CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205580Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`IND 109789
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`
`Eagle Pharmaceuticals, Inc.
`Attention: Foma Rashkovsky
`Senior Director of Regulatory Affairs
`470 Chestnut Ridge Road
`Woodcliff Lake, NJ 07677
`
`
`Dear Mr. Rashkovsky:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for Bendamustine Hydrochloride
` for
`Injection, 25 mg/mL, 100 mg/vial.
`
`We also refer to the September 9, 2012, meeting request for a meeting to be held between
`representatives of your firm and the FDA which was held on December 12, 2012. The purpose
`of the meeting was to clarify the issues raised during the pre-IND teleconference since Eagle
`Pharmaceuticals is preparing to submit an NDA using the 505(b)(2) pathway.
`
` A
`
` copy of the official minutes of the December 12, 2012, meeting is enclosed for your
`information. Please notify us of any significant differences in understanding regarding the
`meeting outcomes.
`
`If you have any questions, call me at (301) 796-4058.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`CDR Diane Hanner
`Senior Program Management Officer
`Division of Hematology Products
`Office of Hematology and Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`Enclosure:
` Meeting Minutes
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`(b) (4)
`
`

`

`IND 109789
`Meeting Minutes
`Type B
`
`
`
`Division of Hematology Products
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`
`End of Phase 2
`
`White Oak Bldg. 22, Room 1311
`
`PIND 109789
`
`Bendamustine Hydrochloride
`
` for Injection.
`
`Chronic Lymphocytic Leukemia (CLL
`Indolent Non-Hodgkin’s Lymphoma (NHL)
`
`Meeting Type:
`
`Meeting Category:
`
`Meeting Date and Time: December 12, 2012
`
`Meeting Location:
`
`Application Number:
`
`Product Name:
`
`Indication:
`
`
`Sponsor/Applicant Name: Eagle Pharmaceuticals, Inc.
`
`Meeting Chair: Virginia Kwitkowski, M.S., R.N., A.C.N.P.-BC, Clinical Team
`Leader, DHP
`
` CDR Diane Hanner, M.P.H., M.S.W.
`
`
`Meeting Recorder:
`
`FDA ATTENDEES
`o Edvardas Kaminskas, M.D., Deputy Director, DHP
`o Virginia Kwitkowski, M.S., R.N., A.C.N.P.-BC, Clinical Team Leader, DHP
`o Adam George, Pharm. D, Clinical Analyst, DHP
`o Joyce Crich, Ph.D., CMC Reviewer, ONDQA, Division 3, Branch 5
`o Janice Brown, Ph.D., CMC Lead, ONDQA, Division 3, Branch 5
`o John Z. Duan, Ph.D., . Biopharmaceutics Reviewer, ONDQA
`o Elizabeth Shang, Ph.D., Clinical Pharmacology Reviewer, DCP5
`o Julie Bullock, Pharm.D., Team Leader, Office of Clinical Pharmacology, DCP5
`o Haleh Saber, Ph.D., Supervisory Pharmacologist
`o CDR Diane Hanner, M.P.H., M.S.W., Senior Program Management Officer
`
`
`
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`Page 2
`
`(b) (4)
`
`

`

`IND 109789
`Meeting Minutes
`Type B
`
`SPONSOR ATTENDEES
`
`Division of Hematology Products
`
`0 Paul Bruinenberg, M.D., Chief Medical Officer, Eagle Pharmaceuticals, Inc.
`
`0 Srikanth Sundaram, Ph.D., Chief Scientific Officer, Eagle Pharmaceuticals, Inc.
`
`0 Jianwei Yu, Ph.D., Senior Director, CMC, Eagle Pharmaceuticals, Inc.
`
`0 Mark Smith, Ph.D., V.P. Preclinical Development, Eagle Pharmaceuticals, Inc.
`
`0
`
`Foma Rashkovsky, Sr. Director of Regulatory Affairs, Eagle Pharmaceuticals, Inc.
`mm)
`
`(b) (4)
`
`0 Steven Krill, Ph.D., VP Pharmaceutical Development, Eagle Pharmaceuticals, Inc.
`
`1.0
`
`BACKGROUND
`
`EAGLE PHARMACEUTICIALS REQUESTED AN END OF PHASE 2 NIEETING ON
`SEPTENIBER 9, 2012, TO OBTAIN AGENCY FEEDBACK ON THE FOLLOWING:
`
`The Sponsor is seeking clarification regarding the issues raised during the pre—IND
`teleconference. The Sponsor is preparing to submit an NDA for a bendamustine HCI ready-to
`dilute liquid product using the 505(b)(2) pathway. The Eagle’s bendamustine hydrochloride is a
`pre-mixed concentrated solution that will be diluted
`(mu) final concentration (0.2 to {'4’}
`mg/mL)
`(m4) prior to administration. The composition of Eagle’s bendamustine has
`remained substantially the same as the formulation discussed during the pre-IND meeting. The
`meeting was granted on October 2, 2012, and it was scheduled for December 12, 2012.
`
`DISCUSSION
`
`Question 1
`Does the Agency concur with the proposed specifications for Eagle’s product?
`
`FDA Response: No. We do not agree with your proposed drug product acceptance criteria
`for individual impurities and total impurities. You should establish acceptance criteria
`based on your batch data. New impurities above the threshold defined in [CH Q3 A/B (as
`appropriate) need to be qualified and impurities that are common to the Listed Drug
`
`should be no more than the level observed in the Listed Drug unless they are below the
`qualification threshold.
`
`Please also see our response to Question 2 for acceptable approaches to qualify impurities.
`
`Meeting Discussion:
`No Discussion
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`Page 3
`
`

`

`Division of Hematology Products
`
`
`IND 109789
`Meeting Minutes
`Type B
`
`
`Question 2
`Does the Agency concur that no additional nonclinical studies are required for the NDA
`submission based on the proposed specifications and given the fact that there are no unknown
`impurities in Eagle’s product above the ICH identification/qualification threshold?
`
`FDA Response: We agree that for impurities that are within the threshold of ICH
`Q3B(R2) no toxicology study will be needed to qualify drug product-related impurities.
`We also agree that impurities are considered qualified if they are at or below levels
`detected in the Listed Drug, in a side-by-side comparison, as long as an appropriate design
`is utilized (e.g. solvent, dilution, etc, as applicable).
`
`However, if your justification of a specification is based on an impurity being a metabolite
`(e.g. for
`), you will need to provide the data to support the claim. A justification based
`on information from the Summary Basis of Approval is not acceptable.
`
`Also see our response to Question 1.
`
`Sponsor Response: On Question 2, we would like clarification of the Agency’s expectation for
`data needed to demonstrate that an impurity is also a metabolite.
`
`Meeting Discussion: The Sponsor asked whether the side-by-side comparison refers to the
`product to be given to patients after dilution. The Agency agreed. The Sponsor will provide
`literature to show that impurities in their drug product are metabolites of Bendamustine.
`
`Question 3
`Based on the data provided herein, does the Agency concur that a pharmacokinetic
`bioequivalence study is not required for this 505(b)(2) NDA and that a Bio-Waiver will be
`granted?
`
`FDA Response: It is possible to grant a biowaiver provided that you submit a comparison
`of the physicochemical properties to show similarities between your proposed product and
`the listed drug. The acceptability of your biowaiver request will be determined during the
`review of your NDA.
`
`Sponsor Response: On Question 3, we have the following specific concerns about the Agency’s
`response and would like to discuss them in more detail at the meeting:
`1. We would like to clarify that the comparison of the physicochemical properties between the
`proposed product and the reference listed drug will be performed at the point of
`administration to the patient; namely TREANDA after reconstitution and dilution in either of
`the two diluents specified in the label, and the Eagle product after dilution to the same
`concentration in the same diluents.
`2. We believe that the physicochemical properties reported in the briefing book (namely pH and
`osmolality) are adequate to establish comparison of the diluted products. Does the Agency
`concur?
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`Page 4
`
`(b) (4)
`
`

`

`IND 109789
`Meeting Minutes
`Type B
`
`
`3. We want to clarify that the grant of the biowaiver is indeed a review issue, and not an issue
`for acceptability of the filing for review.
`
`Division of Hematology Products
`
`
`
`Meeting Discussion:
`The Agency confirmed that the biowaiver will not be a filing issue provided that the NDA
`includes a side-by-side comparison between the listed drug and the Eagle product. This
`includes a comparative characterization of the product in the vial and the admixture.
`
`3.0 IMPORTANT MEETING INFORMATION
`
`PREA PEDIATRIC STUDY PLAN
`
`Please be advised that you must submit a Pediatric Study Plan within 60 days of your scheduled
`end-of-Phase 2 meeting. The PSP must contain an outline of the pediatric study or studies that
`you plan to conduct (including, to the extent practicable study objectives and design, age groups,
`relevant endpoints, and statistical approach); any request for a deferral, partial waiver, or waiver,
`if applicable, along with any supporting documentation, and any previously negotiated pediatric
`plans with other regulatory authorities. For additional guidance on submission of the PSP you
`may contact the Pediatric and Maternal Health Staff at 301-796-2200 or email pdit@fda.hhs.gov.
`
`DATA STANDARDS FOR STUDIES
`
`CDER strongly encourages IND sponsors to consider the implementation and use of data
`standards for the submission of applications for investigational new drugs and product
`registration. Such implementation should occur as early as possible in the product development
`lifecycle, so that data standards are accounted for in the design, conduct, and analysis of clinical
`and nonclinical studies. CDER has produced a web page that provides specifications for sponsors
`regarding implementation and submission of clinical and nonclinical study data in a standardized
`format. This web page will be updated regularly to reflect CDER's growing experience in order
`to meet the needs of its reviewers. The web page may be found at:
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electr
`onicSubmissions/ucm248635.htm
`
`ISSUES REQUIRING FURTHER DISCUSSION
`4.0
`There were no issues identified that required further discussion.
`
`ACTION ITEMS
`5.0
`There were no action items identified.
`
`ATTACHMENTS AND HANDOUTS
`6.0
`There were no attachments or handouts for the meeting minutes.
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`Page 5
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`VIRGINIA E KWITKOWSKI
`12/13/2012
`
`Reference ID: 3230473
`Reference ID: 4266336
`
`