Potential Factors Influencing Regional Differences and Similarities in Multiregional Clinical Trials
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Potential Factors Influencing Regional Differences and Similarities in Multiregional Clinical Trials
Drug Information Journal 46(5) 565-572 ยช The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0092861512443747 http://dij.sagepub.com
Masahiko Ohishi, PhD1
Abstract In a multiregional clinical trial (MRCT), determining whether regional differences occur by chance or whether they are due to differences in pharmacokinetics, pharmacodynamics, or other prognostic factors is important to accurately evaluate the true efficacy of a drug in patients of each region. The general probability that regional results will differ from total results has been studied using statistical simulation. Consideration from the pharmacokinetic perspective is necessary as well to investigate the causes of regional differences. Patient characteristics may vary among regions, and differences in medical environment such as commonly used drugs and treatment guidelines can affect regional efficacy and safety results. Moreover, bias may be introduced in the data collected due to differences such as in diagnosis, assessment criteria, and reporting conditions. In this research, the factors and mechanism potentially influencing results by region in MRCT are examined, referring to the results of MRCTs already published. Keywords multiregional clinical trials, regional differences, potential factors of regional differences
Introduction Globalization of new drug development is progressing, together with an increase in the number of multiregional clinical trials (MRCT) being conducted. In the past, the United States and countries in Europe were the main countries represented in MRCTs. Recently, however, this has expanded to include countries and regions such as central and eastern Europe, Latin and South America, and the Asia-Pacific region. With the expansion of MRCT in geography, we are now faced with the new challenge of observing unexpected differences in efficacy and safety among regions in an MRCT. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)1-4 has highlighted the general risk that efficacy may not be demonstrated for a region in an MRCT. In an MRCT that includes multiple races, ethnicities, or cultures, it is possible that differences in efficacy and safety can be observed among countries or regions. Determining whether differences occur by chance or whether they are due to differences in pharmacokinetics, pharmacodynamics, or other prognostic factors is important to accurately evaluate the true efficacy of a drug in patients of each region. If different findings are due to differences in a prognostic factor, it will be possible to eliminate the effect of that factor in the study planning
and implementation stage by identifying the factor and the mechanism of effect beforehand. In this research, the factors potentially influencing results by region are summarized, referring to the results of MRCTs already published in review reports from the Pharmaceuticals an
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