ICH-GCP(E6) 英文WORD版

International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. GUIDELINE FOR CILINICAL PRACTICE A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. Ethical and scientific quality standards for designing, conducting, recording and reporting trials that involve participation of human subjects to ensure that the RIGHTS, SAFETY and WELLBEING of the trial subjects are protected. Ensure the CREDIBILITY of clinical trial data. TABLE OF CONTENT TOC \o "1-3" \h \z \u INTRODUCTION 5 1. GLOSSARY 5 1.1 Adverse Drug Reaction (ADR) 5 1.2 Adverse Event (AE) 5 1.3 Amendment (to the protocol) 6 1.4 Applicable Regulatory Requirement(s) 6 1.5 Approval (in relation to Institutional Review Boards) 6 1.6 Audit 6 1.7 Audit Certificate 6 1.8 Audit Report 6 1.9 Audit Trail 6 1.10 Blinding/Masking 6 1.11 Case Report Form (CRF) 7 1.12 Clinical Trial/Study 7 1.13 Clinical Trial/Study Report 7 1.14 Comparator (Product) 7 1.15 Compliance (in relation to trials) 7 1.16 Confidentiality 7 1.17 Contract 7 1.18 Coordinating Committee 8 1.19 Coordinating Investigator 8 1.20 Contract Research Organization (CRO) 8 1.21 Direct Access 8 1.22 Documentation 8 1.23 Essential Documents 8 1.24 Good Clinical Practice (GCP) 8 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee) 9 1.26 Impartial Witness 9 1.27 Independent Ethics Committee (IEC) 9 1.28 Informed Consent 9 1.29 Inspection 9 1.30 Institution (medical) 10 1.31 Institutional Review Board (IRB) 10 1.32 Interim Clinical Trial/Study Report 10 1.33 Investigational Product 10 1.34 Investigator 10 1.35 Investigator / Institution 10 1.36 Investigator's Brochure 10 1.37 Legally Acceptable Representative 11 1.38 Monitoring 11 1.39 Monitoring Report 11 1.40 Multicentre Trial 11 1.41 Nonclinical Study 11 1.42 Opinion (in relation to Independent Ethics Committee) 11 1.43 Original Medical Record 11 1.44 Protocol 11 1.45 Protocol Amendment 12 1.46 Quality Assurance (QA) 12 1.47 Quality Control (QC) 12 1.48 Randomization 12 1.49 Regulatory Authorities 12 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) 12 1.51 Source Data 13 1.52 Source Documents 13 1.53 Sponsor 13 1.54 Sponsor-Investigator 13 1.55 Standard Operating Procedures (SOPs) 13 1.56 Subinvestigator 13 1.57 Subject/Trial Subject 13 1.58 Subject Identification Code 14 1.59 Trial Site 14 1.60 Unexpected Adverse Drug Reaction 14 1.61 Vulnerable Subjects 14 1.62 Well-being (of the trial subjects) 14 2. THE PRINCIPLES OF ICH GCP 14 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 15 3.1 Responsibilities 15 3.2 Composition, Functions and Operations 16 3.3 Procedures 17 3.4 Records 18 4. INVESTIGATOR 18 4.1 Investigator's Qualifications and Agreements 18 4.2 Adequate Resources 18 4.3 Medical Care of Trial Subjects 19 4.4 Communication with IRB/IEC 19 4.5 Compliance with Protocol 19 4.6 Investigational Product(s) 20 4.7 Randomization Procedures and Unblinding 20 4.8 Informed Consent of Trial Subjects 21 4.9 Records and Reports 23 4.10 Progress Reports 24 4.11 Safety Reporting 24 4.12 Premature Termination or Suspension of a Trial 25 4.13 Final Report(s) by Investigator 25 5. SPONSOR 25 5.1 Quality Assurance and Quality Control 25 5.2 Contract Research Organization (CRO) 26 5.3 Medical Expertise 26 5.4 Trial Design 26 5.5 Trial Management, Data Handling, and Record Keeping 26 5.6 Investigator Selection 28 5.7 Allocation of Responsibilities 28 5.8 Compensation to Subjects and Investigators 28 5.9 Financing 29 5.10 Notification/Submission to Regulatory Authority(ies) 29 5.11 Confirmation of Review by IRB/IEC 29 5.12 Information on Investigational Product(s) 29 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) 30 5.14 Supplying and Handling Investigational Product(s) 30 5.15 Record Access 31 5.16 Safety Information 31 5.17 Adverse Drug Reaction Reporting 31 5.18 Monitoring 32 5.19 Audit 34 5.20 Noncompliance 35 5.21 Premature Termination or Suspension of a Trial 35 5.22 Clinical Trial/Study Reports 35 5.23 Multicentre Trials 35 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 36 6.1 General Information 36 6.2 Background Information 36 6.3 Trial Objectives and Purpose 37 6.4 Trial Design 37 6.5 Selection and Withdrawal of Subjects 37 6.6 Treatment of Subjects 38 6.7 Assessment of Efficacy 38 6.8 Assessment of Safety 38 6.9 Statistics 38 6.10 Direct Access to Source Data/Documents 39 6.11 Quality Control and Quality Assurance 39 6.12 Ethics 39 6.13 Data Handling and Record Keeping 39 6.14 Financing and Insurance 39 6.15 Publication Policy 39 6.16 Supplements 39 7. INVESTIGATOR’S BROCHURE 39 7.1 Introduction 39 7.2 General Considerations 40 7.3 Contents of the Investigator’s Brochure 41 7.4 APPENDIX 1: 44 7.5 APPENDIX 2: 45 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 46 8.1 Introduction 46 8.2 Before the Clinical Phase of the Trial Commences 47 8.3 During the Clinical Conduct of the Trial 51 8.4 After Completion or Termination of the Trial 57 INTRODUCTION Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects. 1. GLOSSARY 1.1 Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.2 Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 1.3 Amendment (to the protocol) See Protocol Amendment. 1.4 Applicable Regulatory Requirement(s) Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products. 1.5 Approval (in relation to Institutional Review Boards) The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements. 1.6 Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 1.7 Audit Certificate A declaration of confirmation by the auditor that an audit has taken place. 1.8 Audit Report A written evaluation by the sponsor's auditor of the results of the audit. 1.9 Audit Trail Documentation that allows reconstruction of the course of events. 1.10 Blinding/Masking A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s). 1.11 Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. 1.12 Clinical Trial/Study Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous. 1.13 Clinical Trial/Study Report A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports). 1.14 Comparator (Product) An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial. 1.15 Compliance (in relation to trials) Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements. 1.16 Confidentiality Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity. 1.17 Contract A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract. 1.18 Coordinating Committee A committee that a sponsor may organize to coordinate the conduct of a multicentre trial. 1.19 Coordinating Investigator An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial. 1.20 Contract Research Organization (CRO) A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions. 1.21 Direct Access Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information. 1.22 Documentation All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. 1.23 Essential Documents Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial). 1.24 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee) An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. 1.26 Impartial Witness A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. 1.27 Independent Ethics Committee (IEC) An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline. 1.28 Informed Consent A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. 1.29 Inspection The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). 1.30 Institution (medical) Any public or private entity or agency or medical or dental facility where clinical trials are conducted. 1.31 Institutional Review Board (IRB) An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects. 1.32 Interim Clinical Trial/Study Report A report of intermediate results and their evaluation based on analyses performed during the course of a trial. 1.33 Investigational Product A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. 1.34 Investigator A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator. 1.35 Investigator / Institution An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements". 1.36 Investigator's Brochure A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure). 1.37 Legally Acceptable Representative An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial. 1.38 Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 1.39 Monitoring Report A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs. 1.40 Multicentre Trial A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator. 1.41 Nonclinical Study Biomedical studies not performed on human subjects. 1.42 Opinion (in relation to Independent Ethics Committee) The judgement and/or the advice provided by an Independent Ethics Committee (IEC). 1.43 Original Medical Record See Source Documents. 1.44 Protocol A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments. 1.45 Protocol Amendment A written description of a change(s) to or formal clarification of a protocol. 1.46 Quality Assurance (QA) All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s). 1.47 Quality Control (QC) The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. 1.48 Randomization The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. 1.49 Regulatory Authorities Bodies having the power to regulate. In the ICH GCP guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities. 1.50 Seriou