A Noninferiority Test for Treatment-by-Factor Interaction with Application to Bridging Studies and Global Trials
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Jon-poi Liu, PhD Professor, Division of Biometry, Department of Agronomy, National Taiwan University, Taipei. Taiwan; Division of Biostatistics and Bioinfomatics. National Health Research Institutes. Zhunan. Taiwan Jr-Rung Lin, Msc Division of Biometry, Department of Agronomy, National Taiwan University, Taipei. Taiwan Eric Hsiek, MSc Division of Biometry, Department of Agronomy, National Taiwan University, Taipei. Taiwan
Key Words Noninferiority; Treatment-by-factor interaction; General pivotal quantities; Bootstrap technique Correspondence Address ]en-pei Liu. PhD. Professor, Division of Biometry, Department of Agronomy, National Taiwan University, I , Section 4. Roosevelt Road, Taipei. Taiwan (email: jpliu @n tu. edu.tw). The views expressed in this article are personal opinions of the authors and may not necessarily represent the position ofthe National Health Research Institutes and National Taiwan University, Taiwan.
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A Noninferiority Test for Treatment-by-Factor Interaction With Application to Bridging Studies and Global Trials Similarity of the treatment effects of a drug product among different intrinsic and extrinsic ethnic, geographic, or demographic factors is important not only to regulatory agencies in the approval of the drug but also to the public health. Examples include bridging studies in different regions, the extrapolation from the adult population to the pediatric subpopulation, or comparisons between different geographic regions within a global trial. It is an issue of evaluation of the treatment-by-factor interaction. Howevq assessment of similarity
INTRODUCTION The International Conference on Harmonization (ICH) E5 guideline "Ethnic Factors in the Acceptability of Foreign Clinical Data" addresses the issue of extensive duplication of clinical evaluations to address the geographic variation of efficacy and safety of a drug product (1).According to the ICH E5 guideline, the supplementary pharmacodynamic and clinical data on efficacy, safety, dosage, and dose regimen from bridging studies conducted in the new region allow possible extrapolation of the foreign clinical data to the population of the new region. In addition, the ICH E5 guideline suggests the use of the concept of similarity for evaluation of extrapolation of the foreign clinical data. Various statistical procedures or methods were proposed to evaluate the similarity of the treatment effects between the bridging studies in the new region and the original regions (2-9). However, assessment of treatment similarity is not limited only to geographic variation. For example, reductions in blood pressure of an antihypertensive drug may be different among Caucasians, Hispanics, and African Americans. Other examples include whether the treatment effect of a drug for treating chronic hepatitis B
is not to detect the existence of treatment-byfactor interaction but rather to evaluate whether the magnitude of treatment-by-factor interaction is within a clinically allowable margin. As a result, we propose two testing procedures for the n
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