CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208194Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`Date:
`
`From:
`
`Subject:
`
`Re:
`
`July 8, 2016
`
`Andrew Dmytrijuk M.D.
`Medical Officer
`Division of Hematology Products
`
`Correction to Division of Hematology Products (DHP) Clinical Review for
`Bendeka by Dr. Andrew Dmytrijuk, Final Signature Date November 19, 2015
`
`NDA 208194 Bendeka® (Bendamustine Hydrochloride Injection) 100mg/4 mL
`(25mg/mL)
`
`This memorandum is intended to note and correct a typographical error and clarify a sentence in
`the Division of Hematology Products (DHP) Clinical Review of NDA 208194 Bendeka®
`(Bendamustine Hydrochloride Injection) 100mg/4 mL (25mg/mL) by Dr. Andrew Dmytrijuk
`(final signature date November 19, 2015).
`
`On page 6 under section 1.2 Risk Benefit Assessment, third paragraph, the third sentence which
`begins, “Bendeka offers patients a more rapid…” has a typographical error. This sentence
`should be replaced by the following: “Bendeka offers patients a more rapid intravenous infusion
`of bendamustine hydrochloride (10 minutes for Bendeka compared to 60 minutes for Treanda).
`Bendeka does not contain DMA and is compatible with closed system transfer devices (CSTDs),
`adaptors, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).”
`
`Reference ID: 3956682
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ANDREW DMYTRIJUK
`07/08/2016
`
`KATHY M ROBIE SUH
`07/08/2016
`
`Reference ID: 3956682
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`THIS CORRECTED DIVISION DIRECTOR’S REVIEW SUPERCEDES THE
`
`DIVISION DIRECTOR’S REVIEW DATED 12/02/2015
`
`
`Date
`(electronic stamp)
`From
`Edvardas Kaminskas, MD.
`M Summ Review
`NDA#
`208194
`
`Su lement #
`
`.
`3
`Ea- e Pharmaceuticals Inc
`A Iicant Name
`
`Date of Submission
`02/13/2015
`
`PDUFA Goal Date
`
`12/ 13/2015
`
`Proprietary Name /
`Established (USAN) Name
`Dosa e Forms / Stren h
`Proposed Indications
`
`BendekaTM
`Bendamustine hydrochloride
`In'ection, 100 111
`For treatment of patients with
`0
`chronic lymphocytic leukemia
`
`o
`
`Indolent B-cell non-Hodgkin Lymphoma
`(NHL) that has progressed during or within six
`months of treatment with rituximab or a
`
`rituximab-containin re ~ ' n en.
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`
`Andrew Dmytrijuk, M.D./Kathy Robie Suh, M.D.,
`PhD.
`
`Pharmacology Toxicology Review Michael L. Manning, PhD/Christopher M. Sheth,
`Ph.D.
`
`Nina Ni, Ph.D.lVidya Pai, Ph.D.lVinyak Pawar, Ph.D.l
`CMC Review/Biopharmaceutics
`Zhong Li, Ph.D.lJing Li, PhD/Janice Brown, M.S./Paul
`Review/Product Quality
`Microbiology Review
`Perdue, Jr., Ph.D.
`
`OPDP
`Nisha Patel, Pharm.D./Kathleen Davis, Pharm.D.
`
`OSIS/DNDBE
`
`Hansong Chen, Ph.D.,Pharm.D.ICharles R. Bonpace,
`Pharm.D.
`
`CDTL Review
`
`Janice Brown, M.S.
`
`
`
`
`
`OSE/OMEPRM/DMEPA
`
`Michelle Rutledge, Pharm.D./Yelena Maslov/ Pharm.D.
`Todd Bridges, R.Ph.
`
`OND=0flice ofNew Drugs
`0PDP=Ofice of Prescription Drug Promotion
`OSE= Ofice of Surveillance and Epidemiology
`0MEPRM=Ofiioe of Medication Error Prevention and Risk Management
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Divisiion ofRisk Management
`OSIS=Oflice of Study Integrity and Surveillance
`DNDBE=Division ofNew Drug Bioequivalence Evaluation
`CD'I'IFCross—Discipline Team Leader
`
`Reference ID: 3956507
`
`
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`Signatory Authority Review Template
`
`1. Introduction
`
`Bendamustine HC1 is a small molecule alkylating agent approved for treatment of patients
`with chronic lymphocytic leukemia (CLL) and 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 current application for Bendamustine HC1 Injection is submitted as a 505 (b)(2) NDA.
`The Applicant is relying upon information in the public domain, i.e. labeling for the approved
`bendamustine HC1 product (Treanda® for injection) and published studies about bendamustine
`HC1, to support the safety and efficacy of the proposed product. The proposed drug product is
`a ready-to-dilute solution, whereas the listed drug product, Treanda (bendamustine) for
`injection, is a lyophilized powder that requires reconstitution. The proposed drug product
`BendekaTM (bendamustine hydrochloride) Injection is self—preserving and is intended for
`multiple doses.
`
`2. Background
`
`The Applicant Giagle Pharmaceuticals, Inc.) received Tentative Approval for the companion
`NDA 205580 Bendamustine HC1 Injection
`"9 on
`July 2, 2014 for
`M0 indolent B-cell NHL only, as requested by the Applicant. The
`application could not be granted final approval until all exclusivities expired. The last
`exclusivity expiration date for the CLL indication was
`m4) and the last
`exclusivity expiration date for the NHL indication is
`
`(war
`
`The Applicant was granted on July 2, 2014 orphan drug designation of bendamustine for 50
`mL admixture for “treatment offollicular lymphoma, treatment ofsmall lymphocytic
`lymphoma, treatment oflvrllpltoplasmacvtic lymphoma, treatment ofsplenic marginal cell
`lymphoma, treatment ofartranodal marginal zone B—cell lwnphoma ofmucosa—associated
`lymphoma tissue (AlAL T), and treatment ofnodal marginal zone lymphoma (collectively
`indolent B-cell non-Hodgkin ’s lymphoma) Also on July 2, 2014, the Applicant was granted
`orphan drug designation of bendamustine for 50 mL admixture for “treatment ofchronic
`lymphocytic leukemia
`
`On May 11, 2015 Cephalon, Inc. informed the Agency of Waiver of Orphan Drug Exclusivity
`for Eagle NDA 208194. The letter states “Pursuant to 21 CFR § 316.31(a)(3), Cephalon, Inc.
`hereby consents to FDA’s final approval of NDA 208194, submitted by Eagle
`Pharmaceuticals, Inc. on February 13, 2015, notwithstanding the orphan drug and pediatric
`exclusivities applicable to NDA 022249 and NDA 022303 for TREANDA (bendamustine
`hydrochloride) currently held by or granted to Cephalon.”
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`New information in the present NDA 208194 includes a modification of dose preparation and
`administration, allowing administration of the product in a smaller volume (50 mL admixture)
`over a shorter time (10 minutes), three options for admixtures, drug stability data to support a
`24-month shelf life, a bioequivalence study, and a safety and tolerability profile of BendekaTM
`(bendamustine HCl) Injection when infused over 10 minutes in a 50 mL admixture volume.
`
`3. CMC/Device
`
`Drug Substance: The CMC information for the drug substance was provided in DIVIF No.
`(m4) from
`M" DMF
`(m4) was reviewed and found adequate to support the
`manufacture of the drug product as a solution dosage form by Joyce Crich, Ph.D. on
`05/06/2014. There is no new quality update provided in the DMF since the last review. The
`submitted NDA included minor drug substance updates and the drug substance reviewer Dr.
`Nina Ni, Ph.D. formd the information adequate to support NDA 208194.
`
`Drug Product: Bendeka (bendamustine HCl) injection is a ready-to-dilute non-aqueous
`solution of Bendamustine HCl intended for intravenous administration after further dilution in
`
`50 mL of either 0.9% Sodium Chloride Injection, USP, 2.5% Dextrose/0.45% Sodium
`Chloride Injection, USP, or 5% Dextrose Injection, USP. Bendamustine undergoes rapid
`degradation
`(m4)
`consists of polyethylene glycol 400
`(PEG 400), propylene glycol, and monothioglycerol. The excipient levels, in terms of
`maximum daily dose in the drug product and the admixture, are below the levels used in
`currently approved parenteral drug products. A shelf life of 24 months is granted for Bendeka
`(bendamustine HCl) Injection, when stored refrigerated at 2° — 8°C (36° - 46°F), protected
`from light. The drug product reviewer recommended approval of the NDA.
`
`Process Review — Drug Product: The drug product manufacturing process was reviewed and
`found acceptable. The process reviewer recommended approval of the NDA.
`
`
`Biopharmaceutics Review — below under Clinical Pharmacology.
`
`Facilities Review and Inspection: The Office of Process and Facilities found the facilities
`acceptable and concluded that there are no significant outstanding manufacturing risks.
`
`Microbiology Review: Bendamustine HCl is a multi-use vial. Although it does not contain any
`antimicrobial preservative, bendamustine HCl is bacteriostatic and does not support bacterial
`growth. The microbiology section of the NDA was reviewed and found acceptable.
`
`I concur with the conclusions reached by the chemistry reviewers regarding the acceptability
`ofthe manufacturing ofthe drugproduct and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of24 months, when stored in refrigerator
`at 2° — 8°C (36° - 46°F), protectedfrom light. There are no outstanding issues.
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Applicant did not submit any new nonclinical studies since the previous NDA submission
`(NDA 205580). Pharmacology/Toxicology had no concerns with the nonclinical findings and
`the excipients used for Eagle’s Bendamustine HCl Injection. The nonclinical reviewer
`recommended approval of the NDA for Bendamustine HCl Injection administered as a 50 mL
`admixture over an infusion time of 10 minutes, for the proposed indications.
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval.
`5. Clinical Pharmacology/Biopharmaceutics
`
`There was no Clinical Pharmacology review for this NDA. The submitted bioequivalence
`study was reviewed by the Office of Product Quality Biopharmaceutics team.
`
`The bioequivalence study was an open-label, cross-over, randomized bioequivalence study
`designed to evaluate Eagle’s Bendamustine HCl Injection (BDM) administered to patients
`with a histological diagnosis of cancer (solid tumors and hematologic malignancies excluding
`chronic lymphocytic leukemia) who had progressed or relapsed on standard therapy, or for
`whom no curative or standard therapy was appropriate. The primary objective was to
`demonstrate that Eagle-BDM formulation is bioequivalent to the currently marketed Teva-
`BDM (listed drug) with respect to total bendamustine exposure (AUC). The maximum peak
`plasma concentration (Cmax) for Eagle-BDM is higher than for Teva-BDM due to a 6-fold
`longer administration of Teva-BDM (10 minutes versus 60 minutes).
`
`The study was carried out over two 28-day treatment cycles, in which subjects were
`randomized into 3 groups. Group 1 received 1 dose of Eagle-BDM followed by 1 dose of
`Teva-BDM in the 1st cycle, and Teva-BDM followed by Eagle-BDM in the 2nd cycle. Group 2
`received 1 dose of Teva-BDM followed by 1 dose of Eagle-BDM in the 1st cycle, and Teva-
`BDM followed by Eagle-BDM in the 2nd cycle. Group 3 received 1 dose of Teva-BDM
`followed by 1 dose of Teva-BDM in the 1st cycle, and Eagle-BDM followed by Eagle-BDM in
`the 2nd cycle. PK analyses were performed after doses 1, 2, and 3. Safety data were obtained
`throughout the 2 cycles.
`
`The biopharmaceutics review concluded that “the Eagle-BDM is bioequivalent to Teva-BDM
`for BDM AUC0-t and AUC0-∞ for the two PKE populations (FDA requested [n=60] and Eagle
`proposed [n=44]), as well as for the two Secondary Sensitivity populations (FDA requested
`[n=57] and Eagle proposed [n=38]), respectively, by using the RSABE method as well as the
`unscaled-ABE method.” The biopharmaceutics reviewer concluded that the safety profiles of
`the two products are similar based on the clinical safety review in DARRTs, despite the higher
`Cmax achieved by the Eagle-BDM product. No biopharmaceutical issues that would preclude
`
`4
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`were identified and the biopharmaceutics reviewer found the information adequate to support
`the approval of NDA 208194.
`
`I concur with the conclusions reached by the biopharmaceutics reviewer that there are no
`outstanding clinicalpharmacologv issues that preclude approval.
`
`6. Clinical Microbiology
`N/A.
`
`7. Clinica"Statistical-Efficacy
`
`There were no clinical data submitted aside from the bioequivalence study described above.
`No clinical issues that preclude approval were found and the clinical reviewer found the
`information adequate to support the approval of NDA 208194. There was no Statistical review
`for this NDA.
`
`8. Safety
`
`The clinical reviewer concluded that “From a clinical perspective the pharmacokinetic results,
`the proportion of patients with adverse events and severity of adverse events in the
`bioequivalence study were similar for Bendeka infusion over 10 minutes compared to Treanda
`infusion over 60 minutes. Review of safety in the bioequivalence study supporting flle
`Bendeka application (NDA 208194) does not raise new or additional safety concerns for the
`Bendeka formulation and faster infusion rate compared to the marketed Treanda lyophilized
`powder product.”
`
`The increased osmolality of the proposed drug product once diluted into either 0.9% Sodium
`Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP M"
`The clinical review stated, “In
`NDA 208194, there were no reported adverse reactions of phlebitis or hemolysis. The faster
`infusion rate of Bendeka, i.e., 10 minutes, compared to the infusion rate of Treanda, i.e., 60
`minutes, does not appear to increase the risk for hemolysis, phlebitis, or infusion site
`reactions”.
`
`9. Advisory Committee Meeting
`
`This application was not presented at an Advisory Committee meeting.
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`10.
`
`Pediatrics
`
`Bendamustine 50mL admixture was granted Orphan Designation for both indications (see
`above in Background) and is not subject to PREA.
`
`The labeling for the listed drug contains information in the Pediatric Use section based upon a
`study conducted by the listed drug applicant. Information from the study regarding pediatric
`experience was placed into the label based on safety concerns that could arise should the
`product be used off label in pediatric patients. Consequently, this information was retained in
`the label for the new Eagle bendamustine product.
`
`11.
`
`Other Relevant Regulatory Issues
`
`0 Application Integrity Policy (AIP): No issues were identified.
`
`0
`
`Exclusivity or patent issues: The following exclusivities are listed in the Orange
`Book:
`
`
`Exclusivity Data
`Application Number
`
`Exclusivity Code
`
`Product Number
`
`Exclusivity
`Expiration
`N022249 "’""
`
`N022249
`N022249 _—
`
`N022249
`001
`PED
`
`
`
`The holder of the exclusivities, Cephalon, Inc., “consents to FDA’s final approval of NDA
`208194, submitted by Eagle Pharmaceuticals, Inc. on February 13, 2015, notwithstanding the
`orphan drug and pediatric exclusivities applicable to NDA 022249 and NDA 022303 for
`TREANDA (bendamustine hydrochloride) currently held by or granted to Cephalon.”
`
`0 Financial disclosures: In accordance with 21 CFR 54.4, the applicant submitted the
`required financial disclosure requirement and certification.
`
`0 Other GCP issues: None
`
`0 Office of Study Integrity and Surveillance (OSIS) Audits: FDA Office of Scientific
`Investigations performed inspections of the following clinical sites:
`- Oncology Institute of Hope and Innovation, Long Beach, CA
`— Evergreen Hematology & Oncology, Spokane, WA
`- Greenville Hospital System University Medical Center, Greenville, SC
`- Cancer Center of Kansas, Wichita, KS
`
`(m4)
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NBA 208194 Bendeka
`
`om) site where analytical testing in support of the
`The inspection of the
`bioequivalence study was conducted on
`(but) A l-item Form FDA 483 was
`issued at the conclusion of the inspection. OSIS concluded that this observation does not
`affect the data integrity of the study.
`
`The study data from the four clinical sites were found to be acceptable by the
`OSIS/DGDBE review team.
`
`Other discipline consults: None
`
`Any other outstanding regulatory issues: None
`
`There are no other unresolved relevant regulatorv issues.
`
`12.
`
`Labeflng
`
`Proprietary name: DMEPA review of the proprietary name, Bendeka, concluded that
`it was acceptable.
`
`Division of Medication Error Prevention and Analysis (DMEPA): Labeling
`recommendations included an increase the font size, reduction of the size of company
`logo, holding important information and including a re-sealable peel-back label for the
`container carton label.
`
`Office of Prescription Drug Promotion (OPDP): OPDP did not have any labeling
`cements to the draft prescribing information.
`
`Prescribing Information: The wording of the labeling in the PLR format has been
`reviewed and comments from all disciplines (including DMEPA) were conveyed to the
`applicant.
`
`Carton and Immediate container label: The drug product and DMEPA reviewers
`made suggested edits to the carton and immediate container label. All revisions were
`accepted by the applicant.
`
`Patient labeling/Nledication guide: This is not required for this product.
`
`In summary: Final labeling was found acceptable for all the review disciplines and it was
`agreed upon by the Applicant.
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`13.
`
`Decision/Action/Risk Benefit Assessment
` Regulatory Action: Approval
`
` Risk Benefit Assessment: The indications for Bendeka are the same as that for
`Treanda and patients will be treated with the same total drug dose as using
`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 risk benefit assessment favors the approval
`of the Bendeka formulation for the same indications as that of the Treanda
`formulation. Bendeka is compatible with closed system transfer devices,
`adaptors, and syringes containing polycarbonate or acrylonitrile-butadiene-
`styrene.
`
` Recommendation for Postmarketing Risk Management Activities
`None.
`
` Recommendation for other Postmarketing Study Commitments
`None.
`
`8
`
`Reference ID: 3956507
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`EDVARDAS KAMINSKAS
`07/08/2016
`
`Reference ID: 3956507
`
`

`

`DD Summary Review
`NBA 208194 Bendeka
`
`electronic stam
`Date
`
`From
`Edvardas Kaminskas, M.D.
`Sub'ect
`Summ Review
`
`Bendeka
`Proprietary Name /
`Bendamustine h drochloride
`Name
`Established
`S ‘
`
`Dosage Forms / Strength
`Injection, 100 mg/4 mL (25 mg/mL)
`Proposed Indications
`For treatment of patients with
`
`0
`o
`
`chronic lymphocytic leukemia
`Indolent B-cell non—Hodgkin Lymphoma
`(NI-IL) that has progressed during or within six
`months of treatment with rituximab or a
`
`rituximab—containing regimen.
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`
`Andrew Dmytrijuk, M.D./Kathy Robie Suh, M.D.,
`Ph.D.
`
`Pharmacology Toxicology Review Michael L. Manning, PhD/Christopher M. Sheth,
`Ph.D.
`
`CMC Review/Biophannaceutics
`Review/Product Quality
`Microbiology Review
`OPDP
`
`Nina Ni, Ph.D.Nidya Pai, Ph.D.Ninyak Pawar, Ph.D./
`Zhong Li, Ph.D./Jing Li, Ph.D./Janice Brown, M.S./Paul
`Perdue, Jr., Ph.D.
`Nisha Patel, Pharm.D./Kathleen Davis, PharmD.
`
`OSIS/DNDBE
`
`Hansong Chen, Ph.D.,Pharm.D./Charles R. Bonpace,
`PharmD.
`
`CDTL Review
`
`Janice Brown, M.S.
`
`208194
`NDA#
`
`Supplement #
`01
`A licant Name
`Ea e Pharmaceuticals, Inc.
`Date of Submission
`02/13/2015
`
`PDUFA Goal Date
`12/13/2015
`
`
`
`
`
`OSE/OMEPRM/DMEPA
`
`Michelle Rutledge, Pharm.D./Yelena Maslov/ Pharm.D.
`Todd Bridges, R.Ph.
`
`0ND=Oflice ofNew Drugs
`OPDP=0fiice of Prescription Drug Promofion
`08E: omce of Surveillance and Epidemiology
`OMEPRM=Oflioe of Medication Error Prevention and Risk Management
`DMEPA=Division ofMedication Error Prevention and Analysis
`DRISK=Divisiion ofRisk Management
`OSIS=0flice of Study Integrity and Surveillance
`DNDBE=Division ofNew Drug Bioequivalence Evaluation
`CD'I'IFCross—Discipline Ton- Leader
`
`Reference ID: 3855061
`
`
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`Signatory Authority Review Template
`
`1. Introduction
`
`Bendamustine HCl is a small molecule alkylating agent approved for treatment of patients
`with chronic lymphocytic leukemia (CLL) and 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 current application for Bendamustine HCl Injection is submitted as a 505 (b)(2) NDA.
`The Applicant is relying upon information in the public domain, i.e. labeling for the approved
`bendamustine HCl product (Treanda® for injection) and published studies about bendamustine
`HCl, to support the safety and eflicacy of the proposed product. The proposed drug product is
`a ready-to-dilute solution, whereas the listed drug product, Treanda (bendamustine) for
`injection, is a lyophilized powder that requires reconstitution. The proposed drug product
`BendekaTM (bendamustine hydrochloride) Injection is self-preserving and is intended for
`multiple doses.
`
`2. Background
`
`The Applicant received Tentative Approval for the companion NDA 205580 Bendamustine
`HCl Injection
`(b)(o on July 2, 2014 for
`rum
`indolent B-cell NHL only, as requested by the Applicant. The application could not be
`granted final approval until all exclusivities expired. The last exclusivity expiration date for the
`CLL indication was
`0x4) and the last exclusivity expiration date for the NHL
`indication is
`
`war
`
`The Applicant was granted on July 2, 2014 orphan drug designation of bendamustine for 50
`mL admixture for “treatment offollicular lymphoma, treatment ofsmall lymphocytic
`lymphoma, treatment oflvrlmhoplasmacvtic lymphoma, treatment ofsplenic marginal cell
`lymphoma, treatment ofextranodal marginal zone B-cell lymphoma ofmucosa-associated
`lymphoma tissue (ML T), and treatment ofnodal marginal zone lymphoma (collectively
`indolent B-cell non-Hodgkin ’s lymphoma) Also on July 2, 2014, the Applicant was granted
`orphan drug designation of bendamustine for 50 mL admixture for “treatment ofchronic
`lymphocytic leukemia
`
`On May 11, 2015 Cephalon, Inc. informed the Agency of Waiver of Orphan Drug Exclusivity
`for Eagle NDA 208194. The letter states “Pursuant to 21 CFR § 316.31(a)(3), Cephalon, Inc.
`hereby consents to FDA’s final approval ofNDA 208194, submitted by Eagle
`Pharmaceuticals, Inc. on February 13, 2015, notwithstanding the orphan drug and pediatric
`
`Reference ID: 3855061
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`exclusivities applicable to NDA 022249 and NDA 022303 for TREANDA (bendamustine
`hydrochloride) currently held by or granted to Cephalon.”
`
`New information in the present NDA 208194 includes a modification of dose preparation and
`administration, allowing administration of the product in a smaller volume (50 mL admixture)
`over a shorter time (10 minutes), three options for admixtures, drug stability data to support a
`24-month shelf life, a bioequivalence study, and a safety and tolerability profile of BendekaTM
`(bendamustine HCl) Injection when infused over 10 minutes in a 50 mL admixture volume.
`
`3. CMC/Device
`
`Drug Substance: The CMC information for the drug substance was provided in DMF N0.
`M4) from
`m4) DMF
`(m4) was reviewed and found adequate to support the
`manufacture of the drug product as a solution dosage form by Joyce Crich, Ph.D. on
`05/06/2014. There is no new quality update provided in the DIVIF since the last review. The
`submitted NDA included minor drug substance updates and the drug substance reviewer Dr.
`Nina Ni, Ph.D. found the information adequate to support NDA 208194.
`
`Drug Product: Bendeka (bendamustine HCl) injection is a ready-to —di1ute non-aqueous
`solution of Bendamustine HCl intended for intravenous administration after fiuther dilution in
`
`50 mL of either 0.9% Sodium Chloride Injection, USP, 2.5% Dextrose/0.45% Sodium
`Chloride Injection, USP, or 5% Dextrose Injection, USP. Bendamustine undergoes rapid
`degradation
`m4)
`consists of polyethylene glycol 400
`(PEG 400), propylene glycol, and monothioglycerol. The excipient levels, in terms of
`maximum daily dose in the drug product and the admixture, are below the levels used in
`currently approved parenteral drug products. A shelf life of 24 months is granted for Bendeka
`(bendamustine HCl) Injection, when stored refrigerated at 2° — 8°C (36° —46°F), protected
`from light. The drug product reviewer recommended approval of the NDA.
`
`Process Review — Drug Product: The drug product manufacturing process was reviewed and
`found acceptable. The process reviewer recommended approval of the NDA.
`
`
`Biophannaceutics Review — below under Clinical Pharmacology.
`
`Facilities Review and Inspection: The Office of Process and Facilities found the facilities
`acceptable and concluded that there are no significant outstanding manufacturing risks.
`
`Microbiology Review: Bendamustine HCI is a multi-use vial. Although it does not contain any
`antimicrobial preservative, bendamustine HCl is bacteriostatic and does not support bacterial
`growth. The microbiology section of the NDA was reviewed and found acceptable.
`
`Reference ID: 3855061
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`I concur with the conclusions reached by the chemistry reviewers regarding the acceptability
`of the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of 24 months, when stored in refrigerator
`at 2° – 8°C (36° -46°F), protected from light. There are no outstanding issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Applicant did not submit any new nonclinical studies since the previous NDA submission
`(NDA 205580). Pharmacology/Toxicology had no concerns with the nonclinical findings and
`the excipients used for Eagle’s Bendamustine HCl Injection. The nonclinical reviewer
`recommended approval of the NDA for Bendamustine HCl Injection administered as a 50 mL
`admixture over an infusion time of 10 minutes, for the proposed indications.
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval.
`5. Clinical Pharmacology/Biopharmaceutics
`
`There was no Clinical Pharmacology review for this NDA. The submitted bioequivalence
`study was reviewed by the Office of Product Quality Biopharmaceutics team.
`
`The bioequivalence study was an open-label, cross-over, randomized bioequivalence study
`designed to evaluate Eagle’s Bendamustine HCl Injection (BDM) administered to patients
`with a histological diagnosis of cancer (solid tumors and hematologic malignancies excluding
`chronic lymphocytic leukemia) who had progressed or relapsed on standard therapy, or for
`whom no curative or standard therapy was appropriate. The primary objective was to
`demonstrate that Eagle-BDM formulation is bioequivalent to the currently marketed Teva-
`BDM (listed drug) with respect to total bendamustine exposure (AUC). The maximum peak
`plasma concentration (Cmax) for Eagle-BDM is higher than for Teva-BDM due to a 6-fold
`longer administration of Teva-BDM (10 minutes versus 60 minutes).
`
`The study was carried out over two 28-day treatment cycles, in which subjects were
`randomized into 3 groups. Group 1 received 1 dose of Eagle-BDM followed by 1 dose of
`Teva-BDM in the 1st cycle, and Teva-BDM followed by Eagle-BDM in the 2nd cycle. Group 2
`received 1 dose of Teva-BDM followed by 1 dose of Eagle-BDM in the 1st cycle, and Teva-
`BDM followed by Eagle-BDM in the 2nd cycle. Group 3 received 1 dose of Teva-BDM
`followed by 1 dose of Teva-BDM in the 1st cycle, and Eagle-BDM followed by Eagle-BDM in
`the 2nd cycle. PK analyses were performed after doses 1, 2, and 3. Safety data were obtained
`throughout the 2 cycles.
`
`The biopharmaceutics review concluded that “the Eagle-BDM is bioequivalent to Teva-BDM
`for BDM AUC0-t and AUC0-∞ for the two PKE populations (FDA requested [n=60] and Eagle
`proposed [n=44]), as well as for the two Secondary Sensitivity populations (FDA requested
`[n=57] and Eagle proposed [n=38]), respectively, by using the RSABE method as well as the
`
`4
`
`Reference ID: 3855061
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`unscaled-ABE method.” The biopharmaceutics reviewer concluded that the safety profiles of
`the two products are similar based on the clinical safety review in DARRTs, despite the higher
`Cmax achieved by the Eagle-BDM product. No biopharmaceutical issues that would preclude
`were identified and the biopharmaceutics reviewer found the information adequate to support
`the approval of NDA 208194.
`
`I concur with the conclusions reached by the biopharmaceutics reviewer that there are no
`outstanding clinical pharmacology issues that preclude approval.
`6. Clinical Microbiology
`N/A.
`
`7. Clinical/Statistical-Efficacy
`
`There were no clinical data submitted aside from the bioequivalence study described above.
`No clinical issues that preclude approval were found and the clinical reviewer found the
`information adequate to support the approval of NDA 208194. There was no Statistical review
`for this NDA.
`
`8. Safety
`
`The clinical reviewer concluded that “From a clinical perspective the pharmacokinetic results,
`the proportion of patients with adverse events and severity of adverse events in the
`bioequivalence study were similar for Bendeka infusion over 10 minutes compared to Treanda
`infusion over 60 minutes. Review of safety in the bioequivalence study supporting the
`Bendeka application (NDA 208194) does not raise new or additional safety concerns for the
`Bendeka formulation and faster infusion rate compared to the marketed Treanda lyophilized
`powder product.”
`
`The increased osmolality of the proposed drug product once diluted into either 0.9% Sodium
`Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP
`
` The clinical review stated, “In
`NDA 208194, there were no reported adverse reactions of phlebitis or hemolysis. The faster
`infusion rate of Bendeka, i.e., 10 minutes, compared to the infusion rate of Treanda, i.e., 60
`minutes, does not appear to increase the risk for hemolysis, phlebitis, or infusion site
`reactions”.
`9. Advisory Committee Meeting
`
`This application was not presented at an Advisory Committee meeting.
`
`5
`
`Reference ID: 3855061
`
`(b) (4)
`
`

`

`DD Summary Review
`NDA 208194 Bendeka
`
`Pediatrics
`10.
`Bendamustine 50mL admixture was granted Orphan Designation for both indications (see
`above in Background) and is not subject to PREA.
`
`The labeling for the listed drug contains information in the Pediatric Use section based upon a
`study conducted by the listed drug applicant. Information from the study regarding pediatric
`experience was placed into the label based on safety concerns that could arise should the
`product be used off label in pediatric patients. Consequently, this information was retained in
`the label for the new Eagle bendamustine product.
`
`11.
`
`Other Relevant Regulatory Issues
`
`• Application Integrity Policy (AIP): No issues were identified.
`
`•
`
` Exclusivity or patent issues: The following exclusivities are listed in the Orange
`Book:
`
`Exclusivity Data
`Application Number
`
`Product Number
`
`Exclusivity Code
`
`N022249
`N022249
`N022249
`N022249
`
`001
`001
`001
`001
`
`ODE
`PED
`ODE
`PED
`
` Exclusivity
`Expiration
`
`The holder of the exclusivities, Cephalon, Inc., “consents to FDA’s final approval of NDA
`208194, submitted by Eagle Pharmaceuticals, Inc. on February 13, 2015, notwithstanding the
`orphan drug and pediatric exclusivities applicable to NDA 022249 and NDA 022303 for
`TREANDA (bendamustine hydrochloride) currently held by or granted to Cephalon.”
`
`• Financial disclosures: In accordance with 21 CFR 54.4, the applicant submitted the
`required financial disclosure requirement and certification.
`
`• Other GCP issues: None
`
`• Office of Study I