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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 210563/Original 2
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`ACCELERATED APPROVAL
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`Pharmacyclics LLC
`Attention: Usha Ramesh, PhD
`Executive Director, Regulatory Affairs
`995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
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`Dear Dr. Ramesh:
`
`Please refer to your New Drug Application (NDA) dated August 31, 2017, received
`August 31, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Imbruvica® (ibrutinib) tablets, 140 mg, 280 mg, 420 mg,
`and 560 mg.
`
`NDA 210563 provides for the use of Imbruvica® for the following indications which, for
`administrative purposes, we have designated as follows:
`
`
` NDA 210563/Original 1 – Treatment of adult patients with chronic lymphocytic
`leukemia/small lymphocytic lymphoma (CLL), chronic lymphocytic leukemia
`(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion, Waldenström’s
`macroglobulinemia (WM), and chronic graft versus host disease (cGVHD) after failure of
`one or more lines of systemic therapy.
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` NDA 210563/Original 2 – Treatment of adult patients with mantle cell lymphoma (MCL)
`who have received at least one prior therapy, and marginal zone lymphoma (MZL) who
`require systemic therapy and have received at least one prior anti-CD20-based therapy.
`
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`The subject of this action letter is NDA 210563/Original 2. A separate action letter will be
`issued for NDA 210563/Original 1.
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`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved under the
`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug
`product and related activities must adhere to the substance and procedures of the referenced
`accelerated approval regulations.
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`
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`Reference ID: 4223111
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`NDA 210563/Original 2
`Page 2
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`EXPIRATION DATING PERIOD
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`We grant a 24-month expiration period for the drug product when stored at controlled room
`temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C
`(between 59°F and 86°F).
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`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 (package insert and patient package insert).
`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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on February 14, 2018, as soon as they are available, but no more than
`30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry titled Providing Regulatory Submissions in Electronic Format — Certain
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 210563.” Approval of this
`submission by FDA is not required before the labeling is used.
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`ACCELERATED APPROVAL REQUIREMENTS
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`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled clinical trials to verify and describe clinical benefit. You are
`required to conduct such clinical trials with due diligence. If postmarketing clinical trials fail to
`verify clinical benefit or are not conducted with due diligence, we may, following a hearing in
`accordance with 21 CFR 314.530, withdraw this approval. We remind you of your
`postmarketing requirement for treatment of patients with mantle cell lymphoma who have
`received at least one prior therapy, specified in your submission dated February 6, 2018. This
`requirement, along with required completion dates, is listed below.
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`Reference ID: 4223111
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`
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`NDA 210563/Original 2
`Page 3
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`PMR 3343-1 Complete and submit the final results of the ongoing randomized, double-blind,
`placebo controlled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in
`combination with bendamustine and rituximab in patients with newly diagnosed
`mantle cell lymphoma. Enrollment of approximately 520 patients is expected.
`The primary endpoint is progression-free survival as assessed by investigators.
`Overall survival is a key secondary endpoint.
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`Trial Completion:
`Final Report Submission:
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`We remind you of your postmarketing requirement for treatment of patients with marginal zone
`lymphoma who require systemic therapy specified in your submission dated February 6, 2018.
`This requirement, along with required completion dates, is listed below.
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`PMR 3343-2 Submit the complete final report and data from a randomized, Phase 3 trial,
`comparing ibrutinib in combination with bendamustine and rituximab or
`rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone versus
`bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin,
`vincristine, and prednisone in subjects with previously treated follicular
`lymphoma or marginal zone lymphoma. At least 50 enrolled subjects need to
`have a diagnosis of marginal zone lymphoma. The primary endpoint is
`progression-free survival in the overall intent-to-treat population.
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`12/2018
`03/2019
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`Trial Completion:
`Final Report Submission:
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`05/2019
`08/2019
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`Under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of
`each requirement in your annual report to this NDA. The status summary should include
`expected summary completion and final report submission dates, any changes in plans since the
`last annual report, and, for clinical studies/trials, number of patients entered into each trial.
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`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
`submissions relating to this postmarketing requirement must be clearly designated “Subpart H
`Postmarketing Requirement(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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`Reference ID: 4223111
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`NDA 210563/Original 2
`Page 4
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`PROMOTIONAL MATERIALS
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`Under 21 CFR 314.550, you are required to submit, during the application pre-approval review
`period, all promotional materials, including promotional labeling and advertisements, that you
`intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If
`you have not already met this requirement, you must immediately contact the Office of
`Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory
`project manager or the appropriate reviewer to discuss this issue.
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`As further required by 21 CFR 314.550, submit all promotional materials that you intend to use
`after the 120 days following marketing approval (i.e., your post-launch materials) at least 30
`days before the intended time of initial dissemination of labeling or initial publication of the
`advertisement. We ask that each submission include a detailed cover letter together with three
`copies each of the promotional materials, annotated references, and approved package insert
`(PI)/Medication Guide/patient PI (as applicable).
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`Send each submission directly to:
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotions (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with the reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, please contact Jennifer Lee, Regulatory Project Manager, at
`(240) 402-4622.
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`Sincerely,
`
`{See appended electronic signature page}
`
`R. Angelo de Claro, MD
`Deputy Division Director (Acting)
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 4223111
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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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`ROMEO A DE CLARO
`02/16/2018
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`Reference ID: 4223111
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