.2
`
`Apparatus
`Media
`Media Temperam
`Paamespcea
`Media Volume
`3 mo
`
`6 mg
`
`
`
`Sampling timesa
`
`Per current IND specification requirement (currently Q = (4,70 at 30 minutes: report
`dissolution results at 15. 30. 45. and 60 minutes).
`Dissolution profile comparison: 10. 15. 20. 30. 45. and 60 minutes
`
`' Sampling times may be revised.
`
`The proposed dissolution acceptance criterion is as follows.
`
`Q =°m% at 30 minutes
`
`Dissolution Method Development
`
`The Applicant has provided data for the justification of dissolution apparatus, paddle speed,
`dissolution medium and pH for the dissolution method TR-00284.
`
`Dissolution media and mm selection
`
`3
`
`2 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

` QUALITY ASSESSMENT
`
` Dissolution
`
`profiles of plecanatide:
`
`The Applicant has conducted dissolution studies on plecanatide tablets, 3 mg and 6 mg in
`proposed dissolution medium. The summary of the results for 3 mg and 6 mg is provided
`below. The batches utilized in dissolution studies were the same batches that were tested in
`
`clinical studies and in stability testing. Individual dissolution data for all the clinical studies
`are provided in M.2.7.1. Table 6 shows the dissolution summary of plecanatide IR tablets, 3
`and 6 mg.
`
`
`"J ___ . -.- _ _-.--._-_-_ -._---- _-- .._.._-- _.._--.., - __.. .
`-- _____ _....--. _ --__.._-_-
`Table 6: Dissolution summary of plecanatide tablets, _3_mg and 6 mg
`
`500mL(3;900mL
`
` 35mm62mm
`
`
`23MAR2013
`
`Shem:-
`MISCOSO
`17111112013"
`Ill DI:
`2514mm:
`
`93042030),
`930420303
`
`swarm;
`$333331” mm“ 3mm 1mm
`’
`Manhunt Dan:
`9304203413
`16DF£2013
`
`Tablet
`3 mg
`
`m
`
`

`

`‘ .A. B
`
`m;
`
` QUALITY ASSESSMENT
`
`5180-1203-01
`
`1‘IJUN2013
`
`9304203410.
`SP304203-01,
`SP304203—03
`
`SPSMZOS-Ol
`
`09/11/14
`
`Site ofMI;
`Batch: 13C051
`Mamficture Dm:
`26MAR2013
`
`Batdr 13F106
`MamfidIIeDIe:
`2SIUN2013
`
`.-_
`Site of ,
`Batlr 141256
`Mm Die:
`
`CV-eoeficienofwfiznce;D-idmfifiafiuang-m1ficmng;No.-mm0-q|nnfithPM-mohnionspemime;USP-Unindsm
`Plnmmope'n
`
`Analm'cal Method Validation:
`
`In vitro dissolution analytical method validation report for Plecanatide IR tablets (Analytical
`Method Validation Report AC-MVR-00329) was submitted in M.3.2.P.5.3, which were
`validated in terms of specificity,
`linearity, precision, accuracy, solution stability, -
`compatibility, and robustness, and is summarized below in Table 7.
`
`Table 7: Summary of Method Validation for Dissolution of Plecanatide tablets (from
`
`M.3.2.P.5.3)
`
`Mixture
`
`Anydun-norsolv‘m
`peakanhemmHmks
`(“Mm-or
`
`Nopukwasmuthentm
`
`flmeofPlocI-addo Recovcry of AP! tom placebo
`
`couposidon of“ 3 In;W tfimnd. MI in]
`solution
`2596. 5096. 7596. IOOQS. 125“ and
`Rm [5096 of“ nominal would"
`Stuck“! or
`mud-n! Conan-flan of
`m _ Plea-madde-
`single injection: wen made.
`
`bhnd condom spiked at 5098.
`W 10095. and 1 5096
`coma-Hon of I
`Solution:
`Cor-Mn!“ M .
`Pam
`Solution m med In
`triplicate. Single injections wele
`made.
`
`Writ)!"'
`
`Amy
`
`

`

`QUALITY ASSESSMENT
`
`
`
`

`

`"'"""
`
`
`
`m
`
`QUALITY ASSESSMENT
`
`

`

`
`
`nu
`<-:-uofll|e Mmmmmnfihm
`hon-“bu
`mm
`WWW hwnflnuuldlnluuflufi-eof
`kmpflfluwghmiflem
`mmqulvflk mmofupakm
`mfil’five
`WSAnngodfiun
`“A“
`Mmmmhwsan-adm
`to
`MotWSA m
`WWW” mm rand
`bani-WISE”!
`
`of
`
`m”“‘m MphbdhmmI-fil'fle
`m“ Mpuk‘nflnfiflnsud-dAiq‘mh‘m
`“m
`mm—
`IqufllxI—Ind'
`Who!“
`meal-Infill!
`Matilda
`mmA" —...
`
`w” 9"“
`
`AC—AM-OMBG-RID
`03"“)
`
`Does not meetm email
`RefertoCN-Onfl
`
`Reviewer’s Ammo: :
`
`o The Applicant’s proposed dissolution method and its development report are acceptable.
`The Applicant has provided adequate data for the justification of dissolution method
`parameters.
`
`0 The Applicant’s proposed dissolution specification is too liberal based on the data and
`hence is not acceptable. In an email dated June 22, 2016, the following Information
`Request (IR) was sent:
`
`10
`
`

`

`amen
`W!
`
`QUALITY ASSESSMENT
`
`“"9"
`”can..-”
`
`Yourproposed dissolution specification of Q=I % at 30 minutes is too liberal based on
`the dissolution data provided. We recommend that you implement a specification of
`Q=I % at 20 minutes in your drugproduct release and stability specification.
`
`The Applicant accepted the specification and responded as follows:
`
`As recommended by FDA, Synergy has revised the dissolution acceptance criterion to
`m% at 20 minutes (Module 3.2.P.5.I).
`
`
`
`Applicant guestion
`In reference to Module 2. 7.1, Summary 0 Bio harmaceutics Studies, data tables
`submitted in the CIC NDA will be updated
`. Batches
`used in CIC- clinical studies are manufactured and tested using the same
`procedures. At the time ofrelease testing, dissolution was performed using conditions of
`15, 30, 45, and 60 minutes. Based upon a request from the Biophamraceutics group
`during review ofthe CIC NDA, the agreed upon dissolution specification is Q
`% in 20
`minutes. As this specification was agreed upon post release testing of t e clinical
`batches, dissolution data contained in Module 2. 7.1 summary tables will reflect the
`original testing of 15, 30, 45, and 60 minutes. It is noted that 20 minute dissolution
`testing will be added to the stabili
`rotocols and testing criteriafor current and all new
`
`and future batches,#. Synergy does not believe that
`
`submission of the Mo u e 2. 7.1 summary to es without 20 minute dissolution testing
`presents an issue as the 20 minute acce tance criteria was a eed u on based on the
`ori
`'nal I5 and 30 minute data.
`
`Does the Agency agree with this approach?
`
`Meeting Discussion Points:
`FDA and Synergy agree to retain the originally proposed dissolution acceptance
`criteria of Q='% in 30 minutes thru presumed approval ofthe current NBA 208745.
`Synergy will update the drug product specification in Module 3.2.P.5.1. Additional
`dissolution data will be collected at 20 min for the commercial batches up to one year
`post approval. Synergy will generate, analyze, and submit the complete dissolution data
`
`for review in the first CMC annual report, assuming approval of NBA 208745 for
`plecanatide in CIC. This will include the dissolution profile data at 15, 20, 30, and 45
`minutes on thefirst three commercial batches.
`
`o The dissolution testing included the 3 mg, 6 mg, and other strengths that were used in
`the clinical studies.
`
`11
`
`

`

`QUALITY ASSESSMENT
`
`o The analytical method and its validation report are reviewed and considered
`
`acceptable. Linearity was demonstrated over the range 25%-150% of 0.006 mg/mL.
`
`Bridging ofFormulations
`
`Reviewer’s Ammut:
`
`1. The Applicant has bridged the capsule and the tablet formulation. The Applicant
`conducted in vitro dissolution studies
`to compare between plecanatide Phase
`3/commercial tablets and Phase 2 capsule formulations. The dissolution of tablets and
`capsules were rapid and similar (Table 8).
`
`Table 8: Comparison of tablet and capsule dissolution using proposed
`dissolution conditions
`
`3mgTablet (Batch noose)
`
`3mgCapsule (Batch 1111140)
`
`45minutes
`
`RSD = relative standard deviation
`
`No difference was observed in dissolution rates between plecanatide tablets with—
`versus plecanatide tablets with _thereby demonstrating equivalence between these
`2 formulations (Table 5, Table 7, and Table 8).
`
`2. The Applicant also compared dissolution between plecanatide tablets with
`(phase 3/commercial formulation) versus plecanatide tablets with
`food effect study), which were similar between these 2 formulations
`
`e 9 .
`
`(phase 1
`
`Table 9: Comparison of tablet formulation with—
`
`12
`
`

`

` QUALITY ASSESSMENT
`
`
`
`i
`
`tell 12G080
`
`'
`
`»
`
`.
`
`.
`
`. Formulation
`
`| | i |
`
`Mean (11 = 12)
`% RSD
`
`20 minutes
`
`Mean (11 = 12)
`% RSD
`
`Mean (11 = 12) |
`
`%RSD %
`
`Biawaiver Request
`
`Reviewer’s Amman :
`
`The Applicant requested a biowaiver from the requirement of a bioequivalence/bioavailability
`studies for its 3 mg dosage strengths of plecanatide tablets. In a Phase 3 clinical trial (No.
`SP304203—03), a subset of patients (n=95) were enrolled in a pharmacokinetic (PK) substudy;
`approximately 32 patients per dose arm of placebo, 3 mg and 6 mg QD regimen. Blood samples
`were obtained predose and intensive samples were obtained on Day 28, 24—hr sample on Day 29,
`and 72—hr sample on Day 31. PK data, however, show that neither drug nor it’s active metabolite
`levels are measurable in the human systemic circulation. Since 3 mg plecanatide tablet was part
`of a PK substudy in Phase 3 clinical trial, the biowaiver request is considered not needed
`
`Dissolution studies showed similar release profiles for the 3 mg tablet strength in comparison
`with the 6 mg tablet strength (Tables 10 and 11). The in vitro drug release was > '% in 15
`minutes for both strengths. Batches 14E116 and 14E117 were used for comparative dissolution
`study and were manufactured as clinical supplies for phase 3 studies SP304203—00 and
`SP304203-03 using the proposed commercial formulation and process.
`
`Figure 5. Dissolution profile comparison for 3 mg and 6 mg
`Plecanatide tablets
`
`13
`
`

`

`QUALITY ASSESSMENT
`
`
`Table 10: Dissolution of 3 mg plecanatide tablets (Batch: 14E116)
`WDIMNo.
`No.
`»
`..
`min-tel
`
`
`
`Site:-
`
`14131 16(3 mg)
`
`Mfg Date: 07May20|4
`
`She:_
`
`
`
`l4El l7 (6 mg)
`Mfg Date: 08May20 l 4
`
`Alternate dosing Study
`
`The Applicant has provided ven'fication of dosing procedures and in-use stability study for
`plecanatide tablets which are mentioned below.
`
`14
`
`

`

`QUALITY ASSESSMENT
`
`1. Verification of Alternative Dosing Procedures for Plecanatide Tablets
`
`The Applicant submitted protocol entitled "Venfication ofAlternative Dosing Procedures or
`Plecanatide Tablets " and data for the addition of four dosing alternatives for
`)(4)
`(51(4) plecanatide tablets for inclusion in the Medication Guide. The protocol and
`the supporting data were not submitted in the original NDA application. Since the Applicant
`(hm decided to pursue approval of the 3 mg tablet strength in this NDA review cycle, only
`the 3 mg plecanatide tablet will be discussed in the sections below.
`
`The four alternative administration methods were to disperse a tablet in applesauce, dissolve
`a tablet in water for oral ingestion and to di