貝式理論應用在第二期臨床試驗結合安全性考慮下使用二階段方法和第三期臨床試驗下使用多區域臨床試驗概念之設計與評估

Abstract

藥物開發是一個複雜且需要鉅額費用的長時間過程。傳統上，這過程需要有三個階段:尋找最大容忍毒性的劑量，並在這劑量範圍內，測試療效的效果，並尋找是否有其他反映或者副作用。除此之外，為了世界各地患者的權益，全球化臨床試驗分別在許多不同的區域逐漸地實施。這篇論文主要探討在第二期臨床試驗上的二階段臨床試驗設計與第三期臨床試驗的全球化臨床試驗設計。 第一期臨床試驗的主要目的是尋找一個新藥或者療程的最大容忍毒性的劑量(MTD)。而第二階段則是考量在這最大容忍毒性的劑量下，對於預期病症的療效效果如何。這兩個階段分別討論毒性與效性。然而，這篇論文使用貝式兩階段方法來設計同時考量毒性與效性下，設計第二期臨床試驗 為了加速全球化藥物開發，越來越多的臨床試驗需要在世界各地進行。1998年，國際藥品法規協和會(ICH)發表了指導手冊E5討論銜接性臨床試驗，並在2006年的第11屆Q&A 文件中討論多區域臨床試驗的定義。日本厚生勞動省在2006年發表了一篇指導手冊, ‘ Basic Principles on Global Clinical Trials’,對於多區域臨床試驗中各個區域的療效，提供了兩種方法來如何決定各個區域療效的一致性。在2016年，國際藥品法規協和會發表了新的指導手冊E17，更加詳細定義與如何實施多區域臨床試驗。E17建議多區域臨床試驗不只評估整體療效效果的效益，且要分析各個區域的療效情況。 此篇論文主要討論如何利用貝式方法在設計與評估於第二期臨床試驗上兩階段設計與第三期臨床上多區域臨床試驗。第一個主題同時考量毒性與效性作為主要反應，並使用狄利克雷作為先驗分配。這個方法以毒性的大小來評估療效的安全。並提供先驗分配中毒性與效性的相關性作為參考，來設計階段上的選擇或者評估每個階段的結果。考量兩種情況下，每個階段以事後機率作為評估是否此試驗可以繼續進行或者提早終止試驗。第二個主題是在多區域的臨床試驗下，並假設整體療效效果與區域間變異數皆為隨機變數下，來設計與評估此試驗。整體效應假設有均勻分布為其先驗分配，而區域間變異數則假設有半常態與逆伽瑪分配為其先驗分配。最後以整體療效效果的後驗分配來做為評估療效的結果。最後這兩個應用皆以實際例子來做示範評估。

關鍵詞: 二階段設計;毒性;貝式;先驗分配;多區域臨床試驗

Drug development is complicated and expensive with a long life cycle. Traditionally, this process has three phases to find the maximum tolerated dose (MTD); check active efficacy response as a cure, and other response or side effects. Also, global clinical trials are conducting increasingly for benefits of patients in different regions. This thesis discusses two topics related to phase II and III trials, namely two-stage designs and multiregional clinical trial. The goal of a phase I trial is to find the maximum tolerated dose of a proposed drug or treatment is the main goal in the phase I trial. And the phase II trial proceeds with this dose to evaluate the efficacy of the proposed drug or treatment. These two steps consider toxicity and efficacy, respectively. Therefore, this study discusses Bayesian two-stage designs with considering both efficacy and toxicity as main endpoints simultaneously. To accelerate global drug development, clinical trials increasingly need to be conducted around the world. Therefore, in 1998, the International Conference on Harmonisation (ICH) published the ICH E5 guideline about bridge study, and the 11th questions-and-answer Q&A document for the ICH E5 in 2006 discusses the definition of a multiregional clinical trial (MRCT). The Japanese Ministry of Health, Labour, and Welfare (MHLW) published an important guideline in 2007, “Basic Principles on Global Clinical Trials”, which provided two methods for determining of the consistency of regional effects. The ICH published in 2016 a new detailed guideline ICH E17 for designing and conducting of an MRCT. ICH E17 recommends that MRCT designers should evaluate not only the overall treatment effect but also the regional treatment effect. This study constructs and evaluates two-stage designs and MRCT for two applications using Bayesian methods. The first application uses efficacy and safety as main responses, following a Dirichlet distribution as a prior. A phase II trial traditionally only evaluates efficacy. This approach also applies toxicity as main endpoint to evaluate trial safety. The correlation between rates of efficacy and toxicity of priors is influenced by choices made previously in the design stage or evaluation. Sequentially, two scenarios are discussed to evaluate the posterior probabilities at each stage. The MRCT is then designed and evaluated, and the overall treatment effect with given the uniform distribution as prior and between-region variability with given the half-normal or inverse gamma distributions as priors are considered random variables. The posterior probability of the overall treatment effect is then calculated to evaluate efficacy of a treatment. These two applications are then analyzed using two different examples. key word: two-stage design; toxicity; Bayesian; prior; MRCT