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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 appointment

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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。

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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 date

1 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

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, HTA

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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 as

signments.

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計畫書簡介

Written Protocol for submission

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Protocol

Refer to the Word document

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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 decision

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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 inference

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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

歸納結論

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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

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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 trials

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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 Chemistry

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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 syphilis

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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 Trials

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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 heard

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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 esearch

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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 reviews

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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 patients

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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 countries

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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 ng

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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.

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Principles of Ethics

Respects for persons / autonomy

Beneficence and Non-maleficence

Justice (Distributive justice)

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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, Fetus

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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 process

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References

 http://www.fda.gov/opacom/backgrounders /miles.html

FDA Backgrounder: Milestones in U.S. Food a nd Drug Law History

Websites

Academic journals

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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。

14

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。

27~38

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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參考文獻

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