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臨床試驗
課程介紹,歷史,計畫書簡介
2015-2-25 Teachers:
簡國龍老師 klchien@ntu.edu.tw 劉仁沛老師 jpliu@ntu.edu.tw
【 本 著 作 除 另 有 註 明 外 , 採 取 創用 CC
「姓名標示-非商業性-相同方式分享」台灣 3.0 版授權釋出】
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Outline
臨床試驗 (Clinical Trial) , 2 學分 846 M0 340
授課老師:簡國龍 (klchien@ntu.edu.tw) &劉仁沛 (jpliu@ntu.edu.tw)
上課時間:每週三上午 10:20Am-12:10Pm (Room 212);
Schedule:Every Wednesday, 10:20Am-12:1 0pm
Room: Room 212, College of Public Health Building
Office time:By appointment3
上課對象:醫護從業人員,公衛、流行病學、預防醫學、統計背景研究生
Students: Health-professionals backgrou nd, public health-related, or statistics-majo r graduate students修習完成本課程可得到 GCP 認證人體試驗相關訓練共 28 小時
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課程目的:
以臨床試驗研究設計及實際進行時處理的問題作一通盤性的介紹,
使學生能對臨床試驗的方法及運用有一整體的認識。
介紹臨床試驗的研究方法,以系統性說明臨床試驗過程需注意的內 容,使學習者能熟練臨床試驗的步驟,並且能夠評估臨床試驗報告 及設計執行臨床試驗。
課程內容:介紹臨床試驗的歷史演變,研究設計、資料分析以及執 行臨床試驗過程中各種步驟, GCP 及 ICH 的概念,以及相關臨床 試驗之實例介紹等。
學生將以團隊方式,完成一個簡要計畫書及其相關受試者同意書與 個案報告表的期末報告。
授課方式:以演講及文獻回顧討論方式,並邀請專家學者作深入演 講。
Course description:
This course is described for students interested in the scientific, and practic al aspects of clinical trials. Topics include types of clinical research, study design, treatment allocation, randomization, sample size requirement, stati stical methods for analysis of clinical trial data, good clinical practice, ICH, adverse events, clinical trial activity and documents patient consent and et hical concerns, and monitoring and interpretation of the results. Students will complete homework assignments, explore key ideas, criticize a protoco l and recently published medical literature, and design a clinical trial investi gation in their own field of interest. The final project for the course, includin g protocol, informed consent, IRB document and case report form, will be t he most achievement for results of clinical trial practice.
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課程安排:
週別 日期 Title 老師 Homework due date1 2/25 課程介紹 , 歷史,計畫書簡介 簡國龍
2 3/4 研究設計 ( 一 ): 病人族群、臨床試驗之設計 簡國龍
3 3/11 研究設計 ( 二 ): 隨機分派、癌症早期臨床試驗之設計、標靶試驗 劉仁沛
4 3/18 統計分析 ( 一 ): 指標種類與選擇 簡國龍
5 3/25 統計分析 ( 二 ): 無母數、 CMH 檢定、存活分析、非劣性及對等性檢 定、多重比較
劉仁沛
6 4/1 溫書假
7 4/8 藥品優良臨床試驗規範 (GCP & ICH)/ 評估臨床試驗品質 - CONSORT statement
簡國龍 HW-1 due date
8 4/15 統計分析 ( 三 ): 樣本大小、效力計算及期中分析與資料安全監督委員 會
劉仁沛
9 4/22 不良反應及不良事件 簡國龍
10 4/29 期中報告 - 文獻閱讀與批評 簡國龍 / 劉仁沛
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5/6 臨床試驗執行 ( 一 ): 計畫書寫作及 SPIRIT Check List, 文件、人體
試驗委員會、受試者同意書、個案報告表 劉仁沛 HW-2 due date
12 5/13 統計分析 ( 四 ): 交叉設計之分析及對等性檢定 劉仁沛
13 5/20 統計分析 ( 五 ): 檢驗試劑與標靶試驗設計與分析 劉仁沛 Protocol-1 due date
14 5/27 臨床試驗執行 ( 二 ): 監測 , 稽核及查核 劉仁沛
16 6/3 Student Presentation on Protocol 簡國龍 / 劉仁沛 15 6/10 Special talk: Professor 楊志新 , Experience on Phase III Trial of
Afatinib for Lung Cancer
簡國龍 / 劉仁沛
17 6/17 Student Presentation on Protocol 簡國龍 / 劉仁沛 Protocol-2 due date 18 6/24 期末考 (6/22-6/26)
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書名 作者 出版社 版次 出版年 ISBN
Design and analysis of clinical trials: concepts and methodologies
Chow, SC, Liu, JP Wiley 3 2013, Oct 978-0-470-88765-3
http://as.wiley.com/Wile yCDA/WileyTitle/productC d-0470887656.html
簡體中文翻譯本 :
Design and analysis of clinical trials: concepts and methodologies
Chow, SC, Liu,
JP( 周賢忠與劉仁
沛 )
北京大學醫 學出版社
1 2010 978-7-81116-917-1
Fundamentals of clinical trials
Friedman, LM, Furberg, CD, DeMets DL
Springer 4 2010 1441915850
Clinical Trials: A methodologic perspective
Piantadosi, S Wiley 2 2005 978-0-471-72781-1
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Course requirements and Grading:
成績計算 homework 30% ,計畫書 40% ,最後口頭報告與批評 3 0% 成績採用等第制評估。
有關最後報告內容除了自己本身的計畫書以外,也需針對另一組計 畫書之內容提出批評。
計畫書內容需指名特定學生之負責的部分及貢獻,以能對特定同學 之成績交待清楚。修習完成本課程可得到 GCP 認證人體試驗相關訓練共 30 小時
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Reference:
Related Journals: Contemporary Clinical Trials
http://www.journals.elsevier.com/contemporary-clinic al-trials
/
JAMA, New Engl J Med, specialist-oriented
Statistics in Medicine, …,
Internet: FDA, DOH, CDE, HTA10
Course requirements and Grading:
Homework assignments, class participant s, and the final project. Grades will be ba sed on homework: 30%, protocol: 40% an d final presentation and rebuttal to critique : 30%. Letter grades will be given in all assignments.
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計畫書簡介
Written Protocol for submission
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Protocol
Refer to the Word document13
Clinical trial (Introdu
ction)
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Clinical trial (Introduction)
A clinical trial is a scientific research activ ity in human subjects undertaken to deter mine, prospectively, the effect and value o f preventive, diagnostic, and therapeuti c agents, devices, regimens, and proce dures.(Hopwood MD, Mabry JC, Sibley WL. 198 0)
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Reasons to learn clinical trial methodolog y
Interpret literature
Participate in the clinical trials
Conduct clinical trials
Regulatory decision16
Scientific knowledge
The results of clinical trials are regarded a s the gold standard in terms of scientific investigations and regulatory decisions(the definite answer).
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Scientific perspective
The method of randomized clinical trials is a last resort for the evaluation of medical i nterventions. It is slow, ponderous, expen sive, and often stifling of scientific imagina tion and creative changes in ongoing prot ocols. No other method for studying the m erits of clinical treatment regimens can ap proach the precision of estimating effects and the strength of inference18
Regulatory perspective
U.S. Federal Register 1985 Concerning Section 314.126
The purpose of conducting clinical investigations of a drug is to distinguish t he effect of a drug from other influences, such as spontaneous change in th e course of the disease, placebo effect, or biased observation. The FDA con siders (these characteristics) in determining whether an investigation is ade quate and well-controlled for the purposes of section 505 of the Act. Reports of adequate and well-controlled in investigations provide the primary basis f or determining whether there is ‘substantial evidence’ to support the claims of effectiveness for new drug and antibiotics. Therefore the study report sho uld provide sufficient details of study design, conduct and analysis to allow c ritical evaluation and a determination of whether the characteristics of an ad equate and well-controlled study are present.
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Stages of a clinical trial
Define the objectives (Conceptual hypothesis vs. Operational hypothesis)
Design the trial– A written protocol
Conduct the trial
Patient recruitment, treatment, and outcomes assessment
Coordination, Organization, & Monitoring
Data management
Analyze the data: Descriptive statistics, Hypothesis testing, Estimation of effe ct
Draw conclusions
Publish in scientific journals
Submit application to regulatory agencies
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臨床試驗的階段
確立研究的目的,包括觀念性的假設及操作性的假設
臨床試驗的設計 -A written protocol
臨床試驗的進行
病人收集、治療、成果的評估
配合項目、機構及監測 (monitoring)
資料處理
分析資料 - 描述性統計、假設檢定、效果估計
歸納結論21
臨床試驗是針對人類為研究對象的科學研究,以前瞻性了解各種預防性,治療性及 診斷性的藥材設備、處方或程序的效果及 價值。
臨床試驗的結果可以當作是一黃金標準,即是在科學研究及藥政管理決策上的黃金 標準。
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科學研究方面:隨機分配、效果的評估、推論的強度
管理法規方面:
排除疾病本身自然史的變化
安慰劑效應、偏差的觀察
研究設計、試驗進行步驟、分析資料23
Design and conduct of clinical trials Personnel
1. Define the objectives
2. Protocol development Background
Patients, treatment, & Outcomes Required data
Statistical considerations
sample size calculation analytical procedures References
Regulatory considerations
3. Institutional approval
4. Design of data forms
5. Patient recruitment
6. Evaluate outcomes
7. Monitoring/ Audit
8. Data entry and management
9. Data analysis
10. Report preparation
Principal investigator (P.I.) and sponsor P.I., Clinical Research Associates (CRA) & Statistician
Institutional Review Board (IRB) or Human Subject Committee P.I. & CRAs
Clinicians (P.I. & other) P.I. & Clinicians
Monitors
Data manages Statistician
P.I. & statistician
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History and Ethics
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History:
The first clinical trial?
The Book of Daniel in the bible (1:15)
Assize of Bread
1202 English food law: prohibit the adulteratio n of bread with ingredients such as ground pe as or beans
Regulations for foods and medicines safet y and quality
American regulation history in shaping clin ical trials26
Clinical Trial: history
中國古代 神農嘗百草
About 500 B.C. Book of Daniel (bible /Old Testament)
1747 Lind Untreated control group (Vit. C and Scurvy) 1798 Jenner Smallpox inoculation
1799 Haygarth Sham procedure (Perkin’s Tractor vs. wooden rod) 1834 Luis (1)exact observation of patient outcomes
(2) knowledge of the natural history of untreated controls (3) precise definition of disease
(4)careful observation of deviations from intended treatment 1863 Gull Use of placebo treatment
1923 Fisher Random allocation in experiment
1931 U.K. MRC Medical Research Council special committee on clinical trials 1931 Amberson Random allocation of treatment to patients
1946 Nuremberg Code for Human Experimentation 1948 MRC Streptomycin trials
1950 MRC Placebo control an double-blind assessment 1964 World Medical Assembly Declaration of Helsinki
1966 U.S. Institutional Review Board
1947 Chalmers Separation of monitoring and administration 1975 World Medical Assembly revision of Declaration of Helsinki 1985 U.S. FDA Adequate and Well-Controlled studies
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USA history (1)
1848, Drug Importation Act
Stop the entry of adulterated drugs from overs eas
1901, Biological Control Act of 1902
A horse named Jim: antitoxin for diphtheria
Antitoxin and vaccine development
1906, original Food and Drugs Act
Prohibit interstate commerce in misbranded an d adulterated food, drugs, and drinks
Enhanced by the Bureau of Chemistry28
USA history (2)
1931, FDA (Food and Drug Administratio n)
1932, initiated the Tuskegee Study of Untr eated Syphilis in the Negro Male
399 poor blacks late syphilis & 201 men witho ut the disease as controls
Was told treated for “bad blood” and not told of the purpose
1950s, PCN not offered to the men with syphili s
Until 1972, the untreated course of syphilis29
USA history (3)
1937, 107 died after drinking the “Elixir of sulfanilamide”, mislabeled
1938, Food, Drug, and Cosmetic Act
Expand the role of FDA in safety of new drugs and control of cosmetics and devices
1940-45, Nazi medical personnel
In concentration camps, Auschwitz and Dacha u, sterilization, euthanasia, exposure to tempe rature extremes, bacteria and untested drugs
Nuremberg War Crime Trials30
USA history (4)
1947, Nuremberg Code
10 standards were drafted for biomedical expe riments
Prototype for further codes in ethical manner
1962, thalidomide
9/3879 American women gave birth to phocom elia
Both efficacy and safety before marketing
Kefauver-Harris Amendment
Consumer Bill of Rights: the rights to safety, to be informed, to choose and to be heard31
USA history (5)
1964, Declaration of Helsinki
The World Medical Association
Guidelines for the ethical treatment of human s ubjects
1972, regulation of biologics, such as seru ms, vaccines, and blood products, were tr ansferred from NIH to the FDA
1974, National Research Act
Identify the basic ethical principles for clinical r esearch32
USA history (6)
1976, Medical Device Amendments
Exemption from pre-market notification, appro val to encourage the discovery and developme nt of useful medical devices
1979, Belmont Report
Three basic ethical principles and guidelines
Respect for persons, decisions and protection
Beneficence, obligation to do no harm, maximize p ossible benefits and minimize possible harm
Justice, the fair and equal distribution of clinical res
earch burdens and benefits
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USA history (7)
1980-81, Title 21 of the Code of Federal R egulations (21 CFR)
Part 50: protection of human subjects
Part 56: IRBs
Part 312: Investigational New Drug application s, responsibility of investigators, control of dru gs, record keeping and retentions, and assura nce of IRB reviews34
USA history (8)
1983, Orphan Drug Act
Unprofitable drugs needed for treating rare dis eases
1988, Food and Drug Administration Act
An agency of the Department of Health and H uman Service
1990, Safe Medical Devices Act
Report promptly any incident that reasonably s uggest that a medical device caused or contrib uted to the severe events
Tracing and locating patients35
USA history (9)
1990, International Conference on Harmo nization for Technical Requirements for R egistration of Pharmaceuticals for Human Use (ICH)
Europe, Japan and US
Standardization to reduce or eliminate duplicat ion of testing in various countries36
USA history (10)
1991, FDA regulations to accelerate the re view of drugs for life-threatening diseases
1995, FDA declared cigarettes to be “drug delivery devices” and proposed restriction s on marketing and sales to reduce smoki ng by young
1997, Food and Drug Administration Mod ernization Act
Accelerate review of devices, advertising unap proved uses of drugs, health claims of food, go od guidance practice for agency decision-maki ng37
USA history (11)
2000, Gene therapy trial
1999 death of an 18-year-old died from multipl e organ failure by infusion of genetically altere d cold viruses into diseased liver
Ensure patient protection and fully informed co nsent
Monkeys had died from the therapy, and sever al previous participants had suffered serious to xic reactions
Office for Human Research Protection (OHRP)
From NIH, OPRR to the office of the Assistant Sec
retary of the Department of HHS
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USA history (12)
Adverse drug effects
Ceristatin withdrawal
Cox-2 inhibitor withdrawal
Clinical trial registration
Anti-depressant clinical trial
Website: clinicaltrials.org.39
Principles of Ethics
Respects for persons / autonomy
Beneficence and Non-maleficence
Justice (Distributive justice)40
Ethical norms in clinical trials
Good research design
Competent investigators
Potential benefits justify potential risks
Equitable selection of subjects
Informed consent
Compensation for research-induced injur y
Special populations
Children, Mentally incompetent, Prisoner s, Fetus41
Practical considerations in clinical trial
Clinical equipoise: genuine UNCERTAINT Y within the clinical community
About which study treatment would be more b eneficial for a patient
Potential benefits vs. possible risks
Human rights and Confidentiality
Adequate and competent review process42
References
http://www.fda.gov/opacom/backgrounders /miles.html
FDA Backgrounder: Milestones in U.S. Food a nd Drug Law History
Websites
Academic journals頁碼 作品 版權圖示 來源 / 作者
1~43 本作品轉載自 Microsoft Office 2010 PowerPoint 設計主題範本 -Pixel ,依據 Microsoft
服務合約及著作權法第 46 、 52 、 65 條合理使用。
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A clinical trial is a scientific research…
devices, regimens, and procedures.
The role of general clinical research centers in clinical trials: A characterization with recommendations/Marsha D. Hopwood, John C. Mabry, William L. Sibiley
http://www.rand.org/content/dam/rand/pubs/reports/2008/R2669.pdf
瀏覽日期: 2015/03/02 ,本作品依據著作權法第 46 、 52 、 65 條合理使用。
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The purpose of
conducting…adequate and well-controlled study are present
U.S. Federal Register 1985 Concerning Section 314.126
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.126 本作品屬公共領域之著作。
23 《 Design and analysis of clinical trials: concepts and methodologies 》, 作者 :Chow, SC, Liu, JP 。本作品依據著作權法第 46 、 52 、 65 條合理使用。
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USA history (1) 1848, Drug Importation Act
…USA history (12)
Milestones in U.S. Food and Drug Law History / U.S. FDA
http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm 瀏覽日期 : 2015/2/26 ,本作品屬公共領域之著作。
版權聲明
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