A two-stage design for bridging studies.

The ICH E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. Therefore, a bridging study is usually conducted in the new region only after the test product has been approved for commercial marketing in the original region based on its proven efficacy and safety. One of the current issues for evaluation of bridging studies is a cross-study comparison. Therefore, bias occurs when the study is not internally valid. A two-stage approach is proposed to overcome the issue of internal validity and at the same time to meet the objective of minimizing unnecessary duplication of clinical data required by the ICH E5 guideline. Under the framework of the proposed two-stage design, the bridging study of the new region is a second-stage substudy of the whole trial, and the patients for the bridging substudy are enrolled only after the data obtained in the original region demonstrate a statistically significantly positive treatment effect. Methods for the determination of the sample size for each region and the critical values at each stage are also proposed.