BPC-ICH-GCP E6_Guideline Step 5最新版
The European Agency for the Evaluation of Medicinal Products
Human Medicines Evaluation Unit
ICH - Technical Coordination - R. Bass 7 Westferry Circus, Canary Wharf, London E14 4HB, UK ICH Topic E 6
Guideline for Good Clinical Practice
Step 5, Consolidated Guideline 1.5.96NOTE FOR GUIDANCE ON GOOD CLINICAL PRACTICE
(CPMP/ICH/135/95) *TRANSMISSION TO CPMP July 1996FINAL APPROVAL BY CPMP
17 July 1996DATE FOR COMING INTO OPERATION
(STUDIES COMMENCING AFTER)17 January 1997
*including post Step 4 errata
Status: September 1997
GUIDELINE FOR GOOD CLINICAL PRACTICE
ICH Harmonised Tripartite Guideline
TABLE OF CONTENTS
TABLE OF CONTENTS (i)
INTRODUCTION (1)
1.GLOSSARY (1)
2. THE PRINCIPLES OF ICH GCP (9)
3.INSTITUTIONAL REVIEW BOARD / INDEPENDENT
ETHICS COMMITTEE (IRB/IEC) (10)
3.1 Responsibilities (10)
3.2 Composition, Functions and Operations (12)
3.3 Procedures (12)
3.4 Records (13)
4. INVESTIGATOR (14)
4.1 Investigator's Qualifications and Agreements (14)
4.2 Adequate Resources (14)
4.3 Medical Care of Trial Subjects (14)
4.4 Communication with IRB/IEC (15)
4.5 Compliance with Protocol (15)
4.6 Investigational Product(s) (16)
4.7 Randomization Procedures and Unblinding (16)
4.8 Informed Consent of Trial Subjects (17)
4.9 Records and Reports (20)
4.10 Progress Reports (21)
4.11 Safety Reporting (21)
4.12 Premature Termination or Suspension of a Trial (22)
4.13 Final Report(s) by Investigator (22)
5. SPONSOR (22)
5.1 Quality Assurance and Quality Control (22)
5.2Contract Research Organization (CRO) (23)
5.3 Medical Expertise (23)
5.4 Trial Design (23)
5.5 Trial Management, Data Handling, and Record Keeping (23)
5.6 Investigator Selection (25)
5.7 Allocation of Duties and Functions (25)
5.8 Compensation to Subjects and Investigators (26)
5.9 Financing (26)
5.10 Notification/Submission to Regulatory Authority(ies) (26)
5.11 Confirmation of Review by IRB/IEC (26)
5.12 Information on Investigational Product(s) (27)
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) (27)
5.14Supplying and Handling Investigational Product(s) (27)
5.15 Record Access (28)
5.16 Safety Information (29)
5.17 Adverse Drug Reaction Reporting (29)
5.18 Monitoring (29)
5.18.1 Purpose (29)
5.18.2 Selection and Qualifications of Monitors (29)
5.18.3 Extent and Nature of Monitoring (30)
5.18.4 Monitor's Responsibilities (30)
5.18.5 Monitoring Procedures (32)
5.18.6 Monitoring Report (32)
5.19Audit (32)
5.19.1 Purpose (32)
5.19.2 Selection and Qualification of Auditors (32)
5.19.3 Auditing Procedures (33)
5.20 Noncompliance (33)
5.21 Premature Termination of a Trial (33)
5.22 Clinical Trial/Study Reports (34)
5.23 Multicentre Trials (34)
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) (34)
6.1 General Information (34)
6.2 Background Information (35)
6.3 Trial Objectives and Purpose (35)
6.4 Trial Design (35)
6.5Selection and Withdrawal of Subjects (36)
6.6 Treatment of Subjects (36)
6.7 Assessment of Efficacy (37)
6.8 Assessment of Safety (37)
6.9 Statistics (37)
6.10 Direct Access to Source Data/Documents (37)
6.11 Quality Control and Quality Assurance Procedures (38)
6.12 Ethics (38)
6.13 Data Handling and Record Keeping (38)
6.14 Financing and Insurance (38)
6.15 Publication Policy (38)
6.16 Supplements (38)
7. INVESTIGATOR’S BROCHURE (38)
7.1 Introduction (38)
7.2 General Considerations (39)
7.2.1 Title Page (39)
7.2.2 Confidentiality Statement (39)
7.3Contents of the Investigator’s Brochure (39)
7.3.1 Table of Contents (39)
7.3.2 Summary (39)
7.3.3 Introduction (40)
7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation (40)
7.3.5 Nonclinical Studies (40)
7.3.6 Effects in Humans (42)
7.3.7 Summary of Data and Guidance for the Investigator (43)
7.4Appendix 1 (44)
7.5Appendix 2 (45)
8.ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL
TRIAL (46)
8.1 Introduction (46)
8.2 Before the Clinical Phase of the Trial Commences (47)
8.3 During the Clinical Conduct of the Trial (51)
8.4 After Completion or Termination of the Trial (57)
GUIDELINE FOR GOOD CLINICAL PRACTICE
ICH Harmonised Tripartite Guideline
[EMEA Status as of June 1996]
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
1.1Adverse 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).
1.2Adverse 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).
1.3Amendment (to the protocol)
See Protocol Amendment.
1.4Applicable Regulatory Requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
1.5Approval (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.
1.6Audit
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).
1.7Audit Certificate
A declaration of confirmation by the auditor that an audit has taken place.
1.8Audit Report
A written evaluation by the sponsor's auditor of the results of the audit.
1.9Audit Trail
Documentation that allows reconstruction of the course of events.
1.10Blinding/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).
1.11Case 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.
1.12Clinical 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.
1.13Clinical 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).
1.14Comparator (Product)
An investigational or marketed product (i.e., active control), or placebo, used as a reference in
a clinical trial.
1.15Compliance (in relation to trials)
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.
1.16Confidentiality
Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.
1.17Contract
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.
1.18Coordinating Committee
A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
1.19Coordinating Investigator
An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial.
1.20Contract 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.
1.21Direct 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.
1.22Documentation
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.
1.23Essential 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).
1.24Good 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.
1.25Independent 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.
1.26Impartial 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.
1.27Independent Ethics Committee (IEC)
An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical/scientific professionals and non-medical/non-scientific 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.
1.28Informed 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.
1.29Inspection
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).
1.30Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
1.31Institutional 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.
1.32Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
1.33Investigational 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.
1.34Investigator
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.
1.35Investigator / Institution
An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements".
1.36Investigator'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).
1.37Legally 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.
1.38Monitoring
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).
1.39Monitoring 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.
1.40Multicentre 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.
1.41Nonclinical Study
Biomedical studies not performed on human subjects.
1.42Opinion (in relation to Independent Ethics Committee)
The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
1.43Original Medical Record
See Source Documents.
1.44Protocol
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.
1.45Protocol Amendment
A written description of a change(s) to or formal clarification of a protocol.
1.46Quality 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).
1.47Quality 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.
1.48Randomization
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.
1.49Regulatory 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.
1.50Serious 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).
1.51Source 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).
1.52Source 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).
1.53Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.
1.54Sponsor-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.
1.55Standard Operating Procedures (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
1.56Subinvestigator
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.
1.57Subject/Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
1.58Subject 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.
1.59Trial Site
The location(s) where trial-related activities are actually conducted.
1.60Unexpected 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).
1.61Vulnerable 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.
1.62Well-being (of the trial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
2.THE PRINCIPLES OF ICH GCP
2.1Clinical 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).
2.2Before 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.
2.3The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
2.4The available nonclinical and clinical information on an investigational product should
be adequate to support the proposed clinical trial.
2.5Clinical trials should be scientifically sound, and described in a clear, detailed
protocol.
2.6 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.
2.7The 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.
2.8Each individual involved in conducting a trial should be qualified by education,
training, and experience to perform his or her respective task(s).
2.9Freely given informed consent should be obtained from every subject prior to clinical
trial participation.
2.10All clinical trial information should be recorded, handled, and stored in a way that
allows its accurate reporting, interpretation and verification.
2.11The confidentiality of records that could identify subjects should be protected,
respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
2.12Investigational 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.
2.13Systems with procedures that assure the quality of every aspect of the trial should be
implemented.
3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
(IRB/IEC)
3.1Responsibilities
3.1.1An 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.
3.1.2The 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.
3.1.3The 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.
3.1.4The 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.
3.1.5The 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.
3.1.6When 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.
3.1.7Where 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).
3.1.8The 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.
3.1.9The 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.
3.2Composition, Functions and Operations
3.2.1The 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.
3.2.2The 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).
3.2.3An IRB/IEC should make its decisions at announced meetings at which at least a
quorum, as stipulated in its written operating procedures, is present.
3.2.4Only members who participate in the IRB/IEC review and discussion should
vote/provide their opinion and/or advise.
3.2.5The 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.
3.2.6An IRB/IEC may invite nonmembers with expertise in special areas for assistance. 3.3Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
3.3.1 Determining its composition (names and qualifications of the members) and the
authority under which it is established.
3.3.2Scheduling, notifying its members of, and conducting its meetings.
3.3.3Conducting initial and continuing review of trials.
3.3.4Determining the frequency of continuing review, as appropriate.
3.3.5Providing, 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.
3.3.6Specifying that no subject should be admitted to a trial before the IRB/IEC issues its
written approval/favourable opinion of the trial.
3.3.7Specifying 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).
3.3.8Specifying that the investigator should promptly report to the IRB/IEC:
a)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).
b)Changes increasing the risk to subjects and/or affecting significantly the conduct
of the trial (see 4.10.2).
c)All adverse drug reactions (ADRs) that are both serious and unexpected.
d)New information that may affect adversely the safety of the subjects or the
conduct of the trial.
3.3.9Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
concerning:
a)Its trial-related decisions/opinions.
b)The reasons for its decisions/opinions.
c)Procedures for appeal of its decisions/opinions.
3.4Records
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
4.1Investigator's Qualifications and Agreements
4.1.1The 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).
4.1.2The 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.
4.1.3The investigator should be aware of, and should comply with, GCP and the applicable
regulatory requirements.
4.1.4The investigator/institution should permit monitoring and auditing by the sponsor, and
inspection by the appropriate regulatory authority(ies).
4.1.5The investigator should maintain a list of appropriately qualified persons to whom the
investigator has delegated significant trial-related duties.
4.2Adequate Resources
4.2.1The 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.
4.2.2The investigator should have sufficient time to properly conduct and complete the trial
within the agreed trial period.
4.2.3The 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.
4.2.4The 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.
4.3Medical Care of Trial Subjects
4.3.1 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.
4.3.2During 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.
4.3.3It 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.
4.3.4Although 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.
4.4Communication with IRB/IEC
4.4.1Before 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.
4.4.2As 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.
4.4.3During the trial the investigator/institution should provide to the IRB/IEC all
documents subject to review.
4.5Compliance with Protocol
4.5.1The 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.
4.5.2The 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)).
4.5.3The investigator, or person designated by the investigator, should document and
explain any deviation from the approved protocol.
4.5.4The 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:
a)to the IRB/IEC for review and approval/favourable opinion,
b)to the sponsor for agreement and, if required,
c)to the regulatory authority(ies).
4.6Investigational Product(s)
4.6.1Responsibility for investigational product(s) accountability at the trial site(s) rests with
the investigator/institution.
4.6.2Where 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..
4.6.3The 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.
4.6.4The 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).
4.6.5The investigator should ensure that the investigational product(s) are used only in
accordance with the approved protocol.
4.6.6The 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.
4.7Randomization 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