兩階段適應性無縫設計改良-於劑量選擇後加入一新試驗組之調整

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吳緯綸(Wei-Lun Wu) 查詢紙本館藏

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論文名稱

兩階段適應性無縫設計改良-於劑量選擇後加入一新試驗組之調整

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摘要(中)

在臨床試驗的發展中，適應性無縫設計包含兩個階段，學習階段（二期階段）選擇劑量或試驗組，確認階段（三期階段）確認所選劑量或試驗組的治療效果。由於在一個方案中結合傳統的二三期試驗，以至於有可能可以縮短新藥開發所需要的時間而備受製藥公司關注。本研究提出一個除了在二期階段結束時，基於短期終點選擇一個試驗組外，並增加一個新的試驗組在三期階段的無縫設計。在最終分析時，利用封閉檢定法控制由於劑量選擇造成可能的總體型一錯誤率膨脹，另外使用逆常態加權組合函數結合兩階段基於入組受試者晚期終點所得到p值以進行統計推論。本研究提出依序檢定與同時檢定兩種檢定策略，依序檢定首先檢定二期階段選出的試驗組，若達顯著則再檢定新增的試驗組；同時檢定則同時檢定兩個試驗組。本研究透過大量的模擬，以驗證此設計在不同情境下能控制總體型一錯誤率並達到足夠的檢定力。

摘要(英)

In the development of clinical trial design, adaptive seamless design contains learning stage and confirmatory stage corresponding to conventional phase Ⅱ/Ⅲ trial respectively. Typically, experimental groups as doses of test drug or treatment groups compared to an active control are evaluated at the learning stage, based on the results of the learning stage, the efficacy of selected dose or treatment group is to be confirmed at the confirmatory stage. As adaptive seamless design combines conventional phase Ⅱ/Ⅲ trial into a trial design, it might shorten time needed to develop new drugs, which has drawn considerable attention from researchers and pharmaceutical companies. We proposed a seamless design which is able to select an experimental group at the end of learning stage based on short-term outcome and to add a new experimental group into confirmatory stage. The closed testing procedure and weighted inverse normal combination function are used to control the inflation of overall type I error rate due to dose selection and p-values from two stage subjects at the final analysis. We proposed sequentially and simultaneously testing strategy for testing the new experimental group. Sequentially testing strategy tests the selected experimental group first, if significant then test the new experimental group. Simultaneously testing strategy tests the selected and new experimental groups at the same time. Numerical simulation has been conducted to verify the type I error rate and power under several scenarios.

關鍵字(中)

★ 適應性設計
★ 無縫二三期設計
★ 封閉檢定法
★ 早期終點
★ 晚期終點
★ 逆常態加權組合函數

關鍵字(英)

★ adaptive design
★ seamless design
★ closed testing procedure
★ short-term outcome
★ long-term outcome
★ weighted inverse normal combination function

論文目次

內容
摘要 i
Abstract ii
致謝 iii
圖目錄 vi
表目錄 vii
一.緒論 1
1.1臨床試驗 2
1.2適應性設計 6
1.2.1 定義與目的 7
1.2.2 統計考量議題 8
1.2.3 常見適應性設計 11
1.3新生血管型老年性黃斑部病變與其治療發展 16
1.3.1疾病介紹 16
1.3.2 Verteporfin光動力療法 17
1.3.3 抗血管內皮生長因子療法 18
1.3.4 以雷珠單抗治療新生血管型老年性黃斑部病變之三篇關鍵性臨床試驗報告 19
1.4研究動機 24
二.兩階段適應性無縫設計 28
2.1 適應性無縫設計之發展 28
2.2 設計介紹 32
2.3 早期終點、主要終點、統計量計算 33
2.4 多重假設檢定與封閉檢定法 35
2.5 計算p值 37
2.5.1 Bonferroni 檢定 38
2.5.2 Sidak 檢定 39
2.5.3 Simes 檢定 40
2.5.4 適應性Dunnett 檢定 41
2.5.5 組合函數 42
2.5.6 敗者試驗組追蹤問題 43
三.兩階段適應性無縫設計改良-加入一新試驗組之調整 45
3.1 設計介紹 45
3.2 設計調整 46
3.2.1 新試驗組之主要終點 47
3.2.2 統計量計算 48
3.2.3 計算p值 48
四.模擬方法設計 55
4.1 R套件-asd介紹 55
4.2 asd中函數simeans.binormal、select.rule與dunnett.test介紹 59
4.3 模擬情境 64
4.4 應用套件asd內函數設計模擬方法 65
五. 樣本數計算 73
6. 模擬方法設計與模擬結果探討 75
6.1 模擬探討議題 75
6.2 型一錯誤率模擬 76
6.2.1 四種p值計算法在型一錯誤率表現上的比較 78
6.2.2 敗者試驗組處理對型一錯誤率影響 80
6.2.3 早期終點平均差異對型一錯誤率影響 81
6.2.4 四種p值計算法在早期終點平均有差異時的型一錯誤率表現 82
6.2.5 敗者試驗組處理在早期終點平均有差異時的型一錯誤率表現 83
6.2.6 不同的b值對型一錯誤率的影響 84
6.3 檢定力模擬 85
6.3.1 不同非劣性程度對檢定力影響 86
6.3.2 敗者試驗組處理對檢定力影響 88
6.3.3 早期終點平均差異對檢定力影響 89
6.3.4 敗者試驗組處理在早期終點平均有差異時的檢定力表現 90
6.3.5 不同b值的影響 91
6.3.6 新試驗組藥效較低的影響 92
6.4 模擬結果討論 93
7. 結論與討論 94
參考文獻 96
附錄 107
附錄一-使用Bonferroni、Sidak、Simes計算p值 107

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指導教授

曾議寬

審核日期

2021-7-21

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