CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205552Orig2s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`RISK EVAULATION AND MITIGATION STRATEGY REVIEW
`
`
`Date:
`
`Reviewer(s)
`
`September 17, 2013
`Joyce Weaver, Pharm.D., Risk Management Analyst
`Division of Risk Management (DRISK)
`Cynthia LaCivita, Pharm.D., Team Leader, DRISK
`Claudia Manzo, Pharm.D., Director, DRISK
`
`Team Leader
`Division Director:
`
`Review to determine if a REMS is necessary
`Subject:
`Imbruvica (ibrutinib)
`Drug Name(s):
`Tyrosine Kinase Inhibitor
`Therapeutic class &
`140mg capsules
`dosage form:
`Division of Hematological Products
`OND Review Division
`Application Type/Number: NDA 205552
`June 28, 2013
`Application received
`February 28, 2014
`PDUFA/Action Date
`Pharmacyclics, Inc
`Applicant/sponsor:
`2013-1057
`OSE RCM #:
`n/a
`TSI #:
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`Reference ID: 3374873
`
`

`

` 1
`
`
`INTRODUCTION
`This review by the Division of Risk Management evaluates if a Risk Evaluation and
`Mitigation Strategy (REMS) is needed for the tyrosine kinase inhibitor, ibrutinib. The
`proposed indications for ibrutinib include treatment of patients with of previously treated
`mantle cell lymphoma (MCL) and previously treated chronic lymphocytic lymphoma
`(CLL).
`Pharmacyclics, Inc did not submit a Risk Evaluation and Mitigation Strategy (REMS) or
`risk management plan ibrutinib.
`
`1.1 BACKGROUND
`Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. Pharmacyclics, Inc has submitted
`an application to the Agency for the treatment of previously treated MCL and CLL.
`
`1.2 REGULATORY HISTORY
`Pharmacyclics, Inc submitted an application June 28, 2013 to the FDA for ibrutinib, a
`BTK inhibitor, for the following proposed indications:
`
` 
`
` Treatment of patients with MCL who have received at least one prior therapy.
` Treatment of patients with CLL who have received at least one prior therapy.
`
`The following are regulatory milestones pertinent to the application:
` October 29, 2012—The Agency granted Fast Track designation for ibrutinib for
`the treatment of patients with CLL.
` December 18, 2012—The Agency granted Fast Track designation for ibrutinib for
`the treatment of patients with MCL.
` February 8, 2013— The Agency granted Breakthrough Therapy designation for
`ibrutinib for the treatment of patients with MCL
` June 28, 2013—last module of the NDA received
` August 27, 2013—NDA filed; filing communication sent to sponsor accepting the
`application for review, and granting priority review.
`Although the PDUFA goal date for the application is February 28, 2014, the division has
`set an internal goal action date of October 27, 2013. Both indications are being
`considered for subpart H accelerated approval.
`
` 2
`
` MATERIALS REVIEWED
`We reviewed the following:
`o Application submitted June 28, 2013.
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`o FDA’s fast track and breakthrough therapy determinations and notifications
`o Minutes from April 9, 2013 type B meeting
`o Sponsor’s slides from NDA Orientation Meeting, July 12, 2013
`o Discipline handouts and slides from mid-cycle meeting for NDA 205552, meeting
`held August 14, 2013.
`o NDA Safety Update, August 19, 2013
`o Sponsor responses to clinical inquiries (including inquiry regarding bleeding
`events), August 18, 2013
`o FDA-edited draft labeling, edited as of September 16, 2013.
`3 RESULTS OF REVIEW
`
`3.1 OVERVIEW OF CLINICAL PROGRAM1
`Mantle cell lymphoma
`The data submitted in support of the MCL indication were derived from a single-arm,
`multi-center, Phase 2 trial in 111 patients with MCL. Forty-eight of the 111 patients had
`prior treatment with bortezomib; the remaining 63 patients did not have previous
`treatment with bortezomib. Patients were dosed with ibrutinib 560 mg orally once daily.
`The primary endpoint was overall response rate. Over 67% of patients responded to
`treatment. The median duration of response was about 16 months.
`The most frequently reported grade 3 or higher adverse events were neutropenia
`(experienced by 15% of patients), pneumonia (12%), thrombocytopenia (10%),
`abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%). Serious adverse events
`occurred in 56% of patients, the most frequently occurring serious adverse event was
`pneumonia (5%). Fifty-nine percent of patients discontinued the trial, most (44%)
`because of disease progression.
`Four percent of patients receiving ibrutinib in the MCL trial experienced grade 3 or
`higher bleeding events, 49% of patients experienced a bleeding event, and bruising was
`experienced by 23% of the patients. There were no fatalities secondary to bleeding.
`Chronic lymphocytic leukemia
`The data submitted in support of the CLL indication were derived from a dose-finding
`multi-center trial in 133 patients. Patients included the following cohorts:
`relapsed/refractory disease receiving 420 mg daily (27 patients), treatment-naïve
`patients at least 65 years old receiving 420 mg daily (26), relapsed/refractory disease
`receiving 840 mg daily (34 patients), treatment-naïve patients at least 65 years old
`receiving 840 mg daily (5), relapsed/refractory high-risk patients receiving 420 mg
`daily (25), relapsed/refractory patients receiving 420 mg daily with food (16).
`
`
`1 Summary presented here is adapted from the mid-cycle handout, August 14, 2013.
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`The bolded cohorts, relapsed/refractory disease receiving 420 mg daily (27 patients)
`and relapsed/refractory high-risk patients receiving 420 mg daily (25) were included
`in the efficacy analysis. In the cohorts analyzed for efficacy, 38/48 patients (79%)
`responded to the treatment. The 95% confidence interval for the overall response rate was
`67.7 – 90.7 months.
`Grade 3 or 4 adverse events included neutropenia, pneumonia, thrombocytopenia,
`hypertension, dehydration and sinusitis. Serious adverse events occurred in 61% of
`patients.
`Six percent of patients receiving ibrutinib in the CLL trial experienced grade 3 or worse
`bleeding events, 63% of patients experienced a bleeding event, and 54% of the patients
`experienced bruising. There were no fatalities secondary to bleeding.
`
`3.2 SAFETY CONCERNS
`The most concerning safety issue discovered in the review of the data is bleeding. The
`sponsor was asked to provide additional information about bleeding events that have
`occurred with ibrutinib, and to detail their investigation to explore the bleeding signal.
`The sponsor replied that they have focused mostly on CNS hemorrhagic events, the
`events that they consider to be the most serious. As of April 6, 2013, nine of the 636
`patients in the ibrutinib development program experienced a CNS hemorrhage.
`The sponsor concluded that hemorrhage remains an important safety signal for ibrutinib.
`The sponsor said, the following safety monitoring activities for bleeding events were
`taken or are continuing (the following is excerpted from the sponsor’s Aug 18 summary).
`1. External review by hematology and neurology experts of the early case series
`identified that concomitant use of warfarin and head trauma may be the
`confounders of the initial clusters of reports of CNS hemorrhagic events.
`
`Reviewer comment: In the 5 major bleeding events that occurred in the trials
`reviewed for this application, only one patient was receiving warfarin, and head
`trauma was not reported as a confounder in any case.
`2. Major hemorrhage is considered as an Adverse Event of Special Interest.
`Investigators are instructed to report any new cases to Pharmacyclics within 24
`hours. This alert system allows Pharmacyclics to have prompt review of safety
`data. All new cases of major hemorrhages are reviewed in depth to identify risk
`factors and concomitant drug use. Platelet counts and coagulation parameters are
`followed.
`
`Reviewer comment: Unfortunately, this has not elucidated risk factors to guide
`therapy.
`
`
`3. Two Dear Investigator Letters were issued provided appropriate education and
`guidance in the exclusion of warfarin use and the temporary hold of ibrutinib for
`peri-operative management. This information is part of all clinical studies as well
`as the draft prescribing information.
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`Reviewer comment: The guidance was presumptive but was not based on data.
`
`4. Panel of experts in coagulation was assembled to review full safety data, and
`management guidelines in 2012 and agreed that the current study management
`was appropriate.
`
`(m4)
`
`Reviewer comment: The guidance is not based on data.
`
`6. To mitigate the potential risk of leukostasis where bleeding risk is increased,
`guidance for patient management has been added to the protocol, Investigator’s
`Brochure, and the draft prescribing information for patients with high circulating
`malignant cells (>400,000/mcL).
`
`7. Routine aggregate safety surveillance is performed on a regular basis with
`cumulative data to review trends across studies and this safety concern is part of
`the ibrutinib Pharmacovigilance Plan for post market surveillance.
`
`Reviewer comment: DHP and the Division ofPhamzacovigilance are proposing
`enhancedpharmacovigilance.
`
`8. Epidemiological data to ascertain background rates of bleeding in this population
`using the SEER database is ongoing.
`
`9. Future controlled trials data will be available to better understand the background
`rates of the occurrence of major hemorrhage in this patient population.
`
`Overall, bleeding/bruising events have occurred in 23% and 54% of patients who
`received ibrutinib in the MCL trial and the CLL trial, respectively. Five patients have had
`bleeding characterized as a major event. The medical officer identified risk factors
`(concomitant warfarin use, concomitant dabigatran use, clotting factor deficiency, history
`of chronic gastrointestinal bleeding) in four of the five patients who had bleeding events.
`The remaining patient did not have identifiable risk factors for bleeding.
`
`3.3 RISK MANAGEMENT PROPOSED BY THE SPONSOR
`
`The sponsor did not propose a REMS for ibrutinib.
`
`(m4) infections, bleeding, and
`The sponsor’s draft labeling includes
`development of other primary malignancies in the Warnings and Precautions section of
`the labeling.
`m4)
`
`clinical trials excluded patients on warfarin afier a cluster of bleeding events in a trial,
`although only one patient who experienced a major bleeding event was taking warfarin
`concomitantly.
`mu)
`
`The
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`FDA edits to the labeling include placing the bleeding risk as the first issue presented in
`the Warnings and Precautions section of the labeling, and adding potential embryo-fetal
`toxicity to the Warnings and Precautions section of the labeling.
`
`4 DISCUSSION OF A REMS FOR IBRUTINIB
`
`Aside from bleeding events, the adverse reaction profile for ibrutinib appears to be
`favorable. Because of the overall favorable adverse reaction profile, patients who might
`not be able to tolerate other chemotherapeutic agents could be prescribed ibrutinib
`preferentially. This could result in patients at a higher risk of bleeding being prescribed
`ibrutinib. It would be helpful to prescribers to provide guidance regarding which patients
`should not receive ibrutinib because of an unfavorable risk—benefit profile. However,
`data are not available to provide this guidance. At this time, we cannot inform prescribers
`which patients are at increased risk for bleeding, or how to prevent bleeding events. The
`mechanism of bleeding with ibrutinib is not known, and there are no data establishing the
`risk factors that are important to prevent bleeding events.
`M“)
`
`Using a REMS to prevent patients at higher
`risk of bleeding from receiving ibrutinib would not be helpful because we cannot identify
`the important risk factors at this time.
`
`Two postmarketing requirements (PMRs) are being crafted to obtain additional data
`about the bleeding signal. First, an in vitro study will be required to examine the effect of
`ibrutinib on platelet aggregation. This will include samples from patients with and
`without concomitant conditions and medications that could impair platelets. The second
`PMR will require enhanced pharmacovigilance to obtain information about bleeding
`events that occur in patients receiving ibrutinib. Information from the enhanced
`pharmacovigilance program will be used to help identify risk factors for bleeding with
`ibrutinib. The results of both PMRs could guide filture safety studies to examine the
`bleeding signal.
`
`Additionally, clinical trials currently accruing patients will be completed to satisfy the
`requirements of subpart H. Additional safety data will be submitted with these trial
`results.
`
`5 CONCLUSION/RECOMNIENDATION
`
`Based on the information that is currently available, a REMS with a communication plan
`or elements to assure safe use for ibrutinib is not recommended. Implementing a REMS
`for ibrutinib without a better understanding of factors that may contribute to the risk of
`bleeding may restrict therapy without evidence establishing who is at increased risk for
`bleeding events, and may create a barrier that prevents patients who could benefit from
`the drug from receiving it. It would not be appropriate to exclude all patients with risk
`factors for bleeding from receiving ibrutinib until additional data are available to better
`understand the bleeding safety signal. A communication plan REMS would not be
`helpful because there is not a clear message to communicate to prescribers. Better
`understanding of factors that contribute to increased risk of bleeding are needed to create
`an effective risk message.
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`Reference ID: 3374873
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`

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`The risk of bleeding should be addressed by describing what is known about the risk in
`the labeling for ibrutinib. As additional data become available, the utility of
`implementing a REMS can be better appreciated.
`We ask that DHP include DRISK in future discussions regarding this safety signal.
`
`Reference ID: 3374873
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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/
`----------------------------------------------------
`
`JOYCE P WEAVER
`09/17/2013
`
`CLAUDIA B MANZO
`09/17/2013
`concur
`
`Reference ID: 3374873
`
`