CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203565Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`
`Label, Labeling and Packaging Review
`
`Date:
`
`July 15, 2013
`
`Reviewer:
`
`Acting Team Leader:
`
`Associate Director:
`
`Drug Name and Strength:
`
`Kevin Wright, PharmD
`Division of Medication Error and Prevention Analysis
`James Schlick, RPh, MBA
`Division of Medication Error and Prevention Analysis
`Scott Dallas, RPh
`Division of Medication Error and Prevention Analysis
`Injectafer (Ferric Carboxymaltose) Injection
`750 mg per 15 mL (50 mg per mL)
`Application Type/Number: NDA 203565
`Applicant/sponsor:
`Luitpold Pharmaceuticals, Inc.
`OSE RCM #:
`2013-820
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public.***
`
`
`
`Reference ID: 3341321
`
`

`

`
`
`Contents
`
`1
`
`Introduction................................................................................................................. 1
`1.1
`Regulatory History......................................................................................................... 1
`1.2
`Product Information ....................................................................................................... 1
`2 Methods and Materials Reviewed............................................................................... 2
`2.1
`Labels and Labeling....................................................................................................... 2
`2.2
`Previously Completed Reviews ..................................................................................... 2
`3 Conclusions and Recommendations ........................................................................... 2
`4 References................................................................................................................... 3
`Appendices.......................................................................................................................... 4
`
`
`
`
`
`
`Reference ID: 3341321
`
`

`

`
`
`1
`INTRODUCTION
`This review evaluates the proposed container label, carton and insert labeling for
`Injectafer (Ferric Carboxymaltose) NDA 203565 for areas of vulnerability that could lead
`to medication errors.
`
`1.1 REGULATORY HISTORY
`Injectafer (Ferric Carboxymaltose Injection) is currently under review by the Division of
`Hematology Products (DHP). The labels and labeling were previously reviewed in OSE
`RCM# 2011-4401 dated, June 7, 2012. The applicant received a complete response letter
`from the Agency dated, July 23, 2012. On January 30, 2013, the Applicant submitted the
`container labels and carton labeling for review as part of a class 2 resubmission.
`
`1.2 PRODUCT INFORMATION
`The following product information is provided in the January 30, 2013 submission.
`• Active Ingredient: Ferric Carboxymaltose
`•
`Indication of Use: who are intolerant to oral iron, have had unsatisfactory
`response to oral iron, or who have chronic kidney disease not on dialysis.
`• Route of Administration: Intravenous
`• Dosage Form: Solution for Injection
`• Strength: 750 mg per 15 mL (50 mg per mL)
`• Dose and Frequency: administer intravenously either as an undiluted slow
`intravenous push injection or by a drip infusion. The recommended dosage is
`15 mg/kg body weight 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.
`• How Supplied: 15 mL vials in packages of 1
`
`• Storage: store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to
`30°C (59°F to 86°F)
`• Container and Closure System: glass vial with
`
` cap
`
`
`
`
`
`Reference ID: 3341321
`
`1
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`2 METHODS AND MATERIALS REVIEWED
`
`2.1 LABELS AND LABELING
`Using the principles of human factors and Failure Mode and Effects Analysis,1 along
`with post marketing medication error data, the Division of Medication Error Prevention
`and Analysis (DMEPA) evaluated the following:
`• Container Labels submitted January 30, 2013 (Appendix A)
`• Carton Labeling submitted January 30, 2013 (Appendices B and C)
`Insert Labeling submitted January 30, 2013 (no image)
`•
`
`2.2 PREVIOUSLY COMPLETED REVIEWS
`DMEPA had previously reviewed the container labels and carton labels for Injectafer in
`OSE Review# 2011-4401 and we looked at the reviews to ensure all our
`recommendations were implemented.
`
`3
`CONCLUSIONS AND RECOMMENDATIONS
`The updated labels and labeling implemented the majority of the recommendations
`outlined in the letter to the Applicant dated July 11, 2012 and the complete response letter
`dated July 23, 2012. However, there are outstanding recommendations along with some
`newly identified issues.
`A.
`Container Labels
`1. We continue to recommend, the Applicant revise the proprietary name to
`appear in title case (e.g. Injectafer).
`2. Ensure the established name is at least ½ the size of the proprietary name
`taking into account all pertinent factors, including typography, layout,
`contrast, and other printing features. Additionally, the established name
`should have a prominence commensurate with the prominence of the
`proprietary name in accordance with 21 CFR 201.10(g)(2).
`3. Revise the package type term from “
`” to “Single Dose
`Vial”.
`4. Remove the bold font from the distributor’s name and the statement “Rx
`Only” to place emphasis on more important information such as the
`statement “Single Dose Vial. Discard Unused Portion”.
`5. Increase the size of the strength per mL statement, “50 mg/mL”.
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`
`
`
`
`
`Reference ID: 3341321
`
`2
`
`(b) (4)
`
`

`

`
`
`B.
`
`Carton Labeling
`1. Ensure the carton labeling complies for recommendations A1 through A5.
`2. As presented, the use of mixed colors (red and purple) in the color block
`make it difficult to read the proprietary and established names. Revise the
`coloring scheme of the color block containing the proprietary and
`established names to display one color to improve readability of
`proprietary and established names on the carton labeling.
`3. Revise the net quantity statement on the package from
`.
` If you have further questions or need clarifications, please contact Sue Kang, project
`manager, at 301-796-4216.
`
`
`
`REFERENCES
`1. DeFronzo, Kimberly. OSE Review 2011-4401: Labels and Labeling Review for
`Injectafer, June 7, 2012.
`
`4
`
`
`
`
`
`
`
`
`
`Reference ID: 3341321
`
`3
`
`2 Page(s) of Draft Labeling have 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/
`----------------------------------------------------
`
`KEVIN WRIGHT
`07/15/2013
`
`JAMES H SCHLICK
`07/16/2013
`
`SCOTT M DALLAS
`07/17/2013
`
`Reference ID: 3341321
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Pediatric and Maternal Health Staff
`
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Silver Spring, MD 20993
`Tel 301-796-2200
`FAX 301-796-9744
`
`Pediatric and Maternal Health Staff Review
`
`Date:
`
`June 28, 2012
`
`Date Consulted: May 16, 2012
`
`From:
`
`Carrie Ceresa, Phann D, MPH
`
`Regulatory Reviewer, Maternal Health Team
`Pediatric and Maternal Health Staff (PMHS)
`
`Through:
`
`Melissa Tassinari, PhD, DABT
`Acting Team Leader, Maternal Health Team
`Pediatric and Maternal Health Staff
`
`Lisa Mathis, MD, 0ND Associate Director,
`Pediatric and Maternal Health Staff
`
`To:
`
`Division of Hematology Products GDHP)
`
`Drug:
`
`Injectafer® (ferric carboxymaltose) Injection; NDA 203565
`
`Subject:
`
`Labeling Revisions — Pregnancy, Nursing Mothers
`
`Sponsor:
`
`Luitpold Pharmaceuticals, Inc.
`
`Materials Reviewed:
`
`0 Proposed labeling for Injectafer (ferric carboxymaltose) Injection, submitted September
`28, 2011.
`
`o PMHS-MHT reviews dated December 7, 2007 and January 11, 2008 under NDA 22-054.
`0 Clinical review dated June 15, 2007, under NDA 22-054.
`
`Consult Question: “Please review the clinical data submitted with this NDA used to support
`the text in Section 8.3 Nursing Mothers of the proposed labeling.” In addition, this consult also
`includes the review of section 8.1 Pregnancy.
`
`Reference ID: 3151999
`
`

`

`
`
`INTRODUCTION
`On September 28, 2011, Luitpold Pharmaceuticals Inc., submitted a New Drug Application (203-
`565) for Injectafer (ferric carboxymaltose) a parenteral iron replacement product indicated for
`the treatment of iron deficiency anemia.
`
`Luitpold has resubmitted this application as a new NDA with a cross-reference to the clinical and
`non-clinical data previously submitted to NDA 22-054. NDA 22-054 for Injectafer (ferric
`carboxymaltose) was originally submitted on June 15, 2006 and received a non-approvable on
`July 9, 2007. On September 12, 2007, Luitpold Pharmaceuticals submitted a complete response
`to the July 9, 2007, non-approvable action. The 2011 submission provides a response to the
`complete response letter Luitpold received March 11, 2008, for NDA 22-054.
`
`The Division of Hematology Products (DHP) consulted the Pediatric and Maternal Health Staff
`to review and update the pregnancy and nursing mothers information in the Injectafer labeling.
`
`PMHS’s review provides suggested revisions and re-ordering of existing information related to
`pregnancy and nursing mothers in the Injectafer labeling in order to provide clinically relevant
`information for prescribing decisions and to comply with current regulatory requirements.
`
`BACKGROUND
`Injectafer (ferric carboxymaltose)
`Ferric carboxymaltose is a colloidal iron (III) hydroxide complex with carboxymaltose, a
`carbohydrate polymer, that releases iron. It is a dark brown, sterile, aqueous, isotonic colloidal
`solution for intravenous injection. Ferric carboxymaltose, an iron replacement product, is an iron
`carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-
`(14)-O--D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. The proposed
`indication is 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.
`
`
`Iron and Breast Milk
`According to the National Institutes of Health, Office of Dietary Supplements, the adequate
`intake of iron in infants zero to six months of age is 0.27 mg/day.1 A RDA for infants from birth
`to six months has not been established because there is not enough available data.1 Iron found in
`human breast milk is generally well absorbed by infants.1 It is believed that infants are able to
`absorb more than 50% of the iron in human breast milk, whereas iron from infant formula they
`are only able to absorb approximately 12%.2
`
`The transport of iron from maternal plasma into breast milk appears to be regulated and does not
`appear to occur by passive diffusion. A study conducted in Honduras and Sweden found there
`
`1 United States. National Institutes of Health. Office of Dietary Supplements. Dietary Supplement Fact Sheet: Iron.
`Web. 13 June 2012.
`2 United States. Department of Agriculture. National Agricultural Library. Dietary Reference Intakes for Vitamin
`A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon,
`Vanadium, and Zinc (2001). 14 June 2012.
`
`
`
`Reference ID: 3151999
`
`2
`
`

`

`was no significant correlation between milk iron concentration and any indices of maternal iron
`status after controlling for study site and complementary food energy intake.3. A study
`conducted by Faridi et al (2005) in India also suggested that breast milk iron and lactoferrin
`concentrations have no relationship to maternal hemoglobin and iron status.4 Breymann et al
`(2007) published a study on the transfer of parenteral iron sucrose into maternal milk in the
`postpartum period. In this study, 10 healthy lactating mothers with functional iron deficiency
`anemia two to three days postpartum received 100 mg intravenous iron sucrose. They were
`compared to a control group that did not receive iron treatment during the first four postpartum
`days. Mean milk iron levels at baseline were 0.43 and 0.46 mg/kg in the treatment and control
`groups respectively. These levels decreased in both groups by 0.11 mg/kg from baseline to th
`e
`end of the study period. At the prescribed dose, there was no detectable transfer of
`iron sucrose
`5
`to breast milk.
`in
`
`DISCUSSION AND CONCLUSION
`Pregnancy and Nursing Mothers Labeling
`inal The Proposed Pregnancy and Lactation Labeling Rule published in May 2008. While the F
`
`Rule is in clearance, PMHS-MHT is structuring the Pregnancy and Nursing mothers label
`information in the spirit of the Proposed Rule while still complying with current regulations. The
`
`first paragraph in the pregnancy subsection of labeling summarizes available data from published
`
` of literature, outcomes of studies conducted in pregnant women (when available), and outcomes
`
` studies conducted in animals, as well as the required regulatory language for the designated
`pregnancy category. The paragraphs that follow provide more detailed descriptions of the
`available human and animal data, and when appropriate, clinical information that may affect
`patient management. For nursing mothers, when animal data are available, only the presence or
`e
`absence of drug in milk is considered relevant and presented in the label, not the amount. Th
`ancy and lactation section of labeling a more
`goal of this restructuring is to make the pregn
`ffective communication tool for clinicians.
`
`
`
`e P
`
`MHS LABELING RECOMMENDATIONS
`The Sponsor’s proposed labeling is found in Appendix A. PMHS discussed labeling at a
`12. Subsequent to these meetings, the
`meeting with DHP on June 11, 2012 and June 13, 20
`MHS-MHT labeling recommendations are below:
`
`P H
`
`ighlights
`---------------------------USE IN SPECIFIC POPULATIONS----------------------
` Pregnancy: based on animal data, may cause fetal harm. (8.1)
` Nursing Mothe
`rs: Caution should be exercised when Injectafer is administered to a nursing
`woman. (8.3)
`
`
`
`
`
`3 Dommelof M, Hernell O, Dewey KG, Cohen RJ, Lonnerdal B. Factors influencing concentrations of iron, zinc,
`and copper in human milk. Adv Exp Med Biol. 2004; 554: 355-8.
`4 Faridi S, Singh O, Rusia U. Mother’s iron status, breastmilk iron and lactoferrin – are they related? Eur J Clin
`Nutrition 2006; 60: 903-8.
`5 Breymann C, von Seefried B, Stahel M, Geisser P, Canclini C. Milk iron content in breast-feeding mothers after
`administration of intravenous iron sucrose complex. J Perinatol Med. 2007; 35: 115-118.
`
`
`
`Reference ID: 3151999
`
`3
`
`

`

`Reviewer comment: After discussion with the Division, it was agreed that the Use in Specific
`Populations section would be added to the Highlights section to note the Nursing Mothers
`section 8.3. The Pregnancy: based on animal data, may cause fetal harm, will be omitted.
`
` 8
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C
`
`Risk Summary
`Adequate and well controlled studies in pregnant women have not been conducted. In
`reproductive studies, administration of ferric carboxymaltose to rabbits during the period of
`organogenesis caused fetal malformations and increased implantation loss at maternally toxic
`doses; approximately 12% to 23% of the human weekly dose of 750 mg (based on body surface
`area). Injectafer should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Animal Data
`Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 30
`mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal findings. This
`daily dose in rats is approximately 40% of the human weekly dose of 750 mg based on body
`surface area. In rabbits, ferric carboxymaltose was administered as a one-hour infusion on
`gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformations were seen
`starting at the daily dose of 9 mg/kg (23% of the human weekly dose of 750 mg). Abortion
`occurred starting at the daily iron dose of 4.5 mg/kg (12% of the human weekly dose based on
`body surface area). Pre-implantation loss was at the highest dose. Adverse embryofetal effects
`were observed in the presence of maternal toxicity.
`
` A
`
` pre- and post-natal development study was conducted in rats at intravenous doses up to 18
`mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a body surface
`area basis). There were no adverse effects on survival of offspring, their behavior, sexual
`maturation or reproductive parameters.
`
`Reviewer comment: PMHS-MHT concurs with the Division assigned a category C
`
`8.3 Nursing Mothers – To be revised
`A clinical study that collected data on nursing women exposed to Injectafer documented
`observed concentrations of iron in breast milk that would result in newborn iron intake well
`below US RDA maximum iron intake for infants (birth to six months of age) of 40 mg iron /day.
`Injectafer was well tolerated by breast-fed infants. There were no adverse events considered
`related to Injectafer among breast-fed infants. Based on limited data in nursing mothers, it is
`unlikely that Injectafer represents a risk to breast fed infants.
`
`
`
`
`
`
`
`Reference ID: 3151999
`
`4
`
`

`

`Reviewer Comment: This language is from the Sponsor’s proposed label. The clinical study
`from which the information in Section 8.3 is taken was not available for review for this consult.
`Prior PMHS-MHT reviews by Dr. Karen Feibus from 2007 and 2008 and the review by the
`medical officer, Dr. Min Lu in 2007 were reviewed. All indicate that INJECTAFER is present in
`breast milk. The sponsor will be asked for the data supporting their proposed label for review.
`
`Based on current advice from the NIH, the Adequate Intake [AI] for infants 0 – 6 months of age
`is 0.27 mg/day. A RDA for infants 0 to 6 months of age has not been established. The Nursing
`Mothers section will be revised at a later date once the data is received from the sponsor. In
`addition, the correct regulatory language will be added at that time.
`
`APPENDIX A SPONSORS PROPOSED LABELING
`
`
`
`
`
`Reference ID: 3151999
`
`5
`
`22 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CARRIE M CERESA
`06/28/2012
`
`MELISSA S TASSINARI
`06/28/2012
`
`LISA L MATHIS
`07/02/2012
`
`Reference ID: 3151999
`
`

`

`
`
`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:
`
`
`
`
`
`CLINICAL INSPECTION SUMMARY
`
`June 28, 2012
`
`Amy C. Baird, Regulatory Project Manager
`Min Lu, M.D., Medical Officer
`Kathy Robie-Sue, M.D., Ph.D. Team Leader
`Division of Hematology Products (DHP)
`
`Anthony Orencia, M.D., F.A.C.P.
`Medical Officer, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`
`THROUGH: Janice Pohlman, M.D., M.P.H.
`
`
`Team Leader, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`Office of Scientific Investigations
`
`
`THROUGH: Susan D. Thompson, M.D.
`
`
`Acting Branch Chief, GCP Assessment Branch
`Division of Good Clinical Practice Compliance
`
`
`
`
`Office of Scientific Investigations
`
`SUBJECT: Evaluation of Clinical Inspections
`
`NDA:
`
`APPLICANT: Luitpold Pharmaceuticals, Inc.
`
`intravenous ferric carboxymaltose (FCM)
`DRUG:
`Yes
`NME:
`THERAPEUTIC CLASSIFICATION/REVIEW: Standard Review
`
`INDICATION: treatment of iron deficiency anemia
`
`CONSULTATION REQUEST DATE:
`INSPECTION SUMMARY GOAL DATE:
`DIVISION ACTION GOAL DATE:
`PDUFA DATE:
`
`203565
`
`
`
`Reference ID: 3151952
`
`February 22, 2012 (Signed)
`July 3, 2012
`August 3, 2012
`August 3, 2012
`
`
`
`

`

`Page 2 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`I. BACKGROUND:
`
`FCM (Injectafer) for injection/infusion contains iron in a stable ferric state as a colloidal
`iron hydroxide in complex with a carbohydrate polymer designed to release utilizable
`iron to the iron transport and storage proteins in the body (ferritin and transferrin). The
`proposed ferric carboxymaltose (FCM) treatment for iron deficiency anemia is thought to
`be more stable than iron gluconate and iron sucrose (Venofer®) due to its chemical
`structure, producing a slow delivery of the complexed iron to endogenous iron binding
`sites.
`
`Two adequate, controlled studies were submitted in support of this NDA and are outlined
`below. Two U.S. clinical sites for both Protocols IVIT09030 and IVIT09031,
`respectively, were selected for clinical audit.
`
`Protocol IVIT09030
`
`IVIT09030 was a Phase 3, multicenter, randomized, active-controlled, open-label study
`that compared the safety and efficacy of intravenous FCM vs. intravenous iron sucrose in
`subjects with iron deficiency anemia and chronically impaired renal function. The
`primary objective of this study was to estimate the cardiovascular safety and efficacy of
`an investigational intravenous (IV) iron (FCM) compared to IV iron sucrose in subjects
`who had iron deficiency anemia and impaired renal function. The primary efficacy
`measure was the mean change from baseline examination to the highest observed
`hemoglobin any time between baseline and end of treatment period (Day 56) or time of
`intervention.
`
`Protocol IVIT09031
`
`IVIT09031 was a Phase 3, multicenter, randomized, active-controlled open-label study
`that compared the efficacy and safety of FCM in subjects who had iron deficiency anemia
`as compared to: (1) oral iron in subjects who had an unsatisfactory response to a 14-day
`oral iron run-in (Cohort 1), and (2) intravenous standard of care or other intravenous iron
`in subjects who were shown to be intolerant of oral iron during the run-in or were felt to
`be inappropriate for an oral run-in (Cohort 2). The primary objective of this study was to
`demonstrate the efficacy and safety of an investigational intravenous (IV) iron, FCM,
`compared to oral iron in subjects who had iron deficiency anemia and had been shown to
`have an unsatisfactory response to oral iron. The primary efficacy measure was the mean
`change in Cohort 1 (oral iron comparator) from baseline to the highest observed
`hemoglobin observed anytime between baseline and Day 35 or time of intervention.
`
`
`
`Reference ID: 3151952
`
`

`

`Page 3 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`Protocol/Study Site/
`
`Insp. Date
`
`April 4 to 11, 2012
`
`Final
`Classification*
`VAI
`
`
`II. RESULTS:
`
`Name of CI
`City, State
`Gioi N. Smith-
`Nguyen, M.D.
`La Mesa, CA
`
`Andre D.
`Williams, M.D.
`Decatur, GA
`
`
`
`Reference ID: 3151952
`
`Protocol IVIT09031
`Site #4001
`
`
`Protocol IVIT09031
`Site #4102
`
`
`Protocol IVIT09030
`Site #5112
`
`Protocol IVIT09030
`Site #5051
`
`Sponsor
`
`
`May 2 to 10, 2012
`
`Preliminary:
`NAI
`
`
`April 16 to 19, 2012 Preliminary:
`NAI
`
`April 9 to 12, 2012
`
`Preliminary:
`NAI
`
`April 16 to 18, 2012 NAI
`
`John Edward
`Buerkert, M.D.
`Columbia, SC
`Douglas A.
`Hamerski, M.D.
`Wilmington, NC
`Luitpold
`Pharmaceuticals,
`Inc.
`Valley Forge, PA
`
`*Key to Classifications
`NAI = No deviation from regulations. Data acceptable.
`VAI-No Response Requested= Deviations(s) from regulations. Data acceptable.
`VAI-Response Requested = Deviation(s) from regulations. See specific comments below for data
`acceptability
`OAI = Significant deviations from regulations. Data unreliable/Critical findings may affect data integrity.
`Preliminary= The Establishment Inspection Report (EIR) has not been received and findings are based on
`preliminary communication with the field.
`
`
`CLINICAL STUDY SITE INVESTIGATORS
`
`1. Gioi N. Smith-Nguyen, M.D./Protocol IVIT09031 Site #4001
` La Mesa, CA
`
`a. What was inspected:
`The inspection was conducted in accordance with Compliance Program 7348.811, from
`April 4 to 11, 2012. A total of 112 subjects were screened, 57 subjects were enrolled and
`randomized, and 48 subjects completed the study.
`
`
`
`
`

`

`Page 4 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`An audit of 13 subjects’ records was conducted. The inspection evaluated the following
`documents: source records, screening and enrollment logs, case report forms, study drug
`accountability logs, study monitoring visits, and correspondence. Informed Consent
`documents and Sponsor-generated correspondence were also inspected.
`
`b. General observations/commentary:
`Source documents, for randomized subjects whose records were reviewed were verified
`against the case report forms and NDA subject line listings and no discrepancies were
`noted. There was no under-reporting of serious adverse events. The primary efficacy
`endpoint was verifiable. There were no limitations during conduct of the clinical site
`inspection by ORA staff.
`
`In general, this clinical site appeared to be in compliance with Good Clinical Practices.
`However, a Form FDA 483 (List of Inspectional Observations) was issued at the end of
`the inspection for not conducting the clinical investigation according to the study
`protocol. Selected examples included the following:
`
`
`1. Fourteen (14) subjects had their (local or “point of care”) hemoglobin
`concentrations read on the HemoCue Hb 201+ Photometer on days when the
`results of the control tests were out of range. (The hemoglobin results read with
`the HemoCue were used to determine whether subjects met inclusion criteria #2
`and #4 [i.e. Day -15 hemoglobin ≤ 11 g/dL and randomization hemoglobin
`(average of Day -1 and Day 0) < 12 g/dL]). For example:
`
`
`
`Subject #
`
`320010
`
`320142
`
`320143
`
`320150
`
`320145
`320166
`
`320168
`
`310159
`
`320180
`
`
`
`
`
`Reference ID: 3151952
`
`Visit
`
`Screening 1
`(Day -15)
`Screening 1
`(Day -15)
`Screening 1
`(Day -15)
`Screening 1
`(Day -15)
`Day 0
`Screening 1
`(Day -15)
`Screening 1
`(Day -15)
`Day 0
`Screening 1
`(Day -15)
`Screening 1
`(Day -15)
`
`HemoCue
`control result
`5.9
`
`Reference
`range
`5.0±0.7
`
`14.3
`3.4
`14.3
`3.4
`3.6
`
`11.4
`12.3
`
`12.4
`
`3.7
`3.7
`
`12.5
`3.8
`
`15.9±1.4
`4.7±0.7
`15.9±1.4
`4.7±0.7
`4.7±0.7
`
`15.9±1.4
`15.9±1.4
`
`15.9±1.4
`
`4.7±0.7
`4.7±0.7
`
`15.9±1.4
`4.7±0.7
`
`

`

`Page 5 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`
`Subject #
`
`320199
`
`320200
`
`320214
`
`320215
`
`320246
`
`Visit
`
`Screening 1
`(Day -15)
`
`Screening 1
`(Day -15)
`
`Screening 1
`(Day -15)
`
`Screening 1
`(Day -15)
`
`Screening 1
`(Day -15)
`
`HemoCue
`control result
`14.4
`3.9
`
`14.4
`3.9
`
`14.2
`3.4
`
`14.2
`3.4
`
`14.3
`
`Reference
`range
`15.9±1.4
`4.7±0.7
`
`15.9±1.4
`4.7±0.7
`
`15.9±1.4
`4.7±0.7
`
`15.9±1.4
`4.7±0.7
`
`15.9±1.4
`
`
`
`The reference controls used to determine whether or not the equipment was operating
`properly did not fall within the expected range of values when the hemoglobin
`concentration was measured for 14 subjects. Therefore, the local measured hemoglobin
`concentration may have been invalid and allowed subjects not eligible for the trial to be
`enrolled. DHP noted that since this clinical site represented only about 0.5% of the total
`study population, it is unlikely that overall efficacy would be impacted if these subjects
`were excluded from DHP’s analysis.
`
`While the local hemoglobin concentration was used to assess whether or not a subject
`met inclusion criteria, it was noted in the April 24, 2012 clinical investigator’s written
`response to the Form FDA 483 (List of Inspectional Observations), that all fourteen
`subjects cited above met randomization criteria based on central laboratory hemoglobin
`concentrations.
`
`We defer the decision to further assess the local screening and randomization hemoglobin
`concentrations for these 14 subjects and the impact on eligibility criteria to the DHP
`medical team.
`
`
`2. The lot number, expiration date, date opened and reference ranges of the High and
`Low HEMATROL liquid controls were not always recorded in the HemoCue
`Hb201+ Quality Control Log. For example:
`i. No high or low liquid control information was recorded on the following
`dates: 2/1/2010-6/9/2010; 9/28/2010-10/25/2010; and 10/26/2010-
`12/9/2010, and
`ii. No specific calendar date information was recorded when the high and
`low reference controls were opened between 6/10/2010-9/24/2010.
`
`
`
`
`
`Reference ID: 3151952
`
`

`

`Page 6 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`In summary, the above findings were discussed with the DHP Medical Team, who did
`not consider the above findings would likely have a significant impact on safety and
`efficacy assessments for this NDA.
`
`c. Assessment of data integrity:
`Data submitted by this clinical site appear acceptable for this specific indication.
`
`
`2. Andre D. Williams, M.D./Protocol IVIT09031 Site #4102
`Decatur, GA
`
`
`
`a. What was inspected:
`The inspection was conducted in accordance with Compliance Program 7348.811, from
`. A total of 144 subjects were screened, 72 subjects were enrolled and
`randomized, and 70 subjects completed the study. A 100% audit of screened subjects’
`informed consent forms was performed.
`
`An audit of 30 subjects’ records was conducted. The inspection evaluated the following
`documents: source records, screening and enrollment logs, case report forms, study drug
`accountability logs, study monitoring visits, and correspondence. Informed Consent
`documents and Sponsor-generated correspondence were also inspected.
`
`b. General observations/commentary:
`Source documents, for randomized subjects whose records were reviewed were verified
`against the case report forms and NDA subject line listings and no discrepancies were
`noted. There was no under-reporting of serious adverse events. The primary efficacy
`endpoint was verifiable. There were no limitations during conduct of the clinical site
`inspection by ORA staff.
`
`In general, this clinical site appeared to be in compliance with Good Clinical Practices.
`No Form FDA 483 (List of Inspectional Observations) was issued at the end of the
`inspection.
`
`c. Assessment of data integrity:
`Data submitted by this clinical site appear acceptable for this specific indication.
`
`Note: Observations noted above are based on preliminary communications with the field
`investigator; an inspection summary addendum will be generated if conclusions change
`upon receipt and review of the EIR.
`
`
`
`
`
`
`
`
`
`Reference ID: 3151952
`
`(b) (4)
`
`

`

`Page 7 NDA 203565 ferric carboxymaltose
`Clinical Inspection Summary
`
`
`3. John Edward Buerkert, M.D./Protocol IVIT09030 Site #5112
` Columbia, SC
`
`a. What was inspected:
`
`The inspection was conducted in accordance with Compliance Program 7348.811, from
`. A total of 115 subjects were screened, enrolled and randomized,
`and 110 subjects completed the study. A 100% audit of screened subjects’ informed
`consent forms was performed.
`
`An audit of 41 subjects’ records was conducted. The inspection evaluated the following
`documents: source records, screening and enrollment logs, case report forms, study drug
`accountability logs, study monitoring visits, and correspondence. Informed Consent
`documents and Sponsor-generated correspondence wer