Bridging Diversity: Extrapolating Foreign Data to a New Region

In recent years, global collaboration has led to a new strategy for drug development. However, clinical outcomes may be influenced by geographic variations in efficacy and safety; significant ethnic differences seem to exist in the enzymatic activity of several drug metabolizing enzymes and a patient's response to therapeutics may vary from one racial/ethnic group to another. In 1998, the International Conference on Harmonisation (ICH) issued the E5 guideline on 'Ethnic Factors in the Acceptability of Foreign Clinical Data' to determine if clinical data generated from the original region are acceptable in a new region. The purpose of this guideline is not only to permit adequate evaluation of the influence of ethnic factors on clinical efficacy and safety, but also to minimize duplication of clinical studies and, consequently, to not delay the availability of the drug in the new region. More specifically, the ICH E5 guideline suggests that a bridging study be conducted in the new region to generate additional information to bridge the foreign clinical data when the foreign clinical data contained in the Complete Clinical Data Package (CCDP) cannot provide sufficient bridging evidence. In this review, the main points of ICH E5 are described and critiqued. Following publication of the guideline, Japan, South Korea and Taiwan have developed similar but slightly different bridging strategies to extrapolate foreign (e.g. from the US and EU) data to their respective countries. The regulatory requirements for bridging studies adopted by the health authority of Taiwan are discussed in detail and the regulatory guidances for Japan and South Korea are also described briefly. Also in this review, a Bayesian approach with the use of a mixture prior for assessment of similarity between the new and original region, based on the concept of positive treatment effect, is proposed and different bridging strategies are reviewed. Some examples are given to illustrate the bridging strategies discussed and, in addition, some practical issues that are commonly encountered when conducting bridging studies are explored. These practical issues include criteria for assessment of similarity between regions and sample size calculation/allocation for bridging/multi-regional studies. Finally, two successful examples of drugs approved based on a bridging strategy articulated in the ICH E5 guideline are given. [PUBLICATION ABSTRACT]