CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`

`

`EXCLUSIVITY SUMMARY
`
`NDA # 208745
`
`SUPPL #
`
`HFD # 180
`
`Trade Name Trulance
`
`Generic Name plecanatide
`
`Applicant Name Synergy Pharmaceuticals
`
`
`
`Approval Date, If Known January 19, 2017
`
`PART I
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, and all efficacy
`supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes"
`to one or more of the following questions about the submission.
`
`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
`
` YES
`
`NO
`
`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`505(b)1
`
`b) Did it require the review of clinical data other than to support a safety claim or change
`in labeling related to safety?
`(If it required review only of bioavailability or
`bioequivalence data, answer "no.")
`
` YES
`
`NO
`
`If your answer is "no" because you believe the study is a bioavailability study and,
`therefore, not eligible for exclusivity, EXPLAIN why it is a bioavailability study,
`including your reasons for disagreeing with any arguments made by the applicant that the
`study was not simply a bioavailability study.
`
`
`
`If it is a supplement requiring the review of clinical data but it is not an effectiveness
`supplement, describe the change or claim that is supported by the clinical data:
`
`
`
`
`
`Reference ID: 4043851
`
`Page 1
`
`

`

`c) Did the applicant request exclusivity?
`
` YES
`
`NO
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`5 years
`
`d) Has pediatric exclusivity been granted for this Active Moiety?
` YES
`
`NO
`
` If the answer to the above question in YES, is this approval a result of the studies submitted
`in response to the Pediatric Written Request?
`
`
`
`
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY
`TO THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
`2. Is this drug product or indication a DESI upgrade?
`
`
` YES
`
`NO
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE
`BLOCKS ON PAGE 8 (even if a study was required for the upgrade).
`
`FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`PART II
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any drug product containing the
`same active moiety as the drug under consideration? Answer "yes" if the active moiety
`(including other esterified forms, salts, complexes, chelates or clathrates) has been previously
`approved, but this particular form of the active moiety, e.g., this particular ester or salt (including
`salts with hydrogen or coordination bonding) or other non-covalent derivative (such as a
`complex, chelate, or clathrate) has not been approved. Answer "no" if the compound requires
`metabolic conversion (other than deesterification of an esterified form of the drug) to produce an
`already approved active moiety.
`
`
`
`
`
` YES
`
`NO
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the
`NDA #(s).
`
`Reference ID: 4043851
`
`Page 2
`
`

`

`
`NDA#
`
`
`
`NDA#
`
`
`
`NDA#
`
`
`
`2. Combination product.
`
`
`
`
`
`
`
`
`
`If the product contains more than one active moiety(as defined in Part II, #1), has FDA
`previously approved an application under section 505 containing any one of the active moieties
`in the drug product? If, for example, the combination contains one never-before-approved active
`moiety and one previously approved active moiety, answer "yes." (An active moiety that is
`marketed under an OTC monograph, but that was never approved under an NDA, is considered
`not previously approved.)
`
`YES
`
`NO
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the
`NDA #(s).
`
`NDA#
`NDA#
`NDA#
`
`
`
`
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO DIRECTLY TO
`THE SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary
`should only be answered “NO” for original approvals of new molecular entities.)
`IF “YES,” GO TO PART III.
`
`PART III
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or supplement must contain "reports of
`new clinical investigations (other than bioavailability studies) essential to the approval of the
`application and conducted or sponsored by the applicant." This section should be completed
`only if the answer to PART II, Question 1 or 2 was "yes."
`
`1. Does the application contain reports of clinical investigations? (The Agency interprets
`"clinical investigations" to mean investigations conducted on humans other than bioavailability
`studies.) If the application contains clinical investigations only by virtue of a right of reference
`
`Reference ID: 4043851
`
`Page 3
`
`

`

`to clinical investigations in another application, answer "yes," then skip to question 3(a). If the
`answer to 3(a) is "yes" for any investigation referred to in another application, do not complete
`remainder of summary for that investigation.
`
`
`
`YES
`
`NO
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved
`the application or supplement without relying on that investigation. Thus, the investigation is not
`essential to the approval if 1) no clinical investigation is necessary to support the supplement or
`application in light of previously approved applications (i.e., information other than clinical
`trials, such as bioavailability data, would be sufficient to provide a basis for approval as an
`ANDA or 505(b)(2) application because of what is already known about a previously approved
`product), or 2) there are published reports of studies (other than those conducted or sponsored by
`the applicant) or other publicly available data that independently would have been sufficient to
`support approval of the application, without reference to the clinical investigation submitted in
`the application.
`
`(a) In light of previously approved applications, is a clinical investigation (either
`conducted by the applicant or available from some other source, including the published
`literature) necessary to support approval of the application or supplement?
` YES
`
`NO
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for
`approval AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
`
`
`
`(b) Did the applicant submit a list of published studies relevant to the safety and
`effectiveness of this drug product and a statement that the publicly available data would
`not independently support approval of the application?
`
` YES
`
`NO
`
`
`
`(1) If the answer to 2(b) is "yes," do you personally know of any reason to
`disagree with the applicant's conclusion? If not applicable, answer NO.
`
`
`
` YES
`
`NO
`
` If yes, explain:
`
`
`
`
`
`(2) If the answer to 2(b) is "no," are you aware of published studies not conducted
`or sponsored by the applicant or other publicly available data that could
`independently demonstrate the safety and effectiveness of this drug product?
`
`Reference ID: 4043851
`
`Page 4
`
`

`

` YES
`
`NO
`
` If yes, explain:
`
`
`
`(c)
`
`If the answers to (b)(1) and (b)(2) were both "no," identify the clinical
`investigations submitted in the application that are essential to the approval:
`
`
`
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`studies for the purpose of this section.
`
`3. In addition to being essential, investigations must be "new" to support exclusivity. The
`agency interprets "new clinical investigation" to mean an investigation that 1) has not been relied
`on by the agency to demonstrate the effectiveness of a previously approved drug for any
`indication and 2) does not duplicate the results of another investigation that was relied on by the
`agency to demonstrate the effectiveness of a previously approved drug product, i.e., does not
`redemonstrate something the agency considers to have been demonstrated in an already approved
`application.
`
`a) For each investigation identified as "essential to the approval," has the investigation
`been relied on by the agency to demonstrate the effectiveness of a previously approved
`drug product? (If the investigation was relied on only to support the safety of a
`previously approved drug, answer "no.")
`
`Investigation #1
`
`Investigation #2
`
`
`
`YES
`
`YES
`
`
`
`NO
`
`NO
`
`If you have answered "yes" for one or more investigations, identify each such
`investigation and the NDA in which each was relied upon:
`
`
`
`b) For each investigation identified as "essential to the approval", does the investigation
`duplicate the results of another investigation that was relied on by the agency to support
`the effectiveness of a previously approved drug product?
`
`Investigation #1
`
`YES
`
`NO
`
`Reference ID: 4043851
`
`Page 5
`
`

`

`Investigation #2
`
`YES
`
`NO
`
`If you have answered "yes" for one or more investigation, identify the NDA in which a
`similar investigation was relied on:
`
`
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the
`application or supplement that is essential to the approval (i.e., the investigations listed in
`#2(c), less any that are not "new"):
`
`
`
`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have
`been conducted or sponsored by the applicant. An investigation was "conducted or sponsored
`by" the applicant if, before or during the conduct of the investigation, 1) the applicant was the
`sponsor of the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or
`its predecessor in interest) provided substantial support for the study. Ordinarily, substantial
`support will mean providing 50 percent or more of the cost of the study.
`
`a) For each investigation identified in response to question 3(c): if the investigation was
`carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?
`
`
`
`!!
`
`! NO
`! Explain:
`
`
`
`!!
`
`
`! NO
`! Explain:
`
`
`
`(b) For each investigation not carried out under an IND or for which the applicant was
`not identified as the sponsor, did the applicant certify that it or the applicant's predecessor
`in interest provided substantial support for the study?
`
`Reference ID: 4043851
`
`Page 6
`
`Investigation #1
`
`IND #
`
`YES
`
`
`
`Investigation #2
`
`IND #
`
`YES
`
`
`
`
`
`
`
`

`

`!!
`
`
`! NO
`! Explain:
`
`
`!!
`
`
`! NO
`! Explain:
`
`
`Investigation #1
`
`
`
`YES
`Explain:
`
`
`
`
`Investigation #2
`
`
`
`YES
`Explain:
`
`
`
`
`(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe
`that the applicant should not be credited with having "conducted or sponsored" the study?
`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to
`the drug are purchased (not just studies on the drug), the applicant may be considered to
`have sponsored or conducted the studies sponsored or conducted by its predecessor in
`interest.)
`
`YES
`
`NO
`
`If yes, explain:
`
`
`
`=================================================================
`
`Name of person completing form: Maureen Dewey, M.P.H.
`Title: Senior Regulatory Health Project Manager
`Date: December 20, 2016
`
`
`Name of Division Director signing form: Donna Griebel, M.D.
`Title: Director, Division of Gastroenterology and Inborn Errors Products
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05; removed hidden data 8/22/12
`
`Reference ID: 4043851
`
`Page 7
`
`

`

`Reference ID: 4043851
`
`Page 8
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MAUREEN D DEWEY
`01/19/2017
`
`DONNA J GRIEBEL
`01/19/2017
`
`Reference ID: 4043851
`
`

`

`Synergy Phannaceuticals Inc.
`
`SP-304, chanatide
`
`Module 1.3
`Debarment Certification
`
`3.
`
`DEBARMENT CERTIFICATION
`
`Synergy Pharmaceuticals Inc. hereby certifies that it did not and will not use in any capacity the
`services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act
`in connection with this new drug application 208745 for plecanatide (SP—304).
`
`investigators associated with Phase 3 clinical studies
`the list of principal
`Attached is
`SP304203-00, SP304203-01, and SP3 04203-03, respectively.
`
`%Z% L,
`
`velyn Jaege
`Vice President Regulatory Affairs &
`Clinical Quality Assurance
`
`.24 M pan/6
`
`Date
`
`_
`
`CONFIDENTIAL
`
`1
`
`Reference ID: 4047282
`
`

`

`ACTION PACKAGE CHECKLIST
`
`
`
`APPLICATION INFORMATION1
`NDA Supplement #
`If NDA, Efficacy Supplement Type:
`NDA # 208745
`(an action package is not required for SE8 or SE9 supplements)
`BLA Supplement #
`BLA #
`Proprietary Name: TRULANCE
`Established/Proper Name: plecanatide
`Dosage Form: 3 mg tablets
`RPM: Maureen Dewey
`
`Applicant: Synergy Pharmaceuticals, Inc.
`Agent for Applicant (if applicable):
`
`NDA Application Type:
`Efficacy Supplement:
`
` 505(b)(1)
` 505(b)(1)
`
` 505(b)(2)
` 505(b)(2)
`
`BLA Application Type:
`Efficacy Supplement:
`
` 351(k)
` 351(k)
`
` 351(a)
` 351(a)
`
`Division: DGIEP
`For ALL 505(b)(2) applications, two months prior to EVERY action:
`
` Review the information in the 505(b)(2) Assessment and submit
`the draft2 to CDER OND IO for clearance.
` Check Orange Book for newly listed patents and/or
`exclusivity (including pediatric exclusivity)
`
` No changes
` New patent/exclusivity (notify CDER OND IO)
`Date of check:
`
`Note: If pediatric exclusivity has been granted or the pediatric
`information in the labeling of the listed drug changed, determine whether
`pediatric information needs to be added to or deleted from the labeling of
`this drug.
`
` Actions
`Proposed action
`
` User Fee Goal Date is 01/29/2017
`Previous actions (specify type and date for each action taken)
`
` If accelerated approval or approval based on efficacy studies in animals, were promotional
`materials received?
`Note: Promotional materials to be used within 120 days after approval must have been
`submitted (for exceptions, see
`http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
`nces/ucm069965.pdf). If not submitted, explain
` Application Characteristics 3
`
` AP
`
` TA CR
`
` None
`
` Received
`
`1 The Application Information Section is (only) a checklist. The Contents of Action Package Section (beginning on page 2) lists
`the documents to be included in the Action Package.
`2 For resubmissions, 505(b)(2) applications must be cleared before the action, but it is not necessary to resubmit the draft 505(b)(2)
`Assessment to CDER OND IO unless the Assessment has been substantively revised (e.g., new listed drug, patent certification
`revised).
`3 Answer all questions in all sections in relation to the pending application, i.e., if the pending application is an NDA or BLA
`supplement, then the questions should be answered in relation to that supplement, not in relation to the original NDA or BLA.
`
`Version: 2/12/16
`
`Reference ID: 4044394
`
`

`

`NDA 208745
`
`Page 2
`
`[:1 Priority
`IX Standard
`Review priority:
`Chemical classification (new NDAs only):
`Type I
`(confirm chemical classification at time ofapproval)
`
`El Fast Track
`E] Rolling Review
`El Orphan drug designation
`El Breakthrough Therapy designation
`mom.- Set the submission property in DARRTS and notifjr the CDER Breakthrough Theralry Program Manager;
`Refer to the “RPM 81' Checklistfor Considerations after Designation Granted”for other required actions: CST SharePoint)
`
`E] Rx-to-OTC full switch
`E] Rx-to-OTC partial switch
`El Direct-to-OTC
`
`NDAs: Subpart H
`[:I Accelerated approval (21 CFR 3 14.5 10)
`B Restricted distribution (21 CFR 314.520)
`Subpart I
`I:| Approval based on animal studies
`
`BLAs: Subpart E
`D Accelerated approval (21 CFR 601.41)
`D Restricted distributional CFR 601.42)
`Subpart H
`E] Approval based on animal studies
`
`I:| Submitted in response to a PMR
`I:| Submitted in response to a PMC
`D Submitted in response to a Pediatric Written Request
`
`Comments:
`
`REMS: I:I MedGuide
`I:I Communication Plan
`D ETASU
`[j MedGuide w/o REMS
`D REMS not required
`
`BLAs only: Is the product subject to official FDA lot release per 21 CFR 610.2
`(approvals only)
`
`D Yes
`
`El No
`
`Public communications (approvals only)
`
`0 Office of Executive Programs (OEP) liaison has been notified of action
`
`IX Yes D No
`
`0
`
`Indicate what types (if any) of information were issued
`
`|:| None
`[Z FDA Press Release
`|:] FDA Talk Paper
`E] CDER Q&As
`[X] Other: IA
`
`Is approval of this application blocked by any type of exclusivity (orphan, 5-year
`NCE, 3-year, pediatric exclusivity)?
`Ifso,s'
`the 1:-
`
`02° Patent Information (NDAs only)
`
`0
`
`Patent Information:
`Verify that form FDA-3542a was submitted for patents that claim the drug for
`which approval is sought
`
`'2 Verified
`D Not applicable because drug is
`an old antibiotic.
`
`
`
`List ofoflicers/employees who participated in the decision to approve this application and E Included
`consentedtobeldemlfiedonthlshsflappwva’sonlv)
`.
`
`Documentation of consent/non-consent by officers/employees
`
`IX Included
`
`O V
`
`Reference ID: 4044394
`
`

`

`NDA 208745
`
`Page 3
`
` 02° Copies of all action letters (including approval letter withfinal labeling)
`
`
`
`
`
`
`[Z Medication Guide
`
`D Patient Package Insert
`0.. Medication Guide/Patient Package Insert/Instructions for Use/Device labeling (write
`
`E] Instmctions for Use
`
`
`submission/communication date at upper right offirstpage ofeach piece)
`I:I Device Labeling
`
`_ I:I None
`
`
`Package Insert (write submission/communication date at upper right offirstpage ofPI)
`
`. Most $22531"daft.mm"133311.71;'if}?3i;Iiifiiiifiéflk‘éfiié‘iflfifig'iiliZiiiéi'Eé'E}: ' "
`trackchangeSfomat)
`
`0 Original applicant-proposed labeling
`
`0 Most-recent drafi labeling (Ifit is division—proposed labeling, it should be in
`track-changesformat)
`
` O
`
`
`
`AP 01/19/2017
`
`Labels (full color canon and immediate-container labels) (write
`submission/communication date on upper right offirstpage ofeach submission)
`
`0 Most-recent drafi labeling
`
`.
`.
`.
`.
`.
`“WWW Name .
`0 Acceptability/non-acceptabillty letter(s) (Indicate date(s))
`0
`Review(s) (indicate date(s)
`
`05/12/2016
`9/8/2016' 5/11/2016
`’
`
` 0 Original applicant-proposed labeling
`
`Labeling reviews (indicate dates ofreviews)
`
`RPM:
`
`1 1/22/16
`
`DMEPA: 12/2/16; 1/18/2017
`DMPP/PLT (DRISK): 9/19/16
`OPDP/DDMAC: 9/21/16
`COA: 12/5/16
`
`CSS: El None
`Product Quality 1/5/17; 10/18/16
`Other: I:| None
`DPMH (Maternal Health)
`1 1/10/2016
`Peds 10/20/2016
`
`RPM Filing Review‘lMe-o of Filing Meeting (indicate date ofeach review)
`All NDA 505(b)(2) Actions: Date each action cleared by 505(b)(2) Clearance Committee
`
`11/21/16
`
`'2' NDAs/NDA supplements only: Exclusivity Summary (signed by Division Director)
`
`
`
`
`'3' Application Integrity Policy (AIP) Status and Related Documents
`hflp://www fda.gov/ICECI/EnforcementActions/Applicationlntegg'flPolicy/default htm
`
`0 Applicant is on the AIP
`
`
`
`
`
`E Not a (10(2)
`
`
`
`IX Completed
`
`4 Filing reviews for scientific disciplines are NOT required to be included in the action package.
`
`Reference ID: 4044394
`
`

`

`NDA 208745
`
`Page 4
`
`0
`
`This application is on the A]?
`0
`Ifyes, Center Director’s Exception for Review memo (indicate date)
`
`El Yes XI No
`
`0
`
`Ifyes, 0C clearance for approval (indicate date ofclearance
`.
`.
`communication)
`
`El Not an AP action
`
`Pediatrics (approvals only)
`0 Date reviewed by PeRC 09/28/2016
`IfPeRC review not necessary, explain:
`
`Minutes of PeRC 10/14/2016
`
`‘3' Breakthrough Therapy Designation
`
`IX N/A
`
`0 Breakthrough Therapy Designation Letter(s) (granted, denied, an/or rescinded) —
`
`0
`
`0
`
`CDER Medical Policy Council Breakthrough Therapy Designation
`Determination Review T-plate(s) (include only the completed template(s) and
`not the meetin ' minutes
`
`CDER Medical Policy Council Brief — Evaluating a Breakthrough Therapy
`Designation for Rescission Template(s) (include only the completed template(s)
`and not the meeting minutes)
`
`(completed CDER MPC templates can befound in DARRTS as clinical reviews or on
`the MPC SharePoint Site
`
`Outgoing communications: letters, emails, and faxes considered important to include in
`the action package by the reviewing office/division (e.g., clinical SPA letters, RTF letter,
`Formal Dispute Resolution Request decisional letters, etc.) (do not include OPDP letters
`regardingpre—launch promotional materials as these are non—disclosable; do not include
`Master File letters; do not include previous action letters, as these are located elsewhere
`’
`I acka e)
`Internal documents: memoranda, telecons, emails, and other documents considered
`important to include in the action package by the reviewing oflice/division (e.g.,
`
`Ifnot the first review cycle, any end-of-review meeting (indicate date ofmtg)
`
`IX] N/A or no mtg
`
`(14)
`
`Pre—NDA/BLA meeting (indicate date ofmtg)
`
`0
`
`EOP2 meeting (indicate date ofmtg)
`
`0 Mid-cycle Communication (indicate date ofmtg)
`
`0 Other milestone meetings (e.g., EOP2a, CMC focused milestone meetings)
`(indicate dates 0 mt s)
`
`°2° Advisory Committee Meeting(s)
`
`0 Date(s) of Meeting(s)
`
`Oflice Director Decisional Memo (indicate datefor each review)
`
`Division Director Summary Review (indicate datefor each review)
`
`Cross-Discipline Team Leader Review (indicate datefor each review)
`
`PMR/PMC Development Templates (indicate total number)
`
`Reference ID: 4044394
`
`D No mtg
`
`8/5/2015
`
`E] No mtg
`
`7/13/2013
`
`E] N/A 6/29/2016
`
`g No AC meeting
`
`1/19/2017
`
`1/19/2017
`
`1/12/2017
`
`

`

`NDA 208745
`Page 5
`
` Clinical Reviews
`Clinical Team Leader Review(s) (indicate date for each review)
`
`Clinical review(s) (indicate date for each review)
`
`Social scientist review(s) (if OTC drug) (indicate date for each review)
`
` Financial Disclosure reviews(s) or location/date if addressed in another review
` OR
` If no financial disclosure information was required, check here
` review/memo explaining why not (indicate date of review/memo)
`
` and include a
`
` Clinical reviews from immunology and other clinical areas/divisions/Centers (indicate
`date of each review)5
`
` Controlled Substance Staff review(s) and Scheduling Recommendation (indicate date of
`each review)
` Risk Management
`REMS Documents and REMS Supporting Document (indicate date(s) of
`
`submission(s))
`REMS Memo(s) and letter(s) (indicate date(s))
`Risk management review(s) and recommendations (including those by OSE and
`CSS) (indicate date of each review and indicate location/date if incorporated
`into another review)
`
`
`
`
` OSI Clinical Inspection Review Summaries (include copies of OSI letters to investigators)
`
` None
`
`Clinical Microbiology
` Clinical Microbiology Team Leader Review(s) (indicate date for each review)
`Clinical Microbiology Review(s) (indicate date for each review)
`Biostatistics
` Statistical Division Director Review(s) (indicate date for each review)
`Statistical Team Leader Review(s) (indicate date for each review)
`Statistical Review(s) (indicate date for each review)
`Clinical Pharmacology
` None
` Clinical Pharmacology Division Director Review(s) (indicate date for each review)
`Clinical Pharmacology Team Leader Review(s) (indicate date for each review)
`Clinical Pharmacology review(s) (indicate date for each review)
` OSI Clinical Pharmacology Inspection Review Summary (include copies of OSI letters)
`
` None
`
` No separate review
`10/12/2016
` None
`Clinical review (10/12/2016),
` page 81, page 199
`
`
` None OBP 10/11/16
`DPMH (Maternal Health) 11/10/16
`
` N/A
`
`
`
`
`
` None 11/10/2016
`
` None requested 11/21/16;
`9/16/16; 8/31/16; 8/19/16; 8/16/16;
`7/21//16; 7/11/16; 6/28/16; 6/10/16
`
` No separate review
` None       
`
` No separate review
` No separate review
` None 11/2/16
`
` No separate review
` No separate review
` None 10/6/16
` None requested
`
`5 For Part 3 combination products, all reviews from the reviewing Center(s) should be entered into the official archive (for further
`instructions, see “Section 508 Compliant Documents: Process for Regulatory Project Managers” located in the CST electronic
`repository).
`
`Reference ID: 4044394
`
`

`

`NDA 208745
`
`Page 6
`
`Pharmacology/Toxicology Discipline Reviews
`ADP/T Review(s) (indicate datefor each review)
`Supervisory Review(s) (indicate datefor each review)
`
`Eng/(i227:}:16'ev1ew
`I:] No separate review 12/2/16
`
`Pharm/tox review(s), including referenced IND reviews (indicate datefor each
`review)
`
`D None
`
`10/18/2016
`
`Review(s) by other disciplines/divisions/Centers requested by P/T reviewer (indicate date
`for each review)
`
`'2 None
`
`Statistical review of carcinogenicity studies (indicate datefor each review)
`4° ECAC/CAC report/memo ofmeeting
`:° OSI Nonclinical Inspection Review Summary (include copies ofOSI letters)
`
`I:] No carc
`10/13/2016
`1%:13:33:11 111.21.823th .
`[Z None requested
`
`. e
`
`I:] Review & Fmvironmental Impact Statement (indicate date ofeach review)
`
`Product Quality Discipline Reviews‘s
`Tertiary review (indicate datefor each review)
`
`Secondary review (e.g., Branch Chief) (indicate datefor each review)
`miiiiégfiiééiQuahtyAssessmtIEc-(‘iii-ta“-in.-s---the-l§iiecutive-§l-1mm--mu"ary--m"and-the--pn-m:mmarymmn
`reviews from each product quality review discipline) (indicate datefor each
`
`'2 None
`
`X None
`
`D None
`
`10/6/16; 1/12/2017
`
`Reviews by other disciplines/divisions/Centers requested by product quality review team
`(indicate date ofeach review)
`
`E] None
`
`Environmental Assessment (check one) (original and supplemental applications)
`
`X Categorical Exclusion (indicate review date)(all original applications and
`all efi‘icacy supplements that could increase the patientpopulation)
`
`10/3/2016
`
`I:I Review & FONSI (indicate date of review)
`
`Facilities Review/Inspection
`
`IXI Facilities inspections (indicate date of recommendation; within one week of
`IX Acceptable 11/22/16
`taking an approval action, confirm that there is an acceptable recommendation)
`Re-evaluation date: 12/5/2016
`(only original applications and eflicaqv supplements that require a
`Cl Withhold recommendation
`manufacturing facility inspection(e.g., new strength, manufacturingprocess, or
`____________________________Lzlqzmqgamgglitgslzgnse).__________________________________________________________________________________________________________________[:1_._lt{9!.§m>_!_is_§!2.ls____________________________________
`
`
`
`5 Do not include Master File (MF) reviews or communications to MF holders. However, these documents should be made available
`upon signatory request.
`
`Reference ID: 4044394
`
`

`

`NDA 208745
`Page 7
`
`Day of Approval Activities
`
` For all 505(b)(2) applications:
` Check Orange Book for newly listed patents and/or exclusivity (including
`pediatric exclusivity)
`
`Finalize 505(b)(2) assessment
`
` For Breakthrough Therapy (BT) Designated drugs:
` Notify the CDER BT Program Manager
` For products that need to be added to the flush list (generally opioids): Flush List
` Notify the Division of Online Communications, Office of Communications
` Send a courtesy copy of approval letter and all attachments to applicant by fax or secure
`email
` If an FDA communication will issue, notify Press Office of approval action after
`confirming that applicant received courtesy copy of approval letter
` Ensure that proprietary name, if any, and established name are listed in the
`Application Product Names section of DARRTS, and that the proprietary name is
`identified as the “preferred” name
` Ensure Pediatric Record is accurate
`
` Send approval email within one business day to CDER-APPROVALS
`
` No changes
` New patent/exclusivity (Notify
`CDER OND IO)
`
` Done
`
` Done
`(Send email to CDER OND IO)
` Done
`
` Done
`
` Done
`
` Done
`
` Done
`
` Done
`
`Reference ID: 4044394
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MAUREEN D DEWEY
`01/19/2017
`
`Reference ID: 4044394
`
`

`

`MEMORANDUM OF TELECONFERENCE
`
`Teleconference Date:
`Application Number:
`Product Name:
`Indication:
`Applicant Name:
`Call Information:
`Subject:
`
`January 10, 2017; 4:00 PM – 5:00 PM
`NDA 208745
`Trulance (plecanatide) tablets
`chronic idiopathic constipation
`Synergy Pharmaceuticals
`1-855-828-1770
`Label
`
`FDA Participants:
`Office of Drug Evaluation III
`Julie Beitz, MD, Director
`
`Division of Gastroenterology and Inborn Errors Products
`Donna Griebel, M.D., Director
`Laurie Muldowney, M.D., Medical Team Leader,
`Lesley Hanes, M.D., Medical Officer
`Joette Meyer, PharmD., Associate Director for Labeling
`David Joseph, Ph.D., Pharmacology Team Leader
`Yuk-Chow Ng, Ph.D., Nonclinical Reviewer
`Maureen Dewey, M.P.H. Senior Regulatory Project Manager
`
`Office of New Drugs Quality Assessment
`Zhangfang Ge, Ph.D., CMC Team Leader
`
`Office of Clinical Pharmacology (OCP)
`Sue Chih Lee, Ph.D., Team Leader
`Dilara Jappar, Ph.D., Clinical Pharmacology Reviewer
`
`Office of Biostatistics/Division of Biometrics III
`Yeh-Fong Chen, Ph.D., Statistical Team Leader
`
`Division of Pediatric and Maternal Health Staff
`Carolyn Yancy, M.D., Reviewer
`Christos Mastroyannis, M.D., Reviewer
`Tamara Johonson, M.D., Medical Team Leader
`
`Office Biotechnology Products
`Haoheng Yan, Ph.D., Reviewer
`
`Reference ID: 4040761
`
`

`

`APPLICANT ATTENDEES
`
`Svnergv Phammceuticals, Inc.
`Patrick Griffin, M.D., Chief Medical Officer
`Evelyn Jaeger, Head, Quality Assurance and Regulatory Affairs
`
`1.0
`
`BACKGROUND:
`
`NDA 208745 Trulance (plecanatide) was submitted on January 29, 2016 as a 505(b)(l)
`application. Plecanatide (SP-304) is a new molecular entity (NME) that is not approved or
`marketed in the United States. It is an immediate-release solid formulation tablet that is intended
`
`for chronic oral administration for the treatment of CIC in adults.
`
`NDA 208745 has a standard review designation with a PDUFA goal date of January 27, 2017.
`
`On January 9, 2017, the Agency provided the applicant with revisions to labeling (prescribing
`information and Medication Guide). The purpose of this telecon was to discuss the final
`labeling.
`
`2.0
`
`DISCUSSION:
`
`FDA proposed on January 9, 2017:
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`, m functions as a
`Plecanatide is structurally related to human uroguanylin and
`guanylate cyclase—C (GC-C) agonist. Both plecanatide and its active metabolite bind to GC-C
`and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in
`an increase in both intracellular and extracellular concentrations of cyclic guanosine
`monophosphate (cGMP). Elevation of intracellular cGMP stimulates secretion of chloride and
`bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis
`transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid
`and accelerated transit. In animal models, plecanatide has been shown to increase fluid secretion
`into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool
`consistency
`m;
`
`In an animal model of visceral pain, plecan