`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`021825Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/Serial Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`21-825/ SE 0056
`Deferiprone (Ferriprox)
`Treatment of iron overload
`ApoPharma Inc
`Letter Date: April 14 2011
`Stamp Date: April 14 2011
`PDUFA Goal Date:
`
`Review Priority:
`Standard
`Biometrics Division:
`Division of Biometrics V
`Statistical Reviewer:
`Qing Xu, Ph.D
`Concurring Reviewers: Mark Rothmann, Ph.D., Statistical Team Leader
`
`Rajeshwari Sridhara, Ph.D., Director, DBV
`Medical Division:
`Division of Hematology Products
`Clinical Team:
`George Shashaty, M.D., Clinical Reviewer
`Kathy M Robie Suh, M.D., Clinical Team Leader
`Mara Bauman Miller
`
`Project Manager:
`Keywords:
`Bias, Confidence interval, Covariate, Logistic regression, Meta-analysis, Missing data,
`Pooling
`
`
`
`
`
`
`Reference ID: 3016315
`
`

`

`Table of Contents
`LIST OF TABLES.......................................................................................................................................................3
`LIST OF FIGURES.....................................................................................................................................................3
`1. EXECUTIVE SUMMARY .................................................................................................................................4
`2.
`INTRODUCTION ...............................................................................................................................................4
`2.1
`OVERVIEW......................................................................................................................................................4
`2.2
`DATA SOURCES ..............................................................................................................................................5
`3. STATISTICAL EVALUATION ........................................................................................................................5
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................5
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................6
`3.2.1 STUDY OBJECTIVE.............................................................................................................................................6
`3.2.2 STUDY DESIGN, ENDPOINTS AND ANALYSIS POPULATION ................................................................................6
`3.2.3 PATIENT DISPOSITION, DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................................................7
`3.2.4 Statistical Methodologies............................................................................................................................13
`3.2.5 Results and Conclusions .............................................................................................................................14
`3.2.5.1 Analysis results for serum ferritin............................................................................................................14
`3.2.5.2 Analysis results for Secondary Endpoint: LIC.........................................................................................19
`3.2.5.3 Analysis results for Secondary Endpoint: MRI T2*.................................................................................22
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................23
`4.
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................23
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................24
`5. SUMMARY AND CONCLUSIONS ................................................................................................................25
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................25
`5.2
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................27
`SIGNATURES/DISTRIBUTION LIST...................................................................................................................30
`
`
`
`
`
`Reference ID: 3016315
`
`2
`
`

`

`
`LIST OF TABLES
`
`Table 1 Number of eligible patients by study for serum ferritin-ITT population ..........................................................7
`Table 2 Number of eligible patients by study for liver iron concentration-ITT population...........................................8
`Table 3 Number of eligible patients by study for cardiac MRI T2* -ITT population ...................................................8
`Table 4 Summary of eligible petients between the Agency’s results and the sponsor’s results ....................................9
`Table 5 Reviewer’s summary of race by study for serum ferritin (ITT population)......................................................9
`Table 6 Reviewer’s summary of demographic for serum ferritin using ITT population ............................................11
`Table 7 Reviewer’s summary of demographic for serum ferritin, LIC, and MRI T2*................................................11
`Table 8 Reviewer’s summary of number of subjects and drop out rate over time.......................................................12
`Table 9 Reviewer’s summary of success rate by study for serum ferritin (ITT) .........................................................15
`Table 10 Reviewer’s meta-analysis for serum ferritin.................................................................................................16
`Table 11 Reviewer’s summary of descriptive statistics for serum ferritin ..................................................................17
`Table 12 Reviewer’s Estimate for covariates using logistic regression for serum ferritin ..........................................17
`Table 13 Reviewer’s summary of mean serum ferritin over time within 24 month ....................................................18
`Table 14 Reviewer’s summary of success rate by study for LIC ................................................................................19
`Table 15 Reviewer’s meta-analysis of LIC .................................................................................................................20
`Table 16 Reviewer’s summary of descriptive statistics for LIC..................................................................................20
`Table 17 Reviewer’s Summary of estimate for covariates using logistic regression for LIC......................................20
`Table 18 Reviewer’s summary of mean serum ferritin over time within 24 month ....................................................21
`Table 19 Reviewer’s summary of success rate by study for MRI T2*........................................................................22
`Table 20 Reviewer’s summary of descriptive statistics for MRI T2* .........................................................................22
`Table 21 Reviewer’s Summary of estimate for covariates using logistic regression for MRI T2* .............................22
`Table 22 Reviewer’s summary of mean MMRRI T2* over time within 24 month ...........................................................23
`Table 23 Reviewer’s subgroup analysis of gender, race, age and region for serum ferritin........................................24
`Table 24 Reviewer’s summary of subgroup analysis for serum ferritin by baseline of serum ferritin and thalassemia
`.....................................................................................................................................................................................24
`
`LIST OF FIGURES
`Figure 1 Reviewer’s summary of number of subjects over time .................................................................................12
`Figure 2 Reviewer’s summary of drop out rate over time ...........................................................................................13
`Figure 3 Reviewer’s summary of mean serum ferritin over time ................................................................................18
`Figure 4 Reviewer’s analysis of mean serum ferritin change over time (study LA-01, LA-16, LA-28).....................19
`Figure 5 Reviewer’s summary of mean LIC over time ...............................................................................................21
`Figure 6 Reviewer’s summary of mean MMRRII TT22** over time.......................................................................................23
`
`
`
`
`Reference ID: 3016315
`
`3
`
`

`

`
`1.
`
`Deferiprone (Ferriprox) is an orally administered iron chelator that is being developed for the
`indication of the treatment of patients with transfusional iron overload when current chelation
`therapy is inadequate. NDA 21825 for Ferriprox (deferiprone) was submitted on January 29,
`2009 and a Complete Response letter was sent to the sponsor on November 30, 2009. This
`resubmission of NDA 21825/SE0056 including study LA36-0310 was designed as an analysis of
`existing data from studies previously conducted to evaluate the efficacy of Ferriprox. No new
`data were collected and the original purpose of collecting the data and their application did not
`change. Efficacy data for study LA 36-0310 were derived from 12 of 17 studies. The primary
`efficacy endpoint was the change in serum ferritin concentration from baseline within one year
`of Ferriprox therapy. Ferriprox therapy was considered successful in individual patients who
`experienced a ≥20% decline in serum ferritin concentration within one year of therapy.
`
`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.
`
`The Oncology Drug Advisory Committee (ODAC) Meeting discussed NDA 21825/SE0056
`study results on September 14, 2011. For the question:
`
`1. Is there a favorable benefit/risk profile for deferiprone in the treatment of patients in who
`current chelation therapy is inadequate?
`- Committee voted: No 2, Yes 10.
`
`The results for the AC member’s questions are given in the Appendix.
`
`
`
`
`2.
`
`
`
`EXECUTIVE SUMMARY
`
`INTRODUCTION
`
`2.1 Overview
`
`
`The original NDA 21825 was submitted to the Agency on January 29, 2009. The submission of
`the NDA included a single randomized controlled trial. The primary endpoint in that trial was the
`change in cardiac iron as measured by cardiac MRI T2* assessment after one year of treatment
`with Ferriprox. The comparator drug was deferoxamine, which at the time of the study was the
`only approved drug for the indication. The agency was concerned that the primary endpoint
`
`
`
`Reference ID: 3016315
`
`4
`
`

`

`measured was not a validated surrogate for clinical utility. At the conclusion of the review, the
`Agency sent a Complete Response (CR) letter to the sponsor describing the deficiencies of the
`data submitted. In the CR letter dated November 30, 2009, the Agency recommended that the
`sponsor perform “adequate and well-controlled” trials with Ferriprox to support the application
`for approval of the NDA. Subsequently, the FDA communicated to ApoPharma that it would
`consider accelerated approval for the Ferriprox NDA with a single arm study in patients
`intolerant of or not responding to existing therapy, based on pre-existing data from Ferriprox
`clinical program.
`
`This resubmission includes clinical study report of LA36-0310. Study LA36-0310 was designed
`as an analysis of existing data from studies previously conducted to evaluate the efficacy of
`Ferriprox. Efficacy data in LA36-0310 were derived from 12 of 17 studies. Four additional
`studies submitted to the NDA, LA109902, LA14-9907, LA20-BA, and LA21-BE, were not
`included in the current analysis as they did not assess efficacy. Another submitted study LA17-
`9701, was not included as the sponsor did not receive a complete database for the program.
`
`The determination of which patients fulfilled the study criteria was conducted by an Independent
`Committee that reviewed the relevant data from the patients enrolled in studies previously
`submitted to the FDA to determine eligibility. Eligible patients met the following criteria:
`1. Patients were treated with Ferriprox;
`2. At least a single baseline value for serum ferritin or LIC or cardiac MRI T2*was
`available; and
`3. Follow-up assessment of serum ferritin or LIC or cardiac MRI T2* was carried out after
`initiation of Ferriprox therapy and within one year therapy.
`
`
`
`
`
`
`
`
`2.2 Data Sources
`
`
`The applicant submitted this NDA including the data to the FDA CDER Electronic Document
`Room (EDR).The analysis dataset was not adequate and required an information request. The
`clinical study reports and datasets are located at the following location:
`\\CDSESUB1\EVSPROD\NDA021825\021825.ENX
`
`3.
`
`
`
`STATISTICAL EVALUATION
`
`3.1 Data and Analysis Quality
`
`
`
`Study LA36-0310 analyzed data from clinical studies that were conducted to support NDA 21-
`825. Patients were selected from studies submitted to the Agency as part of the NDA, and data
`integrated up to 11 May 2010 for ongoing clinical studies. An integrated lab dataset including all
`
`5
`
`Reference ID: 3016315
`
`

`

`serum ferritin, LIC and cardiac MRI T2* data, and data on demographics, disposition, medical
`history, and exposure, were sent to an Independent Committee responsible for selecting patients
`for analysis. The integrated datasets were prepared according to standard CDISC principles and
`were accompanied by a proper description of each field (i.e., metatables). Patient selection was
`based on inclusion/exclusion criteria previously established and agreed upon with the Agency.
`The Biostatistics group at ApoPharma subsequently assessed the serum ferritin, LIC and cardiac
`MRI T2* data captured during treatment with Ferriprox for up to one year for analysis of its
`efficacy in the cohort of patients selected by the independent committee. The number of
`Ferriprox-treated patients who met the defined criteria for successful treatment outcomes was
`determined and a success rate was calculated. The complete patient dataset, the dataset indicating
`the patient selection, the corresponding analysis dataset and the SAS program for determination
`of responders is presented in NDA 21-825 resubmission.
`
`With the updates from the sponsor upon the statistical reviewer’s information request, the
`reviewer was able to perform all analyses using the submitted data. No additional data
`submission was needed.
`
`
`
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Objective
`
`
`The objective of this study was to evaluate the efficacy of oral administration of Ferriprox in the
`treatment of iron overload in patients in whom previous chelation has failed. Chelation failure
`was defined as iron accumulation above a boundary level, defined by high serum ferritin or LIC
`or low cardiac MRI T2*levels.
`
`
`3.2.2 Study Design, Endpoints and Analysis Population
`
`
`Overall Study Design
`
`In order to evaluate Ferriprox as a second line treatment for transfusion iron overload, Study
`LA36-0310 was designed to analyze existing data from studies previous conducted to evaluate
`the efficacy of Ferrriprox. Efficacy data in LA36-0310 were derived from 12 of 17 studies. Four
`additional studies submitted to the NDA, LA109902, LA14-9907, LA20-BA, and LA21-BE,
`were not included in the current analysis as they did not assess efficacy. Another submitted study
`LA17-9701, was not included as the sponsor did not receive a complete database for the
`program. An integrated lab dataset including all serum ferritin, LIC and cardiac MRI T2* data,
`and data on demographics, disposition, medical history, and exposure, were sent to an
`Independent Committee responsible for selecting patients for analysis.
`
`Primary Endpoint: Change in serum ferritin concentration from baseline within one year of
`Ferriprox therapy (and up to 3 months following the anniversary date or the date of medication
`
`
`
`Reference ID: 3016315
`
`6
`
`

`

`termination). Ferriprox therapy was considered successful in individual patients who experienced
`a ≥20% decline in serum ferritin concentration within one year of therapy.
`
`Secondary Endpoints: Change in cardiac MRI T2* and LIC from baseline within one year of
`Ferriprox therapy (and up to 3 months following the anniversary date or the date of medication
`termination). Ferriprox therapy was considered successful in individual patients who experienced
`a ≥20% increase in cardiac MRI T2* or a ≥20% decline in LIC within one year of therapy.
`
`The Intent-To-Treat (ITT) Population: was the primary population for the efficacy analyses
`for this study. The ITT population was defined by sponsor as patients who had taken at least one
`dose of Ferriprox and had at least one post-baseline measurement of that efficacy measure. The
`ITT population included data from all randomized patients in the studies. For studies in which
`there was no patient randomization (Studies LA-02/06; LA-03; LA-04/06B; LA11; LA12 9907;
`LA15-0002; LA28-CMP; LA30-0307 and Borgna-Pignatti study), data from all patients who had
`received Ferriprox therapy were included.
`
`The Per-Protocol (PP) population: comprised those patients who had completed their study of
`origin or at least one year of Ferriprox therapy for long-term studies, and had no missing data for
`the end-of-study measurement or the last scheduled measurement at the end of the first year,
`respectively, for that efficacy measure.
`
`Reviewer’s Comment:
`During the review of the submissions, the Agency raised a concern of selection bias due to the
`lack of randomization. In order to minimize such bias, the Agency suggested sponsor using an
`Independent Committee to select subjects from the entire integrated dataset following approved
`inclusion and exclusion criteria. The agreement was reached between Agency and sponsor.
`
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`A total of 746 patients with serum ferritin, LIC and MRI T2* data were analyzed by an
`Independent Committee for study eligibility. Of these , 264 were deemed eligible based on the
`serum ferritin criterion, 117 based on the LIC criterion and 39 based on the cardiac MRI T2*
`criterion. These data are shown in the Table 1, Table 2 and Table 3.
`
`
`Table 1 Number of eligible patients by study for serum ferritin-ITT population
`
`Data source: sponsor’s clinical report table 6.1-1
`
`
`
`
`
`7
`
`Reference ID: 3016315
`
`

`

`Table 2 Number of eligible patients by study for liver iron concentration-ITT population
`
`
`
`
`
`Data source: sponsor’s clinical report table 6.1-2
`
`
`Table 3 Number of eligible patients by study for cardiac MRI T2* -ITT population
`
` Data source sponsor’s clinical report table 6.1-3
`
`Reviewer’s comments:
`
`This study is a retrospective study designed to analyze existing data from studies conducted
`previously to evaluate the efficacy of Ferrriprox. Efficacy data in LA36-0310 were derived from
`12 of 17 studies; the study involves pooling data from 12 studies of different designs; different
`durations of drug treatment; different time intervals of patient visits; different inclusion and
`exclusion criteria; and different patient characteristics. This inevitably raises an issue of data
`integrity and heterogeneity that can potentially cause biases. The sponsor followed the
`suggestion from the Agency and used Independent Committee to pick the eligible subjects.
`However, such approach can only limit biases, but can not eliminate biases.
`
`By the entry criteria all patients must have received some prior chelation therapy (deferoxamine
`or deferasirox). The reviewer found that among the 264 patients, there are 23 patients who have
`no record about whether they took the prior chelation therapy. However, excluding these 23
`patients will not alter the conclusion for primary efficacy. These 23 patients are:
`LA_01: 66, 67;
`
`
`8
`
`Reference ID: 3016315
`
`

`

`LA_12: 171, 31, 36;
`LA_0206: 222, 264, 7, 9
`LA_04: 2, 40, 99
`LA_11: 102, 104,106,107,108,109, 112,113,118,121,122, 124
`
`These population overlapped but were not superimposable for the three endpoints
`
`During the review process, the reviewer found there were some discrepancies between the
`Agency’s results and the sponsor’s results regarding the number of subject for the different
`studies for serum ferritin based on dataset that the sponsor sent to the Independent Committee
`for the selection of eligible subject (Table 4). The sponsor clarified as following:
`
`
`1. With the exception of the 2 patients not included by the Agency in the total number of
`patients (744 vs 746), the discrepancies between the Agency’s numbers of subjects and
`ApoPharma’s numbers can be demonstrated to be a consequence of steps taken by the
`company to ensure that patients enrolled in more than one study were counted only once
`when the dataset was integrated
`2. Data on all patients with serum ferritin values were sent by ApoPharma to the
`Independent Committee for consideration. The Independent Committee did not include 2
`of the 746 patients (BP_283 and LA_12_26) in the la36cohort dataset returned to
`ApoPharma. The sponsor surmise that there 2 patients were not included because they
`had neither a baseline value nor a value within the 1-year cut-off period.
`
`Table 4 Summary of eligible petients between the Agency’s results and the sponsor’s results
`Total N
`N for eligible patients
`Study ID
`Sponsor
`Sponsor
`35
`8
`151
`65
`24
`8
`157
`56
`25
`7
`23
`12
`69
`19
`29
`18
`29
`5
`8
`3
`100
`36
`96
`27
`
`
`746
`264
`
`FDA
`8
`59
`7
`58
`7
`12
`22
`18
`5
`24
`15
`26
`3
`264
`
`FDA
`32
`151
`22
`165
`28
`23
`61
`29
`29
`8 3
`25
`86
`10
`744
`
`LA_01
`LA 0206
`LA 03
`LA 04
`LA_08
`LA 11
`LA 12
`LA_15
`LA 16
`LA 28
`LA_30
`BP
`LA 10
`Total
`
`Table 5shows reviewer’s summary of race for serum ferritin using ITT population.
`
`
`
`Table 5 Reviewer’s summary of race by study for serum ferritin (ITT population)
`
`
`
`Reference ID: 3016315
`
`9
`
`

`

`Study
`
`Total
`
`BP
`
`LA_01
`
`LA_0206
`
`LA_03
`
`LA_04
`
`LA_08
`
`LA_11
`
`LA_12
`
`LA_15
`
`LA_16
`
`LA_28
`
`LA_30
`
`ASIAN BLACK MULTI-RACIAL UNKNOWN WHITE Total
`0
`0
`0
`0
`27
`27
`0.00
`0.00
`0.00
`0.00
`10.23
`10.23
`5
`0
`0
`0
`3
`8
`1.89
`0.00
`0.00
`0.00
`1.14
`3.03
`1
`0
`0
`0
`64
`65
`0.38
`0.00
`0.00
`0.00
`24.24
`24.62
`4
`0
`0
`0
`4
`8
`1.52
`0.00
`0.00
`0.00
`1.52
`3.03
`6
`2
`1
`21
`26
`56
`2.27
`0.76
`0.38
`7.95
`9.85
`21.21
`0
`0
`0
`0
`7
`7
`0.00
`0.00
`0.00
`0.00
`2.65
`2.65
`12
`0
`0
`0
`0
`12
`4.55
`0.00
`0.00
`0.00
`0.00
`4.55
`0
`0
`0
`0
`19
`19
`0.00
`0.00
`0.00
`0.00
`7.20
`7.20
`0
`0
`0
`0
`18
`18
`0.00
`0.00
`0.00
`0.00
`6.82
`6.82
`0
`0
`0
`0
`5
`5
`0.00
`0.00
`0.00
`0.00
`1.89
`1.89
`3
`0
`0
`0
`0
`3
`1.14
`0.00
`0.00
`0.00
`0.00
`1.14
`15
`0
`0
`0
`21
`36
`5.68
`0.00
`0.00
`0.00
`7.95
`13.64
`46
`2
`1
`21
`194
`264
`17.42
`0.76
`0.38
`7.95
`73.48
`100.00
`
`
`Reviewer’s Comments:
`There were only 2 black patients in the study LA36-0310. Such patient proportion did not
`represent US patient population.
`
`
`Table 6 shows Reviewer’s summary of demographic for serum ferritin using ITT population
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3016315
`
`10
`
`

`

`Table 6 Reviewer’s summary of demographic for serum ferritin using ITT population
`COUNTRY
`Frequency
`Percent
`23
`8.71
`CANADA
`21
`7.95
`EGYPT
`8
`3.03
`GREECE
`12
`4.55
`INDONESIA
`18
`6.82
`IRAN
`128
`48.48
`ITALY
`4
`1.52
`MALAYSIA
`2
`0.76
`SINGAPORE
`12
`4.55
`THAILAND
`36
`13.64
`USA
`
`
`Reviewer’s Comment
`A majority of patients were from Italy (48.48%). A total of 36 (13.64%) subjects are from USA.
`
`
`Table 7 below shows the reviewer’s summary of demographic for serum ferritin, LIC, and MRI
`T2*, respectively.
`
`
`Table 7 Reviewer’s summary of demographic for serum ferritin, LIC, and MRI T2*
`Serum ferritin
`LIC
`MRI T2*
`
`24.3 ±4.7
`(12, 33)
`
`18 (46%)
`21 (54%)
`
`31 (79%)
`5 (13%)
`3 (8%)
`
`
`
`194 (73%)
`46 (17%)
`2 (1%)
`1 (0.4%)
`21 (8%)
`
`White
`Asian
`Black
`Multi-racial
`Unknow
`
`Reviewer’s Comment:
`For the primary efficacy endpoint of serum ferritin, the subjects ranged from 2 to 76 years in
`age, and mean age were 20.1 years. There were more female patients than male patients (55% vs
`45%). The majority of patients were white in race (73%).
`
`
`
`
`Reference ID: 3016315
`
`11
`
`
`
`Mean ± SD
`(Minimum, Maximum)
`
`20.1±12.3
`(2, 76)
`
`Female
`Male
`
`145 (55%)
`119 (45)
`
`Age
`
`Sex
`
`19.0±6.3
`(6, 40)
`
`54 (47%)
`60 (53%)
`Race
`93 (82%)
`18 (16)
`3 (3%0
`
`
`
`

`

`Table 8, Figure 1 and Figure 2 below show the reviewer’s summary of number of subjects over
`time and drop out rate over time
`
`
`Table 8 Reviewer’s summary of number of subjects and drop out rate over time
`MONTH
`Number of Subjects
`Drop Out Rate
`0
`264
`0
`3
`244
`0.075758
`6
`185
`0.299242
`9
`170
`0.356061
`12
`137
`0.481061
`15
`122
`0.537879
`18
`108
`0.590909
`21
`96
`0.636364
`24
`96
`0.636364
`27
`86
`0.674242
`30
`69
`0.738636
`
`Figure 1 Reviewer’s summary of number of subjects over time
`
`Reviewer's Summary of Number of Subjects over Time
`
`Deferiprone
`
`
`
`300
`250
`200
`150
`100
`50
`0
`
`Number of Subjects
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`Month
`
`18
`
`21
`
`24
`
`27
`
`30
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`12
`
`
`
`Reference ID: 3016315
`
`

`

`
`
`Figure 2 Reviewer’s summary of drop out rate over time
`Reviewer's Summary of Drop Out Rate Over Time
`
`Deferiprone
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`Month
`
`18
`
`21
`
`24
`
`27
`
`30
`
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0
`
`Drop Out Rate
`
`Reviewer’s Comments:
`A total of 20 (7.58%), 79 (29.92%), 94 (35.61%) and 127 (48.11%) subjects dropped out by
`month 3, 6, 9 and 12, respectively. High drop out rate could make the analyses results unreliable
`and misleading. The reviewer conducted primary efficacy analysis using worst-case-scenario
`missing data imputation by treating all missing values as non-response. The result is given in the
`section of 3.5.2.1.
`
`
`
`
`3.2.4 Statistical Methodologies
`
`All statistical tests were two-sided, and a p-value ≤ 0.05 was used for the determination of
`statistical significance.
`
`Analysis of primary efficacy endpoint –Serum Ferritin
`For the primary efficacy endpoint, the success rate was calculated as the proportion of patients
`with a reduction in serum ferrin by ≥ 20% (serum ferritin baseline value >2, 500 ug/L) within
`one year of Ferriprox treatment. The success rate by study and the overall success rate and its
`95% confidence interval (CI) were calculated based on Clopper-Pearson exact confidence
`interval.
`
`Analysis of secondary efficacy endpoint-LIC
`Analysis of LIC data was conducted only in those patients for whom baseline and post-Ferriprox
`LIC values were assessed by the same measurement technique (liver biopsy, SQUID or MRI).
`The success rate was calculated as the proportion of patients with a reduction in LIC by ≥ 20%
`(LIC baseline value > 7 mg Fe/g dw) within one year of Ferriprox treatment. The success rate by
`study and the overall success rate and its 95% confidence interval (CI) were calculated based on
`Clopper-Pearson exact confidence
`
`
`
`13
`
`Reference ID: 3016315
`
`

`

`Analysis of secondary efficacy endpoint-MRI T2*
`The success rate was calculated as the proportion of patients with a increase in cardiac MRI T2*
`by ≥ 20% (MRI T2* baseline value < 20 ms) within one year of Ferriprox treatment. The success
`rate by study and the overall success rate and its 95% confidence interval (CI) were calculated
`based on Clopper-Pearson exact confidence
`
`If the lower limit of the 95% CI for any efficacy measure was greater than the pre-defined
`criterion of treatment success (20%), the therapy was considered to be a success for that
`particular measure.
`
`The last observation carry forward (LOCF) method was used for data imputation for patients
`who had not completed one year on Ferriprox therapy.
`
`Reviewer’s Comments:
`This study is a retrospective study designed to analyze existing data from studies conducted
`previously to evaluate the efficacy of Ferrriprox. Efficacy data in LA36-0310 were derived from
`12 of 17 studies; the study involves pooling data from 12 studies of different designs; different
`durations of drug treatment; different time intervals of patient visits; different inclusion and
`exclusion criteria; and different patient characteristics. This inevitably raises an issue of data
`integrity and heterogeneity that can potentially cause biases. There are variations among all
`studies in the success rates based on the serum ferritin point estimate. For instance, the success
`rate for study LA12 was as low as 26%, while that of study LA15 was as high as 100%. To
`investigate this issue, the reviewer performed meta-analysis for these 12 studies, and presented
`the results in Section 3.2.5
`
`
`
`3.2.5 Results and Conclusions
`
`
`
`
`3.2.5.1 Analysis results for serum ferritin
`
`
`
`For serum ferritin, success rates and its 95% CIs by studies are summarized in the Table 9. The
`overall success rate was 52%, 95% CI was (45% to 58%).
`
`
`
`
`
`
`
`
`Reference ID: 3016315
`
`
`
`
`
`
`
`
`14
`
`

`

`Table 9 Reviewer’s summary of success rate by study for serum ferritin (ITT)
`Frequency
`Success
`Clopper-Pearson
`Row Pct
`95% CI
`N
`%
`12
`44.44
`4
`50.00
`26
`40.00
`5
`62.50
`29
`51.79
`4
`57.14
`10
`83.33
`5
`26.32
`18
`100.00
`4
`80.00
`2
`66.67
`17
`47.22
`136
`51.5
`
`(25.48, 64.67)
`
`(15.70, 84.30)
`
`(28.04, 52.90)
`
`(24.49, 91.48)
`
`(38.03, 65.34)
`
`(18.41, 90.10)
`
`(51.59, 97.91)
`
`(9.15, 51.20)
`
`(81.47, 100)
`
`(28.36, 99.49)
`
`(9.43, 99.16)
`
`(30.41, 64.51)
`
`(45.31, 57.69)
`
`BP
`
`LA_01
`
`LA_0206
`
`LA_03
`
`LA_04
`
`LA_08
`
`LA_11
`
`LA_12
`
`LA_15
`
`LA_16
`
`LA_28
`
`LA_30
`
`Total
`
`Number of
`Patients
`27
`
`8
`
`65
`
`8
`
`56
`
`7
`
`12
`
`19
`
`18
`
`5
`
`3
`
`36
`
`264
`
`
`Reviewer’s Comments:
`The overall success rate was 52% with its 95% CI of (45.3%, 57.7%). These results are
`consistent with the sponsor’s results. As the lower limit of the 95% CI is greater than 20% for
`this subset patient, the results support that Ferriprox is an effective treatment in reducing serum
`in patients who failed standard cheleation therapy. However, there is a large amount of
`variation among these 12 studies. For example: the success rate for LA 12 was 26% with 95% CI
`
`
`
`Reference ID: 3016315
`
`15
`
`

`

`of (9.2%, 51.2%); and the success rate for LA15 was 100% with 95% CI of (81.5%, 100%).
`Therefore, simply pooling these 12 studies together could make the results unreliable.
`
`The lower bounds of the 95% confidence interval for 4 studies (LA-01, LA-12, LA-18, LA-28) are
`less than 20%.
`
`Table 10 shows the reviewer’s meta-analysis of serum ferritin
`
`
`Table 10 Reviewer’s meta-analysis for serum ferritin
`
`Reviewer's Meta Analysis for Serum Ferritin
`
`Statistics for each study
`Event Lower Upper
`rate
`limit
`limit
`0.444
`0.272
`0.631
`0.500
`0.200
`0 800
`0.400
`0.289
`0.523
`0.625
`0.285
`0 875
`0.518
`0.389
`0.645
`0.571
`0.230
`0 856
`0.833
`0.523
`0 958
`0.263
`0.114
`0.498
`0.974
`0.690
`0 998
`0.800
`0.309
`0 973
`0.667
`0.154
`0 957
`0.895
`0.663
`0 974
`0.503
`0.435
`0 572
`
`Z-Value p-Value
`-0.576
`0.565
`0.000
`1.000
`-1.601
`0.109
`0.699
`0.484
`0.267
`0.789
`0.377
`0.706
`2.078
`0.038
`-1.976
`0.048
`2.519
`0.012
`1.240
`0.215
`0.566
`0.571
`2.863
`0.004
`0.096
`0.924
`
`Study name
`
`BP
`LA_01
`LA_0206
`LA_03
`LA_04
`LA_08
`LA_11
`LA_12
`LA_15
`LA_16
`LA_28
`LA_30
`
`Meta Analysis
`
`Event rate and 95% CI
`
`-1.00
`
`-0.50
`
`1.00
`0.50
`0.00
`Favours Ferriprox
`
`
`
`
`Reviewer’s Comments:
`The meta-analysis using the Meta-Analysis software showed t