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Abstract

Ethnic sensitivity to 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-specific treatment effects to global treatment effects have been controversial. Since 1998, the evolution 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 consider and compare an indirect method and a direct method to evaluate the treatment effect in a bridging study by borrowing 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 evaluate a prespecified region-specific treatment effect that has a reasonable number of patients and under the same common protocol.

We discuss the similarities and the differences between the bridging study problem and the noninferiority study problem. Concerns with extrapolating the results of the study to other regions are raised in regard to the bridging approach that prompts consideration of streamlining clinical trials. When the intrinsic versus extrinsic factors may not be well understood, one approach to addressing heterogeneity issues is a two-stage adaptive test that not only builds in an additional region-specific treatment effect hypothesis, but also addresses potential ethnic sensitivity to overall multiregional treatment effects. The two-stage adaptive test provides flexibility to assess variance using the blinded data at the late stage of the trial, and thus has the potential to withdraw the region-specific hypothesis due to large variability in the clinical endpoint, eliminating an uninformative region-specific effect assessment.

Keywords

Nested region Noninferiority Pharmacogenomics Subgroup Two-stage adaptive test

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Bridging Study versus Prespecified Regions Nested in Global Trials

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