Statistical Design for Three-Arm Bioequivalence and Non-Inferiority Confirmatory Clinical Trials Using Binary Outcome as Primary Endpoint

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姓名

王家芸(Chia-Yun Wang) 查詢紙本館藏

畢業系所

統計研究所

論文名稱

(Statistical Design for Three-Arm Bioequivalence and Non-Inferiority Confirmatory Clinical Trials Using Binary Outcome as Primary Endpoint)

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摘要(中)

此篇研究提出新的三臂生物等效性試驗以及三臂非劣性試驗的統計設計方法，本研究在兩個試驗中所用到的皆是二元型態的臨床指標。三臂生物等效性試驗通常包含三個假設檢定，其中兩個檢定實驗藥物和參考藥物分別對於安慰劑的優越性；而另一個檢定實驗藥物和參考藥物之間的等效性。在此項研究中，我們提出只需要透過一個假設檢定就可以證明兩個藥之間的生物等效性，其中的檢定程序是透過比率差異的比值來完成。在二元型態指標的三臂非劣性試驗中，最常使用比率差異的檢定程序。此篇文章提出透過勝算比的檢定程序，並比較在最大概似估計以及有限制的最大概似估計下的樣本數表現。除此之外，我們也比較了在兩種檢定程序下的樣本數表現。

摘要(英)

This study developed new methodology of statistical design on non-inferiority trial and bioequivalence trial. The three-arm bioequivalence trial usually consists of three hypothesis tests in practice, where two hypothesis tests demonstrate the superiority of experimental drug and reference drug against placebo, and the last one demonstrates the equivalence of experimental drug and reference drug. We derived a single set of null and alternative hypotheses for three arm equivalence trial with binary endpoints which is based on the ratio of proportion differences. For the thee-arm non-inferiority trial with binary endpoints, the test procedure via rate difference is the most common used. An alternative test procedure via odds ratio was proposed for the three-arm non-inferiority trial. We compared the sample size performance of our test procedure based on the MLE and RMLE. In addition, we compared the sample size performance of our test procedure with rate difference procedure.

關鍵字(中)

★ 二元變項
★ 有限制最大概似估計量
★ 三臂等效性試驗
★ 三臂非劣性試驗

關鍵字(英)

★ binary outcomes
★ RMLE
★ three-arm equivalence trial
★ three-arm non-inferiority

論文目次

摘要 i
Abstract ii
致謝 iii
Contents iv
List of Figures vi
List of Tables vii
1. Introduction 1
1.1 Clinical Trials 2
1.2 Introduction to a Confirmatory Trials 6
1.3 Statistical Considerations in Confirmatory Trials 9
1.4 Bioequivalence 11
2. A Real-Life Bioequivalence Trial 15
2.1 Introduction 15
2.2 Statistical Design 16
2.2.1 Efficacy Endpoints 16
2.2.2 Equivalence Test 17
2.2.3 Test Strategy and Sample Size Calculation 18
3. An Alternative Statistical Design for Three-Arm Bioequivalence Trial 20
3.1 Literature Review 20
3.2 Assumption 21
3.3 Hypothesis and Test Procedure 21
3.4 Power and Sample Size 23
3.5 Simulated Example 25
3.6 Numerical Studies 27
4. A Novel Statistical Design for Three-Arm Non-Inferiority Trial 29
4.1 Literature Review 29
4.2 Assumption 30
4.3 Hypothesis and Test Procedure 30
4.4 Power and Sample Size 34
4.5 Numerical Studies 37
4.5.1 Comparison of the Test procedure based on the MLE and the RMLE 37
4.5.2 Comparison of the Proposed Test procedure and the Hida and Tango Procedure 40
5. Discussion 45
Appendix 47
Appendix A.1 Derivation of the Asymptotical Bivariate Normal Distribution 47
Appendix A.2 Simplification of The Correlation Coefficient 48
Appendix B.1 Derivation of the Asymptotic Variance of Log Odds Ratio 49
Appendix B.2 Derivation of π_E,π_R and π_P 50
Appendix B.3 Derivation of the approximated value of ρ 52
Appendix C.1 Non-Inferiority Trial with Time-To-Event Data 53
Appendix C.2 Derivation of the MLEs 56
Appendix C.3 Discussion of asymptotic variance σ_(ψ ̂_ER)^2and σ_(ψ ̂_RP)^2 57
Appendix C.4 Derivation of λ_E, λ_R and λ_P 58
Reference 59

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指導教授

曾議寬(Yi-Kuan Tseng)

審核日期

2019-7-1

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