CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208194Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA (505(b)(2))
`Application Number
`208194 Supporting Document 1
`
`Priority or Standard Standard
`Submit Date February 13, 2015
`Received Date
`February 13, 2015
`PDUFA Goal Date December 13, 2015
`
`Division Division of Hematology Products
`Reviewer Name Andrew Dmytrijuk M.D.
`Review Completion Date November 17, 2015
`
`Established Name Bendamustine Hydrochloride Injection
` Trade Name Bendeka®
`Therapeutic Class Alkylating Drug
`Applicant Eagle Pharmaceuticals Inc.
`50 Tice Blvd.
`Suite 315
`Woodcliff Lake, NJ 07677
`
`Formulation
`Dosing Regimen
`
`Injection
`100mg/4mL (25mg/mL)
`
`Indication
`
`Treatment Of Patients With Chronic
`Lymphocytic Leukemia (CLL).
`Treatment Of Patients With Indolent B-
`Cell Non-Hodgkin Lymphoma (NHL)
`That Has Progressed During Or Within
`Six Months Of Treatment With
`Rituximab Or A Rituximab-Containing
`Regimen.
`Intended Population Patients With Chronic Lymphocytic
`Leukemia and Indolent B-Cell Non-
`Hodgkin Lymphoma
`
`Reference ID: 3849075
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT..........................................5
`1.1 Recommendation on Regulatory Action ..............................................................5
`1.2 Risk Benefit Assessment .....................................................................................6
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ....7
`1.4 Recommendations for Postmarket Requirements and Commitments.................7
`INTRODUCTION AND REGULATORY BACKGROUND .........................................7
`2.1 Product Information .............................................................................................7
`2.2 Tables of Currently Available Treatments for Proposed Indications....................9
`2.3 Availability of Proposed Active Ingredient in the United States .........................11
`2.4
`Important Safety Issues With Consideration to Related Drugs..........................11
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ...........11
`3 ETHICS AND GOOD CLINICAL PRACTICES........................................................12
`3.1 Submission Quality and Integrity .......................................................................12
`3.2 Compliance with Good Clinical Practices ..........................................................12
`3.3 Financial Disclosures.........................................................................................12
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES...........................................................................................................12
`4.1 Chemistry Manufacturing and Controls .............................................................12
`4.2 Clinical Microbiology ..........................................................................................13
`4.3 Preclinical Pharmacology/Toxicology ................................................................13
`4.4 Clinical Pharmacology .......................................................................................13
`5 SOURCES OF CLINICAL DATA.............................................................................14
`5.1 Table of Studies.................................................................................................14
`5.2 Review Strategy.................................................................................................14
`5.3 Discussion of Individual Studies ........................................................................15
`6 REVIEW OF CLINICAL EFFICACY ........................................................................24
`7 REVIEW OF SAFETY..............................................................................................26
`7.1.1 Methods .............................................................................................................26
`7.1.2 Categorization of Adverse Events...............................................................26
`7.2 Adequacy of Safety Assessments .....................................................................26
`7.3 Major Safety Results..........................................................................................26
`7.3.1 Deaths.........................................................................................................26
`7.3.2 Nonfatal Serious Adverse Events................................................................27
`7.3.3 Dropouts and/or Discontinuations ...............................................................28
`7.3.4 Significant Adverse Events..........................................................................28
`7.4.1 Supportive Safety Results .................................................................................28
`
`Reference ID: 3849075
`
`2
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Laboratory Findings.....................................................................................29
`7.4.2
`7.4.3 Vital Signs and Electrocardiograms (ECGs) ...............................................29
`7.4.4
`Immunogenicity ...........................................................................................29
`7.5 Additional Safety Evaluations ............................................................................29
`8 POSTMARKET EXPERIENCE................................................................................31
`9 APPENDICES..........................................................................................................32
`9.1
`Literature Review/References ...........................................................................32
`9.2 Advisory Committee Meeting.............................................................................32
`9.3
`Labeling Recommendations ..............................................................................32
`
`Reference ID: 3849075
`
`3
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Table Number
`1
`2
`3
`4
`5
`6
`7
`
`8
`
`Table of Tables
`Table Title
`Bendamustine Hydrochloride NDA Applications
`Current Bendamustine Hydrochloride Presentations
`Table of Studies
`EGL-BDM-C-1301 Study Schedule
`Key Patient Demographics
`Pharmacokinetic Results Study EGL-BDM-C-1301
`Frequency of Serious Adverse Events and Treatment Related Averse
`Events
`Most Common Adverse Events in Study EGL-BDM-C-1301
`
`Figure Number
`1
`
`Table of Figures
`Figure Title
`EGL-BDM-C-1301 Study Schema
`
`Reference ID: 3849075
`
`4
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`NDA 208194 supporting document 1 letter date February 13, 2015 is a 505(b)(2)
`application for Bendeka® (bendamustine hydrochloride injection) 100mg/4mL
`(25mg/mL) in a 50 mL admixture, a new formulation of bendamustine hydrochloride.
`From a clinical perspective NDA 208194 should be granted approval for the following
`indications which are the same indications as the reference drug.
`
` Bendamustine hydrochloride is an alkylating drug indicated for treatment of
`patients with:
`o Chronic lymphocytic leukemia (CLL).
`o Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during
`or within six months of treatment with rituximab or a rituximab-containing
`regimen.
`
`The reference drug is bendamustine hydrochloride (Treanda®) manufactured by Teva
`Pharmaceuticals. Treanda (NDA 22303 and NDA 22249) manufactured as a lyophilized
`powder for injection, was approved for marketing on March 20, 2008 (for the CLL
`indication) and on October 31, 2008 (for the NHL indication) and is the reference listed
`drug for this new application. An injectable solution formulation of Treanda was
`approved for marketing on September 13, 2013 as a Chemistry, Manufacturing and
`Controls (CMC) Manufacturing Supplement (NDA 22249 Supplement-015). Both of the
`approved bendamustine hydrochloride formulations (lyophilized powder and injectable
`solution) have the same indications as those proposed for Bendeka. The sponsor
`asserts that the new formulation of bendamustine hydrochloride (Bendeka) is
`compatible with closed system transfer devices (CSTDs), adaptors, and syringes
`containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) because it does not
`contain N, N-dimethylacetamide (DMA) compared to the reference drug. The CMC
`reviewer should also comment on the compatibility of the new formulation. Also, the
`Bendeka product may be administered intravenously over 10 minutes compared to the
`reference bendamustine product (Treanda) intravenous administration of 60 minutes
`because of the higher concentration, i.e., 100mg/4mL (25mg/mL) in a 50 mL admixture,
`of the Bendeka product than is required for the Treanda lyophilized powder product, i.e.,
`25mg/vial or 100mg/vial reconstituted to 5mg/mL. From a clinical perspective the
`pharmacokinetic results, the proportion of patients with adverse events and severity of
`adverse events in the bioequivalence study EGL-BDM-C-1301 were similar for Bendeka
`infusion over 10 minutes compared to Treanda infusion over 60 minutes.
`
`The Bendeka product label along with my labeling recommendations in section 9.3
`Labeling Recommendations in this review should be forwarded to the sponsor.
`
`Reference ID: 3849075
`
`5
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`1.2 Risk Benefit Assessment
`
`The clinical recommendation for the approval of Bendeka is based on the safety and
`efficacy of the marketed bendamustine (Treanda) lyophilized powder for injection
`product (NDA 22249), supportive safety and efficacy information from the marketed
`bendamustine (Treanda) products and the available Bendeka supportive safety
`information from the bioequivalence study EGL-BDM-C-1301.
`
`Study EGL-BDM-C-1301 titled, “Phase 1, Open-Label, Crossover, Randomized,
`Bioequivalence Study To Evaluate Two Formulations Of Bendamustine (Bdm)
`Hydrochloride (Hcl) Administered To Cancer Patients” was conducted in a total of 83
`patients with a histologically confirmed diagnosis of any malignant disease, i.e., solid
`tumors and hematologic malignancies, for which no curative or standard therapy is
`appropriate. In this study the extent (AUC) of drug exposure was within 80-125% of the
`acceptance range for bioequivalence according to the sponsor’s analysis. From a
`clinical perspective the results of these studies demonstrated that the new
`bendamustine product (Bendeka) and the reference bendamustine product (Treanda)
`had similar bioequivalence. The Clinical Pharmacology reviewer should also comment
`on the acceptability of the results of study EGL-BDM-C-1301 to support approval of the
`drug. A summary of the key clinical pharmacology results from the clinical perspective
`is shown in section 4.4 Clinical Pharmacology in this review.
`
`No new or additional safety concerns were identified in this Clinical Review of NDA
`208194 for the new bendamustine hydrochloride formulation (Bendeka). Overall, the
`risk benefit assessment favors the approval of the Bendeka formulation for the same
`indications as that of the Treanda formulation. Bendeka offers patients a more rapid
`intravenous infusion of bendamustine hydrochloride (10 minutes for Bendeka compared
`to 60 minutes for Treanda) and does contain DMA which is compatible with closed
`system transfer devices (CSTDs), adaptors, and syringes containing polycarbonate or
`acrylonitrile-butadiene-styrene (ABS). Overall the proportion of patients with adverse
`events and severity of adverse events were similar for Bendeka infusion over 10
`minutes compared to Treanda infusion over 60 minutes in study EGL-BDM-C-1301. For
`example, a similar proportion of patients reported serious adverse events (SAEs) after
`treatment with Treanda (12/81, 15%) or Bendeka (12/73, 16%). It does not appear that
`the more rapid infusion of Bendeka compared to Treanda increases the risk or severity
`of adverse reactions for the intended populations, i.e., patients with CLL or indolent B-
`cell NHL.
`
`The sponsor is requesting a Waiver for Pediatric Studies for Bendeka (NDA 208194) for
`patients
`. The sponsor requests that a Waiver of Pediatric Studies
`be granted because Bendeka does not differ from Treanda except for dosage form.
`The Treanda label states in section 8.4 Pediatric Use that the effectiveness of Treanda
`in pediatric patients has not been established. Treanda was evaluated in a single
`Phase 1/2 trial in pediatric patients with leukemia. The Treanda label also states that the
`
`Reference ID: 3849075
`
`6
`
`(b) (4)
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`safety profile for Treanda in pediatric patients was consistent with that seen in adults,
`and no new safety signals were identified. Bendeka contains the same active ingredient
`as Treanda but may be infused more rapidly, i.e., over 10 minutes compared to Treanda
`which is infused over 60 minutes. The indications for Bendeka are the same as that for
`Treanda and patients will be treated with the same total drug dose as that for Treanda.
`There are no new active ingredients, no new indications, no change in the route of
`administration and no significant differences in the safety profiles of Bendeka compared
`to Treanda even though Bendeka is more rapidly infused compared to Treanda. The
`difference in the dosage form pertains to the final administration of the product, i.e., rate
`of infusion of drug. The sponsor’s request is reasonable and I recommend that the
`sponsor’s Pediatric Waiver Request be granted. Also, the bendamustine 50mL
`admixture was granted Orphan Designation for both indications on July 2, 2014 and is
`not subject to PREA (see Orange Book
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`No post-marketing risk evaluation and mitigation strategy (REMS) is recommended for
`the Bendeka formulation.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`No Postmarketing Requirements (PMRs) or Postmarketing Commitments (PMCs) for
`this application for Bendeka (NDA 208194 supporting document 1) are recommended.
`There are no outstanding PMRs or PMCs for the reference bendamustine product
`Treanda.
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`The sponsor submits NDA 208194 for Bendeka which is a new injectable bendamustine
`hydrochloride formulation. The sponsor cross-references NDA 22303 for Treanda
`(bendamustine hydrochloride) lyophilized powder formulation to support the safety and
`efficacy of the Bendeka formulation. The sponsor proposes the same indications for
`Bendeka as for Treanda as follows.
`
` Bendamustine hydrochloride is an alkylating drug indicated for treatment of
`patients with:
`o Chronic lymphocytic leukemia (CLL). The efficacy relative to first line
`therapies other than chlorambucil has not been established.
`
`Reference ID: 3849075
`
`7
`
`(b) (4)
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`o Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during
`or within six months of treatment with rituximab or a rituximab-containing
`regimen.
`
`A Dear Health Care Provider (DHCP) Letter regarding important safety and
`incompatibility information for Treanda injection (45 mg/0.5 mL or 180 mg/2 mL solution)
`was issued on March 09, 2015. The DHCP letter states that Treanda Injection (45
`mg/0.5 mL or 180 mg/2 mL solution) is not compatible with closed system transfer
`devices (CSTDs), adaptors, and syringes containing polycarbonate or acrylonitrile-
`butadiene-styrene (ABS) due to contact with N,N-dimethylacetamide (DMA). This
`incompatibility leads to device failure, e.g., leaking, breaking, or operational failure of
`CSTD components, possible product contamination, and potential serious adverse
`health consequences to the practitioner including skin reactions, or to the patient,
`including but not limited to the risk of small blood vessel blockage if they receive product
`contaminated with dissolved ABS or polycarbonate.
`
`In NDA 208194 supporting document 4 letter date March 13, 2015 the sponsor (Eagle
`Pharmaceuticals) states that their bendamustine hydrochloride injection product, i.e.,
`Bendeka 100 mg/4 mL (25 mg/mL) in a 50 mL admixture, is DMA free and does not
`have the same incompatibility safety concerns as the Teva Pharmaceuticals
`bendamustine product (Treanda). The CMC reviewer should also comment on the
`compatibility of the new formulation. The sponsor’s table below shows a comparison of
`the currently available bendamustine hydrochloride formulations. Also, Bendeka may
`be administered intravenously over 10 minutes compared to the reference
`bendamustine product (Treanda) intravenous administration of 60 minutes because of
`the higher concentration, i.e., 100mg/4mL (25mg/mL) in a 50 mL admixture, of the
`Bendeka product than is required for the Treanda lyophilized powder product, i.e.,
`25mg/vial or 100mg/vial reconstituted to 5mg/mL.
`
`Reference ID: 3849075
`
`8
`
`

`

`Clinical Review
`
`Andrew Dmytrijuk MD-
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Table 1. Available Bendamustine (BDM) Hydrochloride Formulations
`Treanda (heudamustine
`Treanda (bendamustine HCI)
`Bendamustine HO Injection,
`11(1) for Injection
`Injection, 90 mg/mL
`25 mg/mL
`100 mg“
`180 ng.InL‘
`100 ug4mL
`
`Product
`
`Lyophilized Powder
`
`Sterile Solution
`
`How
`
`.
`
`.
`
`.
`
`Amount
`
`r
`
`.
`
`r
`
`.
`
`.
`
`Sterile Solution
`
`.
`
`-
`
`.
`
`7
`
`Amount
`
`.
`
`Amount
`
`r
`
`
`
`
` (5) (4)
`
`ww---
`
`
`USP- 400).NF‘
`
`Mannitol
`USP
`
`Propylene Glycol
`USP
`
`NWN-
`Drm'MAlacmnnEPdc
`
`Monothioglycerol
`NE
`
`
`
`Polyethylene
`Glycol 400 (PEG
`
`
`
`DMA = NN—Dimethylacetamide; EP = European Pharmacopeia; HC1= hydrochloride; NF = National Formulary. PEG =
`polyethylene glycol: USP = United States Pharmacopeia
`' Treanda (bendanmstinc HCl) for Injection (Lyophilized) is also available in a 25 mg vial which has the same product
`composition
`b Treanda (bendanmstine HCl) Injection (Sterile Solution) is also available in a 45 mg/0.5 mL trial which has the same
`product composition
`‘ PEG 400 acidity may be modified using sodium hydroxide (NaOI-I) in water-for-injection solution.
`
`Sponsor’s table NDA 208194 Module 2 Introduction page 2
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`The reviewer’s table below shows the currently available treatments and their
`indications.
`
`Reference ID: 3849075
`
`

`

`Clinical Review
`
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`
`Table 2. Bendamustine Hydrochloride NDA Applications
`Generic
`Bendamustine
`Bendamustine
`
`Bendamustine
`
`Name
`H drochloride
`H drochloride
`H drochloride
`
`Trade Name
`Treanda
`None
`
`NDA Number
`
`22249
`
`22303
`
`205580
`
`Sponsor
`
`Teva
`Pharmaceuticals
`Dosage Form lnjectable solution
`
`Eagle
`Pharmaceuticals _
`lnjectable
`“"9
`
`Pharmaceuticals
`Lyophilized
`powder for
`in'ection
`
`
`
`
`
`
`
`Original
`Approval
`Date
`
`Indications
`
`March 20, 2008
`
`October 31, 2008
`
`July 2, 2014
`(Tentative Approval
`Granted
`
`Bendamustine
`
`Same as for NBA Bendamustine
`
`hydrochloride injection
`"m
`
`o
`
`Indolent B-cell
`
`non-Hodgkin
`lymphoma
`(NHL
`
`"M
`
`hydrochloride is an
`alkylating drug
`indicated for
`
`treatment of patients
`with:
`
`0 Chronic
`
`lymphocytic
`leukemia
`(CLL). The
`efficacy
`relative to first
`
`line therapies
`other than
`
`chlorambucil
`
`has not been
`
`established.
`
`0
`
`Indolent B-cell
`
`non-Hodgkin
`lymphoma
`(NHL) that has
`progressed
`during or
`within six
`
`months of
`
`treatment with
`
`rituximab or a
`
`rituximab-
`
`containing
`re imen.
`
`
`
`Reviewer's table.
`
`Reference ID: 3849075
`
`10
`
`

`

`Clinical Review
`
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`The active ingredient for Bendeka is the same as that for Treanda, i.e., bendamustine
`hydrochloride.
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`The safety concerns for Bendeka are similar to those of Treanda. The Treanda product
`label contains the following wording in the Warnings and Precautions section.
`
`Myelosuppression:
`
`Infections:
`
`Anaphylaxis and Infusion Reactions:
`Monitor clinically and discontinue drug for severe reactions.
`
`(W)
`
`(b) (4)
`
`(b) (4)
`
`(It) (4)
`
`Tumor Lysis Syndrome: May lead to acute renal failure and death;
`
`M"
`
`Skin Reactions:
`
`M" Cases of Stevens-
`
`Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), some fatal, have
`been reported when bendamustine hydrochloride was administered
`concomitantly with allopurinol and other medications known to cause these
`syndromes.
`
`Other Malignancies: Pre—malignant and malignant diseases have been reported.
`Extravasation:
`“m
`
`Embryo-fetal toxicity:
`
`(W)
`
`during and after administration.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`On July 2, 2014 the sponsor (Eagle Pharmaceuticals Inc.) received Tentative
`Marketing Approval for NDA 205580 which was a 505(b)(2) application for "9‘"
`“x" bendamustine hydrochloride
`"9‘"
`
`Only a Tentative Marketing Approval was granted
`because Cephalon Inc.’s product, Treanda (bendamustine hydrochloride), had
`orphan drug exclusivity that blocked regular approval of Eagle Pharmaceutical’s
`NDA 205580 application.
`
`The Filing Meeting for NDA 208194 was held on April 13, 2015.
`
`Reference ID: 3849075
`
`11
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Reviewer comment for section 2. The sponsor proposes the same indications and
`labeling information for Bendeka as for Treanda.
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`An Office of Study Integrity and Surveillance (OSIS) review was conducted for the
`analytical portion of the bioequivalence study EGL-BDM-C-1301 by Dr. Hansong Chen
`(Pharmacologist, Division of New Drug Bioequivalence Evaluation (DNDBE), final
`signature date August 4, 2015). In his review Dr. Chen states that the data from the
`audited study were found to be reliable. Therefore, this reviewer recommends that the
`data be accepted for further Agency review.
`
`3.2 Compliance with Good Clinical Practices
`
`EGL-BDM-C-1301 was conducted in compliance with the current revision of the
`Declaration of Helsinki, the International Conference on Harmonization Guidelines for
`Good Clinical Practices and local regulatory requirements. The protocol was approved
`by an Institutional Review Board prior to initiation and implementation of the study.
`Written informed consent provided by the patient was required in order to enroll into the
`study EGL-BDM-C-1301. The informed consent, protocol violations and site-specific
`issues were reviewed and found to be within accepted standards.
`
`3.3 Financial Disclosures
`
`No investigators participating in the trials supporting NDA 208194 reported a financial
`interest.
`
`Reviewer comment for section 3: All studies were conducted in compliance with the
`current revision of the Declaration of Helsinki, the International Conference on
`Harmonization Guidelines for Good Clinical Practices and local regulatory requirements.
`No investigators in the studies supporting NDA 208194 reported an equity interest. The
`ethics and good clinical practices considerations for this application are acceptable.
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`The CMC review of NDA 208194 supporting document 1 is ongoing. No review issues
`were noted by CMC reviewers for the Filing Communication – No Filing Review Issues
`Identified letter which was sent to the sponsor on April 13, 2015.
`
`Reference ID: 3849075
`
`12
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`4.2 Clinical Microbiology
`
`No Clinical Microbiology issues were identified in the Filing Communication – No Filing
`Review Issues Identified letter which was sent to the sponsor on April 13, 2015. The
`Clinical Microbiology review of NDA 208194 supporting document 1 is ongoing.
`
`4.3 Preclinical Pharmacology/Toxicology
`
`In his review of NDA 208194 supporting document 1 Dr. Michael Manning (Division of
`Hematology Oncology Toxicology Reviewer, final signature date October 1, 2015)
`states that the sponsor’s nonclinical testing strategy was designed in accordance with
`FDA/CDER Draft Guidance for Industry and Review Staff: Nonclinical Safety Evaluation
`of Reformulated Drug Products and Products Intended for Administration by an
`Alternate Route (March 2008). The review by Dr. Manning states that the sponsor
`submitted reports to assess the hemolytic and irritant potential of bendamustine
`hydrochloride at a concentration of up to 5.6 mg/mL, the highest final admixture
`concentration covering the clinical dose range. Dr. Manning states in his review that
`from the Pharmacology/Toxicology perspective, bendamustine hydrochloride,
`administered as a 50mL admixture over an infusion time of 10 minutes may be
`approved for the proposed indications.
`
`4.4 Clinical Pharmacology
`
`Clinical Pharmacology review of NDA 208194 supporting document 1 is ongoing. No
`Clinical Pharmacology issues were identified in the Filing Communication – No Filing
`Review Issues Identified letter which was sent to the sponsor on April 13, 2015.
`Support for the approval of this application for Bendeka comes from one bioequivalence
`study EGL-BDM-C-1301. Additional details regarding this study can be found in section
`5.1 Table of Studies in this review. A summary of study EGL-BDM-C-1301 can be
`found below in section 5.3 Discussion of Individual Studies. Key efficacy results (from a
`clinical perspective) and safety results from study EGL-BDM-C-1301 are summarized in
`section 6 Review of Clinical Efficacy and section 7 Review of Safety, respectively, in this
`review.
`
`Reviewer comment for section 4. CMC, Clinical Microbiology and Clinical
`Pharmacology reviews of NDA 208194 are ongoing. These reviewers should comment
`on the approvability of NDA 208194. No CMC, Clinical Microbiology or Clinical
`Pharmacology concerns for NDA 208030 have been identified from a Clinical
`perspective.
`
`Reference ID: 3849075
`
`13
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`5 Sources of Clinical Data
`
`5.1 Table of Studies
`
`The table below shows the study included to support NDA application 208194 for
`Bendeka.
`
`Table 3. Table of Studies
`
`BDM = bendamustine; Eagle-BDM = Bendeka; Teva-BDM = Treanda
`Sponsor’s table NDA 208194 section 5.2 Tabular list of Clinical Studies
`
`5.2 Review Strategy
`
`NDA 208194 supporting document 1 is a 505b(2) application for Bendeka that cross-
`references the safety and efficacy data of the marketed bendamustine product Treanda
`in NDA 22249. Clinical review of the study shown in section 5.1 Tables of Studies is in
`this review. This Clinical Review for Bendeka (NDA 208194) focuses on the available
`safety information from study EGL-BDM-C-1301.
`
`Reference ID: 3849075
`
`14
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`5.3 Discussion of Individual Studies
`
`The study supporting the Bendeka application NDA 208194 is described in section 5.1
`Table of Studies in this review, i.e., study EGL-BDM-C-1301. Briefly, study EGL-BDM-
`C-1301 was an open-label, randomized, crossover (3-period, partially replicated) Phase
`1 study to demonstrate the bioequivalence (BE), safety and tolerability profile of 2
`formulations of bendamustine hydrochloride (120 mg/m2) administered to cancer
`patients with histologically confirmed diagnosis of cancer (solid tumors and hematologic
`malignancies excluding CLL) who had progressed or relapsed on standard therapy, or
`for whom no curative or standard therapy was appropriate. The formulations of
`bendamustine administered were Eagle-Bendamustine (Eagle-BDM, Bendeka) given
`intravenously (IV) over 10 minutes and Teva-Bendamustine (Teva-BDM, Treanda)
`given IV over 60 minutes. The study was a partially replicated design where the
`reference product was replicated across 2 periods. Each patient participated in a
`Screening Visit and a 56-day treatment period (2 Study Treatment cycles of 28 days [±
`2 days]). Two single doses of Study Treatment were administered during each 28-day
`cycle. The End-of-Study (EOS) Visit occurred on Cycle 2, Day 28 (or 28 days [± 2 days]
`from administration of the last Study Treatment) for the purpose of assessing safety and
`tolerability. A total of 81 subjects (34 male and 47 female) adult (age 40-82 years) were
`enrolled in the study. The EGL-BDM-C-1301 Study Schema is shown in the sponsor’s
`figure below.
`
`Reference ID: 3849075
`
`15
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Figure 1. EGL-BDM-C-1301 Study Schema
`
`Sponsor’s figure EGL-BDM-C-1301 study report page 40
`
`Patients were monitored and evaluated according to the study schedule shown in the
`sponsor’s table below.
`
`Reference ID: 3849075
`
`16
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Table 4. EGL-BDM-C-1301 Study Schedule
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`Reference ID: 3849075
`
`17
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
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`Reference ID: 3849075
`
`18
`
`

`

`Clinical Review
`Andrew Dmytrijuk M.D.
`NDA 208194 Supporting Document 1
`Bendeka® 100mg/4mL (25mg/mL) (Bendamustine Hydrochloride Injection)
`
`Sponsor’s table Study Report EGL-BDM-C-1301 pages 42-44
`
`The key inclusion criteria were as follows.
` Histologically confirmed diagnosis of any malignant disease for which no curative
`or standard therapy is appropriate. Patients with chronic ly