基因異質性在銜接性試驗設計與評估之應用

Abstract

ICH E5 定義銜接性試驗是在新地區所執行的增補性試驗，以提供新藥的藥物動力學或療效、安全性、用法用量等臨床試驗數據，並使國外臨床試驗數據能外推至新地區的相關族群。因此，銜接性試驗通常只在新藥已經在某一地區證實其有效性與安全性且批准上市之後，在新地區來執行。在本篇論文中，我們建立用來檢驗新地區的結果是否與原地區結果一致的準則。此外，有越來越多的證據顯示基因遺傳因素可能傳達了病人之間對於藥效反應的變異性。因此，我們建立統計方法將基因多樣性對藥的變異結合用在評估銜接性試驗上。我們也提出對於銜接性試驗所需要的樣本數的計算方法。數值的例子說明在不同情形下我們所提出的方法的應用。

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. In this paper, we establish criteria to examine whether the results from the new region are consistent with the results from the original region. On the other hand, there has increasing evidence that genetic determinants may mediate variability among persons in the response to a drug. Therefore, we also develop statistical methodologies to incorporate the variation among genetic polymorphism for drug into the evaluation of bridging studies. Methods for sample size determination for the bridging study are also proposed. Numerical examples illustrate applications of the proposed procedures in different scenarios.