`
`
`
`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 T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
`
`NDA/BLA #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`NDA 204063
`
`BG00012 (Dimethyl Fumarate) delayed release capsules
`
`Relapsing multiple sclerosis
`
`Biogen Idec Inc.
`
`Submission date: 02/27/2012
`PDUFA Date: 12/27/12
`Standard
`
`
`
`Division of Biometrics I
`
`Biometrics Division:
`Statistical Reviewer:
`Xiang Ling, Ph.D.
`Concurring Reviewers: Kun Jin, Ph.D., Team Leader
`James Hung, Ph.D., Director
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`
`
`Division of Neuropharmacological Drug Products, HFD-120
`
`Heather Fitter, M.D., Clinical reviewer
`Billy Dunn, M.D., Clinical Team Leader
`Nicole Bradley
`
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`Reference ID: 3203073
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`Page 1 of 31
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`Biogen Exhibit 2376
`Coalition v. Biogen
`IPR2015-01993
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`Table of Contents
`
`3
`
`1 EXECUTIVE SUMMARY .................................................................................................................................4
`2
`INTRODUCTION ...............................................................................................................................................5
`2.1
`OVERVIEW......................................................................................................................................................5
`2.2
`DATA SOURCES ..............................................................................................................................................5
`STATISTICAL EVALUATION ........................................................................................................................6
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................6
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................6
`3.2.1
`Study Design and Endpoints..................................................................................................................6
`3.2.2
`Statistical Methodologies.......................................................................................................................9
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics........................................................12
`3.2.4
`Results and Conclusions ......................................................................................................................17
`3.3
`EVALUATION OF SAFETY..............................................................................................................................25
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................25
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................25
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................27
`SUMMARY AND CONCLUSIONS ................................................................................................................29
`5.1
`STATISTICAL ISSUES.....................................................................................................................................29
`5.2
`COLLECTIVE EVIDENCE................................................................................................................................29
`5.3
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................30
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`LIST OF TABLES
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`
`Table 1. Study Efficacy Endpoints ................................................................................................................................7
`Table 2. Subject Disposition (Study 301)....................................................................................................................12
`Table 3. Subject Disposition (Study 302)....................................................................................................................13
`Table 4. Demography for Studies 301 and 302, ITT population .................................................................................15
`Table 5. Baseline MS Disease Characteristics in Studies 301 and 302, ITT population .............................................16
`Table 6. Summary of Proportion of Subjects Relapsed at 2 Years (Study 301) ..........................................................17
`Table 7. Estimated Proportion of Relapsing Patients based on the presence of the adverse event of flushing (Study
`301)..............................................................................................................................................................................18
`Table 8. Number of New or Newly Enlarging T2 Lesions at 2 Years (Study 301).....................................................19
`Table 9. Number of Gd-Enhancing Lesions at 2 Years (Study 301) ...........................................................................19
`Table 10. Summary of Annualized Relapse Rate at 2 Years (Study 301) ...................................................................20
`Table 11. Summary of Disability Progression by EDSS at 2 Years (Study 301) ........................................................21
`Table 12. Summary of Annualized Relapse Rate at 2 Years (Study 302) ...................................................................22
`Table 13. Estimated ARR based on the presence of the adverse event of flushing (Study 302) .................................22
`Table 14. Number of New or Newly Enlarging T2 Lesions at 2 Years (Study 302)...................................................23
`Table 15. Number of New or Newly Enlarging T1 Lesions at 2 Years (Study 302)...................................................23
`Table 16. Summary of Proportion of Subjects Relapsed at 2 Years (Study 302) ........................................................24
`Table 17. Summary of Disability Progression by EDSS at 2 Years (Study 302) ........................................................24
`Table 18. Summary of proportion of subjects relapsed by demographics subgroups (Study 301)..............................25
`Table 19. Summary of annualized relapse rate by demographics subgroups (Study 302)...........................................26
`Table 20. Summary of proportion of subjects relapsed by other subgroups (Study 301)............................................27
`Table 21. Summary of annualized relapse rate by other subgroups (Study 302).........................................................28
`Table 22. Summary of Primary and Secondary Endpoints for Study 301 and 302 .....................................................30
`
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`LIST OF FIGURES
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`Figure 1. Time to discontinuation of study drug - Studies 301 and 302 Pooled..........................................................14
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`1 EXECUTIVE SUMMARY
`
`The data overall provided adequate evidence to support for the efficacy of BG00012 as treatment
`of patients with relapsing multiple sclerosis.
`
`In both pivotal studies, treatment with BG00012 BID and TID resulted in a statistically
`significant effect on relapses and MRI lesion accumulation. Study 301 also yielded a statistically
`significant effect of BG00012 on disability progression, and in Study 302 BG00012 groups had
`numerically fewer subjects with disability progression compared to the placebo group. The effect
`of BG00012 was generally consistent across a variety of subgroups defined by demographic and
`baseline disease characteristics.
`
`Since flushing is a known side effect of BG00012 and occurred to high percentage of subjects,
`the agency was concerned about perceived unblinding of subjects’ treatment assignments by
`observing flushing related events. To assess the robustness of the primary analysis result against
`potentially biased relapse assessment in case of perceived unblinding, this reviewer conducted
`worst case scenario analyses, in which all relapses prior to and after alternative MS medications
`were included for subjects in BG00012 groups but only relapses that met objective criteria as
`assessed by sites, confirmed by a blinded Independent Neurology Evaluation Committee (INEC),
`and occurred prior to alternative MS medications, were included for placebo subjects. The results
`of the worst case analysis still reached statistical significance.
`
`The treatment discontinuation rate was high in both studies, partly because the studies allowed
`subjects to cross over to alternative MS treatments. However, as shown in a series of sensitivity
`analyses including analyses of the worst case scenario, treatment discontinuation or the switch to
`alternative MS medications did not appear to have a significant effect on the efficacy results or
`conclusions.
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`INTRODUCTION
`
`2
`
`
`2.1 Overview
`
`
`BG00012 is an oral formulation containing the single active ingredient dimethyl fumarate (DMF)
`for the intended treatment of subjects with relapsing multiple sclerosis (MS). BG00012 was
`developed under IND 73061. SPA was submitted for pivotal Studies 109MS301 and 109MS302
`(hereafter referred to as “Study 301” and “Study 302,” respectively) without reaching Agency
`agreement. However, advices from the Agency were incorporated into the study protocols before
`the studies were initiated, such as inclusion of the 240 mg BID dose group, changing the primary
`endpoint in one study from proportion relapsed to annualized relapse rate, and requiring subjects
`to remain on study treatment for 1 year before being eligible for rescue treatment with an
`approved therapy due to relapse. Statistical analysis plan (SAP) was submitted for Agency
`review (SN143) and revised according to the agency’s comments.
`
`Studies 301 and 302 were Phase 3, randomized, placebo-controlled studies that evaluated the
`efficacy and safety of 2 dosing regimens of BG00012 (240 mg BID and 240 mg TID) versus
`placebo. Study 302 also included an active reference comparator (GA). A total of 1237 RRMS
`subjects were enrolled into Study 301 and 1430 subjects into Study 302. Subjects were required
`to have an EDSS between 0 and 5 at randomization and must have experienced a least 1 relapse
`within the year prior to randomization or have had a Gd-enhancing lesion on MRI scan obtained
`within 6 weeks prior to randomization. The only difference between the eligibility criteria of the
`2 studies was in exposure to GA. In Study 302, no prior exposure to GA was allowed, whereas in
`Study 301, subjects could have received prior treatment with GA but had to have discontinued
`for at least 3 months prior to randomization.
`
`
`
`2.2 Data Sources
`
`Materials reviewed for this application include the clinical study reports, raw and derived
`datasets, SAS codes used to generate the derived datasets and tables, protocols, statistical
`analysis plans, and documents of regulatory communications, which are located in the following
`directory: \\cdsesub5\EVSPROD\NDA204063\0000.
`
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`3 STATISTICAL EVALUATION
`
`
`3.1 Data and Analysis Quality
`
`From raw tabulation, key efficacy endpoints were reproduced by this reviewer. Documentation
`of statistical analysis methods was included with sufficient details for this reviewer to reproduce
`the applicant’s key efficacy results.
`
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`Enrollment into Study 301 began under Version 1, dated 21 September 2006. The protocol was
`subsequently amended 5 times with most of the amendments occurred early in the study and the
`last amendment dated 26 May 2010. The first subject was treated on 14 March 2007, and the last
`subject completed the study on 23 February 2011. Statistical Analysis Plan (SAP) was finalized
`on 10 March 2011, prior to database lock.
`
`Enrollment into Study 302 began under Version 1, dated 16 October 2006. The protocol was
`subsequently amended 3 times with the final version dated 09 January 2008. The first subject
`was treated on 28 July 2007, and the last subject completed the study on 24 August 2011. SAP
`was finalized on 3 October 2011, prior to database lock.
`
`Study design
`Studies 301 and 302 were Phase 3, randomized, placebo-controlled studies that evaluated the
`efficacy and safety of 2 dose regimens of BG00012 (240 mg BID and 240 mg TID) versus
`placebo. Study 302 also included an active reference comparator (GA 20 mg SC injection QD).
`Oral treatments (placebo or BG00012) were double-blind and GA treatment was single-blind.
`Both studies were also rater-blinded.
`
`The sample size was planned to be approximately 1010 subjects for Study 301 and 1230 for
`Study 302. A total of 1237 RRMS subjects were enrolled into Study 301 and 1430 subjects into
`Study 302. Subjects were randomized equally to the study arms. All subjects who were
`randomized at sites where MRI was deemed feasible had the option of participating in the MRI
`portion of the study (MRI cohort). In both studies, approximately 90% to 95% of subjects at
`qualified sites chose to participate in the MRI scanning, and about 40% to 45% of the
`randomized subjects were part of the MRI cohort. Randomization in both Studies 301 and 302
`was stratified by investigational site to ensure that the number of subjects in the MRI cohort
`would be approximately balanced across treatment groups.
`
`The duration of blinded study treatment in both studies was 96 weeks and clinic visits occurred
`every 4 weeks. Subjects who discontinued the study treatment prematurely for any reason were
`to remain in the study and continue with an abbreviated visit schedule.
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`If subjects experienced confirmed disability progression or if they had completed 48 weeks of
`blinded treatment and experienced INEC- confirmed relapses (1 relapse on or after Week 24 in
`Study 301 or 2 relapses at any time in Study 302), they were offered the option of remaining on
`blinded treatment, discontinuing treatment and continuing in the study, or switching to
`alternative MS medications and continuing in the study. Data after such medications were
`administered were excluded from analyses unless stated otherwise.
`
`
`Efficacy Endpoints in Studies 301 and 302
`
`In Study 302, the primary efficacy endpoint was annualized relapse rate at 2 years, which is the
`most common measure of relapse used in confirmatory MS trials. In Study 301, the primary
`efficacy endpoint was the proportion of subjects relapsed at 2 years.
`
`
`Table 1. Study Efficacy Endpoints
`
`
`
`
`
`Clinical Relapses
`Relapses were defined as new or recurrent neurologic symptoms not associated with fever or
`infection, lasting at least 24 hours, and accompanied by new objective neurological findings
`upon examination by the examining neurologist. New or recurrent neurologic symptoms that
`evolved gradually over months were considered disease progression, not an acute relapse. New
`or recurrent neurologic symptoms that occurred fewer than 30 days following the onset of a
`relapse as defined above were to be considered part of the same relapse.
`
`Subjects who experienced new neurologic symptoms were to contact the site to determine the
`necessity of an Unscheduled Relapse Assessment Visit. If required, the subject was then
`evaluated by the treating neurologist, subsequently assessed by the examining neurologist, and
`then, based on the examining neurologist’s findings, the treating neurologist determined whether
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`new objective findings (i.e., an objective relapse) had occurred. The protocol-defined objective
`relapses assessed by the sites then had to be reviewed and confirmed by a blinded Independent
`Neurology Evaluation Committee (INEC). The same INEC was used in both studies.
`
`The annualized relapse rate (ARR) for an individual subject was calculated as the number of
`relapses for that patient divided by the number of patient-years followed. The proportion of
`subjects who experienced a relapse was estimated as the probability of relapse at 2 years from
`the Kaplan-Meier curve.
`
`Confirmed disability progression
`Over the time course of MS, recovery from clinical relapses tends to be incomplete, leading to
`the accumulation of functional disability. In the Phase 3 studies, confirmed disability progression
`was defined as at least a 1.0 point increase on the EDSS from a baseline EDSS >=1.0 that was
`sustained for 12 weeks or a 1.5 point increase on the EDSS from a baseline EDSS = 0 that was
`sustained for 12 weeks. The EDSS score is based on scores determined for ambulation and 7
`functional systems and ranges from 0.0 (normal exam) to 10.0 (death due to MS). EDSS scores
`were obtained at regular clinic visits (i.e., every 12 weeks) as well as at any unscheduled relapse
`assessment visits.
`
`The date of the initial visit at which the minimum increase in the EDSS score was met was the
`date of onset of the progression (tentative progression). Death due to MS was counted as
`progression. If the subject was in the midst of a tentative progression at the time of death, the
`progression date was the date of the start of the progression. Otherwise, the progression date was
`the date of death.
`
`Progression was defined as confirmed when this minimum EDSS change is present on the next
`study visit occurring after 74 days or longer from the initial observation. The 74 day interval was
`based on the visit windows allowed in the protocol around the target visit day. A progression
`could start but could not be confirmed when a subject was experiencing an INEC-confirmed
`relapse. If a subject met the above criteria for confirmed progression and was also experiencing a
`relapse, the subject had to meet the defined minimum criteria at the next visit in order for the
`progression to be confirmed. Progression could be confirmed at the Premature Study Withdrawal
`Visit or after the start of alternative MS medications, or the Week 12 data from the safety
`extension study 109MS303.
`
`Subjects who did not have a sustained progression based on the above rules were censored. The
`censoring date was the last EDSS evaluation that is not a tentative progression prior to end of
`study or alternative MS medications.
`
`MRI endpoints
`In each study, brain MRI scans with and without Gd were performed at baseline, 6 months, 1
`year, and 2 years. MRI scans were forwarded to a central MRI reading center for evaluation by
`staff who were blinded to individual subjects’ treatment assignments. MRI endpoints included
`the number of new or newly enlarging T2 hyperintense lesions, the number of T1 hypointense
`Lesions and the number of Gd-enhancing lesions.
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`Reviewer’s comment:
`Flushing is a known side effect of BG00012. The study had taken measures to protect against
`perceived unblinding of subjects’ treatment assignments, such as using separate study personnel
`to conduct efficacy assessments and treat subjects, requiring confirmation of relapses by INEC,
`instructing subjects not to take their dose of study treatment within 4 hours before a clinic visit to
`prevent site personnel from observing any drug-induced symptoms. Still, as flushing is a
`common event that has been observed for high percentage of subjects on BG00012, the agency is
`concerned about the possible blind breaking. Sensitivity analyses were conducted by this
`reviewer to check the robustness of the study result against potential unblinding, as discussed in
`the following sections.
`
`
`3.2.2 Statistical Methodologies
`
`
`Analysis Population
`Statistical analyses of clinical endpoints were based on the intent-to-treat (ITT) population,
`defined as all subjects who were randomized and received at least one dose of study treatment.
`Subjects were analyzed according to their randomized treatment assignment.
`
`MRI endpoints were analyzed using the MRI Cohort, consisting of ITT subjects participating at
`sites that had adequate MRI equipment, who had at least one MRI scan available for analysis.
`
`Statistical Testing Procedures
`The endpoints were tested in the fixed order as shown in Table 1. If statistical significance was
`not achieved for an endpoint for a particular dose level, all endpoint(s) of a lower rank for that
`dose level were not considered statistically significant. For each endpoint, the TID group was
`compared with placebo and if statistically significant (p(cid:148)0.050), the BID group was compared
`with placebo.
`
`Missing Data
`In the primary analyses of all efficacy endpoints, except for that of confirmed disability
`progression based on EDSS scores, observed data after the initiation of alternative MS
`medications were excluded, or subjects were censored at the time the alternative MS medications
`were started if the subject had not experienced the event. In the analysis of disability progression
`based on EDSS, EDSS evaluations performed after the initiation of alternative MS medications
`were used to confirm tentative progression that started prior to the switch to alternative MS
`medications.
`
`For the analysis of MRI secondary endpoints, post-baseline data that were missing for any reason
`(e.g., early withdrawal, skipped visits, or the exclusion of data after alternative MS medications
`were started) were imputed.
`
`Details on missing data handling were discussed below in the analysis methods for each
`endpoint.
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`Analysis Methods
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`Proportion of subjects who experienced a relapse
`The analysis method for the proportion of subjects relapsed was a Cox proportional hazards
`model for time to first relapse, adjusted for baseline number of relapses in the year prior to study
`entry, baseline age (<40 versus (cid:149)40 years), EDSS score ((cid:148)2.0 versus >2.0), and region. The
`proportion of subjects who experienced a relapse was estimated as the probability of relapse at 2
`years from the Kaplan-Meier curve.
`
`Note that in the final protocol for both studies, the baseline EDSS score used in primary analysis
`of the proportion of subjects relapsed at 2 years was categorized as (cid:148)3.5 vs. >3.5. However, the
`SAPs used EDSS score (cid:148)2.0 versus >2.0. Since the SAPs were dated after the protocols, this
`reviewer accepted the use of EDSS score (cid:148)2.0 versus >2.0 in the primary analysis and conducted
`additional analyses using EDSS score (cid:148)3.5 versus >3.5 to check the robustness of the primary
`analysis result.
`
`Only INEC-confirmed relapses were included in the primary analyses. Data after subjects
`switched to alternative MS medications were excluded, and the subject’s time on study were
`censored at the time the alternative MS medication was started. The following pre-specified
`sensitivity analyses were performed:
`1) A logistic regression with the outcome of relapse (Yes/No) over the course of 2 years in the
`ITT population. Each subject with unknown relapse status (subject did not experience an INEC-
`confirmed relapse prior to withdrawal from study or switch to alternative MS medications) were
`classified as having experienced a relapse in the analysis if the reasons on either CRF page were
`indicative of relapse, death due to MS, disease worsening, disease progression, or lack of
`efficacy, or switch to alternative MS medication;
`2) Logistic regression on INEC confirmed relapses in which subjects with unknown relapse
`status were considered as relapsed;
`3) Cox proportional hazards model on INEC-confirmed relapses in the per-protocol population;
`4) Cox proportional hazards model on all relapses recorded on CRF, regardless of whether they
`met objective criteria or were INEC-confirmed;
`5) Cox proportional hazards model on objective relapses; and
`6) Cox proportional hazards model on INEC-confirmed relapses including those prior to and
`after alternative MS medications.
`All sensitivity analyses adjusted for the same covariates used in the primary analysis.
`
`
`Annualized relapse rate (ARR)
`ARR was analyzed using a negative binomial regression model adjusted for baseline EDSS score
`((cid:148)2.0 versus>2.0), baseline age (<40 versus (cid:149)40 years), region, and the number of relapses in the
`year prior to study entry. The logarithmic transformation of the time on study was included in the
`model as the offset parameter. Dispersion was evaluated from the Pearson Chi-Square statistic. It
`was planned that if the data were underdispersed, or if the negative binomial regression model
`did not converge, a Poisson regression model would be used instead.
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`The primary analysis of ARR was based on INEC-confirmed relapses. Relapses that occurred
`after subjects received alternative MS medications were excluded from the analyses of relapse
`rate, and the subject’s time on study was censored at the time the alternative MS medication was
`started. The following four sensitivity analyses were pre-specified for ARR using the same
`negative binomial regression model as the primary analysis, on different population or with
`additional relapses:
`(1) INEC-confirmed relapses in the per-protocol population;
`(2) objective relapses (INEC confirmed or not);
`(3) all relapses recorded on the Unscheduled Relapse (regardless of whether they met objective
`criteria or were INEC-confirmed)
`(4) INEC-confirmed relapses both before and after initiation of alternative MS medications.
`
`
`Disability progression
`Disability progression measured by EDSS over 2 years was analyzed using a Cox proportional
`hazards model, adjusted by baseline EDSS value as a continuous variable, region, and age (<40
`versus (cid:149)40 years). Two pre-specified sensitivity analyses were performed by the sponsor, which
`differed from the primary analysis only in that they used the per-protocol population or required
`that disability progression be confirmed after 24 weeks.
`
`
`MRI endpoints
`Negative binomial regression was used to analyze the number of new or newly-enlarging T2
`hyperintense lesions and the number of new T1 hypointense lesions over 2 years. The model
`included treatment group and adjusted for region and baseline volume of T2/T1 lesions. Missing
`post-baseline data were imputed based on the assumption that new lesions develop at a constant
`rate (constant rate assumption). For example, if a subject had 1 new lesion that developed
`between Week 24 and 48, then had a missing value for Week 96, the number of new lesions
`developed at Week 96 was assumed to be 2, since the time interval between Week 48 to Week
`96 is twice that between Week 24 to Week 48. Missing data were not imputed for subjects with
`no post-baseline data. To reduce the influence of outliers, any imputed values greater than the
`biggest observed value were truncated at the biggest observed value in the analysis. Two
`sensitivity analyses will be performed using 1) the observed data prior to start of alternative MS
`treatments; and 2) all observed data, prior to and after alternative MS medications.
`
`Since the majority of subjects have no Gd-enhancing lesions, ordinal logistic regression was used
`for the analysis of the number of Gd-enhancing lesions at 2 years. The categories for the number
`of lesions are 0, 1, 2, 3-4 and (cid:149)5. The model included treatment group, and adjusted for region
`and the baseline number of Gd-enhancing lesion. If there were a few subjects with an extremely
`large number of Gd-enhancing lesions at baseline, extreme values above 30 were considered as
`30 in the model. Missing data for Gdenhancing lesions were imputed using the method of last
`observation carried forward. Baseline data were not carried forward. A sensitivity analysis using
`only observed data prior to start of alternative MS treatment was performed.
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`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`
`In Study 301, a total of 1237 subjects were randomized at 198 sites in 28 countries worldwide.
`The highest enrolling countries were the US (203 subjects), Germany (172 subjects), Poland
`(132 subjects), and India (114 subjects). Of the randomized subjects, 3 subjects were not dosed
`hence excluded from the ITT population; 540 dosed subjects at 76 sites in 14 countries
`participated in the MRI cohort (180, 176, and 184 subjects in the placebo, BG00012 BID and
`BG00012 TID groups, respectively).
`
`Table 2. Subject Disposition (Study 301)
`
`
`
`
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`Source: Study 301 CSR Table 10-1.
`
`
`In Study 302, a total of 1430 subjects were randomized at 200 sites in 28 countries worldwide.
`The highest enrolling countries were Poland (282 subjects), US (267 subjects), India (107
`subjects), and Ukraine (104 subjects). Thirteen subjects (3 randomized to BG00012 BID and 10
`randomized to GA) were randomized but not dosed. Among the 10 subjects randomized to GA, 8
`withdrew consent upon learning that they had been randomized to open-label GA treatment. One
`subject randomized to BG00012 240 mg TID actually received GA. The MRI cohort comprised
`48% of the ITT population and included 681 subjects (167, 169, 170, and 175 subjects in the
`placebo, BG00012 BID, BG00012 TID, and GA groups, respectively) who were enrolled at 111
`sites in 17 countries.
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`Table 3. Subject Disposition (Study 302)
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`Note: The consent withdrawn descriptions recorded on the study case report forms were reviewed by the team and
`the reason of consent withdrawn and other were reclassified for 31 subjects.
`Source: Study 302 CSR Table 69.
`
`In Study 301, a total of 952 subjects (77%) completed the study and 838 subjects (68%)
`completed study treatment. The treatment discontinuation rate was similar across treatment
`groups. In Study 302, a total of 1127 subjects (80%) completed the study and 1000 subjects
`(71%) completed study treatment. The percentage of subjects who discontinued study treatment
`was 30% in the BG00012 BID group, 28% in the BG00012 TID group, 25% in the GA group,
`and 36% in the placebo group. For both studies, the most common reasons for discontinuing the
`study treatment were MS relapse or “other” in the placebo group, and experiencing an AE in the
`BG00012 groups. Treatment discontinuations were more common with BG00012 than with
`placebo in the first 3 months, due to AEs and/or tolerability issues associated with initiation of
`BG00012 treatment. After Week 48 more placebo subjects discontinued treatment (Figure 1).
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`Figure 1. Time to discontinuation of study drug - Studies 301 and 302 Pooled
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`Source: NDA module 2.7.3 Figure 3.
`
`
`The treatment discontinuation rate in both studies is high, partly because the studies allowed
`subjects to cross over to alternative MS treatments. In Study 301, the proportion of subjects who
`switched to alternative MS medications was higher in the placebo group (13%) than in the
`BG00012 BID (6%) and BG00012 TID (5%) groups. Similarly, in Study 302, the proportions of
`subjects who switched to alternative MS medications were 11%, 7%, 8% and 6% in the placebo,
`BG00012 BID & TID, and GA groups respectively. Subjects who prematurely discontinued
`study treatment, including those who switched to an alternative MS medication, were given the
`option of remaining in the study and continuing a modified schedule of follow-up evaluations.
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`

`For both studies, the treatment groups were generally well balanced with respect to baseline
`demographic characteristics in the ITT population (Table 4). Subjects were enrolled from 34
`countries, which were grouped into 3 pre-defined regions based on geography, type of health
`care system, and access to health care: Region 1 (US), Region 2 (Canada, Western Europe,
`Israel, New Zealand, Australia (Study 301 only), South Africa (Study 301 only) and Costa Rica
`(Study 302 only)]), and Region 3 (Eastern Europe, India, Mexico, and Guatemala (Study 301
`only)