CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203565Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NBA 203565
`
`Cross-Discipline Team Leader Review
`
`__
`m_——
`
`
`Applicant
`Luitpold Pharmaceuticals, Inc.
`Date of Submission
`Jan .
`30, 2013; received Janna
`
`30, 2013
`
`Jul 30, 2013
`PDUFA Goal Date
`
`
`
`
`Injectafer (ferric carboxymaltose)
`Proprietary Name /
`
`Established (USAN) names
`Dosage forms / Strength
`
`Injection (single-use vials
`
`(h) (4)
`
`Pro nosed Indication s
`
`750 mg iron/ 15 mL
`for the treatment of iron deficienc anemia
`
`Page 1 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
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`1. Introduction
`
`Injectafer (ferric carboxymaltose; FCM) is an iron formulation developed for parenteral
`administration for the treatment of iron deficiency anemia. The sponsor’s proposed indication
`is:
`
`“Injectafer is indicated for the treatment of iron deficiency anemia:
`.
`(hm (hm are intolerant to oral ironaihave had unsatisfactory
`response to oral iron,
`(‘
`(I'm
`(m4) chronic kidney disease”
`
`0
`
`The proposed dosing is 15 mg/kg up to a maximum single dose of 750 mg of iron on two
`occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron delivered by
`intravenous infilsion or injection.
`
`Ferric carboxymaltose (marketed as Ferinjectk) is approved in the European Union (2007) and
`in over 40 countries worldwide.
`
`The current submission is a resubmission in response to a Complete Response (CR) letter
`issued for this 505(b)(1) application on July 23, 2012. The application was not able to be
`approved at that time due to Chemistry, Manufacturing and Controls (CMC) deficiency for the
`drug product manufacture leading to an overall withhold recommendation for the inspections
`of the manufacturing and testing facilities. The CR letter also included Agency
`recommendations for labeling and the current submission includes the sponsor’s draft labeling.
`Please refer to the previous CDTL Review (K Robie Suh, signed July 21, 2012) for summary
`of the findings of the first cycle application review.
`
`2. CMCIDevice
`
`The chemistry, manufacturing and controls (CMC) information in this resubmission has been
`reviewed by WM Adams, Office of New Drug Quality Assessment (ONDQA) (review signed
`in DARRTS June 26, 2013). The review states:
`
`Complete and acceptable chemistry. marnrfacturing and controls (CMC) information has been
`provided to support approval of this application however an overall recommendation by the
`Ofice of Compliance (0C) for the GMP inspections of the proposed manufacturing and testing
`facilities for the drug substance and drug product is still pending. Therefore. the application
`cannot be approved.
`
`Based on the provided stability data a 24-month expiration dating period is granted for the drug
`product when stored at the USP controlled room temperature.
`
`Some recommendations are made for labeling revisions for Section 11, Section 16 and Footer
`and for the Patient Information leaflet.
`
`Page 2 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
`
`
`Subsequent to the June 16, 2013 CMC review the final Office of Compliance (OC)
`recommendation for the NDA was entered in EES. The followup CMC Memorandum (WM
`Adams, 7/21/2013) states:
`
`
`
`
`
`
`3. Nonclinical Pharmacology/Toxicology
`
`
`The non-clinical Pharmacology/Toxicology primary review of the resubmission was
`conducted by BJ Gehrke (final signature 6/25/2013). The review referenced the previous
`Pharmacology/Toxicology review (BJ Gehrke, 6/13/12) stating there were no
`pharmacology/toxicology concerns with the application and indicated that the resubmission
`does not contain any new pharmacology/toxicology information. The review concluded:
`
`
`
`Comments and recommendations for labeling are included in the June 13, 2012
`Pharmacology/Toxicology review.
`4. Clinical Pharmacology/Biopharmaceutics
`
`
`
`
`Please refer to the previous CDTL Review (K Robie Suh, signed July 21, 2012) for summary
`of the findings of the first cycle Clinical Pharmacology review of the application.
`
`Note that the clinical pharmacology information for FCM was reviewed by J Christy
`(5/30/2007 under NDA 22054). That review concluded that the dose of FCM had not been
`optimized and recommended that the sponsor study doses lower than the 1000 mg dose being
`proposed in that NDA, because “a lower dose such as 500 mg and 800 mg may be equally
`efficacious clinically.”
`
`There was no Clinical Pharmacology review for this review cycle. Clinical Pharmaocology
`participated in the labeling discussions.
`
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`Page 3 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
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`5. Clinical Microbiology
`
`Product Quality Microbiology Review by SP Donald (signed 4/30/2013) stated the following:
`
`W"
`c. REMARKS: Analtematemanufacturing site,
`is proposed The applicant's letter of December 5. 2012 indicates a manufacturing site
`change. Section 3.12.113 inthesubject submission lists only the
`"’""ioeauon
`as the manufacturing site for the subject drug product. but at the top of the page it
`states: “In addition to those facilities previously identified within this NDA. the
`following facilities may be used for the indicated services associated with the
`marmfiicture ofInjectafier at the alternate
`mmmarmfacturing facility“.
`The subject submission provides only data for the 15 ml vial containing 750 mg iron
`References to the
`o) (”vial are stated to have been removed from the batch records
`
`andother configurations ofthe drugproductarenotmemiomd It appearsthatatthis
`time. this alternate facility will mamfacture only the 750 mg configuration and
`manufacturing at the previously reviewed ficility will remain unchanged The
`Product Oualitbeobiology review. dated 5/08.I'2012. which covered manufacturing
`at the
`ficility. recommended the submission for approval. Alter the
`initial review of the 130.9013 submission. an infornntion request was sent to the
`sponsor on 43.92013. A response dated 4.1’121'2013 was provided for review and is
`
`The Microbiology review found the resubmission acceptable and recommended for approval.
`There were no recommendations for Phase 4 commitments.
`
`6. Clinical/Statistical- Efficacy
`
`The sponsor conducted two pivotal studies in support of this application, lVIT09030 and
`1VIT09031. Both were randomized, open-label, active controlled studies. The detailed
`Clinical Review of this application was conducted by M. Lu (signed 6/8/2012); secondary
`clinical review was conducted by KM Robie Suh (signed 7/20/2012); and Statistical Review
`was conducted by K—Y Lee (signed 6/28/2012). The review concluded that efficacy had been
`demonstrated. See those reviews for detailed discussion of efficacy findings.
`
`See the previous CDTL review (KM Robie Suh, 7/21/2012) for summary of efficacy findings.
`
`No efficacy data are included in the resubmission.
`
`7. Safety
`
`The detailed Clinical Review of this application was conducted by M. Lu (signed 6/8/2012);
`secondary clinical review was conducted by KM Robie Suh (signed 7/20/2012); and Statistical
`Review was conducted by K-Y Lee (signed 6/28/2012). See those reviews for detailed
`presentation of the clinical safety findings from the initial NDA submission. See the previous
`
`Page 4 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
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`CDTL review (KM Robie Suh, 7/21/2012) for a summary of safety findings from the previous
`cycle review.
`
`
`The updated clinical safety information in the resubmission has been reviewed by M. Lu
`(review signed 7/9/2013). Secondary clinical review was conducted by K.M. Robie Suh
`(signed 7/22/2013). No Statistical Review was conducted for the resubmission.
`
`In the Clinical Review Dr. Lu summarizes the post-marketing experience from June 18, 2011
`to January 31, 2013. The review states:
`
`
`
`
`
`
`
`
`
`The review describes seven serious pregnancy-related cases (four likely related to
`hypersensitivity reactions in mothers), six new fetal deaths, a post-marketing case of
`hypophosphatemic rickets and osteomalacia, and a case of overdose. The review recommends
`the following:
`
`
`
`
`
`The review concludes “From clinical perspective, this application should be approved with
`revised labeling.” The additional labeling recommendations are as provided in Dr. Lu’s June
`8, 2012 Clinical Review.
`
`
`
`
`8. Advisory Committee Meeting
`
`
`N/A
`
`
`Page 5 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
`9. Pediatrics
`
`
`The sponsor has not provided additional pediatric information in the resubmission. Please refer
`to the previous Clinical Reviews (M Lu, M.D., June 8, 2012; KM Robie Suh, 7/20/2012) and
`CDTL Review (K Robie Suh, 7/21/2012) for summary of the sponsor’s plan for pediatric
`studies to address Pediatric Research Equity Act (PREA) requirements.
`
`Briefly, no pediatric patients were studied for the current NDA. The sponsor has requested a
`waiver for conducting pediatric studies in patients less than 2 years of age, “due to logistical
`challenges associated with subjects of this age range” and citing previous pediatric experience
`with its other intravenous iron product, Venofer (iron sucrose), recruiting patients from birth to
`<2 years of age into Phase III trials. The sponsor proposes a PK study and an efficacy and
`safety study in older pediatric patients. The clinical review recommended granting the
`requested waiver and deferral.
`
`During the previous review cycle, the labeling was reviewed by the Pediatric and Maternal
`Health Staff (PMHS)(C Ceresa, Pharm.D., final signature in DARRTS July 2, 2012) and
`recommendations for the labeling were made with regard to pregnancy, nursing mothers and
`pediatric use. PMHS also has participated in the labeling discussions.
`
`
`10.
`
`Other Relevant Regulatory Issues
`
`
`Please refer to the previous CDTL Review (K Robie Suh, signed July 21, 2012) for comments
`on Office of Scientific Investigations (OSI) inspections, labeling review by Division of
`Professional Drug Promotion (DPPP), and name review by Division of Medication Error
`Prevention and Analysis (DMEPA). After resubmission, DMEPA re-review of the proposed
`proprietary name, ‘Injectafer”, again found the name acceptable (K Wright, 6/26/2013).
`
`
`11.
`
`Labeling
`
`
`The sponsor included proposed labeling in the submission.
`
`Final wording for the labeling has been developed by the review team with discussion and
`consideration of the recommendations from each of the review disciplines and consulting
`review divisions and with negotiation with the sponsor.
`
`The recommended wording for the indication is as follows:
`
` 1
`
`INDICATIONS AND USAGE
`
`Injectafer is indicated for the treatment of iron deficiency anemia in adult patients;
`
`
`• who have intolerance to oral iron or have had unsatisfactory response to oral iron;
`• who have non-dialysis dependent chronic kidney disease.
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`Page 6 of 7
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`Reference ID: 3345716
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`Cross Discipline Team Leader Review
`NDA 203565
`
`
`
`
`
`12.
`
`Recommendations/Risk Benefit Assessment
`
`
`Please refer to the previous CDTL Review (K Robie Suh, signed July 21, 2012) for risk
`benefit discussion and assessment for Injectafer during the first cycle application review.
`Based on the previous review and the review of the resubmission the risk benefit profile for
`Injectafer remains favorable for the indication listed above.
`
`The CMC deficiency with regard to GMP inspections of the proposed manufacturing and
`testing facilities for the drug substance and drug product has been resolved and CMC
`recommends approval of the application.
`
`The sponsor’s proposed labeling has been reviewed and edited by all appropriate review
`disciplines and revised labeling has been developed.
`
`Regarding possible post-marketing study requirements, the clinical review recommends that
`the sponsor’s requested waiver for pediatric studies required under PREA for the indication be
`granted for studies of Injectafer in patients less than 2 years of age, because of too few children
`with disease to study, and that the sponsor’s requested deferral for pediatric studies in older
`children be granted; however, protocols for proposed studies should be submitted for review.
`
`No other post-marketing studies are recommended at this time.
`
`The application is acceptable for approval with the final recommended labeling and post-
`marketing commitment.
`
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`Page 7 of 7
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`Reference ID: 3345716
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATHY M ROBIE SUH
`07/23/2013
`
`Reference ID: 3345716
`
`