临床试验总结报告英文版.pdf

1、Reviewer:Cynthia A.Rask,M.D.Through:Marc K.Walton,M.D.,Ph.D.Karen Weiss,M.D.Date:23 January 2002 Biologics License Application Supplement Medical Officers Review Rebif(Interferon-1a)FOR TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS Submitted by Serono,Inc.STN#:103780/0Rebif BLA(STN#103780/0)Se

2、rono,Inc.Page 2 of 66 TABLE OF CONTENTS OVERVIEW.4 Scope of this review.4 Abbreviations and Definitions of Terms Used in This Review.5 INTRODUCTION.7 Multiple Sclerosis.7 Background and Diagnostic Criteria.7 Current Treatment of MS.8 The Orphan Drug Act and Orphan Drug Exclusivity Regulations.8 Over

3、view of Prior Clinical Studies of Rebif.10 PROTOCOL XXXXXXXXXX.12 Objectives.12 Design.12 Material Source.13 Randomization.14 Inclusion Criteria.14 Exclusion Criteria.14 Treatment.15 Evaluations Performed During the Study.17 Efficacy Endpoints.21 Primary Endpoint.21 Secondary Endpoints.21 Tertiary E

4、ndpoints.21 Safety Endpoints.21 Safety Measurements Analyzed.21 Statistical Analysis Plan.22 Determination of Sample Size.22 Analysis Populations.22 Planned Interim Analysis.23 Significance Testing,Allocation of Alpha.23 Analysis of Baseline Parameters.23 Primary Endpoint Proportion of Subjects Exac

5、erbation-Free at 24 Weeks.24 Rebif BLA(STN#103780/0)Serono,Inc.Page 3 of 66 Secondary Endpoints MRI Analytic Methods.24 Safety Analyses.26 Study Administration.26 STUDY RESULTS.27 Formal Protocol Modifications.27 Changes in the Conduct of the Study or Planned Analyses.27 Protocol Deviations/Violatio

6、ns.28 Study Conduct at Specific Study Sites.30 Subject Enrollment and Disposition.31 Randomization.31 Time on Study.31 Time on Treatment:.32 Adverse Events Leading to Premature Discontinuation.33 Demographics and Baseline Characteristics.35 EFFICACY RESULTS.38 Primary Endpoint Results.38 CBER-Perfor

7、med Analyses on the Primary Endpoint.42 Secondary Endpoints.48 MRI-Determined CU Activity.48 Exacerbation Rate per Subject.49 Mean Number of T2 Active Lesions per Subject per Scan.50 Tertiary Endpoints.51 Exploratory Analyses.53 Safety Analyses.55 Serious Adverse Events and Deaths.55 Important Rare

8、Serious Adverse Events.58 Severe Adverse Events.59 Analysis by Body System and Event.60 Pregnancies.62 Development of Antibodies to Interferon-.62 Assessment and Conclusions.63 Financial Disclosure Statements.65 References.65 Rebif BLA(STN#103780/0)Serono,Inc.Page 4 of 66 Overview Interferon -1a(Reb

9、if)has been under development by Serono,Inc.for the treatment of multiple sclerosis(MS).Serono,Inc.submitted a Biologics License Application(BLA)on February 27,1998 for the approval of Rebif for the treatment of patients with relapsing-remitting MS(RRMS).The focus of the application was a 560-subjec

10、t study that was a randomized,double-blind,placebo-controlled study of 22 g vs.44 g Rebif vs.placebo administered subcutaneously(SC)three times per week for 2 years.The application also contained additional open-label safety data from other studies.Based on the review of the BLA submission conducted

11、 by CBER,it was concluded that both doses of Rebif were demonstrated to be safe and effective and to be approvable for treatment of RRMS.However,Serono was prevented from marketing Rebif in the United States by the Orphan Drug Exclusivity previously granted to Biogen for the marketing of their inter

12、feron-1a,Avonex and to Berlex/Chiron for the marketing of their interferon-1b,Betaseron Betaserons exclusivity expired in July 2000.Rebif was,however,successfully approved and marketed in other countries,and thus has been commercially available in other portions of the world for several years.The su

13、bject of the current BLA amendment is a comparative study that Serono conducted to compare the efficacy of Rebif to marketed doses of Avonex in the treatment of relapsing-remitting MS.The study design was discussed with CBER and the design was agreed upon prior to initiation of the study.The study w

14、as a randomized,open-label study in which subjects with RRMS were treated with either Rebif 44 g SC three times per week or Avonex 30 g IM once weekly,with neurologic examinations performed by physicians blinded to the treatment assignment and with subjects MRIs read at a central reading facility by

15、 neuroradiologists blinded to treatment assignment.Although the duration of the study was to be 48 weeks,the pre-specified primary outcome measure was the proportion of subjects who remained relapse-free following 24 weeks of treatment.Supportive evidence(secondary endpoints)were comparisons of MRI

16、abnormalities.The Applicant conducted and submitted this BLA amendment in the belief that demonstration of superior clinical benefit of Rebif over Avonex would allow them to break Biogens orphan drug exclusivity and thus,to market Rebif in the U.S.for the treatment of relapsing-remitting MS.Scope of this review The focus of this document is upon efficacy information obtained primarily from a single study,XXXXXXXXXX,a randomized,open-label comparative study of the use of Rebif 44 g administered S