CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`
`
`OTHER REVIEW(S)
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`Pharmacovigilance Memo
`
`March 14, 2014
`
`Katherine Coyle, PharmD, BCPS
` Division of Pharmacovigilance II (DPV II)
`
`Tracy Salaam, PharmD
`DPV II
`
`Scott Proestel, MD
`DPV II
`
`Imbruvica (ibrutinib)
`
`Type B meeting response
`
`NDA 205552
`
`Pharmacyclics, Inc.
`
`2014-148
`
`Date:
`
`Safety Evaluator:
`
`
`Team Leader:
`
`
`Division Director:
`
`
`Product Name:
`
`Subject:
`
`Application Type/Number:
`
`Applicant/Sponsor:
`
`OSE RCM #:
`
`
`
`Reference ID: 3471635
`
`

`

`
`
`INTRODUCTION
`
`1
`The Division of Pharmacovigilance II (DPV II) was asked by the Division of Hematology
`Products (DHP) to provide a response to Question 12 posed by Pharmacyclics, Inc. in their Type
`B (Pre-supplemental NDA) meeting package. The purpose of the Type B Pre-supplemental
`NDA meeting is to discuss the efficacy and safety analysis data from the Phase 3 study PCYC-
`1112-CA in support of regular (full) approval of ibrutinib as monotherapy for the treatment of
`patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have
`received at least one prior therapy. Additionally, Pharmacyclics would like to discuss the content
`of the proposed supplemental NDA (sNDA) including: the collective clinical efficacy and safety
`data in support of the sNDA filing. Specifically pertaining to DPV II, Pharmacyclics would like
`to discuss and obtain agreement with the Agency on the proposed update to the pharmacovigilance
`plan.
`
`
`1.1 BACKGROUND
`Imbruvica is a Bruton's tyrosine kinase (BTK) inhibitor indicated for the treatment of patients
`with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) who have received
`at least one prior therapy.1 Imbruvica was FDA-approved November 13, 2013.
`
`Atrial fibrillation is a labeled adverse event found in the following sections of the ibrutinib
`label:1
`
`Section 6 Adverse Reactions
`Subsection 6.1 Mantle Cell Lymphoma and 6.2 Chronic Lymphocytic Leukemia
`
`Section 8 Use in Specific Populations
`
`Subsection 8.5 Geriatric Use
`
`On August 26, 2013, Pharmacyclics, Inc. submitted a pharmacovigilance plan as requested by
`FDA on August 8, 2013. On February 5, 2014, Pharmacyclics, Inc. submitted a Type B Pre-
`supplemental NDA meeting package for the upcoming March 12, 2014 Type B meeting with
`FDA. Pharmacyclics, Inc. provided the following question and rationale that was referred to
`DPV II for a response:
`
`Question 12
`Is the proposed update to the pharmacovigilance plan acceptable to the FDA?
`
`Based on the available safety data on PCYC-1112-CA, atrial fibrillation has been
`identified as a new important potential risk compared to the pharmacovigilance (PV)
`plan in the original NDA dated 23 August 2013. The original PV plans includes the
`following risk and potential risks:
`
`Important Identified Risk
`Leukostasis
`
`
`Reference ID: 3471635
`
`2
`
`

`

`Important Potential Risks
`Infections
`Hemorrhage
`Hypersensitivity
`Other malignancy
`Drug-drug interaction
`Teratogenicity
`
`Other potential area of safety information:
`Off-label use
`Medication errors, overdose, and accidental exposure
`
`New Important Potential Risk: Atrial fibrillation
`
`The following activity is proposed:
`1. Routine pharmacovigilance (ongoing/post-marketing): Targeted surveillance with use
`of a guided collection form to obtain additional clinical and diagnostic information
`related to atrial fibrillation.
`2. Additional PV (for ongoing clinical studies): Case series analyses on controlled
`studies to clarify background incidence.
`
`
`
` 2
`
` 3
`
` RESULTS AND DISCUSSION
`On March 2, 2014, DPV II searched the FDA Adverse Event Reporting System (FAERS)
`database utilizing the higher level term (HLT) supraventricular arrhythmias to identify cases of
`atrial fibrillation or atrial flutter with ibrutinib since the approval date of November 13, 2013.
`After removing duplicates, the search retrieved 11 cases of atrial fibrillation (8) and atrial flutter
`(3). All 11 cases reported a primary serious outcome of hospitalization (10) or other medically
`serious outcome (1). All 11 cases were either confounded by concomitant medications labeled
`for an association with atrial fibrillation or cardiac arrhythmia (10) or provided limited
`information to assess the case (1).
`
`DPV II agrees with the sponsor’s addition of atrial fibrillation to the PV plan based on the
`available information.
`
` REFERENCES
`
` 1
`
` Imbruvica (ibrutinib) [package insert]. Pharmacyclics, Inc. Sunnyvale, CA. Label issued November 2013.
`
`Reference ID: 3471635
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATHERINE M COYLE
`03/14/2014
`
`TRACY M SALAAM
`03/14/2014
`
`SCOTT E PROESTEL
`03/14/2014
`
`Reference ID: 3471635
`
`

`

`PMR/PMC Development Template PMR 2122-2
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA#
`Product Name:
`
`PMR Description:
`
`205552
`IMBRUVICA, PCI-32765 (ibrutinib) capsules,140 mg
`
`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.
`
`
`
`
`
`PMR/PMC Schedule
`Milestones:
`
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`Other:
`
`
` Completed
` (September /2013)
`July 2016
`
` November 2016
`
`
`
`
`
`Relapsed or refractory chronic lymphocytic leukemia (CLL) is a life-threatening condition. Although
`most patients who undergo chemotherapy for CLL achieve an initial response, disease relapse invariably
`occurs. The median progression free-survival varies according the subsequent treatment regimen, with
`reported median PFS for FCR, FR, and single-agent fludarabine of 52 months, 42 months, and 18 months,
`respectively.
`
`In the single-arm clinical trial PCYC-1102-CA, the applicant reports a 58% overall response rate in 48
`patients with relapsed or refractory CLL. The duration of response ranged from 5.6 to 24.2+ months. The
`median DOR was not reached.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 1 of 4
`
`Reference ID: 3452288
`
`

`

`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`The Agency has previously accepted overall response rates supported by duration of response from a
`single-arm clinical trial as a basis for initial approval.
`
`The goal for this PMR would be to obtain long-term efficacy outcomes including progression-free survival
`from a randomized clinical trial. Time-to-event endpoints cannot be adequately interpreted in single-arm
`clinical trials due to confounding effects of the natural history of the disease.
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess
`or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined
`below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious
`risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation, list here.
`Required: Submit the clinical study report and data from 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.
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 2 of 4
`
`Reference ID: 3452288
`
`

`

`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Confirmatory clinical trial under subpart H
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 3 of 4
`
`Reference ID: 3452288
`
`

`

`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`
`RCK_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 4 of 4
`
`Reference ID: 3452288
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`02/11/2014
`
`ROBERT C KANE
`02/11/2014
`
`Reference ID: 3452288
`
`

`

`PMR/PMC Development Template PMR 2122-1:
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA#
`Product Name:
`
`PMR Description:
`
`205552
`IMBRUVICA, PCI-32765 (ibrutinib) capsules,140 mg
`
`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 (January 2014)
`
`
`
`PMR Schedule
`Milestones:
` Completed (January 2014 )
`Trial Completion:
`
`
`June 2014
`Final Report Submission:
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Relapsed or refractory chronic lymphocytic leukemia (CLL) is a life-threatening condition. Although
`most patients who undergo chemotherapy for CLL achieve an initial response, disease relapse invariably
`occurs. The median progression free-survival varies according the subsequent treatment regimen, with
`reported median PFS for FCR, FR, and single-agent fludarabine of 52 months, 42 months, and 18 months,
`respectively.
`
`In the single-arm clinical trial PCYC-1102-CA, the applicant reports a 58% overall response rate in 48
`patients with relapsed or refractory CLL. The duration of response ranged from 5.6 to 24.2+ months. The
`median DOR was not reached.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 1 of 4
`
`Reference ID: 3452285
`
`

`

`The Agency has previously accepted overall response rates supported by duration of response from a
`single-arm clinical trial as a basis for initial approval.
`
`The goal for this PMR would be to obtain long-term efficacy outcomes including progression-free survival
`from a randomized clinical trial. Time-to-event endpoints cannot be adequately interpreted in single-arm
`clinical trials due to confounding effects of the natural history of the disease.
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess
`or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined
`below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious
`risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation, list here.
`Required: Submit the clinical study report and data from the recently 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.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 2 of 4
`
`Reference ID: 3452285
`
`

`

`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Confirmatory clinical trial under subpart H
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`
`PMR/PMC Development Coordinator:
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 3 of 4
`
`Reference ID: 3452285
`
`

`

` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`
`RCK_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/11/2014
`
`Page 4 of 4
`
`Reference ID: 3452285
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`02/11/2014
`
`ROBERT C KANE
`02/11/2014
`
`Reference ID: 3452285
`
`

`

`REGULATORY PROJECT MANAGER LABELING REVIEW
`Division of Hematology Products (DHP)
`
`
`
`Application: 205552-Original #2
`
`Name of Drug: Imbruvica® (ibrutinib) capsules, 140 mg.
`
`Applicant: Pharmacyclics, Inc.
`
`Labeling Reviewed
`
`
`Submission Date: January 9, 2014
`
`
`Receipt Date: January 9, 2014
`
`
`
`
`Background and Summary Description:
`
`The NDA 205552-Original #1 was approved on November 13, 2013, for Mantle Cell Lymphoma
`(MCL) that has received at least one prior therapy.
`The NDA was initially received on June 28, 2013, and it was split on October 11, 2013, in order
`to accommodate taking an earlier action on Original #1 Mantle Cell Lymphoma.
`
`This new drug application – Original #2 provides for the use of Imbruvica® (ibrutinib) capsules,
`140 mg for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) that have
`received at least one prior therapy.
`
`
`Review
`
`
`This review is based on the applicant’s submitted word format of the PI. The proposed PI was
`compared to the (11/13/13) Mantle Cell Lymphoma –Original #1 currently approved PI. This was
`done to ensure that all the changes were shown as track changes to allow for an appropriate review
`of the PI. The following changes have been identified as follows: Deletions are shown as
`strikeouts and additions are shown as double underlines. The following revisions were noted.
`
`The labeling meetings for Chronic Lymphocytic Leukemia (CLL) –Original #2 have been
`scheduled for January 16, 23, 27, and February 4, 2014, at which time the clinical team will be
`reviewing the PI.
`
`
`
`
`
`
`
`Reference ID: 3446667
`
`26 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/
`TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`02/04/2014
`
`MONSURAT O AKINSANYA
`02/04/2014
`
`Reference ID: 3446667
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`Pharmacovigilance Memo
`
`January 31, 2014
`
`Tracy Salaam, PharmD
`Division of Pharmacovigilance II (DPV II)
`
`Scott Proestel, MD
`DPV II
`
`Imbruvica (ibrutinib)
`
`CLL Indication and PMR 2060-4
`
`NDA 205552
`
`Pharmacyclics, Inc.
`
`2014-281
`
`Date:
`
`Team Leader:
`
`
`Division Director:
`
`
`Product Name:
`
`Subject:
`
`Application Type/Number:
`
`Applicant/Sponsor:
`
`OSE RCM #:
`
`
`
`Reference ID: 3445997
`
`

`

`
`
`1
`
`INTRODUCTION
`
`The Division of Pharmacovigilance II (DPV II) was asked by the Division of Hematology
`Products (DHP) to provide a memo regarding whether DPV recommends applying the
`postmarketing requirement (PMR) 2060-4, approved under the mantle cell lymphoma (MCL)
`indication for Imbruvica (ibrutinib), to the proposed indication of chronic lymphocytic leukemia
`(CLL), which is presently under review by FDA.
`
`1.1 BACKGROUND
`
`Imbruvica is a Bruton's kinase inhibitor indicated for the treatment of patients with MCL who
`have received at least one prior therapy.1 Imbruvica was FDA-approved November 13, 2013
`under Fast Track designation, priority review, and accelerated approval, as a first-in-class
`breakthrough therapy with orphan drug status.
`
`In the approval letter, FDA determined that among other postmarketing requirements (PMRs),
`the sponsor was required to conduct the following2:
`
`
`PMR 2060-4
`Conduct an assessment and an analysis of data from clinical trials and all post-
`marketing sources in order to characterize the risk of serious bleeding in patients treated
`with Imbruvica®,(ibrutinib) Capsules. The risks of special interest are major
`hemorrhagic events and their potential association with concomitant use of anti-platelet
`and/or anticoagulant drugs. Major hemorrhagic events are defined as any one of the
`following:
`
`
`I. Symptomatic bleeding in a critical area or organ, such as intracranial,
`intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or
`intramuscular with compartment syndrome,
`
`II. Bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to
`transfusion of two or more units of whole blood or red cells,
`
`III. Bleeding resulting in a serious adverse drug experience [as per 21 CFR
`314.80(a)]
`
`
`This enhanced pharmacovigilance study will include:
`
`1. Targeted and expedited surveillance with a guided collection form (as referenced in
`Pharmacyclics’ Pharmacovigilance Plan dated August 23, 2013) to obtain additional
`salient clinical and diagnostic information related to major hemorrhagic events.
`
`2. Submission of Post-marketing 15-day Alert Reports for all initial and follow-up reports
`of serious hemorrhagic adverse events from clinical trials and all post-marketing
`sources, including consumer reports, solicited reports, and foreign reports, utilizing the
`
`Reference ID: 3445997
`
`2
`
`

`

`
`
`Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) –
`Haemorrhages.
`
`3. Submission of interval and cumulative analyses, as well as line listing for all major
`hemorrhagic events (utilizing the SMQ Haemorrhages) from clinical trials and all
`postmarketing sources, including consumer reports, solicited reports, and foreign
`reports.
`
`4. The interval and cumulative analyses should assess potential risk factors for
`cumulative major hemorrhagic events identified from both clinical trials and all
`postmarketing sources, and an overall assessment about these events in patients treated
`with Imbruvica® (ibrutinib) Capsules. In the overall assessment, discuss whether the
`data warrants further detailed assessment, labeling changes and/or other communication
`about these adverse events.
`
`Continue the study for a period of four years from the date of final protocol submission
`as noted below. Prior to starting the study, submit for FDA review, a protocol describing
`how you will conduct the study and report results, according to the timeline below.
`
`The timetable you submitted on November 13, 2013, states that you will conduct this
`study according to the following schedule:
`Draft Protocol Submission: 03/2014
`Final Protocol Submission: 06/2014
`#1 Interim Report Submission 12/2014
`#2 Interim Report Submission 06/2015
`#3 Interim Report Submission 12/2015
`#4 Interim Report Submission 06/2016
`#5 Interim Report Submission 12/2016
`#6 Interim Report Submission 06/2017
`#7 Interim Report Submission 12/2017
`Study Completion: 06/2018
`Final Report Submission: 11/2018
`
`2 RECOMMENDATION
`
`DPV II recommends applying the Imbruvica (ibrutinib) PMR 2060-4, approved under the mantle
`cell lymphoma (MCL) indication, to the proposed indication of CLL.
`
` 3
`
` REFERENCES
`
` 1
`
` Imbruvica (ibrutinib) [package insert]. Pharmacyclics, Inc. Sunnyvale, CA. Label issued November 2013.
`2 Imbruvica (ibrutinib) Pazdur R. Approval Letter. DHHS, dated November 13, 2013. Accessed January 28, 2014 at
`http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label ApprovalHistory#labeli
`nfo
`
`
`Reference ID: 3445997
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`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TRACY M SALAAM
`01/31/2014
`
`SCOTT E PROESTEL
`01/31/2014
`
`Reference ID: 3445997
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`January 22, 2014
`
`Ann Farrell, MD
`Director
`Division of Hematology Products (DHP)
`Robert Kane, MD
`Deputy Director for Safety
`Division of Hematology Products (DHP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`Barbara Fuller, RN, MSN, CWOCN
`Team Leader, Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Karen Dowdy, RN, BSN
`Division of Medical Policy Programs (DMPP)
`Nisha Patel, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`Subject:
`
`IMBRUVICA (ibrutinib)
`Drug Name (established
`name):
`
`Dosage Form and Route: capsules, for oral use
`
`Application
`Type/Number:
`Applicant:
`
`
`
`
`
`
`
`
`NDA 205552
`
`Pharmacyclics, Inc.
`
`
`
`
`Reference ID: 3439740
`
`

`

`INTRODUCTION
`On June 28, 2013, Pharmacyclics, Inc. submitted for the Agency’s review an original
`New Drug Application (NDA) 205552 for IMBRUVICA (ibrutinib) capsules, with
`the proposed indication for the treatment of patients with:
`• mantle cell lymphoma (MCL) who have received at least one prior therapy
`• chronic lymphocytic leukemia (CLL) who have received at least one prior
`therapy
`On October 11, 2013, this NDA was administratively separated with the MCL
`indication identified as Original #1 and the CLL indication identified as Original #2.
`On November 13, 2013, IMBRUVICA (ibrutinib) capsules was approved with the
`indication for the treatment of patients with mantle cell lymphoma (MCL) who have
`received at least one prior therapy.
`On January 10, 2014, DMPP and OPDP were consulted to review the PPI for the
`IMBRUVICA (ibrutinib) Original # 2 indication for the treatment of patients with
`chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
`This collaborative review is written by the Division of Medical Policy Programs
`(DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to the
`requests by the Division of Hematology Products (DHP) on January 10, 2014, for
`DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI)
`for IMBRUVICA (ibrutinib)