Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials
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Hri Oran Sanofi-Aventis Mingyr Li Celgene
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Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials
Joshua Chon Merck P a d Gallo Novartis Brute Binkowitz Merck Ekopimo lbia Merck
Yoko Tanaka Eli Lilly So0
Peter Oryang Celgene Xiaolong Lro Celgene
Gong Li Johnson &Johnson
Multiregional clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and )idly realize the opportunities, a PhRMA MRCT Cross-Functional Key Zssue Team (KIT) was fnmed in 2008. One ofthe work streums within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for supmhiQ trials with continuous endpoints, then extend briefly to noninfm'ority trials, random efied models,
binary endpoints, and survivalendpoints.Computations and simulationsare used to study the properties of the proposed definitions, particulany the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerationsfor trial design as well as for data analysis. nte consistency assessment relies heavily on the dejinition of regions and the number ofregions. We recommend working with health authorities to dejine region in a manner that is sensible from a practical interpretation standpoint and also makes region consistencyassessment a feasible undertaking.
Shailendra Menioge Boehringer Ingelheim Steven Talerico Merck Kimitorhi lkeda Novartis Key Words Ethnic effect; Sample size; Power; Noninferiority; Interaction; Random effect model Correspondrice Address Hui @an, Biostatistics and Programming, SanofrAventis. BX2-403A, 200 Crossing Boulevard, PO Box 6890, Bridgewater, NJ 08807 (email: hui.quan@ sanofi-aventis.com).
I NTR 0 D U CTI 0 N Heterogeneity resulting from differences in ethnicity, genetic factors, culture, and clinical practice across regions can present challenges for the conduct and interpretation of multiregional clinical trials (MRCTs), as such differences may potentially have an impact on details of the treatment administration or dosing regimen, as well as on the observed treatment efficacy and safety. Nevertheless, the duplication of large-scale confirmatory clinical studies in individual regions is grossly inefficient and can delay the availability of needed new treatments for patients in all regions. As a result, the ICH (International Conference on Harmonization) E5 guideline (1)was adopted in 1998 to recommend a framework for evaluating the impact of ethnic factors on drug effects. Basically, for compounds that might be sensitive to ethnic factors, if a sponsor can show evidence of similarity of treatment effects across regions through either an MRCT or a bridging study, results can be extrapolated across regions. However, while ICH E5 recommended strategies for accepting foreign clinical dat
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