臨床試驗 臨床試驗執行(三) 監測、稽核、查核 授課老師: 劉仁沛教授 國立台灣大學 與 國家衛生研究院 【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】

Cooperative Research Group Example of Misconduct of Clinical Research National Surgical Adjuvant Breast and Bowel Project (NSABP), 484 institutions with 5,000 physicians funded by NCI since 1960 NEJM, May 14, 1994, Vol. 330 (20): 1448-62 Chairman: Dr. Bernard Fisher Principle Statistician: Dr. Carol Redmond In June, 1990, discrepancy of dates of surgery of two identical operative reports by data managers and a protocol statistician Dr. Roger Poisson – L’ Hôpital Saint-Luc, University of Montreal participated 22 NSABP trials with enrolling about 1500 patients (7%) 2018/11/15

Cooperative Research Group Changes in the dates of biopsy, surgery, pathology report, and hormone receptor values 115 instances of data falsification or fabrication in data from 99 patients B-06 lumpectomy vs. mastectomy B-13 adjuvant chemotherapy B-14, 16 Tamoxifen 2018/11/15

Cooperative Research Group Funding agency: NCI Cooperative group: NSABP Investigative Body: Office of Research Integrity (ORI), FDA Finding published in: Federal Register, ORI Newsletters, NIH Guide for Grants and Contracts,Chicago Tribune Congressional hearing by John, D. Dingell on 4/13/1994 Dr. R. Poisson was charged of scientific misconduct and as disqualified for life by the US FDA from receiving investigational drugs 2018/11/15

Gene Therapy University of Pennsylvania – 9/99 Death of a 18 year old volunteer after a genetically altered virus to treated an inherited liver disease in a gene therapy clinical trial. FDA inspection (Jay Siegel) Problems with the protocol Informed consent Patient exclusion criteria Stopping rule Initiating protocol changes Reporting adverse events 2018/11/15

Gene Therapy Reporting AEs by gene therapy trials to NIH Recombinant DNA advisory committee Before the death – 39 After the death – 652 Actions Stopping the trial Congressional hearings Investigations by HHS and University Advisory committee meeting 2018/11/15

Asthma Study Johns Hopkins University Alkis Togias, MD, Associate Prof. of Medicine Hexamethonium Fluka: Sigma-Aldrich corp. Approved for HBP, and decrease bleeding (1950) Withdrawal from market in 1970’s A 24-year old female healthy volunteer died from lung failure on June 2, 2001. 2018/11/15

Asthma Study FDA FORM 483 Inspectional Observations Failure of submission an IND to FDA Failure of reporting an unanticipated AE to the IRB Failure to follow the protocol Changes to the approval protocol without notifying the IRB and without IRB approval Failure to obtain effective informed consents from subject: Similar AE reported by UCSF in 1978 2018/11/15

Contract Research Organization (CRO) Eichenwald, K. and Kolata, G. “A Doctor’s Drug Trials Turned into Fraud”. New York Times, May 17, 1999 Dr. Fiddes, President of Southern California Research Institute, a clinical research company in Whittier, California Conducted over 200 studies for as many as 47 drug companies beginning in the early 1990’s Engaged in extensive fabrication and falsification of data Aug. 1997 plead guilty to felony charge of conspiracy to make false statements to the FDA in connection with the Drug approval process 2018/11/15

Contract Research Organization (CRO) Sept. 1998 sentenced to 15 months in federal prison Ordered to pay $800,000 in restitution June 1999 disqualified as a clinical investigator by Commissioner of FDA 2018/11/15

Contract Research Organization (CRO) Made up fictitious study subjects Fabricated lab results by substituting clinical specimens and manipulating lab instrumentation Prescribed prohibited medications to manipulate data 2018/11/15

Contract Research Organization (CRO) “Another study on an antibiotic required that patients have a certain type of bacteria growing in their ear. No problem for Fiddes. He bought the bacteria from a commercial supplier and shipped them to testing labs, saying they had come from his patients’ ears.” 2018/11/15

2018/11/15

Duke Scandal 2018/11/15

Duke Scandal 2018/11/15

Duke Scandal 2018/11/15

Duke Scandal 2018/11/15

PREDICTORS OF CHEMOTHERAPY RESPONSE: Duke Scandal PREDICTORS OF CHEMOTHERAPY RESPONSE: BACKGROUND INFORMATION In relation to the topics and questions suggested by the IOM, the following document outlines some of the scientific and administrative responses around the attempted development of chemotherapy sensitivity predictors and is being provided by Duke Medicine administration to the IOM Committee in advance of its upcoming “Workshop on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials.” The circumstances and events related to work conducted by Dr. Anil Potti, in collaboration with Dr. Joseph Nevins, at the Duke Institute for Genome Sciences & Policy that have led to the IOM Committee’s review of this field are regrettable and have led to significant organizational self evaluation in an attempt to learn from the events of the past two years. Understanding that the committee is scheduled to receive additional information at future meetings, this document is limited in scope to some of the thought processes and actions relevant to the topics defined for this workshop. It is our hope and belief that the work of this committee will serve to provide much needed guidance for this emerging area of translational research and we are grateful to the IOM for taking on this project. 2018/11/15

Duke Scandal Further analyses revealed corruption of multiple datasets compiled by Dr. Potti that had been used as sources of validation of the various chemotherapy sensitivity signatures. These included data derived not only from Duke sources, but also publicly available data. As an example, a dataset of 133 samples from a neoadjuvant breast cancer study at MD Anderson involving patients treated with the combined regimen TFAC was used for validation of an adriamycin signature. The clinical annotation that was assumed to be used by Dr. Potti included 34 responders and 99 non-responders, the same distribution as reported by MD Anderson. However, a detailed comparison of the two datasets revealed that the response information was reversed for 24 cases with 12 labeled incorrectly in each direction. In this case, the corrupted data yielded positive validation results whereas the accurate data did not provide evidence for validation. Similar findings of corruption of data in key validation datasets were observed in other instances. As a result, three publications were retracted, a manuscript describing the methods for implementing signatures in the clinical trials that was under review was removed from further consideration, and other publications are currently being analyzed.  Dr. Potti issued his resignation statement on November 19, 2010, and a statement of responsibility for the problems with the work.  A research misconduct investigation is in progress. 2018/11/15

Duke Scandal There are many lessons to be learned from this experience, but the immediate lessons that Duke and the IGSP have learned are that all data and methods for clinical research must be assessed at multiple levels and that quantitative expertise is needed for complex analyses; furthermore, for translation to clinical trials these analyses must be done using systems that maintain independence between the data generation and the analysis and enable replication of the results, along with documentation of all changes to data and analyses. 2018/11/15

小保方晴子與STAP幹細胞 2014年1月日本理化研究所小保方晴子在Nature期刊發表兩篇有效製作STAP多功能幹細胞的論文，轟動一時。 發現論文中影像造假。 其他學者及自已無法重複實驗結果。 2014年7月2日Nature期刊撤銷論文。 2014年8月5日小保方晴子日本指導教授井芳樹自殺。 2014年8月12日小保方晴子美國哈佛大學指導教授Charles Vacanti辭職。 2018/11/15

Diederik Stapel and Marc Hauser Diederik Stapel of Tilburg University, Netherlands Retracted 55 papers, including the one in Science and 10 PhD dissertation due to fabrication of data Marc Hauser of Harvard University Committed falsification of data Forced to resign from Harvard 2018/11/15

ISSUES ◆ Fictitious trials Subjects ◆ Non-adherence to the protocol ◆ Informed consent form ◆ Fictitious trials Subjects ◆ Non-adherence to the protocol ◆ Records and diagnosis unverifiable ◆ Data falsification or fabrication ◆ Failure to notice and report SAEs ◆ Drug Accountability 2018/11/15

Good Clinical Practice 「藥品優良臨床試驗規範」- 行政規範 8章232條 - 85.11.20 & 91.9.20 「藥品優良臨床試驗準則」- 法規命令 8章123條 - 94.1.6 查驗登記用之藥品臨床試驗-應遵守 學術研究用之藥品臨床試驗-建議參考 實施日期 原產國尚未核准上市: 86年7月1日 原產國已上市: 87年1月1日 2018/11/15

監測者 監測者〈Monitor〉：指由試驗委託者或受託研究機構所指派，並直接向試驗委託者或受託研究機構負責，以監測並報告試驗的進度和驗證試驗資料之人。   根據標準作業程序執行，在試驗執行前、執行中及完成後前往觀察試驗主持人，是否確實依循試驗計畫書的規定程序進行，並確認所有過程資料均予正確與完整的記錄與報告；受試同意書均在受試驗者參與試驗前簽署。 與試驗主持人每次之會面、電話及信件等討論後，均應提報試驗委託者一份書面的監測紀錄。 2018/11/15

品質保證 為確保試驗結論係自原始資料逐步推論獲得，所有觀察結果與發現，特別是資料的可靠性均得被再確認。 為確保所有資料數據之可靠與被正確處理，資料處理的每一步驟均應實施品質管制。 試驗之稽核應由試驗委託者或由醫療機構委託與該計畫無關之人員執行。 所有本規範提及之文件，含建議書、申請書等均應對試驗委託者及中央衛生主管機關公開，並接受其稽查。 試驗地點、醫療機構、檢驗室以及所有資料〈包括原始資料〉及文件均應接受中央衛生主管機關之查核。 2018/11/15

稽核 vs.查核 查核 稽核 試驗中.後期 試驗初期(~20% 收案) 著重試驗計畫順從性 改善試驗流程及順從性 由主管機關為之 試驗是否成功並非重點 稽核 試驗初期(~20% 收案) 改善試驗流程及順從性 試驗委託者委託獨立稽核者 企求試驗成功 2018/11/15

臨床試驗查核 確保臨床試驗品質 保護受試者之權益 落實GCP之實施 評估及改進查核小組架構與執行 提昇國內臨床試驗水準 2018/11/15

臨床試驗查核 實施日期 原產國尚未核准上市 86年7月1日 原產國已上市 87年1月1日 2018/11/15

PROCEDURES Flow of Data Source Documents ↓ Case Report Forms Report and Listings 2018/11/15

PROCEDURES Inspection of Data Flow: Source Documents ↓↑investigator Case Report Forms ↓↑sponsor Report and Listings 2018/11/15

查核手冊與記錄表格之製定 藥品臨床試驗查核手冊及記錄表格 醫療機構 藥界、公會 學術單位 試驗主持人及醫療機構 試驗委託者、受託研究機構、監測者 人體試驗委員會 醫療機構 藥界、公會 學術單位 2018/11/15

訓練課程 臨床試驗查核說明會 7場382人 臨床試驗查核工作人員訓練 模擬查核 臨床試驗查核結果說明會 2018/11/15

臨床試驗查核作業流程 TFDA 查核小組 通知試驗委託者準備資料 安排查核小組成員及聯絡試驗主持人 確定臨床試驗查核日期＼時間＼地點 資料寄送給查核成員 TFDA行文通知查核 執行查核工作 完成查核 記錄報告 影本提供TFDA藥 物諮詢委員會審查 影本供查核計畫主持人存查 正本歸檔 2018/11/15

實地查核作業流程 TFDA查核小組 中途進出人員 雙方簡介並確定在場人員身份 試驗主持人簡報臨床試驗 查核小組開始執行查核工作 拜訪試驗相關之醫院場所 查核結果報告與討論試驗 主持人列席 2018/11/15

臨床試驗查核委員 TFDA委員 臨床委員 統計委員 藥物動力學委員 查核計畫召集人 2018/11/15

臨床試驗查核記錄表 授權與管理 試驗計畫書 受試者同意書 人體試驗委員會 受試者資料 研究用藥品之處置與管理 記錄保存 電腦化資料與資訊系統 藥物動力學 2018/11/15

臨床試驗查核記錄表填寫委員 TFDA委員 臨 床 委 員 統 計 委 員 藥 動 委 員 藥物動力學 授權與管理 試驗計畫書 受試者同意書 4. 人體試驗委員會 6. 研究用藥品之處置與管理 TFDA委員 臨 床 委 員 受試者資料 5.1-5.11項 5. 受試者資料 5.12-5.15項 7. 記錄保存 8. 電腦化資料與資訊系統 統 計 委 員 藥物動力學 藥 動 委 員 2018/11/15

GCP查核結果 1.備查（通過） 2.補充說明後通過 3.重查 4.不准備查 5.自行撤案 2001年至2008年不准備查的比例為7.66% 2018/11/15

PROCEDURES Preparation for an inspection: ● Read thoroughly the protocol (future tense). ● Read thoroughly the report (past tense). ● Review the self-filled inspection forms. ● Check any discrepancy among them. ● Look for changes in conduct and analysis. ● Write down a list of items for your inspection. ● Understand the current status of regulation. 2018/11/15

PROCEDURES Preparation for an inspection: ● Example The primary endpoint is the change from baseline of HbA1c. The baseline HbA1cs were not provided in the patient listing of HbA1c 2018/11/15

PROCEDURES Check the subject identification list: How many screened? How many randomized? How many withdrawal (cf. charts)? How many AEs? How many Serious AEs? Status of the individual site being inspected for multi-center trials. 2018/11/15

PROCEDURES Chart: a surrogate for existence of trial subjects. Check the number of charts. Reasons for unavailable charts. Check the date, and demographic information on the front page of the chart against those of CRF, report, and subject identification list. Check whether the subjects were registered through the center Electronic form of medical charts??? 2018/11/15

PROCEDURES Blindness Check appearance and packages of drugs. Check random codes. Original code list with programs and logs with date generated. Random codes vs. CRFs vs. patient listings. Official document for unblinding codes for analysis with authorized signature and date Documents for breaking codes for other reasons during the study. 2018/11/15

PROCEDURES Monitoring Check the number of monitoring reports. Monitoring should be signed by CRAs and their supervisors. Read thoroughly the monitoring reports of initiation and close-up visits. Monitoring reports should reflect the conduct of trials. Important events should be recorded in monitoring reports, e.g., serious adverse events. 2018/11/15

PROCEDURES Data should be obtained in a proper order. Example: Form for physical exam was completed before the visit by the CRA and attached to the chart. However, the subject missed the visit and form was crossed out and left on the chart. An example of data fabrication. 2018/11/15

PROCEDURES Data should be obtained in a proper order. Example: Results of one of inclusion criteria for the primary endpoint were obtained after the date of randomization An example of non-adherence to protocol. 2018/11/15

PROCEDURES Inclusion/exclusion should be checked with documented data before enrollment. Example: One of inclusion criteria for prohibited medicines was not verified before randomization of patients and was found out after completion of the study An example of non-adherence to protocol. 2018/11/15

CURRENT STATUS Monitoring failed to identify the patients who were not meet inclusion/exclusion criteria such as prohibited medicine. Insufficient training (simulation) at the investigator meeting and initiation of trial and site visit for adherence to the protocol. Inclusion/exclusion criteria were not completely verified and checked. Computer system also failed to identify the patients on prohibited medicines even when they were entered into the database of concomitant medications. 2018/11/15

CURRENT STATUS Only charts for randomized patients available (not screened patients). Inconsistent records on SAEs between charts, patient listing and reporting. No individual center results available for the center being inspected. Incorrect methods for generation of random codes. Different methods for generation of random codes by different centers. 2018/11/15

Correct Random Assignment Patient No. Random Code Date 001 13 01022007 002 14 01032007 003 15 01042007 004 16 01062007 006 17 01102007 007 18 01152007 008 19 01202007 009 20 02012007 010 21 02022007 013 22 02152007 014 23 02172007 016 24 02202007 2018/11/15

Incorrect Random Assignment Patient No. Random Code Date 001 20 01022007 002 16 01032007 003 24 01042007 004 14 01062007 006 19 01102007 007 17 01152007 008 15 01202007 009 23 02012007 010 13 02022007 013 22 02152007 014 18 02172007 016 21 02202007 2018/11/15

不預警查核 - 臨床試驗A 多國多中心臨床試驗 台灣共4個醫學中心 標的藥物 非小細胞肺癌 可能會引起心律不整 QT/QTc Prolongation Torsade de Pointes (TdP) CYP450 3A4 2018/11/15

不預警查核 - 臨床試驗A 禁用藥品 引起Torsades de Pointes Group 1 藥物 (26 個) Not allowed During study Within 2 weeks of study entry Avoided for up to 4 weeks following discontinuation of study treatment 2018/11/15

不預警查核 - 臨床試驗A 禁用藥品 引起Torsades de Pointes Group 2 藥物 (52 個) Screening QTc ≤ 460 msec Additional ECG 4-8 hours after the 1st dose Closely monitoring QTc + electrolytes CYP450 3A4 (15個) Inducers Inhibitors 2018/11/15

不預警查核 - 臨床試驗A QTc Prolongation QTc > 550 msec or ΔQTc from baseline > 100 msec  withhold study medication and follow for resolution of QTc prolongation. 480 msec  QTc < 550 msec or ΔQTc from baseline > 60 msec ( QTc  460 msec for Group 2 藥物)  continue double-blind study drug and repeat 3 QTc evaluations within 48 hours. 2018/11/15

不預警查核 - 臨床試驗A QTc Prolongation 480 msec  QTc < 550 msec or ΔQTc from baseline > 60 msec ( QTc  460 msec for Group 2 藥物)  withhold study medication and follow for resolution of QTc prolongation. 2018/11/15

不預警查核 - 臨床試驗A 廠商主動通報三家中心發生服用禁藥。 衛生署於2008年五月至八月至所有4家參與試驗的醫學中心進行不預警查核。 中心甲: 5位受試者服禁用藥品。 中心乙: 1位受試者服禁用藥品。 中心丙: 1位受試者overdose 衛生署於2008年五月至八月至所有4家參與試驗的醫學中心進行不預警查核。 2018/11/15

不預警查核 - 中心甲 篩選：17人 隨機：11人 5位受試者服用Group 1引起Torsades de Pointes的禁用藥品。 一位受試者在隨機指派前即退出 發生比例：36.4% 2018/11/15

不預警查核 - 中心甲 Baseline日期 服用禁用藥品日期 03/16/2007 12/28/2006 - 08/28/2007 03/16/2007 12/28/2006 - 08/28/2007 04/10/2007 11/26/2006 - 07/18/2007 07/19/2007 06/26/2007 - 07/24/2007 09/04/2007 10/16/2006 - 11/27/2007 2018/11/15

不預警查核 - 中心甲 所有受試者均服用同一種Group 1禁用藥品。 有些受試者在進入試驗前即服用。 有些受試者是在試驗中服用。 2018/11/15

不預警查核 - 中心甲 研究護士未確認受試者未服用Group 1禁用藥品即在排除條件勾選“No”。 在事件發生後才進行檢查全部受試者是否服用Group 1禁用藥品後，才將試驗前服用Group 1禁用藥品改為“Yes”。(Falsification of data) 2018/11/15

不預警查核 - 中心甲 試驗委託者的個案報告表登錄併用藥品時，亦未檢查併用藥品是否為禁用藥品。 發生服用Group 1禁用藥品事件後廠商並未立刻進行稽核。 2018/11/15

不預警查核 - 中心乙 篩選：16人 隨機：13人 查核當天查核人員至中心乙進行查核時才被告知主持人無法出席，改由協同主持人代為出席。 因由協同主持人代為出席故無法回答所有委員的問題。 2018/11/15

不預警查核 - 中心乙 一位受試者因肺炎急診，由急診醫師開立並服用一個劑量的Group 1禁用藥品。 發生比例：7.69% 發生比例：23.1% 2018/11/15

不預警查核 - 中心乙 二個受試者發生QTc Prolongation。 未按計畫書在48小時內重複三次QTc之評估。 發生比例：11.8% 2018/11/15

不預警查核 - 中心丙 篩選：20人 隨機：17人 未發生服用Group 1或Group 2禁用藥品。 一位受試者多服用試驗研究用藥1顆。 一位受試者發生QTc prolongation後，當天重複三次ΔQTc from baseline < 60 msec。 2018/11/15

不預警查核 - 中心丁 篩選：12人 隨機：10人 提供11位受試者病歷。 僅提供某一位受試者4/28/2008後之病歷。此一受試者參與試驗所有原始資料均紀錄於4/28/2008前之病歷。 Screening log未登錄Screen failure的受試者。 2018/11/15

不預警查核 - 中心丁 一位受試者由住院醫師開立並服用一個劑量的Group 1禁用藥品。 發生QTc Prolongation後，才檢查併用藥品才發現服用Group 1禁用藥品19天。 停用研究藥物後QTc恢復正常，但仍然服用Group 1禁用藥品，至受試者死亡。 2018/11/15

不預警查核 - 中心丁 另一位受試者發生QTc Prolongation，因遇週末晚4天停藥。 另一位受試者服用Group 2禁用藥品未發生QTc Prolongation。 未通報服用Group 1禁用藥品。 2018/11/15

討論 主持人 未按計畫書執行臨床試驗。 服用禁用藥品長達11個月且均有主持人蓋章，所以主持人不可能不知自己所開之藥物。 不暸計畫書的內容與執行步驟，導致所開藥物為Group 1禁用藥品。 填寫個案報告表時未確認資料正確性。 未監督其團隊確實執行臨床試驗。 2018/11/15

討論 試驗委託者 主動通報。 試驗前主持人會議未充分告知禁用藥品之資訊。 事件發生前不熟悉禁用藥品。 未發現受試者長期服用禁用藥品。 試驗委託者併用藥品資料庫亦未能與禁用藥品相互比對。 試驗委託者並不重視違反服用禁用藥品之事件。 2018/11/15

討論 醫療機構 倫理委員會為功能性單位，無編制內專業人員。 倫理委員會未能做好監督工作。 中心丁之倫理委員會在衛生署告知後，亦未通報違反服用禁用藥品之事件。 所有參加臨床試驗受試者之病歷應標籤。非主持人開立處方應與主持人商確。 應確實執行保存臨床試驗受試者之病歷。(醫療法第70條:人體試驗之病歷，應永久保存。) 2018/11/15

討論 Disqualified / Totally Restricted List for Clinical Investigators FDA regulates scientific studies that are designed to develop evidence to support the safety and effectiveness of investigational drugs (human and animal), biological products, and medical devices. Physicians and other qualified experts ("clinical investigators") who conduct these studies are required to comply with applicable statutes and regulations intended to ensure the integrity of clinical data on which product approvals are based and, for research involving human subjects, to help protect the rights, safety, and welfare of those subjects. The following list contains the names of all clinical investigators who have been disqualified or "totally restricted." FDA may disqualify a clinical investigator if the clinical investigator has repeatedly or deliberately failed to comply with applicable regulatory requirements or the clinical investigator has repeatedly or deliberately submitted false information to the sponsor or, if applicable, to FDA. A disqualified clinical investigator is not eligible to receive investigational drugs, biologics, or devices. In the past, the phrase "totally restricted" was also used to refer to clinical investigators who had been disqualified. Where an investigator has been reinstated, it is so noted. 2018/11/15

Disqualified / Totally Restricted List for Clinical Investigators It is important to underscore the difference between "totally restricted" clinical investigators and "restricted" clinical investigators. "Totally restricted" investigators are ineligible to receive investigational products (absent reinstatement). "Restricted" investigators, on the other hand, are still eligible to receive investigational products, provided they conduct regulated studies in accordance with the restrictions specified in their agreement with FDA and all applicable regulatory requirements. FDA maintains separate lists for all clinical investigators who have agreed to certain restrictions with respect to their conduct of FDA regulated studies; clinical investigators who were previously subject to restrictions which have been removed; and clinical investigators who, under regulations in effect until 1987, provided adequate assurances with respect to their future compliance with requirements applicable to the use of investigational drugs and biologics 2018/11/15

討論 查核作業 十年來未有重大的改變。 制式化、書面審查。 無編制內專職、專業查核單位及人員進行獨立查核。 不同醫療機構的委員互相查核，無法公正、深入，以免得罪同僚。 球員vs. 裁判(均為業餘)。 Conflict of interest and financial disclosure。 2018/11/15

討論 2018/11/15

建議 查核制度、作業應作重大改變 查核結果列入查驗登記 查核結果列入醫院評鑑 查核結果列入倫理委員會評鑑 專職機構與專人 方向與重點 方式 查核結果列入查驗登記 查核結果列入醫院評鑑 查核結果列入倫理委員會評鑑 預防重於治療，教育與觀念-建立主持人正確的心態。不要鑽法規漏洞。按計畫書確實執行試驗。 2018/11/15

建議 建立編制內專職、專業查核單位及人員進行獨立查核。 國內查核-可延至一天、國外查核-可為一至二天。 建立編制內專職、專業查核單位及人員進行獨立查核。 專業查核人員不一定為醫師、藥動專家、或統計專家。但必須充分授權，代表政府，行使公權力。 書面審查+人員一對一訪談+場所視查。 查核臨床試驗的執行與過程，而不是聽取結果的報告或詮釋。(結果發表於NEJM，但資料處理作假，paper仍然被retracted) 建立查核新的SOP及查核結果之分類與處置。 2018/11/15

建議 預防重於治療 主持人會議 模擬臨床試驗 按計畫書執行試驗 利用資訊系統執行監測工作 倫理委員會監督 教育與觀念 2018/11/15

建議 查核作業應作重大改變 查核結果列入查驗登記 查核結果列入醫院評鑑 查核結果列入倫理委員會評鑑 專職機構與專人 方向與重點 方式 2018/11/15

There is no shortcuts in clinical trials BUZZ WORDS There is no shortcuts in clinical trials 2018/11/15

版權聲明 頁碼 作品 版權圖示 來源/作者 12 《A Doctor's Drug Studies Turn Into Fraud》-The New York Times http://partners.nytimes.com/library/national/science/health/051799drug-trials-industry-2.html 本作品依據著作權法第 46、52、65 條合理使用。 13 Potti A, Mukherjee S, Petersen R, et al., A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med. 2006 Aug 10;355(6):570-80 14-17 《The Cancer Letter Editor's note》-www.cancerletter.com www.cancerletter.com/downloads/20100906_7/download

版權聲明 頁碼 作品 版權圖示 來源/作者 《PREDICTORS OF CHEMOTHERAPY RESPONSE: 18-20 《PREDICTORS OF CHEMOTHERAPY RESPONSE: BACKGROUND INFORMATION》 http://www.google.com.tw/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CB4QFjAAahUKEwjY8eyfjv7GAhWBE5QKHfRfClU&url=http%3A%2F%2Fwww.cancerletter.com%2Fdownloads%2F20110401_1%2Fdownload&ei=upu3VdisIYGn0AT0v6moBQ&usg=AFQjCNFVrPJGlkgewDXxYFZSUVlpUhXjMw&sig2=8tv9TO5jGrPjs18bJFRErw 本作品依據著作權法第 46、52、65 條合理使用。 24-28 《藥品優良臨床試驗規範》 http://www.ibmi.org.tw/client/RuleDetail.php?REFDOCTYPID=0ksvgni9wnc2kdx6&REFDOCID=0ksz6i2wow5hc1qd 34-35 《臨床試驗申請書》-財團法人醫藥品查驗中心

版權聲明 頁碼 作品 版權圖示 來源/作者 台灣大學劉仁沛教授。 以創用CC「姓名標示－非商業性－相同方式分享」臺灣3.0版授權釋出。 38 台灣大學劉仁沛教授。 以創用CC「姓名標示－非商業性－相同方式分享」臺灣3.0版授權釋出。 40-48 《Good Clinical Practice》-- Food and Drug Administration http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm090259.htm 本作品依據著作權法第 46、52、65 條合理使用。 51 52

版權聲明 頁碼 作品 版權圖示 來源/作者 74 《Good Clinical Practice》-- Food and Drug Administration http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm090259.htm 本作品依據著作權法第 46、52、65 條合理使用。 75 《Court Updates and Other Enforcement Activities continued 2001》-DISQUALIFIED/TOTALLY RESTRICTED LIST FOR CLINICAL INVESTIGATORS http://ppt.cc/C9B4A 77 《Review Casts More Doubts on a Lung Cancer Study》- The New York Times By GARDINER HARRISAPRIL 29, 2011 http://www.nytimes.com/2011/04/30/health/research/30lung.html