`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`021825Orig1s000
`
`Ferriprox® 500 mg Tablet
`
`Trade Name:
`
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`deferiprone
`
`ApoPharma, Inc.
`
`October 14, 2011
`
` Treatment of patients with transfusional iron overload
`due to thalassemia syndromes when current chelation
`therapy is inadequate
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`021825Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`X
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`021825Orig1s000
`
`APPROVAL LETTER
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`ACCELERATED APPROVAL
`
`NDA 021825
`
`
`Cato Research
`Attention: Lynda Sutton
`U.S. Agent for ApoPharma, Inc
`4364 South Alston Avenue
`Durham, NC 27713-2220
`
`
`Dear Ms. Sutton:
`
`Please refer to your New Drug Application (NDA) dated January 29, 2009, received
`January 30, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Ferriprox®
` (deferiprone) 500 mg Tablet.
`
`We acknowledge receipt of your amendments dated February 25; April 14, 29; May 6 and 10;
`June 7, 14, and 22; July 11, 25, and 27; August 12, 19, 22, and 26; September 6, 16, 22, 26, and
`29; October 3, 5, 7, 13, and 14, 2011.
`
`The April 14, 2011 submission constituted a complete response to our November 30, 2009 action
`letter.
`
`This new drug application provides for the use of Ferriprox®
` (deferiprone) Tablet for the
`treatment of patients with transfusional iron overload due to thalassemia syndromes when current
`chelation therapy is inadequate.
`
`We have completed our review of this application, as amended. It is approved under the
`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon labeling text and required patient
`labeling. Marketing of this drug product and related activities must adhere to the substance and
`procedures of the referenced accelerated approval regulations.
`
`Based on the stability data provided in your application, the drug product is granted a 24-month
`expiry when stored at USP controlled room temperature 20-25ºC (68-77ºF); excursions permitted
`to 15-30ºC (59-86ºF).
`
`Reference ID: 3029317
`
`

`

`NDA 021825
`Page 2
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling text for the package insert, and Medication
`Guide). Information on submitting SPL files using eLIST may be found in the guidance for
`industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`IMMEDIATE CONTAINER LABELS
`
`Submit the final printed container label that is identical to the immediate container label
`submitted on October 13, 2011 as soon as they are available, but no more than 30 days after they
`are printed. Please submit these labels electronically according to the guidance for industry titled
`“Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (June 2008).”
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 021825.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled clinical trials to verify and describe clinical benefit. We remind
`you of your postmarketing requirement specified in your submission dated October 13, 2011.
`
`You are required to conduct such trials with due diligence. If postmarketing trials fail to verify
`that clinical benefit is conferred by deferiprone, or are not conducted with due diligence, we
`may, following a hearing in accordance with 21 CFR 314.530(b), withdraw or modify approval.
`
`Granting of these approvals are contingent upon completion of clinical trials to verify the clinical
`benefit of deferiprone. These postmarketing trials are subject to the reporting requirements of 21
`CFR 314.81.
`
`This requirement, along with required completion dates, is listed below.
`
`
`
`Reference ID: 3029317
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`NDA 021825
`Page 3
`
`
`PMR 1828-1 Conduct a trial to determine the efficacy and safety of the use of deferiprone to
`treat iron overload in patients with sickle cell disease and transfusional
`hemosiderosis who have not been adequately treated with available chelating
`agents. Submit the protocol for review and concurrence prior to commencing.
`The trial will enroll a sufficient number of patients with sickle cell disease as
`described above, to provide sufficient evidence to assess the efficacy and safety in
`the sickle cell disease population described. The trial may enroll patients with
`other conditions who have developed transfusional iron overload. The trial will
`stratify for hematologic diagnosis for the randomization. The primary and
`secondary endpoints will measure changes in cardiac iron concentration and liver
`iron concentration.
`
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
` February 2012
` January 2016
` July 2016
`
`
`
`
`
`
`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
`submissions relating to this postmarketing requirement must be clearly designated "Subpart H
`Postmarketing Requirement(s).”
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess known serious risks for
`agranulocytosis.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`Reference ID: 3029317
`
`

`

`NDA 021825
`Page 4
`
`
`PMR 1828-2 Establish a registry in order to perform an enhanced pharmacovigilance study of
`agranulocytosis. Submit a protocol to establish the registry and describe
`procedures for this enhanced pharmacovigilance prior to commencing the study.
`Procedures should include: Creation of marketing materials to inform and
`encourage clinicians to report agranulocytosis events to the sponsor; monitoring
`of all reported cases and active follow-up to characterize the demographics, recent
`prior blood counts, concomitant medications, co-existing conditions, duration of
`drug exposure prior to onset, outcomes of the event, and other factors that may
`help to characterize the agranulocytosis event. Sponsor also will institute
`procedures to obtain blood samples from patients with reported cases of
`agranulocytosis to store for later analysis of possible genetic underlying factors
`that may predict the risk of agranulocytosis. Submit interim reports annually
`describing the above results.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Final Protocol Submission:
`Annual Interim Report #1:
`Annual Interim Report #2:
`Annual Interim Report #3:
`Annual Interim Report #4:
`Annual Interim Report #5:
`Annual Interim Report #6:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`
`
`
`
`
`
`
`
`April 2012
`April 2013
`April 2014
`April 2015
`April 2016
`April 2017
`April 2018
`October 2018
`April 2019
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify unexpected serious risks of QT prolongation, alterations in
`metabolism and drug effect related to hepatic or renal impairment.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`PMR 1828-3 Conduct a clinical trial per ICH E14 to assess the potential for deferiprone to
`
`
`prolong the QT interval. Submit the protocol for IRT review and concurrence
`
`
`prior to commencing.
`
`
`
`
`
`
`January 2012
`July 2013
`December 2013
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`PMR 1828-4 Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-
`
`
`glucuronide metabolite in subjects with hepatic impairment. This pharmacokinetic
`
`
`trial should be conducted in a population with mild to severe hepatic insufficiency
`
`
`and the number of patients enrolled in the trial should be sufficient to detect PK
`
`
`differences. The subjects enrolled in this trial should have demographics that are
`
`
`representative of the indicated population (e.g., age, weight, gender, race). Submit
`
`
`the protocol for review and concurrence prior to commencing.
`
`Reference ID: 3029317
`
`

`

`NDA 021825
`Page 5
`
`
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`September 2012
`February 2014
`July 2014
`
`
`PMR 1828-5 Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-
`
`
`glucuronide metabolite in subjects with renal impairment. This pharmacokinetic
`
`
`trial should be conducted 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. The subjects enrolled in this trial should have demographics that
`
`
`represent the indicated population (e.g., age, weight, gender, race) to the extent
`
`
`possible. Submit the protocol for review and concurrence prior to commencing.
`
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`September 2012
`February 2014
`July 2014
`
`
`
`
`
`
`
`
`
`
`
`Submit the protocols to your IND 045724, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`PMC 1828-6 Conduct in vitro studies to determine the affect of moderate to strong UDP
`glucuronosyltransferase (UGT) inhibition and moderate to strong UGT induction
`
`
`
`Reference ID: 3029317
`
`

`

`
`The timetable you submitted on October 13, 2011, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
`
`
`
`
`January 2012
`July 2013
`October 2013
`
`NDA 021825
`Page 6
`
`
`
`on the metabolism of deferiprone. The results of the in vitro evaluations will
`determine the need for additional in vivo drug interaction trials.
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`PMC 1828-7 To submit results of the “Tanner” trial comparing the effects of deferoxamine
`
`
`alone to the combination of deferoxamine plus Deferiprone in patients with
`
`
`thalassemia major, reported in the journal “Circulation” in 2007.
`
`
`Submit the clinical trial report and complete, raw datasets and analysis
`
`
`programs.
`
`The timetable you submitted on October 13, 2011, states that you will conduct this trial
`according to the following schedule:
`
`
`
`
`
`Submit clinical protocols to your IND 045724 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all study final reports to this NDA. In
`addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status
`summary of each commitment in your annual report to this NDA. The status summary should
`include expected summary completion and final report submission dates, any changes in plans
`since the last annual report, and, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`PROMOTIONAL MATERIALS
`
`Immediately submit all promotional materials (both promotional labeling and advertisements) to
`be used within the first 120 days after approval. Send one copy to the Division of Hematology
`Products and two copies of the promotional materials and the package insert directly to:
`
`
`
`
`
`
`
`
`
`
`
`
`March 2012
`July 2012
`October 2012
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Reference ID: 3029317
`
`

`

`NDA 021825
`Page 7
`
`
`In addition, as required by 21 CFR 314.550, submit all subsequent promotional materials at least
`30 days before the intended time of initial distribution of labeling or initial publication of the
`advertisement. Send two copies of the promotional materials and the package insert to the
`address above.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with the reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Mara Miller, Regulatory Project Manager, at (301) 796-0683.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Office Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`Medication Guide
`Container Labeling
`
`Reference ID: 3029317
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`10/14/2011
`
`Reference ID: 3029317
`
`