CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`021825Orig1s000
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`

`

`Summary Review for Regulatory Action
`
`1
`
`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`
`
`
`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication(s)
`
`(electronic stamp)
`Richard Pazdur, MD, Office Director
`Office Director Summary Review
`21825
`
`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, M.D./ Karen Feibus, M.D./ Lisa Mathis, M.D.
`
`
`
`Action/Recommended Action for
`NME:
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`
`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`DSI
`CDTL Reviews
`OSE/DMEPA
`
`OSE/Epidemiology
`OSE/DRISK
`Other - statistical safety
`Other – Pediatrics
` Maternal Health Team
`
`
`
`
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`
`
`
`Reference ID: 3029235
`
`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`
`
`1. Introduction
`
`2
`
`
`Apotex/ApoPharma Inc. submitted the complete New Drug Application (NDA) for deferiprone, an oral
`iron chelator, on January 29, 2009 for the proposed indication of “treatment of iron overload in patients
`with excessive body iron stores due to chronic transfusion therapy.” On November 30, 2009, a complete
`response letter was issued for this application due to clarifications needed for clinical data issues; clinical
`pharmacology issues; chemistry, manufacturing and control issues; and a failed facility inspection. The
`applicant responded to the complete response letter on April 14, 2011 addressing the major clinical issue
`of the pivotal trial; the clinical pharmacology issues including the lack of studies conducted; and the CMC
`issues which involved a failed site inspection, problems with a drug master file, and multiple process
`issues.
`
`
`2. Background
`
`
`In the original submission, the sponsor provided data from a single, controlled trial (Study LA-16-0102)
`as primary support for efficacy. 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 several deficiencies including 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.
`With the current submission, in response to the CR letter, the sponsor 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”. 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.
`
`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 (e.g., subcutaneous or intramuscular infusion via pump over 10-12 hours 5 of 7 days each
`week). In 2005, Exjade (deferasirox) was granted accelerated approval for use as an iron chelator.
`
`Consistent with our Guidance for Industry: Available Therapy (July 2004), only deferoxamine can be
`considered available therapy.
`
`Deferiprone has been approved in Europe since 1999.
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`3. CMC/Device
`There are no outstanding CMC issues that would preclude approval.
`
`The CMC review team granted a 24-month expiry for deferiprone when stored at USP controlled room
`temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF).
`
`
`3
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`There are no nonclinical issues which would preclude approval of deferiprone. From the current
`Pharmacology/Toxicology Team Leader review:
`
`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.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`There are no issues which would preclude approval from a clinical pharmacology perspective. However,
`the clinical pharmacology team recommends post-marketing requirements (PMRs) to conduct PK trials
`to assess deferiprone and its primary metabolite in patients with renal and hepatic impairment; TQT
`assessment; and a commitment (PMC) to conduct in vitro studies to determine the affect of UDP
`glucuronosyltransferase (UGT) inhibition and induction on the metabolism of deferiprone to evaluate the
`need for additional in vivo drug interaction trials
`
`
`6. Clinical Microbiology
`
`
`Not applicable.
`
`
`7. Clinical/Statistical-Efficacy
`
`
`The following text from Dr. Robie-Suh 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
`
`
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`Reference ID: 3029235
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`

`

`4
`
`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`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... 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.
`
`As stated in Dr. Farrell’s summary review, 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:
`
`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 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.
`
`
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`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.
`
`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.
`
`
`5
`
`From Dr. Robie-Suh’s second cycle review:
`
`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 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 the data from one investigator site 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 another study (LA-03) . For that analysis 109 of 220 (50%) patients achieved treatment
`success.
`
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`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.
`
`6
`
`
`
`
`
`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.
`
`
`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): 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
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`
`7
`
`contain a description of the proposed methods of analysis, the study report should describe how the
`methods used were selected.
`(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).
`
`
`As stated in Dr. Farrell’s review, 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 September 14, 2011 Oncologic Drugs Advisory Committee (ODAC) meeting. The sponsor had
`proposed the 20% reduction based on their outside expert consultants. The ODAC members voted (10
`to 2) supporting a favorable risk to benefit evaluation using the 20% reduction in serum ferritin as the
`primary endpoint.
`
`The Accelerated Approval regulations (21 CFR Part 314, Subpart H) 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.
`8. Safety
`
`
`As stated in Dr. Farrell’s Division Director Summary Review, during the investigation and foreign
`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 paper published in the New England Journal of Medicine in 1998. However, this finding has
`
`
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`Reference ID: 3029235
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`

`

`8
`
`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`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.
`
`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.
`
`
`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
`
`
`The sponsor has agreed to meet with the Agency to discuss the development of a pediatric formulation.
`
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`
`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 8 additional clinical trials submitted in the NDA for deferiprone.
`
`
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`Reference ID: 3029235
`
`

`

`9
`
`Office Director Decisional Memo
`NDA 21825_Ferriprox (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 is 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 8 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.
`
`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
`
`• The revised indication differs from that originally sought by the applicant. The originally
`requested indication was for the “treatment of iron overload in patients with excessive
`body iron stores due to chronic transfusion therapy.” Our November 30, 2009, letter to
`the applicant rejecting approval of this indication did not address our requirements for
`approval of a more narrow indication. The approved indication is the following: “For the
`treatment of patients with transfusional iron overload due to thalassemia syndromes
`when current chelation therapy is inadequate.”
`
`
`
`• We are approving this drug for the treatment of a subpopulation affected by a rare,
`serious, and life-threatening condition for which other available therapy is inadequate.1
`The indication is limited to thalassemia syndromes reflecting the population of patients
`studied in the submitted clinical trials. Labeling specifically states “Safety and
`effectiveness have not been established for the treatment of transfusional iron overload
`in patients with other chronic anemias”. The Sponsor has made a commitment to study
`the drug in patients with sickle cell anemia.
`
`
`
`1 By “other available therapy” we mean other drugs that have received regular approval for treatment of iron
`overload. This excludes drugs that have received accelerated approval, for which postapproval studies to verify
`and describe clinical benefit are still pending. Thus, deferoxamine is the only drug we consider “currently
`available” in this context.
`
`
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`
`10
`
`• This approval is supported by an adequate and well controlled study. This approval is
`supported by a prospectively planned analysis of data from twelve trials. We have
`approved applications based on prospectively planned analysis of data from multiple
`trials for hematological indications (Mylotarg and Angiomax).
`
`• The Agency has used single arm trials for the approval of many agents in the setting of
`serious and life-threatening diseases. The single-arm design of this submission (i.e., the
`absence of a randomized control arm) is appropriate when the endpoint is directly
`attributed to the drug introduced and cannot be attributed to chance alone or the natural
`history of the disease. For example, the endpoint of tumor size reduction (“response
`rate” in hematology/oncology trials) is used in single arm trials for accelerated approval
`since a reduction in size of the tumor by a pre-specified amount does not occur
`spontaneously or by a chance finding. A similar scenario exists for the endpoint of a
`decrease in serum ferritin by 20%. With the continued use of blood transfusions, a
`decrease in serum ferritin is attributed directly to the drug and would not occur due to
`chance alone or the natural history of the disease.
`
`• When a single-arm trial demonstrates an outcome that would not occur spontaneously,
`the finding may provide substantial evidence of safety and effectiveness in support of
`approval even in the absence of a concurrent control. In addition, secondary endpoints
`studied in these trials (a decrease in hepatic iron and radiographic assessment of
`cardiac iron) provide supporting evidence of the effect of the drug in the iron overload
`states.
`
`• As noted above, our regulations describe the characteristics of an adequate and well
`controlled study (21 CFR 314.126). These regulations acknowledge that historical
`controls (i.e., comparison of a test drug with experience derived from the adequately
`documented natural history of a disease) are appropriate in this indication.
`
`• When a surrogate endpoint is used to support accelerated approval, it must be
`“reasonably likely to predict clinical benefit.” The accelerated approval regulations
`specifically acknowledge that endpoints used for accelerated approval may have a
`degree of uncertainty in relationship to the ultimate clinical outcome, hence requiring
`further study in post-approval clinical trials to confirm clinical benefit. A 20% decrease in
`serum ferritin is an appropriate degree of improvement for use in defining the primary
`endpoint, according to a consensus opinion among investigators and as agreed by
`ODAC by their supporting vote recommending approval (10 to 2). We reasonably
`conclude that a decline of 20% reflects a real treatment effect, rather than random
`fluctuation, a spontaneous change in the disease, a placebo effect, or biased
`observation.
`
`• CDER’s Office of Scientific Investigations (OSI) inspected 2 studies included in NDA 21-
`825, study LA16-0102 and LA-01. Regarding study LA16-0102, OSI concluded that the
`data are reliable in support of NDA 21-825. Regarding study LA-01, OSI concluded that
`its inspection was inconclusive with respect to data regarding hepatic toxicity.
`
`
`
`
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`
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`Reference ID: 3029235
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`

`

`Office Director Decisional Memo
`NDA 21825_Ferriprox (deferiprone)
`
`
`11
`
`
`
`
`
`
`
`• The prospectively planned analysis on which our approval of NDA 21-825 relies is not
`affected by the inclusion or exclusion of data from studies LA-01 and LA-03. The
`prospectively planned analysis points to the same conclusion regarding the safety and
`effectiveness of deferiprone for its approved indication whether or not data from studies
`LA-01 and LA-03 are included.
`
`• On September 14, 2011, the ODAC considered approval of NDA 21-825. ODAC voted
`10-2 in favor of accelerated approval. Some ODAC members in favor of approval while
`emphasizing the importance of additional studies, as required under our accelerated
`approval framework.
`
`• As with all Subpart H approvals supported by data showing an effect on a surrogate
`endpoint, the applicant is required to conduct postapproval studies to verify and describe
`clinical benefit in patients. This approval is contingent on the applicant’s submission of a
`successful postapproval trial in which deferiprone is used to treat iron overload in
`patients with sickle cell disease and transfusional hemosiderosis who have not been
`adequately treated with available chelating agents. Under Subpart H, we often accept
`postapproval confirmatory trials in a setting other than the approved indication. For
`example, in hematology/oncology indications where the accelerated approval trial may
`enroll a heavily pretreated and refractory population, the confirmatory trials may be
`conducted in a different stage of the disease or in a less heavily pre-treated population.
`
`• Our accelerated approval framework in Subpart H does not require the use of validated
`surrogate endpoints. If a surrogate endpoint is validated (as with the association
`between reduced blood pressure and the risk of cardiovascular disease), a study
`showing an effect on that surrogate endpoint would support regular approval rather than
`accelerated approval. Under our Subpart H regulations, a surrogate endpoint must be
`“reasonably likely” to predict clinical benefit, and confirmatory studies are required
`because uncertainty is attached to that determination. A 20% decline in serum ferritin is
`reasonably likely to predict clinical benefit in this case and was corroborated by
`secondary endpoints including a decrease in liver iron and improvement in cardiac iron
`concentration.
`
`• Regarding risks associated with deferiprone, the Agency is requiring a boxed warning on
`the drug’s label concerning the risk of agranulocytosis and a Medication Guide for
`patients highlighting several risks. Additionally, we are requiring 4 postapproval safety
`studies enforceable under section 505(o) of the Food, Drug, and Cosmetic Act. Please
`see Section 8 (Safety) above regarding discussion of potential hepatotoxicity.
`
`• Finally, our approval of deferiprone is consistent with initiatives to provide important
`flexibility in the approval of drugs that treat rare and serious diseases, in the interest of
`patie