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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021688/S-024
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Amgen Inc.
`Attention: Juliana Sholter, M.S., R.A.C.
`Manager, Regulatory Affairs
`601 13th Street NW
`12th Floor
`Washington, DC 20005
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`Dear Ms. Sholter:
`
`Please refer to your supplemental New Drug Application (sNDA) dated and received
`March 31, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Sensipar (cinacalcet) tablets.
`
`We also refer to our letter dated March 1, 2017, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for Sensipar.
`This information pertains to the risk of gastrointestinal bleeding.
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`This supplemental new drug application provides for revisions to the labeling for Sensipar,
`consistent with our March 1, 2017, letter.
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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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`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 prescribing information), 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: 4097661
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`NDA 021688/S-024
`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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`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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`Because none of these criteria apply to your application, you are exempt from this requirement.
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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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`Since Sensipar (cinacalcet) was approved on March 8, 2004, we have become aware of the
`serious risk of gastrointestinal bleeding (GIB) with Sensipar (cinacalcet) through cases identified
`in postmarketing data. We consider this information to be “new safety information” as defined
`in section 505-1(b)(3) of the FDCA.
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`As previously communicated to you in our letter dated March 1, 2017, 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 assess the signal of a serious risk of gastrointestinal bleeding.
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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. Therefore, based on
`appropriate scientific data, FDA has determined that you are required to conduct the following:
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`Reference ID: 4097661
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`NDA 021688/S-024
`Page 3
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`3202-1
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`Conduct a hypothesis-testing observational study to provide data regarding the
`potential association between Sensipar (cinacalcet) and fatal and non-fatal
`gastrointestinal bleeding. The study should have a comparator group, be powered
`to detect the outcomes of interest, with justification for the proposed detectable
`differences in incidence rates. Special attention should be given to complete data
`availability in dialysis patients with secondary hyperparathyroidism above and
`below the age of 65 years, the ability to ascertain cause of death in a timely
`manner, and a statistical consideration of competing risks. Secondary analyses
`should aim to quantify the exposure-risk window, including periods after
`exposure discontinuation. The choice of study design, data source(s), and sample
`size should be supported by a feasibility analysis submitted to and reviewed by
`FDA prior to protocol finalization.
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`The timetable you submitted on April 25, 2017, states that you will conduct this study according
`to the following schedule:
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`06/2017
`11/2017
`06/2018
`09/2018
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`Draft Protocol (with Feasibility Analysis):
`Final Protocol Submission:
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`Study Completion:
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`Final Report Submission:
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`Submit the protocol to your IND 056010, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing 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)”.
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`Submission of the protocol for required postmarketing observational studies to your IND is for
`purposes of administrative tracking only. These studies do not constitute clinical investigations
`pursuant to 21 CFR 312.3(b) and therefore are not subject to the IND requirements under
`21 CFR part 312 or FDA’s regulations under 21 CFR parts 50 (Protection of Human Subjects)
`and 56 (Institutional Review Boards).
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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
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`Reference ID: 4097661
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`NDA 021688/S-024
`Page 4
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`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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`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
`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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`Reference ID: 4097661
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`

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`NDA 021688/S-024
`Page 5
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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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`We remind you of our March 1, 2017, request that for a period of 2 years, you submit all cases of
`gastrointestinal ulceration and bleeding events reported with Sensipar (cinacalcet) as 15-day alert
`reports, and that you provide detailed analyses of gastrointestinal ulceration and bleeding events
`reported from clinical study and postmarketing reports of gastrointestinal bleeding events as
`adverse events of special interest in your periodic safety report (i.e., the Periodic Adverse Drug
`Experience Report [PADER] required under 21 CFR 314.80(c)(2) or the ICH E2C Periodic
`Benefit-Risk Evaluation Report [PBRER] format). These analyses should show cumulative data
`relative to March 1, 2017, as well as relative to prior periodic safety reports. Medical literature
`reviews for case reports/case series of gastrointestinal bleeding events reported with Sensipar
`(cinacalcet) should also be provided in the periodic safety report.
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`If you have any questions, call Meghna M. Jairath, Pharm.D., Regulatory Project Manager, at
`(301) 796-4267.
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`Sincerely,
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`{See appended electronic signature page}
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`Jennifer Rodriguez Pippins, M.D., M.P.H.
`Deputy Director for Safety
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 4097661
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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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`JENNIFER R PIPPINS
`05/15/2017
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`Reference ID: 4097661
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