CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`021825Orig1s000
`
`MEDICAL REVIEW(S)
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` E M O R A N D U M
`
` M
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` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
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`
`
`Date:
`
`From:
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`
`
`Subject:
`
`
`September 20, 2011
`
`Kathy M. Robie-Suh, M.D., Ph.D.
`Medical Team Leader, Hematology
`Division of Hematology Products
`Office of Hematology and Oncology Products
`
`Medical Team Leader Secondary Clinical Review
`Ferriprox (deferiprone), resubmission received 4/14/2011; amended study
`report received 7/25/2011
`
`
`
`NDA 21-825
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`
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`
`
`To:
`
`
`Ferriprox (deferiprone) is an orally active iron chelator developed for use in treating iron
`overload. This is the second review cycle for this product. The NDA was initially
`submitted 1/29/2009 for the indication, “treatment of iron overload in patients with
`transfusion-dependent thalassemia and for treatment in patients with other transfusion-
`dependent anemias for whom the use of other iron chelators has been considered
`inappropriate”. A complete response (CR) letter was issued on 11/30/2009. The current
`resubmission (received 4/14/2011) seeks approval of deferiprone for the indication: “for
`the treatment of patients with transfusional iron overload when current chelation therapy
`is inadequate.” The proposed dose is Ferriprox is 25 to 33 mg/kg body weight, orally,
`three times a day for a total daily dose of 75 to
`mg/kg body weight.
`
`Background
`Patients with certain inherited anemias (importantly β-thalassemia and increasingly sickle
`cell disease in the U.S.) require frequent transfusion of red blood cells beginning at a
`young age to offset anemia that occurs because of inability to manufacture normal
`hemoglobin. Normal dietary absorption is about 1 mg daily which maintains a total body
`iron of approximately 3 to 5 grams in adults. One unit of packed red blood cells contains
`about 200 mg of iron. Because the body has no physiologic mechanism to excrete excess
`iron, repeated red blood cell transfusions over time result in massive iron overload. The
`excess iron becomes deposited in tissues and causes tissue damage due to iron-catalyzed
`peroxidation of membrane lipids and leads to morbidity and often eventually mortality,
`mainly due to cardiac damage. The liver and endocrine organs also are notably affected.
`Assessment of liver iron content (LIC) has been the generally accepted standard for
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`Reference ID: 3021195
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`(b) (4)
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`NDA 21-825
`Page 2 of 13
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`assessment of body iron burden; however, serum ferritin, a nonspecific parameter, is
`commonly followed clinically.
`
`Currently available treatment options for management of iron overload due to
`transfusions include Desferal (deferoxamine mesylate), an injectable iron chelator
`approved in 1968 and Exjade (deferasirox), an orally active iron chelator approved in
`2005.
`
`Deferiprone binds iron in a 3:1 complex which is then excreted in the urine. The drug
`was first administered to humans in 1987, was approved in the European Union in 1999
`and currently is approved in 61 countries, mostly for the indication of the treatment of
`iron overload in patients with thalassemia major when deferoxamine therapy is
`contraindicated or inadequate. The U.S. IND for deferiprone (IND 45724) was opened
`7/15/1994. Orphan Drug designation was granted on 12/12/2001 and Fast track
`designation was granted 1/26/2004. The fact that the drug was granted Fast Track
`designation reflects the serious nature of the condition for which the drug is intended to
`be used and the fact that at the time the designation was granted the only therapeutic
`option for these patients was deferoxamine which must be administered via continuous
`subcutaneous infusion over many hours each day and which, therefore, is difficult for
`many patients to comply with and/or tolerate.
`
`For detailed background please refer to Dr. George Shashaty’s Clinical Review
`(10/19/2009) and my Cross-Disciplinary Team Leader (CDTL) review (11/25/2009;
`addendum 12/31/2009) of the first cycle NDA submission.
`
`Complete Response (CR) Letter
`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., dated 7/26/2009 [signed hard copy
`11/4/2009]) and the Division of Medical Imaging and Hematology (Dr. M. Fedowitz,
`4/15/2009 [signed 4/28/2009]) 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
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`Reference ID: 3021195
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`NDA 21-825
`Page 3 of 13
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`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.
`
`Clinical deficiencies listed in the 11/30/2009 CR letter and information needed to address
`the concerns were as follows:
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`Reference ID: 3021195
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`NDA 21-825
`Page 4 of 13
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`NDA 21-825
`Page 5 of 13
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`Reference ID: 3021195
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`NDA 21-825
`Page 6 of 13
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`Importantly, an additional prospective, randomized, controlled clinical study was
`recommended. Following issuance of the CR letter, further discussions with the
`applicant were held. Those discussions concluded that there still was an unmet medical
`need for iron chelating agents. It was considered that possibly data for deferiprone could
`support an application for 2nd or 3rd line use of deferiprone for patients in whom the
`existing therapies are inadequate. To support use in this more restricted population the
`sponsor reanalyzed data from the completed studies examining change in serum ferritin
`levels in patients identified as being inadequately treated with other iron chelators. The
`results of this reanalysis of the data are presented in the current resubmission as Study
`LA36-0310. Additionally, updated safety information has been submitted. A revised
`study report for LA36-0310 was submitted 7/25/2011 to incorporate patients from Study
`LA11. These current submissions have been reviewed in detail by Dr. George Shashaty
`(see review dated 9/16/2011).
`
`Study LA36-0310
`Study LA36-0310 was a retrospective selection of a subset of patients from pooled
`previously conducted studies. All studies except for a single arm study (LA30-0307) of a
`deferiprone solution in pediatric patients with thalassemia and iron overload had been
`submitted in the initial NDA. The LA36-0310 study population consisted of patients
`with transfusional iron overload who were inadequately responsive to previous iron
`chelation treatment defined as having one or more of the following: serum ferritin >2500
`μg/L, cardiac MRI T2* value <20 msec, and/or LIC >7 mg/g dry weight. Selected
`patients must have received chelation therapy prior to deferiprone. In addition, to be
`enrolled in the study for the primary efficacy analysis (change in serum ferritin), patients
`must have at least one serum ferritin value available for baseline prior to initiation of
`deferiprone therapy and at least one follow-up ferritin value within one year after starting
`deferiprone. (The 1 year value was the last available value up to 15 months after starting
`deferiprone). An Independent Committee was employed for selecting eligible patients.
`For data analysis the primary efficacy endpoint: was change in serum ferritin from
`baseline to end of study (up to 1 year of deferiprone therapy). Secondary efficacy
`endpoints included change in LIC and cardiac MRI T2* from baseline to end of study (up
`to 1 year of deferiprone therapy). Treatment success for change in serum ferritin was
`defined by the sponsor as >20% decline in serum ferritin from baseline within 1 year of
`starting deferiprone therapy. For the secondary efficacy endpoints, the sponsor defined
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`Reference ID: 3021195
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`NDA 21-825
`Page 7 of 13
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`treatment success similarly with cardiac MRI T2* treatment success defined as >20%
`increase in cardiac MRI T2* and in LIC treatment success defined as >20% decline in
`LIC.
`Results: A total of 264 patients were eligible for the primary efficacy analysis. These
`patients were selected from 12 clinical studies, 11 of which had been included in the
`initial submission and 1 more recent study of deferiprone in pediatric patients with
`thalassemia. Four studies--LA-02/06, LA-04/06B, LA30-0307 and the Borgna-Pignatti
`study [Borgna-Pignatti C et al., Blood 2006; 107:3733-3737]-- accounted for 184 (70%)
`of the enrolled patients. LA-02/06 was a single arm safety study in patients with
`transfusion-dependent β-thalassemia and evaluated treatment with deferiprone for a
`planned total of 4 years (1 year in LA-02 and 3 years in LA-06) LA-04/06B was a
`compassionate use study in patients with thalassemia or other chronic iron overloaded
`conditions requiring iron chelation and for whom deferoxamine was inadequate or
`contraindicated. Treatment compliance was not assessed. LA30-0307 was a single arm
`study in pediatric patients with thalassemia and transfusional iron overload. It used a
`deferiprone solution administered orally for 24 weeks. Treatment compliance was said to
`“very high” based on drug exposure tables. Borgna-Pignatti et al was a published
`observational study that retrospectively evaluated cardiac morbidity and mortality with
`deferoxamine- or deferiprone-treatment in patients with thalassemia major. The paper
`states that no data were available regarding compliance. The mean age of the patients in
`the LA36-0310 study primary efficacy analysis was 20 years; 55% of these patients were
`females, 73% were Caucasian, 17% were Asian and 1% were Black. Among these
`patients 94.3% had β-thalassemia syndromes as the underlying disease; underlying
`disease was sickle cell disease in only 1.1% (2) of patients and was myelofibrosis in 1.9%
`(3) of patients. About 76.9% of patients received a deferiprone dose of 75 mg/kg/day,
`17.8% received about 100 mg/kg/day and 5.3% received a dose of 50 mg/kg/day.
`Deferoxamine was the prior chelator in 250 (94.6%) of these patients. Eight (8) patients
`had received deferasirox (Exjade) only as prior chelator and 6 patients had received both
`deferoxamine and deferasirox prior to receiving deferiprone. Though the study was
`planned to assess deferiprone treatment for 1 year, only 27% of enrolled patients were
`treated for 1 year or longer. About 76% of enrolled patients had a treatment duration of
`at least 6 months.
`
`The sponsor’s primary efficacy analysis is shown below:
`
`
`
`
` 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
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`Reference ID: 3021195
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`NDA 21-825
`Page 8 of 13
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`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.
`
`
`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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`Reference ID: 3021195
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`NDA 21-825
`Page 9 of 13
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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.
`
`Safety Update
`The safety of deferiprone was reviewed in detail during the first review cycle for the
`NDA. Please refer to Dr. George Shashaty’s Clinical Review (10/19/2009) and my
`Cross-Disciplinary Team Leader (CDTL) review (11/25/2009) of the first cycle NDA
`submission. For this resubmission no new patients have been treated in clinical trials and
`the sponsor has simply updated the safety database with additional post-European Union
`(EU) approval surveillance adverse event reporting data. The new data do not change the
`adverse event profile for deferiprone. The safety profile for the patients included in
`Study LA36-0310 was similar to that for the overall safety database. The most frequent
`adverse drug reactions were chromaturia, nausea, vomiting, and arthralgia.
`
`The most important adverse drug reaction was agranulocytosis, which was seen in 1.7%
`of patients in the overall safety database and 1.3% (3) of patients in the LA36-0310
`study. Neutropenia occurred in 5-10% of patients in the individual studies. In the post-
`EU approval surveillance experience there have been 94 reports of agranulocytosis
`including 13 deaths.
`
`Among the 642 patients in the clinical trials safety database, during deferiprone treatment
`increased alanine aminotransferase was reported in 8.7% of patients and was considered
`possibly drug related in 7.5% of patients. Three patients experienced serious
`hepatobiliary events (cholelithiasis, hepatitis, hepatic congestion). Among the patients in
`the clinical trials 40.2% were positive for hepatitis C prior to deferiprone administration,
`43.5% were negative and status was missing for 16.4%. The sponsor reported that 50
`patients were known to have hepatic fibrosis at study entry. One patient
`([2007AP000570], a patient β-thalassemia major and history of Hepatitis C and
`splenectomy), had progression after about 6 years on deferiprone, developed
`hepatocellular carcinoma, underwent liver transplant and subsequently died due to
`complications of cirrhosis. No new cases of hepatic fibrosis were reported in the clinical
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`Reference ID: 3021195
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`NDA 21-825
`Page 10 of 13
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`studies. The sponsor reports that no cases of hepatic fibrosis have been reported among
`the 234 post-EU approval surveillance adverse event reports that have been received. Dr.
`Shashaty indicates in his 10/19/2009 Clinical Review that in the post-EU marketing
`experience drug-induced hepatitis associated with the administration of deferiprone was
`reported in 1 case with a positive-rechallenge. In clinical trials with deferiprone an
`elevation in liver enzymes occurred in 6% of treated patients at a rate of 3.7 per 100
`patient years of exposure.
`
`In the clinical studies there was one case of torsades de pointes, one case of seizure and
`one case of Henoch-Schönlein purpura.
`
`Also, with regard to safety it should be noted that based on animal studies deferiprone is
`genotoxic and causes developmental toxicity (skeletal and soft tissue malformations in
`offspring of rats and rabbits). Dr. Shashaty’s 10/19/2009 review reports that there have
`been 6 reports of pregnancy in persons receiving deferiprone. Deferiprone was
`discontinued between the 5th and 6th month of pregnancy in 3 patients (not known for
`other 3). Four pregnancies producted apparently healthy offspring at term, one
`pregnancy terminated spontaneously and outcome information was not available for the
`other case. Two pregnancies occurred in the partners of 2 patients with thalassemia
`treated with deferiprone. The offspring in one case had mild hypospadias and the other
`had normal growth and development.
`
`Reviewer’s Comments and Discussion
`Efficacy: The sponsor has conducted an analysis (Study LA36-0310) of a subpopulation
`of patients drawn from its previously conducted studies and defined as being
`inadequately treated with current chelation therapy, based on having previously been
`treated with a chelator (mostly deferoxamine) prior to deferiprone and having serum
`ferritin 2500 μg/L, cardiac MRI T2*<20 msec and/or liver iron concentration (LIC) >7
`mg Fe/g dry weight. The vast majority (94.3%) of patients had β-thalassemia syndromes
`as the underlying disease. Important for the U.S. population, only 2 patients had sickle
`cell disease as the underlying disease. For patients in the analysis population who
`received deferiprone for up to one year and had baseline and follow-up data for serum
`ferritin (primary efficacy endpoint) 52% (136/264) had a 20% or greater decline in serum
`ferritin from baseline up to 1 year after starting deferiprone. Excluding patients who
`received concurrent other chelators and those from Dr. Olivieri’s site where there were
`questions of data quality, 50% (109/220) of patients met the primary efficacy endpoint
`for success. For the secondary endpoints the sponsor-defined success rate was 42% for
`LIC and 62% for cardiac MRI T2*.
`
`As stated by Dr. Shashaty in his Clinical Review (9/16/2011), “The sponsor has met its
`benchmarks for the primary efficacy endpoint for Study LA36-0310.” Nevertheless,
`there are some limitations in the design of the study. These include: that the study was
`single-arm and non-randomized; data were pooled from heterogeneous studies that
`differed in deferiprone doses, treatment duration, objectives, and other aspects; for most
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`Reference ID: 3021195
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`NDA 21-825
`Page 11 of 13
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`patients there was limited information available on prior therapies including specific
`drug, doses, times and duration of treatment, and compliance. There also are issues with
`regard to the interpretation of the study results. These include: that the change in serum
`ferritin is a non-specific endpoint and at best a surrogate for clinical improvement with
`removal of iron from the body; change in LIC was available for only 117 patients and
`showed the weakest efficacy results (42% of patients with sponsor-defined success);
`change in cardiac MRI T2* was small and data to show quantitative relationship between
`the amount of change in cardiac MRI T2* and cardiac function is lacking. Also, there
`was limited information on duration of responses and exploration of dose-response
`relationship was limited.
`
`Regarding interpretation of the LA36-0310 study results, the FDA Statistical Review of
`the application (Qing Xu, Ph.D., 9/16/2011) comments:
`
`“The sponsor’s efficacy analysis for serum ferritin by pooling 12 studies showed
`that the overall success rate was 52% with 95% CI of (45%, 58%). As the lower
`limit of the 95% CI is larger than 20%, the protocol defined endpoint was met for
`this trial. However, this study has several serious limitations including lack of
`randomization, lack of control group, high rate of missing data and ignoring the
`variation between studies by simple pooling, all of which can introduce biases to
`the primary outcome. Therefore, it is unclear whether the efficacy shown in the
`study is solely due to the Ferriprox therapy, and the interpretation of these
`analysis results should be taken cautiously.”
`
`
`Safety: The safety profile of deferiprone in the current resubmission is unchanged from
`that reflected in the original submission. Agranulocytosis remains the major concern.
`Regarding agranulocytosis, in his Clinical Review (9/16/2011) Dr. Shashaty comments,
`“The clinically most important adverse reaction associated with the use of deferiprone
`continues to be the development of agranulocytosis. This adverse reaction occurred in
`1.7% of patients treated with the drug in clinical trials. It appears to be more common in
`patients with non-thalassemic disorders than in patients with thalassemia, perhaps
`because in the latter there is often a deficiency of bone marrow production and these
`patients may be more susceptible to an additional marrow insult caused by deferiprone.
`The development of neutropenia may be a herald of progression to agranulocytosis, but
`this is not clear. In patients who survive the episode of agranulocytosis, thus far no
`apparent permanent bone marrow incapacitation has been observed.”
`
`Deferiprone appears to be able to cause hepatotoxicity (elevation of hepatic
`transaminases). Long-term hepatic sequelae are not clear and may be difficult to evaluate
`because of confounding due to high rates of underlying history of hepatitis C infection
`and natural history of disease in the population treated.
`
`Deferiprone is genotoxic and causes developmental toxicity and the labeling should
`reflect this risk.
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`Reference ID: 3021195
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`NDA 21-825
`Page 12 of 13
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`There was one case of torsades de pointes. A thorough QT study has not yet been
`conducted for deferiprone.
`
`Benefit/Risk and Recommendations
`Clinical review of the application finds that based on the available information in the
`NDA application, deferiprone treatment appears to significantly decrease serum ferritin, a
`commonly used parameter for following body iron burden in patients undergoing chronic
`red blood cell transfusions, in about 50% of patients who have been assessed as being
`inadequately treated with other iron chelators. The safety profile for this “second-line”
`use appears similar to that for the overall population of patients who have received
`deferiprone. Also, this NDA for deferiprone was presented to a meeting of the Oncology
`Drugs Advisory Committee on September 14, 2011. Considering the available
`information, the Committee concluded with a 10 yes to 2 no vote that there was a
`favorable benefit/risk profile for deferiprone in the treatment of patients in whom current
`chelation therapy is inadequate.
`
`The primary Clinical Review (Dr. George Shashaty, 9/16/2011) recommends that:
`
`“Deferiprone should not be approved for “the treatment of patients with
`transfusional iron overload when current chelation therapy is inadequate”.
`However, if the sponsor agrees to change the indication to “the treatment of
`patients with thalassemia with transfusional iron overload when previous
`chelation therapy with other approved iron chelators has been unsuccessful”,
`deferiprone should receive Accelerated Approval under the requirements of
`21CFR314.500-314.560 (Subpart H- Accelerated Approval of New Drugs for
`Serious of Life-Threatening Illnesses).”
`I concur with Dr. Shashaty’s recommendation for approval of deferiprone under Subpart
`H for a revised indication for treatment of transfusional iron overload in thalassemia
`patients in whom prior treatment with other chelators has proven inadequate.
`
`Unfortunately, at present there are no data to support expanding the indication to
`populations other than thalassemia. For the U.S. population, patients with thalassemia
`are likely to constitute a minority of those who might potentially be exposed to
`deferiprone. Based on Dr. Shashaty’s 3/18/2011 review of the Periodic Safety Update
`Report (PSUR) for Exjade (deferasirox) (NDA 21882), approved for the indication “for
`the treatment of chronic iron overload due to blood transfusions (transfusional
`hemosiderosis) in patients 2 years of age and older”, patients with thalassemia accounted
`for approximately 10 – 11%, myelodysplastic syndrome for approximately 20 – 42%,
`sickle cell diseases (SCD) for approximately 18 – 39%, other forms of anemia for
`approximately 18 – 22% and unknown diseases for approximately 8 – 10% of the total
`use of deferasirox. It is not unlikely that once deferiprone enters the U.S. market patients
`with SCD may be the largest population actually using the drug. Therefore, it should be
`required as a condition of approval that the sponsor conduct a post-marketing clinical
`study to evaluate efficacy and safety of deferiprone in patients with SCD.
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`Reference ID: 3021195
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`NDA 21-825
`Page 13 of 13
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`Other considerations for post-marketing study requirements should include the following:
`• Because changes in serum ferritin are at best a surrogate for clinical benefit of
`chelation therapy in transfusional iron overload, the sponsor should conduct a
`study to evaluate effect of deferiprone on survival or important morbidity (such as
`cardiac dysfunction) in treated patients.
`• Because deferiprone will be a life-long treatment for patients and currently
`experience with long-term use is limited, a registry should be established to
`follow patients long-term for evidence of hepatic toxicity (particularly fibrosis),
`development of cancer, and evidence of long-term clinical benefit.
`• The sponsor should perform a thorough QT study.
`• Evaluation of deferiprone use in pediatric patients with β-thalassemia should be
`encouraged.
`
`
`See Dr. Shashaty’s 9/16/2011 Clinical Review for additional recommendations for
`further studies and labeling recommendations. Final wording of the labeling should be
`negotiated with the sponsor.
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`Reference ID: 3021195
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KATHY M ROBIE SUH
`09/27/2011
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`Reference ID: 3021195
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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 21825
`Priority or Standard Standard
`
`Submit Date(s) April 13, 2011, July 25, 2011
`Received Date(s) April 14, 2011, July 25, 2011
`PDUFA Goal Date October 14, 2011
`
`Reviewer Name(s) George Shashaty
`Review Completion Date September 16, 2011
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`Established Name Deferiprone
`(Proposed) Trade Name Ferriprox
`Therapeutic Class
`Iron Chelator
`Applicant ApoPharma
`
`Formulation(s) Tablet
`Dosing Regimen 25-33 mg/kg three times daily
`Indication(s) Transfusion-related hemosiderosis
`Intended Population(s) Thalassemia
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`Reference ID: 3016417
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`Clinical Review
`George Shashaty, M.D.
`NDA 21825 (Resubmission)
`Ferriprox (deferiprone)
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`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.................................................................................6
`1.1 Recommendation on Regulatory Action.............................................................................................................6
`1.2 Risk Benefit Assessment.....................................................................................................................................7
`1.3 Recommendations for Postmarket Risk Management Activities........................................................................9
`1.4 Recommendations for Postmarket Studies/Clinical Trials..................................................................................9
`2 INTRODUCTION AND REGULATORY BACKGROUND ...............................................................................9
`2.1 Product Information..........................................................................................................................................10
`2.2 Tables of Currently Available Treatments for Proposed Indications................................................................10
`2.3 Availability of Proposed Active Ingredient in the United States ......................................................................10
`2.4 Important Safety Issues With Consideration to Related Drugs.........................................................................10
`2.5 Summary of Presubmission Regulatory Activity Related to Submission.........................................................10
`2.6 Other Relevant Background Information..........................................................................................................15
`3 ETHICS AND GOOD CLINICAL PRACTICES ...............................................................................................16
`3.1 Submission Quality and Integrity .....................................................................................................................16
`3.2 Compliance with Good Clinical Practices ........................................................................................................16
`3.3 Financial Disclosures........................................................................................................................................16
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ............16
`4.1 Chemistry Manufacturing and Controls............................................................................................................16
`4.2 Clinical Microbiology.......................................................................................................................................16
`4.3 Preclinical Pharmacology/Toxicology..............................................................................................................16
`4.4 Clinical Pharmacology......................................................................................................................................17
`4.4.1 Mechanism of Action................................................................................................................................17
`4.4.2 Pharmacodynamics .......................................