二元滿足點之Phase II/III調適性無縫臨床試驗設計

Abstract

對於製藥發展來說，如何設計一個臨床試驗、分析其數據，以及評估藥物的效益已成為一門重要課題。成功開發新藥物的價格急劇上升，而且在發展過程中有超過一半的時間和費用被使用於臨床試驗中。因此，在新藥開發中減少開支和時間，並且證明新藥的效益是一項挑戰。我們了解儘管在生物醫學研究方面的開支增加，並不能反映藥物開發的成功率增加。目前存在大量的候選藥物以及蓬勃的臨床研究發展，新藥物的研究和開發的成功率仍然令人失望。所以需要發展一種快速、經濟且適當的方法以減少藥物發展的時間與花費。為了減少時間跟成本，對於二元滿足點的臨床試驗，提出了一個phase II/III的調適性無縫設計。此研究中，有兩種調適性無縫臨床試驗設計:一種是停止於無效(Design I)以及另一種停止於無效以及有效(Design II)。設計分成兩階段，第一階段即phase II的試驗中，幾個不同劑量的試驗藥物與對照組相比，這樣我們可以評估在對照組的試驗藥物劑量的療效。經過第一階段（phase II階段），我們進行分析是否進行第二階段（phase III階段）。最後，還給出數值例子來說明我們的設計。

How to design a clinical trial, to analyze the data, and to evaluate the benefit of drugs becomes an important course for pharmaceutical development. The price of successfully developing new drugs has risen steeply, and more than half of the time and expense in the development process are spent in clinical trials. Hence, one challenge in the development of new drug is reducing expenses and time, moreover demonstrating the benefits of a new drug. It is recognized that, in spite of increasing spending of biomedical research does not reflect an increase of the success rate of pharmaceutical development. The success rate of researching and developing new drugs is disappointing even though there are many potential candidates and lengthy process of clinical development. Therefore, there is a reason to find ways in which drug development could be expedited and made more efficient. In this thesis, two adaptive seamless phase II/III designs are developed: one permits early stopping only for futility (Design I), and the other allows early stopping for either efficacy or futility (Design II). The resulting designs are in practice two-stage designs. At the stage one (the phase II stage), several doses of an experiment are compared with a control group so that we can evaluate the efficacy of doses of the experiment over the control group. After stage one (phase II stage), an interim analysis is performed and a decision is made on whether to proceed to stage two (phase III stage). Numerical examples are also given to illustrate our designs.