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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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` Silver Spring MD 20993
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`NDA 205552/Original 2
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`ACCELERATED APPROVAL
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` Pharmacyclics, Inc.
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` Attention: Christine Salido
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` Executive Director, Regulatory Affairs
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` 9995 East Arques Avenue
` Sunnyvale, CA 94085-4521
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`Dear Ms. Salido:
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`Please refer to your New Drug Application (NDA) dated June 28, 2013, received June 28, 2013,
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`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Imbruvica® (ibrutinib) capsules, 140 mg.
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`For administrative purposes we designated your originally submitted NDA as follows:
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`• NDA 205552/Original 1 – for the treatment of patients with Mantle Cell lymphoma
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`(MCL). This indication was approved on November 13, 2013, under the provisions of
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`accelerated approval regulations (21 CFR 314.500).
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`• NDA 205552/Original 2 – for the treatment of patients with Chronic Lymphocytic
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`Leukemia (CLL) who have received at least one prior therapy.
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`The subject of this action letter is NDA 205552/Original 2.
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`We acknowledge receipt of your amendments dated May 6, 13, 2013; June 6, 20, 2013;
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`July 12, 25(2), 26 (3), 30, 2013; August 1, 2 (7), 5 (2), 6, 7, 9, 12, 13 (3), 14 (11), 15, 16, 19, 20,
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`21, 23, 26, 29, 30, 2013; September 4, 6, 9 (3), 11, 12, 17 (2), 18, 23, 24, 25, 2013;
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`October 1, 3 (2), 8, 11, 16 (3), 18, 23, 24, 29 (2), 31, 2013; November 5, 12, 13 (3), 15 (2), 18,
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`19 (6), 20 (2), 26 (3), 29, 2013; December 4 (2), 5, 12, 13 (5), 16, 17, 27, 2013;
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`January 6, 7, 22, 2014; February 6, 7 (4), 10 and 11, 2014.
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved under the
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`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
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`letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug
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`product and related activities must adhere to the substance and procedures of the referenced
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`accelerated approval regulations.
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`Reference ID: 3452395
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` NDA 205552/Original 2
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` Page 2
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` We note that your February 11, 2014, submission includes final printed labeling (FPL) for your
` package insert and patient package insert. We have not reviewed this FPL. You are responsible
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` for assuring that the wording in this printed labeling is identical to that of the approved content
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` of labeling in the structured product labeling (SPL) format.
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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
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` 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
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` http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
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`patient package insert). Information on submitting SPL files using eLIST may be found in the
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`guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`ADVISORY COMMITTEE
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`Your application for Imbruvica® (ibrutinib) capsules, 140 mg was not referred to an FDA
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`advisory committee because the application did not raise significant safety or efficacy issues in
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`the intended population.
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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 studies/clinical trials to verify and describe clinical benefit. You
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` are required to conduct such studies/clinical trials with due diligence. If postmarketing
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` studies/clinical trials fail to verify clinical benefit or are not conducted with due diligence, we
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` may, following a hearing in accordance with 21 CFR 314.530, withdraw this approval. We
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` remind you of your postmarketing requirements specified in your submission dated,
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` February 6, 2014. These requirements, along with required completion dates, are listed below.
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`PMR 2122-1:
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`Submit the results of the completed randomized, open-label Phase 3 clinical trial (PCYC-1112
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`CA) of ibrutinib versus ofatumumab in patients with relapsed or refractory chronic lymphocytic
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`leukemia or relapsed or refractory small lymphocytic lymphoma. Enrollment of 391 patients was
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`completed. The primary endpoint is progression-free survival as assessed by an Independent
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`Review Committee.
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`Final Protocol Submission: Completed (01/2014)
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`Completed (01/2014)
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`Trial Completion:
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`Final Report Submission:
`06/2014
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`Reference ID: 3452395
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` NDA 205552/Original 2
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` Page 3
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` PMR 2122-2:
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`Complete and submit the results of the ongoing randomized, double-blind, placebo-controlled
`Phase 3 clinical trial (PCI-32765CLL3001) of ibrutinib in combination with bendamustine and
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` rituximab in patients with relapsed or refractory chronic lymphocytic leukemia or relapsed or
` refractory small lymphocytic lymphoma. Enrollment of 578 patients was completed. The
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` primary endpoint is progression-free survival as assessed by an Independent Review Committee.
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`Final Protocol Submission: Completed (09/2013)
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`Trial Completion:
`07/2016
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`Final Report Submission:
`11/2016
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`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
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`submissions relating to this postmarketing requirement must be clearly designated “Subpart H
`Postmarketing Requirement(s).”
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`Successful completion of either PMR 2122-1 or PMR 2122-2 could verify clinical benefit and
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`fulfill accelerated approval requirements for the Chronic Lymphocytic Leukemia (CLL)
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`indication.
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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
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
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`from this requirement.
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`POSTMARKETING REQUIREMENTS UNDER 505(o) AND POSTMARKETING
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`COMMITMENTS
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`We remind you of your Postmarketing Requirements PMR 2060-3; PMR 2060-4; PMR 2060-5;
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`PMR 2060-6; PMR 2060-7 and your Postmarketing Commitment PMC 2060-8 listed in the
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`approval letter dated November 13, 2013, for NDA 205552-Original #1 that are still open and
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`which also apply to NDA 205552-Original #2.
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`Reference ID: 3452395
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` PROMOTIONAL MATERIALS
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` NDA 205552/Original 2
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` Page 4
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`Under 21 CFR 314.550, you are required to submit, during the application pre-approval review
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`period, all promotional materials, including promotional labeling and advertisements, that you
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`intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If
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`you have not already met this requirement, you must immediately contact the Office of
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`Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory
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`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
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`after the 120 days following marketing approval (i.e., your post-launch materials) at least 30
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`days before the intended time of initial dissemination of labeling or initial publication of the
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`advertisement. We ask that each submission include a detailed cover letter together with three
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`copies each of the promotional materials, annotated references, and approved package insert
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`(PI)/Medication Guide/patient PI (as applicable).
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`Send each submission directly to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotions (OPDP)
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`5901-B Ammendale Road
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`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
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`(21 CFR 314.80 and 314.81).
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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
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`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
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`copies of reports for this product. To participate in the program, please see the enrollment
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`instructions and program description details at
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`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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`POST-APPROVAL FEEDBACK MEETING
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`New molecular entities and new biologics qualify for a post-approval feedback meeting. Such
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`meetings are used to discuss the quality of the application and to evaluate the communication
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`process during drug development and marketing application review. The purpose is to learn
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`from successful aspects of the review process and to identify areas that could benefit from
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`Reference ID: 3452395
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`Sincerely,
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`{See appended electronic signature page}
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`Richard Pazdur, M.D.
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`Director
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`Office of Hematology and Oncology Products
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`Center for Drug Evaluation and Research
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` NDA 205552/Original 2
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` Page 5
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` improvement. If you would like to have such a meeting with us, call the Regulatory Project
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` Manager for this application.
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`PDUFA V APPLICANT INTERVIEW
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` FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
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` and final assessment of the Program for Enhanced Review Transparency and Communication for
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`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
`Letter states that these assessments will include interviews with applicants following FDA action
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`on applications reviewed in the Program. The purpose of the interview is to better understand
`applicant experiences with the Program and its ability to improve transparency and
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`communication during FDA review.
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`You will be contacted by ERG to schedule the interview following this action on your
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`application; ERG will provide specifics about the interview process at that time. Your responses
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`during the interview will be confidential with respect to the FDA review team. ERG has signed a
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`non-disclosure agreement and will not disclose any identifying information to anyone outside
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`their project team. They will report only anonymized results and findings in the interim and final
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`assessments. Members of the FDA review team will be interviewed by ERG separately. While
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`your participation in the interview is voluntary, your feedback will be helpful to these
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`assessments.
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`If you have any questions, call CAPT Diane Hanner, Regulatory Project Manager, at
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`(301) 796-4058.
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`ENCLOSURES:
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`Content of Labeling
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`Reference ID: 3452395
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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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`RICHARD PAZDUR
`02/12/2014
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`Reference ID: 3452395
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