CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`021825Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`2. A decrease in the cardiac content of iron, as measured by magnetic resonance imaging
`(MRI) T2* alterations, was the proposed treatment effect in the single confirmatory study
`intended to verify deferiprone safety and efficacy. Listed below are requests for
`additional information if you use this endpoint in any future regulatory submissions:
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`COMPLETE RESPONSE
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`
`NDA 21-825
`
`Cato Research
`Attention: Lynda Sutton
`U.S. Agent for ApoPharma, Inc.
`4364 South Alston Avenue
`Durham, NC 27713-2220
`
`
`Dear Ms. Sutton:
`
`Please refer to your new drug application (NDA) dated January 29, 2009, received
`January 30, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`and under the Continuous Marketing Application (CMA)-Pilot 1 program, for Ferriprox®
`(deferiprone) 500 mg Tablet.
`
`We acknowledge receipt of your submissions dated December 21, 2006; March 12 and 28,
`September 26, and December 21, 2007; March 19 and 27, June 12 and 27, September 15 and 29,
`October 29, and November 25, 2008; and amendments dated February 17 and 24 (2), March 5,
`10 and 17 (2), May 7 and 28, June 9, 15 and 30, July 9 and 16, August 12 and 25, September 3,
`9, 15, 22 and 23, October 8, 20 and 27, 2009.
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`We also acknowledge receipt of your amendments dated August 6 and October 13, 2009, which
`were not reviewed for this action. You may incorporate applicable sections of the amendment by
`specific reference as part of your response to the deficiencies cited in this letter.
`
`We have completed the review of your application, and have determined that we cannot approve
`this application in its present form. We have described below our reasons for this action and,
`where possible, our recommendations to address these issues.
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`CLINICAL
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`1. The application contains insufficient information about the drug to determine whether the
`product is safe for use under the conditions prescribed, recommended, or suggested in its
`proposed labeling and lacks substantial evidence of efficacy from adequate and well-
`controlled investigations. Listed below are our requests for additional data, followed by a
`summary of the basis for these requests.
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`

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`NDA 21-825
`Page 2
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`a. Supply data from at least one additional prospective, randomized, controlled clinical
`study that verifies the proposed deferiprone treatment effect.
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`b. Supply data that verify the clinical meaningfulness (e.g., improved survival,
`symptoms, functional status or other clinical benefits) of incremental changes in
`cardiac MRI T2* values. These data should establish the minimum millisecond
`increase in T2* that is indicative of a clinical benefit.
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`c. In developing subsequent clinical studies, we encourage you to enroll pediatric
`patients with transfusional hemosiderosis. Data within the submitted confirmatory
`study were obtained entirely from adult patients.
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`3. Submit data that verify the absence of a mortality disadvantage when deferiprone is
`administered over a prolonged time period. These data could be obtained from follow-up
`survival information for all patients enrolled in Study LA-01 ("Randomized Trial of
`Deferiprone and Deferoxamine in Thalassemia Major”) and Study LA-16-0102
`("Randomized Trial Comparing the Relative Efficacy of Deferiprone to that of
`Deferoxamine in Removing Excess Cardiac Iron in Thalassemia Major Patients").
`Alternatively, supply data from other randomized, controlled studies that allow an
`assessment of survival in comparison to a clinically appropriate control therapy. The
`need for survival data cannot be addressed by the submission of uncontrolled study data
`or data from historically controlled/observational-type studies.
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`4. Submit data that more thoroughly assess the arrhythmogenic potential of deferiprone. In
`addition to any other information, supply data from an assessment of the effect of
`deferiprone and its primary 3-O-glucuronide metabolite on the electrocardiographic QT
`interval in patients and/or healthy volunteers.
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`5. FDA inspectional findings could not fully verify the accuracy of data submitted by you
`for Study LA-01, with respect to the Toronto, Canada clinical site. The principal
`investigator at that site was Dr. Nancy Olivieri. We understand that you terminated that
`study site in May 1996, prior to study completion. Our comments below pertain solely to
`data that was generated at that study site prior to the termination of the site. Supply
`information that addresses the items listed below:
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`a. A Good Clinical Practice (GCP) inspection of Dr. Olivieri’s data revealed
`discrepancies between superconducting quantum interference device (SQUID) values
`verified by source documents at the site in comparison to the data submitted to the
`NDA.
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`Address these discrepancies.
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`b. The GCP Inspection of Dr. Olivieri’s data also revealed that the liver biopsy iron
`concentration values reported in the NDA listings as provided by you in 2.2.1 could
`not be verified by source documents, because the source documents were not
`available.
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`NDA 21-825
`Page 3
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` Provide all source documents to support the iron content as measured by liver biopsy.
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`6. With regard to Study LA-01, there appear to be inconsistencies in your analyses of the
`data and the exclusion of certain subjects and data points from the analysis. Specifically:
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`a. Per Data Listing 2.2.2 in the NDA, several iron concentration data points were
`excluded from analysis and the rationale for each exclusion was provided in this data
`listing. However, the rationale for exclusion was inconsistently applied in your
`analyses. For example, Subjects 42, 43, 51, and 55, had all of their iron concentration
`data excluded from analyses because "patient[s] did not complete 24 months of
`chelator therapy." However, Subjects 25, 34, 37, and 59, were included in your
`analyses (as provided in Data Listing 2.2.1) even though these subjects apparently did
`not receive 24 months of chelator therapy.
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`Address this inconsistency.
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`b. We also note that Table 12.2, Patient Listing of Discontinued Patients, includes
`information for subjects from Dr. Olivieri's site from 1997, which was after the study
`site was terminated. Therefore, you appear to have access to at least some data
`collected after termination of the site.
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`Confirm that all relevant data in your possession at the time of NDA submission,
`regardless of whether those data were generated after termination of the study site,
`were included in the application.
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`We cite the following information as the basis for the clinical requests listed above:
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`7. You provided data from a single, controlled trial as confirmatory evidence of deferiprone
`efficacy and safety (Study LA-16-0102). In this study, 61 adult patients were
`randomized to therapy with either deferiprone or deferoxamine.
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`a. Regarding efficacy, you claimed that greater increases in cardiac magnetic resonance
`measures of T2* were observed in the deferiprone group than in the control group, a
`primary endpoint outcome which you proposed as indicative of a decrease in cardiac
`iron and a clinical benefit. However, the supplied data did not establish the specific
`clinical benefit attributed to the increase in T2* measurements. Additionally, we do
`not regard the primary endpoint result as a robust observation due to the study's
`relatively small sample size, which precluded subset and other exploratory analyses.
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`Secondary endpoints also were not consistently corroborative of the primary endpoint
`result. For example, changes in serum ferritin and liver iron concentration were not
`significantly different between the two study groups.
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`b. Regarding safety, adverse events related to elevation of serum alanine
`aminotransferase levels were reported in 38% of the deferiprone group but in only
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`NDA 21-825
`Page 4
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`13% of the deferoxamine group. In the context of additional concerns (below), this
`observation signals the potential for deferiprone-induced liver toxicity.
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`8. The supplied supportive study (LA 12-9907) used an uncontrolled design and statistical
`features consistent with an exploratory study. Hence, this study was incapable of
`verifying deferiprone efficacy and safety.
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` 9. The other supplied clinical data are of very limited value to verification of deferiprone
`effects, particularly when the proposed confirmatory study failed to verify safety and
`efficacy. The supportive data included the occurrence of an important cardiac arrhythmia
`(torsade de pointes) that was assessed by a cardiologist as possibly related to deferiprone
`therapy. Overall, the supportive studies contained numerous deficiencies, such as the use
`of retrospective designs, relatively small sample sizes, the lack of control groups, missing
`data and inconsistency in results. Post-marketing reports indicated the occurrence of
`agranulocytosis followed by death in 13 patients.
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`10. In consideration of the submitted data, complete and accurate submission of clinical data
`from Study LA-01 is relevant to the evaluation of deferiprone safety and efficacy because
`the sample size exceeded that of all other controlled studies. Study LA-01 is also of
`interest because it used a primary endpoint that has previously been accepted by FDA.
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`11. Published literature does not consistently support the efficacy or safety of deferiprone.
`Some studies have suggested loss of effectiveness over expanded time periods and others
`have suggested increased liver toxicity among patients who remain on prolonged
`deferiprone therapy (Blood 1998;91:295-300 and the New England Journal of Medicine
`1998;339:417-423). We note that other reports have not cited these problems. In the
`context of the safety and efficacy deficiencies cited above, the inconsistency within the
`published literature underscores the importance of complete data submission from
`adequate and well controlled clinical studies that rigorously assess clinically meaningful
`outcomes, including overall survival.
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`CLINICAL PHARMACOLOGY
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`1. Conduct a pharmacokinetic study of both deferiprone and its primary 3-O-glucuronide
`metabolite in patients with hepatic impairment. Submit the protocol to the Agency prior
`to conduct of the study for agreement with the study design. Conduct this
`pharmacokinetic study in a patient population with mild to severe hepatic insufficiency,
`according to the Child-Pugh classification.
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`2. Conduct a pharmacokinetic study of both deferiprone and its primary 3-O-glucuronide
`metabolite in patients with renal impairment. Submit the protocol to the Agency prior to
`conduct of the study for agreement with the study design. Conduct this pharmacokinetic
`study in a patient population with mild to severe renal insufficiency.
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`3. Conduct two in vitro studies; one to determine the affect of moderate to strong UDP
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`NDA 21-825
`Page 5
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`glucuronosyltransferase (UGT) inhibition and one to determine affect of moderate to
`strong UGT induction on the metabolism of deferiprone. The results of these studies will
`determine the need for additional in vivo drug interaction studies.
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`PRODUCT QUALITY
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`1. “Apotex, Inc.” is listed as the site for several method validation studies. Identify the
`location of this facility and briefly describe the manufacturing and control functions
`performed at this site. Also, indicate which of these functions are performed in support
`of the new drug application supported by Drug Master File 10,867.
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`2. For the drug substance lots used in the method transfer, validation and comparison
`studies, identify the manufacturing site, date of manufacture and batch size, and provide a
`certificate of analysis.
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`3. The submitted analytical method transfer documents (certificates of technology transfer)
`are not adequate in that the documents are incomplete, the studies they summarize are not
`sufficient for the intended purpose, and not all sites using these methods have been
`addressed.
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`a. In each document, clearly identify the location of the initiating and the receiving
`laboratories and summarize the study protocol.
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`b. For the Residual Solvents method, in each document address specificity, accuracy,
`precision, linearity and quantitation limit. Spiked samples may be used. Include
`copies of chromatograms labeled with the peak identity and the system suitability
`criteria from the specificity study. Address each system suitability criterion.
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`c. For the Assay method, the documents do not address transfer from Apotex
`Pharmachem to
` or to Apotex - Etobicoke. In each document,
`address specificity, accuracy, precision and linearity. Include copies of
`chromatograms labeled with the peak identity and the SS criteria from the specificity
`study. Address each system suitability criterion.
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`d. For the Related Substances method, the documents do not address transfer from
`Apotex Pharmachem to
` or to Apotex - Etobicoke. In each
`document, address specificity, accuracy, precision, linearity and quantitation limit.
`Include copies of chromatograms labeled with the peak identity and the system
`suitability criteria from the specificity study. Address each system suitability
`criterion.
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`4. Regarding the validation summary and comparison study for method AP66-DS-10-
`SG.01:
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`a. The method description indicates drug substance retention time of
`system suitability criterion. The specificity study reports values
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` as a
` and
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 21-825
`Page 6
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` for nominal conditions with
`the robustness study reports values of
`significant effect for all four method parameters tested. Revise the system suitability
`criteria for the method such that consistent values for drug substance retention time
`are obtained with each analysis.
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`b. For the specificity study, identity the compounds represented by the peaks with
`retention times at
`.
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`c. For the method precision study, identify the location of each of the chemists.
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`d. Revise the method comparison study to include data on same set of multiple drug
`substance lots.
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`5. Regarding the validation summary and comparison study for method AP66-DS-20-
`SG.01:
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`a. For the specificity study, identity the compounds represented by the peaks with
`retention times at
`.
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`b. For the method precision study, identify the location of each of the chemists.
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`c. For the robustness study, provide data to address the effect of variations in the cited
`method parameters on each of the proposed system suitability criteria for drug
`substance and for
` Also, provide copies of the chromatograms labeled with
`each of the system suitability criteria from this study.
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`d. Revise the method comparison study to provide test results for both drug substance
`and
` on the same set of multiple drug substance lots which contain impurities.
`Either spiked or degraded samples may be used.
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`6. The proposed retest period is based on bulk drug substance stored at ICH long term
`conditions and the post approval protocol indicates the use of ICH long term conditions.
`Revise the label storage statement to reflect the current USP controlled room temperature
`definition (20-25°C with excursions to 40°C). In addition, DMF 10,867 includes stress
`degradation studies which support a light protection statement. Revise the label storage
`statement to reflect protection from light.
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`7. We have reviewed the referenced dissolution profile data and recommend that the
`dissolution specification be revised to the following:
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`Apparatus: USP apparatus II (paddle) at 50 rpm
`Medium: 900 mL 0.1N HCl at 37°C
`Sampling: Single point with Q =
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`.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 21-825
`Page 7
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`8. For the drug product lots used in the method transfer, validation and comparison studies,
`identify the manufacturing site, date of manufacture, batch size, drug substance lot, and
`provide a certificate of analysis.
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`9. Regarding method APP66-IMTB-10-SG:
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`a. The methods for drug substance and drug product assay use the same analytical
`system and differ only in the sample preparation; however the system suitability
`criterion for drug substance retention time is
` for drug substance and
`for drug product. Explain the differences in this criterion.
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`b. The release specification indicates drug identity is established by comparison of
`retention time and the method description indicates drug identification is by
`comparison of UV scans. Specify which procedure is to be used and make the
`correction to the necessary documents.
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`10. Regarding the validation summary and comparison study for method AP66-IMTB-10-
`SG:
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`a. The data submitted for the linearity and robustness was that taken from the method
`validation study for drug substance. Revise these studies to address the effects of
`drug product and excipients on the test values.
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`b. For the method precision study, identify the location of the chemists referenced in the
`study.
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`c. For the robustness study, the drug substance retention time is shown to vary
`significantly with each of the four method parameters evaluated and the retention
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`time for nominal conditions is
` while the system suitability criterion is
`. Explain the discrepancy and revise the system suitability criteria to obtain a
`consistent value for drug substance retention time in each analysis.
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`d. Revise the method comparison study to include data on the same set of multiple drug
`product lots.
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`11. Regarding the validation summary and comparison study for method AP66-IMTB-20-
`SG.02:
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`a. The submitted validation summary is the method validation study for drug substance
`with a cover page indicating the use of drug product. Provide an acceptable method
`validation study for this method.
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`b. Revise the method comparison study to include data on the same set of multiple drug
`product lots. Spiked or degrades samples may be used.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 21-825
`Page 8
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`12. Regarding the validation summary and comparison study for method AP66-IMTB-41-
`SG.02:
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`a. Revise the linearity study to use drug product samples instead of drug substance.
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`b. Revise the method comparison study to include drug release profile data (sampling at
`10, 20, 30, 45 minutes) on the same set of multiple drug product lots.
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`13. Regarding the submitted drug product stability data:
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`a. There are completed 60 month studies at ICH long term conditions for four tablet lots
`manufactured with Apotex Pharmachem material; one tablet lot made with
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` material; and no tablet lots made with
` material.
`Provide additional data supporting a 60 month initial expiration date for tablets made
`with
` material. Also, specify how the drug product lot numbering
`system will differentiate between tablets made with drug substance from each of the
`three possible sites.
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`b. Provide dissolution profiles (10, 20, 30 and 45 minutes) for tablets used in the
`stability studies.
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`14. Regarding the proposed Patient Information Leaflet:
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`a. In section 16, revise the storage statement used to reflect the standard USP controlled
`room temperature statement.
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`b. In section 16, delete the statement
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`c. Identify the location of the lot number and expiration date on the label.
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`15. DMF 10,867 has been reviewed and found deficient to support approval of this NDA. A
`deficiency letter detailing the deficiencies has been issued the agent for the DMF holder.
`These deficiencies must be resolved before the application can be approved.
`
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`LABELING
`
`We reserve comment on the proposed labeling until the application is otherwise adequate. If you
`revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)]
`in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`FACILITY INSPECTIONS
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`After a December, 2008 inspection of the Apotex, Inc. (Etobicoke site, Ontario, Canada)
`manufacturing facility for this application, the Office of Compliance issued a warning letter
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 21-825
`Page 9
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`dated June 25, 2009, which conveyed cGMP deficiencies at this facility. Satisfactory resolution
`of these deficiencies is required before this application may be approved.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
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`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
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`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`

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`NDA 21-825
`Page 10
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will
`consider your lack of response a request to withdraw the application under 21 CFR 314.65. A
`resubmission must fully address all the deficiencies listed. A partial response to this letter will
`not be processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants, May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`If you have any questions, call Hyon-Zu Lee, Pharm.D., Regulatory Project Manager, at
`301-796-2050.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-21825
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`------------------------------------------
`--------------------
`APOPHARMA INC FERRIPROX (DEFERIPRONE)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`11/30/2009
`
`