CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`021825Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`
`
` 21-825/(N-000)
`09/22/11, 09/23/11
`Ferriprox
`Deferiprone
`Immediate release (IR) tablet
`500 mg (one strength)
`ApoPharma
`Applicant’s Response to Information Requests
`Tien-Mien Chen, Ph.D.
`
`NDA#:
`Submission Dates:
`Brand Name:
`Generic Name:
`Formulation:
`Strength:
`
`
`Applicant:
`
`
`Type of submission:
`Reviewer:
`
`
`REVIEW
`This document is an Addendum to the Biopharmaceutics review in DARRTS dated
`September 16, 2011, addressing the Applicant responses submitted on September 22,
`2011, for the Biopharmaceutics comments conveyed to them on the Information Request
`(IR) Letters dated August 10, 2011 and September 19, 2011, for NDA 21-825 for
`Ferriprox IR tablet 500 mg.
`
`RECOMMENDATION
`ONDQA- Biopharmaceutics had evaluated the information provided by the Applicant
`and considers that their response to the Biopharmaceutics comments included in the IR
`Letter dated August 10, 2011 is adequate.
`
`Based on the evaluation of the dissolution data provided by the Applicant on September
`22nd in response to the Agency’s IR Letter dated September 19th, Biopharmaceutics
`agrees with the Applicant that the provided dissolution data support an acceptance
`criterion of Q=
` in 45 minutes. Therefore, it is recommended that this criterion be set
`for their product.
`
`The above recommendation was conveyed to the Applicant on September 23rd, and on the
`same day ApoPharma agreed to implement the recommended dissolution criterion.
`Therefore, the approved dissolution method and acceptance criterion for Ferriprox IR
`Tablets are as follow:
` USP Apparatus II (Paddle)
`Apparatus:
`
`
`Rotation Speed:
`50 rpm
`
`Dissolution Medium: 1,000 mL of 0.1 N HCl at 37ºC
` Acceptance Criterion: Q =
` at 45 min
`
`OVERALL ASSESSMENT: From the Biopharmaceutics perspective, NDA 21-825 is
`recommended for approval.
`
` ______________________________
`__________________________
`
`Angelica Dorantes, Ph.D.
`Tien-Mien Chen, Ph.D.
`
`Biopharmaceutics Team Leader
`Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`Office of New Drug Quality Assessment
`
`ONDQA BIOPHARMACEUTICS REVIEW ADDENDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3019970
`
`1
`
`(b) (4)
`
`(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/
`----------------------------------------------------
`
`ANGELICA DORANTES
`09/25/2011
`
`Reference ID: 3019970
`
`

`

`ONDQA BIOPHARMACEUTICS REVIEW
`
`
`
`
`
`
`
`NDA#:
`Submission Date:
`Brand Name:
`Generic Name:
`Formulation:
`Strength:
`
`
`Applicant:
`
`
`Type of submission:
`Reviewer:
`
`
`SUMMARY
`Background: Deferiprone was developed under IND 45,724 by ApoPharma as an oral
`treatment for chronic iron overload in transfusion-dependent anemias. Ferriprox
`(deferiprone) is a 500-mg, film-coated, IR tablet (one strength only).
`
`Submission: ApoPharma submitted NDA 21-825 for Ferriprox in 2006 and was granted
`an orphan drug status. A Complete Response (CR) letter was sent to the sponsor on
`11/30/09. The applicant submitted on 04/13/11 through its US Agent, Cato Research Ltd.,
`a full response to the CR letter. The review time clock is 6 months.
`
`Biopharmaceutics Review: The dissolution development report, dissolution data/profiles,
`the proposed dissolution method, and the specifications are formally reviewed here.
`
`Prior to resubmission on 04/13/11, the revised dissolution method and Acceptance
`criterion as previously agreed upon between the Agency and the applicant are shown
`below.
`
`
` USP Apparatus II (Paddle)
`Apparatus:
`Rotation Speed:
` 50 rpm
`
`Dissolution Medium: 1,000 mL of 0.1 N HCl at 37ºC
`
` Acceptance Criterion:
`
`
`After a formal review by the Biopharmaceutics team on the dissolution development
`report, dissolution data/profiles, it is concluded that the dissolution method is acceptable.
`However, since
` of drug is dissolved in
`, the data clearly support a tighter
`value and the above dissolution criterion should be further revised as follows:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 21-825/(N-000)
`04/13/11, 06/22/11,
`Ferriprox
`Deferiprone
`Immediate release (IR) tablet
`500 mg (one strength)
`ApoPharma
`Resubmission (6-month review)
`Tien-Mien Chen, Ph.D.
`
`
`
`
`Acceptance Criterion:
`
`Change from Q =
`
`
` to Q =
`
`
`
`
`
`
`Reference ID: 3016508
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`RECOMMENDATION
`From the Biopharmaceutics perspective, information is lacking and the resubmission of
`NDA 21-825 is not recommended for approval at this time.
` The following
`deficiencies/comments need to be conveyed to the applicant.
`
`COMMENTS: (Need to be sent to the applicant)
`1. An information request was sent on 08/10/11 asking you to clarify if the dissolution
`medium used for the dissolution testing was
` instead of the
`proposed 0.1 N HCl medium. No response has been received yet. We request that
`you address this question adequately.
`
` USP Apparatus II (Paddle)
`Apparatus:
`Rotation Speed: 50 rpm
`Medium:
` 1,000 mL of 0.1 N HCl at 37ºC
`
`
`2. Your proposed dissolution method as shown below has been accepted:
`
`
`
`
`
` However, after a further evaluation on the dissolution profiles/data we consider that
`the previously agreed dissolution value needs further revision since
` of the drug
`is dissolved in
`. Please revise the dissolution acceptance criterion as follows:
`
`
`
`
`Change from Q =
`
` to Q =
`
`
`
`
`
`Provide an updated specification sheet for your product including the revised criterion
`for the dissolution test.
`
`
`
`
`
`
`
`
`
`
`
`________________________________
`Tien-Mien Chen, Ph.D.
`
`Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`________________________________
`Angelica Dorantes, Ph.D.
`
`Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment
`
`
`CC:
`
`
`NDA
`Tien-Mien Chen
`
`
`
`
`
`
`
`
`______09/16/11_________
`
`Date
`
`______09/16/11_________
`
`Date
`
`
`
`
`
`Reference ID: 3016508
`
`2
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`BACKGROUND
`Deferiprone was developed under IND 45,724 by ApoPharma as an oral treatment for
`chronic iron overload in transfusion-dependent anemias. Deferiprone, a bidentate iron
`chelator with a molecular weight of 139.15 g/mol, preferentially binds trivalent iron
`cations (Fe3+) in a 3:1 (deferiprone:Fe3+) complex. Ferriprox that is intended for
`marketing is a 500-mg, film-coated, IR tablet (one strength only). ApoPharm submitted
`NDA 21-825 for Ferriprox in 2006 and was granted an orphan drug status. On 11/30/09,
`the Agency’s CR letter was sent to the applicant.
`
`CURRENT SUBMISSION
`ApoPharma Inc. submitted on 04/13/11 through its US Agent, Cato Research Ltd., a full
`response to the Agency’s 11/30/09 CR letter. The review tine clock is 6 months.
`
`The dissolution information on Ferriprox IR tablet that was included in the original
`submission, however, was briefly reviewed previously due to the CR letter. Therefore,
`the dissolution development report, dissolution data/profiles, the proposed dissolution
`method, and the specifications are formally reviewed here.
`
`FORMULATION COMPARISONS
`Several formulations were developed previous for clinical use. The formulation No. F7
`that was tested in the pivotal clinical trials is selected as the to-be-marketed (TBM)
`formulation. The composition of the TBM formulation is shown below. The commercial
`manufacturing scale is reported to be
` per run.
`
`
`
`
`DISSOLUTION METHODOLOGY AND SPECIFICATIONS
`The originally proposed dissolution method and specification are shown below.
`
`
`
`
`
`In the question #7 in the 11/30/09 CR letter, the Agency accepted the proposed
`dissolution method, but requested a change to the dissolution acceptance criterion from
`Q
` at 45 min to
`. In the applicant’s response on 02/24/11, the
`
`Apparatus: USP Apparatus II (Paddle) x 50 rpm
`Medium:
`1,000 mL of 0.1 N HCl at 37ºC
`
`Specification: Q =
` at 45 min
`
`
`
`Reference ID: 3016508
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`applicant agreed that the dissolution acceptance criterion would be revised to
`.
`
`
`Upon formal review on the dissolution development report, it was found that the report
`was for Exferrum (deferiprone) tablet which is approved in Europe. The applicant
`responded affirmatively on 06/22/11 to the Agency’s request for clarification that the
`composition/formulation of Exferrum is the same as the TBM formulation (No. F7) of
`Ferriprox. The dissolution development report is formally reviewed here. The applicant
`selected 0.1N HCl as the proposed dissolution medium and it is found acceptable. Please
`see the summary of the dissolution development in Appendix 1 for details.
`
`The mean dissolution profiles of the two typical batches are shown below.
`
`Figure 1. Mean Dissolution Profiles of These Two Typical Batches
`
`
`
`
`
`Please see mean and individual dissolution data in Appendix 2 for details.
`
`The manufacturing information on the above batches employed, however, was not
`included in the NDA. The applicant responded on 06/22/11 to the Agency’s information
`request and provided the needed information as shown below.
`
`Table 1. The information on the Manufacture of Two Typical Batches
`Batch
`Date of
`Batch Size
`Use
`Mean% (Range)
`No.
`Manufacture
`(Tablets)
`
`
`(n=12 tablets/batch)
`
`80434A
`90696F
`
`07/30/1998
`11/01/1999
`
`Clinical/Stability
`Primary Stability
`
`
`
`It was noticed that the above dissolution profiles were obtained at
`, instead of the proposed 0.1 N HCl medium. An information request was further
`sent out on 08/10/11 for additional clarification. No response has been received yet.
`
`
`
`
`Reference ID: 3016508
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The applicant also responded on 06/22/11 to the request on the assay method validation.
`The applicant reported that 1). The validated assay method used for the above two
`batches for the dissolution study was FP0024-1 and 2). This assay method has been
`demonstrated to be equivalent to a new assay method AP66-IMTB-10-SG. The
`applicant’s response is acceptable.
`
`Reviewer’s Comments:
`1. An information request was sent out on 08/10/11 asking to clarify if the dissolution
`medium used was,
`, instead of the proposed 0.1 N HCl
`medium. No response has been received yet. The applicant needs to address this
`issue adequately.
`
`
`2. The proposed dissolution method was reviewed and found acceptable and the
`originally proposed dissolution specification was revised (as agreed upon between the
`Agency and the applicant) from Q
` at 45 min to
`.
`
`
` However, after evaluation of the overall dissolution data, it is concluded that the data
`clearly support a tighter acceptance criteria value
`
`and Q=
` is recommended for this product. Therefore, the following
`dissolution acceptance criterion of Q=
` should be conveyed to the
`applicant.
`
`
`
`
`
`
`Reference ID: 3016508
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 21-825 for Ferriprox (Deferiprone)
`IR Oral Tablet 500 mg
`
`
`
`
`
`
`
`
`
`Appendix 1
`
`
`
`
`
`
`
`
`
`Summary of Dissolution Development
`
`6
`
`
`
`
`
`
`
`
`
`Reference ID: 3016508
`
`3 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`NDA 21-825 for Ferriprox (Deferiprone)
`IR Oral Tablet 500 mg
`
`
`
`
`
`
`
`
`
`Appendix 2
`
`
`
`
`
`
`
`
`
`Mean and Individual Dissolution Data
`
`10
`
`
`
`
`
`
`
`
`
`Reference ID: 3016508
`
`1 Page(s) has 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/
`----------------------------------------------------
`
`TIEN MIEN CHEN
`09/16/2011
`
`ANGELICA DORANTES
`09/16/2011
`
`Reference ID: 3016508
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`ADDENUM TO THE 3/27/08, 9/24/09, AND 10/22/09 REVIEWS
`
`
`
`
`
`NDA: 21-825
`Brand Name
`Generic Name
`Reviewer
`Team Leader
`OCPB Division
`ORM division
`Sponsor
`Relevant IND(s)
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`
`Submission Date(s): 4/14/ 2011
`Ferriprox
`Deferiprone
`Joseph A. Grillo, Pharm.D.
`
`Julie Bullock, Pharm.D.
`DCP-5
`OND/OODP/DHP
`ApoPharma
`45-724
`Resubmission of NDA (SDN 59), Standard Review
`500 mg Tablet
`Iron chelator for the treatment of thalassemia patients with
`transfusional iron overload when current chelation therapy
`is inadequate
`
`
`
`Table of Contents
`1 EXECUTIVE SUMMARY ................................................................................................................................. 2
`1.1 RECOMMENDATION ..............................................................................................................2
`1.2 POST MARKETING REQUIREMENTS .......................................................................................2
`1.3 POST MARKETING COMMITMENTS.........................................................................................3
`1.4 COMMENTS TO THE APPLICANT ............................................................................................3
`1.5 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS .....3
`2 QUESTION BASED REVIEW ......................................................................................................................... 5
`2.1 GENERAL ATTRIBUTES.........................................................................................................5
`2.2 GENERAL CLINICAL PHARMACOLOGY ...................................................................................5
`2.3
`INTRINSIC FACTORS .............................................................................................................5
`2.4 EXTRINSIC FACTORS............................................................................................................6
`2.5 GENERAL BIOPHARMACEUTICS ............................................................................................7
`2.6 ANALYTICAL SECTION..........................................................................................................7
`3 DETAILED LABELING RECOMMENDATIONS............................................................................................. 8
`4 APPENDICES................................................................................................................................................ 14
`4.1
`INDIVIDUAL STUDY REVIEWS...............................................................................................14
`4.2 CONSULT REVIEW..............................................................................................................15
`4.3 CITED REFERENCES...........................................................................................................16
`
`
`
`Reference ID: 3014812
`
`1
`
`

`

` 1
`
`
`
` Executive Summary
`
`Ferriprox (deferiprone) is an orally active iron chelator that preferentially chelates Fe3+. Ferriprox is being
`developed for the treatment of thalassemia patients with transfusional iron overload when current chelation
`therapy is inadequate. The final submission of the original “rolling” NDA for Ferriprox was submitted on
`January 28, 2009, and a complete response letter was issued on November 30, 2009, due to Clinical,
`Clinical Pharmacology, and Quality related issues. This resubmission includes a response to the clinical
`pharmacology issues regarding the need for a dedicated hepatic impairment trial, a dedicated renal
`impairment, a thorough QT/QTc trial (TQT), and two in vitro studies to determine the affect of moderate to
`strong UDP glucuronosyltransferase (UGT) inhibition and induction on the metabolism of deferiprone.
`The reviewer does not agree with the applicant’s proposal that a dedicated hepatic impairment trial should
`not be conducted due to the estimated size of the target population resulting from the proposed new
`restricted indication given this drug primary route of elimination is metabolic. The reviewer recommends
`that the completion of this trial should be a PMR.
`The reviewer also does not agree with the applicant’s proposal that a TQT trial is not warranted based on
`combined safety data from clinical trials since IRT finds them inconclusive since Cmax was not captured.
`The reviewer recommends that the completion of this trial per the ICH E-14 guidelines should be a PMR.
`The reviewer agrees with the applicant’s proposal to complete the dedicated renal trial and two in vitro
`studies to determine the affect of moderate to strong UDP glucuronosyltransferase (UGT) induction and
`inhibition on the metabolism of deferiprone as a PMR and PMC, respectively. However, the reviewer
`disagrees with the applicant’s proposed design of the renal impairment trial. The applicant should conduct
`this pharmacokinetic trial in a population with mild to severe renal insufficiency and the number of patients
`enrolled in the trial should be sufficient to detect PK differences large enough to warrant dosage
`adjustments for each level of impairment. This should be clearly communicated in the PMR.
`
`1.1 Recommendation
`From a clinical pharmacology perspective, this resubmission of the original application is ACCEPTABLE
`provided that the applicant and the Agency come to a mutually satisfactory agreement regarding the
`language in the package insert and the applicant commits to the following post marketing commitments
`addressing clinical pharmacology related safety concerns with deferiprone treatment.
`
`1.2 Post Marketing Requirements
`
`1.2.1 Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-glucuronide metabolite in
`subjects with hepatic impairment. The subjects enrolled in this trial do not necessarily need to be in the
`target population (e.g., patients with thalassemia or sickle cell disease), but should have demographics
`that represent this population (e.g., age, weight gender, race) to the extent possible. The applicant will
`submit the protocol to the agency prior to conduct of the trial for agreement with the trial design. The
`applicant will conduct this pharmacokinetic trial in a patient population with mild to severe hepatic
`insufficiency, according to the Child-Pugh classification.
`Protocol submission Date: 45 days from date of action.
`Submission Date: 12 months after FDA agreement to submitted protocol.
`
`1.2.2 Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-glucuronide metabolite in
`subjects renal impairment. The applicant should conduct this pharmacokinetic trial in a population with
`mild to severe renal insufficiency and the number of patients enrolled in the trial should be sufficient to
`detect PK differences large enough to warrant dosage adjustments for each level of impairment. The
`subjects enrolled in this trial do not necessarily need to be in the target population (e.g., patients with
`thalassemia or sickle cell disease), but should have demographics that represent this population (e.g.,
`age, weight gender, race) to the extent possible. The applicant will submit the protocol to the agency
`prior to conduct of the trial for agreement with the trial design. The applicant will conduct this
`pharmacokinetic trial in a patient population with mild to severe renal insufficiency.
`Protocol submission Date: 45 days from date of action.
`Submission Date: 12 months after FDA agreement to submitted protocol.
`
`Reference ID: 3014812
`
` 2
`
`

`

`1.2.3 As per the ICH E-14 guidelines the sponsor should conduct a TQT assessment for deferiprone.
`Protocol submission Date: 45 days from date of action.
`Submission Date: 12 months after FDA agreement to submitted protocol.
`
`1.3 Post Marketing Commitments
`
`1.3.1 Conduct in vitro studies to determine the affect of moderate to strong UDP glucuronosyltransferase
`(UGT) inhibition and moderate to strong UGT induction on the metabolism of deferiprone. The results of
`the in vitro evaluations will determine the need for additional in vivo drug interaction trials.
`Protocol submission Date: 45 days from date of action.
`Submission Date: 12 months after FDA agreement to submitted protocol.
`
`1.4 Comments to the Applicant
`
`1.4.1 The FDA suggests that the applicant evaluate the affect of obesity (e.g., BMI >30) on exposure to
`deferiprone given the weight based regimen proposed.
`1.4.2 The FDA suggests that the applicant assess the potential for accumulation of deferiprone and 3-O-
`glucuronide metabolite by conducting a pharmacokinetic trial evaluating single dose vs. steady state
`dosing of the 33 mg/kg tid dosage regimen.
`1.4.3 The FDA suggests that the applicant conduct a pharmacokinetic trial (deferiprone and 3-O-glucuronide
`metabolite) evaluating linearity or lack thereof of single doses at the labeled dosage of 25 and 33 mg/kg.
`1.4.4 The FDA suggests that the applicant explore the relationship between measures of exposure to
`deferiprone and 3-O-glucuronide metabolite and measures of effectiveness as well as toxicity in both
`adult and pediatric populations.
`1.4.5 The FDA suggests that the applicant genotype participants in any post-marketing pharmacokinetic trials
`for a comprehensive panel of UGT1A6 polymorphisms.
`1.4.6 The FDA suggests that the applicant collect DNA in future trials and attempt to identify genetic or other
`biomarkers for agranulocytosis and other severe adverse events (e.g., arthropathy).
`
`1.5 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`Deferiprone is an orally active iron chelator that preferentially chelates Fe3+. Ferriprox is being developed
`the treatment of thalassemia patients with transfusional iron overload when current chelation therapy is
`inadequate. The goal of therapy with Ferriprox is to induce neutral or negative iron balance. The proposed
`dosing for Ferriprox is 25 to 33 mg/kg body weight, orally, three times a day (TID) for a total daily dose of
`75 to
`mg/kg body weight. The starting dose is 75 mg/kg/day with monitoring of serum ferritin
`concentrations every 2 to 3 months. Dose adjustments are tailored to the individual patient’s response and
`therapeutic goals to a maximum of
`mg/kg/day.
`A complete response letter was issued on November 30, 2009, due to Clinical, Clinical Pharmacology,
`and Quality related issues. This resubmission includes a response to the clinical pharmacology issues
`regarding the need for a dedicated hepatic impairment trial, a dedicated renal impairment, a TQT, and two
`in vitro studies to determine the affect of moderate to strong UDP glucuronosyltransferase (UGT) inhibition
`and induction on the metabolism of deferiprone.
`In its response the applicant states that it had not conducted any of the trials or studies cited as clinical
`pharmacology related deficiencies. Regarding the deficiency for the dedicated hepatic impairment trial,
`the applicant states that given its estimate of the prevalence of hepatic impairment in the target population
`a dedicated hepatic impairment trial should not be conducted and that the results from a single arm trial in
`cirrhotic patients, already reviewed by FDA and deemed inadequate, should be sufficient. The reviewer
`does not agree with the applicant’s proposal and recommends it be considered a PMR.
`Regarding the deficiency addressing the dedicated renal impairment trial, the applicant states that given
`its estimate of the prevalence of renal impairment in the target population a dedicated renal impairment
`trial should be conducted
` following the FDA action. The reviewer finds the
`applicant’s proposal acceptable as a PMR; however, the dedicated renal trial should enroll a population
`with mild to severe renal insufficiency and the number of patients enrolled in the trial should be sufficient
`to detect PK differences large enough to warrant dosage adjustments for each level of impairment. This
` 3
`
`Reference ID: 3014812
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`should be clearly communicated in the PMR. The trial does not need to be completed in patients provided
`demographics of subjects enrolled represent the target population.
`Concerning the deficiency for the TQT trial, the applicant states that based on submitted nonclinical and
`data from its clinical trials and post-marketing experience deferiprone treatment does not represent either
`a significant absolute risk of QT prolongation, or a greater risk than does Desferoxamine (DFO) treatment.
`Therefore, the applicant concludes that a TQT is not warranted. These clinical data were deemed
`inconclusive by the IRT since Cmax was not captured. Based on recommendations from the IRT, the
`reviewer finds the applicant’s proposal unacceptable and the sponsor should conduct a TQT assessment
`for deferiprone per the ICH E-14 guidelines as a PMR.
`With reference to the deficiency for an in vitro study to determine the affect of moderate to strong UDP
`glucuronosyltransferase (UGT) induction and inhibition on the metabolism of deferiprone, the applicant
`proposes that these in vitro studies be conducted following the FDA action on the application. The
`reviewer finds the applicant’s proposal acceptable as a PMC; however, the labeling should communicate
`that coadministration of Ferriprox with UGT1A6 inhibitors (e.g., troglitazone and silymarin (milk thistle)) on
`the systemic exposure of Ferriprox has not been evaluated and patients should be closely monitored.
`
`
`Signatures
`
`
`______________________________________
`Joseph A. Grillo, Pharm.D
`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology 5
`______________________________________
`Nam Atiqur Rahman, Ph.D.
`Division Director
`Division of Clinical Pharmacology 5
`
`
`
`
`
`
`
`
`
`______________________________________
`Julie M. Bullock, Pharm.D.
`Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology 5
`
`
`
`Reference ID: 3014812
`
` 4
`
`

`

`2 Question Based Review
`
`2.1 General Attributes
`
`Not applicable to this submission
`
`2.2 General Clinical Pharmacology
`
`2.2.1 Exposure-response
`
`2.2.1.1 Does this drug prolong the QT or QTc interval?
`In its response to the deficiency regarding the need for assessment of the effect of deferiprone and its
`primary 3-O-glucuronide metabolite on the electrocardiographic QT interval in patients and/or healthy
`volunteers, the applicant provided 1) background information on malignant arrhythmia risk in
`thalassemia, 2) Non-clinical information regarding the affect of deferiprone on the hERG potassium
`channel in vitro and affect on heart rate, duration of the PR interval, QRS wave and uncorrected QT
`interval in a primate model, and 3) pooled clinical experience from trials LA20-BA, LA21-BE and LA26
`and post marketing experience outside the USA in lieu of the requested assessment. Based on this
`information, the applicant concludes that the data do not indicate that deferiprone treatment
`represents either a significant absolute risk of QT prolongation, or a greater risk than does DFO
`treatment.
`The IRT reviewed the applicant’s response (see 06/19/2011 QT-IRT Consult) to this deficiency
`identified by FDA in its 11/30/09 complete response letter. The IRT finds that The ECGs collected in
`the clinical trials are inconclusive since Cmax was not captured. There has been one case of TdP in
`the clinical program with temporal association to deferiprone although congenital long-QT syndrome
`and cardiomyopathy secondary to thalassemia were confounders. Similarly, in trial LA-26, there is
`possible association of QTc prolongation to deferiprone in the HIV infected subject. While the
`sponsor’s statement that patients with thalassemia are at increased risk for malignant arrhythmia and
`sudden death due to cardiomyopathy secondary to iron overload has to be considered in context, pro-
`arrhythmic liability secondary to deferiprone has not been excluded based on available information.
`Therefore the IRT concludes that, as per the ICH E-14 guidelines, the sponsor should conduct a TQT
`assessment for deferiprone. If safety or tolerability issues preclude administration of a supra-
`therapeutic dose to healthy volunteers, an ECG-substudy should be conducted in patients with
`replicate, centrally read ECGs collected at multiple time points and time-matched ECG and PK
`sampling. The clinical pharmacology reviewer agrees with the IRT assessment and recommendation,
`but defers to the Clinical reviewer regarding whether any safety or tolerability issues should preclude
`administration of a supra-therapeutic dose to healthy volunteers.
`
`2.3
`
`Intrinsic Factors
`
`2.3.1 What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism,
`pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and what
`is the impact of any differences in exposure on efficacy or safety responses?
`Renal impairment, hepatic impairment, and genetic polymorphism may influence exposure to
`deferiprone and/or its metabolite and were identified as factors that may influence exposure and/or
`response in the previous clinical pharmacology reviews for this application (see the 3/27/08, 9/24/09,
`and 10/22/09 clinical pharmacology reviews).
`
`2.3.2 Based upon what is known about exposure-response relationships and their variability and the
`groups studied, healthy volunteers vs. patients vs. specific populations (examples shown
`below), what dosage regimen adjustments, if any, are recommended for each of these groups? If
`dosage regimen adjustments are not based upon exposure-response relationships, describe the
`alternative basis for the recommendation.
`
`
`
`
`Reference ID: 3014812
`
` 5
`
`

`

`2.3.2.1 Renal impairment
`In its response to the deficiency regarding the need for a dedicated renal impairment FDA’s 11/30/09
`complete response letter, the applicant states that, given the restrictive indication, it is estimated that
`Ferriprox will be prescribed to a very small number of patients in the US. The applicant speculates
`that this represents approximately 25 to 100 of the patients with thalassemia, and about 600 patients
`with Sickle Cell Anemia in the US that would be eligible to be prescribed Ferriprox. The applicant
`further speculates that renal failure has been reported to occur in 0.6% of thalassemia patients and
`12% of patients with sickle cell disease; however it is unclear if this also includes mild or moderate
`impairment.
`
`
`
`
`
`
`
`
`
`
`The majority (about 95%) of deferiprone is excreted in the urine as the glucuronide with 5% excreted
`as the parent. The effect of renal impairment on deferiprone exposure was not assessed by the
`applicant. Given the concerns outlined in the previous FDA reviews (see the 3/27/08, 9/24/09, and
`10/22/09 clinical pharmacology reviews) that the potential for accumulation and toxicity of the
`glucuronide metabolite is unknown and the contribution of renal UGT1A6 to the metabolism of
`deferiprone, is unknown1 the reviewer finds the applicant’s proposal to conduct a dedicated renal
`impairment trial acceptable; however, it disagrees with the proposed design
` The applicant should conduct this pharmacokinetic trial in a
`population with mild to severe renal insufficiency and the number of patients enrolled in the trial
`should be sufficient to detect PK differences large enough to warrant dosage adjustments for each
`level of impairment. It is the applicant’s decision whether or not the trial subjects should also have
`Sickle Cell Anemia. This should be clearly communicated in the PMR.
`
`
`
`
`2.3.2.2 Hepatic impairment
`In its response to the deficiency regarding the need for a dedicated hepatic impairment in FDA’s
`11/30/09 complete response letter, the sponsor again reiterated that it believes that it believes
`Ferriprox will be prescribed to a very small number of patients in the US. The ap