CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`021825Orig1s000
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`SUMMARY REVIEW
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`

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`Summary Review for Regulatory Action
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`1
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`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Agency Proposed Indication(s)
`
`(electronic stamp)
`Ann T. Farrell, M.D., Acting Division Director
`Division Director Summary Review
`21825
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`ApoPharma, Inc.
`4/14/11
`10/14/11
`Ferriprox/deferiprone
`
`500 mg Tablet, immediate release
`for the treatment of patients with transfusional iron
`overload due to thalassemia syndromes when current
`chelation therapy is inadequate
`Accelerated Approval
`
`George Shashaty, M.D./Kathy Robie-Suh, M.D., Ph.D.
`Qing Xu, Ph.D./Mark Rothmann, Ph.D.
`Yash Chopra, PhD./Adebayo Laniyonu, Ph.D. and Haleh Saber,
`Ph.D.
`W. Michael Adams, Ph.D./Janice Brown, Ph.D./Sarah Pope-
`Miksinski, Ph.D. Tien-Mien Chen, Ph.D./Angelica Dorantes, Ph.D.
`N/A
`Joseph Grillo, Ph.D./Julie Bullock, Ph.D.
`James Dvorsky
`Anthony Orencia, M.D./Tejashari Purohit Sheth, M.D./Leslie Ball,
`M.D.
`Kathy Robie-Suh, M.D., Ph.D.
`Loretta Holmes, BSN, PharmD/ Irene Z. Chan, PharmD,
`BCPS/Carol Holquist, RPh
`
`
`
`Alyson Karesh, M.D./Hari C. Sachs, M.D./Lisa Mathis, M.D.
`Leyla Sahin, MD/ Karen Feibus, M.D./ Lisa Mathis, M.D.
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`
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`Action/Recommended Action for
`NME:
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`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
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`CMC Review/OBP Review
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`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`DSI
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`CDTL Reviews
`OSE/DMEPA
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`OSE/Epidemiology
`OSE/DRISK
`Other - statistical safety
`Other – Pediatrics
` Maternal Health Team
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`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
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`Reference ID: 3029069
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`Signatory Authority Review Template
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`1. Introduction
`Ferriprox is an oral formulation iron chelator. Apotex/ApoPharma Inc. initially
`submitted this New Drug Application (NDA) on December 21, 2006 under the
`Continuous Marketing Application program allowing for the submission of parts of the
`NDA as long as the parts consisted of Reviewable Units (RUs). The applicant
`proposed the application for “the treatment of iron overload in patients with excessive
`body iron stores due to chronic transfusion therapy.” The first RU was the PharmTox
`unit which was submitted on December 21, 2006. The subsequent RUs were
`Chemistry, Manufacturing and Control, and Clinical Pharmacology units (submitted on
`September 26, 2007). The last combined Clinical and Statistical unit was submitted
`on January 29, 2009 which triggered the review clock. However, the application could
`not be approved during the first cycle due to the need to clarify clinical data issues,
`clinical pharmacology issues, chemistry, manufacturing and control issues, and a
`failed facility inspection. The applicant was sent a complete response (CR) letter on
`November 30, 2009. Following receipt of the CR letter, the applicant met with the
`Agency and submitted several proposals to address the clinical concerns outlined in
`the CR letter. The applicant responded to the complete response letter on April 14,
`2011.
`
`Deferiprone has been approved since 1999 in Europe. From the European Medicines
`Agency website:
`
`The European Commission granted a marketing authorisation valid throughout the
`European Union for Ferriprox on 25 August 1999. The marketing authorisation holder
`is Apotex Europe B.V. The marketing authorisation is valid for an unlimited period.
`
`The following is the language is from the therapeutic indication section:
`
`Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia
`major when deferoxamine therapy is contraindicated or inadequate.
`
`
`2. Background
`Regulatory History
`ApoPharma’s April 14, 2011 submission is a complete response to the Agency’s
`November 30, 2009 CR letter for the original NDA for deferiprone. The indication has
`been narrowed to for the treatment of patients with transfusional iron overload when
`current chelation therapy is inadequate. The complete response addressed issues
`identified with the clinical data, clinical pharmacology data, chemistry, manufacturing
`and control, and a failed facility inspection. The major clinical issue concerned the
`pivotal trial. The clinical pharmacology issues included the lack of some needed
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`studies. The CMC issues were complicated and involved a failed site inspection,
`problems with a drug master file, and multiple process issues.
`
`In the original submission, the sponsor provided as primary support for efficacy, data
`from a single, controlled trial (Study LA-16-0102). In this study, 61 adult patients with
`thalassemia were randomized to therapy with either deferiprone or deferoxamine.
`The primary efficacy measure was cardiac magnetic resonance imaging (MRI) T2* to
`assess cardiac iron burden. Secondary endpoints included changes in serum ferritin
`and liver iron concentration. The initial NDA submission received a Complete
`Response (CR) due to a number of deficiencies including the following clinical
`concerns: insufficiency of evidence for efficacy from adequate and well-controlled
`investigations; lack of sufficient information to establish the clinical meaningfulness
`(e.g., improved survival, symptoms, functional status or other clinical benefits) of
`incremental changes in cardiac MRI T2*, a major efficacy parameter in the clinical
`studies of deferiprone; and lack of data to verify absence of a mortality disadvantage
`when deferiprone is used over a long period of time. Recommendations to correct
`these and other deficiencies were provided to the sponsor in the CR letter.
`
`Now the sponsor has submitted data from a prospective, planned multi-institutional
`study (LA36-0310) entitled “Analysis of Data from Clinical Studies of Ferriprox to
`Evaluate its Efficacy in Patients with Iron Overload for Whom Previous Chelation
`Therapy Has Been Inadequate” which consists of an analysis of data across multiple
`studies. The application also includes data from other clinical trials, some performed
`by the sponsor and others performed by independent investigators, as well as a
`number of publications related to the use of deferiprone.
`
`Thalassemia
`Patients with thalassemia have an inherited disorder characterized by defective
`synthesis of subunits of hemoglobin (Hgb) with resulting decreased Hgb production
`and reduced red blood cell survival. The clinical manifestations of the disorder can be
`diverse and vary from an absence of symptoms to profound fatal anemias in utero or
`in early childhood. Treatment for the more severe forms of the disease includes red
`blood cell transfusions, iron chelation therapy and allogeneic bone marrow
`transplantation.
`
`Patients with thalassemia also have increased iron absorption in the gastrointestinal
`tract. One basic clinical problem for patients with thalassemia syndromes requiring
`transfusions is that these patients develop iron overload because of an inability to
`remove the excess iron. The excess iron accumulates as a result of transfusions and
`the increased gastrointestinal absorption. Since the body cannot get rid of the excess
`iron, the iron deposits in tissues such as the liver and heart and endocrine glands
`disrupting normal function. Excessive accumulation in the heart can lead to cardiac
`failure and arrhythmias leading to death.
`
`The treatment for excess iron is chelation therapy. An iron chelator binds to iron in the
`blood or organs of deposition with the subsequent excretion of the bound complex in
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`the urine or feces. The first drug approved for iron chelation, Desferal
`(deferoxamine), was approved for use in 1968. However, not all patients can tolerate
`deferoxamine because of side effects and difficulties with its administration (the need
`for subcutaneous or intramuscular infusion with the use of a pump over 10-12 hours 5
`of 7 days each week). In 2005, Exjade (deferasirox), an orally administered agent,
`was granted accelerated approval for use as an iron chelator.
`
`Consistent with the Guidance for Industry on Available Therapy, only deferoxamine
`can be considered available therapy.
`
`
`3. CMC/Device
`Drs. Adams, Brown, and Pope-Miksinski reviewed this NDA. From the primary CMC
`review:
`
`From a CMC standpoint, this application is recommended for approval pending the
`receipt of an overall acceptable recommendation from the Office of Compliance. The
`submission is complete and all other CMC review issues have been resolved.
`
`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).
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`Dissolution criteria are acceptable.
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`The Office of Compliance recommendation is acceptable.
`4. Nonclinical Pharmacology/Toxicology
`There are no issues which would preclude approval of deferiprone based on the
`pharmacology reviews. From the current Pharmacology/Toxicology Team Leader
`review:
`
`Nonclinical studies needed in support of the proposed indication have been
`conducted and reviewed by the Agency. Deferiprone is considered genotoxic,
`carcinogenic, and teratogenic. It is recommended that this drug be used in a serious
`disease, when other therapies are considered inadequate. Women of reproductive
`potential should be advised to avoid pregnancy when taking Ferriprox. Based on the
`Indications and Usage of the label, Ferriprox is indicated for the treatment of patients
`with transfusional iron overload due to thalassemia syndromes when current chelation
`therapy is inadequate. There are no nonclinical issues at this time to preclude
`approval of Ferriprox (deferiprone) for the proposed indication considering the life-
`threatening nature of the disease and lack of adequate chelation therapy.
`
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`Reference ID: 3029069
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`5. Clinical Pharmacology/Biopharmaceutics
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`There are no issues which would preclude approval of deferiprone based on the
`clinical pharmacology reviews. However, the clinical pharmacology review team
`recommends the following post-marketing requirements and commitment from their
`second cycle review:
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`Requirements/Commitment
`
`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.
`
`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.
`
`3. Conduct a TQT assessment
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`4. Conduct in vitro studies to determine the effect 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.
`
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`6. Clinical Microbiology
`Not applicable
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`7. Clinical/Statistical-Efficacy
`I have read the first cycle clinical reviews from Drs. Rieves, Robie-Suh, and Shashaty.
`The following text from Dr. Robie-Suh nicely summarizes the clinical findings during
`the first cycle.
`
`For the initial NDA submission the sponsor provided a single randomized controlled
`trial (Study LA16-0102) comparing the use of deferiprone versus the use of
`deferoxamine in removing excess cardiac iron in subjects with thalassemia major.
`The study used a primary efficacy endpoint that employed magnetic resonance
`imaging of the heart (cardiac MRI) with measurement of a parameter termed T2* (T2
`star) to evaluate extent of iron overload and effectiveness of chelation therapy. The
`primary efficacy analysis of change in cardiac MRI T2* from baseline to 12 months
`showed a 3.9 msec increase in cardiac MRI T2* in the deferiprone treatment group
`(N=29) and 2.3 msec increase in the deferoxamine treatment group (N=32). The
`study did not find a significant correlation between change in cardiac MRI T2* and
`measures of cardiac function and there were no differences between treatments in
`change in liver iron concentration (LIC). A retrospective supportive study, LA 12-
`9907, evaluating occurrence of cardiac disease also was submitted. Consultations
`were obtained from the Center for Devices and Radiological Health (CDRH) (S.S.
`Rajan, Ph.D.) and the Division of Medical Imaging and Hematology (Dr. M. Fedowitz,
`4/15/2009) regarding the use of MRI for imaging cardiac iron and from the Division of
`Cardiovascular and Renal Products (DCRP) (Dr. S. Targum, 4/20/2009) regarding
`significance of measured changes in cardiac function parameters in the LA16-0102
`study and these consultative reviews were considered in the clinical review of the
`application. Safety concerns for the drug were agranulocytosis (which occurred in
`1.7% of patients in the deferiprone clinical studies), hepatic toxicity, gastrointestinal
`adverse reactions, arthropathy, cardiac (a case of torsades de pointes), neurological,
`and miscellaneous reactions. Also, (based on non-clinical studies) deferiprone is
`genotoxic and teratogenic.
`
`Due to uncertainty about the clinical meaning of the observed millimeters of change in
`T2* the sponsor received a Complete Response letter and the Agency recommended
`a prospective randomized trial. The sponsor decided to pursue an indication for those
`patients in whom current available chelation therapy was inadequate. The sponsor
`prospectively developed a protocol and statistical analysis plan to identify patients
`from their extensive database of clinical trials who had an inadequate response to
`prior iron chelation. The sponsor utilized an independent selection committee to
`identify the patients meeting the criteria for enrollment in the prospective trial (LA36-
`0310). Nearly all the patients enrolled in LA36-0310 had thalassemia.
`
`From Dr. Shashaty’s second cycle review:
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`Study LA36-0310 assessed the change in serum ferritin from baseline to the end of
`one year’s treatment with deferiprone in patients (almost all with thalassemia) with
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`transfusion related hemosiderosis who appeared to be unsuccessfully treated with
`other chelators (almost exclusively deferoxamine). Patients were considered to be
`unsuccessfully chelated if, despite the use of a chelator, they continued to have a
`serum ferritin in excess of 2,500 μg/L prior to the initiation of deferiprone therapy.
`Secondary endpoints analyzed included changes in cardiac magnetic resonance
`imaging (MRI) T2* in patients with a baseline MRI T2* of less than 20 msec, and
`changes in liver iron concentration (LIC) in patients with a baseline LIC of greater than
`7 mg Fe/g dry weight (dw). These latter values were also considered to be consistent
`with unsuccessful treatment with an iron chelator.
`
`The patients were selected for inclusion in the Study LA36-0310 by an independent
`committee based on a review of all patients who had been previously enrolled in
`sponsor supported studies, almost all of which had been submitted to the original
`NDA. The committee selected patients for possible inclusion based on a pre-specified
`protocol. Inclusion required that the patient must have been receiving iron chelating
`therapy and that, despite such therapy, continued to have one or more measurements
`indicating a persistently elevated body iron burden as described above. All patients
`were screened from data provided by the sponsor and available in its database from
`previous trials. The independent committee had no knowledge of the outcomes of
`deferiprone treatment. After receiving the list of potential enrollees for the study from
`the independent committee, the sponsor’s statistics facility examined the same
`database for patients who had had at least one post-baseline measurement of any of
`the primary or secondary endpoint assessments within one year of commencing
`treatment with deferiprone. These patients were then enrolled and analyzed for the
`primary and secondary endpoints. Success was defined as a decrease in serum
`ferritin of 20% or more, a decrease in LIC of 20% or more or an increase in MRI T2*
`of 20% or more.
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`Seven hundred forty seven (747) subjects were evaluated by the independent
`committee for possible enrollment. Of these, 264 met the inclusion criteria for serum
`ferritin, 117 for LIC and 39 for MRI T2* based on a review of the sponsor’s database.
`The overall success rate for the serum ferritin endpoint was 52% (C.I.,45%, 58%),
`while those for the LIC and MRI T2* were 42% (C.I.,33%, 51%) and 62% (C.I., 45%,
`77%), respectively.
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`From Dr. Robie-Suh’s review:
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`The sponsor’s primary efficacy analysis is shown below:
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`A total of 136 (52%) of patients had a 20% or greater decrease in serum ferritin from
`baseline to end of study. Mean serum ferritin at study entry was 4416 μg/L. The
`mean change in serum ferritin in the study was a decrease of 962 μg/L and ranged
`from a decrease of 10385 μg/L to an increase of 10002 μg/L. Success rates for
`patients from the various studies ranged from 26% in Study LA12-9907 (which
`contributed 19 patients) to 100% in Study LA15-0002 (which contributed 18 patients).
`Based on the sponsor’s definition of treatment success as 20% of patients achieving a
`20% or greater decrease in serum ferritin, treatment success for the study was
`declared for the primary efficacy endpoint.
`
`Because some patients (about 11%) had received deferoxamine as well as
`deferiprone during the deferiprone treatment period of the study, an analysis was
`performed excluding these patients. The results of this analysis are shown below.
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`
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`In this analysis, 118 of 236 patients (50%) achieved sponsor-defined treatment
`success. Additionally, because questions regarding data quality for one investigator
`site (Dr. Nancy Olivieri, Toronto, Canada) were raised regarding one of the studies
`(LA-01) [see the 11/30/09 CR letter], an analysis was performed further excluding all
`data from that study and all data from the other study (LA-03) to which that
`investigator had contributed. For that analysis 109 of 220 (50%) patients achieved
`treatment success.
`Finally, because the patients in the pediatric study (LA30-0307) were treated with a
`deferiprone solution that is not the subject of this NDA, an additional analysis was
`conducting excluding those patients as well as patients who had received
`combination/concurrent therapy. In that analysis 99/197 (50%) of patients achieved
`treatment success for the primary efficacy endpoint.
`Results of the secondary efficacy analyses for change in liver iron concentration (LIC)
`and change in cardiac MRI T2* are shown in the following tables.
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`The sponsor-defined success rate was 42% for LIC and 62% for cardiac MRI T2*.
`The mean change in LIC was a decrease of 1.7 mg Fe/g dry weight and ranged from
`a decrease of 32.6 mg Fe/g dry weight to an increase of 14.5 mg Fe/g dry weight.
`The mean change in Cardiac MRI T2* was an increase of 3.3 msec and ranged from
`a decrease of 2 msec to an increase of 12.7 msec.
`
`It should be noted that while the populations for the primary and secondary efficacy
`analyses overlapped, the populations for the secondary efficacy analyses were not
`subsets of the primary efficacy population for change in serum ferritin. Among the
`patients enrolled in the study, 228 were evaluable for serum ferritin only, 68 were
`evaluable for LIC only, and 9 were evaluable for cardiac MRI T2* only. Thirty-one
`(31) were evaluable for both serum ferritin and LIC, 12 for both serum ferritin and
`cardiac MRI T2* and 25 for both LIC and cardiac MRI T2*. Only 7 patients were
`included in the analysis populations for all three of the efficacy endpoints.
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` I
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` have read the clinical and statistical reviews regarding the demonstrations of efficacy
`for the indication.
`
`Other sponsors have proposed prospectively planned pooling of trial data when
`seeking approval for hematologic indications (Mylotarg and Angoimax).
`
`LA36-0310 enrolled patients with iron overload due to thalassemia whose current
`chelation therapy was inadequate. In the absence of effective therapy for these
`patients, the serum ferritin, liver iron concentration, and cardiac iron concentration
`would be expected to worsen not improve as excess iron would continue to
`accumulate and cannot be removed from the body. LA36-0310 is a baseline-
`controlled trial, where the patient’s baseline result is compared to their result after
`being on therapy, and is an externally controlled trial [historical controlled trial (21
`Code of Federal Regulations (CFR) 314.126 (b) 2(v)]. From 21 CFR 314.126 (b) (2):
`An adequate and well-controlled study has the following characteristics:
`(1) There is a clear statement of the objectives of the investigation and a summary
`of the proposed or actual methods of analysis in the protocol for the study and in
`the report of its results. In addition, the protocol should contain a description of the
`proposed methods of analysis, and the study report should contain a description of
`the methods of analysis ultimately used. If the protocol does not contain a
`description of the proposed methods of analysis, the study report should describe
`how the methods used were selected.
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`(2) The study uses a design that permits a valid comparison with a control to
`provide a quantitative assessment of drug effect. The protocol for the study and
`report of results should describe the study design precisely; for example, duration of
`treatment periods, whether treatments are parallel, sequential, or crossover, and
`whether the sample size is predetermined or based upon some interim analysis.
`Generally, the following types of control are recognized: …
`
`(v) Historical control. The results of treatment with the test drug are compared with
`experience historically derived from the adequately documented natural history of
`the disease or condition, or from the results of active treatment, in comparable
`patients or populations. Because historical control populations usually cannot be as
`well assessed with respect to pertinent variables as can concurrent control
`populations, historical control designs are usually reserved for special
`circumstances. Examples include studies of diseases with high and predictable
`mortality (for example, certain malignancies) and studies in which the effect of the
`drug is self-evident (general anesthetics, drug metabolism).
`
`
`LA36-0310’s use of an external control allows comparison to a control and provides a
`quantitative assessment of drug effect. The use of a prospectively planned protocol
`and independent selection committee allowed an adequate selection of patients for
`the trial and minimized the possibility of bias. The use of a prospectively planned
`statistical analysis plan allowed an adequate assessment of drug effect. Thus this trial
`can be considered an adequate and well-controlled trial under the CFR and ICH E10
`guidance for regulatory purposes.
`
`The choice of the primary endpoint, 20% reduction in baseline serum ferritin over a
`year, was discussed at the Oncologic Drugs Advisory Committee meeting. The
`sponsor had proposed the 20% reduction based on their outside expert consultants.
`In the absence of effective therapy, the serum ferritin would not be expected to be
`reduced by 20% as excess iron would continue to accumulate and cannot be
`removed from the body. In the absence of effective therapy, the serum ferritin would
`be expected to increase.
`
`The Accelerated Approval regulations (21 CFR 314.500 and 21 CR 601) apply to
`certain new drug products that have been studied for their safety and effectiveness in
`treating serious or life-threatening illnesses and that provide meaningful therapeutic
`benefit to patients over existing treatments (e.g., ability to treat patients unresponsive
`to, or intolerant of, available therapy, or improved patient response over available
`therapy). LA36-0310 enrolled patients with transfusional iron overload due to
`thalassemia who were unresponsive to available therapy (deferoxamine) and
`demonstrated an effect on the basis of an effect on a clinical endpoint other than
`survival or irreversible morbidity and thus meets criteria for accelerated approval.
`
`One issue that has been raised in the scientific literature with this product is whether
`there is loss of effectiveness over time. Effectiveness can be monitored by routine
`clinical assessment of the patient’s underlying condition (blood, liver and cardiac
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`function). If this loss occurs, other therapy including experimental should be
`considered for an individual patient.
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`8. Safety
`During the investigational and marketing of this product two prominent safety issues
`have been discussed. One is hepatic fibrosis and the other is agranulocytosis.
`
`The scientific issue of progression or development of hepatic fibrosis with deferiprone
`use was first raised in a New England Journal of Medicine article in 1998. However,
`this finding has not been consistently observed in other published studies. Review of
`scientific literature reveals that hepatic fibrosis can be observed in the setting of
`thalassemia with iron overload and/or hepatitis C without use of deferiprone so
`determining causality in this patient population is difficult. Post-European Union
`approval, few cases of hepatoxicity have been reported.
`
`Agranulocytosis was seen in approximately 1.7% of patients treated with deferiprone.
`Thirteen patients have died as a result of sepsis associated with agranulocytosis. The
`development of agranulocytosis appears to be idiosyndiocratic. The labeling will
`discuss the recommendations for monitoring and recommendations for what should
`occur if a patient develops neutropenia. The sponsor will conduct a registry in an
`attempt to better characterize those patients at risk.
`
`Other side effects include gastrointestinal adverse reactions (e.g., nausea, vomiting),
`chromaturia, arthropathy, and thrombocytopenia. One case of Torsades-de-Pointes
`was reported.
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` concur with the conclusions of the clinical review team regarding the safety.
`
`Any post-marketing concerns about long term toxicity such as hepatic fibrosis or any
`other safety issue can be addressed through mechanisms such as labeling, a registry
`or post-approval study.
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`9. Advisory Committee Meeting
`This product was discussed at an Oncologic Drugs Advisory Committee meeting on
`September 14, 2011. The Committee voted 10 (yes) to 2 (no) that the available
`clinical data demonstrate a favorable risk-benefit profile for deferiprone.
`10.
`Pediatrics
`Although the sponsor has submitted some data from a trial conducted in pediatric
`patients with thalassemia, the sponsor does not have a pediatric-friendly formulation
`proposed for the US market. The sponsor does market a liquid formulation in Europe.
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`The sponsor has agreed to meet with the Agency to discuss the development of a
`pediatric formulation.
`11.
`Other Relevant Regulatory Issues
`Maternal Health Team and Pediatrics were consulted and provided labeling
`recommendations which were incorporated into labeling.
`
`
`Office of Surveillance and Epidemiology was consulted including DMEPA who
`provided labeling input.
`
`Division of Scientific Investigation (DSI)
`In January 2009, Apotex/ApoPharma initially submitted a New Drug Application for
`deferiprone as a first-line iron chelation therapy for approval. The clinical support for
`this application was based primarily on the main study, Study LA16-0102 which was a
`multicenter, randomized, open label, active control clinical trial comparing the use of
`deferiprone versus the use of deferoxamine. This study was conducted from 2003 to
`2004. The clinical review team requested a Division of Scientific Investigation
`inspection of the LA16-0102 study as the main study as is typically done for new drug
`applications. The clinical review team also requested a “for cause” inspection of a
`clinical site from another study, LA-01, due to concerns about adverse event reporting
`particularly for hepatic toxicity. LA-01 was a tri-center, randomized, parallel-group trial
`which evaluated iron chelation by liver iron concentration. One group received
`deferoxamine and the other group received deferiprone. LA-01 was terminated prior
`to completion in 1996. There were other clinical trials submitted in the NDA for
`deferiprone.
`
`The DSI inspection of LA16-0102, the main study did not reveal any significant issues
`and the data were considered reliable for regulatory use. Inspection of the sponsor in
`conjunction with LA-16-0102 also did not reveal significant issues related to sponsor
`conduct. The DSI inspection of LA-01 did not allow a definitive conclusion because of
`missing source documentation.
`
`Trials, where source documentation are lacking, are problematic for the Agency to
`use because these data are considered incomplete. Since LA-01 was not the main
`study for a regulatory decision, since source data was not able to be found for all
`enrolled, since supportive data could be provided from the remaining other clinical
`trials, and since concerns regarding hepatic fibrosis could be addressed in other
`ways; we determined that the data from LA-01 were not crucial for efficacy or safety
`considerations.
`
`Excluding data from the site where source documentation were not available did not
`change the overall conclusions regarding safety and effectiveness.
`
`
`
`Reference ID: 3029069
`
`

`

`
`
`13
`
`In the resubmission, the sponsor was also asked to address inspectional concerns in
`the 2009 complete response letter. The sponsor’s response addressed the concerns.
`No additional concerns were raised after review of that data.
`
`There are no other unresolved relevant regulatory issues.
`
`
`
`Labeling
`12.
`The labeling was reviewed by all disciplines and consultant staff.
`13.
`Decision/Action/Risk Benefit Assessment
`
`• Recommended regulatory action
`
`Accelerated Approval
`
` I
`
` concur with the recommendation of the review staff that deferiprone should be
`approved and the indication should be restricted to those who were studied in
`the prospective planned analysis. Almost 95% of the enrolled patients had
`thalassemia. Few patients with diseases other than β-thalassemia syndromes
`such as sickle cell disease or myelodysplastic syndrome were enrolled in the
`main trial (LA36-0310). Therefore with such limited numbers of patients with
`other underlying diseases, a concrete assessment of efficacy and safety
`cannot be made for those patients. I concur with the findings of the statistical
`review team that the data are limited so this application at best supports
`accelerated approval. This approval will be subje