Assessing Sensitivity and Similarity in Bridging Studies

Abstract

In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry--Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.

Sample Size Calculation for Comparing Means

“…A clinical trial without sufficient sample size may not provide a desired reproducibility probability (6)(7)(8). In other words, the observed clinical results may not be reproducible at a certain level of significance.…”

The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging

“…Due to the complex interaction among the drugs' pharmacological class, indication, and demography of the population [86], the ICH E5 guideline does not provide definitive criteria for evaluation of a drug's ethnic sensitivity in terms of the evaluating the complete clinical data package or assessing the similarity of clinical results between regions [87]. Various statistical models and strategies have been proposed to assess sensitivities and similarities in ethnicities [87,88,89]; however, no gold standard has yet been established.…”

“…Various statistical models and strategies have been proposed to assess sensitivities and similarities in ethnicities [87,88,89]; however, no gold standard has yet been established. Specific methodology for extrapolating foreign clinical data is not provided, either.…”

Approaches to Allocate Sample Size Rationally Into Individual Regions for a Multi-regional Trial Under Heterogeneous Effect Size

“…He also suggested that the result from the new region is consistent with the previous results if it falls within the previous experience. Chow et al (2002) employed the reproducibility probability and generalizability to assess the necessity of bridging studies in the new region. proposed a hierarchical model approach to incorporating the foreign bridging information into the data generated by the bridging study in the new region.…”