`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
`ACCELERATED APPROVAL
`
`
`
`
` Pharmacyclics LLC
`
` Attention: Jill Herendeen, PharmD, RAC
`
`
` Senior Director, Regulatory Affairs
`
` 995 E. Arques Avenue
` Sunnyvale, CA 94085-4521
`
`
`
`
`Dear Ms. Herendeen:
`
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated September 23, 2016,
`
`
`
`
`
`received September 23, 2016, 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 treatment of patients with Marginal Zone Lymphoma (MZL) who require systemic
`
`
`
`therapy and have received at least one prior anti-CD20-based therapy.
`
`
`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.
`
`CONTENT OF LABELING
`
`
`
`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
`
`
`
`
` 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.
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 205552/S-016
`
`
`
`
`
`
`
`Reference ID: 4043198
`
`

`

`
`
`
`
` NDA 205552/S-016
`
` Page 2
`
`
`
` 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).
`
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`
`
`
`
`adequate and well-controlled studies/clinical trials to verify and describe clinical benefit. You
`
`
`are required to conduct such studies/clinical trials with due diligence. If postmarketing
`
`
`
`studies/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 specified in your submission dated January 11,
`
`
`2017. This requirement, along with required completion dates, is listed below.
`
`
`PMR 3150-1 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.
`
`
`
`
`Final Protocol Submission:
`Completed
`
`
`
`Trial Completion:
`05/2019
`
`
`
`
`Final Report Submission:
`08/2019
`
`
`
`
`
`Submit clinical protocols to your IND 102688 for this product. In addition, 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 study/trial.
`
`
`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).”
`
`
`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
`
`
`
`
`
`
`Reference ID: 4043198
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
` NDA 205552/S-016
`
` Page 3
`
`
` 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 this drug product for this indication has an orphan drug designation, you are exempt
`
`from this requirement.
`
`
`PROMOTIONAL MATERIALS
`
` 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.
`
`
`
` 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).
`
` Send each submission directly to:
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`Alternatively, you may submit promotional materials for accelerated approval products
`
`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 ).
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`Reference ID: 4043198
`
`

`

` NDA 205552/S-016
`
` Page 4
`
`
`
` If you have any questions, call Suria Yesmin, Regulatory Project Manager, at (301) 348-1725.
`
`
`
`
`
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`
`Edvardas Kaminskas, MD
`
`
`Deputy Division Director
`
`
`Division of Hematology Products
`
`Office of Hematology and Oncology Products
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
`ENCLOSURE:
`
`
`
`Content of Labeling
`
`
`
`
`Reference ID: 4043198
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`01/18/2017
`
`Reference ID: 4043198
`
`