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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 208745/S-001
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Synergy Pharmaceuticals, Inc.
`Attn: Evelyn Jaeger
`Vice President Regulatory Affairs & Clinical Quality Assurance
`420 Lexington Avenue
`Suite 2012
`New York, NY 10170
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`Dear Ms. Jaeger:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received March 24,
`2017, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Trulance™ (plecanatide) oral tablets, 3mg.
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`This Prior Approval supplemental new drug application proposes a new indication for irritable
`bowel syndrome with constipation (IBS-C).
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`We note that your January 24, 2018, submission includes final printed labeling (FPL) for your
`package insert and Medication Guide. We have not reviewed this FPL. You are responsible for
`assuring that the wording in this printed labeling is identical to that of the approved content of
`labeling in the structured product labeling (SPL) format.
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`CONTENT OF LABELING
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`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 the enclosed labeling (text for the package insert and Medication
`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
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`Reference ID: 4211838
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`

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`NDA 208745/S-001
`Page 2
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your January 19, 2018, submission containing final printed carton and
`container labels.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`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(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`We are waiving the pediatric study(ies) requirement for ages birth to <6 years of age because
`necessary studies are impossible or highly impracticable. IBS is not generally described in
`patients younger than 6 years of age and is therefore not an appropriate indication for study in
`this age group.
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`We are deferring submission of your pediatric study(ies) for ages 6 to <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.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act/FDCA are required postmarketing studies. The status of these postmarketing
`studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(C) of the
`Federal Food, Drug, and Cosmetic Act/FDCA. These required studies are listed below.
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`3304-1
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`Perform a double-blind, dose ranging study in pediatric patients ages 6 years to
`less than 18 years in order to evaluate the safety and efficacy of once daily oral
`Trulance (plecanatide) for 4 weeks as treatment of IBS-C. Patients will be
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`Reference ID: 4211838
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`

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`NDA 208745/S-001
`Page 3
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`3304-2
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`stratified by age group (6 years to 11 years and 12 years to less than 18 years of
`age).
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`Final Protocol Submission: 06/18
`Study/Trial Completion:
`03/20
`Final Report Submission:
`08/20
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`Confirm the efficacy and safety of Trulance (plecanatide) treatment in pediatric
`patients with IBS-C 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. Patients will be stratified by age (6 years to 11 years and 12 years to less
`than 18 years of age).
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`Final Protocol Submission: 09/20
`Study/Trial Completion:
`08/22
`Final Report Submission:
`11/22
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`3304-3 Assess the long-term safety of Trulance (plecanatide) once-daily treatment for
`chronic idiopathic constipation (CIC) or IBS-C in pediatric patients who are 6
`years to less than 18 years of age and have completed the confirmatory efficacy
`and safety study with Trulance (plecanatide) by performing an open-label, active,
`comparator-controlled, safety and tolerability study for up to 24 weeks.
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`Final Protocol Submission: 02/21
`Study/Trial Completion:
`08/23
`Final Report Submission:
`11/23
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`Submit the protocol(s) to your IND 115118, with a cross-reference letter to this NDA.
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`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.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient:
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`Reference ID: 4211838
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`

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`NDA 208745/S-001
`Page 4
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`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
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`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 this serious risk. Finally, we have
`determined that only a clinical trial (rather than a nonclinical or observational study) will be
`sufficient.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`3304-4
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` Assess development of anti-drug antibody (ADA) responses in patient samples
`using the immunogenicity serum samples collected in the plecanatide studies
`(SP304203-04 and SP304203-05, and SP304203-06). 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) in patients with IBS-C.
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`Final Report Submission: 04/2019
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`3304-5
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`Use the validated cross reactivity assays developed under PMR 3117-8 to test the
`ADA positive samples detected under PMR 3304-4. Evaluate the relationships
`between cross reactivity status and the safety and efficacy of Trulance
`(plecanatide) in patients with IBS-C.
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`Final Report Submission: 6/2020
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`3304-6
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`Use the validated neutralizing antibody assay developed under PMR 3117-9 to
`test the ADA positive samples detected under PMR 3304-4. Evaluate the
`relationships between neutralizing antibody status and the safety and efficacy of
`Trulance (plecanatide) in patients with IBS-C.
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`Final Report Submission: 08/2021
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`Submit the protocol(s) to your IND 115118, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final
`report(s) 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)”.
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`Reference ID: 4211838
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`

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`NDA 208745/S-001
`Page 5
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`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.
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`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) on the date required will be considered a violation of FDCA section
`505(o)(3)(E)(ii) and could result in enforcement action.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`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/U
`CM443702.pdf ).
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`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. 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.
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`Reference ID: 4211838
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`

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`NDA 208745/S-001
`Page 6
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Evangela Covert, Regulatory Project Manager, at (301) 796-4075.
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`Sincerely,
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`{See appended electronic signature page}
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`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn Errors
`Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
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`Reference ID: 4211838
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`

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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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`DONNA J GRIEBEL
`01/24/2018
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`Reference ID: 4211838
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