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

`

`505(b)(2) ASSESSMENT
`
`NDA # 208194
`
`NDA Supplement #2 8— N/A
`
`Efficacy Supplement Type SE- N/A
`
`m" which
`Proprietary Name: With submission dated 2/13/l 5. Eagle initially requested “
`M" and
`was concluded conditionally acceptable on 4/2/15. Then Eagle withdrew "
`requested “Bendeka,” which was concluded conditionally acceptable on June 16. 2015.
`Established/Proper Name: bendamustine hydrochloride
`Dosage Form: Injection
`-.: 100m 4mL(25m7 mL)
`
`Apphcant Eagle Pharmaceuticals Inc
`
`Date of Receipt: February 13. 2015
`
`rituximab or a rituximab containing regimen.
`
`PDUFA Goal Date: December 13. 2015
`
`Action Goal Date (if different):
`
`RPM: Laura Wall
`
`Proposed Indication(s): (1) Treatment of patients with chronic lymphocytic leukemia. Eflicacy
`relative to first line therapies other than chlorambucil. (2) Treatment of patients with indolent B
`cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically—derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YES|:I
`
`NO&
`
`If “YES “contact the (b) (2) review stafi"in the Immediate Oflice, Oflice ofNew Drugs.
`
`Reference ID: 3856843
`
`Page 1
`Version: January 2015
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug by reliance on published
`literature, or by reliance on a final OTC monograph. (If not clearly identified by the
`applicant, this information can usually be derived from annotated labeling.)
`
`
`Source of information* (e.g.,
`published literature, name of listed
`drug(s), OTC final drug
`monograph)
`TREANDA® (bendamustine HCl)
`for injection (the listed drug)
`Published literature
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`Various sections of the label
`
`Product quality, nonclinical; and clinical
`
`
`
`
`
` *each source of information should be listed on separate rows, however individual
`literature articles should not be listed separately
`
`
`3) The bridge in a 505(b)(2) application is information to demonstrate sufficient similarity
`between the proposed product and the listed drug(s) or to justify reliance on information
`described in published literature for approval of the 505(b)(2) product. Describe in detail how
`the applicant bridged the proposed product to the listed drug(s) and/or published literature1.
`See also Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug
`and Biological Products.
`
`In order to bridge the proposed product, Eagle-BDM, to the listed drug, Treanda®, the
`Applicant conducted an open-label, randomized, crossover (partially replicated) phase 1
`study in cancer patients to demonstrate the bioequivalence of the two drug products.
`Both Treanda® and Eagle-BDM were administered at the same dose of 120 mg/m2. However,
`Treanda® was diluted into 500 mL infusion and infused over 60 minutes, while Eagle-BDM
`was diluted into 50 mL infusion and infused over 10 minutes.
`Plasma PK of bendamustine was measured and statistical analysis was performed using both
`the average BE and reference-scaled BE approaches due to the high within-subject
`variability. It was agreed upon by the Agency at the IND116448 meeting held in 2013, that
`only AUCs would be used for BE determination, because Cmax would be different due to the
`differences in concentration and administration duration of the two drug products. The results
`showed that the AUCs (AUC0-t & AUC0-∞) of bendamustine met the bioequivalence criteria
`in both FDA-recommended PK evaluation populations, though the Cmax of bendamustine of
`Eagle-BDM was about 2.5 fold higher than that of Treanda®. The safety profiles of the two
`products are similar.
`Overall, the proposed product is bioequivalent to Treanda® based on AUCs comparison, and
`the bridge between the proposed product and the listed drug was established.
`
`
`
`
`
`
`
`
`RELIANCE ON PUBLISHED LITERATURE
`
`
`1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative
`physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may
`include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s)
`For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product
`
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`
`Reference ID: 3856843
`
`

`

`4) (a) Regardless of whether the applicant has explicitly stated a reliance on published literature
`to support their application, is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved as labeled
`without the published literature)?
`
` NO
`
` YES
`If “NO,” proceed to question #5.
`
`
`
`(b) Does any of the published literature necessary to support approval identify a specific (e.g.,
`brand name) listed drug product?
`
` NO
`
` YES
`If “NO”, proceed to question #5.
`If “YES”, list the listed drug(s) identified by name and answer question #4(c).
`
`
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
` YES
`
` NO
`
`
`
`1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative
`physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may
`include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s)
`For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product
`
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`
`Reference ID: 3856843
`
`

`

`
`
`RELIANCE ON LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordingly.
`
`
`5) Regardless of whether the applicant has explicitly cited reliance on listed drug(s), does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e., the application
`cannot be approved without this reliance)?
` YES
`
` NO
`
`If “NO,” proceed to question #10.
`
`
`6) Name of listed drug(s) relied upon, and the NDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`
`Name of Listed Drug
`
`NDA #
`
`TREANDA® (bendamustine HCl) for injection NDA # 022249
`
`Did applicant
`specify reliance on
`the product? (Y/N)
`Y
`
`
`
`
`
`
`
`
`
`Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent
`certification/statement. If you believe there is reliance on a listed product that has not been
`explicitly identified as such by the applicant, please contact the (b)(2) review staff in the
`Immediate Office, Office of New Drugs.
`
`
`7) If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
`
` NO
`
` YES
` N/A
`If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental
`application, answer “N/A”.
`If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.
`
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application:
`
`
`b) Approved by the DESI process?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a final OTC drug monograph?
`
` NO
`
` YES
`If “YES”, please list which drug(s).
`
`
`
`
`
`
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`
`Reference ID: 3856843
`
`

`

`Name of drug(s) described in a final OTC drug monograph: N/A
`
`
`
`d) Discontinued from marketing?
`
` NO
`
` YES
`If “YES”, please list which drug(s) and answer question d) i. below.
`If “NO”, proceed to question #9.
`
`Name of drug(s) discontinued from marketing:
`
`i) Were the products discontinued for reasons related to safety or effectiveness?
` YES
`
` NO
`(Information regarding whether a drug has been discontinued from marketing for
`reasons of safety or effectiveness may be available in the Orange Book. Refer to
`section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If
`a determination of the reason for discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archive file and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`This application will provide for a change to the infusion time, admixture volume, and
`additional admixture options.
`
`
`
`
`
`The purpose of the following two questions is to determine if there is an approved drug product
`that is equivalent or very similar to the product proposed for approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product
`and/or protein or peptide product is complex. If you answered YES to question #1, proceed to
`question #12; if you answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`
`
`
`
`
`
`
`(Pharmaceutical equivalents are drug products in identical dosage forms intended for the
`same route of administration that: (1) contain identical amounts of the identical active drug
`ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of
`modified release dosage forms that require a reservoir or overage or such forms as prefilled
`syringes where residual volume may vary, that deliver identical amounts of the active drug
`ingredient over the identical dosing period; (2) do not necessarily contain the same inactive
`ingredients; and (3) meet the identical compendial or other applicable standard of identity,
`strength, quality, and purity, including potency and, where applicable, content uniformity,
`disintegration times, and/or dissolution rates. (21 CFR 320.1(c), FDA’s “Approved Drug
`Products with Therapeutic Equivalence Evaluations” (the Orange Book)).
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`equivalent must also be a combination of the same drugs.
`
` YES
`
`
`
` NO
`
`
`
`
`
`
`
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`
`Reference ID: 3856843
`
`

`

`
`
` If “NO” to (a) proceed to question #11.
`If “YES” to (a), answer (b) and (c) then proceed to question #12.
`
`
`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`
` NO
`
`
`
`
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent?
` N/A
` YES
`
` NO
`
`If this application relies only on non product-specific published literature, answer “N/A”
`If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to
`question #12.
`If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all
`of the products approved as ANDAs, but please note below if approved approved generics are
`listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office,
`Office of New Drugs.
`
`Pharmaceutical equivalent(s):
`
`
`11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?
`
`(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its
`precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each
`such drug product individually meets either the identical or its own respective compendial or other
`applicable standard of identity, strength, quality, and purity, including potency and, where applicable,
`content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage
`forms and strengths within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are extended-release products when compared with immediate- or standard-release
`formulations of the same active ingredient.)
`
`Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical
`alternative must also be a combination of the same drugs.
`
`
` NO
`
` YES
`If “NO”, proceed to question #12.
`
`
`
`
`
` NO
`
`
`
`
`
`(b) Is the pharmaceutical alternative approved for the same indication for which the
`505(b)(2) application is seeking approval?
` YES
`
`(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)?
` N/A
` YES
`
` NO
`
`If this application relies only on non product-specific published literature, answer “N/A”
`If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question
`#12.
`If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the
`application, list the NDA pharmaceutical alternative(s); you do not have to individually list all
`
`
`
`
`
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`
`Reference ID: 3856843
`
`

`

`
`
` proceed to question #14
`
` No patents listed
`
`
`
`13) Did the applicant address (with an appropriate certification or statement) all of the unexpired
`patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the
`(b)(2) product?
`
` NO
`
` YES
`If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.
`
`Listed drug/Patent number(s): 8609863; 8669279; 8791270; 8883836; and 8895756
`
`14) Which of the following patent certifications does the application contain? (Check all that
`apply and identify the patents to which each type of certification was made, as appropriate.)
`
`
`of the products approved as ANDAs, but please note below if approved generics are listed in
`the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of
`New Drugs.
`
`
`Pharmaceutical alternative(s):
`
`
`PATENT CERTIFICATION/STATEMENTS
`
`
`12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed
`drug(s) for which our finding of safety and effectiveness is relied upon to support approval of
`the (b)(2) product.
`
`Listed drug/Patent number(s): 8436190; 8445524; 8609863; 8669279; 8791270; 8883836; and
`8895756
`
`The 505(b)(2) committee agreed to not require the applicant to certify to the 8344006
`patent, as it was confirmed that the applicant did not rely upon either of the two
`presentations that list the ‘006 patent.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3856843
`
` No patent certifications are required (e.g., because application is based solely on
`published literature that does not cite a specific innovator product)
`
` 21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to
`FDA. (Paragraph I certification)
`
`
` 21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`
`Patent number(s):
`
` 21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph
`III certification)
`
`Patent number(s):
`
`
`
`
`
`Expiry date(s):
`
` 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be
`infringed by the manufacture, use, or sale of the drug product for which the
`application is submitted. (Paragraph IV certification). If Paragraph IV certification
`
`
`
`Page 7
`Version: January 2015
`
`

`

`
`
`
`
`
`
`
`
`was submitted, proceed to question #15.
`
` 21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the
`NDA holder/patent owner (must also submit certification under 21 CFR
`314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the
`NDA holder/patent owner, proceed to question #15.
`
` 21 CFR 314.50(i)(1)(ii): No relevant patents.
`
`
` 21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent
`and the labeling for the drug product for which the applicant is seeking approval
`does not include any indications that are covered by the use patent as described in
`the corresponding use code in the Orange Book. Applicant must provide a
`statement that the method of use patent does not claim any of the proposed
`indications. (Section viii statement)
`
`Patent number(s):
`Method(s) of Use/Code(s):
`
`
`
`
`
`15) Complete the following checklist ONLY for applications containing Paragraph IV
`certification and/or applications in which the applicant and patent holder have a licensing
`agreement:
`
`
`
`
`
`
`
`(a) Patent number(s): 8436190 and 8445524
`(b) Did the applicant submit a signed certification stating that the NDA holder and patent
`owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]?
`
` YES
`
` NO
`If “NO”, please contact the applicant and request the signed certification.
`
`
`(c) Did the applicant submit documentation showing that the NDA holder and patent
`owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the
`form of a registered mail receipt.
`
` NO
`
` YES
`If “NO”, please contact the applicant and request the documentation.
`
`
`(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder
`and patent owner(s) received notification):
`
`
`
`Date(s): June 10, 2015
`
`
`Note, the date(s) entered should be the date the notification occurred (i.e., delivery
`date(s)), not the date of the submission in which proof of notification was provided
`
`(e) Has the applicant been sued for patent infringement within 45-days of receipt of the
`notification listed above?
`
`Note that you may need to call the applicant (after 45 days of receipt of the notification)
`to verify this information UNLESS the applicant provided a written statement from the
`notified patent owner(s) that it consents to an immediate effective date of approval.
`
`
`
`
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`
`Reference ID: 3856843
`
`

`

`YES
`
` NO
`
` Patent owner(s) consent(s) to an immediate effective date of
`approval
`
`
`
`
`
`Page 9
`Version: January 2015
`
`
`
`
`
`Reference ID: 3856843
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LAURA C WALL
`12/07/2015
`
`Reference ID: 3856843
`
`

`

`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:
`TO:
`
`FROM:
`
`THROUGH:
`
`SUBJECT:
`
`November 30, 2015
`Ann T. Ferrel, M.D.
`Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Office of New Drugs
`Hasan A. Irier, Ph.D.
`Division of Generic Drug Bioequivalence Evaluation
`Office of Study Integrity and Surveillance
`Office of Translational Sciences
`Sam H. Haidar, Ph.D., R.Ph.
`Director (Acting)
`Division of Generic Drug Bioequivalence Evaluation
`Office of Study Integrity and Surveillance
`Office of Translational Sciences
`Review of EIR covering NDA 208194, Eagle Pharmaceuticals,
`Inc., Bendamustine Hydrochloride Injection, 100 mg/4 mL
`(25mg/mL)
`
`At the request of the Division of Hematology Products (DHP), Division
`of Generic Drug Bioequivalence Evaluation (DGDBE, Office of Study
`Integrity and Surveillance (OSIS)) arranged inspections of clinical
`portions of the following in vivo clinical endpoint study:
`Study Number:
`EGL-BDM-C-1301
`Study Title:
`“Phase 1, open-label, crossover, randomized,
`bioequivalence study to evaluate two formulations of
`Bendamustine (BDM) hydrochloride (HCl) administered to
`
`cancer patients”
`ORA investigators audited the clinical portions of multi-site study
`EGL-BDM-C-1301 conducted at four (4) different facilities (Table-1).
`For each inspection listed in Table-1, the audits included a review of
`the business organization, a thorough examination of study records,
`clinical operations and records such as source documents; case report
`forms (CRFs), concomitant medications, number of evaluable subjects,
`drug accountability, communication between the CRO and sponsor, dosing
`logs and informed consent.
`
`Reference ID: 3854670
`
`

`

`Page 2 – Eagle Pharmaceuticals, Inc., NDA 208194, Bendamustine Hydrochloride
`Injection, 100 mg/4 mL (25mg/mL)
`
`Inspection
`Date
`10/08/15-
`10/16/2015
`
`ORA
`Auditor
`Michael
`Kopf
`
`483
`issued?
`YES
`
`Response
`Received?
`YES
`(10/20/15)
`
`10/26/15-
`11/02/2015
`
`Lakecha
`Lewis
`
`NO
`
`11/02/15-
`11/6/2015
`
`Gerard
`De Leon
`
`NO
`
`11/02/15-
`11/05/2015
`
`Venessa
`Coulter
`
`NO
`
`NA
`
`NA
`
`NA
`
`104
`
`105
`
`Table-1.
`Site# Site Name
`Cancer Center
`101
`of Kansas,
`818 N. Emporia,
`Suite 403
`Wichita, KS
`67214
`Oncology
`Institute of
`Hope 3300 E.
`South Street,
`Suite 304 Long
`Beach, CA 90805
`Evergreen
`Hematology &
`Oncology(EHO)*,
`309 E. Farwell
`Road, Suite 100
`Spokane, WA
`99218
`Greenville
`Hospital System
`University
`Medical Center,
`(ITOR) 900 W.
`Faris Road
`3rd Floor
`CTC/CRU
`Greenville, SC
`29605
`
`108
`
`[*Evergreen Hematology & Oncology(EHO)filed Bankruptcy, moved out of their
`building and closed on 6/15/2015. All the study records were transferred to
`Cancer Care Northwest(CCNW, 1204 N. Vercler Rd Spokane Valley, WA 99216
`Contact person is Rose Miller: 509-228-1000), which had signed a “Patient and
`Financial Records Agreement” on 4/30/2015 with EHO to act solely as a
`custodian for all their records. ORA investigator all the study related
`records and documents at CCNW.]
`During inspections, the ORA investigators who inspected sites 104, 105
`and 108 did not observe any objectionable condition, and did not issue
`Form FDA 483 at the conclusion of inspection. However, the ORA
`investigator at the site 101 (Cancer Center of Kansas) was not able to
`collect reserve samples at the site and issued form 483 (Attachment
`1). The site provided a response letter to the form 483 on 10/20/15
`(Attachment 2). The response letter described that the reserves
`samples were not collected by the site instead they were retained at
`. After
`an independent facility,
`
`2
`
`Reference ID: 3854670
`
`(b) (4)
`
`

`

`Page 3 – Eagle Pharmaceuticals, Inc., NDA 208194, Bendamustine Hydrochloride
`Injection, 100 mg/4 mL (25mg/mL)
`evaluation of the response along with a memo collected at another site
`(Site 104), this reviewer determined that the test and reference
`products were randomly collected and sent to each site by
`appeared independent from the sponsor as well as the drug
`manufacturer. Also,
` was not under contract with the sponsor.
`Furthermore, once the drug products were shipped to
`, they were
`not returned to the sponsor or the drug manufacturer (Attachment 3).
`This reviewer is of the opinion that the observed failure of the
`reserve sample retention by the site does not have impact on the study
`outcome, and that the data from Site 101 along with the other three
`sites (104, 105 and 108) should be accepted for review.
`
`Conclusions:
`Following the review of establishment inspectional reports (EIRs) and
`FDA Form-483, this OSIS/DGDBE reviewer provides the following
`recommendations for each site( Table-2):
`
`Table-2.Final OSIS/DGDBE Recommendations
`Site #
`Site Name/FEI#/Classification
`
`101
`
`104
`
`105
`
`108
`
`Cancer Center of Kansas,
`FEI: 3007381886
`NAI
`Oncology Institute of Hope
`FEI: 3011899089
`NAI
`Evergreen Hematology & Oncology,
`FEI: 3011883080
`NAI
`Greenville Hospital System
`University Medical Center, (ITOR)
`FEI: 3005478248
`NAI
`
`Accept study data for
`further Agency review?
`YES
`
`YES
`
`YES
`
`YES
`
`Hasan A. Irier, Ph.D.
`Division of Generic Drug Bioequivalence Evaluation
`Office of Study Integrity and Surveillance
`Office of Translational Sciences
`
`CC:
`OSIS/DGDBE/Kassim/Taylor/Dejernett/Fenty-Stewart/Nkah
`OSIS/DGDBE/Haidar/Bonapace/Choi/Dasgupta/Skelly/Cho/Irier
`OND/OHOP/DHP/Ferrel/Wall
`Draft: HI 11/17/2015, 11/30/2015
`
`3
`
`Reference ID: 3854670
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 4 – Eagle Pharmaceuticals, Inc., NDA 208194, Bendamustine Hydrochloride
`Injection, 100 mg/4 mL (25mg/mL)
`Edit: YMC 12/1/2015; SHH 12/1/2015
`ATTACHMENTS:
`Attachmen-1. Form FDA-483, Issued to Cancer Center of Kansas
`Attachmen-2. Response Letter to Form 483 issued to Cancer center of
`Kansas
`Attachmen-3. Eagle Pharmaceuticals Memo regarding Reserve Sample
`Retention by
`Hasan Irier
`-S
`
`Digitally signed by Hasan Irier -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People, cn=Hasan Irier -S,
`0.9.2342.19200300.100.1.1=2001568214
`Date: 2015.12.02 08:11:40 -05'00'
`
`Sam H. Haidar -A
`
`Digitally signed by Sam H. Haidar -A
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People, cn=Sam H. Haidar -A,
`0.9.2342.19200300.100.1.1=1300123664
`Date: 2015.12.02 08:33:27 -05'00'
`
`Reference ID: 3854670
`
`4
`
`11 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`HASAN A IRIER
`12/02/2015
`
`SAM H HAIDAR
`12/02/2015
`
`Reference ID: 3854670
`
`

`

`LABEL AND LABELING REVIEW
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`September 16, 2015
`Requesting Office or Division:
`Division of Hematology Products(DHP)
`Application Type and Number: NDA 208194
`Product Name and Strength:
`Bendeka (bendamustine) Injection
`100 mg/4 mL (25 mg/mL)
`Single
`Rx
`Eagle Pharmaceuticals, Inc.
`February 13, 2015
`2015-353
`Michelle Rutledge, PharmD
`Yelena Maslov, PharmD
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`Submission Date:
`OSE RCM #:
`DMEPA Primary Reviewer:
`DMEPA Team Leader:
`
`Reference ID: 3820758
`
`1
`
`

`

`REASON FOR REVIEW
`1
`This review responds to a request from DHP to evaluate the proposed carton labeling, vial label,
`and prescribing information for Bendeka for areas of vulnerability that could lead to medication
`errors. This product is a 505(b)(2) to reference listed drug Treanda for Injection. The reference
`listed drug, Treanda (bendamustine hydrochloride) for injection, was approved on March 20,
`2008 under NDA 022249, and is marketed as 25 mg or 100 mg per vial.
`2 MATERIALS REVIEWED
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`
`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section (for Methods
`Material Reviewed
`and Results)
`A
`B
` C – N/A
`D
` E - N/A
` F – N/A
`G
`
`Product Information/Prescribing Information
`Previous DMEPA Reviews
`Human Factors Study
`ISMP Newsletters
`FDA Adverse Event Reporting System (FAERS)*
`Other
`Labels and Labeling
`N/A=not applicable for this review
`*We do not typically search FAERS for label and labeling reviews unless we are aware of
`medication errors through our routine postmarket safety surveillance
`
`3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED
`Eagle Pharmaceuticals, Inc submitted a 505(b)2 to reference listed drug (RLD) Treanda for
`Injection. Although, the proposed Bendeka product will be marketed as a similar strength (100
`mg/4mL (25 mg/mL after dilution) versus 100 mg/vial (5 mg/mL after reconstitution) and 25
`mg/vial (5 mg/mL after reconstitution) for Treanda for Injection), there are differences such as
`formulations, concentration, infusion time administration, and multiple versus single use
`between the proposed Bendeka and reference listed drug, Treanda. Treanda is supplied as a
`powder for injection and is administered over 30 minutes for chronic lymphocytic leukemia
`(CLL) and over 60 minutes for Indolent B-cell non-Hodgkin lymphoma (NHL). The proposed
`Bendeka product will be supplied as ready-to-dilute injection and will be administered over 10
`minutes for both the CLL and NHL indications. In addition, the proposed multi-use vial Bendeka
`product can have an expanded stability window if undiluted (up to 28 days when stored in its
`original carton under refrigeration) versus t