`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`
` Trulance tablets, 3 mg.
`Trade Name:
`plecanatide
`Generic or Proper
`Name:
`
`
`Synergy Pharmaceuticals Inc.
`Sponsor:
`
`
`January 19, 2017
`Approval Date:
`
`
`Provides for the use of Trulance tablets for the treatment
`of chronic idiopathic constipation (CIC) in adults.
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`208745Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208745Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 208745
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Synergy Pharmaceuticals Inc.
`Attention: Evelyn Jaeger
`Head of Regulatory Operations
`420 Lexington Avenue, Suite 2012
`New York, NY 10170
`
`Dear Ms. Jaeger:
`
`Please refer to your New Drug Application (NDA) dated January 29, 2016, received January 29,
`2016, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Trulance (plecanatide) tablets, 3 mg.
`
`This new drug application provides for the use of Trulance (plecanatide) tablets for the treatment
`of chronic idiopathic constipation (CIC) in adults.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the agreed-upon labeling text and with the minor
`editorial revisions to Section 8.1 indicated in the enclosed labeling.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to, except with the revisions indicated, the enclosed labeling (text
`for the package insert and Medication Guide). Information on submitting SPL files using eLIST
`may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs
`and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and immediate container labels that are identical to the enclosed
`carton and immediate container labels and carton and immediate container labels submitted on
`January 3, 2017, as soon as they are available, but no more than 30 days after they are printed.
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 2
`
`
`Please submit these labels electronically according to the guidance for industry Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Final Printed Carton
`and Container Labels for approved NDA 208745.” Approval of this submission by FDA is
`not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`ADVISORY COMMITTEE
`
`Your application for Trulance was not referred to an FDA advisory committee because the
`application did not raise significant public health questions on the role of the drug in the
`diagnosis, cure, mitigation, treatment, or prevention of a disease.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric studies requirement for ages birth to less than 2 years because there
`is evidence strongly suggesting that the drug product would be unsafe in this pediatric group. In
`non-clinical studies of plecanatide, a guanylate cyclase-C (GC-C) agonist, deaths due to
`dehydration occurred within 24 hours in young juvenile mice. This data and the literature
`regarding GC-C receptor ontogeny indicate that plecanatide would not be safe to administer to
`pediatric patients under 2 years of age.
`
`We are deferring submission of your pediatric studies for ages 6 years to less than 18 years of
`age for this application because this product is ready for approval for use in adults and the
`pediatric studies have not been completed. We are deferring submission of your pediatric studies
`for ages 2 years to less than 6 years of age because this product is ready for approval for use in
`adults, and pediatric studies should be delayed in this age group until additional safety data from
`a study evaluating GC-C receptor ontogeny and the results of the clinical studies of plecanatide
`in older pediatric cohorts have been evaluated. In order to avoid severe diarrhea and its serious
`sequelae, nonclinical data and literature findings suggest special caution should be exercised in
`defining the initial plecanatide dose range for young pediatric patients.
`
`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
`postmarketing studies. The status of these postmarketing studies must be reported annually
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 3
`
`
`according to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. These required studies are
`listed below.
`
`
`3117-1. Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients
`with chronic idiopathic constipation (CIC) who are 12 years to less than 18 years of
`age by assessing the safety and efficacy of once daily oral plecanatide in an eight (8)
`week, proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling
`study.
`
`
`
`Final Protocol Submission: 12/31/15 (completed)
`Study Completion:
`
`12/18
`Final Report Submission:
`02/19
`
`
`3117-2. Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients
`with chronic idiopathic constipation (CIC) who are 6 years to less than 12 years of age
`by assessing the safety and efficacy of once daily oral plecanatide in an eight (8) week,
`proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling study.
`
`
`
`
`Final Protocol Submission: 12/18
`Study Completion:
`
`12/20
`Final Report Submission:
`02/21
`
`
`
`3117-3. Confirm the efficacy and safety of Trulance (plecanatide) in pediatric patients with
`chronic idiopathic constipation (CIC) who are 6 years to less than 18 years of age by
`performing a randomized, double-blind, placebo-controlled, parallel group, 12 week
`treatment study.
`
`
`
`
`
`
`
`
`3117-4. Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients
`with chronic idiopathic constipation (CIC) who are 2 years to less than 6 years of age
`by assessing the safety and efficacy of once daily oral plecanatide in an eight (8) week,
`proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling study.
`
`Final Protocol Submission: 12/18
`Study Completion:
`
`12/21
`Final Report Submission:
`02/22
`
`Final Protocol Submission: 12/20
`Study Completion:
`
`12/22
`Final Report Submission:
`02/23
`
`
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 4
`
`
`
`3117-5. Confirm the efficacy and safety of Trulance (plecanatide) treatment in pediatric
`patients with chronic idiopathic constipation (CIC) who are 2 years to less than 6 years
`of age by performing a randomized, double-blind, placebo-controlled, parallel group,
`12 week treatment study.
`
`
`
`
`Final Protocol Submission: 12/22
`Study Completion:
`
`12/25
`Final Report Submission:
`02/26
`
`
`
`3117-6. Assess the long-term safety of Trulance (plecanatide) in pediatric patients with chronic
`idiopathic constipation (CIC) who are 2 years to less than 18 years of age and have
`completed a confirmatory efficacy and safety study with plecanatide.
`
`
`
`
`Final Protocol Submission: 02/17
`Study Completion:
`
`06/26
`Final Report Submission:
`08/26
`
`
`
`Submit the protocols to your IND 74883, with a cross-reference letter to this NDA.
`
`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient:
`to identify an unexpected serious risk of development of immune-mediated reactions
`•
`with the use of Trulance (plecanatide);
`to identify unexpected serious risks related to use of Trulance (plecanatide) in the
`development of anti-drug antibodies that may cross react with endogenous guanylin
`peptide family members and theoretically lead to deficiency syndromes; or
`to assess a signal of a serious potential risk of a significant fluid shift into the intestine
`due to age-dependent expression of the target receptor (GC-C), leading to severe
`
`•
`
`•
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 5
`
`
`
`dehydration and possibly death, in pediatric patients from birth to 6 years of age exposed
`to a GC-C receptor agonist.
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`3117-7. Develop and validate a sensitive and precise assay for the detection of anti-plecanatide
`antibodies (ADA), including IgM, IgG, and IgA, that may be present in the serum at
`the time of patient sampling.
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this study
`according to the following schedule:
`
`
`Final Report Submission: 04/18
`
`
`The final report should include screening, confirmation and titer assay validation reports and
`assay standard operating procedures (SOPs).
`
`3117-8. Develop and validate assays to evaluate the cross reactivity of anti-plecanatide
`antibodies to guanylin and uroguanylin.
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this study
`according to the following schedule:
`
`
`Final Report Submission: 04/20
`
`
`The final report should include assay validation reports and the assay standard operating
`procedures (SOPs).
`
`3117-9. Develop and validate an assay to evaluate the neutralizing capacity of ADAs detected
`in the patient samples taking Trulance (plecanatide).
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this study
`according to the following schedule:
`
`
`Final Report Submission: 08/20
`
`
`The final report should include assay validation report and the assay standard operating
`procedures (SOPs).
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 6
`
`
`
`
`3117-10. A study to characterize guanylate cyclase-C (G-CC) mRNA expression in duodenal
`and colonic mucosal biopsies in pediatric patients ages 0 to 6 years undergoing
`diagnostic gastrointestinal endoscopies as part of their medical care.
`
`The timetable you submitted on October 13, 2016, states that you will conduct this study
`according to the following schedule:
`
`
`12/17
`04/19
`07/19
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission
`
`Finally, we have determined that only clinical trials (rather than a nonclinical or observational
`study) will be sufficient:
`to identify an unexpected serious risk of development of immune-mediated reactions with
`•
`the use of Trulance (plecanatide);
`to identify unexpected serious risks related to use of Trulance (plecanatide) in the
`development of anti-drug antibodies that may cross react with endogenous guanylin
`peptide family members and theoretically lead to deficiency syndromes; or
`to identify an unexpected serious risk associated with the presence of plecanatide, or its
`active metabolite, in human breast milk.
`
`•
`
`•
`
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`3117-11. Assess development of anti-drug antibody (ADA) responses in patient samples using
`the immunogenicity serum samples collected in the plecanatide studies (SP304203-00
`and SP304203-03 and SP304203-01). Validated assays capable of sensitively and
`accurately detecting ADA responses, developed under PMR 3117-7, will be used.
`Evaluate the anti-drug antibody (ADA) rates, individual patient titers and the
`relationships between ADA status and the safety and efficacy of Trulance
`(plecanatide).
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Report Submission: 04/19
`
`
`3117-12. Use the validated cross reactivity assays developed under PMR 3117-8 to test the
`ADA positive samples detected under PMR 3117-11. Evaluate the relationships
`between cross reactivity status and the safety and efficacy of Trulance (plecanatide).
`
`
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 7
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Report Submission: 06/20
`
`3117-13. Use the validated neutralizing antibody assay developed under PMR 3117-9 to test the
`ADA positive samples detected under PMR 3117-11. Evaluate the relationships
`between neutralizing antibody status and the safety and efficacy of Trulance
`(plecanatide).
`
`
`The timetable you submitted on November 29, 2016, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Report Submission: 08/21
`
`3117-14. Perform a milk-only lactation trial in lactating women who have received multiple,
`once daily, doses of Trulance (plecanatide) therapeutically to assess concentrations of
`plecanatide and its active metabolite in breast milk using a validated assay in order.
`
`
`The timetable you submitted on October 13, 2016, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 12/17
`Trial Completion:
` 06/18
`Final Report Submission: 12/18
`
`
`
`Submit the protocols to your IND 74883, with a cross-reference letter to this NDA. Submit all
`final reports to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report Under
`505(o),” “Required Postmarketing Correspondence Under 505(o).”
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 8
`
`
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert,
`Medication Guide, and patient PI (as applicable) to:
`
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM443702.pdf ).
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. Form FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 9
`
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`FDA BENEFIT-RISK FRAMEWORK APPLICANT INTERVIEW
`
`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an assessment of
`FDA’s initial phase implementation of the Benefit-Risk Framework (BRF) in human drug
`review. A key element of this evaluation includes interviews with applicants following FDA
`approval of New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologic
`License Applications (BLAs). The purpose of the interview is to assess the extent to which the
`BRF provides applicants with a clear understanding of the reasoning behind FDA’s regulatory
`decisions for NME NDAs and original BLAs.
`
`ERG will contact you to schedule a BRF applicant interview and provide specifics about the
`interview process. Your responses during the interview will be confidential with respect to the
`FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
`identifying information to anyone outside their project team. They will report only anonymized
`results and findings in the interim and final reports. Members of the FDA review team will be
`interviewed by ERG separately. While your participation in the interview is voluntary, your
`feedback will be helpful to this evaluation.
`
`Reference ID: 4044252
`
`

`

`NDA 208745
`Page 10
`
`
`
`If you have any questions, call Maureen Dewey, Regulatory Project Manager, at (301) 796-0845.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Julie Beitz, M.D.
`Director
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`Content of Labeling
`Medication Guide
`Carton and Container Labeling
`
`
`
`Reference ID: 4044252
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JULIE G BEITZ
`01/19/2017
`
`Reference ID: 4044252
`
`(
`
`
`
`