CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205580Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 205580 Resubmission/Class 1
`
`Deputy Division Director Summary Review
`
`Deputy Division Director Summary Review for Regulatory Action
`
`Date
`
`(electronic stamp)
`From
`R. Angelo de Claro, MD
`
`Deputy Division Director Summary Review
`Subject
`NDA 205580
`NDA/BLA # and Supplement #
`
`Resubmission/Class 1
`
`Eagle Pharmaceuticals, Inc.
`Applicant
`Date of Submission
`4 April 2018
`4 June 2018
`PDUFA Goal Date
`
`Not applicable
`Proprietary Name
`Established or Pro t er Name
`
`In'ection: 100m 4mL 25m mL
`
`Chronic lymphocytic leukemia (CLL). Efficacy
`relative to first line therapies other than
`chlorambucil has not been established.
`
`Indolent B-cell non-Hodgkin lymphoma (NHL)
`that has progressed during or within six months of
`treatment with rituximab or a rituximab—
`
`Dosa _e Form 5
`
`Applicant Proposed
`Indication(s)/Population(s)
`
`Action or Recommended Action:
`
`Approved/Recommended
`Indication(s)/Population(s) (if
`applicable)
`
`containino
`
`Reference ID: 4268338
`
`'
`
` Bendamustine H drochloride
`
`containin ‘
`
`'
`
`A I n'oval
`
`Chronic lymphocytic leukemia (CLL). Efficacy
`relative to first line therapies other than
`chlorambucil has not been established.
`
`Indolent B-cell non-Hodgkin lymphoma (NHL)
`that has progressed during or within six months of
`treatment with rituximab or a rituximab-
`
`

`

`NDA 205580 Resubmission/Class 1
`Deputy Division Director Summary Review
`
`
`
`1. Regulatory Action
`
`
`Recommended Regulatory Action: Approval
`
`All review team members recommend approval. The outstanding patent-related issue
`described in the March 30, 2018, tentative approval letter has been resolved, and there are no
`barriers to final approval.
`
`
`2. Background
`
`
`On September 6, 2013, Eagle Pharmaceuticals, Inc. (Applicant) submitted a 505(b)(2) New
`Drug Application (NDA 205580) for Bendamustine Hydrochloride Injection 100 mg/4 mL (25
`mg/mL) in a 500 mL admixture. The Agency granted a tentative approval on July 2, 2014, for
`the NHL indication because the listed drug upon which the 505(b)(2) application relied was
`subject to a period of patent protection and because Treanda (bendamustine hydrochloride) had
`orphan drug exclusivity that blocked approval of the application. Refer to the Tentative
`Approval Letter on July 2, 2014.
`
`On January 31, 2018, the Applicant resubmitted the application which included updated CMC
`information and revised labeling. In the resubmission, the Applicant sought to add the CLL
`indication to the labeling. The Applicant identified Treanda powder 100 mg vial (NDA
`22249) as the listed drug product that is the basis for the submission. In an amendment to the
`resubmission, the Applicant submitted new paragraph IV certifications to the following
`patents: U.S. Patent Nos. 8,445,524 (‘524 patent), 8,791,270, 8,883,836, and 8,669,279. The
`Applicant provided notice of these paragraph IV certifications to Cephalon, the patent owner
`and NDA holder for Treanda, and submitted adequate documentation of timely sending and
`receipt of notice. The NDA holder for Treanda submitted information on the ‘524 patent to
`FDA before the date on which the Applicant submitted its 505(b)(2) application. Accordingly,
`the 45-day period provided for in section 505(c)(3)(C) of the Federal Food, Drug, and
`Cosmetic Act (FD&C Act) applied with respect to this patent. However, because the 45-day
`period described in section 505(c)(3)(C) of the FD&C Act had not yet expired, final approval
`could not be granted at that time. Thus, the application received a tentative approval on March
`30, 2018, because the listed drug upon which the 505(b)(2) application relied was subject to a
`period of patent protection.
`
`On April 4, 2018, the Applicant resubmitted the application for final approval. On May 14,
`2018, the 45-day period described in section 505(c)(3)(C) of the FD&C Act expired. On May
`15, 2018, the Applicant confirmed that no action for patent infringement had been brought by
`Cephalon, the NDA holder and patent owner for the ‘524 patent within the 45-day period.
`
`
`
`
`
`
`Reference ID: 4263238Reference ID: 4266336
`
`2
`
`

`

`NDA 205580 Resubmission/Class 1
`Deputy Division Director Summary Review
`
`3. Product Quality
`
`
`Refer to previous CMC reviews. No issues that would preclude approval were identified.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Refer to previous pharmacology-toxicology review. No issues that would preclude approval
`were identified.
`
`
`5. Clinical Pharmacology
`
`
`Refer to previous clinical pharmacology review. No issues that would preclude approval were
`identified.
`
`
`6. Clinical Microbiology
`
`
`No issues that would preclude approval were identified.
`
`
`7. Clinical/Statistical-Efficacy
`
`
`No new clinical data were submitted. The clinical review team reviewed the proposed labeling
`and found it acceptable for both the NHL and CLL indications.
`
`
`8. Safety
`
`
`No new safety issues were identified.
`
`
`9. Advisory Committee Meeting
`
`
`This product is not a new molecular entity.
`
`
`10.
`
`Pediatrics
`
`
`Pediatric study requirement for this application is waived because necessary studies are
`impossible or highly impracticable.
`
`
`
`
`
`Reference ID: 4263238Reference ID: 4266336
`
`3
`
`

`

`NDA 205580 Resubmission/Class 1
`Deputy Division Director Summary Review
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`The application was reviewed by the 505(b)(2) clearance committee.
`
`
`12.
`
`Labeling
`
`
`All the review teams participated in the labeling discussions. On April 25, 2018, the Applicant
`submitted a request to withdraw the previously proposed proprietary name.
`
`
`13.
`
`Postmarketing
`
` Postmarketing Risk Evaluation and Mitigation Strategies (REMS)
`
`
`The review teams did not identify a need for a REMS for this application.
`
` Other Postmarketing Requirements and Commitments
`
`Routine pharmacovigilance
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4263238Reference ID: 4266336
`
`4
`
`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ROMEO A DE CLARO
`05/15/2018
`
`
`
`Reference ID: 4263238Reference ID: 4266336
`
`

`

`NDA 205580 Resubmission/Class 1
`
`Deputy Division Director Summary Review
`
`Deputy Division Director Summary Review for Regulatory Action
`
`Date
`
`electronic stam
`
`From
`R. An elo de Claro, MD
`
`Deputy Division Director Summary Review
`Subject
`NDA 205580
`NDA/BLA # and Supplement #
`
`Resubmission/C lass 1
`
`Eagle Pharmaceuticals, Inc.
`Applicant
`Date of Submission
`31 Jan .
`2018
`
`PDUFA Goal Date
`31 March 2018
`
`Not applicable
`Proprietary Name
`Established or Pro 0 er Name
`Bendamustine
`
`Dosa _e Form 5
`
`Applicant Proposed
`Indication(s)/Population(s)
`
`In'ection: 100m 4mL 25m mL
`
`Chronic lymphocytic leukemia (CLL). Efficacy
`relative to first line therapies other than
`chlorambucil has not been established.
`
`Indolent B-cell non-Hodgkin lymphoma (NHL)
`that has progressed during or within six months of
`treatment with rituximab or a rituximab—containing
`
`regimen.
`
`Action or Recommended Action:
`
`Approved/Recommended
`Indication(s)/Population(s) (if
`
`Chronic lymphocytic leukemia (CLL). Efficacy
`relative to first line therapies other than
`chlorambucil has not been established.
`
`Indolent B-cell non—Hodgkin lymphoma (NHL)
`that has progressed during or within six months of
`treatment with rituximab or a rituximab-containing
`
`applicable) Tentative A roval
`
`
`
`
`Material Reviewed/Consulted
`Names of disci line reviewers
`0ND Action Packa e, includin 7:
`Alexandria Schwarsin / Yvette Kasamon
`Amit Mitra / Sherita McLamore
` Clinical Pharmacology Review
`John Christy / Gene Williams
`
`OSE/DMEPA Nicole Ganison / Hina Mehta
`0ND=0flice ofNew Drugs; 0PQ=Ofice of Pharmaceutical Quality; OPDP=0flice of Prescription Drug Promotion;
`OSE= Office of Surveillance and Epidemiology; DMEPA=Division of Medication Error Prevention and Analysis
`
`Reference ID: 4242522
`Reference ID: 4266336
`
`

`

`NDA 205580 Resubmission/Class 1
`Deputy Division Director Summary Review
`1. Regulatory Action
`
`Recommended Regulatory Action: Tentative approval
`
`All review team members recommend approval.
`
`Tentative approval is the recommended regulatory action, however, because at this time there
`is patent protection on the listed drug relied upon. In response to FDA’s information request
`dated March 29, 2018, regarding the requirements under 21 CFR 314.60(f), Eagle submitted
`new paragraph IV certifications to the following patents: U.S. Patent Nos. 8,445,524 (‘524),
`8,791,270 (‘270), 8,883,836 (‘836), and 8,669,279 (‘279). Eagle has provided notice of these
`paragraph IV certifications to Cephalon, the NDA holder and patent owner, and submitted
`adequate documentation of timely sending and receipt of notice. The NDA holder submitted
`information on the ‘524 patent to FDA before the date on which Eagle submitted its 505(b)(2)
`application. Accordingly, the 45-day period provided for in section 505(c)(3)(C) of the FD&C
`Act applies with respect to this patent. Because the 45-day period described in section
`505(c)(3)(C) of the Act has not yet expired, final approval cannot be granted to Eagle’s
`pending 505(b)(2) application at this time.
`
`This application represents a resubmission of a prior tentative approval for this NDA. The
`application included updated CMC information and revised labeling.
`
`2. Background
`
`On September 6, 2013, Eagle Pharmaceuticals, Inc. (Applicant) submitted a 505(b)(2) New
`Drug Application (NDA 205580) for Bendamustine Hydrochloride Injection 100 mg/4 mL (25
`mg/mL) in a 500 mL admixture. The Agency granted a tentative approval on July 2, 2014, for
`the NHL indication because the listed drug upon which the 505(b)(2) application relied was
`subject to a period of patent protection and because Treanda (bendamustine hydrochloride) had
`orphan drug exclusivity that blocked approval of the application. Refer to the Tentative
`Approval Letter on July 2, 2014.
`
`On January 31, 2018, the Applicant resubmitted the application which included updated CMC
`information and revised labeling. In the resubmission, the Applicant sought to add the CLL
`indication to the labeling. The Applicant identified Treanda powder 100 mg vial (NDA
`22249) as the listed drug product that is the basis for the submission.
`
`3. Product Quality
`
`From the OPQ review,
`
`OPQ recommends APPROVAL of NDA 205580 for Bendamustine Hydrochloride
`
`Reference ID: 4242522
`Reference ID: 4266336
`
`2
`
`

`

`NDA 205580 Resubmission/Class 1
`
`Deputy Division Director Summary Review
`
`Injection, 100 mg/4 ml. (25 mg/mL). As part ofthis action, OPQ grants a ail-month
`retestperiodfor the drug substance when stored in
`M“)
`
`and an 24-month drugproduct
`expiration period when stored between 2°—8°C. There are no outstanding issues and no
`post-approval agreements to be conveyed to the applicant.
`
`Allfacilities are acceptable and recommendedfor approvalfor thefunctions listed in
`the application.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Refer to previous pharmacology-toxicology review. No issues that would preclude approval
`were identified.
`
`5. Clinical Pharmacology
`
`Refer to previous clinical pharmacology review. No issues that would preclude approval were
`identified.
`
`6. Clinical Microbiology
`
`No issues that would preclude approval were identified.
`
`7. Clinical/Statistical—Efl'icacy
`
`No new clinical data was submitted. The clinical review team reviewed the proposed labeling
`and found it acceptable for both the NHL and CLL indications.
`
`8. Safety
`
`No new safety issues were identified.
`
`9. Advisory Committee Meeting
`
`This product is not a new molecular entity.
`
`Reference ID: 4242522
`Reference ID: 4266336
`
`

`

`NDA 205580 Resubmission/Class 1
`Deputy Division Director Summary Review
`
`10.
`
`Pediatrics
`
`This product is not a new molecular entity.
`
`11.
`
`Other Relevant Regulatory Issues
`
`The application was reviewed by the 505(b)(2) clearance committee.
`
`12.
`
`Labeling
`
`All the review teams participated in the labeling discussions.
`
`13.
`
`Postmarketing
`
` Postmarketing Risk Evaluation and Mitigation Strategies (REMS)
`
`The review teams did not identify a need for a REMS for this application.
`
` Other Postmarketing Requirements and Commitments
`
`Routine pharmacovigilance
`
`Reference ID: 4242522
`Reference ID: 4266336
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROMEO A DE CLARO
`03/30/2018
`
`Reference ID: 4242522
`Reference ID: 4266336
`
`

`

`
`
`Ea ' le Pharmaceuticals, Inc.
`
`June 30, 2013 received Jul 01, 2013
`
`Jul 06, 2014
`
`Bendamustine Hydrochloride
`
`In'ection, 100 m 4 mL 25 m mL
`
`For treatment of patients with:
`. Chronic lymphocytic leukemia (CLL). Efficacy relative
`to first line therapies other than chlorambucil has not
`been established.
`
`Cross-Discipline Team Leader Review
`
`Date
`
`June 15, 2014
`
`Janice Brown, M.S.
`From
`
`Subject
`Cross-Discipline Team Leader Review
`NDA #
`NDA 205580
`
`A licant
`
`Date of Submission
`
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) names
`Dosa_e forms / Stren_ h
`
`Proposed Indication(s)
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`Introduction
`
`Bendamustine is a small molecule, alkylating agent that is 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 Hydrochloride Injection is submitted as a 505(b)(2)
`NDA. The innovator product, Treanda (bendamustine hydrochloride) for Injection, is supplied
`as a single-use vial containing either 100 mg or 25 mg of bendamustine hydrochloride as a
`lyophilized powder that requires reconstitution with 20 mL (for the 100 mg vial) or 5 mL (for
`the 25 mg vial) of sterile water for injection. The solution is further diluted in into 500 mL (of
`either normal saline or 2.5% dextrose/0.45% saline prior to administration.
`
`In this NDA, the product is ready-to-dilute solution, and will not require reconstitution as is
`the case for the reference drug, Treanda®, which is a lyophilized powder. This product is a
`self-preserving, multiple-use drug product. Similar to the innovator product, the proposed
`bendamustine hydrochloride injection also must be diluted in 500 mL of 0.9% Sodium
`Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP prior to
`intravenous infusion.
`
`The applicant is seeking approval for the NHL drug indication only. The Agency is not able to
`approve the marketing application submitted by Eagle Pharmaceuticals for the use of
`bendamustine for the treatment of Indolent B-Cell Non-Hodgkin’s Lymphoma prior to the
`expiration of exclusivity afforded Treanda for the Indolent B-Cell Non-Hodgkin’s Lymphoma
`that expires October 31, 2015.
`
`1. Background
`
`The subject of the current NDA application is a new formulation for bendamustine
`hydrochloride. The applicant for this NDA is relying upon information in the public domain
`(labeling for approved bendamustine hydrochloride product and published studies about
`bendamustine hydrochloride) to support the safety and efficacy of the new product. No clinical
`data was submitted to support the application.
`
`This NDA application was originally submitted on June 30, 2013 (received July 01, 2013).
`The initial submission was deemed insufficiently complete since the DMF holder did not
`submit a minimum of 12 months long term stability testing on at least three primary drug
`substance batches and a Refusal to File letter was sent to the applicant on August 28, 2013.
`
`The NDA was resubmitted on September 6, 2014 (received September 6, 2014). The
`application was filed and Biopharmaceutics deficiencies were identified and communicated to
`the applicant in a filing letter on September 16, 2013.
`
`Page 2 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`2
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`2. CMC
`
`Drug Substance
`
`The CMC information for the drug substance was provided in DMF No. mm from (m4)
`The applicant provided adequate reference to their Type II DIVIF M“) for information
`pertaining to the drug substance, bendamustine hydrochloride. The DMF contains the
`necessary information related to manufacturing, characterization, physical properties,
`manufacture, process controls, analytical methods, specifications, validation, container closure
`system, reference standard and stability data for bendamustine hydrochloride. DMF mm
`was reviewed and found adequate to support the manufacture of a drug product as a solution
`dosage form by Joyce Crich, Ph.D. on May 6, 2014.
`
`Bendamustine hydrochloride is a white crystalline powder that is slightly soluble in water. (m4)
`
`Drug Product
`
`This NDA was jointly reviewed by Gaetan Ladouceur, Ph.D. who performed the drug product
`review and Erika Pfeiler, PhD. who performed the manufacturing process review and was a
`member of the facility inspection team. No product quality issues which preclude approval
`were found and the CMC Review (Gaetan Ladouceur, Ph.D. and Erika Pfeiler, Ph.D. final
`signature May 14, 2014) recommended approval of the NDA.
`
`The drug product is a multiple use, ready-to—dilute, clear and colorless yellow non-aqueous
`solution of bendamustine hydrochloride. Each vial contains 25 mg/mL of bendamustine
`hydrochloride, 5 mg/mL of monothioglycerol
`(”wand 0.1 mL/mL of
`propylene glycol
`«mo in polyethylene glycol 400. The drug product does not
`contain an antimicrobial preservative, since it demonstrates self-preserving characteristics.
`
`(mu The container closure
`mm
`mm)
`The drug product is sterilized by
`system consists of a 5 mL glass vial with 20 mm rubber stopper and 20 mm aluminum flip-off
`seal. The equipment used for equipment and container closure
`M“) is appropriately
`qualified and operated using validated loading patterns.
`
`Bendamustine hydrochloride injection is further diluted into either 0.9% Sodium Chloride
`Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, prior to intravenous
`administration. Bendamustine is susceptible to hydrolysis and undergoes rapid degradation in
`the presence of water to form mainly one degradant, monohydroxy bendamustine.
`Monohydroxy bendamustine (also known as HPl), is a metabolite and a not more than (NMT)
`
`Page 3 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`3
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`% limit is established for HP1 in the admixture and is controlled in the drug product
`specification.
`
`An 18-month expiration dating period is granted for the drug product when stored at 2° to 8°C
`(36° to 46°F). Since the drug product is light sensitive the following statement is included in
`the label “Retain in original package until time of use to protect from light” and “After first
`use, the multi-use vial should be stored in original carton at 2 °C to 8 °C, and then discarded
`after 28 days.”
`
`Facilities review and inspection
`
`An Establishment Evaluation Request (EER) was submitted to the Office of Compliance, and
`an overall acceptable recommendation was issued for the application on June 2, 2014.
`
`3. Nonclinical Pharmacology/Toxicology
`
`Pharmacology/Toxicology has no concerns with the nonclinical findings and the excipients
`used for Eagle’s bendamustine HCl injection at the defined levels. No
`pharmacology/toxicology issues which preclude approval were found and the
`Pharmacology/Toxicology Review (Christopher Sheth, Ph.D., final signature December 20,
`2013) recommended approval of the NDA.
`
`According to the nonclinical review, “Eagle conducted local tolerance studies in rabbits, in
`addition to in vitro hemolytic potential studies in human whole blood, comparing their
`bendamustine HCl product with the LD (Treanda®). There was no indication of hemolysis in
`human blood exposed to EPI’s bendamustine HCl. Intravenous administration of EPI’s
`bendamustine HCl was well tolerated in the rabbit local tolerance study, as exemplified by
`results typical of minor trauma associated with injection procedures. Eagle did not perform any
`animal pharmacology studies in support of the NDA approval for bendamustine HCl.”
`
`4. Clinical Pharmacology/Biopharmaceutics
`
`Clinical Pharmacology
`
`This submission contains no clinical pharmacology information. The Clinical Pharmacology
`review (Young Jin Moon, Ph.D. signed May 29, 2014) recommended approval of the NDA
`from a clinical pharmacology perspective.
`
`Biopharmaceutics
`
`The NDA includes a request for a waiver of the CFR requirement to submit data from an in
`vivo bioequivalence study, based on the similarity between the proposed product and the listed
`product. Comparative data showed very similar pH values but differences were observed in the
`osmolality range for the diluted admixture solutions for the proposed and the listed drug
`products. The proposed admixture drug product’s osmolality is hypertonic and is higher than
`
`Page 4 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`4
`
`(b)
`(4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`that of Treanda which is consistently hypotonic. Based on the nonclinical information
`provided by the application to support the osmolality, sufficient data was provided justifying
`that the higher osmolality range of their product when compared to that of the listed product,
`and will not have an impact on the clinical safety profile. The Clinical Reviewer, Dr. Adam
`George, agrees with this conclusion (see his review in DARRTS dated 5/13/14).
`
`According to the biopharmaceutics review, data was provided that adequately supports the
`absence of mannitol and the inclusion of monothioglycerol, propylene glycol, and PEG 400 in
`the proposed formulation do not affect the distribution and/or elimination of bendamustine
`HCl when compared to those of the listed product. According to the biopharmaceutics review,
`the applicant provided evidence from literature supporting the safety of the intravenous
`infusions of bendamustine HCl solutions containing the proposed concentrations of
`monothioglycerol, propylene glycol, and PEG 400. The applicant adequately resolved the
`outstanding issues and the biopharmaceutics review (Elsbeth Chikhale, Ph.D., final signature
`May 13, 2014) recommended approval of the NDA.
`
`5. Clinical Microbiology
`
`No Clinical Microbiology review was required for this NDA.
`
`6. Clinical/Statistical- Efficacy
`
`Eagle did not conduct any human clinical studies and therefore no efficacy information is
`included in the NDA. No Statistical Review was done for this NDA.
`
`7. Safety
`
`A potential safety issue was identified by the biopharmaceutics reviewer regarding 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.
`According to the clinical review, “the increased osmolality of the Eagle formulation of
`bendamustine will not result in a clinically meaningful increase in toxicities associated with
`administration of a hyperosmotic intravenous solution (i.e., phlebitis and/or infusion site
`reactions). In clinical practice chemotherapy is typically administered to patients via central
`venous access (e.g., peripherally inserted central catheter or Hickman catheter). Administration
`of chemotherapeutic agents through central venous access minimizes the risks of phlebitis
`associated with drugs that are hyperosmolar due the increased venous blood flow with central
`venous access.”
`
`The clinical reviewer also cites an article by Gazitua et. al. that evaluated the risk of phlebitis
`based upon the osmolality of the infusion solution. The lowest identified risk group was
`solutions with an osmolarity lower than 450 mOsm/L. The upper limit for the range of
`osmolality with the proposed Eagle formulation is
`mOsm/kg. Dr. George also stated that
`“it would not be feasible to conduct a clinical trial to quantify the possible increased risk of
`phlebitis with the Applicant’s hyperosmolar formulation compared to Treanda as this would
`require an extremely large number of patients.”
`
`Page 5 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`5
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`The Clinical Review of the NDA was completed by Adam George, Pharm.D. (final signature
`on May 13, 2014). The reviewer found no new safety concerns from review of the recent
`literature and recommended approval of the NDA from a clinical perspective.
`
`8. Advisory Committee Meeting
`
`There was no Advisory Committee meeting held for this application.
`
`9. Pediatrics
`
`The labeling for the LD contains information in the Pediatric Use section based upon a study
`conducted by the LD 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.
`
`10. Other Relevant Regulatory Issues
`
`None.
`
`11. Labeling
`
`General
`
`The proposed labeling for the Eagle’s bendamustine is essentially the same in content as that
`of the innovator LD product, except for the relevant sections of the Dosage and Administration
`section on the dilution of the drug product, How Supplied, Description, and Storage and
`Handling sections of the labeling. The formatting of the applicant’s proposed labeling has been
`constructed to comply with the requirements of the Physician’s Labeling Rule (PLR).
`
`The exact wording of the labeling in the PLR format has been reviewed and comments from
`all disciplines (including DMEPA) were conveyed to the applicant on April 11, 2014. The
`most recent DRAFT labeling text was received from the Applicant on June 18, 2014.
`
`In this application, the Applicant included the FDA Form 256h, which requested only the NHL
`indication. Both the existing CLL and NHL indications for the Treanda NDA are currently
`protected by orphan drug and pediatric exclusivity. This application cannot be granted final
`approval until all exclusivities expire. For purposes of attaching labeling to the approval letter,
`the labeling will contain the NHL indication only, because it is the only indication requested in
`the FDA Form 256h submitted by the Sponsor. The final indications included in labeling at
`the time of final approval of this Eagle application, will depend upon existing exclusivities
`remaining. The last exclusivity expiration date for the CLL indication is September 20, 2015.
`The last exclusivity expiration date for the NHL indication is May 1, 2016.
`
`Page 6 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`6
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`Proprietary name
`
`There was no proprietary name proposed for this product.
`
`DMEPA comments
`
`In an initial review dated December 24, 2014, the DMEPA reviewer (Tingting Gao, PharmD.)
`and again on April 9, 2014 and identified several specific deficiencies in the proposed
`container and carton labeling.
`
`These deficiencies were conveyed to the applicant and .
`
`Patient labeling/Medication guide
`
`This is not required for this product.
`
`⦁
`
`12. Recommendations/Risk Benefit Assessment
`
`Recommended Regulatory Action
`
`No clinical, pharmacology/toxicology, CMC or clinical pharmacology issues have been found
`to preclude approval. EES gave an overall acceptable recommendation for the manufacturing
`sites. From a technical review discipline viewpoint, this application may be approved,
`provided regulatory legal requirements are met for existing exclusivity for the innovator
`bendamustine product (tentative approval).
`
`⦁
`
`Risk Benefit Assessment
`
`The review of this NDA is based primarily on chemistry, manufacturing and controls
`and nonclinical data. Pharmacology/Toxicology has no concerns with the nonclinical findings
`and the excipients used for Eagle’s bendamustine HCl injection at the defined levels. The
`Applicant has satisfactorily responded to the identified CMC and biopharmaceutics
`deficiencies, and the application has received an overall acceptable recommendation from the
`Office of Compliance.
`
`Recommendation for Postmarketing Risk Management Activities
`
`This does not apply to this NDA.
`
`Recommendation for other Postmarketing Study Commitments
`
`⦁
`⦁
`⦁
`
`None
`
`Recommended Comments to Applicant
`
`Page 7 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`7
`
`

`

`Cross Discipline Team Leader Review
`NDA 205580
`
`The standard language for conveying a tentative approval should be inserted into the action
`letter.
`
`Page 8 of 8
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JANICE T BROWN
`06/19/2014
`
`ALI H AL HAKIM
`06/19/2014
`
`Reference ID: 3528476
`Reference ID: 4266336
`
`

`

`Date
`
`205580
`
`Name
`
`-—=—
`Dosa_e Forms / Stren_ h
`Proposed Indication(s)
`
`25 mg/mL
`For the treatment of non-Hodgkin’s Lymphoma (NHL)
`and for the treatment of chronic Lymphocytic
`Leukemia (CLL)
`
`Action/Recommended Action for
`
`Tentative Approval
`
`electronic stamp)
`Ann. T. Farrell, M.D., Division Director
`
`Subject
`Summary Review
`NDA/BLA #
`Sn u ilement #
`
`Eagle Pharmaceuticals
`Applicant Name
`Date of Submission
`September 6, 2013
`PDUFA Goal Date
`July 6, 2014
`Proprietary Name /
`Bendamustine Hydrochloride Concentrate for Injection
`Established
`S .
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`Statistical Review
`
`thmacoloa Toxicoloa Review
`CMC Review/OBP Review
`
`Microbioloa Review
`Clinical Phaimacoloa Review
`
`Adam Geor e, Pharm.D.l Vir ' n 'a Kwitkowski, RNP
`
`Tin in Gao, Pharm.D.erlena Maslov, PhannD.
`——
`——
`——
`OND=0flice ofNew Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Oflice of Surveillance and Epidemiology
`DMETS=Division ofMedication Errors and Technical Support
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DSRCS=Division of Surveillance, Research and Communication Support
`CD'IL=Cross—Discipline Team Leader
`
`Reference ID: 3526194
`Reference ID: 4266336
`
`

`

`
`
`
`
`
`Signatory Authority Review Template
`
`1. Introduction
`
`
`This submission for NDA 205580, a 505 b2 application for bendamustine
`hydrochloride concentrate for injection.
`
`
`2. Background
`
`
`The Reference Listed Drug (RLD) for this submission is Treanda (bendamustine
`hydrochloride) (NDA )22249 and 022303), which is currently marketed by Teva
`Pharmaceuticals.
`
`
`3. CMC/Device
`
`
`From the product quality review:
`
`The data support a post-dilution hold times of 3 hours at room temperature and 24
`hours under refrigeration. No microbiological in-use stability data are necessary to
`support these hold times…
`
`Therefore, an expiration date of 18 months, under the recommended controlled room
`temperature storage conditions, is granted. Also, storage precautions are required as
`the drug product is light sensitive. The primary container must be kept in the
`secondary packaging in order to protect the drug product from light.
`
`No issues were identified which would preclude approval.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Drs. Sheth and Palmby noted in their review:
`
`EPI’s to-be-marketed formulation that is the subject of this NDA is different from the
`Treanda® formulation, in that it will be supplied as a ready-to-dilute concentrated
`sterile solution containing bendamustine HCl (100 mg), monothioglycerol (20 mg),
`propylene glycol (0.4 mL), and polyethylene glycol 400 (QS to 4 mL), rather than a
`
`Reference ID: 3526194
`Reference ID: 4266336
`
`

`

`lyophilized powder of bendamustine HCl (100 mg) and mannitol (170 mg). Prior to IV
`administratio