Bridging studies

In a 'bridging study,' dosage is optimized early in development by determining the maximum tolerated dose of a compound in patients. Consecutive panels of patients each receive higher doses of study drug until a minimum intolerated dose is reached. The dose immediately below this one is then considered the maximum tolerated dose. Careful subject selection, adequate facilities, and highly qualified, experienced personnel are critical to the successful implementation of a bridging study. Correctly done, bridging can streamline the overall drug development process, while making the Phase II and III trials safer for patients. The International Conference on Harmonization (ICH) E5 (1998) guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data to facilitate global drug development and registration of NCEs, and to reduce the number of clinical trials for international approval. An essential prerequisite for the acceptance of foreign data is a Complete Clinical Data Package including foreign data that have to meet all regional regulatory requirements. Furthermore, sponsors were requested to show whether the 'foreign clinical data' could be appropriately extrapolated to the new geographical region. The assessment of medicines sensitivity to ethnic factors has to be done according to given intrinsic as well as extrinsic ethnic factors. Supplemental 'bridging studies' may become necessary to provide clinical or PD as well as PK data allowing an extrapolation to the population of the new region. Extrapolation via a bridging study can avoid the need to conduct additional, expensive clinical trials in the new region, and can facilitate access to superior treatment to patients in a timely fashion. The technical challenge of a bridging study is to demonstrate 'similarity' of profile (statistics, sample size, etc.) of an NCE.

While the requirements of major regions such as North America and Europe are met largely by a global clinical development program within multinational Phase II/III trials, the acceptability of foreign data for registration in Japan and other Asian countries is still a substantial challenge. During the 5-year period following the adoption of ICH E5 by the Prescription Drug Marketing Act (PDMA), it became clear that Complete Clinical Data Packages were not accepted without a supplemental bridging study allowing sufficient extrapolation to the Japanese patient population. In the majority of cases, extrinsic ethnic factors, such as different medical practice in the new region, were the source of concern in terms of affecting the efficacy and safety of new medicines. Data on clinical efficacy addressing the dose-response relationship in the Japanese population are essential for sufficient extrapolation. Stand-alone PK studies were not considered valid for the bridging of foreign data. In the case of extrapolation of foreign data from a clinical Phase III program to the Japanese population, a Phase II dose-response study accompanied by a set of domestic single and repeated dose Phase I trials and/or an early Phase II study is requested to provide the dose-response data in the Japanese population. Sponsors should consult with the Japanese authorities early on in the development process to define the necessity, topic, and design of bridging studies.

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