ICH美国临床试验法规选编：汉英对照电子书

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前言

国际人用药品注册技术协调会（ICH）

——临床试验质量管理规范指导原则（E6_R2）

引 言

1 术 语

2 ICH GCP 的原则

3 机构审查委员会/独立伦理委员会（IRB/IEC）

3.1 职责

3.2 组成、职责和运作

3.3 程序

3.4 记录

4 研 究 者

4.1 研究者的资格和协议

4.2 足够的资源

4.3 受试者的医疗保健

4.4 与IRB/IEC沟通

4.5 依从试验方案

4.6 试验用药

4.7 随机化程序和破盲

4.8 受试者的知情同意

4.9 记录和报告

4.10 进展报告

4.11 安全性报告

4.12 试验的终止或暂停

4.13 研究者的最终报告

5 申 办 者

5.0 质量管理

5.1 质量保证和质量控制

5.2 合同研究组织（CRO）

5.3 医学专家

5.4 试验设计

5.5 试验管理、数据处理与记录保存

5.6 研究者的选择

5.7 责任的分配

5.8 对受试者和研究者的补偿

5.9 财务

5.10 通知/申报管理当局

5.11 IRB/IEC审评和确认

5.12 有关试验用药信息

5.13 试验用药的生产、包装、标签和编码

5.14 试验用药的供应和管理

5.15 记录查阅

5.16 安全性信息

5.17 药品不良反应报告

5.18 监查

5.19 稽查

5.20 不依从

5.21 提前终止或暂停试验

5.22 临床试验/研究报告

5.23 多中心试验

6 临床试验方案和方案增补

6.1 一般信息

6.2 背景信息

6.3 试验目标和目的

6.4 试验设计

6.5 受试者的选择和退出

6.6 受试者的治疗

6.7 有效性评价

6.8 安全性评价

6.9 统计

6.10 直接查阅原始数据/文件

6.11 质量控制和质量保证

6.12 伦理学

6.13 数据处理与记录保存

6.14 财务和保险

6.15 出版策略

6.16 补充

7 研究者手册

7.1 引言

7.2 总论

7.3 研究者手册的内容

7.4 附录1

7.5 附录2

8 实施临床试验的核心文件

8.1 引言

8.2 临床试验开始之前

8.3 临床试验进行期间

8.4 临床试验完成或终止之后

美国联邦法案

21CFR 第11部分 电子记录/电子签名

子部分A 总则

11.1 适用范围

11.2 履行

11.3 定义

子部分B 电子记录

11.10 封闭系统的控制

11.30 开放系统的控制

11.50 签名显示

11.70 签名/记录链接

子部分C 电子签名

11.100 一般要求

11.200 电子签名构成要素及管控

11.300 识别码/密码的管控

21CFR 第50部分 保护人类受试者

子部分A 总则

50.1 范围

50.3 定义

子部分B 人类受试者知情同意

50.20 对知情同意的一般要求

50.23 一般要求之外的例外情形

50.24 为急救研究豁免知情同意的要求

50.25 知情同意要素

50.27 记录知情同意过程

子部分C ［保留］

子部分D 在临床研究中对儿童的额外保护

50.50 IRB责任

50.51 不高于最低风险的临床研究

50.52 涉及高于最低风险，但呈现出对受试者直接受益前景的临床研究

50.53 临床研究涉及高于最低风险，且对受试者没有直接有益的前景，但可能获得对受试者的机能失调或健康状况的一般性知识

50.54 只有通过进行临床研究才有机会了解、预防或减轻影响儿童健康或福祉的严重问题的临床研究

50.55 由家长或监护人代替儿童同意参加试验的要求

50.56 受监护的儿童

21CFR 第54部分 临床研究者财务公开

54.1 目的

54.2 定义

54.3 范围

54.4 财务证明和财务公开声明要求

54.5 FDA对财务利益的评估

54.6 保存记录及记录保留

21CFR 第56部分 机构审查委员会

子部分A 总则

56.101 范围

56.102 定义

56.103 需要IRB审核的情形

56.104 豁免IRB要求

56.105 免除IRB要求

子部分B 组织和人员

56.106 登记

56.107 IRB组成成员

子部分C IRB的功能及运营

56.108 IRB的功能及运营

56.109 IRB审核研究

56.110 快速审核程序：涉及不高于最低风险及对已批准的研究进行微小变更

56.111 IRB审核研究的标准

56.112 机构审查委员会审核

56.113 暂停或终止IRB对研究的批准

56.114 合作研究

子部分D 记录和报告

56.115 IRB记录

子部分E 对不依从的行政处罚

56.120 行政措施

56.121 取消IRB或研究机构的资格

56.122 公开披露撤销信息

56.123 恢复IRB或机构

56.124 取消资格的替代措施或补充措施

21CFR 第312部分 研究新药申请

子部分A 一般条款

312.1 范围

312.2 适用性

312.3 定义和释义

312.6 研究新药标签

312.7 研究用药的推广

312.8 对IND下研究用药的收费

312.10 免除要求

子部分B 研究新药申请（IND）

312.20 对IND的要求

312.21 研究阶段

312.22 提交IND的一般原则

312.23 IND内容和格式

312.30 方案增补

312.31 信息增补

312.32 IND安全性报告

312.33 年度报告

312.38 撤销IND

子部分C 行政措施

312.40 在临床研究中对使用研究新药的一般要求

312.41 对IND的意见和建议

312.42 临床研究暂停和修改要求

312.44 终止

312.45 非活动状态

312.47 会议

312.48 解决争议

子部分D 申办者和研究者的责任

312.50 申办者的一般责任

312.52 向合同研究组织（CRO）转让义务

312.53 选择研究者和监查员

312.54 符合本章50.24规定的急救研究

312.55 告知研究者

312.56 审核正在进行的研究

312.57 记录保存和记录保留

312.58 对申办者记录和报告的视察

312.59 处置未使用的研究用药

312.60 研究者的一般责任

312.61 对研究用药的管控

312.62 研究者记录和记录保留

312.64 研究者报告

312.66 IRB审核的保证

312.68 对研究者记录和报告的视察

312.69 处理受管制物质

312.70 取消临床研究者的资格

子部分E 用于治疗危及生命和严重衰弱疾病的药物

312.80 目的

312.81 范围

312.82 提早咨询

312.83 治疗方案

312.84 审核用于治疗危及生命和严重衰弱疾患药物上市许可申请的风险利益分析

312.85 Ⅳ期临床研究

312.86 FDA重点监管的研究

312.87 主动监查临床研究的实施和评估

312.88 受试者安全保护

子部分F 其他

312.110 进出口要求

312.120 不受IND监管的美国以外的临床研究

312.130 公开披露IND数据和信息

312.140 通信地址

312.145 指南文件

子部分G 用于实验室动物研究和体外试验的研究用药

312.160 用于实验室动物研究和体外试验的研究用药

子部分H ［保留］

子部分I 扩展研究用药的治疗用途

312.300 总论

312.305 对扩展研究用药治疗范围的要求

312.310 个别患者，包括急救使用药物者

312.315 中等规模患者人群

312.320 治疗性IND或治疗性方案

21CFR 第812部分 研究器械豁免

子部分A 一般规定

812.1 范围

812.2 适用性

812.3 定义

812.5 研究器械标签

812.7 禁止宣传和其他行为

812.10 免除要求

812.18 进出口要求

812.19 IDE通信地址

子部分B 申请和行政措施

812.20 申请

812.25 研究计划

812.27 研究前报告

812.30 FDA对申请的行动措施

812.35 补充申请

812.36 研究器械的治疗使用

812.38 数据和信息的保密

子部分C 申办者责任

812.40 申办者的一般责任

812.42 FDA和IRB批准

812.43 选择研究者和监查员

812.45 告知研究者

812.46 监查研究

812.47 本章50.24监管下的急救研究

子部分D IRB审核和批准

812.60 IRB的组成，职责和职能

812.62 IRB批准

812.64 IRB持续审核

812.65 ［保留］

812.66 重大风险器械确定

子部分E 研究者的责任

812.100 研究者的一般责任

812.110 研究者的具体责任

812.119 取消临床研究者的资格

子部分F ［保留］

子部分G 记录和报告

812.140 记录

812.145 视察

812.150 报告

45CFR 第46部分 保护人类受试者

子部分A 保护人类受试者的基本卫生和公共服务（HHS）政策

46.101 政策适用范围（略）

46.102 定义

46.103 确保遵守本政策——由联邦部门或政府机构进行或支持的研究

46.104—46.106 ［保留］

46.107 IRB会员资格

46.108 IRB的功能和操作

46.109 IRB审核研究

46.110 快速审核程序，涉及不高于最低风险的某些研究，以及批准研究的微小变更

46.111 IRB批准研究的标准

46.112 机构审核

46.113 暂停或终止IRB批准的研究

46.114 合作研究

46.115 IRB记录

46.116 知情同意的一般要求

46.117 知情同意记录

46.118 申请和提案缺乏明确的人类受试者参与计划

46.119 无意涉及人类受试者的研究

46.120 评估和处理由联邦部门或政府机构执行或支持的研究申请与提案

46.121 ［保留］

46.122 使用联邦资金

46.123 提前终止研究支持：评估申请和提案

46.124 条件

子部分B 涉及孕妇、胎儿和新生儿研究的额外保护

46.201 规定适用范围？（略）

46.202 定义

46.203 IRB在涉及孕妇、胎儿和新生儿相关研究的职责

46.204 涉及孕妇或胎儿的研究

46.205 涉及新生儿的研究

46.206 研究涉及分娩后胎盘、死胎或胎儿物质

46.207 不批准研究就没有机会进行了解、预防或减轻影响孕妇、胎儿或新生儿健康或福祉的严重问题

子部分C 涉及将囚犯作为受试者的生物医学和行为研究的附加保护

46.301 适用范围（略）

46.302 目的

46.303 定义

46.304 囚犯参与研究时机构审查委员会的组成

46.305 机构审查委员会对囚犯参与研究的附加职责

46.306 允许涉及囚犯的研究

子部分D 研究中涉及儿童作为受试者的其他保护

46.401 本规定适用范围（略）

46.402 定义

46.403 IRB的职责

46.404 不涉及高于最低风险的研究

46.405 研究涉及的风险高于最低风险，但对受试者有直接受益的前景

46.406 研究涉及的风险大于最低风险，对个体受试者无直接受益前景，但可能获得关于受试者的疾病或病症的一般性知识

46.407 不批准研究就没有机会了解、预防或减轻影响儿童健康或福祉的严重问题

46.408 父母或监护人许可儿童参与研究的要求

46.409 受监护的儿童

子部分E 机构审查委员会的登记（略）

ICH GUIDELINE FOR GOOD CLINICAL PRACTICE（GCP）（E6_R2）

Current Step 4 version dated 9 November 2016

Introduction

1.Glossary

2.The Principles of ICH GCP

3.Institutional Review Board/Independent Ethics Committee（IRB/IEC）

3.1 Responsibilities

3.2 Composition，Functions and Operations

3.3 Procedures

3.4 Records

4.Investigator

4.1 Investigator’s Qualifications and Agreements

4.2 Adequate Resources

4.3 Medical Care of Trial Subjects

4.4 Communication with IRB/IEC

4.5 Compliance with Protocol

4.6 Investigational Product（s）

4.7 Randomization Procedures and Unblinding

4.8 Informed Consent of Trial Subjects

4.9 Records and Reports

4.10 Progress Reports

4.11 Safety Reporting

4.12 Premature Termination or Suspension of a Trial

4.13 Final Report（s） by Investigator

5.Sponsor

5.0 Quality Management

5.1 Quality Assurance and Quality Control

5.2 Contract Research Organization（CRO）

5.3 Medical Expertise

5.4 Trial Design

5.5 Trial Management，Data Handling，and Record Keeping

5.6 Investigator Selection

5.7 Allocation of Responsibilities

5.8 Compensation to Subjects and Investigators

5.9 Financing

5.10 Notification/Submission to Regulatory Authority（ies）

5.11 Confirmation of Review by IRB/IEC

5.12 Information on Investigational Product（s）

5.13 Manufacturing，Packaging，Labelling，and Coding Investigational Product（s）

5.14 Supplying and Handling Investigational Product（s）

5.15 Record Access

5.16 Safety Information

5.17 Adverse Drug Reaction Reporting

5.18 Monitoring

5.19 Audit

5.20 Noncompliance

5.21 Premature Termination or Suspension of a Trial

5.22 Clinical Trial/Study Reports

5.23 Multicentre Trials

6.Clinical Trial Protocol and Protocol Amendment（s）

6.1 General Information

6.2 Background Information

6.3 Trial Objectives and Purpose

6.4 Trial Design

6.5 Selection and Withdrawal of Subjects

6.6 Treatment of Subjects

6.7 Assessment of Efficacy

6.8 Assessment of Safety

6.9 Statistics

6.10 Direct Access to Source Data/Documents

6.11 Quality Control and Quality Assurance

6.12 Ethics

6.13 Data Handling and Record Keeping

6.14 Financing and Insurance

6.15 Publication Policy

6.16 Supplements

7.Investigator’s Brochure

7.1 Introduction

7.2 General Considerations

7.3 Contents of the Investigator’s Brochure

7.4 Appendix 1

7.5 Appendix 2

8.Essential Documents for the Conduct of a Clinical Trial

8.1 Introduction

8.2 Before the Clinical Phase of the Trial Commences

8.3 During the Clinical Conduct of the Trial

8.4 After Completion or Termination of the Trial

Code of Federal Regulations

21CFR PART11 ELECTRONIC RECORDS；ELECTRONIC SIGNATURES

Subpart A - General Provisions

Sec.11.1 Scope.

Sec.11.2 Implementation.

Sec.11.3 Definitions.

Subpart B - Electronic Records

Sec.11.10 Controls for closed systems.

Sec.11.30 Controls for open systems.

Sec.11.50 Signature manifestations.

Sec.11.70 Signature/record linking.

Subpart C - Electronic Signatures

Sec.11.100 General requirements.

Sec.11.200 Electronic signature components and controls.

Sec.11.300 Controls for identification codes/passwords.

21CFR PART50 PROTECTION OF HUMAN SUBJECTS

Subpart A - General Provisions

Sec.50.1 Scope.

Sec.50.3 Definitions.

Subpart B - Informed Consent of Human Subjects

Sec.50.20 General requirements for informed consent.

Sec.50.23 Exception from general requirements.

Sec.50.24 Exception from informed consent requirements for emergency research.

Sec.50.25 Elements of informed consent.

Sec.50.27 Documentation of informed consent.

Subpart C ［Reserved］

Subpart D - Additional Safeguards for Children in Clinical Investigations

Sec.50.50 IRB duties.

Sec.50.51 Clinical investigations not involving greater than minimal risk.

Sec.50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.

Sec.50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects， but likely to yield generalizable knowledge about the subjects’ disorder or condition.

Sec.50.54 Clinical investigations not otherwise approvable that present an opportunity to understand， prevent， or alleviate a serious problem affecting the health or welfare of children.

Sec.50.55 Requirements for permission by parents or guardians and for assent by children.

Sec.50.56 Wards.

21CFR PART54 FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS

Sec.54.1 Purpose.

Sec.54.2 Definitions.

Sec.54.3 Scope.

Sec.54.4 Certification and disclosure requirements.

Sec.54.5 Agency evaluation of financial interests.

Sec.54.6 Recordkeeping and record retention.

21CFR PART56 INSTITUTIONAL REVIEW BOARDS

Subpart A-General Provisions

Sec.56.101 Scope.

Sec.56.102 Definitions.

Sec.56.103 Circumstances in which IRB review is required.

Sec.56.104 Exemptions from IRB requirement.

Sec.56.105 Waiver of IRB requirement.

Subpart B-Organization and Personnel

Sec.56.106 Registration.

Sec.56.107 IRB membership.

Subpart C-IRB Functions and Operations

Sec.56.108 IRB functions and operations.

Sec.56.109 IRB review of research.

Sec.56.110 Expedited review procedures for certain kinds of research involving no more than minimal risk，and for minor changes in approved research.

Sec.56.111 Criteria for IRB approval of research.

Sec.56.112 Review by institution.

Sec.56.113 Suspension or termination of IRB approval of research.

Sec.56.114 Cooperative research.

Subpart D-Records and Reports

Sec.56.115 IRB records.

Subpart E-Administrative Actions for Noncompliance

Sec.56.120 Lesser administrative actions.

Sec.56.121 Disqualification of an IRB or an institution.

Sec.56.122 Public disclosure of information regarding revocation.

Sec.56.123 Reinstatement of an IRB or an institution.

Sec.56.124 Actions alternative or additional to disqualification.

21CFR PART312 INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A-General Provisions

Sec.312.1 Scope.

Sec.312.2 Applicability.

Sec.312.3 Definitions and interpretations.

Sec.312.6 Labeling of an investigational new drug.

Sec.312.7 Promotion of investigational drugs.

Sec.312.8 Charging for investigational drugs under an IND.

Sec.312.10 Waivers.

Subpart B-Investigational New Drug Application（IND）

Sec.312.20 Requirement for an IND.

Sec.312.21 Phases of an investigation.

Sec.312.22 General principles of the IND submission.

Sec.312.23 IND content and format.

Sec.312.30 Protocol amendments.

Sec.312.31 Information amendments.

Sec.312.32 IND safety reporting.

Sec.312.33 Annual reports.

Sec.312.38 Withdrawal of an IND.

Subpart C-Administrative Actions

Sec.312.40 General requirements for use of an investigational new drug in a clinical investigation.

Sec.312.41 Comment and advice on an IND.

Sec.312.42 Clinical holds and requests for modification.

Sec.312.44 Termination.

Sec.312.45 Inactive status.

Sec.312.47 Meetings.

Sec.312.48 Dispute resolution.

Subpart D-Responsibilities of Sponsors and Investigators

Sec.312.50 General responsibilities of sponsors.

Sec.312.52 Transfer of obligations to a contract research organization.

Sec.312.53 Selecting investigators and monitors.

Sec.312.54 Emergency research under 50.24 of this chapter.

Sec.312.55 Informing investigators.

Sec.312.56 Review of ongoing investigations.

Sec.312.57 Recordkeeping and record retention.

Sec.312.58 Inspection of sponsor’s records and reports.

Sec.312.59 Disposition of unused supply of investigational drug.

Sec.312.60 General responsibilities of investigators.

Sec.312.61 Control of the investigational drug.

Sec.312.62 Investigator recordkeeping and record retention.

Sec.312.64 Investigator reports.

Sec.312.66 Assurance of IRB review.

Sec.312.68 Inspection of investigator’s records and reports.

Sec.312.69 Handling of controlled substances.

Sec.312.70 Disqualification of a clinical investigator.

Subpart E-Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

Sec.312.80 Purpose.

Sec.312.81 Scope.

Sec.312.82 Early consultation.

Sec.312.83 Treatment protocols.

Sec.312.84 Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses.

Sec.312.85 Phase 4 studies.

Sec.312.86 Focused FDA regulatory research.

Sec.312.87 Active monitoring of conduct and evaluation of clinical trials.

Sec.312.88 Safeguards for patient safety.

Subpart F-Miscellaneous

Sec.312.110 Import and export requirements.

Sec.312.120 Foreign clinical studies not conducted under an IND.

Sec.312.130 Availability for public disclosure of data and information in an IND.

Sec.312.140 Address for correspondence.

Sec.312.145 Guidance documents.

Subpart G-Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests

Sec.312.160 Drugs for investigational use in laboratory research animals or in vitro tests.

Subpart H ［Reserved］

Subpart I-Expanded Access to Investigational Drugs for Treatment Use

Sec.312.300 General.

Sec.312.305 Requirements for all expanded access uses.

Sec.312.310 Individual patients，including for emergency use.

Sec.312.315 Intermediate-size patient populations.

Sec.312.320 Treatment IND or treatment protocol.

21CFR PART812 INVESTIGATIONAL DEVICE EXEMPTIONS

Subpart A-General Provisions

812.1 Scope.

812.2 Applicability.

812.3 Definitions.

812.5 Labeling of investigational devices.

812.7 Prohibition of promotion and other practices.

812.10 Waivers.

812.18 Import and export requirements.

812.19 Address for IDE correspondence.

Subpart B-Application and Administrative Action

812.20 Application.

812.25 Investigational plan.

812.27 Report of prior investigations.

812.30 FDA action on applications.

812.35 Supplemental applications.

812.36 Treatment use of an investigational device.

812.38 Confidentiality of data and information.

Subpart C-Responsibilities of Sponsors

812.40 General responsibilities of sponsors.

812.42 FDA and IRB approval.

812.43 Selecting investigators and monitors.

812.45 Informing investigators.

812.46 Monitoring investigations.

812.47 Emergency research under 50.24 of this chapter.

Subpart D-IRB Review and Approval

812.60 IRB composition，duties，and functions.

812.62 IRB approval.

812.64 IRB’s continuing review.

812.65 ［Reserved］

812.66 Significant risk device determinations.

Subpart E-Responsibilities of Investigators

812.100 General responsibilities of investigators.

812.110 Specific responsibilities of investigators.

812.119 Disqualification of a clinical investigator.

Subpart F ［Reserved］

Subpart G-Records and Reports

812.140 Records.

812.145 Inspections.

812.150 Reports.

45CFR PART46 PROTECTION OF HUMAN SUBJECTS

Subpart A-Basic HHS Policy for Protection of Human Research Subjects

46.101 To what does this policy apply？（Omit）

46.102 Definitions.

46.103 Assuring compliance with this policy—research conducted or supported by any Federal Department or Agency.

46.104—46.106 ［Reserved］

46.107 IRB membership.

46.108 IRB functions and operations.

46.109 IRB review of research.

46.110 Expedited review procedures for certain kinds of research involving no more than minimal risk，and for minor cha-nges in approved research.

46.111 Criteria for IRB approval of research.

46.112 Review by institution.

46.113 Suspension or termination of IRB approval of research.

46.114 Cooperative research.

46.115 IRB records.

46.116 General requirements for informed consent.

46.117 Documentation of informed consent.

46.118 Applications and proposals lacking definite plans for involvement of human subjects.

46.119 Research undertaken without the intention of involving human subjects.

46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency.

46.121 ［Reserved］

46.122 Use of Federal funds.

46.123 Early termination of research support： Evaluation of applications and proposals.

46.124 Conditions.

Subpart B-Additional Protections for Pregnant Women，Human Fetuses and Neonates Involved in Research

46.201 To what do these regulations apply？（Omit）

46.202 Definitions.

46.203 Duties of IRBs in connection with research involving pregnant women，fetuses，and neonates.

46.204 Research involving pregnant women or fetuses.

46.205 Research involving neonates.

46.206 Research involving，after delivery，the placenta，the dead fetus or fetal material.

46.207 Research not otherwise approvable which presents an opportunity to understand，prevent，or alleviate a serious problem affecting the health or welfare of pregnant women，fetuses，or neonates.

Subpart C-Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects

46.301 Applicability（Omit）.

46.302 Purpose.

46.303 Definitions.

46.304 Composition of Institutional Review Boards where prisoners are involved.

46.305 Additional duties of the Institutional Review Boards where prisoners are involved.

46.306 Permitted research involving prisoners.

Subpart D-Additional Protections for Children Involved as Subjects in Research

46.401 To what do these regulations apply？（Omit）

46.402 Definitions.

46.403 IRB duties.

46.404 Research not involving greater than minimal risk.

46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.

46.406 Research involving greater than minimal risk and no prospect of direct benefit to individual subjects，but likely to yield generalizable knowledge about the subject’s disorder or condition.

46.407 Research not otherwise approvable which presents an opportunity to understand，prevent，or alleviate a serious problem affecting the health or welfare of children.

46.408 Requirements for permission by parents or guardians and for assent by children.

46.409 Wards.

Subpart E-Registration of Institutional Review Boards（Omit）