`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`
`
`Imbruvica
`
`Ibrutinib capsules, 140 mg
`
`Pharmacyclics, Inc.
`
`February 12, 2014
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` For the treatment of patients with Chronic
`Lymphocytic Leukemia (CLL) who have received at
`least one prior therapy.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`205552Orig2s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
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`X
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`X
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`X
`X
`X
`X
`X
`X
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`X
`X
`X
`X
`X
`X
`X
`X
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`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205552Orig2s000
`APPROVAL LETTER
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`

`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
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`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA 205552/Original 2
`
`ACCELERATED APPROVAL
`
`
`Pharmacyclics, Inc.
`Attention: Christine Salido
`Executive Director, Regulatory Affairs
`9995 East Arques Avenue
`Sunnyvale, CA 94085-4521
`
`
`Dear Ms. Salido:
`
`Please refer to your New Drug Application (NDA) dated June 28, 2013, received June 28, 2013,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Imbruvica® (ibrutinib) capsules, 140 mg.
`
`For administrative purposes we designated your originally submitted NDA as follows:
`
`
`• NDA 205552/Original 1 – for the treatment of patients with Mantle Cell lymphoma
`(MCL). This indication was approved on November 13, 2013, under the provisions of
`accelerated approval regulations (21 CFR 314.500).
`• NDA 205552/Original 2 – for the treatment of patients with Chronic Lymphocytic
`Leukemia (CLL) who have received at least one prior therapy.
`
`
`The subject of this action letter is NDA 205552/Original 2.
`
`We acknowledge receipt of your amendments dated May 6, 13, 2013; June 6, 20, 2013;
`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,
`21, 23, 26, 29, 30, 2013; September 4, 6, 9 (3), 11, 12, 17 (2), 18, 23, 24, 25, 2013;
`October 1, 3 (2), 8, 11, 16 (3), 18, 23, 24, 29 (2), 31, 2013; November 5, 12, 13 (3), 15 (2), 18,
`19 (6), 20 (2), 26 (3), 29, 2013; December 4 (2), 5, 12, 13 (5), 16, 17, 27, 2013;
`January 6, 7, 22, 2014; February 6, 7 (4), 10 and 11, 2014.
`
`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.
`
`Reference ID: 3452395
`
`

`

`NDA 205552/Original 2
`Page 2
`
`
`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
`for assuring that the wording in this printed labeling is identical to that of the approved content
`of labeling in the structured product labeling (SPL) format.
`
`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, text for the
`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.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`ADVISORY COMMITTEE
`
`Your application for Imbruvica® (ibrutinib) capsules, 140 mg was not referred to an FDA
`advisory committee because the application did not raise significant safety or efficacy issues in
`the intended population.
`
`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 requirements specified in your submission dated,
`February 6, 2014. These requirements, along with required completion dates, are listed below.
`
`PMR 2122-1:
`
`Submit the results of the completed randomized, open-label Phase 3 clinical trial (PCYC-1112
`CA) of ibrutinib versus ofatumumab in patients with relapsed or refractory chronic lymphocytic
`leukemia or relapsed or refractory small lymphocytic lymphoma. Enrollment of 391 patients was
`completed. The primary endpoint is progression-free survival as assessed by an Independent
`Review Committee.
`
`
`
`
`Final Protocol Submission: Completed (01/2014)
`Trial Completion:
`
`Completed (01/2014)
`Final Report Submission:
`06/2014
`
`
`
`Reference ID: 3452395
`
`

`

`NDA 205552/Original 2
`Page 3
`
`
`PMR 2122-2:
`
`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
`rituximab in patients with relapsed or refractory chronic lymphocytic leukemia or relapsed or
`refractory small lymphocytic lymphoma. Enrollment of 578 patients was completed. The
`primary endpoint is progression-free survival as assessed by an Independent Review Committee.
`
`
`
`Final Protocol Submission: Completed (09/2013)
`
`Trial Completion:
`
`07/2016
`Final Report Submission:
`11/2016
`
`
`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).”
`
`Successful completion of either PMR 2122-1 or PMR 2122-2 could verify clinical benefit and
`fulfill accelerated approval requirements for the Chronic Lymphocytic Leukemia (CLL)
`indication.
`
`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 this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o) AND POSTMARKETING
`COMMITMENTS
`
`We remind you of your Postmarketing Requirements PMR 2060-3; PMR 2060-4; PMR 2060-5;
`PMR 2060-6; PMR 2060-7 and your Postmarketing Commitment PMC 2060-8 listed in the
`approval letter dated November 13, 2013, for NDA 205552-Original #1 that are still open and
`which also apply to NDA 205552-Original #2.
`
`
`
`
`Reference ID: 3452395
`
`

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`NDA 205552/Original 2
`Page 4
`
`
` 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
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with the reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`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
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST-APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`
`Reference ID: 3452395
`
`

`

`NDA 205552/Original 2
`Page 5
`
`
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`PDUFA V APPLICANT INTERVIEW
`
`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
`and final assessment of the Program for Enhanced Review Transparency and Communication for
`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
`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
`communication during FDA review.
`
`You will be contacted by ERG to schedule the interview following this action on your
`application; ERG will provide specifics about the interview process at that time. Your responses
`during the interview will be confidential with respect to the FDA review team. ERG has signed a
`non-disclosure agreement and will not disclose any identifying information to anyone outside
`their project team. They will report only anonymized results and findings in the interim and final
`assessments. Members of the FDA review team will be interviewed by ERG separately. While
`your participation in the interview is voluntary, your feedback will be helpful to these
`assessments.
`
`If you have any questions, call CAPT Diane Hanner, Regulatory Project Manager, at
` (301) 796-4058.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`Content of Labeling
`
`Reference ID: 3452395
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`02/12/2014
`
`Reference ID: 3452395
`
`