建立連續性滿足點的Phase II/III調適設計來評估來藥物之效能性

Abstract

醫藥發展是一具風險的、複雜的、昂貴和費時的產業。大部分的發展時間皆耗費於臨床實驗的執行。儘管目前仍存在大量的候選藥物以及蓬勃的臨床研究發展，但成功率仍然令人非常失望。因此，急需發展有效率且節省成本的新方法。一般而言，以連續性滿足點的phase II試驗，主要目的為檢驗藥物的有效性、以及決定劑量範圍與劑量反映的相關性。因而從phase II試驗，便有一種或多種不同劑量之藥物，可能會同時進入phase III的試驗。目前以連續性滿足點的phase II試驗，大部份均利用標準平行藥物反映與安慰劑群組的設計，經由不同劑量與安慰劑兩兩間之比較，藉由p-value的調整，來決定劑量範圍與劑量反映。因此在phase II階段，便可能需要數以百計甚致於數以千計的病人，而且花費的時間也可能需要兩到三年。儘管如此，能夠進到phase III的試驗，成功的機率也是非常的小。此研究中，我們針對連續性滿足點的臨床試驗，發展一個phase II/III的試驗設計來評估候選藥物的效能性。在phase II 試驗，包含多種不同劑量之群組與安慰劑群組。在此階段，如果藥物劑量有效性與劑量所對應的直線斜率大於預先假設值時，亦即此藥物各劑量的效能均比安慰劑群組為佳，如此我們便可選擇ㄧ種藥效最好的劑量與安慰劑群組進入phase III試驗，否則便停止此藥物的試驗。而且，所有進到phase III試驗群組之phase II的病人均可進到phase III 試驗，如此便可減少試驗所需的樣本數，因而縮短試驗所需的時間。於控制型一錯誤與統計檢定力的條件下，我們可計算各個階段所需的樣本數以及各個階段之檢定統計量的臨界值。

Pharmaceutical development is a risky, complex, costly and time-consuming endeavor. More than half of development duration is spent in clinical trials. Despite of a large amount of the potential candidates available and the lengthy process of clinical development, success rate is disappointed. Accordingly, there is an urgent need of new strategies and methodology for efficient and cost-effective designs towards the conduct of clinical trials in a rapid and reliable manner to minimize the total sample size and hence to shorten the duration of the trials. In this paper, a phase II/III adaptive design based on continuous efficacy endpoints is proposed. For the phase II part, the design is a randomized parallel group with several doses and a concurrent placebo group. Suppose that the dose-response relationship can be described by the simple linear regression. If the slope is greater than a pre-specified positive number, we will continue the accrual for the best dose group as well as the placebo group for the phase III trial. After the recruitment of the patients in the phase III trial is completed, we then perform the final analysis with the cumulative data of patients from both phases for both groups. We can also determine the sample size required for each group in each phase.