CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`021825Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review
`
`Cross Discipline Team Leader Review
`NDA 21-825
`
`
`
`Date
`From
`Subject
`NDA/BLA #
`Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`Proposed Indication(s)
`
`September 28, 2011
`Kathy M. Robie Suh, M.D., Ph.D.
`Cross-Discipline Team Leader Review
`21-825
`
`ApoPharma Inc.
`April 13, 2011
`October 14, 2011
`
`Ferriprox (deferiprone)
`
`500 mg film-coated tablets
`for the treatment of patients with transfusional iron
`overload when current chelation therapy is inadequate
`Approval for revised indication: “for the treatment of
`patients with transfusional iron overload in patients with
`thalassemia syndromes when current chelation therapy is
`inadequate”
`
`Recommended:
`
`
`
`
`
`Cross Discipline Team Leader Review Template
`1. Introduction
`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 deferiprone 25 to 33 mg/kg body weight, orally, three times a day for a total daily dose of 75
`to
`mg/kg body weight.
`2. 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
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`Cross Discipline Team Leader Review
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`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 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 initial NDA submission 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 showed a 3.9 msec increase in cardiac MRI
`T2* from baseline to 12 months in the deferiprone treatment group and 2.3 msec increase in
`the deferoxamine treatment group but no 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 complete response (CR) letter was issued on
`11/30/2009 citing a number of clinical deficiencies and well as deficiencies for Clinical
`Pharmacology, product quality, and facility inspections. See Dr. George Shashaty’s Clinical
`Review (10/19/2009) for details of the first cycle clinical review. See my Cross-Disciplinary
`Team Leader (CDTL) review (11/25/2009; addendum 12/31/2009) and Dr. Dwaine Rieves’
`Division Director Summary Review (11/20/2009) for a summary of issues from the first cycle
`review.
`
`The current resubmission narrows the indication from the initially proposed “treatment of iron
`overload in patients with transfusion-dependent thalassemia and treatment of iron overload in
`patients with other transfusion-dependent anemias for whom the use of other iron chelators has
`been considered inappropriate” to the currently proposed “treatment of patients with
`transfusional iron overload when current chelation therapy is inadequate.” A single
`retrospective, single-arm study (LA36-0310) is submitted for the indication. Results of the
`study are discussed under section “7. Clinical/Statistical –Efficacy” below.
`3. CMC
`
`
`The Chemistry, Manufacturing and Controls (CMC) Review (W.M. Adams, Ph.D., final
`signature 9/27/2009) states, “From a CMC standpoint, this application is recommended for
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`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.
`Insert the following language into the action letter: 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).” There are
`no CMC recommendations for post-marketing commitments.
`
`
`4. Nonclinical Pharmacology/Toxicology
`Phararmacology/Toxicology Review during the first cycle noted that lifetime carcinogenicity
`studies had not been conducted but the sponsor’s proposal to conduct a 2-year carcinogenicity
`study in rats and a 6-month study in p53 knockout mice during Phase 4 is adequate.
`Pharmacology found the application acceptable for approval with appropriate warnings in the
`product labeling regarding the genotoxicity and carcinogenic risk and fetal and developmental
`toxicity (Pregnancy Category C) (D. E. Bailey, Ph.D. (reviews signed 6/27/07, 8/4/08 and
`9/22/09). At the time of this CDTL review Pharmacology/Toxicology review for the current
`review cycle has not been finalized.
`
`5. Clinical Pharmacology/Biopharmaceutics
`Clinical Pharmacology review was completed by Joseph Grillo, Pharm.D. (final signature,
`9/21/2011). The review stated that, “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.” Recommended
`postmarketing requirements included that the sponsor: Conduct a pharmacokinetic trial of
`both deferiprone and its primary 3-O-glucuronide metabolite in subjects with hepatic
`impairment; conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-
`glucuronide metabolite in subjects with renal impairment and; conduct a TQT assessment for
`deferiprone. In addition, the review recommended that the sponsor 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 to determine the need for
`additional in vivo drug interaction trials. Additional comments for the sponsor were included
`in the review.
`
`In an additional consultation review at the request of the Division of Hematology Products,
`Clinical Pharmacology reviewed the bioavailability of the deferiprone solution formulation
`used in ApoPharma's pediatric study LA30-0307 compared to the bioavailability of the to-be-
`marketed tablets (Joseph Grillo, Pharm.D., final signature 9/21/2011). The review found that
`the deferiprone solution formulation used in the submitted bioequivalence study (LA21-BE) is
`bioequivalent to the Ferriprox tablet formulation. The same deferiprone solution formulation
`was used in trial LA30-0307. Clinical Pharmacology deferred to CMC regarding the integrity
`of the deferiprone solution batches used in these studies.
`
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`The Office of New Drugs Quality Assessment (ONDQA) review conducted by Tien-Mien
`Chen, Ph.D. (9/16/2011) identified a need for the sponsor to revise the dissolution acceptance
`criterion to change from “Q =
` and indicated that
`the sponsor needed to provide an updated specification sheet for the product including the
`revised criterion for the dissolution test. The deficiency was communicated to the sponsor and
`the sponsor replied. Review of the sponsor’s reply (9/25/2011 review, signed by Angelica
`Dorantes, Ph.D.) found the sponsor’s response acceptable agreeing with the sponsor that the
`provided dissolution data support an acceptance criterion of Q=
` in 45 minutes and
`concluded that, “From the Biopharmaceutics perspective, NDA 21-825 is recommended for
`approval.”
`
`
`6. Clinical Microbiology
`N/A
`
`
`
`7. Clinical/Statistical- Efficacy
`In this resubmission a single study (LA36-0310) in which data from patients in the completed
`studies identified as being inadequately treated with other iron chelators were analyzed
`examining change in serum ferritin levels from baseline up to one year after starting
`deferiprone was submitted. The sponsor’s primary efficacy analysis showed 136 of 264
`patients (52%) had a 20% or greater decrease in serum ferritin from baseline to end of study.
`See the Clinical Review (Dr. George Shashaty, 9/16/2011), the Statistical Review (Qing Xu,
`Ph.D., 9/16/2011) and my Medical Team Leader review (signed 9/27/2011) for detailed
`presentation and discussion of Study LA36-0310. The Clinical and Statistical reviews
`identified a number of deficiencies of the study design (including that it was retrospective,
`single arm, pooled patients from heterogeneous studies and had limited information on prior
`treatment) that limit interpretation of the study results.
`
`The Clinical Review (Dr. George Shashaty, 9/16/2011) recommended that, “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). The Secondary Medical Team Review concurs with
`the recommendation of Accelerated Approval for the indication revised as per Dr. Shashaty
`(Kathy Robie Suh, M.D., Ph.D., signed 9/27/2011)
`
`
`8. Safety
`Updated safety information was reviewed by Dr. George Shashaty in his Clinical Review
`(9/16/2011). The safety profile of deferiprone for the resubmission is not changed from the
`profile described during the first cycle review. The major safety consideration is
`agranulocytosis which occurred in 1.7% of patients in the clinical studies. In the post-
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`Cross Discipline Team Leader Review
`NDA 21-825
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`European Union marketing surveillance there have been 94 reports of agranulocytosis
`including 13 deaths.
`
`Deferiprone is genotoxic and teratogenic as described in the first cycle
`Pharmacology/Toxicology review (David Bailey, Ph.D., reviews signed 6/27/2007, 8/4/2008
`and 9/22/2009) and this risk should be reflected in the labeling.
`9. Advisory Committee Meeting
`A meeting of the Oncology Drugs Advisory Committee (ODAC) was held on September 14,
`2011 to discuss the deferiprone application. As Dr. Shashaty states in his review, “The agenda
`included presentations made by the sponsor and FDA, and an open public hearing. Members
`of the committee addressed questions to the sponsor and FDA. There was a discussion of the
`merits of the application. In response to the question “Is there a favorable benefit/risk profile
`for deferiprone in the treatment of patients in whom current chelation therapy is inadequate?”,
`the Committee, by a margin of 10 to 2, voted in the affirmative.”
`10.
`Pediatrics
`The current application does not seek approval for use of deferiprone in pediatric patients.
`Also, the drug is an orphan product for the indication. Nevertheless, the indication is relevant
`to pediatric populations and the sponsor has conducted a study of a deferiprone oral solution in
`pediatric patients. Clinical Pharmacology review has determined that the oral formulation
`used in that study is bioequivalent to the tablet formulation. (See discussion under “5. Clinical
`Pharmacology/Biopharmaceutics” above).
`
`Maternal and Pediatric Health Team (PMHT) comments have not been finalized at the time of
`this review. However, the PMHT has participated in labeling discussions.
`
`
`11.
`None.
`
`Other Relevant Regulatory Issues
`
`
`
`Labeling
`12.
`All the review disciplines have provided relevant recommendations in their reviews and have
`participated in labeling meetings discussing the wording in the label.
`
`Additional recommendations have been provided by the Division of Drug Marketing,
`Advertising, and Communications (James S. Dvorsky, 8/30/2011) and these have been
`considered in the labeling discussions.
`13.
`Recommendations/Risk Benefit Assessment
`
`
`
`• Recommended Regulatory Action
`
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`The application should be granted Accelerated Approval under Subpart H regulations for the
`indication: “for treatment of transfusional hemosiderosis in patients with thalassemia who are
`inadequately treated with other iron chelators.”
`
`At the time of this review the recommendation for approval is contingent upon the receipt of
`an overall acceptable recommendation from the Office of Compliance as per CMC review.
`
`
`• Risk Benefit Assessment
`
`There continues to be a need for iron chelating agents for use in patients who are not
`adequately treated with currently available products. While the studies of deferiprone are
`imperfect in design and provide limited information on clinical effects of deferiprone therapy,
`the available data for patients with thalassemia who are identified as being inadequately
`treated with currently available chelators appear to show an adequate benefit risk profile to
`support approval of deferiprone for use in these patients. As Dr. Shashaty summarizes in his
`Clinical Review (9/16/2011):
`
`
`
`“Patients with transfusional hemosiderosis treated with either deferoxamine or
`deferasirox may have an inadequate reduction in total body iron burden. Reasons for
`this include the difficulty of administration leading to suboptimal compliance,
`intolerance to drug induced symptoms (particularly gastrointestinal and
`dermatological), the development of adverse reactions that lead to dose modifications
`or withdrawal, or unexplained causes that limit the iron excretion effects of the
`currently approved iron chelators. For such patients, there are no alternative therapies
`and, since many of them have a continuing requirement for transfusion therapy, iron
`overloading progresses, eventually leading to organ dysfunction and, possibly, death.
`The organ most commonly compromised, and which is the most common cause of
`death (at least in persons with thalassemia), is the heart. Cardiac failure and
`arrhythmias are responsible for approximately 70% of deaths in patients with
`thalassemia (Borgna-Pignatti C et al 2004. Survival and complications in patients with
`thalassemia major treated with transfusion and deferoxamine. Haematologica 89:1187-
`93).
`Therefore, an additional iron chelator would be of utility for such patients, even if there
`are risks associated with its administration. For deferiprone, whose most important
`adverse reaction is the development of agranulocytosis (approximately 1.7% of users),
`because of the lack of alternative drugs, the risks of deferiprone might be acceptable to
`gain its benefits in persons with thalassemia.
`
`I believe that the indication for the use of deferiprone should be restricted to patients
`with thalassemia. Approximately 95% of all of the patients in whom the drug was
`studied had thalassemia as the anemia that led to the requirement for chronic
`transfusion therapy. There have only been a total of 35 patients with sickle cell
`disease, myelodysplastic syndrome (MDS) with variants, and other transfusion
`dependent anemias who have been treated with deferiprone in the clinical studies. All
`of the non-thalassemic patients were enrolled in a Compassionate Use Treatment
`protocol (LA-04) and the interpretation of the data from that study is complicated by
`
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`the multiplicity of physicians involved, variability in inclusion/exclusion criteria, the
`adequacy of data regarding efficacy, compliance and safety assessments and the use of
`concomitant chelators in a number of the enrollees.”
`
` concur with Dr. Shashaty’s assessment.
`
` I
`
`
`
`• Recommendation for other Postmarketing Requirements and Commitments
`
`The following are recommendations for postmarketing requirements and commitments that
`should be considered:
`o A registry of patients with thalassemia and transfusion related hemosiderosis who
`cannot be effectively treated with either deferoxamine or deferasirox with data
`accumulated for a time span sufficient in length to determine the natural history and the
`efficacy and safety of the use of deferiprone in these individuals. The registry should
`focus on mortality and morbidity in patients receiving deferiprone, hepatic function,
`the development of malignancies and persistence of drug effect on body iron load.
`o A prospective randomized safety and efficacy trial in patients with sickle cell disease
`and transfusion related hemosiderosis who cannot be effectively treated with
`deferoxamine should be conducted to better address the U.S. population likely to
`receive deferiprone.
`o A prospective randomized trial in patients with thalassemia and transfusion related
`hemosiderosis who cannot be effectively treated with deferoxamine comparing the
`efficacy and safety of the use of deferasirox with the efficacy and safety of the use of
`deferiprone in that population. An alternative acceptable trial in a similar population
`could compare the use of deferasirox alone with the combination of deferasirox and
`deferiprone.
`o A pharmacokinetic trial of both deferiprone and its primary 3-O-glucuronide
`metabolite in subjects with hepatic impairment;
`o A pharmacokinetic trial of both deferiprone and its primary 3-O-glucuronide
`metabolite in subjects with renal impairment and;
`o A thorough QT assessment for deferiprone;
`o
`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 to determine the need for additional in vivo drug
`interaction trials.
`
`Evaluation of deferiprone for use in pediatric patients with β-thalassemia should be
`encouraged.
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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
`09/29/2011
`
`Reference ID: 3022191
`
`