考慮區域性差異之多區域藥物臨床試驗之評估與設計

Abstract

在藥物臨床試驗的發展過程，銜接性試驗(bridging study)扮演著重要的角色， 但是銜接性試驗始終存在著時間延遲的缺點，導致新藥物的延遲上市與臨床試驗成本的過度花費，為了要消弭藥物延遲與節省試驗成本等等原因，希望能夠建構一個大型臨床試驗，稱之為多區域臨床試驗(multi-regional clinical rial)，在此試驗中，同時於世界上多個區域或國家進行試驗，試驗的執行必須依照相同試驗計畫。根據國際醫藥法規協合會(The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH)以及日本厚生勞動省(Ministry of Health, Labor, and Welfare of Japan, MHLW)所提出的指導原則書，研究臨床試驗領域的統計學者提出相當多針對多區域臨床試驗的統計方法，內容包含多區域臨床試驗的評估與設計。然而近期大部份多區域臨床試驗的樣本數決定的方法都假設不同的區域間療效指標(連續或二項)存在一個共同的處理效應。現實的情況中，可以預期的是，因為種族的差異導致區域差異性(regional difference)的存在，例如人種的遺傳基因、生活環境及習慣、醫療體系及習慣等等差異，所以不同區域之處理效應也會有所差異，而非固定且均一的處理效應。對於連續型的指標，提出一個考慮跨區域間藥效異質性的隨機效應模型，並將此模型應用於多區域臨床試驗的設計與評估。而對於二項型的指標，則利用一個power-function 分布描述不同區域間的藥效反應異質性，藉以應用在多區域臨床試驗的設計與評估。另一方面，我們建立參試區域處理效應與整個參試族群處理效應之間的一致性準則，透過此一準則，我們希望決定特定參試區域樣本數時能確保特定參試區域處理效應與整個參試族群處理效應之間的一致性。

To speed up drug development to allow faster access to medicines for patients globally, conducting multi-regional clinical trials incorporating subjects from many countries around the world under the same protocol may be desired. Several statistical methods have been purposed for the design and evaluation of multi-regional clinical trials. However, in most of recent approaches for sample size determination in multi-regional clinical trials, a common treatment effect of the primary endpoint (continuous or binary endpoint) across regions is usually assumed. In practice, it might be expected that there is a difference in treatment effect due to regional difference (e.g., ethnic difference). For continuous endpoint, a random effect model for heterogeneous treatment effect across regions is proposed for the design and evaluation of multi-regional clinical trials in this dissertation. For binary endpoint, a power-function distribution is used to describe heterogeneous treatment effect across regions for the design and evaluation of multi-regional clinical trials. We also address consideration on the determination of the number of subjects in a specific region to establish the consistency of treatment effects between the specific region and the entire group.