Good Clinical Practice International Conference on Harmonization GCP

臨床試驗 Good Clinical Practice & International Conference on Harmonization 藥品優良臨床試驗規範(GCP & ICH)/ 評估臨床試驗品質-CONSORT statement 簡國龍老師 2015 -4 -8 1

Outline n n n Background History of GCP & ICH Laws ¨ US ¨ Taiwan n Guidelines of GCP Responsibilities of PI, IRB, and sponsors Other topics such as financial disclosure & federally funded clinical trials 2

Developing new drugs and devices n IND application ¨ Investigational n NDA ¨ New n new drug application FDA review groups ¨ CDER: center for drug evaluation and research ¨ CBER: center for biologics evaluation and research n n Devices Post-marketing surveillance 3

Good clinical practice, GCP Accepted standards for conducting clinical research studies n All aspects of clinical trials n The process used to conduct clinical trials n 4

Good Clinical Practice n n A set of guidelines to define the roles of the investigator, the sponsor, and the regulatory agency Designed for appropriate conduct (drug safety, data integrity, and human rights) of the trials 5

GCP的發展 1 n n n n 有關醫學倫理意識的發展 Helsinki宣言，1964：〝受試者的利益比科學及社會更為優先考量〞 受試者同意書Informed Consent 各國GCP的發展 美國FDA GCP Regulations：在 1960年左右即有相關法律，其中有三 項立法： 1981. Informed Consent 1981. Standards for IRBS for Clinical Investigate 1987. IND (Investigational new drug，治驗藥) Rewrite 8

International Conference on Harmonization for Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) n 1990, Europe, Japan and US n Developing standard international guidelines and regulations n Greater standardization to reduce or eliminate duplication of testing in various countries 10

Aims of ICH n Primary: ¨ Better n use of human, animal, and material resources Secondary: ¨ Elimination of delays in global drug development while maintaining safeguards on quality, safety, efficacy, and regulatory obligations to protect public health 11

ICH-GCP 1996年 5月完成ICH-GCP STEP-4，是美國、歐洲及日本三 地共通互相確立的原則，此乃是基於〝使新藥儘早給必要 的患者使用〞的原則。 n ICH guideline for Good Clinical Practice n ¨ International standards to promote greater harmonization of technical guidelines and requirements for product registration ¨ Prevent or reduce unnecessary duplication of testing without compromising safety and effectiveness 12

Categories of ICH Guidelines Chemical and pharmaceutical quality assurance n Safety in pre-clinical studies n Efficacy of clinical studies n Multidisciplinary topics such as medical terminology and electronic standards for transmission of regulatory documents n E 1 -E 12 n E 6: Good clinical practice n 13

Contents of GCP Regulations that are enforceable by law n Guidelines that are part of the generally accepted practice although not enforced by law n Local laws that affect a specific region, city or state n 14

Regulations n n Food and Drugs Act, 1906 Code of Federal Regulations, CFR ¨ Good laboratory practice ¨ Good manufacture practice n 50 “Titles”, ¨ Title 21: food and drugs administration ¨ Title 45: public welfare n Chapters, parts, subparts 15

Regulatory authorities n United States ¨ n Canada ¨ n Committee for Proprietary Medicine Products, CPMC Germany ¨ n Ministry of Health and Welfare, MHW European Union, EU ¨ n Committee on Safety of Medicines, CSM Japan ¨ n Health Protection Branch, HPB United Kingdom ¨ n Food and Drug Administration, FDA Bundestinstitut fur Azneimettel und Modezen Produkte, Bf. Arm Taiwan ¨ Department of Health, DOH 16

Guideline for Good Clinical Practice Introduction and Principles II. Medical Institutions III. Protection of Trial Subjects IV. Investigator V. Sponsor VI. Monitor VII. Records and Reports VIII. Statistical Analyses IX. Management of Investigational Product X. Quality Assurance I. 17

Responsibilities identified in the Code of Federal Regulations n Principal Investigator responsibilities ¨ Investigational drug studies ¨ Investigational device exemption studies Institutional Review Board (IRB) responsibilities n Sponsor responsibilities n Financial disclosure regulations n 19

Principal investigator responsibilities n n n Individual who actually conducts a clinical investigation, responsible leader of the team Conducting study according to the protocol Obtaining IRB approval Obtaining informed consent from subjects Reporting adverse events Maintaining accurate study records and drug accountability records 20

Investigational drug studies n n n n n Reading and understanding the protocol and the investigator’s brochure Sign a FORM Personally conduct or supervise according to protocol Meet the requirements for obtaining informed consent Report adverse experiences to the sponsor Maintain adequate and accurate records and make them available for inspection Ensure all associates, colleagues, and employees assisting the conduct Ensure that the IRB complies with its requirements Promptly report to the IRB all changes in activity and unanticipated problems Comply with all other requirements regarding the obligations 21

General responsibilities for PI n n n n Maintain professional credentials Adhere to protocol Recruit and enroll appropriate subjects Maintain appropriate source documentation Ensure data quality Maintain drug/device accountability Maintain proper study files and documentation Communicate with IRB 22

Institutional Review Board responsibilities n n n Reviewing, approving/disapproving, or requiring modification of all activities covered by the regulations Required informed consent in accordance with the regulations Providing investigators with written documentation Reviewing the research at least once a year in according with the regulations Ensuring the IRB committee membership consists of at least 5 members 23

Membership in IRB n n n Who have no conflicting interest in any project reviewed by the IRB Of both sexes, when possible, and sufficiently qualifies with different backgrounds, expertise, experience, and diversity At least one of whom is not employed by or otherwise affiliated with the institution; this member may not be part of the immediate family of someone employed by or affiliated with the institution One whose primary concern or work is in a scientific area One whose primary concern or work is non-scientific 24

IRB n Objectives ¨ Assure the rights and welfare of human subjects are protected Continuing review of previously approved protocols at interval appropriate to the degree of risk involved in the study, but not less than once a year n Expedited review n 25

Institutional Review Board Approval n IRB ¨ The nature of the treatment used, if any (standard vs. experimental) ¨ The patient burden and risk involved ¨ The protection of patient identity n Examples ¨ Clinical trial protocol ¨ Genetic samples collection 26

Sponsor responsibilities n n n Person or other entity that initiates a clinical investigation, but that does not actually conduct the investigation May transfer any or all responsibilities to a contract or academic organization, must be described in writing This organization must comply with all applicable regulation and is subject to the same regulation action for failure to comply 27

Contents of sponsor responsibilities n n n n Selecting qualified investigators Providing investigators with information to conduct the study properly Ensuring proper monitoring, per protocol and with applicable ethical and regulatory considerations Ensuring the study according to the general plan and protocol contained in IND application Maintaining an effective IND with respect to the study and protocol Ensuring that the FDA and all investigators are promptly informed of significant new AE Submitting financial disclosure information 28

Financial disclosure regulations n n n Stock in the sponsoring company Proprietary interest (e. g. , patent, trademark, copyright, licensing agreement) Payment arrangement that benefit the investigator if a certain study outcome occurs Honoraria (禮金) Gifts of equipment Retainers (顧問費) of ongoing consultation 29

Rules about financial disclosure n n n n Investigators who are directly involved in the treatment or evaluation of research subjects Spouses and dependent children Compensation affected by the outcome Significant payments from the sponsor Propriety interest in the test product Significant equity interest in the sponsor Before shipment to the investigator 30

Federally funded clinical trials, investigatorinitiated trials n Government funded ¨ Department of Health and Human Service, HHS, NIH conducts Training n Data and safety monitoring n Vulnerable subjects ? n Written document n ¨ Assurance of compliance, assurance 31

Vulnerable subjects n Prisoners ¨ At n least one member of IRB is a prisoner Pregnant woman, No, unless ¨ Mother and fetus health will be placed at risk only minimum extent ¨ The risk to fetus is minimal n Children ¨ Provision to solicit the assent of the children 32

Summary of GCP Design of clinical trials : scientific principles and feasibility n Conduct of clinical trials : paying attention to details and regulatory compliance n Analysis and report of clinical trials : scientific principle and clinical significance n 33

GCP, good clinical practice Pharmaceutical company n FDA, US Food and Drug Administration n Modern economic issues n ¨ African HIV infection ¨ Lifestyle medication ¨ Generic patent 34

Where to obtain information about GCP? n Food and Drug Administration ¨ http: //www. fda. gov. n Code of Federal Regulations ¨ http: //www. access. gpo. gov/nara/cfr-table-search. html n Federal Register ¨ http: //www. nara. gov/fedreg/ n ICH Guidelines ¨ http: //www. ifpma. org/ich 1. html 35

Supplements n n n n Good Manufacturing Practice GMP Good Laboratory Practice GLP Good Clinical (Research) Practice GCP(藥品優良臨床試驗規範) Inspection of the conduct of clinical trials General considerations for clinical evaluation of drugs Disease-specific guidelines Clinical trials and promotion 36

版權聲明 頁碼 作品 6 來源/作者 本作品轉載自Microsoft Office 2010 Power. Point 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。 1 5 版權圖示 A set of guidelines to define the roles of the investigator, the sponsor, and the regulatory agency 從事藥品臨床研究應符合 的基本事項，內容包括確 保研究合乎科學和倫理考 量的研究設計、處理、監 測、稽核、分析、報告及 各項書面紀錄。 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health P. 1 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 藥品優良臨床試驗規範 http: //www. ibmi. org. tw/client/Rule. Detail. php? REFDOCTYPID=0 ksvgni 9 wnc 2 kd x 6&REFDOCID=0 ksz 6 i 2 wow 5 hc 1 qd 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 17 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health Summary http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 18 《藥品優良臨床試驗準則 》- 衛生福利部食品藥物管理署 http: //ksph. kcg. gov. tw/13/irb 7 -2. pdf Summary 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 37

版權聲明 頁碼 19 20 21 22 作品 版權圖示 來源/作者 Principal Investigator responsibilities Investigational drug studies… 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health p. 10 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 Individual who actually conducts a clinical investigation, responsible leader of the team… 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health p. 13 -15 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health p. 16 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health p. 17 -21 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 38

版權聲明 頁碼 28 作品 Selecting qualified investigators Providing investigators with information to … 版權圖示 來源/作者 《Good Clinical Practice: Consolidated Guidance》U. S. Food and Drug Administration Protecting and Promoting Your Health p. 24 http: //www. fda. gov/downloads/Drugs/Guidances/ucm 073122. pdf 本作品屬公共領域之著作。瀏覽日期： 2015/06/03 39