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研究生：	王家芸 Chia-Yun Wang
論文名稱：	Statistical Design for Three-Arm Bioequivalence and Non-Inferiority Confirmatory Clinical Trials Using Binary Outcome as Primary Endpoint
指導教授：	曾議寬 Yi-Kuan Tseng
口試委員:
學位類別：	碩士 Master
系所名稱：	理學院 - 統計研究所 Graduate Institute of Statistics
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	74
中文關鍵詞：	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
外文關鍵詞：	binary outcomes, RMLE, three-arm equivalence trial, three-arm non-inferiority
相關次數：	點閱：16 下載：0
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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。

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.

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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