`
`
`
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
` NDA 205552/S-007
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
` Pharmacyclics LLC
`
`
` Attention: Jill Herendeen, PharmD, RAC
` Senior Director, Regulatory Affairs
`
`
` 995 East Arques Avenue
`
` Sunnyvale, CA 94085-4521
`
`
`
`
`Dear Dr. Herendeen:
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated September 10, 2015,
`
`
`
`
`
`received September 10, 2015, 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 a frontline indication of
`
`
`
`
`
` IMBRUVICA® (ibrutinib) for the treatment of Chronic Lymphocytic Leukemia.
`
`
`
`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.
`
`
`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(s) in pediatric patients unless this requirement is waived,
`
`
`deferred, or inapplicable.
`
`
`
`
`
`
`Because the drug product for this indication has orphan drug designation, you are exempt from
`
`this requirement.
`
`
`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.
`
`
`
`
`
`
`Reference ID: 3896712
`
`

`

`
`
`
`
`
`
`
`
` NDA 205552/S-007
`
` Page 2
`
`
`
`
` Since IMBRUVICA® (ibrutinib) was approved on February 12, 2014, we have become aware of
` the possibility of increased risks with long-term use of IMBRUVICA® (ibrutinib) based on the
`
`
`
`
`
`
` results from clinical trials submitted to the NDA: PCYC-1102-CA, PCYC-1104-CA, PCYC­
`
`
`
` 1118E, PCYC-1112-CA, and PCYC-1115-CA. These include, but are not limited to,
`
`
`
`
` hemorrhage, infection, cytopenias, atrial fibrillation, hypertension, and second primary
`
`
` malignancies. We consider this “new safety information” as defined in section 505-1(b)(3) of the
`
`
`
`
`
`
` FDCA.
`
`
`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 signals of serious risks of
` long-term IMBRUVICA® (ibrutinib) treatment including hemorrhage, infection, cytopenias,
`
`
`
`
`
` atrial fibrillation, hypertension, and second primary malignancies.
`
`
`
`
`
`
`
`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:
`
`
`
`
`
`PMR 3038-1 Conduct a study to characterize the safety of long-term exposure to Imbruvica
`
`
`based on data and pooled analyses from trials of patients with mantle cell
`
`
`
`
`
`lymphoma and chronic lymphocytic leukemia. Submit 3-year, 4-year, and 5-year
`
`safety follow-up data and reports for a minimum population of 1000 patients
`treated with approved ibrutinib dosing regimens. Datasets should include patient-
`
`
`
`level data on ibrutinib dosing, treatment-emergent adverse events, and treatment-
`
`
`
`emergent laboratory information. This patient set may include approximately 350
`
`
`
`patients who continue receiving long-term ibrutinib therapy after completion of
`
`
`
`primary analysis of the parent study, where study procedures are then limited to
`
`collect a minimum of Grade 3+ adverse events, available treatment emergent
`
`
`laboratory data, adverse events leading to treatment discontinuation and SAEs.
`
`
`
`
`Study reports should include analyses of adverse event categories listed in the
`
`
`
`
`current Warnings and Precautions section of the prescribing information, adverse
`
`
`
`
`
`events leading to treatment discontinuation, and serious adverse events.
`
`
`
`
`
`
`The timetable you submitted on February 19, 2016, states that you will conduct this study
`
`
`according to the following schedule:
`
`
`
`
`
`
`Final Protocol Submission:
`
`
`
`Interim 3-year Data and Report Submission:
`
`
`
`Interim 4-year Data and Report Submission:
`
`
`
`
`Final Data and Report Submission:
`
`
`08/2016
`
`04/2017
`
`04/2018
`
`04/2019
`
`
`
`
`
`
`
`Submit the protocol to your IND 102688, with a cross-reference letter to this NDA. Submit all
`
`
`
`
`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
`
`
`
`
`
`
`Reference ID: 3896712
`
`

`

`
`
`
`
` NDA 205552/S-007
`
` Page 3
`
`
` 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) 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 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:
`
`
`
`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
`
`
`
`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.
`
`
`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
`
`
`Reference ID: 3896712
`
`

`

`
`
`
`
`
`
` NDA 205552/S-007
`
` Page 4
`
`
` 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).
`
`
`
`
`
`If you have any questions, call Elleni Alebachew, Regulatory Project Manager, at
`
`(301) 796-5225.
`
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`
`Edvardas Kaminskas, M.D.
`
`
`Deputy Director
`
`Division of Hematology Products
`
`Office of Hematology and Oncology Products
`
`
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`
`
`Content of Labeling
`
`
`Reference ID: 3896712
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`EDVARDAS KAMINSKAS
`03/04/2016
`
`Reference ID: 3896712
`
`