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系統識別號 U0026-1707201318530100
論文名稱(中文) 以非對稱損失函數改良之一階段連續性評估設計
論文名稱(英文) Modified one-stage continual reassessment method with asymmetric loss function
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 101
學期 2
出版年 102
研究生(中文) 林貞妤
研究生(英文) Chen-Yu Lin
學號 R26004085
學位類別 碩士
語文別 英文
論文頁數 57頁
口試委員 指導教授-杜宜軒
共同指導教授-張升懋
口試委員-黃錦輝
口試委員-吳雅琪
中文關鍵字 一階段連續性評估設計  第一階段臨床試驗  非對稱損失函數  最大耐受劑量 
英文關鍵字 continual reassessment method  phase I clinical trial  asymmetric loss function  maximum tolerated dose 
學科別分類
中文摘要   為了確保新藥物或新治療技術不會造成人體無法承受的嚴重副作用且具有療效,在核准上市前都必須經過四個階段的臨床試驗。其中,第一階段臨床試驗是首次將新藥物作用於人體身上的一個階段。第一階段臨床試驗的主要研究目的為瞭解新藥物的安全劑量範圍,也就是訂定最大耐受劑量(maximum tolerated dose, MTD)。然而,由於癌症用藥的第一階段臨床試驗的受試者為癌末患者而非健康的人,因此對於第一階段癌症用藥臨床試驗而言,其主要研究目的除了訂定MTD外,也必須考量療效的問題。連續性評估設計(continual reassessment method, CRM)是首次以模型為根基,針對第一階段臨床試驗而做出的設計。若以CRM進行試驗,確實有較少的受試者會服用到較不具療效的低劑量,不過這個設計也會讓較多的受試者服用高過MTD的劑量而讓研究者認為太過危險。因此,本論文提出以非對稱損失函數給予過高劑量固定懲罰及彈性懲罰的設計,藉此降低受試者接受高過MTD劑量的機會。我們進行模擬並對本論文提出的方法與CRM進行比較。模擬結果顯示,本論文提出的方法相對於CRM而言,有效地降低受試者接受過高劑量的比例,且產生毒性反應的人數也較少,特別是賦予過高劑量固定懲罰的設計。除此之外,以本論文提出的方法進行臨床試驗時,受試者接受過高劑量的人數之變異及高估MTD的比率相對於CRM也都來的小許多。由此可知,本論文提出的方法有效地改善了CRM傾向給予受試者過高劑量的缺點。
英文摘要 To ensure the drugs are therapeutic and will not cause serious side effects on human, the drugs are required to go through four phases of clinical trials before they are approved for sale and marketing. Phase I clinical trial is the study where a drug is initially given to human. The main objective of phase I clinical trial is to identify the maximum tolerated dose (MTD). The purpose of phase I oncology clinical trial is not only to estimate MTD but also to treat the subject at a therapeutic dose since the participants in a phase I oncology trial are patients at advanced disease stages rather than healthy volunteers. Continual reassessment method (CRM) is the first model-based designs for phase I oncology clinical trial. The advantage of CRM is that it assigns few patients are treated at low and potentially non-therapeutic doses. But, the investigators consider it assigns too many patients to receive the doses which have high toxicity. Therefore, in this thesis, we propose an asymmetric loss function with fixed and flexible penalties to reduce the chance that patients receive overdosing assignment. We conducted simulations to compare the proposed methods with CRM. The results showed that relative to the CRM, the proposed methods efficiently decrease the proportion of patients who received overdoses and exhibited fewer toxicities, asymmetric loss function with fixed penalty especially. Additionally, both the standard deviation of number of patients who received an overdose and the proportion of overestimated MTD under CRM are lower than that under the proposed methods. Hence, the proposed methods improve the shortcomings of CRM.
論文目次 1. Introduction 1
2. Literature Review 4
2.1 Continual Reassessment Method 4
2.1.1 Setting and Notation 4
2.1.2 Dose-Toxicity Model 5
2.1.3 Dose Labels 7
2.1.4 Dose Assignment Process 7
2.1.5 Numerical Illustration 8
2.1.6 Model Regularity Conditions 12
2.1.7 Practical Modifications 13
2.2 Two-stage Continual Reassessment Method 14
2.3 Escalation With Overdose Control 15
3. Modified one-stage CRM with asymmetric loss function 17
3.1 Asymmetric loss function with fixed penalty 18
3.1.1 Method 18
3.1.2 Numerical Illustrations 20
3.1.3 Simulation trials: one-stage CRM-AL and one-stage CRM 25
3.1.4 Results 27
3.2. Asymmetric loss function with flexible penalties 30
3.2.1 Motivation 30
3.2.2 Method 30
3.2.3 Simulation trials: one-stage CRM- ALf and one-stage CRM 32
3.2.4 Results 33
3.3 Consistency 40
3.4 Comparison 42
4. Concluding Remarks 49
References 51
Appendix 53
參考文獻 Ahn, C. (1998), “An evaluation of phase I clinical trial designs”, Statistics in medicine, 17: 1537-1549.
Babb, J., Rogatko, A. & Zacks, S. (1998), “Cancer phase I clinical trials: efficient dose escalation with overdose control”, Statistics in medicine, 17: 1103-1120.
Cheung, Y. K. (2011), Dose finding by the continual reassessment method (1st ed.), New York: Chapman and Hall/CRC Press.
Eichhorn, B. H. & Zacks, S.(1973), “Sequential search for an optimal dosage, I”, Journal of the American Statistical Association, 68: 594-598.
Moller, S. (1995), “An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses”, Statistics in medicine, 14: 911-922.
O’Quigley, J., Pepe, M. & Fisher, L. (1990), “Continual reassessment method: a practical design for phase 1 clinical trials in cancer”, Biometrics, 46: 33-48.
Percy Ivy, S., Siu, L., & Garrertt-Mayer, E., et al. (2010), “Approaches to phase I clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee”, Clinical Cancer Research, 16: 1726-1736.
Rosenberger, W. F., & Haines, L. M. (2002), “Competing designs for phase I clinical trials: a review”, Statist. Med., 21: 2757-2770
Shen, L.Z. & O’Quigley, J. (1996), “Consistency of continual reassessment method under model misspecification”, Biometrika, 83 (2): 395-405.
Simon, R., Freidlin, B., Rubinstein, L., Arbuck, S.G., Collins, J. & Christian, M.C. (1997), “Accelerated Titration Designs for Phase I Clinical Trials in Oncology”, Journal of National Cancer Institute, 89: 1138–1147.
Storer, B. E. (1989), “Design and analysis of phase I clinical trials”, Biometrics, 45: 925–937.
Ting, N. (2006), Dose Finding in Drug Development (1st ed.), New York: Springer.
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