ICH-GCP      




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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
INTRODUCTION
1. GLOSSARY
1.1 Adverse Drug Reaction (ADR)
1.2 Adverse Event (AE)
1.3 Amendment (to the protocol)
1.4 Applicable Regulatory Requirement(s)
1.5 Approval (in relation to Institutional Review Boards)
1.6 Audit
1.7 Audit Certificate
1.8 Audit Report
1.9 Audit Trail
1.10 Blinding/Masking
1.11 Case Report Form (CRF)
1.12 Clinical Trial/Study
1.13 Clinical Trial/Study Report
1.14 Comparator (Product)
1.15 Compliance (in relation to trials)
1.16 Confidentiality
1.17 Contract
1.18 Coordinating Committee
1.19 Coordinating Investigator
1.20 Contract Research Organization (CRO)
1.21 Direct Access
1.22 Documentation
1.23 Essential Documents
1.24 Good Clinical Practice (GCP)
1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)
1.26 Impartial Witness
1.27 Independent Ethics Committee (IEC)
1.28 Informed Consent
1.29 Inspection
1.30 Institution (medical)
1.31 Institutional Review Board (IRB)
1.32 Interim Clinical Trial/Study Report
1.33 Investigational Product
1.34 Investigator
1.35 Investigator / Institution
1.36 Investigator’s Brochure
1.37 Legally Acceptable Representative
1.38 Monitoring
1.39 Monitoring Report
1.40 Multicentre Trial
1.41 Nonclinical Study
1.42 Opinion (in relation to Independent Ethics Committee)
1.43 Original Medical Record
1.44 Protocol
1.45 Protocol Amendment
1.46 Quality Assurance (QA)
1.47 Quality Control (QC)
1.48 Randomization
1.49 Regulatory Authorities
1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
1.51 Source Data
1.52 Source Documents
1.53 Sponsor
1.54 Sponsor-Investigator
1.55 Standard Operating Procedures (SOPs)
1.56 Subinvestigator
1.57 Subject/Trial Subject
1.58 Subject Identification Code
1.59 Trial Site
1.60 Unexpected Adverse Drug Reaction
1.61 Vulnerable Subjects
1.62 Well-being (of the trial subjects)
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
5.1 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
 
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 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
Any untoward medical occurrence that at any dose:
results in death,
is life-threatening,
requires inpatient hospitalization or prolongation of existing hospitalization,
results in persistent or significant disability/incapacity,
or
is a congenital anomaly/birth defect
(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
 
1.51 Source Data
All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
 
1.52 Source Documents
Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).
 
1.53 Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.
 
1.54 Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
 
1.55 Standard Operating Procedures (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
 
1.56 Subinvestigator
Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.
 
1.57 Subject/Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
 
1.58 Subject Identification Code
A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial related data.
 
1.59 Trial Site
The location(s) where trial-related activities are actually conducted.
 
1.60 Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
 
1.61 Vulnerable Subjects
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
 
1.62 Well-being (of the trial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
 
2. THE PRINCIPLES OF ICH GCP
Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).
Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion.
The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
Freely given informed consent should be obtained from every subject prior to clinical trial participation.
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.
The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
Systems with procedures that assure the quality of every aspect of the trial should be implemented.
 
3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1 Responsibilities
An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.
The IRB/IEC should obtain the following documents:
trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written information to be provided to subjects, Investigator’s Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following:
approval/ favourable opinion;
modifications required prior to its approval/favourable opinion;
disapproval / negative opinion; and
termination/suspension of any prior approval/favourable opinion.
The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.
The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects.
When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.
Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations).
The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.
The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.
 
3.2 Composition, Functions and Operations
The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:
a) At least five members.
b) At least one member whose primary area of interest is in a nonscientific area.
c) At least one member who is independent of the institution/trial site.
Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their qualifications should be maintained.
The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s).
An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present.
Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.
The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
 
3.3 Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
Determining its composition (names and qualifications of the members) and the authority under which it is established.
Scheduling, notifying its members of, and conducting its meetings.
Conducting initial and continuing review of trials.
Determining the frequency of continuing review, as appropriate.
Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.
Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial.
Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
Specifying that the investigator should promptly report to the IRB/IEC:
Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).
Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
All adverse drug reactions (ADRs) that are both serious and unexpected.
New information that may affect adversely the safety of the subjects or the conduct of the trial.
Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
Its trial-related decisions/opinions.
The reasons for its decisions/opinions.
Procedures for appeal of its decisions/opinions.
 
3.4 Records
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists.
 
4. INVESTIGATOR
4.1 Investigator’s Qualifications and Agreements
The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator’s Brochure, in the product information and in other information sources provided by the sponsor.
The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.
 
4.2 Adequate Resources
The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.
The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.
The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.
 
4.3 Medical Care of Trial Subjects
A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights.
 
4.4 Communication with IRB/IEC
Before initiating a trial, the investigator/institution should have written and dated approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.
As part of the investigator’s/institution’s written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator’s Brochure. If the Investigator’s Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
 
4.5 Compliance with Protocol
The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).
The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.
The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
to the IRB/IEC for review and approval/favourable opinion,
to the sponsor for agreement and, if required,
to the regulatory authority(ies).
 
4.6 Investigational Product(s)
Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.
Where allowed/required, the investigator/institution may/should assign some or all of the investigator’s/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution.
The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).
The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.
The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.
 
4.7 Randomization Procedures and Unblinding
The investigator should follow the trial’s randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).
 
4.8 Informed Consent of Trial Subjects
In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.
The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC’s approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.
The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.
The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject’s legally acceptable representative and the impartial witness, where applicable.
Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject’s legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject’s legally acceptable representative.
Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject’s legally acceptable representative, and by the person who conducted the informed consent discussion.
If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject’s legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.
Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
That the trial involves research.
The purpose of
the trial.
The trial treatment(s) and the probability for random assignment to each treatment.
The trial procedures to be followed, including all invasive procedures.
The subject’s responsibilities.
Those aspects of the trial that are experimental.
The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.
The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
The compensation and/or treatment available to the subject in the event of trial-related injury.
The anticipated prorated payment, if any, to the subject for participating in the trial.
The anticipated expenses, if any, to the subject for participating in the trial.
That the subject’s participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject’s original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject’s legally acceptable representative is authorizing such access.
That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.
That the subject or the subject’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject’s willingness to continue participation in the trial.
The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.
The foreseeable circumstances and/or reasons under which the subject’s participation in the trial may be terminated.
The expected duration of the subject’s participation in the trial.
The approximate number of subjects involved in the trial.
Prior to participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.
When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.
Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:
The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally.
The foreseeable risks to the subjects are low.
The negative impact on the subject’s well-being is minimized and low.
The trial is not prohibited by law.
The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
In emergency situations, when prior consent of the subject is not possible, the consent of the subject’s legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.
 
4.9 Records and Reports
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.
Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.
Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e. an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 5.18.4 (n)). Sponsors should provide guidance to investigators and/or the investigators’ designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor’s designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.
The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.
Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (see 5.5.12).
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.
 
4.10 Progress Reports
The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.
The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects.
 
4.11 Safety Reporting
All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC.
Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.
For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).
 
4.12 Premature Termination or Suspension of a Trial
If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension.
If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
 
4.13 Final Report(s) by Investigator
Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.
 
 
5. SPONSOR
5.1 Quality Assurance and Quality Control
The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.
Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.
 
5.2 Contract Research Organization (CRO)
A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.
Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.
Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.
All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.
 
5.3 Medical Expertise
The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.
 
5.4 Trial Design
The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.
For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.
 
5.5 Trial Management, Data Handling, and Record Keeping
The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings.
When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
Maintains SOPs for using these systems.
Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail).
Maintain a security system that prevents unauthorized access to the data.
Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
Maintain adequate backup of the data.
Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).
If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.
The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject.
The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).
The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).
If the sponsor discontinues the clinical development of an investigational product (i.e. for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).
If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.
Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).
The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.
The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.
5.6 Investigator Selection
The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.
Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.
The sponsor should obtain the investigator’s/institution’s agreement:
to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see 4.5.1);
to comply with procedures for data recording/reporting;
to permit monitoring, auditing and inspection (see 4.1.4) and
to retain the trial related essential documents until the sponsor informs the investigator/ institution these documents are no longer needed (see 4.9.4 and 5.5.12).
The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.
 
5.7 Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.
 
5.8 Compensation to Subjects and Investigators
If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.
The sponsor’s policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).
 
5.9 Financing
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
 
5.10 Notification/Submission to Regulatory Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.
 
5.11 Confirmation of Review by IRB/IEC
The sponsor should obtain from the investigator/institution:
The name and address of the investigator’s/institution’s IRB/IEC.
A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.
If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.
The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion.
 
5.12 Information on Investigational Product(s)
When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.
The sponsor should update the Investigator’s Brochure as significant new information becomes available (see 7. Investigator’s Brochure).
 
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.
The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.
If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.
 
5.14 Supplying and Handling Investigational Product(s)
The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)).
The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).
The sponsor should:
Ensure timely delivery of investigational product(s) to the investigator(s).
Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim).
Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition.
The sponsor should:
Take steps to ensure that the investigational product(s) are stable over the period of use.
Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
5.15 Record Access
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.
The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
 
5.16 Safety Information
The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC’s approval/favourable opinion to continue the trial.
 
5.17 Adverse Drug Reaction Reporting
The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).
 
5.18 Monitoring
Purpose
The purposes of trial monitoring are to verify that:
The rights and well-being of human subjects are protected.
The reported trial data are accurate, complete, and verifiable from source documents.
The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
 
Selection and Qualifications of Monitors
Monitors should be appointed by the sponsor.
Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
 
Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the xtent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
 
Monitor’s Responsibilities
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:
Acting as the main line of communication between the sponsor and the investigator.
Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
Verifying, for the investigational product(s):
That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
Verifying that written informed consent was obtained before each subject’s participation in the trial.
Ensuring that the investigator receives the current Investigator’s Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
Ensuring that the investigator and the investigator’s trial staff are adequately informed about the trial.
Verifying that the investigator and the investigator’s trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
Verifying that the investigator is enrolling only eligible subjects.
Reporting the subject recruitment rate.
Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:
The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
Any dose and/or therapy modifications are well documented for each of the trial subjects.
Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.
Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator’s trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).
Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.
 
Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
Monitoring Report
The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.
Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
Reports should include a summary of what the monitor reviewed and the monitor’s statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.
The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.
 
5.19 Audit
If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
Purpose
The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
 
Selection and Qualification of Auditors
The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.
 
Auditing Procedures
The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
The observations and findings of the auditor(s) should be documented.
To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
When required by applicable law or regulation, the sponsor should provide an audit certificate.
 
5.20 Noncompliance
Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance.
If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).
 
5.21  Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).
 
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.)
 
5.23 Multicentre Trials
For multicentre trials, the sponsor should ensure that:
All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.
The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.
The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.
All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.
Communication between investigators is facilitated.
 
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
The contents of a trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.
 
6.1  General Information
Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
Name and address of the sponsor and monitor (if other than the sponsor).
Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
Name, title, address, and telephone number(s) of the sponsor’s medical expert (or dentist when appropriate) for the trial.
Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.
 
6.2  Background Information
Name and description of the investigational product(s).
A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
Summary of the known and potential risks and benefits, if any, to human subjects.
Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
Description of the population to be studied.
References to literature and data that are relevant to the trial, and that provide background for the trial.
 
6.3  Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the trial.
 
6.4  Trial Design
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design, should include:
A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
A description of the measures taken to minimize/avoid bias, including:
Randomization.
Blinding.
A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
A description of the “stopping rules” or “discontinuation criteria” for individual subjects, parts of trial and entire trial.
Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
Maintenance of trial treatment randomization codes and procedures for breaking codes.
The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.
 
6.5  Selection and Withdrawal of Subjects
Subject inclusion criteria.
Subject exclusion criteria.
Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
When and how to withdraw subjects from the trial/ investigational product treatment.
The type and timing of the data to be collected for withdrawn subjects.
Whether and how subjects are to be replaced.
The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
 
6.6  Treatment of Subjects
The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
Procedures for monitoring subject compliance.
 
6.7  Assessment of Efficacy
Specification of the efficacy parameters.
Methods and timing for assessing, recording, and analysing of efficacy parameters.
 
6.8  Assessment of Safety
Specification of safety parameters.
The methods and timing for assessing, recording, and analysing safety parameters.
Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
The type and duration of the follow-up of subjects after adverse events.
 
6.9  Statistics
A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
The level of significance to be used.
Criteria for the termination of the trial.
Procedure for accounting for missing, unused, and spurious data.
Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).
 
6.10  Direct Access to Source Data/Documents
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.
 
6.11 Quality Control and Quality Assurance
 
6.12 Ethics
Description of ethical considerations relating to the trial.
 
6.13 Data Handling and Record Keeping
 
6.14 Financing and Insurance
Financing and insurance if not addressed in a separate agreement.
 
6.15 Publication Policy
Publication policy, if not addressed in a separate agreement.
 
6.16 Supplements
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
7. INVESTIGATOR’S BROCHURE
7.1 Introduction
The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data.
This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB.
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline.
 
7.2 General Considerations
The IB should include:
Title Page
This should provide the sponsor’s name, the identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided. An example is given in Appendix 1.
Confidentiality Statement The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator’s team and the IRB/IEC.
 
7.3 Contents of the Investigator’s Brochure
The IB should contain the following sections, each with literature references where appropriate:
Table of Contents
An example of the Table of Contents is given in Appendix 2
Summary
A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product.
Introduction
A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the investigational product (s ) pharmacological class and its expected position within this class (e.g. advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product.
Physical, Chemical, and Pharmaceutical Properties and Formulation
A description should be provided of the investigational product substance(s) (including the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties.
To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.
Any structural similarities to other known compounds should be mentioned.
Nonclinical Studies
Introduction:
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
Species tested
Number and sex of animals in each group
Unit dose (e.g., milligram/kilogram (mg/kg))
Dose interval
Route of administration
Duration of dosing
Information on systemic distribution
Duration of post-exposure follow-up
Results, including the following aspects:
Nature and frequency of pharmacological or toxic effects
Severity or intensity of pharmacological or toxic effects
Time to onset of effects
Reversibility of effects
Duration of effects
Dose response
Tabular format/listings should be used whenever possible to enhance the clarity of the presentation.
The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed).
The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis.
Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g. efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).
Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species.
Toxicology
A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:
Single dose
Repeated dose
Carcinogenicity Special studies (e.g. irritancy and sensitisation)
Reproductive toxicity
Genotoxicity (mutagenicity)
Effects in Humans
Introduction:
A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use of the investigational product(s) other than from in clinical trials, such as from experience during marketing.
Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available:
Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination).
Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form.
Population subgroups (e.g., gender, age, and impaired organ function).
Interactions (e.g., product-product interactions and effects of food).
Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
Safety and Efficacy
A summary of information should be provided about the investigational product’s/products’ (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials (including those for all the studied indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed.
The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
Marketing Experience
The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarised (e.g., formulations, dosages, routes of administration, and adverse product reactions). The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration.
Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical and clinical data, and should summarise the information from various sources on different aspects of the investigational product(s), wherever possible. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials.
Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials.
The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product.
 
7.4 APPENDIX 1:
TITLE PAGE (Example)
SPONSOR’S NAME
 
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
 
INVESTIGATOR’S BROCHURE
Edition Number:
Release Date:
 
Replaces Previous Edition Number:
Date:
 
7.5 APPENDIX 2:
TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)
- Confidentiality Statement (optional)…………………………………………………………………
- Signature Page (optional)…………………………………………………………………………………
1. Table of Contents ………………………………………………………………………………………….
2. Summary …………………………………………………………………………………………………….
3. Introduction …………………………………………………………………………………………………
4. Physical, Chemical, and Pharmaceutical Properties and Formulation ………………….
5. Nonclinical Studies ……………………………………………………………………………………….
5.1 Nonclinical Pharmacology ……………………………………………………………………………
5.2 Pharmacokinetics and Product Metabolism in Animals ……………………………………
5.3 Toxicology ………………………………………………………………………………………………….
6. Effects in Humans …………………………………………………………………………………………
6.1 Pharmacokinetics and Product Metabolism in Humans ……………………………………
6.2 Safety and Efficacy ……………………………………………………………………………………….
6.3 Marketing Experience ………………………………………………………………………………….
7. Summary of Data and Guidance for the Investigator …………………………………………
 
NB: References on  1. Publications
2. Reports
These references should be found at the end of each chapter
Appendices (if any)
 
8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.1 Introduction
Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor’s independent audit function and inspected by the regulatory authority (ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable.
Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor’s office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
 
8.2 Before the Clinical Phase of the Trial Commences
During this planning stage the following documents should be generated and should be on file before the trial formally starts
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.2.1 INVESTIGATORI’S   BROCHURE To document that relevant and current scientific information   about the investigational product has been provided to the investigator X X
8.2.2 SIGNED   PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF) To   document investigator and sponsor agreement to the protocol/amendment(s) and   CRF X X
8.2.3 INFORMATION   GIVEN TO TRIAL SUBJECT- INFORMED CONSENT FORM(including   all applicable translations)  To   document the informed consent X X
 ANY   OTHER WRITTEN INFORMATION To document that subjects will be given   appropriate written information (content and wording) to support their   ability to give fully informed consent X X
 -ADVERTISEMENT   FOR SUBJECT RECRUITMENT (if used) To   document that recruitment measures are appropriate and not coercive X 
8.2.4 FINANCIAL   ASPECTS OF THE TRIA To   document the financial agreement between the investigator/institution and the   sponsor for the trial X X
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.2.5 INSURANCE   STATEMEN(where required) To   document that compensation to subject(s) for trial-related injury will be   available X X
8.2.6 SIGNED   AGREEMENT BETWEEN INVOLVED PARTIES, e.g.:-   investigator/institution and sponsor-   investigator/institution and CRO
 
-   sponsor and CRO
-   investigator/institution and authority(ies) (where required) To document agreements X
X
 
 
X X
X
(where   required)
X
X
8.2.7 DATED,   DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)   /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING: - protocol and any amendments- CRF (if applicable)
- informed consent form(s)
- any other written information to be   provided to the subject(s)
- advertisement for subject recruitment (if   used)
- subject compensation (if any)
- any other documents given approval/   favourable opinion To document that the trial has been subject   toIRB/IEC   review and given approval/favourable opinion. To identify the version number   and date of the document(s) 
 
 
 
 
 
 
 
 
 
 
 
  X X
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.2.8 INSTITUTIONAL   REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITION  To   document that the IRB/IEC is constituted in agreement with GCP X X(where   required)
8.2.9 AUTHORISATION/APPROVAL/NOTIFICATION   OF PROTOCOL (where required) To   document appropriate authorisation/approval/notification by the regulatory   authority(ies) has been obtained prior to initiation of the trial in   compliance with the applicable regulatory requirement(s) X(where   required) X(where   required)
8.2.10 CURRICULUM   VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF   INVESTIGATOR(S) AND SUB-INVESTIGATOR(S) To   document qualifications and eligibility to conduct trial and/or provide   medical supervision of subjects  X X
8.2.11 NORMAL   VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR   TEST(S) INCLUDED IN THE PROTOCO To   document normal values and/or ranges of the tests  X X
8.2.12 MEDICAL/LABORATORY/TECHNICAL   PROCEDURES /TEST-   certification or-   accreditation or
-   established quality control and/or external quality assessment or
- other   validation (where required) To   document competence of facility to perform required test(s) , and support   reliability of results 
 
 
 
  X(where   required) X
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.2.13 SAMPLE   OF LABEL(S) ATTACHED TO INVESTIGATIONAL PRODUCT CONTAINER(S) To   document compliance with applicable labelling regulations and appropriateness   of instructions provided to the subjects  X
8.2.14 INSTRUCTIONS   FOR HANDLING OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS(if not included in protocol or Investigator’s Brochure) To   document instructions needed to ensure proper storage, packaging, dispensing   and disposition of investigational products and trial-related materials X X
8.2.15 SHIPPING   RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS To   document shipment dates, batch numbers and method of shipment of   investigational product(s) and trial-related materials. Allows tracking of   product batch, review of shipping conditions, and accountability X X
8.2.16 CERTIFICATE(S)   OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPED To   document identity, purity, and strength of investigational product(s) to be   used in the trial  X
8.2.17 DECODING   PROCEDURES FOR BLINDED TRIALS To   document how, in case of an emergency, identity of blinded investigational   product can be revealed without breaking the blind for the remaining   subjects’ treatment  X X(third   party if applicable)
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.2.18 MASTER   RANDOMISATION LIST To   document method for randomisation of trial population  X(third   party if applicable)
8.2.19 PRE-TRIAL   MONITORING REPORT To   document that the site is suitable for the trial (may be combined with 8.2.20)  X
8.2.20 TRIAL   INITIATION MONITORING REPORT To   document that trial procedures were reviewed with the investigator and the   investigator’s trial staff ( may be combined with 8.2.19) X X

8.3 During the Clinical Conduct of the Trial
In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available
 Title of Document Purpose Located in Files of 
     Investigator/Institution                     Sponsor 
8.3.1 INVESTIGATOR’S   BROCHURE UPDATES To   document that investigator is informed in a timely manner of relevant   information as it becomes available X X 
8.3.2 ANY   REVISION TO: -   protocol/amendment(s) and CRF-   informed consent form
- any   other written information provided to subjects
-   advertisement for subject recruitment (if used)
  To   document revisions of these trial related documents that take effect during   trial X X 
8.3.3 DATED,   DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)   /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:-   protocol amendment(s)-   revision(s) of:
-   informed consent form
- any   other written information to be provided to the subject
-advertisement   for subject recruitment
(if   used)
- any   other documents given approval/favourable opinion
-   continuing review of trial (where required)
  To   document that the amendment(s) and/or revision(s) have been subject to   IRB/IEC review and were given approval/favourable opinion. To identify the   version number and date of the document(s). X X 
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.3.4 REGULATORY   AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFICATIONS WHERE REQUIRED FOR:-   protocol amendment(s) and other documents  To   document compliance with applicable regulatory requirements X(where   required) X 
8.3.5 CURRICULUM   VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB-INVESTIGATOR(S)  (see 8.2.10) X X 
8.3.6 UPDATES   TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/   LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL  To   document normal values and ranges that are revised during the trial (see 8.2.11) X X 
8.3.7 UPDATES   OF MEDICAL/LABORATORY/ TECHNICAL PROCEDURES/TESTS-   certification or-   accreditation or
-   established quality control and/or external quality assessment or
- other   validation (where required)
  To   document that tests remain adequate throughout the trial period (see 8.2.12) X(where   required) X 
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.3.8 DOCUMENTATION   OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT (see 8.2.15.) X X 
8.3.9 CERTIFICATE(S)   OF ANALYSIS FOR NEW BATCHES OF INVESTIGATIONAL PRODUCTS (see 8.2.16)  X 
8.3.10 MONITORING   VISIT REPORTS  To   document site visits by, and findings of, the monitor  X 
8.3.11 RELEVANT   COMMUNICATIONS OTHER THAN SITE VISITS-   letters-   meeting notes
–notes   of telephone calls To   document any agreements or significant discussions regarding trial   administration, protocol violations, trial conduct, adverse event (AE)   reporting X X 
8.3.12 SIGNED   INFORMED CONSENT FORMS To   document that consent is obtained in accordance with GCP and protocol and   dated prior to participation of each subject in trial. Also to document   direct access permission (see 8.2.3) X  
8.3.13 SOURCE   DOCUMENTS To   document the existence of the subject and substantiate integrity of trial   data collected. To include original documents related to the trial, to   medical treatment, and history of subject X  
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.3.14 CASE   REPORT FORMS (CRF) To   document that the investigator or authorised member of the investigator’s   staff confirms the observations recorded X(copy) X(original) 
8.3.15 DOCUMENTATION   OF CRF CORRECTIONS To   document all changes/additions or corrections made to CRF after initial data   were recorded X(copy) X(original) 
8.3.16 NOTIFICATION   BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS AND RELATED   REPORTS Notification   by originating investigator to sponsor of serious adverse events and related   reports in accordance with 4.11 X X 
8.3.17 NOTIFICATION   BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY   AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS   AND OF OTHER SAFETY INFORMATION Notification   by sponsor and/or investigator, where applicable, to regulatory authorities   and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance   with 5.17 and 4.11.1 and of other safety   information in accordance with 5.16.2 X(where   required) x 
8.3.18 NOTIFICATION   BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION Notification   by sponsor to investigators of safety information in accordance with 5.16.2 X X 
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.3.19 INTERIM   OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES) Interim   or annual reports provided to IRB/IEC in accordance with 4.10 and to   authority(ies) in accordance with 5.17.3 X X(where   required) 
8.3.20 SUBJECT   SCREENING LOG To   document identification of subjects who entered pre-trial screening X X(where   required) 
8.3.21 SUBJECT   IDENTIFICATION CODE LIST To   document that investigator/institution keeps a confidential list of names of   all subjects allocated to trial numbers on enrolling in the trial. Allows   investigator/institution to reveal identity of any subject X  
8.3.22 SUBJECT   ENROLMENT LOG To   document chronological enrolment of subjects by trial number X  
8.3.23 INVESTIGATIONAL   PRODUCTS ACCOUNTABILITY AT THE SITE To   document that investigational product(s) have been used according to the protocol X X 
8.3.24 SIGNATURE   SHEET To   document signatures and initials of all persons authorised to make entries   and/or corrections on CRFs X X 
8.3.25 RECORD   OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY) To   document location and identification of retained samples if assays need to be   repeated X X 
        
8.4 After Completion or Termination of the Trial
After completion or termination of the trial, all of the documents identified in sections 8.2 and 8.3 should be in the file together with the following
 Title of Document Purpose Located in Files of 
     Investigator/Institution                              Sponsor 
8.4.1 INVESTIGATIONAL   PRODUCT(S) ACCOUNTABILITY AT SITE To   document that the investigational product(s) have been used according to the   protocol. To documents the final accounting of investigational product(s)   received at the site, dispensed to subjects, returned by the subjects, and   returned to sponsor X X 
8.4.2 DOCUMENTATION   OF INVESTIGATIONAL PRODUCT DESTRUCTION To   document destruction of unused investigational products by sponsor or at site X(if   destroyed at site) X 
8.4.3 COMPLETED   SUBJECT IDENTIFICATION CODE LIST To   permit identification of all subjects enrolled in the trial in case follow-up   is required. List should be kept in a confidential manner and for agreed upon   time X  
8.4.4 AUDIT   CERTIFICATE (if   available) To   document that audit was performed  X 
8.4.5 FINAL   TRIAL CLOSE-OUT MONITORING REPORT To   document that all activities required for trial close-out are completed, and   copies of essential documents are held in the appropriate files  X 
 Title of Document Purpose Located in Files of
     Investigator/Institution Sponsor
8.4.6 TREATMENT   ALLOCATION AND DECODING DOCUMENTATION Returned   to sponsor to document any decoding that may have occurred  X 
8.4.7 FINAL   REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO   THE REGULATORY AUTHORITY(IES) To   document completion of the trial X  
8.4.8 CLINICAL   STUDY REPORT To document   results and interpretation of trial X(if applicable) X 
        
 
临床试验管理规范
目录
前言
1. 术语
2. ICH GCP 的原则
3. 机构评审委员会/独立的伦理委员会(IRB/IEC)
3.1 职责
3.2 组成、职责和操作
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 试验对象的医疗保健
4.4 与IRB/IEC交流
4.5 对试验方案的依从性
4.6 试验用药品
4.7 随机化程序和破盲
4.8 试验对象的知情同意
4.9 记录和报告
4.10 进展报告
4.11 安全性报告
4.12 试验的中止或暂停
4.13 研究者的最终报告
5. 申办者
5.1 质量保证和质量控制
5.2 合同研究机构(CRO)
5.3 医学专家
5.4 试验设计
5.5 试验管理、数据处理和记录保存
5.6 研究者的选择
5.7 责任的分配
5.8 给对象和研究者的补偿
5.9 财务
5.10 向管理当局通报/提交
5.11  IRB/IEC审评的确认
5.12 有关试验用药品的资料
5.13 试验用药品的生产、包装、标签和编码
5.14 研究产品的供应和管理
5.15 记录访问
5.16 安全性资料
5.17 药品不良反应报告
5.18 监察
5.19 稽查
5.20 不依从
5.21 一个试验的过早终止或暂停
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的修改
6.1 概要资料
6.2 背景资料
6.3 试验的目标和目的
6.4 试验设计
6.5 对象的选择和退出
6.6 对象的治疗
6.7 有效性评价
6.8 安全性评价
6.9 统计
6.10 直接访问源数据/文件
6.11 质量控制和质量保证
6.12 伦理学
6.13 数据处理和记录保存
6.14 财务和保险
6.15 结果发表办法
6.16 补充
7. 研究者手册
7.1 前言
7.2 一般考虑
7.3 研究者手册的内容
7.4 附录1
7.5 附录2
8. 临床试验必需文件
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
 
 
 
 
 
 
 
 
 
 
 
 
临床试验管理规范指导原则
前 言
临床试验管理规范(GCP)是设计、实施、记录和报告设计人类对象参加的试验国际性伦理和科学质量标准。遵循这一标准为保护对象的权利、安全性和健康,为与源于赫尔辛基宣言的原则保持一致以及临床试验数据的可信性提供了公众保证。
ICH-GCP指导原则的目的是为欧盟、日本和美国提供统一的标准,以促进这些管理当局在其权限内相互接受临床数据。
本指导原则的发展考虑了欧盟、日本、美国,以及澳大利亚、加拿大、北欧国家和世界卫生组织(GCP)的现行GCP。
在产生打算提交给管理当局的临床数据时应当遵循本指导原则。
本指导原则中确立的原则也可应用于可能影响人类对象安全和健康的其他临床研究。
 
1.术语
1.1 药品不良反应(ADR)
在一个新的药品或药品的新用途在批准之前的临床实践,尤其是治疗剂量尚未确定前,ADR是指与药物任何剂量有关的所有有害的和非意求的反应都应被考虑为药物不良反应。该术语用于药品是指在药品与不良反应之间的因果关系至少有一个合理的可能性,即不能排除这种关系。
对已上市药品,ADR指人对用于预防、诊断或治疗疾病或改善生理功能的药物在常用剂量出现的有害和非意求反应(参见ICH临床安全性数据管理指导原则:快速报告的定义和标准)。
 
1.2 不良事件(AE)
在用药病人或临床研究对象中发生的任何不幸医疗事件,他不一定要与治疗有因果关系。因此,一个不良事件(AE)可以是与使用(研究)药物在时间上相关的任何不利的和非意求的征兆(包括异常的实验室发现)、症状或疾病,而不管其是否与药物有关(参见ICH临床安全性数据管理指导原则:快速报告的定义和标准)。
 
 
1.3 修改(试验方案)
见试验方案修改。
 
1.4 适用的管理要求
有关实施试验用药品临床试验的任何法律和法规。
 
1.5批准(机构审评委员会)
IRB表示赞成的决定:指对一项临床试验已经进行审评,并可在IRB、研究机构、GCP和适用管理要求的约束下由研究机构方实施。
 
1.6 稽查
对试验相关活动和文件进行系统和独立的监察,以判定试验的实施和数据的记录、分析与报告是否符合试验方案、申办者的标准操作程序(SOP)、临床试验管理规范(GCP)以及适用的管理要求。
 
1.7 稽查证书
稽查员确认已进行稽查的声明。
 
1.8 稽查报告
申办者方稽查关于稽查结果的书面评价。
 
1.9 稽查轨迹
允许重复出现事件过程的文件。
 
1.10 设盲
一种使试验的一个或几个部分的人员不知道治疗分配的程序。单盲通常指对象不知道;双盲通常指对象、研究人员、监察员以及在某些情况下数据分析人员也不知道治疗分配。
 
1.11 病例报告表(CRF)
设计用来记录试验方案要求向申办者报告的有关每一例对象的全部信息的印刷的、光学的或电子的文件。
 
1.12 临床试验/研究
在人类对象进行的任何意在发现或证实一种试验用药品的临床、药理学和/或其他药效学作用;和/或确定一种试验用药品的任何不良反应;和/或研究一种试验用药品的吸收、分布、代谢和排泄,以确定药物的安全性和/或有效性的研究。术语临床试验和临床研究同义。
 
1.13 临床试验/研究报告
在人类对象进行的任何治疗、预防或诊断剂的试验/研究的书面描述。临床和统计描述、陈述和分析全部列入该单份报告(见ICH临床研究报告的结构和内容指导原则)。
 
1.14 对照(药物)
临床试验中用做对照的试验用药品或市售药物(即阳性对照)或安慰剂。
 
1.15依从性(关于试验的)
遵循与试验有关的所有要求、临床试验管理规范(GCP)要求和适用的管理要求。
 
1.16保密性
不得向未经授权的个人泄漏申办者所有的资料或对象的身份。
 
1.17 合同
在两个或几个有关方之间的一份书面的、有日期和签字的协议,其中陈述了关于工作和责任和分派的安排,以及关于财务问题的安排。试验方案可以作为合同的基础。
 
1.18 协调委员会
申办者组织的协调实施多中心试验的委员会。
 
1.19 协调研究者
受指派负责协调参加一项多中心试验的各中心研究者的一名研究者。
 
1.20 合同研究组织(CRO)
与申办者订立契约完成一个或多个有关申办者方的试验任务和功能的个人或组织(商业性的,学术的或其他)。
 
1.21 直接访问
允许监察、分析、核对和复制任何对于评价临床试验有重要意义的记录和报告。直接访问的任何一方(如国内和国外的管理当局,申办者方的监察员和稽查员)应当受适用管理要求的缺书,采取一切合理的预防措施维护对象身份和申办者资料的保密性。
 
1.22 文件
描述或记录试验的方法、实施和/或结果,影响试验的因素,以及采取的措施等的任何形式的记录(包括但不限于书面、电子、磁性和光学的记录,以及扫描、X射线和心电图)。
 
1.23 必需文件
指各自和合在一起允许评价一个研究的执行情况和所得数据的质量文件(见8.实施临床试验的必需文件)。
 
1.24 临床试验管理规范(GCP)
是临床试验设计、实施、执行、监察、稽查、记录、分析和报告的标准,它为数据和所报告结果的可信性和准确性提供了保证,并保护试验对象的权利、完整性和机密性。
 
1.25 独立的数据监察委员会(IDMC)(数据和安全监察委员会,监察委员会,数据监察委员会)
由申办者设立一个独立的数据监察委员会,它定期对研究进展、安全性数据和有效性终点进行评估,向申办者建议是否继续、调整或停止试验。
 
1.26 公平的见证人
独立与临床试验、不受与试验有关人员的不公正影响的个人。如果对象或对象的合法接受代表人不能阅读,他/她将参与知情同意过程,并向对象阅读提供给她们的知情同意书和其他书面资料。
1.27 独立的伦理委员会(IEC)
一个由医学专业人员和非医学专业人员组成的独立机构(研究机构的、地区的、国家的或超国家的审评机构或委员会),其职责是保证参加试验对象的权益、安全性和健康;并通过对试验方案、研究人员、设施以及用于获得和记录试验对象知情同意的方法和材料的合理性进行审评和批准/提供起促进作用的意见以对这种保护提供公众保证。
在不同的国家,独立的伦理委员会的法律地位、组成、职责、操作和适用的管理要求可能不用,但是应当如本指导原则所述,允许独立的伦理委员会按GCP进行工作。
 
1.28 知情同意
一个对象在被告知与其作出决定有关的所有试验信息后,资源确认他或她参加一个特定试验的意愿过程。知情同意采用书面的、签字并注明日期的知情同意书。
 
1.29 视察
管理当局在试验单位、申办者和/或合同研究组织或管理当局认为何时的其他机构对其认为与临床试验有关的文件、设备、记录和其他资源进行的官方审查的活动。
 
1.30 (医学)研究机构
实施临床试验任何或私人的实体、代理机构、医学或齿科设施。
 
1.31 机构审评委员会(IRB)
由医学、科学和非科学成员组成的一个独立机构,其职责是通过对试验方案及其修订本,获得受试对象知情同意所用的方法和资料进行审评、批准和继续审评,确保一项试验的受试对象的权利、安全和健康得到保护。
 
1.32 临床试验/研究中期报告
根据试验进行过程中所做的分析写出的中期结果和评价的报告
 
1.33 试验用药品
一种在临床试验中供试验的或作为对照的活性成分或安慰剂的药物制剂。包括一个已上市药品以不同于所批准的方式适用或组合(制剂或包装),或用于一个未经批准的适应证,或用于收集一个已批准用法的更多资料。
 
1.34 研究者
负责在一个试验单位实施临床试验的人。如果在一个试验单位是由一组人员实施试验,研究者指这个组的负责人,也称为主要研究者。见次级研究人员。
 
1.35 研究者/研究机构
表示“符合适用管理要求的研究者和/或研究机构”
 
1.36 研究者手册
与试验药品在人类对象中的研究有关的临床和非临床资料的汇编(见7.研究者手册)
 
1.37 法律上可接受的代表
在适用法律下被授权代表一位未来的对象同意参加临床试验的个人,或司法人员或其他机关。
 
1.38 监察
监督一个临床试验的进展,保证临床试验按照试验方案、标准操作程序(SOP)、临床试验管理规范(GCP)和适用的管理要求实施、记录和报告的活动。
 
1.39 监察报告
监察员在每一次现场访问和/或其他与试验有关的交流后,根据申办者的SOP写给申办者的书面报告。
 
1.40 多中心试验
按照一个试验方案,在一个以上试验单位实施,因此由一名以上研究者完成的临床试验。
 
1.41 非临床试验
不是在人类对象进行的生物医学研究。
 
1.42 意见(与独立的伦理委员会相关)
由独立的伦理委员会(IEC)给出的评价和/或建议
 
1.43 原始医学记录
见源文件。
 
1.44 试验方案
一个阐明试验的目的、设计、方法学、统计学考虑和组织的文件。试验方案通常也给出试验的背景和理论基础,但者这可以写在与方案有关的其他参考文件中。在ICH指导原则中,试验方案这一术语指试验方案和方案的修改。
 
1.45 试验方案的修改
对试验方案的改变或澄清的书面描述。
 
1.46 质量保证(QA)
为保证试验的进行和数据产生、记录以及报告都符合临床试验管理规范(GCP)和适用管理要求所建立的有计划的系统活动。
 
1.47 质量控制(QC)
在质量保证系统内所采取的操作技术和活动,以查证与试验相关的活动都符合质量要求。
 
1.48 随机化
为了减少偏倚,采用机遇决定分配的原理将试验对象分配倒治疗组或对照组的过程。
 
1.49 管理当局
有权进行管理的基构。在ICH GCP指导原则中,管理当局一词包括审评所提交的临床数据和实施视察的机构(见1.29)。这些机构有时指主管当局。
 
1.50 严重不良事件(SAE)或严重药品不良反应
发生在任何剂量的任何不幸医学事件:
- 导致死亡
- 危及生命
- 需要住院治疗或延长住院时间
- 导致永久或严重的残疾/能力丧失,或
- 先天性异常/出生缺陷
(见ICH临床安全性数据管理指导原则,快速报告的定义和标准)
 
1.51 源数据
临床试验中的临床发现、观察或其他活动的原始记录及其可靠副本中的全部资料,他们对于重建和评价试验是必要的。源数据包含在源文件中(原始记录或可靠副本)。
 
1.52 源文件
原始文件、数据和记录(如医院记录,临床和办公室图标,实验室笔记,备忘录,对象日记卡或评价表,药房发药记录,自动仪器的记录数据,在核对后做为准确副本的可靠复印件或抄件,显微胶片,摄影负片,缩微胶卷或磁介质,X线,对象文件,以及保存在药房、实验室和与参与临床试验的医学技术部门中的记录。
 
1.53 申办者
对一个临床试验的发起、管理和/或财务负责的个人、公用、机构或组织。
 
1.54 申办者-研究者
单独与其他人一起,发起并实施一个临床试验的个人。在他(们)的直接指示下,给对象服用、发给对象或由对象使用试验药品。该术语并不包括除了个人以外的任何人(如不包括一个公司或一个机构)。一个申办者-研究者的义务包括一个申办者和一个研究者两者的义务。
 
1.55 标准操作程序(SOP)
为达到均一性完成一个特定职责指定的详细书面说明。
1.56 次级研究人员
在一个试验单位,在主要研究者指定和监督下的临床试验组中完成与试验有关的重要程序和/或作出与有关试验的重大决定的成员(如同事,住院医生,特别是研究生)。见研究者。
 
1.57 对象/试验对象
参加一个临床试验作为试验药品的接受者或作为对照的个人。
 
1.58 对象识别编码
研究者为每一名受试对象指定的独特识别号码,以保护对象的身份并在研究者报告不良事件和/或其他与试验有关数据时代替对象姓名。
 
1.59 试验单位
真正开展与临床试验有关活动的地方。
 
1.60 非预期的药品不良反应
一种不良反应,其性质或严重程度与现有的产品资料(如一种未批准试验用药品的研究者手册,或包装插入页/一个已经批准药物的产品性能摘要)不符的不良反应(见ICH临床安全性数据管理指导原则:快速报告的定义和标准)。
 
1.61 弱势对象
指受到不正当的影响而称为一个临床志愿者的人,他们可能由于期望(无论正当与否)参加试验而伴随的利益,或者拒绝参加会受到等级中资深成员的报复。有等级结构的团体的成员,如医学、药学、齿科或护理专业的学生,附属医院和实验室人员,制药公司的雇员,军人,以及被监禁的人。其他弱势对象包括无可救药的患者,住在福利院利的人,失业者或穷人,处于危急状况的病人,少数民族,无家可归者,流浪者,未成年者,和那些无能力给出知情同意的人。
 
1.62(试验对象的)健康
参加临床试验对象的体格和精神的完整性。
 
2.  ICH GCP 的原则
2.1 临床试验的实施应符合源自赫尔辛基宣言的伦理原则,与GCP和适用管理要求一致。
 
2.2 在开始一个试验之前,应当权衡个体试验对象和社会的可预见风险、不方便和预期的受益。只有当预期的受益大于风险时,才开始和继续一个临床试验。
 
2.3 试验对象的权利、安全和健康是最重要的考虑,应当胜过科学和社会的利益。
 
2.4 关于试验用药品可得到的非临床和临床资料应足以支持所提议的临床试验。
 
2.5 临床试验应当有坚实的科学基础,有明确、详细描述的试验方案。
 
2.6 临床试验的实施应当遵循事先已经得到研究机构审查委员会(IRB)/独立的伦理委员会(IEC)批准/赞成的试验方案。
 
2.7 一名合格医生或合格牙医的职责永远是给予对象医疗保健,代表对象作出医学决定。
 
2.8 参与实施临床试验个每一个人应当在受教育、培训和经验方面都有资格完成他或她的预期任务。
 
2.9 应当在参加临床试验前每一个对象获得自由给出的知情同意书。
 
2.10 所有临床试验资料被记录、处理和储存的方式应当允许资料的准确报告、解释和核对。
 
2.11 可能鉴别对象身份的记录的保密性应当得到保护,依照适用的管理要求尊重隐私和保密规定。
 
2.12 试验用药品应当按照适用的药品生产质量管理规范(GMP)生产、处理和储存。试验用药品应按照已批准的方案使用。
 
2.13 应当建立保证试验各方面质量的程序系统。
 
3. 机构审查委员会/独立的伦理委员会(IRB/IEC)
3.1 职责
3.1.1  IRB/IEC应当保护所有试验对象的权利、安全和健康。应当特别注意那些可能包括有弱势对象的试验。
3.1.2  IRB/IEC应当得到以下文件:
试验方案/修改,研究人员申请用于试验的书面知情同意书及其更新件,对象招募程序(如广告),提供给对象的书面材料,研究者手册(IB),可得到的安全性材料,对象可获得的付款和补偿,研究人员的最新简历/或其他证明其资格的文件,以及IRB/IEC履行其职责所需要的任何其他文件。
IRB/IEC应当在合理的时限内审查所提议的临床研究,提供书面审评意见,明确的确认试验、所审评的文件和日期如下:
- 批准/赞成意见
- 在批准/赞成之前所需要的修改
- 不批准/负面的意见;和
- 中止/暂停先前的批准/赞成意见
3.1.3 IRB/IEC应当参照现行简历和/或IRB/IEC要求的其他相关文件考虑所提议试验的研究人员的资格。
3.1.4 IRB/IEC应当根据人类对象的危险度,间隔一定事件对正在进项的试验继续审评,但至少每年一次。
3.1.5 在IRB/IEC评价中,当补充资料对于保护对象的权利、安全和/或健康有意义时,IRB/IEC可能需要比4.8.10段概述的给予对象的更多资料。
3.1.6 当一个将进行的非治疗试验是由对象的可接受的合法代表给出知情同意时(见4.8.12.4.8.14),IRB/IEC应当确定,所建议的方案和/或其他文件已经充分说明了相关的伦理学考虑,并符合这一类试验的适用管理要求。
3.1.7 试验方案指出试验对象或其合法的可接受的代表的不可能先给出知情同意时(见4.8.15),IRB/IEC应当确定所提议的方案和/或其他文件充分说明了相关的伦理学考虑,并符合这一类试验的适用管理要求。
3.1.8 IRB/IEC应当审评支付给对象款项的数量和方式,以确认没有对试验对象的胁迫问题或不正当影响。给对象的支付应当按比例分配,而不是完全以对象完成试验而定。
3.1.9 IRB/IEC应当保证,关于支付给对象的资料,包括支付方式、数量和支付给试验对象的时间表已列于知情同意书和将提供给对象任何其他书面资料上,应注明按比例支付的方式。
 
3.2 组成、职责和操作
3.2.1 IRB/IEC应由合理数目的成员组成,他们全体都有审评和评价科学、医学和和所提议试验的伦理学方面的资料和经验。建议IRB/IEC应包括:
(a) 至少5名成员;
(b) 至少一名成员关心的重要领域时非科学领域;
(c) 至少一名成员独立于研究机构/试验单位。
只有那些独立于试验研究者和申办者的IRB/IEC成员才能对一个试验的相关事项投票/提出建议。
应当提供一份IRB/IEC成员的名单和他们的资格表。
3.2.2 IRB/IEC应但按照书面的操作程序完成其职责,应当保存其活动的书面记录和会议记录,并应当遵守GCP和适用的管理要求。
3.2.3 IRB/IEC应当在达到其书面操作程序中规定的法定人数的正式会议上作出决定。
3.2.4 只有参加IRB/IEC评审和讨论的成员才可投票/提出他们的评价和/或意见。
3.2.5 研究者应当提供试验各方面的资料,但不应当参加IRB/IEC的审议或IRB/IEC的投票/意见。
IRB/IEC可邀请在特别领域有专门知识的非成员来帮助。
 
3.3 程序
IRB/IEC应当建立书面文件和遵循其程序,程序应包括:
3.3.1确定其组成(成员单娥姓名和资格)和授权。
3.3.2 安排时间,通知其成员,举行会议。
3.3.3 对试验进行初始审评和继续审评。
3.3.4 酌情确定继续审评的频度。
3.3.5依照适用的管理要求,为已经获得IRB/IEC批准/赞成的正在进行的试验的较小修改提供快速审评和批准/赞成意见。
3.3.6 说明在IRB/IEC书面签署对试验的批准/赞成意见之前不得接纳对象进入试验。
3.3.7说明在方案的适当修改预先得到IRB/IEC的书面批准/赞成之前,不能偏离或改变试验方案,除非有必要排除对于对象的直接危害,或方案的改变只涉及试验的后勤或管理方面(如更换监察员,改变电话号码)(见4.5.2)。
3.3.8 说明研究人员应当立即报告IRB/IEC的事项:
(a)偏离或改变方案以消除试验对象的直接危害(见3.3.7,4.5.2,4.5.4);
(b)增加对象风险的改变和/或明显影响试验实施的改变(见4.10.2);
(c) 所有严重的和非预期的药品不良反应(ADR);
(d)对试验的进行或对象的完全可能不利影响的新资料。
3.3.9 确保IRB/IEC迅速通知研究者/研究机构的事项:
(a)与试验有关的决定/建议;
(b)IRB/IEC决定/意见的理由;
(c)请求IRB/IEC决定/意见的程序。
 
3.4记录
IRB/IEC应当保留全部有关记录(如书面的程序,成员名单,成员的职业/联系表,提交的文件,会议记录,以及往来信件)至完成试验后至少3年,并在管理当局需要时可以提供其书面程序和成员名单。
 
4. 研究者
4.1 研究者的资格和协议
4.1.1 研究者应当在受教育、培训和经验方面有资格承担实施试验的责任,应当符合适用的管理要求所说明的所有条件,并应当通过现时的个人简历/或申办者、IRB/IEC和/或管理当局要求的其他相关文件提供这种资格证明。
4.1.2 研究者应当充分熟悉在试验方案、研究者手册、产品自料以及申办者提供的其他资料中所述的试验用药品的合适用途。
4.1.3 研究者应当了解并遵循GCP和适用的管理要求。
4.1.4 研究者/研究机构应当允许申办者的监察和稽查,以及管理部门的视察。
4.1.5 研究者应当有一份合适资格、并已委派给他们与试验相关的和总要任务的人员名单。
 
4.2 足够的资源
4.2.1 研究者应能证明(如根据遗忘的数据)在协议的招募期内接纳所需要数目的合适对象的可能性。
4.2.2 研究者在协议的试验期内应当有足够的时间实施和完成试验。
4.2.3 在可预见的试验期内,研究者应当有足够数量的合格职员和充足的设备来争取、安全的实施试验。
4.2.4 研究者应当保证所有的试验辅助人员已充等了解试验方案,试验用药品,及他们与试验相关的责任和职能。
 
4.3 试验对象的医疗保健
4.3.1 作为一名研究者或次级研究人员的合格医生(或牙医)应当对与试验有关的所有医学(牙科)决定负责。
4.3.2 在对象参加一个试验期间或以后,研究者/研究机构应当保证为对象的任何不良反应,包括与试验有关的临床上有意义的实验室测定值提供合宜的医疗保健。研究者知道并发疾病需要医疗保健时,研究者/研究机构应当通知对象。
4.3.3 如果对象有出击医生并且对象同意让初级医生知道,建议研究者将对象参加试验的事通知对象的初级医生。
4.3.4 尽管一名对象没有义务给出他/她中途退出试验的理由,研究者仍应当在充分尊重对象权利的同时作出合理的努力确认其退出理由。
 
4.4 与IRB/IEC的交流
4.4.1 在开始一个试验前,研究者/研究机构应当有IRB/IEC对试验方案、知情同意书、知情同意书的更新、对象招募程序(如广告)、以及提供给对象的任何其他书面资料的书面的、注明日期的批准/赞成意见。
4.4.2 作为研究者/研究机构向IRB/IEC书面申请的一部分,研究者/研究机构应当向IRB/IEC提供研究者手册的当前文本。如果研究者手册在试验中更新,研究者/研究机构应当向IRB/IEC提供更新的研究者手册。
4.4.3 在试验期间,研究者/研究机构应当向IRB/IEC提供全部供审评的文件。
 
4.5 对试验方案的依从性
4.5.1 研究者/研究机构应当按照申办者和(如有必要)管理当局同意、并得到IRB/IEC批准/赞成的方案实施试验。研究者/研究机构和申办者应当在方案上或另立的合同上签字,确认同意方案。
4.5.2 研究者在没有取得申办者同意和事先得到IRB/IEC对于一个修改的审评与书面批准/赞成时,不应当偏离或改变方案,除非必需消除试验对象的直接危险或这些改变只涉及试验的供应或管理方面(如更换监察员,改变电话号码)。
4.5.3 研究者,或由研究者指定的人,应当记录和解释已批准方案的任何偏离。
4.5.4 为了消除对试验对象的直接危险,研究者可以没有IRB/IEC的预先批准/赞成意见偏离或改变方案。所实施的偏离或改变、改变的理由、以及所提议的方案修改尽可能地提交给:
(a)IRB/IEC审评并得到批准/赞成;
(b)申办者征得同意和,如果需要;
(c)管理当局;
 
4.6 试验用药品
4.6.1 在试验单位,试验用药品计数地责任归于研究者/研究机构。
4.6.2 只要允许/需要,研究者/研究机构可以/应当将试验单位研究者地/机构对试验用药品计数的责任部分或全部指派给在研究者/研究机构监督下的合适的药师或其他适当的人员。
4.6.3 研究者/研究机构和/或受研究者/研究机构指派的一名药师或其他合适的个人,应当保存试验用药品交到试验单位的记录,在试验单位的存货清单,每位对象的使用记录,和未使用的药品交还给申办者或另法处置的记录。这些记录应包含日期、数量、批号/系列号、时效期(如有)、和分配给试验用药品和试验对象的特别编码。研究者应保持记载有按方案说明给予对象药量的记录,并应与从申办者处收到的试验用药品总数一致。
4.6.4 试验用药品应按申办者的说明储存(见5.13.2和5.14.3)并符合适用的管理要求。
4.6.5 研究者应当保证试验用药品只按已批准的方案使用。
4.6.6 研究者或研究者/研究机构指定的人,应当向每一位对象解释试验用药品的娥正确用法,并应在适合于该试验的一定间隔检查每一位对象完全遵照使用说明用药。
 
4.7 随机化程序和破盲
研究者应当遵循试验的随机化程序(如果有),并应保证依照方案打开随机号码。如果试验采用盲法,研究者应当立即记录并向申办者解释试验用药品的任何提前破盲(如以外破盲,因严重不良事件破盲)。
 
4.8 试验对象的知情同意
4.8.1 在获得和证明知情同意过程中,研究者应当遵循适用的管理规定,应当符合GCP和源自赫尔辛基年宣言的伦理原则。在开始试验前,研究者应当有IRB/IEC对于书面的知情同意书和提供给对象的其他文字资料的书面批准/赞成意见。
4.8.2 无论何时得到与对象的知情同意可能相关的新的资料后,提供给对象的书面知情同意书和其他文字资料都应当进行修改。修改后的书面知情同意书和其他文字资料在适用前都应当得到IRB/IEC的批准/赞成。如果有与对象继续参加试验的愿望可能相关的新资料,应及时通知对象和对象的合法可接受代表。这种资料的交流应当被记录下来。
4.8.3 无论试验就人员还是试验职员,都不应强迫或不正当地影响一个对象参加或继续参加一个试验。
4.8.4 关于试验的口述或书面的资料,包括书面的知情同意书,都不应包含会引起对象或对象的合法可接受代表放弃或看来象是放弃任何合法利益的语言;或者免除或看来象是免除研究者、机构、申办者或他们的代理由于疏忽应负责任的语言。
4.8.5 研究者或由研究者指定的人,至少应当告诉对象,或如果对象不能提供知情同意时告诉对象的合法可接受的代表,所有与试验相关的方面,包括文字资料和IRB/IEC的批准/赞成意见。
4.8.6 关于试验的口述和书面资料,包括书面知情同意书,所用的语言应当是非技术术语性的实用语言,对于对象或对象的合法可接受代表或公正的见证人应当是易懂的。
4.8.7在可能得到知情同意之前,研究者或研究者指定的人应当让对象或对象的合法接受代表有充足的时间和机会询问关于试验的详细情况和决定是否参加试验。应当回答所有问题,让对象或对象的合法可接受代表满意。
4.8.8 在对象参加试验之前,对象或对象的合法可接受代表以及执行知情同意讨论的人应亲自前述知情同意书并注明日期。
4.8.9 如果一名对象不能阅读,或一位合法可接受的代表不能阅读,在整个知情同意讨论期间必需有一位合法可接受的代表不能在书面的知情同意书和其他文件资料交给对象后,向对象或对象的合法可接受代表进行阅读并解释,在对象或对象的合法可接受代表已经口头同意对象参加试验、并且如果可能已在知情同意书上签字并注明日期。见证人通过签署知情同意书证明,知情同意书和其他文字资料已被准确的向对象或对象的合法可接受代表作了解释,对象或对象的合法可接受代表显然懂得这些解释,知情同意是对象或对象的合法可接受代表自由的给出的。
4.8.10 知情同意讨论和提供给对象的书面的知情同意书以及其他文字资料应当包括以下问题的解释:
(a)试验涉及的研究;
(b)试验目的;
(c)试验治疗和随机分配到各种治疗的可能性;
(d)试验就行的程序,包括所有侵袭性程序;
(e)对象的责任;
(f)试验的实验性方面;
(g)带给对象、可能时带给胚胎、胎儿或哺乳婴儿的合理预见的危险或不方便;
(h)可合理预见的受益。不存在预期的临床受益时,对象应当知道这一点;
(i)对象可能得到的可替代治疗程序或过程,以及这些治疗的重要潜在受益和风险;
(j)在与试验相关的伤害事件中对象可获得的补偿和/或治疗;
(k)给参加试验对象的预期按比例分配的支付(如果有);
(l)对象因参加试验的预期花费(如果有);
(m)对象参加试验是自愿的,对象可以拒绝参加试验,或在任何时候退出试验而不会收到出发或损失本来对象有权利得到的利益。
(n)监察员、稽查员、IRB/IEC和管理当局将被准予在不违反对象的保密性、在适用法律与规定准许的程度直接访问对象的原始医学记录以查证临床试验程序和/或数据,对象或对象的合法可接受的代表通过签署书面的知情同意书授权这种访问。
(o)在适用法律和/或规定允许的范围,能鉴别对象的记录应保密,不得公开这些记录。如果试验结果发表,对象鉴别仍然是保密的。
(p)如果得到与对象继续参加试验的愿望可能相关的资料,对象或对象的合法可接受代表将得到及时通报。
(q)需要进一步了解有关试验资料和试验对象的权利时的联系人,以及在发生与试验有关的伤害时的联系人。
(r)对象参加试验可能被终止的可预见情况和/或理由
(s)对象参加试验的预期持续时间
(t)参加试验对象的大约人数
4.8.11 在参加试验前,对象或对象的合法可接受代表应收到一份已签署并注明日期的书面知情同意书的复印件和其他提供给对象的书面资料。对象参加试验期间,对象或对象的合法可接受代表应收到已签署并注明日期的知情同意书的更新的复印件和提供给对象的书面资料的修改文本。
4.8.12 当一个临床试验(治疗的或非治疗的)包括那些职能由其合法可接受代表表示进入试验的对象时(如未成年人,或严重痴呆病人),应当在对象能理解的程度告知对象关于试验的信息。如果可能,对象应当亲自签署书面的知情同意并注明日期。
4.8.13 除非如4.8.14所描述的情况外,一个非治疗试验(如对于对象没有可预期的直接临床好处的试验)应当在那些亲自同意并在书面的知情同意书上签字和注明日期的对象中进行。
4.8.14 只要符合下列条件,非治疗试验可以在由合法可接受代表同意的对象中进行:
(a)试验的目的不能通过在能亲自给出知情同意的对象中进行的试验达到。
(b) 对象的可预见风险很低
(c)对于对象健康的负面影响被减到最小,并且是最低的
(d) 法律不禁止该试验
(e)明确的寻求IRB/IEC对接纳这些对象的批准/赞成意见;书面的批准/赞成意见同意接纳这些对象。
除非被证明是一个例外,这类试验应当在具有预期适用试验用药品的疾病或状况的病人中进行。这些试验中对象应当受到特别的密切检查,如果他们显得过分痛苦,应当退出试验。
4.8.15 在紧急情况下,不可能事先得到对象的知情同意时,应该请求对象的合法可接受代表(如果在场)的同意。当对象的接纳需要按方案和/或其他文件中描述的、得到IRB/IEC的书面批准/赞成意见的方法进行,以保护对象的权利、安全和健康,并保证依从适用的管理要求。应尽可能地通知对象或对象地合法可接受代表关于试验地事,并应得到他们继续参加试验和其他事项(见4.8.10)的知情同意。
 
4.9记录和报告
4.9.1 研究者应当保证给申办者的病历报告表(CRF)和所有需要的报告中的数据的准确性、完整性、易辩性和及时性。
4.9.2 CRF中来自源文件的数据应当与源文件一致,如由不一致应作出解释。
4.9.3 CRF中数据的任何改变或变更,应当注明日期、姓名首字母和说明(如有必要),并应当使原来的记录依然可见(即应保留核查痕迹);这同样适用于文字和电子的改变或更正(见5.18.4(n))。申办者应当向研究者和/或研究者指定的代表提供关于进行这种更正的指南。申办者应当有书面的程序以保证在CRF中由申办者指定的代表作出的改变或更正是有记录的、有必要的,并得到研究者的认可。研究者应当保留改变和更正的记录。
4.9.4 研究者/研究机构应当按《实施临床试验的基本文件》(见8.)所述和适用管理要求保存试验文件。研究者/研究机构应当采取措施防止这些文件的以外或过早破坏。
4.9.5 基本文件应当保留到最后批准在一个ICH地区上市后至少2年,和直到最后在一个ICH地区没有未决的或仍在考虑的上市应用,或试验用药品的临床研究正式停止后至少已过去2年。但是,如果适用的管理要求需要或申办者签署的协议需要,这些文件应当被保存更长时间。申办者有责任统制研究者/研究机构,到什么时候这些文件不必再保存(见5.5.12)
4.9.6 试验的财务方面事宜应在申办者与研究者/研究机构的协议书中说明。
4.9.7 根据监察员、稽查员、IRB/IEC或管理当局的要求,研究者/研究机构应当提供他们查阅所需的与试验有关的全部记录。
 
4.10进展报告
4.10.1 研究者应当每年一次,或应IRB/IEC要求的频度向IRB/IEC提交书面的试验情况摘要。
4.10.2 研究者应当迅速向申办者、IRB/IEC(见3.3.8)和(如果合适)向研究机构提供关于明显影响试验实施和/或增加对象风险的任何改变的书面报告。
 
4.11 安全性报告
4.11.1 除了试验方案或其他文件(如研究者手册)认为不必即时报告的那些严重不良事件(SAE)以外,所有SAE都应当立即向申办者报告。即时报告应理解为迅速的详细书面报告。即时和随访报告中的对象鉴别应当采用采用指定给试验对象的独特号码,而不是对象姓名、个人身份号码和/或地址。
4.11.2 研究者还应当服从关于管理当局和IRB/IEC报告非预期的药物严重不良反应的适用管理要求。
4.11.3 在试验方案中被确定为对安全性评价是关键的不良事件和/或实验室异常应当按照报告要求和申办者在方案中说明的时限内向申办者报告。
对于所报告的死亡事件,研究者应当向申办者和IRB/IEC提供所需要的全部附加资料(如解剖报告和最终医学报告)。
 
4.12 试验的中止或暂停
如果一个试验因为任何理由过早的停止或暂停,研究者/研究机构应当迅速通知试验对象,应当保证对象的合适治疗和随访,和根据适用的管理要求应当通知管理当局。另外:
4.12.1 如果研究者未与申办者事先协议便中止或暂停一个试验,研究者应当通知研究机构,研究者/研究机构应当立即通知申办者和IRB/IEC提供中止或暂停试验的详细书面解释。
4.12.2 如果申办者中止或暂停一个试验(见5.21),研究者应当立即通知研究机构,研究者/研究机构应立即通知IRB/IEC并向IRB/IEC提供中止和暂停的详细书面解释。
4.12.3 如果IRB/IEC终止或暂停它对一个试验的批准/赞成意见(见3.12和3.3.9),研究者应当通知研究机构,研究者/研究机构应当立即通报申办者并提供终止或暂停的详细书面解释。
 
4.13 研究者的最终报告
在试验完成后,研究者应当通知研究机构,研究者/研究机构应当向IRB/IEC提供试验结果的摘要,向管理当局提供所需要的所有报告。
 
5.申办者
5.1 质量保证和质量控制
5.1.1 申办者负责按照书面SOP执行和维持质量保证和质量控制系统,保证试验的实施和数据的产生、记录和报告询询试验方案、GCP、及适用的管理要求。
5.1.2 申办者有责任保护各有关方面的协议,保证申办者以检查和稽查为目的的直接访问(见1.21)各有关试验单位、源数据/文件、报告,以及保证国内和国外管理当局的视察。
5.1.3 在数据处理的每一阶段都应当有质量控制,以保证所有的数据是可靠的并已经得到正确处理。
5.1.4 申办者和研究者/研究机构以及参加临床试验的其他方应当订立书面协议;协议可以是方案的一部分,也可以上单独的协议。
 
5.2 合同研究机构(CRO)
5.2.1 申办者可以将与试验有关的责任和任务部分或全部转移给一个CRO,但是试验数据的质量和完整性的最终责任永远在申办者。CRO应当建立质量保证和质量控制。
5.2.2 转移给CRO的或CRO承担的任何与试验有关的责任和职能应当有书面说明。
5.2.3 没有明确转移给CRO或由CRO承担的任何与试验有关责任和职能仍然由申办者承担。
5.2.4 本指导原则中涉及申办者的一切也适用于一个CRO,就像CRO已经承担了一个申办者的与试验相关责任和职能。
 
5.3 医学专家
申办者应当指定有合适资格的医学人员,他们能迅速对试验有关疑问或问题提出建议。如果必要,可以人民外来顾问。
 
5.4试验设计
5.4.1 在试验过程的各个阶段,从设计试验方案、CRF、计划分析到分析和准备中期与最终临床试验报告,申办者应当任用有合适资格的人(如生物统计学专家,临床药理学家和医生)。
5.4.2 进一步的指导原则:《临床试验方案和方案修改》(见6.),《ICH临床试验报告的结构和内容指导原则》和关于试验设计、方案和执行的其他ICH指导原则。
 
5.5 试验管理、数据处理与记录保存
5.5.1 申办者应当任用有合适资格的人监督试验的全面实施、处理数据、核对数据,进行统计分析和准备试验报告。
5.5.2 申办者应考虑建立一个独立的数据监察委员会(IDMC),定期评价临床试验的进展、修改或停止试验。IDMC应当有书面的操作程序并保存它所有的会议记录。
5.5.3应用电子试验数据处理和/或遥控电子试验数据系统时,申办者应当:
(a)确保并证明电子数据处理系统符合申办者所设定的关于完整性、准确性、可靠性和一致期望的性能(如数据确认)的要求。
(b)有使用这些系统的SOP
(c)保证系统的设计允许数据修改按如下方式进行:数据的改变被记录下来而不删除已经录入的数据(即保留稽查痕迹、数据痕迹和编辑痕迹)
(d)有一个防止未经授权访问数据的安全系统
(e)有一份被授权修改数据的人员名单(见4.1.5和4.9.3)
(f)足够的数据备份
(g)如采用盲法,保护盲法安全(在数据输入和处理期间维持盲法)
5.5.4 如果再处理中数据作了转换,将原始数据和观测值与处理后得数据进行比较。
5.5.5 申办者应当使用明确得对象识别码(见1.58),以鉴别所报告得每一位对象得所有数据。
5.5.6 申办者或数据得其他拥有者应当保留申办者当得有关试验得所有基本文件(见8.实施临床试验得基本文件)。
5.5.7申办者应当保留所有申办者方的、与产品被批准和/或申办者打算申请批准的国家适用管理要求一致的基本文件。
5.5.8 如果申办者停止一个试验用药品的临床研究(如某个或所有适应证,给药途径,或剂型),申办者应当保留所有申办者方的基本文件至正式停止后至少2年,或与适用管理规定一致。
5.5.9 如果申办者停止一个试验用药品的临床研究,申办者应当通报所有研究者/研究机构和所有管理部门。
5.5.10 数据所有权的转移应当根据适用的管理要求向适当的部门报告。
5.5.11申办者方的基本文件应当被保留到最后批准在一个ICH地区上市应用后至少2年,和直至在一个ICH地区没有未决的或仍在考虑的上市应用,或试验用药品的临床研究正式停止后已过去至少2年。但如果适用管理要求需要或申办者要求,这些文件应当被保留更长时间。
5.5.12申办者应当以书面通知研究者/研究机构关于记录保存得要求,当试验相关记录不再需要时应书面通报研究者/研究机构。
 
5.6 研究者的选择
5.6.1申办者有责任选择研究者/研究机构。每一个研究者应当时通过培训合格的和有经验的,应当有足够的自愿(见4.1,4.2)正确的实施其被选择来进行的试验。如果在多中心试验中将组织一个协调委员会组织和/或选择协调研究者,他们的组织和/或选择是申办者的责任。
5.6.2在与研究者/研究机构签署一个进行试验的协议之前,申办者应当向研究者/研究机构提供试验方按和最新的研究者手册,并应当提供足够的时间让研究者/研究机构去审议方按和所提供的资料。
5.6.3申办者应当得到研究者/研究机构的同意:
(a)按照GCP、适用管理要求(见4.1.3)和经申办者同意、IRB/IEC批准/赞成(见4.5.1)和方按实施临床试验。
(b)遵循数据记录/报告程序
(c)允许检查、稽查和视察(见4.1.4)以及
(d)允许保留与试验有关的基本文件直至申办者通知研究者/研究机构这些文件不再需要为止(见4.9.4和5.5.12)
申办者和研究者/研究机构应当共同签署方按或另外一个文件以确认协议。
 
5.7 责任的分配
在开始一个试验前,申办者应当定义、规定和分配与试验相关的责任和职能。
 
5.8 给对象和研究者补偿
5.8.1 如果适用管理要求需要,申办者应当提供保险或应当补偿(法律和财政的范围)研究者/研究机构因试验而提出的要求,但因治疗不当和/或过失所致的除外。
5.8.2申办者的保险单和程序应当说明符合适用管理要求的与试验相关的伤害事件中试验对象治疗的费用。
5.8.3 试验对象收到补偿时,补偿的方法和方式应当符合适用管理要求。
 
 
5.9财务
试验的财务方面内容应当列入申办者和研究者/研究机构之间的协议中。
 
5.10 向管理当局通报/提交
在开始临床试验前,申办者(或适用管理要求需要,申办者和研究者)应当向相应的管理部门提交所需要的申请表,供审评、接受和/或许可(如适用管理要求需要)开始试验。通报/提交的资料应当注明日期,并包括足够鉴定试验方按的资料。
 
5.11 IRB/IEC评审的确认
5.11.1   申办者应当从研究者/研究机构方得到:
(a)研究者/研究机构方的IRB/IEC成员的姓名和地址
(b)IRB/IEC关于其组织和操作符合GCP和适用法律法规的陈述
(c)书面的IRB/IEC批准/赞成;如果申办者要求,最新的试验方按、书面知情同意书和其他将提供给对象书面资料的复印件,对象接纳程序,和给予对象的支付和补偿的有关文件,以及IRB/IEC所要的其他文件。
5.11.2 如果IRB/IEC以修改试验的某个方面作为批准/赞成的条件,如修改方按,书面的知情同意书和其他提供给对象和/或其他程序的书面资料,申办者应当从研究者/研究机构得到已作出修改的副本和IRB/IEC给出批准/赞成日期。
5.11.3 申办者应当从研究者/研究机构得到所有IRB/IEC给出赞成意见的再批准/再评价,以及撤销或暂停批准/赞成的文件和日期。
 
5.12 有关试验用药品的资料
5.12.1 计划试验时,申办者应当保证有足够的非临床研究和/或临床研究的安全性和有效性数据支持所研究的试验人群暴露的给药途径、剂量和持续时间。
5.12.2 当有重要的新资料时,申办者应当更新研究者手册(见7.研究者手册)。
 
5.13 试验用药品的生产、包装、标签和编码
5.13.1 申办者应当保证试验用药品(包括活性对照品和安慰剂)具有适合产品开发阶段的特性,按照适用的GMP生产、编码和标签的方式应适合于保护盲法。此外,标签应当符合适用管理要求。
5.13.2 申办者应当确定试验用药品的允许储存温度、储存条件(如避光)、储存时间、重组溶液和程序,以及必要时药物的输注装置。申办者应当将这些决定通知所有有关各方(如监察员、研究者、药师、储存管理人员)。
5.13.3 试验用药品的包装应当能防止在运输和储存期间受污染和不可接受的变质。
5.13.4在盲法试验中,试验用药品的编码系统应当包括一种在医学紧急情况下允许迅速鉴别药品、但不允许不可监测的破盲机制。
5.13.5 在临床研究其间如果试验用药品或对照产品的配方有明显改变,应当在新制剂用于临床试验之前获得制剂产品的附加研究结果(如稳定性、溶出速率,生物利用度),以评价这些改变是否明显改变产品药代动力学特征。
 
5.14 研究产品供应和管理
5.14.1 申办者负责向研究者/研究机构提供试验用药品
5.14.2 申办者在得到全部多需要文件(如IRB/IEC和管理当局的批准/赞成意见)之前不得向研究者/研究机构提供试验药物。
5.14.3 申办者应当确保书面操作程序包含研究者/研究机构应当遵循的关于试验用药品的处理和储存的说明及其文件。程序应当说明适当和安全的接受、处理、储存、分发、从对象处取回未使用的药物以及将未使用的试验用药品返回给申办者(或经申办者授权并遵照适用管理要求销毁)。
5.14.4申办者应当:
(a)确保按时将试验用药品送达研究者
(b)保存证明运输、接收、分发、收回和销毁试验用药品的记录(见8.实施临床试验的基本文件)
(c)有一个取回试验用药品和记录取回的规定(如有缺陷产品的收回,在试验结束后归还,过期药品归还)。
(d)有一个处置未使用研究药品和记录这种处置的规定。
5.14.5   申办者应当:
(a)采取步骤以保证试验药品在整个使用期内的稳定性。
(b)维持足够数量的用于试验中的试验用药品,以在万一有必要时再确认其规格,并保存批样分析和特性记录。只要产品稳定性许可,样品应当被保留到试验数据分析完成或适用管理要求的需要时间,取两者中较长的期限。
5.15 记录访问
5.15.1 申办者应当确保在方按中或其他书面协议中已经说明,研究者/研究机构应允许试验有关的监察员、稽查员、IRB/IEC审评和管理部门视察直接访问原始数据。
5.15.2 申办者应当核实,每一例对象已经书面同意,在进行鱼试验相关的检查、稽查、IRB/IEC审评和管理部门视察时直接访问他/她的原始医学记录
 
5.16 安全性资料
5.16.1 申办者负责试验用药品正在进行的安全性评价。
5.16.2申办者应当立即通知所有有关研究者/研究机构和管理当局关于可能对对象的安全性有不良影响、影响试验实施的或改变IRB/IEC对继续试验的批准/赞成的发现。
 
5.17 药物不良反应报告
5.17.1 申办者应当迅速向所有有关研究者/研究机构、有关的IRB/IEC、管理当局报告所有严重的和非预期的药品不良反应。
5.17.2 这种快速报告应当符合适用管理要求和《ICH临床安全性数据管理指导原则:快速报告的定义和标准》
5.17.3 申办者应当根据使用管理要求向管理当局提交全部安全性更新和定期报告。
 
5.18 监察
5.18.1目的
试验监察的目的是核实:
(a)对象的权利和健康得到保护
(b)所报告的试验数据是准确和完整的,并能从原始文件得到证实。
(c)试验的实施符合最近批准的方按/方按修改,符合GCP和适用管理要求
5.18.2监察员的选择和资格
(a)监察员应当由申办者指定
(b)监察员应当受过核实的培训,应当有足够的监察试验的科学/活临床知识。监察员的资格应当有文件证明。
(c)监察员应当透彻了解试验用药品、研究方按、知情同意书和其他提供给对象的书面资料、申办者的各种SOP、GCP和适用管理要求。
5.18.3监察的范围和性质
申办者应当保证试验得到适当的监察。申办者应当决定监察的合适范围和性质。监察的范围和性质应当根据目标、目的、设计、复杂性、盲法、样本大小和试验终点确定。通常需要在试验前、试验期间和试验后进行现场监察,但是在特别的场合,申办者可以决定与某些步骤,如研究人员培训和研究人员会议,合在一起的终点监察。多方面的书面指导原则可以保证恰当地按照GCP实施试验。统计学上控制地抽样可能是一个可以接受地选择需要核对的数据的方法
5.18.4 监察员的责任
按照申办者的要求,在对试验和试验单位恰当和必要时,监察员应当通过下列活动保证试验被正确的实施和记录:
(a)在申办者和研究者之间的交流起干线作用。
(b)验证研究者有足够的资格和自愿(见4.1,4.2,5.6),并且在整个试验期间仍然是足够的;设备,包括实验室、仪器和职员足以安全和正确地实施试验,并在整个试验期间也是足够地。
(c)对于试验用药品,核实:
(ⅰ)储存时间和条件是可以接受的,在整个试验中供应充足
(ⅱ)试验用药品只按试验方案规定地剂量提供给合格地对象
(ⅲ)向对象提供正确使用、处理、储存和归还试验用药品地说明
(ⅳ)在试验单位,试验用药品接收、使用和归还试验用药品地说明
(ⅴ)试验单位对未使用地试验用药品地处置符合管理要求和申办者地要求。
(d)核实研究者遵循已批准地方案和所有已批准的修改
(e)核实在每个研究对象参加试验前已经得到书面的知情同意
(f)确保研究者收到最近的研究者手册、所有的文件和按照适用管理要求正确实施试验必需的所有试验用品。
(g)保证研究者及其试验职员对试验有充分的知识
(h)核实研究者及其试验职员正在按照方案和申办者与研究者/研究机构之间的其他书面协议执行特定的试验职责,没有将这些职责委派给未经授权的人。
(i)核实研究者只招募合格的对象
(j)报告对象招募速度
(k)核实源文件和其他试验记录是准确的、完整的、保持更新并都保存着
(l)确保研究者提供所有需要的报告、通知、申请和递交的文件,并且这些文件都是准确、完整、按时、清晰易读、注明日期和试验鉴别
(m)彼此对照检查CRF记录、源文件和其他试验有感记录的准确系国内和完整性。监察员尤其应当检查:
(ⅰ)试验方案需要的数据在CRF上有准确记录,并与源文件一致
(ⅱ)每一位试验对象的剂量和治疗的任何修改均与有良好记录
(ⅲ)不良事件,伴随用药和试验过程中发生的疾病根据方案在CRF上作了报告
(ⅳ)试验未来随访,未进行的检验,未完成的检查应同样在CRF上有清楚报告
(ⅴ)已接纳对象的撤出或中途退出试验应在CRF上报告并给出说明
(n)通知研究者关于CRF的填写错误、遗漏或字迹不清楚。监察员应当确保所做的更正、附加或删除是合宜的、注明日期的、有说明的(如有必要),并由研究者或研究者授权修正的CRF的试验工作人员签上姓名首字母。授权应当有证明。
(o)确定是否所有不良事件(AE)在GCP、试验方案、IRB/IEC、申办者和适用管理要求所规定的期限内恰当地作了报告。
(p)确定研究者是否保持有基本文件(见8.实施临床试验地基本文件)
(q)通知研究者关于与试验方案、SOP、GCP和适用管理要求地偏离,并采取适当措施防止再发生上述偏离。
5.18.5 监察程序
监察者应当遵循申办者制订地各种SOP以及申办者为监察一个特定试验制订地特定程序。
5.18.6   监察报告
(a)监察者在每一次进行试验单位现场访问或与试验有关地交流后,应当向申办者递交书面报告。
(b)报告应当包括日期、地点、监察者姓名、研究者或接触地其他人员的姓名
(c)报告应当包括监察者检查内容的摘要,监察员关于有意义发现/事实的陈述,偏离和不足,结论,已采取的或将采取的措施,和/或为保护依从性建议的措施。
(d)申办者对监察报告的审评和随访应当有申办者制订的代表作成文件
 
5.19 稽查
作为实现质量保证的一部分,申办者进行稽查时应当考虑
5.19.1 目的
独立的、与常规监察或质量控制分开的申办者的稽查,其目的应当是评价试验的实施和对试验方案、SOP、GCP和适用管理要求的依从性
5.19.2稽查员的选择和资格
(a)申办者应当指定一个独立于临床试验/体系的人实施稽查
(b)申办者应当保证稽查员是通过培训合格并有经验正确的实施稽查。稽查员的资格应当有证明。
5.19.3   稽查程序
(a)申办者应当保证临床试验/体系是按照申办者的关于稽查什么、如何稽查、稽查频度的书面程序、稽查报告表及其内容进行
(b)申办者方对一个试验稽查的稽查计划和程序应当根据试验对于向管理当局提交的重要性、试验中的对象数目、试验的类型和复杂成都、试验对象的风险水平以及所识别的其他问题而定。
(c)稽查的观察资料和发现应当做成文件
(d)未保持稽查职能的独立性和价值,管理当局不应当例行公事地要求稽查报告。当有严重不依从GCP地证据存在时,或在法律诉讼期间,管理当局可能寻求逐例试验稽查报告。
(e)在适用法律或法规要求,申办者应当提供稽查许可证。
 
5.20 不依从
5.20.1 一个研究者/研究机构或申办者的职员对于试验方案、SOP、GCP和/或适用管理要求不依从时,申办者应当立即采取措施促成依从性。
5.20.2 如果监察和/研究机构的某一部门严重的和/或持续的不依从,申办者应当停止研究者/研究机构参加临床试验。一个研究者/研究机构因为不依从被终止参加试验时,申办者应当立即通报管理当局。
 
5.21 一个试验的过早终止或暂停
如果一个试验过早终止或停止,申办者应当立即通知各研究者/研究机构以及管理当局关于终止或暂停事宜及其理由。根据适用管理要求的说明,申办者或研究者/研究机构还应当立即通知IRB/IEC并提供终止或暂停的理由。
 
5.22 临床试验/研究报告
不管临床试验是完成了还是过早停止,申办者应当确保按照适用管理规定要求准备临床试验报告,并提供给管理部门。
申办者也应当保证,上市申请的临床试验报告符合《ICH临床研究报告的结构和内容指导原则》的标准。(注:《ICH临床研究报告的结构和内容指导原则》说明了在某些情况下 间断的研究报告是可接受的。)
 
5.23 多中心试验
对于多中心试验,申办者应当保证:
5.23.1实施试验的所有研究者严格遵循申办者同意的、必要时经管理当局同意并得到IRB/IEC批准/赞成意见的试验方案。
5.23.2 在多中心研究中,CRF被设计用来记录所需要的数据。对于那些收集附加数据的研究者,应向他们提供设计来用于收集股价数据的补充CRF
5.23.3向所有研究者提供关于理解试验方案、遵循评价临床和实验室发现的同意标准以及完成CRF的指导性原则
5.23.4 促进研究者之间的交流
 
6. 临床试验方案和方案的修改
试验方案的内容通常应当包括以下主题。但是试验单位的特别信息可以分开列在方案的单独一(几)页上,或写在一个单独的协议中,下列的某些资料可写在方案的其他参考文件,如研究者手册中。
 
6.1 概要资料
6.1.1 试验方案的题目,方案鉴别号和日期。任何修改应当有修改编号和日期
6.1.2 申办者和监察员(如与申办者非同一个人)的姓名和地点
6.1.3 被授权为研究者签署试验方案和方案修改人员的姓名和头衔
6.1.4 申办者方的医学专家(或牙医,如合适)的姓名、头衔、地址和电话号码
6.1.5 负责实施试验的研究者和研究者的姓名和头衔,以及试验单位的电话号码
6.1.6 负责试验单位所有医学(或牙医)决定的有资格医生(或牙医)(如与研究者不是同一人)的姓名、头衔、地址及电话号码
6.1.7 临床试验室和其他医学和/或技术部门、和/或参与试验的机构的名称和地址
 
6.2 背景资料
6.2.1 试验用药品的名称和描述
6.2.2 非临床研究中有潜在临床意义的发现,临床试验中与试验有关的发现摘要
6.2.3 对人类(如有)已知的和潜在的风险和利益的摘要
6.2.4 所用的给药途径、剂量、剂量方案和治疗时间的描述和理由
6.2.5 将会按照方案、GCP和适用管理要求进行试验的陈述
6.2.6 试验人群描述
6.2.7 与试验相关,并提供试验背景资料的文献和数据
 
6.3 试验的目标和目的
详细描述试验的目标和目的
 
6.4试验设计
试验的科学完整性和试验数据的可信性主要取决于试验设计。试验设计的描述应当包括:
6.4.1 试验期间要测量的主要终点和次要终点(如有)的详细说明
6.4.2 要实施试验的类型/设计的描述(如双盲,安慰剂对照,平行设计),和试验设计、成都及步骤的系统示意图
6.4.3       减少/避免偏倚所采取的措施的描述,包括:
(a)随机化
(b)盲法
6.4.4 试验治疗和试验用药品的剂量、剂量方案的描述,包括试验用药品的剂型、包装、标签的描述
6.4.5 对象参加试验的预期持续时间;全部试验周期,包括随访的次序和期限的说明
6.4.6 关于停止个别对象、部分试验和全部试验的“停止规则”或“终止标准”的描述
6.4.7 试验用药品,也包括安慰剂和对照药物的可计数性
6.4.8 保持试验治疗随机化编码和破盲程序
6.4.9 直接记录在CRF上的所有数据(即不是先前写下的数据或电子记录数据)和被考虑作为源数据的鉴别
 
6.5 对象的选择和退出
6.5.1 对象的接纳标准
6.5.2 对象的排除标准
6.5.3       对象的停止标准(即停止试验用药品治疗/试验治疗)和程序说明:
(a)什么时候和怎样停止对象的试验/试验用药品治疗
(b)从退出对象收集的数据的类型和时间选择
(c)是否和如何替换对象
(d)退出试验用药品治疗/试验治疗的对象的随访
 
6.6 对象的治疗
6.6.1 所给予的治疗,包括所有试验用药品的名称、剂量、给药方案、给药的途径/方法和疗程,包括对象在每个试验用药品治疗/试验治疗组/试验待命中断的随访期。
6.6.2 在试验前和/或试验期间允许的(包括营救性治疗)和不允许药物治疗/治疗
6.6.3 监察对象依从性的程序
 
6.7 有效性评价
6.7.1 有效信参数的说明
6.7.2 评价,记录和分析有效性参数的方法和时间选择
 
6.8 安全性评价
6.8.1 安全性参数的说明
6.8.2 评价、记录和分析安全性参数的方法和时间选择
6.8.3 记录和报告不良事件与并发疾病的程序,和发出报告的程序
6.8.4 经历不良事件后对象的随访形式和期限
 
6.9 统计
6.9.1 描述将采用的统计方法,包括计划进行中期分析的时间选择
6.9.2 计划招募的对象数目。如为多中心试验,应当说明每个试验点计划招募的对象熟。样本大小的选择理由,包括试验的把握度和临床方面的理由
6.9.3 所采用的显著性水平
6.9.4 终止试验的标准
6.9.5 处理缺失数据、未用数据和不合理数据的程序
6.9.6 报告偏离原定统计计划的程序(原定统计计划的任何变更应当在方案中和/或在最终报告中说明并给出理由)
6.9.7 列入分析对象的选择(如所有随机化的对象,所有给药的对象,所有合格的对象,可评价的对象)
 
6.10 直接访问源数据/文件
申办者应当确保在方案中或在其他书面协议中说明了研究者/研究机构应当允许试验有关的监察、稽查、IRB/IEC审评和管理部门视察,直接访问源数据/文件
 
6.11 质量控制和质量保证
 
6.12 伦理学
描述与试验有关的伦理学考虑
 
6.13 数据处理与记录保存
 
6.14 财务和保险
如果没有关于财务和保险的单独协议
 
6.15 结果发表方法
如果没有结果发表的单独协议
 
6.16 补充
(注:由于试验方案与临床试验/研究报告密切相关,在《ICH临床研究报告的结构和内容指导原则》中可找到更多的相关资料。)
 
7.研究者手册
7.1 前言
研究者手册(IB)是与试验用药品的人类对象研究有关的临床资料和非临床资料的汇编。手册的目的是向研究者和参与试验的其他人员提供资料,帮助他们了解方案的许多关键特征的基本原理并遵循这些关键特征,如剂量,剂量频度/间隔,给药方法和安全性监察程序。IB也提供支持在临床试验期间对研究对象的临床管理的见解。资料应当是简明、简单、可观、均衡、非宣传性的形式,使医生或潜在的研究者了解手册的内容,对于所提议的试验的合理性作出他们自己的无偏倚的风险-利益评价。因此,合格的医学人士一般会参加IB的编写,但是IB的内同应当得到产生所描述地数据的学科的认可。
本指导原则描述的是IB应当包括最低限度资料并为其编排提出建议。可以预料,可用到的资料类型和范围将随试验用药品的开发阶段变化。如果试验用药品上市,并且它的药理学为广大医学从业者了解,可能就不需要一本详尽的IB。若管理当局许可,一本基本的产品资料手册,包装说明,或标签可能是合适的选择,只要他们包括对研究者是重要的关于试验用药品最近的、综合性的、详细的各方面的资料。如果正在研究一个已上市产品的新用途(即一个新的适应证),应当特别准备一份关于该新用途的IB.IB至少应当一年审评一次,必要时按照申办者的书面程序修改。根据新药的发展阶段和得到的有关新资料,或许需要更频繁地进行修改。但是,依照GCP要求,有关地新资料可能很重要,在将其列入修改地IB之前,需要通知研究者、机构审评委员会(IRB)/独立的伦理委员会(IEC),和/或管理当局。
通常,申办者负责保证向研究者提供最新的IB,研究者有责任将最新的IB提供给负责的IRB/IEC。在由研究者申办试验时,申办者-研究者应当决定手册是否可从制造商处得到。如果由申办者-研究者提供试验用药品,那么他或她应当向言菊人员提供必要的资料。当准备一个正式的IB是不符合实际时,作为一种替代,申办者-研究者应当在试验方案中提供扩展的背景资料,包含本指导原则所述的最低限度的最近资料。
 
7.2一般考虑
IB应当包含:
 
7.3扉页
扉页应当提供申办者姓名,每一个试验用药品的鉴别(即研究编号,化学命或已批准的通用名,法律允许的申办者所希望的商品名),以及发布日期。还建议列出版本号码以及该号码的参考索引,以及该版本替换和被批准的日期。示例见附录1
7.3.1 保密性陈述
申办者可能希望包括一段陈述,指示研究者/收件人将IB做机密文件处理,仅供研究人员小组和IRB/IEC使用。
 
7.4 研究员手册的内容
IB应当包括下列章节,每一节附参考文献:
7.4.1 目录
附录2为目录的例子
7.4.2 摘要
应当有一个简短的摘要(最好不超过2页),重点是与试验用药品发展阶段有关的、有意义的物理、化学、药学、药理学、毒理学、药代动力学、代谢学和临床资料。
7.4.3 前言
应当有一个简短的前言,说明试验用药品的化学名(批准时的通用名和商品名),所有活性成分,试验用药品的药理学分类和它在这一类中的预期位置(如优势),试验用药品正在进行研究的基本原理,预期的预防、治疗或诊断适应证。最后,前言应当提供评价试验用药品的一般方法。
7.4.4 物理学、化学和药学特性和处方
应当有关于试验用药品的描述(包括化学式和/或结构式),以及关于物理学、化学和药学特性的简短摘要。
在试验过程中允许采取合宜的安全措施,如果临床上相关,应当提供所用配方包括赋形剂的描述,并应提出配方理由。也应当给出制剂储存和处理的说明。
应当提及与其他已知化合物的结构相似性。
7.4.5 非临床研究
前言
应当以摘要形式提供所有非临床的药理学、毒理学、药代动力学和试验用药品的代谢研究的有关结果。摘要应当说明所采用的方法学、结果,以及这些发现对所研究的治疗的关系,和对人类可能的不利与以外的影响。
如果知道/可以得到,可以适当提供下列资料:
l 试验的(动物)种属
l 每组动物的数目和性别
l 剂量单位(如:毫克/公斤(mg/kg))
l 剂量间隔
l 给药途径
l 给药持续时间
l 系统分布的资料
l 暴露后随访的期限
l 结果,包括下列方面
-            给药或毒性作用的性质和频度
-            药理或毒性作用的严重性或强度
-            开始作用时间
-            作用的可逆性
-            作用持续时间
-            剂量反应
只要可能应采用表格/列表增强陈述的清晰度
随后的章节应当讨论研究的最重要发现,包括所观察到的作用的剂量反应关系,与人类的相关性,以及在人类中研究的各个方面。如果合适,在同一动物种属的有效剂量和非毒性剂量的发现应当做比较(即应当讨论治疗指数)。应当说明这一资料与所提议的人用剂量的相关性。只要可能,应根据血/组织水平而非mg/kg进行比较
(a)非临床药理学
应当包括试验用药品的药理学方面的摘要,如有可能还包括药品在动物的重要代谢研究摘要。这样一个摘要应当合并评价潜在治疗活性(如有效性模型,受体结合和特异性)以及评价安全性的研究(如不同于评价治疗作用的评价药理学作用的专门研究)
(b)动物的药物动力学和药物代谢
应当给出试验用药品在所研究种属动物中的药物动力学、生物转化以及处置的摘要。对发现物的讨论应当说明试验用药品的说明及其部位、系统的生物利用度及其代谢,以及它们与人类的药理学和毒理学发现物的关系
(c)毒理学
在不同动物种属中进行的相关研究所发现的毒理学作用摘要应按以下栏目描述
-            单剂量给药
-            重复给药
-            致癌性
-            特殊毒理研究(如刺激性和致敏性)
-            生殖毒性
-            遗传毒性(致突变性)
7.4.6 在人类的作用
前言
应当提供试验用药品在人类的已知作用的充分讨论,包括关于药物动力学、代谢、药效学、剂量反应、安全性、有效性和其他药理学领域。只要可能,应当提供每一个已经完成的临床试验的摘要。还应当提供试验用药品在临床试验以外的用途的结果,如上市期间的经验。
(a)试验用药品在人体的药物动力学和代谢 应当写出试验用药品的药物动力学资料摘要,包括以下方面:
-            药物动力学(包括代谢和吸收,血浆蛋白结合,分布和消除)
-            试验用药品的一个参考剂型的生物利用度(绝对和/或相对生物利用度)
-            人群亚组(如性别、年龄和脏器功能受损)
-            相互作用(如药物-药物相互作用和药物与食物的相互作用)
-            其他药物动力学数据(如在临床试验期间完成的群体研究结果)
(b)安全性和有效性
应当提供从先前人体试验(健康志愿者和/或病人)中得到的关于试验用药品(包括代谢物)的安全性、药效学、有效性和剂量反应资料的摘要。应讨论这些资料的含义。如果已经完成许多临床试验,从多个研究以及亚组适应证的安全性和有效性得出的摘要可能清楚地展示有关数据。将所有临床试验地药品不良反应制成表格的摘要(包括所有被研究的适应证)将是有用的。对于在适应证或亚组之间药品不良反应类型/发生率的重要差异应当进行讨论
(c)销售经验
IB应当识别试验用药品已经上市或已经批准的国家。从上市使用中得到的任何重要资料应当摘要陈述(如处方、剂量、给药途径和药品不良反应)。IB也应当识别试验用药品还没有得到批准/注册上市或退出上市/注册的所有国家。
7.4.7 数据和研究人员指南摘要
本届应当提供一个非临床和临床数据的全面讨论,只要可能,对试验用药品不同方面的各种来源的资料作一摘要。这样,研究者可以得到现有数据的最见闻博广的解释,和这些资料对于将来临床试验意义的评价。
只要合适,应对有关产品已发表的报告进行讨论。这有助于研究者预料药品不良反应或临床试验中的其他问题。
这一节的总目滴是让研究者对可能的风险和不良反应,以及临床试验中可能需要的特殊监察、观察资料和防范措施有一个清楚的了解。这种了解应当以可得到的关于研究该药物的物理、化学、药学、药理、毒理和临床资料为基础。根据先前人类的经验和试验用药品的药理学,指南也应向临床研究者提供可能的过量服药和药品不良反应的识别和处理。
 
7.5 附录1
扉页(样本)
 
申办者名称
药品:
研究代号:
名称:化学命,通用名(已批准)
商品名(合法而且符合申办者意愿)
 
研究者手册
版本编号:
发布日期:
 
被替代的版本编号:
日期:
 
7.6 附录2
研究者手册目录(举例)
保密性陈述(供选择)
签字页(供选择)
1 目录
2 概要
3 引言
4 物理、化学及药学特性和处方
5 非临床研究
5.1 非临床药理学
5.2 动物体内药物动力学和药物代谢
5.3 毒理学
6 人体内作用
6.1 人体内的药物动力学和药物代谢
6.2 安全性和有效性
6.3 上市经验
7 数据概要和研究者准则
注意:参考资料 1. 公开发表物
2. 报告
参考资料应在每一章节末列出
附录(若有)
 
8. 临床试验必需文件
8.1引言
必需文件式指那些可单独和合起来用于评价试验的实施及所产生的数据质量的文件。这些文件反映研究者、申办者和监察员对GCP和所有的现行管理要求的依从性。
必需文件也用于其他一些目的。在研究者/研究机构和申办者驻地现场及时的将必需文件归档,能够极大地帮助研究者、申办者和监察员对试验进行成功的管理。作为确认试验实施的有效性和所收集数据完整性的过程的一部分,这些文件也经常受申办者委派的独立稽查员稽查并接收管理当局视察。
下面简要列出最低限度的必需文件。根据其在试验的不同阶段的征程产生,可将不同文件分为三个部分:(1)在临床试验开始之前;(2)临床试验进行期间;(3)完成或终止临床试验后。每一文件都要说明其目的,以及是否将该文件列入研究者/研究机构或申办者或双方的档案中。如果每个部分都易于辨认的,那么将一些文件合并也是可以接受的。
试验开始时,在研究者/研究机构驻地及申办者办公室都该建立试验总档案。只有当监察员审核了研究者/研究机构及申办者双方的档案并确定所有必要的文件都在适宜的档案卷宗内,试验才能最后结束。
在该指导原则内提及的任何或所有文件可能受到,也应当提供让申办者方稽查员的稽查和主管部门的视察。
 
8.2 临床试验开始之前
在指定研究计划阶段,应产生下列文件并在试验正式开始之前归档。
 文件标题 目的 归档在
   研究者/研究机构 申办者
8.2.1 研究者手册 证明有关试验药品的相关信息和最新科研动态已经提供给研究者 X X
8.2.2 已签字的试验方案和修改(若有)及病例报告表(CRF)样本 证明研究者和申办者同意试验方案/修改和CRF X X
8.2.3 受试对象应知信息  X X
 -知情同意书(包括所有实用的译文-任何其他书面信息 
 
 
 
-招募对象的广告(若使用) 证明知情同意证明受试对象获得恰当的书面信息(内容及措辞)以支持他们提供完全知情同意的能力
证明招募手段是合宜的且无胁迫嫌疑 X
 
 
 
X X
8.2.4 试验的财务状况 记录研究者/研究机构和申办者之间关于试验的财务协议 X X
8.2.5 保险陈述(必要时) 证明受试对象遭受与试验相关伤害时将获得补偿 X X
8.2.6 参与试验各方之间签署的协议,例如:-研究者/研究机构和申办者-研究者/研究机构和CRO
-申办者和CRO
-研究者/研究机构和主管部
门(必要时) 证明一致同意 X
X
X X
X(需要时)
X
X
8.2.7  IRB/IEC对以下各项内容的书面批准/赞成意见并注明日期-试验方案和任何修改-CRF(如适用)
-知情同意书
-任何其他提供给受试对象的书面资料
-招募志愿者广告(若使用)
-对受试对象的补偿(若有)
-任何其他获得批准/赞成意见的文件 证明试验已经过IRB/IEC评估并获得批准/赞成意见。确认文件的版本编号和形成日期 X X
8.2.8 IRB/IEC的组成 证明IRB/IEC的组成符合GCP要求 X X(必要时)
8.2.9 主管部门对试验方案的认可/批准/通报(必要时) 证明在试验开始之前已经按照现行的管理要求获得了主管部门适宜的任何/批准/通报 X(必要时) X(必要时)
8.2.10 研究者和次级研究人员履历和/或证明其资格的其他相关文件 证明有资格并适合执行试验和/或为受试对象提供医疗指导 X X
8.2.11 试验方案中涉及的医学/实验室/技术程序和/或测试的正常值和/或正常范围 记录各项测试的正常值和/或正常范围 X X
8.2.12 医疗/实验室/技术程序/测试-资格证明,或-认可证明,或
-已建立的质量控制和/或外部质量评价,或
-其他验证体系(必要时) 证明研究设备完成所需要测试项目的能力,支持研究结果的可靠性 X(必要时) X
8.2.13 研究药物容器标签样本 证明对现行标签规定的依从性及提供给受试对象的用法说明书的适宜性  X
8.2.14 研究药物及试验相关材料(如果在试验方案或研究者手册没有提及)传递指南 记录确保研究药物和试验相关材料被恰当贮存、包装、分发和处置的指导原则 X X
8.2.15 研究药物及试验相关材料的物理运送 证明研究药物及试验相关材料的运送日期、批号和运送方法。允许追踪药物批号、运送条件状况和责任 X X
8.2.16 所运送的研究药物的分析证明 证明用于试验的研究药物的成分、纯度和浓度  X
8.2.17 盲法试验的解码程序 说明在紧急状况下,如何揭示加盲研究药物的身份而不使其余受试对象的治疗破盲 X X(若可行应有第三方)
8.2.18 总随机表 证明受试人群的随机化方法  X(若可行应有第三方)
8.2.19 试验前监察报告 证明试验场所适于开展试验(可与8.2.20合并)  X
8.2.20 试验开始的监察报告 证明研究者及研究小组成员已评估了试验程序(可与8.2.19合并) X X
8.3 临床试验进行期间除了上述文件应归档外,在试验进行过程中,下述文件也应添加到档案中以证明所有获得的新的相关资料都记录在案。
8.3.1 更新的研究者手册 证明所获得的相关信息被及时反馈给研究者 X X
8.3.2 对下列内容任何的更改:-试验方案/修改和CRF-知情同意书
-任何提供给受试对象的书面资料
-招募受试对象的广告(若使用) 记录对这些试验相关文件的修改,这些改变在试验期间生效 X X
8.3.3 -IRB/IEC对以下各项内容的书面批准/赞成意见(注明日期)-试验方案修改-下列文件修订本
-知情同意书
-任何其他提供给受试对象的书面资料
-招募志愿者广告(若使用)
-任何其他获得批准/赞成意见的文件
-对试验的持续审评(必要时) 证明这些修改和修订都经过IRB/IEC的审评并获得批准/赞成意见。确认记录的版本的编号和日期 X X
8.3.4 必要时管理当局对下列内容的认可/批准/通报-试验方案修改及其他文件   证明符合现行管理要求 X(必要时) X
8.3.5 新的研究者和/或次级研究人员的履历 (见8.2.10) X X
8.3.6 试验方案中涉及的医学/实验室/技术程序和/或测试的正常值范围的更新 记录在试验期间修订的正常值和正常范围(见8.2.11) X X
8.3.7 医学/实验室/技术程序和/测试的更新-资格证明,或-认可证明,或
-已建立的质量控制和/或外部质量评价,或
-其他验证体系(必要时) 证明在整个试验期间各项测试都是符合要求的(见8.2.12) X(必要时) X
8.3.8 研究药物及试验相关材料运送记录 (见8.2.15) X X
8.3.9 新批次研究药物的分析证明 (见8.2.16)  X
8.3.10 监察随访报告 记录监察员的现场访问及结论  X
8.3.11 现场访问之外的相关通讯联络记录-信件-会议记录
-电话记录 记录关于试验管理、违背试验方案、试验实施、不良事件(AE)报告等方面的协议或重要讨论 X X
8.3.12 署名的知情同意书 证明知情同意遵照GCP和试验方案在每一受试对象参加研究之前获得;并证明受试对象对直接访问数据的许可(见8.2.3) X 
8.3.13 原始记录源文件 记录受试对象的状态,证明所收集试验数据的完整性。包括与试验和医学治疗有关的原始文件以及受试对象的病史记录 X 
8.3.14 已签字、注明日期且完整的病例记录表(CRF) 证明研究者或授权的研究小组成员确认所记录的观测值 X(复印件) X(复印件)
8.3.15 CRF更正记录 证明获得初始数据记录后对CRF的所有更改/补充或更正 X(复印件) X(复印件)
8.3.16 一线研究者向申办者通报有关严重不良事件及相关报告 一线研究者根据4.11向申办者通报严重不良事件及相关报告 X X
8.3.17 申办者和/或研究者向主管部门和IRB/IEC提交的非预期的药物严重不良反应及其他安全性资料 申办者和/或研究者向主管部门和IRB/IEC通报非预期的药物严重不良反应(根据5.17和4.11.1)及其他安全性资料(根据5.16.2和4.11.2) X(必要时) X
8.3.18 申办者向研究者通报的安全性资料 申办者根据5.16.2向研究者通报安全性资料 X X
8.3.19 向IRB/IEC和主管部门提交的中期报告或年度报告 分别根据4.1和5.17.3向IRB/IEC和管理当局提交中期报告或年度报告 X X(必要时)
8.3.20 受试对象筛选记录 记录进入试验前筛选程序的受试对象的身份证明 X X(必要时)
8.3.21 受试对象身份证明编码表 研究人员/研究机构保存得一份被招募进入试验并获得试验号码得所有受试对象姓名得保密名单 X 
8.3.22 受试对象招募日志 记录按试验流水号根据时间顺序招募试验对象 X 
8.3.23 研究药物在试验点的可计数性 证明试验药品是按咋后试验方案使用的 X X
8.3.24 签字页 记录所有授权在CRF上进行数据登录和/或更正的人员的签名及姓名首字母 X X
8.3.25 保存体液/组织样本的记录(若有) 记录如果需重复分析时保留样本的存放位置和标识 X X
8.4 临床试验完成或终止之后在试验完成或中止之后,8.2及8.3节所列文件及下列文件皆应归档。
8.4.1 试验药品在试验点的可计数性 证明试验药品是根据试验方案使用。证明在研究现场收到的、发放给受试对象的、受试对象送还的、返还给申办者的试验药品的最后计数 X X
8.4.2 试验药品销毁记录 证明未被使用的试验药品由申办者或在研究现场销毁的情况 X(若在研究现场销毁的话) X
8.4.3 完整的受试对象身份鉴别编码表 在需要随访时允许鉴别被招募进入试验的所有受试对象的身份。编码表必需保密并存放至约定时间 X 
8.4.4 稽查证明(如需要) 证明已进行过稽查  X
8.4.5 试验结束监察报告 证明所有试验结束所必需的活动都已完成,必需文件的副本保存在合适的档案中  X
8.4.6 治疗分配表及解码记录 返还给申办者以证明任何发生过的解码操作  X
8.4.7 必要时研究者向IRB/IEC及合适时向主管部门提交的总结报告 证明试验的完成 X X
8.4.8 临床研究报告 提供试验的结果和解释 X(如合适) X
 

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