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研究生：	陳嘉民 Chen, Chia-min
論文名稱：	第二期臨床試驗下二元試驗指標之縮減二階段試驗設計 Curtailed two-stage designs with binary endpoint in phase II clinical trials
指導教授：	嵇允嬋 Chi, Yun-Chan
學位類別：	博士 Doctor
系所名稱：	管理學院 - 統計學系 Department of Statistics
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	69
中文關鍵詞：	雙變量二元指標、二階段設計、提早停止、期望樣本個數、單變量二元指標、縮減抽樣程序
外文關鍵詞：	bivariate binary endpoints, two-stage designs, early stopping, expected sample size, curtailed sampling procedure, univariate binary endpoint
相關次數：	點閱：93 下載：12
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在新藥研發的過程中，第二期臨床試驗主要目的是要瞭解藥品的有效性 (efficacy)與安全性，以作為是否進一步進行第三期臨床試驗的依據。然而，藥品通常會產生副作用 (side effect)，對於受試者充滿了無法預知的風險，因此，基於道德上的考量，避免提供無療效或者副作用過高的藥給太多受試者，Simon (1989) 二階段設計被廣泛的應用在第二期臨床試驗。然而，當研究人員欲同時考慮藥品的有效性與副作用時，Simon二階段設計並不適合。因此Conaway和 Petroni (1995) 和Jin (2007) 等學者分別提出了新的臨床試驗設計，以同時探討藥物的有效性及副作用。一般而言，在新藥臨床試驗的過程中，對於病人的招募通常有嚴格的限制，所以往往等待很長的時間才能招募到足夠的病人。因此，本論文應用縮減抽樣程序 (curtailed sampling procedure)，發展出一種縮減兩階段設計，此設計一旦有足夠的訊息判定新藥療效與安全性時，即可立即停止招募病人，做成決策，進而有效減少受試者數目，縮短臨床試驗時間，加速進入第三期臨床試驗。

The goal of the phase II clinical trials is to determine whether a new drug has enough clinical activity and safety to make it worth further studying in a phase III clinical trial. Ethical concerns that a trial must be stopped early if experimental treatment appears to be ineffective or unsafe. In Simon’s two-stage design (1989), the hypothesis testing procedure is based on a single endpoint, the response rate. Even though the trials based on Simon’s design implicitly consider safety information, sample size determination and stopping rules are based on the single endpoint of interest. Recently, several two-stage designs have been developed for bivariate binary endpoints, such as Conaway and Petroni (1995), and Jin (2007). In these designs, the hypothesis testing procedure is based on two dependent binary responses, the treatment response and toxicity side effect. To reduce the number of recruited patients and hence the drug development process, this dissertation proposes an alternative two-stage design with univariate endpoint based on the curtailed sampling procedure to allow for stopping early as soon as the treatment shows lack of efficacy or very effective. Moreover, this dissertation extends curtailed sampling procedure for bivariate endpoints to allow for early termination once the treatment shows lack of efficacy or safety, or very effective and safe. The numerical results are provided and confirm the usefulness of the proposed curtailed two-stage design in reducing sample size.

Chapter 1 Introduction............................................. 1
Chapter 2 Literature review........................................ 5
2.1 Simon’s two-stage designs...................................... 5
2.2 The single-stage designs for bivariate binary responses........ 8
2.3 The two-stage designs for bivariate binary responses...........12
2.4 Curtailed sampling procedure...................................15
Chapter 3	Univariate curtailed two-stage designs.............19
3.1 The decision rules of univariate curtailed two-stage designs...19
3.2 The probability distribution and expected sample size..........21
3.3 Design parameters for univariate curtailed two-stage designs...24
3.4 Comparison with stochastically curtailed Simon’s designs…….....27
3.5 Simulation study in univariate curtailed two-stage designs…....28
3.6 An example for univariate curtailed two-stage designs..........29
Chapter 4 Bivariate curtailed two-stage designs....................31
4.1 Preliminaries..................................................31
4.2 Bivariate curtailed two-stage designs..........................37
4.3 The probability distribution and expected sample size..........40
4.4 Design parameters for bivariate curtailed two-stage designs....43
4.5 Comparison with Conaway and Petroni’s two-stage designs….......46
Chapter 5 Concluding remarks and future work.......................49
5.1 Concluding remarks.............................................49
5.2 Future works...................................................50
Appendices.........................................................52
Appendix A.........................................................52
Appendix B.........................................................55
Bibliography.......................................................58
Tables.............................................................61
                                    

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校內：2010-02-09公開
校外：2010-02-09公開

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