Bridging Study versus Prespecified Regions Nested in Global Trials
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Bridging Study Versus Prespecified Regions Nested in Global Trials
Sue-Jane Wang, PhD Associate Director for Adaptive Design and Phannacogenomics. Office of Biosfatistics. Office of Translational Sciences. Center for Drug Evaluation and Research, US Food and Drug Administration. Silver Spring, Maryland
Ethnic sensitivityto drug treatment has received worldwide attention since the development of the ICH E-5 guidance. The concept of a bridging study was first introduced in the 1990s. The informativeness of statistical inference from small bridging clinical trials with a study size as small as 40 patients is often questionable. In addition, statistical metrics for evaluating the consistency of region-specifictreatment effects toglobal treatment effectshave been controversial. Since 1998, the evdution of the approaches to ethnic sensitivity of a drug effect has ranged from criteria to accept foreign clinical data to partnership in harmonization for global drug development. We considerand compare an indirect method and a direct method to evaluate the treatment effect in a bridging study by bowowing the strength of effect observed in the foreign trial. When a multiregional clinical trial is the drug development approach, we consider a prospectively planned evaluation of global treatment effect without sacrificing the opportunity to also
Key Words Nested region; Noninferiori ty; Phannacogenomics; Subgroup; Two-stage adaptive test
Correspondence Address Sue-Jane Wang. PhD. Office of Biosfatistics, Office of Translational Sciences, Centerfor Drug Evaluation and Research, U S FDA. H F D - 7 0 0 . W O 21, MailStop Room 3562, 1 0 9 0 3 New Hampshire Ave., Silver Spring. MD 2 0 9 9 3 (email: suejane. [email protected]). The research views expressed in this article are the author? professional views and are nof necessarily those of the U S Food and Drug Administration.
INTRODUCTION Globalization of medical drug product development is attractive, particularly from the perspective of pharmaceutical drug manufacturers. However, due to differences in ethnic composition by countries or regions, new regions often prefer to request clinical data of their own for the purpose of reconfirming the existence of a treatment effect shown in large foreign clinical data and the applicability to their own countries or regions. In the ICH E-5 guidance (l),ethnic factors are defined as those factors relating to the genetic and physiologic (intrinsic) and the cultural and environmental (extrinsic) characteristics of a population. Ideally, an adequate and well-controlled trial in the new region would provide evidence most applicable to address the public health question of its own region. On the other hand, harmo-
evaluate a prespecified region-specific treatment effect that has a reasonablenumber of patients and under the same common protocd. We discuss the similaritiesand the differences between the bridging study problem and the noninfen'ority study problem. Concerns with extrapdating the results of the study to other regions are
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