CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`210563Orig1s000
`210563Orig2s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`CLINICAL REVIEW MEMORANDUM
`
`DATE:
`
`February 13, 2017
`
`TO:
`
`FROM:
`
`NDA 210563
`Ibrutinib Tablets
`
`Margret Merino, MD
`Clinical Reviewer, DHP/OHOP/CDER
`
`SUBJECT:
`
`Financial Disclosure Review
`
`The Applicant submitted financial disclosure information from investigators and sub-
`investigators participating in trials 54179060CLL1018, Ibrutinib 54179060CLL1019, Ibrutinib
`54179060CLL1021 and Ibrutinib 54179060CLL1022 indicating that none of the investigators
`reported disclosable financial interests or arrangements at any time during the trials.
`
`Yes X
`
`Was a list of clinical investigators provided:
`
` (Request list from
`No
`Applicant)
`Total number of investigators identified: 15 Investigators/Sub-investigators and 15 Trial
`nurses/pharmacists
`Number of investigators who are Sponsor employees (including both full-time and part-time
`employees): 2
`
`Number of investigators with disclosable financial interests/arrangements (Form FDA 3455):
`
`0 I
`
`f there are investigators with disclosable financial interests/arrangements, identify the
`number of investigators with interests/arrangements in each category (as defined in 21 CFR
`54.2(a), (b), (c) and (f)):
`Compensation to the investigator for conducting the study where the value could be
`influenced by the outcome of the study: 0
`Significant payments of other sorts: 0
`Proprietary interest in the product tested held by investigator: 0
`Significant equity interest held by investigator in Sponsor of covered study: 0
`Is an attachment provided with details
`Yes
` No
` (Request details from
`of the disclosable financial
`Applicant)
`interests/arrangements: N/A
`Is a description of the steps taken to
`minimize potential bias provided:
`
`Yes
`
` (Request information
` No
`from Applicant)
`
`Reference ID: 4221268
`
`

`

`Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0
`Is an attachment provided with the
`Yes
` No
` (Request explanation
`reason:
`from Applicant)
`
`In addition to self-disclosure by the investigators, the sponsor assessed any royalty payments to
`investigators not related to study conduct who were listed as suppliers in the sponsor commercial
`payment system. The sponsor reported that none of the investigators who participated in the
`clinical studies appeared on the royalties schedule for the sponsor.
`
`Reviewer Comment: There were no identified financial conflicts of interests for this application.
`
`Reference ID: 4221268
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARGRET E MERINO
`02/13/2018
`
`TANYA M WROBLEWSKI
`02/13/2018
`
`Reference ID: 4221268
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Application Number(s)
`Priority or Standard
`
`NDA
`NDA 210563
`Priority
`
`Submit Date(s)
`Received Date(s)
`PDUFA Goal Date
`Division / Office
`
`September 12, 2017
`September 12, 2017
`February 28, 2018
`DHP/OHOP
`
`Margret Merino, MD
`Reviewer Name(s)
`Tanya Wroblewski, MD
`Clinical Team Leader
`Review Completion Date 1/16/2017
`
`Established Name
`Trade Name
`Therapeutic Class
`Applicant
`
`Formulation(s)
`Dosing Regimen
`
`Indication(s)
`
`Ibrutinib
`Imbruvica®
`Bruton Tyrosine kinase inhibitor
`Pharmacyclics, LLC.
`
`Tablets 140mg, 280mg, 420mg and 560mg, for oral use
`Provides new tablet formulations
`
`
`No new indications, provides new dosage formulation
`-Mantle cell lymphoma (MCL)
`-Marginal zone lymphoma (MZL)who require systemic
`therapy and have received at least one prior anti-CD20
`based therapy
`-Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic
`Lymphoma (SLL)
`-CLL/SLL with 17p deletion
`-Waldenström’s macroglobulinemia (WM)
`-Chronic Graft vs. Host disease (cGVHD) after failure of one
`or more lines of systemic therapy
`
`Intended Population(s)
`
`No change to intended population
`Patients ≥ 18 years of age
`
`Reference ID: 4209497
`
`1
`
`

`

`2
`
`Table of Contents
`1 EXECUTIVE SUMMARY ...........................................................................................3
`1.1 Recommendation on Regulatory Action ..............................................................3
`1.2 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ....3
`1.3 Recommendations for Postmarket Requirements and Commitments.................3
`INTRODUCTION AND REGULATORY BACKGROUND .........................................3
`2.1 Product Information .............................................................................................4
`2.2 Availability of Proposed Active Ingredient in the United States ...........................4
`2.3
`Important Safety Issues with Consideration to Related Drugs ............................5
`2.4 Summary of Pre-submission Regulatory Activity Related to Submission............5
`3 ETHICS AND GOOD CLINICAL PRACTICES..........................................................6
`3.1 Submission Quality and Integrity .........................................................................6
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES.............................................................................................................5
` 4.1 Metabolic, Clearance, and Interaction Workup…………………………................6
`5 SOURCES OF CLINICAL DATA...............................................................................6
`6 REVIEW OF EFFICACY ............................................................................................7
`7 REVIEW OF SAFETY................................................................................................7
`7.1 Safety Summary......................................................................................................7
`7.2 Pediatrics and Assessment of Effects on Growth……………………………………7
`8 POSTMARKET EXPERIENCE..................................................................................7
`9
`LABELING RECOMMENDATIONS .........................................................................8
`10 ADVISORY COMMITTEE MEETING.........................................................................9
`
`Summary of Tables
`
`Table 1 Summary of Pre-submission regulatory activity...........................................5
`
`Table 2: Summary of Recommended Labeling Changes...........................................8
`
`Reference ID: 4209497
`
`2
`
`

`

`Executive Summary
`1.1 Recommendation on Regulatory Action
`The clinical review team recommends approval of Imbruvica® 140mg, 280mg, 420mg
`and 560mg tablets for the treatment of patients with who require Imbruvica® therapy.
`Currently, 70mg and 140mg capsules are available which requires patients receiving
`the approved doses of 420mg (CLL, WM, cGVHD) and 560mg (MCL, MZL) to take
`multiple capsules. The new tablet formulations are intended to improve pill burden.
`This NDA includes updates to the dosage and administration, dosage forms and
`strengths, drug interactions, and product description section of the USPI.
`
`This application provides CMC and clinical pharmacology data to support stability and
`bioequivalence of the tablet formulations. There was no new clinical efficacy or safety
`data included in this NDA andno updates to the indication or efficacy sections of the
`USPI, hence no risk-benefit assessment.
`
`Patients receiving ibrutinib at the current recommended doses (either 480 or 520mg)
`are currently required to take multiple 140mg capsules daily. This may result in missed
`doses or incomplete doses and places and additional burden on patients. The new
`tablets will provide for appropriate doses with a single tablet and may improve safety.
`
`There were no clinically meaningful differences in the pharmacokinetics of the tablet
`formulations at the various dose ranges.
`
`The recommendation for approval of new tablet formulations (140mg, 280mg, 420mg
`and 560mg) is based primarily on pharmacokinetic (demonstration of bioequivalent AUC
`of the tablet formulations to the commercial ibrutinib capsule 140mg) and updated CMC
`data. Please refer to the clinical pharmacology review by Liang Li Ph.D. and the CMC
`review by Sherita McLamore, Ph.D.review for details.
`
`Recommendations for Post Market Risk Evaluation and Mitigation
`1.2
`Strategies
`There are no recommendations for additional post marketing risk evaluation and
`mitigation strategies for this application. .
`
`1.3 Recommendations for Post Market Requirements and Commitments
`There are no recommendations for additional postmarketing requirements for this
`application. .
`
`3
`
`Reference ID: 4209497
`
`

`

`2 Introduction and Regulatory Background
`Ibrutinib is currently approved for the treatment of patients with mantle cell lymphoma
`(MCL) who have received one prior therapy, chronic lymphocytic leukemia/small
`lymphocytic leukemia (CLL/SLL), CLL/SLL with 17p deletion, marginal zone lymphoma
`(MZL) who require systemic therapy and have received at least one prior anti-CD20
`based therapy, Waldenström’s macroglobulinemia (WM), and chronic graft versus host
`disease (cGVHD).
`
`Ibrutinib is currently available as 70mg and 140mg capsules. The recommended doses
`are
`mg once daily for MCL and MZL and 420mg once daily for CLL/SLL, WM and
`cGVHD. The recommended dose for patients with mild hepatic impairment is 140mg
`and for patients with moderate hepatic impairment is 70mg.
`
`This submission primarily pertains to clinical pharmacology and chemistry
`manufacturing and controls.
`
`No new clinical efficacy data were submitted with this supplement. The tablet
`formulations are relevant to all the current indications for patients who currently take
`multiple capsules of Imbruvica®. Refer to complete clinical pharmacology review for
`analysis of drug-drug interaction data and bioequivalence data provided with this
`supplement.
`
`2.1 Product Information
`Imbruvica® (Ibrutinib, also known as PCI-32765) is a first-in-class, orally administered
`inhibitor of Bruton Tyrosine Kinase (BTK) that was co-developed by Pharmacyclics, LLC
`and Janssen Research & Development, LLC for the treatment of B-cell malignancies.
`
`Imbruvica® received initial U.S. approval in November 2013. The current approved
`indications for Imbruvica include:
` Mantle cell lymphoma (MCL) after at least one prior therapy
`o At the time of this review, the MCL indication has accelerated
`approval.
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
` Chronic lymphocytic leukemia/Small lymphocytic lymphoma with 17p
`deletion
` Waldenström’s macroglobulinemia (WM)
` Marginal Zone lymphoma
`o At the time of this review, the marginal zone lymphoma as
`accelerated approval
` Chronic Graft vs. Host Disease
`
`Applicant’s ProposedDosage for Approved Indications: The 140mg, 128mg,
`420mg and 560mg tablets are provided for patients receiving Ibrutinib for one of the
`approved indications.
`
`4
`
`Reference ID: 4209497
`
`(b) (4)
`
`

`

`Proposed Dose and Schedule: The recommended dose of Imbruvica® for the
`treatment of MCL, MZL, is 560mg (four 140mg capsules) orally once daily. The
`recommended dose for patients with CLL/SLL, WM and chronic graft vs. host disease is
`420mg orally once daily. The recommended dose of Imbruvica® for patients with
`moderate hepatic impairment and those patients with B cell malignancies who
`requirement concomitant CYP3A inhibitor therapy is 70mg orally once daily.
`
`2.2 Availability of Proposed Active Ingredient in the United States
`Imbruvica® is available in the U.S. The initial U.S. approval was in November 2013.
`
`2.3 Important Safety Issues
`Imbruvica is a first-in-class Bruton tyrosine kinase inhibitor. The most common adverse
`reactions in patients with B cell malignancies (MCL, CLL/SLL, WM, and MZL) are
`neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal pain, hemorrhage,
`rash, nausea, bruising, fatigue, hemorrhage and pyrexia.
`
`The most common adverse reactions in patients with cGVHD are fatigue, bruising,
`diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia
`and pneumonia.
`
`The U.S. Prescribing Information (USPI) for Imbruvica® includes Warnings and
`Precautions for hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension,
`second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity.
`
`2.4 Summary of Pre-submission Regulatory Activity Related to Submission
`A type C meeting to discuss the Ibrutinib tablet development plan was held on 27 April
`2016. A Type B pre-NDA meeting was held on 13 March 2017. Topics included
`adequacy of bioequivalence data and dissolution methods. A summary of regulatory
`activity provided by the applicant in this submission is included in the table below:
`
`Table 1 Summary of Pre-submission regulatory activity
`
`Date
`02 May 2016
`
`Description
`Type C Meeting:
`Ibrutinib Tablet Development Plan
`
`13 March 2017
`
`Ibrutinib Tablet pre-NDA meeting
`
`Comments
`Clarification on bioequivalence
`study design and dissolution
`methods. Acceptance of proposed
`dissolution methods for QC
`testing.
`Discussion of Cmax decrease in
`tablet vs capsule formulation.
`Discussion of biowaiver strategy
`for 280 and 420 strength tablets
`Discussion of stability
`assessments
`Discussion of review timeline
`
`5
`
`Reference ID: 4209497
`
`

`

`3 Ethics and Good Clinical Practices
`3.1 Submission Quality and Integrity
`
`The application was provided in accordance with the International Council for
`Harmonization (ICH) Electronic Common Technical Document (eCTD). There were no
`clinical data sets submitted with this application.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`There are no new safety issues with chemistry manufacturing and controls, clinical
`microbiology, preclinical pharmacology/toxicology. Refer to the reviews of the original
`NDA and to the discipline specific reviews for this application. Refer to the clinical
`pharmacology review Liang LI, Ph.D for details
`
`4.1
`
`Metabolic, Clearance, and Interaction Workup
`
`Bioequivalence evaluations demonstrated no clinically significant difference in AUC
`between the tablet and capsule formulations at the 140 and 520mg doses. There was a
`Cmax decreases of 10.2% and 27.7% at the 140mg and 520mg doses respectively.
`These were not assessed to be clinically relevant by the clinical pharmacology team.
`Refer to Clinical Pharmacology review for additional details.
`
`Patients with moderate hepatic impairment have increased exposure to Ibrutinib. A
`dose reduction to 70mg for these patients provides similar exposure to those patients
`receiving standard dosing. The 140mg tablet should not be crushed
`
`
` Refer to Clinical Pharmacology review for additional details.
`
`5 Sources of Clinical Data
`
`There was no clinical data submitted for this supplement.
`
`6
`
`Reference ID: 4209497
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`5.1 Review Strategy
`This clinical review was focused on labeling updates. There was no submission of
`datasets for review for safety.
`
`6 Review of Efficacy
`There was no new clinical efficacy data included in this submission.
`
`7 Review of Safety
`7.1 Safety Summary
`No new safety data was provided as part of this submission. The USPI was updated
`with new safety information to include cardiac arrhythmias with the recent 70mg
`supplement (S20) in December of 2017.
`The availability of several tablet formulations potentially increases the risk of dosing
`errors, however each tablet strength is manufactured with a different color which should
`help mitigate this risk.
`
`Reviewer comment: The safety profile of Ibrutinib remains acceptable. The addition of
`new tablet formulations does not introduce any significant additional safety concerns.
`The availability of several tablet formulations potentially increases the risk of dosing
`errors, however each tablet strength is manufactured with a different color which should
`help mitigate this risk.
`
`7.2
`
`Pediatrics and Assessment of Effects on Growth
`
`FDA granted Orphan Drug Designation for ibrutinib in 2013 for the treatment of patients
`with relapsed or refractory mantle cell lymphoma. There is one ongoing trial evaluating
`the safety and efficacy of ibrutnib in pediatric and young adult patients with relapsed or
`refractory mature B-cell Non-Hodgkin Lymphoma. Currently there is limited information
`on the use of ibrutinib in pediatric patients.
`
`8 Postmarket Experience
`
`There is an estimated post-marketing patient exposure of 33,591 person years as of 31
`August 2016. Ibrutinib has been approved in approximately 70 countries worldwide.
`
`Reviewer Comment: Overall, the safety profile of ibrutinib remains acceptable.
`Ongoing monitoring for cardiac, infectious, bleeding and secondary malignancies is
`warranted. The Sponsor has an active pharmacovigilance plan that includes cardiac
`arrhythmias and hepatotoxicity.
`
`7
`
`Reference ID: 4209497
`
`

`

`9
`
`Labeling Recommendations
`
`Recommended Changes to Prescribing Information
`Table 2: Summary of Recommended Labeling Changes
`
`Label Section
`
`HIGHLIGHTS
`
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`
`DOSAGE FORMS AND STRENGTHS
`
`DRUG INTERACTIONS
`
`7.1 Effect of CYP3A Inhibitors on Ibrutinib
`
`7.2 Effect of CYP3A Inducers on Ibrutinib
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`12.2 Pharmacodynamics
`
`Patient Information
`
`Recommended Changes
`● Addition of instructions not to cut,
`crush, or chew tablets
`● Addition of the tablets 140, 280, 420,
`560 listed to the dosage forms and
`strengths
`● Addition of instructions not to cut,
`crush, or chew tablets
`
`● Added Tablet: 140 mg, 280 mg, 420
`mg, and 560 mg
`
`● Removed list of examples of CYP3A
`inhibitors and inducers based on current
`labeling recommendations.
`
`● Identifying characteristics of the
`tablets moved to section 3 and 16 per
`current labeling guidance
` Cardiac Electrophysiology
`subheading heading was added with
`new information regarding lack of
`clinically relevant QT prolongation
`● Addition of tablet formulation and
`instructions not to break or chew tablets
`
`Reference ID: 4209497
`
`8
`
`

`

`10 Advisory Comtee Meeting
`This application was not referred to the Oncologic Drugs Advisory Committee (ODAC)
`because the application did not raise significant safety or efficacy issues.
`
`Reference ID: 4209497
`
`9
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARGRET E MERINO
`01/19/2018
`
`TANYA M WROBLEWSKI
`01/22/2018
`
`Reference ID: 4209497
`
`