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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 205552/S-017
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
`FULFILLMENT OF POSTMARKETING
`REQUIREMENT
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`Pharmacyclics LLC
`Attention: Tania Bekerman
`Senior Manager, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
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`Dear Ms. Bekerman:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated February 2, 2017,
`received February 2, 2017, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutinib) capsules, 140 mg.
`
`This Prior Approval supplemental new drug application provides for the addition of a new
`indication for the treatment of adult patients with chronic graft versus host disease (cGVHD)
`after failure of one or more lines of systemic therapy.
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`APPROVAL & LABELING
`
`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.
`
`WAIVER OF HIGHLIGHTS SECTION
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
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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 the patient
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`Reference ID: 4133530
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`

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`NDA 205552/S-017
`Page 2
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`package insert), 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.
`
`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.
`
`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 this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`FULFILLMENT OF POSTMARKETING REQUIREMENT(S)/COMMITMENT(S)
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`We have received your submission dated December 14, 2016, containing the final report for the
`following postmarketing requirement listed in the November 13, 2013 approval letter.
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`PMR 2060-3 Determine the effect of a broad range of concentrations of ibrutinib on the
`potential to inhibit platelet function by conducting in vitro studies. Assessment
`methods should include evaluation of effects on platelet aggregation, including
`GPIb-mediated aggregation. Evaluation should include samples from subjects
`with and without concomitant conditions associated with platelet dysfunction
`(e.g., severe renal dysfunction, use of concomitant anticoagulant, and use of
`aspirin).
`
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`The timetable you submitted on November 13, 2013, states that you will conduct this trial
`according to the following schedule:
`
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`Reference ID: 4133530
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`

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`NDA 205552/S-017
`Page 3
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`Draft Protocol Submission: 06/2014
`Final Protocol Submission: 12/2014
`Trial Completion:
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`06/2016
`Final Report Submission:
`12/2016
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`We have reviewed your submission and conclude that the above requirement was fulfilled.
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`We remind you that there are postmarketing requirements listed in the November 13, 2013
`approval letter and a postmarketing commitment listed in the January 29, 2015 approval letter
`and a postmarketing requirement listed in the March 4, 2016 approval letter that are still open.
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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 Imbruvica (ibrutinib) capsules was approved on November 13, 2013, we have become
`aware of severe diarrhea, fatigue, pneumonia, and sepsis occurring in greater than 10% of
`patients with cGVHD in the single-arm clinical trial submitted with this application.
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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 to assess these signals.
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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.
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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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`PMR 3250-1 Conduct an analysis of safety in patients with chronic graft-versus-host-disease
`treated with ibrutinib. Submit the complete primary study report and datasets
`from Study PCYC-1140-IM: A Randomized, Double-Blind Phase 3 Study of
`Ibrutinib in Combination with Corticosteroids versus Placebo in Combination
`with Corticosteroids in Subjects with New Onset Chronic Graft-Versus-Host
`Disease (cGVHD). Include safety analyses that evaluate impact of concomitant
`medications (for example, corticosteroids and additional immunosuppressants) on
`the safety profile for ibrutinib.
`
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`The timetable you submitted on July 18, 2017, states that you will conduct this study according
`to the following schedule:
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`12/2021
`Primary Study Completion:
`Primary Study Report Submission: 12/2022
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`
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`Reference ID: 4133530
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`

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`NDA 205552/S-017
`Page 4
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`Submit the protocol(s) to your IND 102688, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final
`report 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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`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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`Reference ID: 4133530
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`

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`NDA 205552/S-017
`Page 5
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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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`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, please call Esther Park, Regulatory Project Manager, at
`(301) 796-2811.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Ann T. Farrell, MD
`Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 4133530
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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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`ANN T FARRELL
`08/02/2017
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`Reference ID: 4133530
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