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系統識別號 U0026-0812200910362468
論文名稱(中文) 銜接性試驗下比較不同統計方法之研究
論文名稱(英文) The Evaluation of Different Statistical Procedures for Bridging Study
校院名稱 成功大學
系所名稱(中) 統計學系碩博士班
系所名稱(英) Department of Statistics
學年度 91
學期 2
出版年 92
研究生(中文) 周伯彥
研究生(英文) Bo-Yan Jou
電子信箱 iltajou@yahoo.com.tw
學號 R2690101
學位類別 碩士
語文別 英文
論文頁數 94頁
口試委員 口試委員-王新台
指導教授-劉仁沛
指導教授-馬瀰嘉
口試委員-戴政
中文關鍵字 模擬研究  國際藥物法規協和會  銜接性試驗  相似性  統計方法 
英文關鍵字 bridging study  statistical method  simulation study  similarity  ICH 
學科別分類
中文摘要 台灣地區在過去對於新藥上市的規定為,只要有三個以上的先進國家核准該藥上市,即可開放進口供國人使用。近年來,有鑑於藥物的特性可能因種族的差異而有不同的療效,藥政機關執行了約四十位試驗者的小型臨床試驗,並交由相關的專家學者,根據試驗結果,評估新藥的療效及安全性,再經由決議後才開放進口。然而,由這些少數病人的臨床結果作為判斷是否核准新藥上市的依據,其代表性可議。因此,為解決這個問題,國際藥物法規協和會發表了一篇導論。其目的在於減少不必要重複的臨床試驗,使國外的臨床資料可外推到新地區使用﹔若有必要,於新地區執行銜接性試驗,進而將兩地區的臨床結果以統計方法評估其相似性,以加速新開發的藥物在其他國家上市。不過,這篇導論中也提及,對於評估地區間療效的相似性,尚未有明確的統計方法。目前已發表的統計方法中,較具有代表性的包含劉仁沛等學者(2002)提出以階層式模型的雙邊對等性及單邊非劣性檢定;周賢忠等學者(2002)利用美國食品藥物管理局評估總體生體對等性的觀念建構的相似性檢定;以及施維中(2001)所提出的一致性試驗的統計觀點。本篇論文的研究,主要針對周賢忠等學者提出的統計方法,對於相同的檢定問題,提出另外三種不同的統計檢定方法,以評估療效在地區間的相似性。同時也建構一個模擬研究,比較這些統計方法在不同情況下其經驗型誤及經驗檢定力的優劣,進而提供給藥政單位及藥廠作為日後評估新藥上市參考的依據。
英文摘要 In the past, the registration of new drugs in Taiwan were approved under the condition that the new drugs had been approved by three advanced countries at least. However, ethnic factors might be one of the essential reasons influence the efficacy of some drugs. In recent years, the regulatory agency has conducted a small clinical trial with around forty patients, and assessed the characteristics of the drug by these clinical responses in this trial. Yet the results of a trial with few clinical responses might fail to give strong evidences to the efficacy of certain drugs. In order to solve this problem, the International Conference on Harmonization (ICH) has published a tripartite guidance entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data.” (ICH E5, 1998) The main purpose of this guidance is to minimize the duplication of clinical data and allow extrapolation to the new region for facilitating the approval of new drugs in the new region. If needed, a bridging study to evaluate the similarity between two regions could be conducted. Unfortunately, the criteria for assessing the similarity between two regions have not been rigorously defined. Therefore various statistical approaches have already been proposed based on different definitions of similarity. Liu, et al. (2002) used a hierarchical model to construct a two-one sided test and a non-inferiority test for assessing similarity between the new and original regions. Chow, et al. (2002) suggested a statistical method using the concept of population bioequivalence. Shih (2001) proposed a consistency trial. Alternative statistical procedures for the evaluation of the similarity between two regions are proposed. A simulation study was conducted to empirically evaluate and compare the size and power.
論文目次 Chapter 1 Introduction 1

Chapter 2 Literature Review 6
2.1 The Equivalence/Non-inferiority approach 8
2.2 The Population similarity approach 9
2.3 The consistency approach 12

Chapter 3 Proposed Methods 14
3.1 The Asymptotic Normality method 14
3.2 The Moment Estimate method 17
3.3 The P-value method 18

Chapter 4 Simulation Study 25
4.1 Simulation process 25
4.2 Simulation results 28
4.2.1 Descriptive statistics 29
4.2.2 Empirical size 30
4.2.3 Empirical power 32
4.2.4 Cover of consistency expanse 34

Chapter 5 Discussion 36

Reference 40
Appendix A. 41
Appendix B. 44
參考文獻 1. Chow, S.C.; Shao, J.; Hu, O.Y.P. “Assessing Sensitivity and Similarity in Bridging Studies.” J. Biopharm. Stat. 2002, Vol. 12, No. 3, pp. 385-400.
2. Chung Kai Lai, A Course in probability Theory, 3rd ed. Academic Press, San Diego, 2001.
3. Hsylop T., F. Hsuan, D.J. Holder, “A small-sample confidence interval approach to assess individual bioequivalence.” Statistic in Medicine, 2000, 19: 2885-2897.
4. ICH. “International Conference on Harmonization Tripartite Guidance E5, 1997; Ethnic Factors in the Acceptability of Foreign Data.” The U.S. Federal-Register, 1998; Vol.83, 31790-31796.
5. Liu, J.P.; Hsueh, H.-M.; Chen, J.J. “Sample Size Requirement for Evaluation of Bridging Evidence.” Biometrical J. 2002, 44, 8, 969-981.
6. Shih, W.J. “Clinical Trials for Drug Registrations in Asian-Pacific Countries:
Proposal for a New Paradigm from a Statistical Perspective.” Control. Clin. Trials 2001, 22, 357-366.
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