CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203565Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`(electronic stamp)
`_ Ann- T- Farrell, MD, Division Director
`
`Subject
`Summary Review
`NDA/BLA #
`Sn u ilement #
`
`Applicant Name
`Luitpold Pharmaceuticals, Inc.
`Date of Submission
`01/30/13
`
`203565
`
`PDUFA Goal Date
`
`07/30/13
`
`Proprietary Name /
`Established
`S .
`
`Name
`
`Injectafer/Ferrous Carboxymaltose
`
`Dosa_e Forms I Stren_ h
`
`Proposed Indication(s)
`For the treatment of iron deficiency anemia
`Action/Recommended Action for
`Full Approval
`NME:
`
`Material Reviewed/Consulted
`
`0ND Action Package. including:
`Medical Officer Review
`
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`
`Microbiology Review
`
`Min Lu, M.D.IKathy Robie-Suh. M.D.IPhD.
`Kyung Y- Lee. PhD/Mark Rothmann. PhD.
`Brenda Gehrke. PhD./Haleh Saber, PhD.
`William M. Adams. M.S.lAli Al-Hakim. Ph.D.lSue Ching Lin.
`Ph.D.lJanice Brown. M.S.lSarah Miksinski. Ph.D.
`
`John Metcalfe. Ph.D.lStephen P. Donald. M.S.lStephen Langille.
`Ph.D.
`
`
`
`Clinical Pharmacolo 3 Review
`
`Bahru Habtemariam. Ph.D.lJulie Bullock. PharmD.
`
`David X. Gan. M.D.lLeslie Ball. M.D.
`Anthony Orencia. M.D.lJanice K. Pohlman. M.D.lSusan D.
`
`——
`-——
`——
`—_—
`Other — Maternal Health Team
`Jeanine Best. RN.
`
`Other—
`
`OND=0flicc ofNew Drugs
`DDMAC=Division of Drug Marketing, Advertising and Comnnmication
`OSE= Oflice of Surveillance and Epidemiology
`
`Reference ID: 3346410
`
`

`

`Signatory Authority Review Template
`
`2
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`
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`
`
`1. Introduction
`Luitpold’s current submission is a class 2 resubmission and the response is based on
`an Agency complete response letter sent on July 23, 2012.
`
`An application for ferrous carboxymaltose was originally submitted on July 5, 2006 as
`NDA 022054 and received a non-approval letter on July 9, 2007 due to clinical safety
`concerns. Since that time the applicant has resubmitted the application on September
`18, 2007 and received another non-approval letter on March 11, 2008 due to clinical
`safety concerns. The applicant responded to the March 11, 2008 complete response
`letter on October 3, 2011 and provided additional clinical studies.
`
`The only remaining issue is the identification of an adequate facility for manufacturing.
`
`From Dr. Lu’s review:
`
`FCM has been authorized for use and marketed in other countries by Vifor Pharma or
`a subsidiary company since 2007. It is currently registered under 3 different trade
`names: Ferinject®, Injectafer®, and Iroprem®, varying by country. As of 17 June
`2011, the product is approved for use and marketed in 20 European countries. It has
`been approved but it has not yet been marketed in 15 other countries. The Summary
`of Product Characteristics in U.K. lists that Ferinject is indicated for treatment of iron
`deficiency when oral iron preparations are ineffective or cannot be used.
`2. Background
`Products to treat iron deficiency include oral as well as injectable preparations. The iron
`injection products are available by prescription only. The oral iron products are available
`without a prescription.
`
`The currently marketed products are:
`Iron dextran (InFed and generics): indicated for patients with iron deficiency (any
`cause) who are assessed as not appropriate for oral iron therapy.
`Ferrlecit (ferric gluconate): indicated for patients with iron deficiency who are
`undergoing dialysis and receiving erythropoietin therapy.
`Venofer (iron sucrose): indicated for patients with iron deficiency who are:
`-non-dialysis chronic kidney disease patients (either receiving an erythropoietin
`or not)
`-hemodilaysis patients receiving an erythropoietin
`-peritoneal dialysis patients receiving an erythropoietin
`
`
`
`Luitpold originally submitted an application to market Ferrous Carboxymaltose
`(proposed tradename – Ferinject) in 2006 for the following indications:
`
`Reference ID: 3346410
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`3
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`is an intravenous iron product indicated for the treatment of iron deficiency anemia in:
`• Heavy Uterine Bleeding
`• Postpartum
`•
`Inflammatory Bowel Disease and
`• Hemodialysis patients
`
`The application received a non-approval letter due to safety concerns. Review of the
`controlled studies for the indication showed an imbalance in deaths observed in
`controlled trials. More deaths occurred in the ferrous carboxymaltose treatment arms
`than in the control subjects.
`
`The original database had 8 randomized controlled trials in subjects who were post-
`partum, had uterine bleeding, had inflammatory bowel disease, or were receiving
`hemodialysis. The control treatment was oral iron for the all trials with the exception of
`the hemodialysis trial.
`
`Dr. Rieves’s summary review noted:
`
`Overall, the totality of the efficacy data supports the Ferinject dose regimen's efficacy
`in a pattern indicative of acceptable treatment of iron deficiency anemia, regardless of
`the cause for the iron deficiency…
`
`Overall, the most notable safety findings relate to:
`-mortality among subjects receiving Ferinject
`
`-increased rate of serious adverse events among subjects receiving Ferinject,
`compared to oral iron
`-clinically important hypophosphatemia
`
`
`Dr. Rieves also noted that no clinical data was provided to support the safety of
`repeated “cycles” of ferrous caboxymaltose injections.
`
`Luitpold received a non-approval letter requesting that any resubmission provide the
`following:
`
`Clinical data to resolve the safety risks identified (excess mortality and severe
`hypophosphatemia) and verify the safety of more than one iron replenishment cycle
`
`The following text from Dr. Lu’s review highlights Agency and Applicant interactions
`from the receipt of the Complete Response letter.
`
`The Agency issued a Not Approvable action on March 11, 2008. The letter indicated
`that the risk for mortality must be more thoroughly assessed and additional safety
`data should be obtained from clinical studies of Injectafer use among the applicable
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`Reference ID: 3346410
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`4
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`patient population of women who are intolerant to oral iron or who had an
`unsatisfactory response to oral iron. The Agency recommended that these studies
`use appropriate control groups in order to meaningfully interpret the data. The Agency
`stated that the proposed dosage regimen may deliver an excessive iron dose during a
`single administration and recommended that the sponsor consider the development of
`an alternate dosage regimen that delivers a lower (single dose) amount of iron. A
`meeting was held on May 18, 2009 under IND 63,243 between the Agency and the
`sponsor to discuss the proposed further clinical studies (1VIT09031 and 1VIT09030)
`to evaluate the efficacy and safety of a low dose of Injectafer (maximum single dose
`of 750 mg with maximum total dose of 1500 mg) in patients who are intolerant to oral
`iron or who had an unsatisfactory response to oral iron with a oral iron run-in period
`and also in patients with chronic renal disease (CKD). The Agency agreed on the
`proposed studies and the proposed cardiovascular composite safety endpoint to be
`evaluated in these studies. In the proposed studies, other intravenous iron were
`selected as control in patients with CKD and in patients who are intolerant to oral iron.
`The Agency emphasized the double-blind design to assess the safety endpoint.
`
`During the last review cycle, all the clinical (efficacy and safety) and statistical issues
`were satisfactorily resolved. In addition new clinical trial data was reviewed and no
`new efficacy or safety issues were identified.
`
`The last review cycle identified inspectional issues which precluded approval.
`3. CMC/Device
`Mr. Adams and Dr. Al-Hakim reviewed this application most recently. In the primary
`review they stated the following:
`
`Complete and acceptable chemistry, manufacturing, and controls (CMC) information
`has been provided to support approval of this application, however an overall
`recommendation by the Office of Compliance (OC) 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 proposed controlled room temperature.
`
`During this review cycle the Office of Compliance issued an acceptable rating for
`manufacturing.
`4. Nonclinical Pharmacology/Toxicology
`The pharmacology and toxicology information was referenced the previous
`submission under NDA 22-054. This application was reviewed and no deficiencies
`were identified for NDA 22-054.
`
`
`
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`Reference ID: 3346410
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`5
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`5. Clinical Pharmacology/Biopharmaceutics
`The clinical pharmacology information was referenced the previous submission under
`NDA 22-054. This application was reviewed and no deficiencies precluding approval
`were identified for NDA 22-054.
`
`
`6. Clinical Microbiology
`The Product Quality Microbiology review recommends approval.
`
`
`7. Clinical/Statistical-Efficacy
`I have read NDA 22-054 summary and clinical reviews by Drs. Rieves, Robie-Suh,
`and Lu.
`
`The following text is from Dr. Lu’s review of the prior submission regarding efficacy:
`
`Two randomized controlled pivotal trials (1VIT09031 and 1VIT09030) were conducted
`to support the efficacy of Injectafer with the proposed dose regimen of 15 mg/kg with
`the maximum individual dose of 750 mg and a total dose of 1,500 mg. Study
`1VIT09031 was conducted in patients with iron deficiency anemia who had an
`inadequate response to oral iron treatment, who were intolerant to oral iron during the
`14-day run-in period, or who were deemed unsuitable by the Investigator for the oral
`iron, mainly due to low hemoglobin level with or without co-morbidities. Study
`1VIT09030 was conducted in patients with non-dialysis dependent chronic kidney
`disease (NDD-CKD). Both clinical studies were randomized, open-label, controlled
`studies. In Study 1VIT09031, oral iron was used as control in patients who had an
`inadequate response to oral iron treatment in Cohort 1 and other IV iron products
`(mostly Venofer) were used as control in patients who were intolerant to oral iron in
`Cohort 2. In Study 1VIT09030, Venofer was used as control in patients with CKD. The
`primary efficacy endpoint was the mean change from baseline to the highest
`hemoglobin observed anytime between baseline and Day 35 or time of intervention in
`Study 1VIT09031 and between baseline and Day 56 or time of intervention in Study
`1VIT09030.
`
`In Study 1VIT09031, the results show that the mean increase in hemoglobin from
`baseline to the highest value between baseline and Day 35 or time of intervention in
`the Injectafer group was statistically significantly greater than that in the oral iron
`group in Cohort 1 (1.57 g/dL vs. 0.80 g/dL, p<0.01) and also higher than that in the IV
`standard care group (2.90 g/dL vs. 2.16 g/dL,p<0.01) in Cohort 2. This study
`demonstrated that Injectafer increased hemoglobin level in patients with iron
`deficiency anemia who had an inadequate response to oral iron treatment or
`who were intolerant to oral iron.
`
`In Study 1VIT09031, the mean increase in hemoglobin from baseline to the highest
`value between baseline and Day 56 or time of intervention in the Injectafer group was
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`Reference ID: 3346410
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`6
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`non-inferior to Venofer (1.13 g/dL vs. 0.92 g/dL, treatment difference 0.21 g/dL [95%
`CI 0.13-0.28 g/dL]). The results from the secondary efficacy endpoints analyses
`including hemoglobin response and iron indices were consistent with the primary
`efficacy analysis results in both studies. The results from subgroup analyses including
`baseline hemoglobin level and etiology of iron deficiency anemia in Study 1VIT09031
`and baseline hemoglobin, EPO use and CKD stage in Study 1VIT09030 were all
`consistent with the results from the primary efficacy endpoint analyses. This
`study demonstrated that Injectafer increased hemoglobin level in patients with iron
`deficiency anemia in NDD-CKD population.
`
` I
`
` have concurred with the conclusions of the clinical and statistical review teams
`regarding the demonstration of efficacy for indication during the last cycle.
`8. Safety
`During the original NDA review (22-054), the review team identified excess mortality
`and hypophosphatemia as areas of concern for this product.
`
`Mortality and Cardiovascular Events
`Dr. Lu’s most recent in-depth review did a focused analysis of mortality and
`Cardiovascular Events. The following text is from her most recent in-depth clinical
`review:
`
`The mortality rates were similar between Injectafer for the proposed dosing regimen
`and the comparators in pooled analysis of the two pivotal studies (16/1775, 0.9% vs.
`21/1783, 1.2%) and were also similar between Injectafer with the maximum single
`dose of 750 mg with the different total doses and the comparator in pooled analysis of
`the five clinical studies (17/2566, 0.7% vs.22/2590, 0.8%). For all completed studies,
`the overall mortality rate was 0.5% (33/6679) in the Injectafer-treated patients and
`0.6% (30/5394) in comparator-treated patients.
`
`In the two pivotal trials, no significant difference was found for the pre-specified
`primary cardiovascular composite safety endpoint (including death, MI, stroke,
`unstable angina, CHF, hypertension and hypotension) between Injectafer and Venofer
`or pooled comparators (10.8%, 11.1%, and 9.7%, respectively). Hypertensive events
`were found to be significantly higher in the Injectafer group as compared to the
`Venofer group, or the pooled comparator group (6.0%, 4.1%, and 3.5%, respectively).
`
` I
`
` noted in my prior review:
`
`
`Treatment-emergent serious adverse events were similar among Injectafer, Venofer,
`and the pooled comparators groups numerically and by organ group. The incidence of
`treatment-emergent serious or severe hypersensitivity/allergic adverse events was
`1.5% for Injectafer and 1.6% for Venofer. Flushing and hypertension were the most
`common adverse events resulting in premature discontinuation from the trial.
`
`Overall assessment of drug-related adverse events
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`Reference ID: 3346410
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`7
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`From Dr. Lu’s most recent in-depth clinical review:
`
`The incidence of any drug-related treatment-emergent adverse event was greater in
`the FCM group (23.5%) compared with the Venofer (17.3%) and pooled comparators
`(15.9%) group.
`
`The most common ( ≥1.0%) drug-related treatment-emergent adverse events in the
`FCM group were nausea (7.2%), hypertension (3.8%), flushing (2.7%),
`hypophosphatemia (2.1%),dizziness (2.0%), vomiting (1.7%), injection site
`discoloration (1.4%), headache (1.2%), ALT increased (1.1%), and dysgesusia
`(1.1%). Drug-related treatment-emergent adverse events that occurred more
`frequently (by ≥1%) with Injectafer than with pooled comparator included
`nausea, hypertension, flushing, hypophosphatemia, vomiting, and injection site
`discoloration.
`
` I
`
` have concurred with the conclusions of the clinical and statistical review teams.
`
`
`Dr. Lu’s most recent in-depth review recommends approval. The following is the text
`from her review:
`
`From a clinical perspective, Injectafer should be approved for the indication for the
`treatment of iron deficiency anemia in patients who are intolerant to oral iron or have
`had unsatisfactory response to oral iron and in patients with non-dialysis dependent
`chronic kidney disease.
`
`
`9. Advisory Committee Meeting
`Not applicable for this class 2 resubmission necessary to address CMC issues
`10.
`Pediatrics
`From Dr. Lu’s most recent in-depth review:
`
`The applicant requested a deferral of pediatric studies in and 17 years of age group
`under PMRs and requested a waiver of a pediatric study in the 0- years of age group
`to meet the requirements of Pediatric Research Equity Act (PREA). The proposed
`pediatric studies in and 17 years of age group include one
`pharmacokinetic/pharmacodynamic study and one safety and efficacy study in
`pediatric patients with iron deficiency anemia. The applicant proposed to submit full
`pediatric study protocols within one year of approval and recruitment will begin
`within the first 18 months after the NDA is approved with the final study report being
`submitted on or before December 31, 2016.
`
`This application was discussed at PeRC. The deferral will be granted. However the
`waiver will be approved for the 0-1 years of age group so the deferral will be revised
`to cover ages 1-17 years of age.
`
`Reference ID: 3346410
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
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`

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`
`8
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`Other Relevant Regulatory Issues
`11.
`The original and subsequent applications complied with financial disclosure
`requirements and trials were conducted with good clinical practice.
`
`
`Office of Surveillance and Epidemiology was consulted including DMEPA who
`provided labeling input.
`
`Division of Scientific Investigation (DSI)
` did not reveal any unreliable data.
`Inspection of trial sites submitted for NDA
`Inspection of trial sites submitted for NDA 203565 did not reveal any unreliable data.
`
`There are no unresolved issues.
`
`
`
`Labeling
`12.
`The labeling was reviewed by all disciplines and consultant staff.
`13.
`Decision/Action/Risk Benefit Assessment
`
`
`
`• Recommended regulatory action
`Approval
`• Risk Benefit Assessment – The product is an intravenous iron formulation
`to be used for the treatment of iron deficiency anemia and for patients with
`chronic kidney disease who are not on dialysis. Based on an assessment of
`all safety and efficacy data, the benefit outweighs risks (hypertension,
`nausea, hypersensitivity, dizziness, flushing, hypophosphatemia)
`associated with use of this product.
`• Recommendation for Post marketing Risk Management Activities – routine
`post-marketing surveillance
`• Recommendation for other Post marketing Study Requirements (PMR)/
`Commitments (PMC) – pediatric drug development studies
`
`Reference ID: 3346410
`
`(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/
`----------------------------------------------------
`
`ANN T FARRELL
`07/24/2013
`
`Reference ID: 3346410
`
`